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Impaired kidney function no problem for dabigatran reversal
ORLANDO – Idarucizumab, the reversal agent for the anticoagulant dabigatran, appeared as effective in quickly reversing dabigatran’s effects in patients with severe renal dysfunction as in patients with normally working kidneys, in a post hoc analysis of data collected in the drug’s pivotal trial.
A standard dose of idarucizumab “works just as well in patients with bad kidney function as it does in patients with preserved kidney function,” John W. Eikelboom, MD, said at the annual meeting of the American College of Cardiology. “The time to cessation of bleeding and the degree of normal hemostasis achieved was consistent” across the entire range of renal function examined, from severe renal dysfunction, with a creatinine clearance rate of less than 30 mL/min, to normal function, with an estimated rate of 80 mL/min or greater.
The ability of idarucizumab (Praxbind), conditionally approved by the Food and Drug Administration in 2015 and then fully approved in April 2018, to work in patients with impaired renal function has been an open question and concern because dabigatran (Pradaxa) is excreted renally, so it builds to unusually high levels in patients with poor kidney function. “Plasma dabigatran levels might be sky high, so a standard dose of idarucizumab might not work. That’s been a fear of clinicians,” explained Dr. Eikelboom, a hematologist at McMaster University in Hamilton, Ont.
To examine whether idarucizumab’s activity varied by renal function he used data from the patients enrolled in the RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabigatran) study, the pivotal dataset that led to idarucizumab’s U.S. approval. The new, post hoc analysis divided patients into four subgroups based on their kidney function, and focused on the 489 patients for whom renal data were available out of the 503 patients in the study (N Engl J Med. 2017 Aug 3;377[5]:431-41). The subgroups included 91 patients with severe dysfunction with a creatinine clearance rate of less than 30 mL/min; 127 with moderate dysfunction and a clearance rate of 30-49 mL/min; 163 with mild dysfunction and a clearance rate of 50-79 mL/min; and 108 with normal function and a creatinine clearance of at least 80 mL/min.
Patients in the subgroup with severe renal dysfunction had the worst clinical profile overall, and as predicted, had a markedly elevated average plasma level of dabigatran, 231 ng/mL, nearly five times higher than the 47-ng/mL average level in patients with normal renal function.
The ability of a single, standard dose of idarucizumab to reverse the anticoagulant effects of dabigatran were essentially identical across the four strata of renal activity, with 98% of patients in both the severely impaired subgroup and the normal subgroup having 100% reversal within 4 hours of treatment, Dr. Eikelboom reported. Every patient included in the analysis had more than 50% reversal.
The study followed patients to 12-24 hours after they received idarucizumab, and 55% of patients with severe renal dysfunction showed a plasma dabigatran level that crept back toward a clinically meaningful level and so might need a second idarucizumab dose. In contrast, this happened in 8% of patients with normal renal function.
In patients with severe renal dysfunction given idarucizumab, “be alert for a recurrent bleed,” which could require a second dose of idarucizumab, Dr. Eikelboom suggested.
SOURCE: Eikelboom JW et al. ACC 18, Abstract 1231M-11.
ORLANDO – Idarucizumab, the reversal agent for the anticoagulant dabigatran, appeared as effective in quickly reversing dabigatran’s effects in patients with severe renal dysfunction as in patients with normally working kidneys, in a post hoc analysis of data collected in the drug’s pivotal trial.
A standard dose of idarucizumab “works just as well in patients with bad kidney function as it does in patients with preserved kidney function,” John W. Eikelboom, MD, said at the annual meeting of the American College of Cardiology. “The time to cessation of bleeding and the degree of normal hemostasis achieved was consistent” across the entire range of renal function examined, from severe renal dysfunction, with a creatinine clearance rate of less than 30 mL/min, to normal function, with an estimated rate of 80 mL/min or greater.
The ability of idarucizumab (Praxbind), conditionally approved by the Food and Drug Administration in 2015 and then fully approved in April 2018, to work in patients with impaired renal function has been an open question and concern because dabigatran (Pradaxa) is excreted renally, so it builds to unusually high levels in patients with poor kidney function. “Plasma dabigatran levels might be sky high, so a standard dose of idarucizumab might not work. That’s been a fear of clinicians,” explained Dr. Eikelboom, a hematologist at McMaster University in Hamilton, Ont.
To examine whether idarucizumab’s activity varied by renal function he used data from the patients enrolled in the RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabigatran) study, the pivotal dataset that led to idarucizumab’s U.S. approval. The new, post hoc analysis divided patients into four subgroups based on their kidney function, and focused on the 489 patients for whom renal data were available out of the 503 patients in the study (N Engl J Med. 2017 Aug 3;377[5]:431-41). The subgroups included 91 patients with severe dysfunction with a creatinine clearance rate of less than 30 mL/min; 127 with moderate dysfunction and a clearance rate of 30-49 mL/min; 163 with mild dysfunction and a clearance rate of 50-79 mL/min; and 108 with normal function and a creatinine clearance of at least 80 mL/min.
Patients in the subgroup with severe renal dysfunction had the worst clinical profile overall, and as predicted, had a markedly elevated average plasma level of dabigatran, 231 ng/mL, nearly five times higher than the 47-ng/mL average level in patients with normal renal function.
The ability of a single, standard dose of idarucizumab to reverse the anticoagulant effects of dabigatran were essentially identical across the four strata of renal activity, with 98% of patients in both the severely impaired subgroup and the normal subgroup having 100% reversal within 4 hours of treatment, Dr. Eikelboom reported. Every patient included in the analysis had more than 50% reversal.
The study followed patients to 12-24 hours after they received idarucizumab, and 55% of patients with severe renal dysfunction showed a plasma dabigatran level that crept back toward a clinically meaningful level and so might need a second idarucizumab dose. In contrast, this happened in 8% of patients with normal renal function.
In patients with severe renal dysfunction given idarucizumab, “be alert for a recurrent bleed,” which could require a second dose of idarucizumab, Dr. Eikelboom suggested.
SOURCE: Eikelboom JW et al. ACC 18, Abstract 1231M-11.
ORLANDO – Idarucizumab, the reversal agent for the anticoagulant dabigatran, appeared as effective in quickly reversing dabigatran’s effects in patients with severe renal dysfunction as in patients with normally working kidneys, in a post hoc analysis of data collected in the drug’s pivotal trial.
A standard dose of idarucizumab “works just as well in patients with bad kidney function as it does in patients with preserved kidney function,” John W. Eikelboom, MD, said at the annual meeting of the American College of Cardiology. “The time to cessation of bleeding and the degree of normal hemostasis achieved was consistent” across the entire range of renal function examined, from severe renal dysfunction, with a creatinine clearance rate of less than 30 mL/min, to normal function, with an estimated rate of 80 mL/min or greater.
The ability of idarucizumab (Praxbind), conditionally approved by the Food and Drug Administration in 2015 and then fully approved in April 2018, to work in patients with impaired renal function has been an open question and concern because dabigatran (Pradaxa) is excreted renally, so it builds to unusually high levels in patients with poor kidney function. “Plasma dabigatran levels might be sky high, so a standard dose of idarucizumab might not work. That’s been a fear of clinicians,” explained Dr. Eikelboom, a hematologist at McMaster University in Hamilton, Ont.
To examine whether idarucizumab’s activity varied by renal function he used data from the patients enrolled in the RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabigatran) study, the pivotal dataset that led to idarucizumab’s U.S. approval. The new, post hoc analysis divided patients into four subgroups based on their kidney function, and focused on the 489 patients for whom renal data were available out of the 503 patients in the study (N Engl J Med. 2017 Aug 3;377[5]:431-41). The subgroups included 91 patients with severe dysfunction with a creatinine clearance rate of less than 30 mL/min; 127 with moderate dysfunction and a clearance rate of 30-49 mL/min; 163 with mild dysfunction and a clearance rate of 50-79 mL/min; and 108 with normal function and a creatinine clearance of at least 80 mL/min.
Patients in the subgroup with severe renal dysfunction had the worst clinical profile overall, and as predicted, had a markedly elevated average plasma level of dabigatran, 231 ng/mL, nearly five times higher than the 47-ng/mL average level in patients with normal renal function.
The ability of a single, standard dose of idarucizumab to reverse the anticoagulant effects of dabigatran were essentially identical across the four strata of renal activity, with 98% of patients in both the severely impaired subgroup and the normal subgroup having 100% reversal within 4 hours of treatment, Dr. Eikelboom reported. Every patient included in the analysis had more than 50% reversal.
The study followed patients to 12-24 hours after they received idarucizumab, and 55% of patients with severe renal dysfunction showed a plasma dabigatran level that crept back toward a clinically meaningful level and so might need a second idarucizumab dose. In contrast, this happened in 8% of patients with normal renal function.
In patients with severe renal dysfunction given idarucizumab, “be alert for a recurrent bleed,” which could require a second dose of idarucizumab, Dr. Eikelboom suggested.
SOURCE: Eikelboom JW et al. ACC 18, Abstract 1231M-11.
REPORTING FROM ACC 18
Key clinical point: Renal function had no impact on idarucizumab’s efficacy for dabigatran reversal.
Major finding: Complete dabigatran reversal occurred in 98% of patients with severe renal dysfunction who received idarucizumab.
Study details: Post hoc analysis of data from RE-VERSE AD, idarucizumab’s pivotal trial with 503 patients.
Disclosures: RE-VERSE AD was funded by Boehringer Ingelheim, the company that markets idarucizumab (Praxbind) and dabigatran (Pradaxa). Dr. Eikelboom has been a consultant to and has received research support from Boehringer Ingelheim, as well as from Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, and Pfizer.
Source: Eikelboom JW et al. ACC 18, Abstract 1231M-11.
Sodium bicarbonate and acetylcysteine for prevention of contrast-related morbidity and mortality in CKD patients
Clinical question: Do either intravenous sodium bicarbonate or oral acetylcysteine prevent renal morbidity and mortality in patients with chronic kidney disease (CKD) undergoing angiography?
Background: Both intravenous sodium bicarbonate and acetylcysteine are commonly used therapies aimed at preventing contrast-induced nephropathy. However, data regarding their efficacy are controversial, and prior studies have largely included patients with normal renal function.
Setting: Medical centers (53) throughout the United States, Australia, New Zealand, and Malaysia.
Synopsis: This study included 4,993 patients with CKD, stage III and IV, who were scheduled for angiography. The study population was predominately male (93.6%) and had diabetes (80.9%). Patients were randomized to receive either sodium bicarbonate or normal saline infusion, and oral acetylcysteine or placebo. The primary outcome was a composite of death, dialysis, or a sustained increase in creatinine by 50% at 90 days, and the secondary outcome was contrast-associated acute kidney injury. There was no interaction between sodium bicarbonate and acetylcysteine. Neither therapy prevented the primary or secondary outcome. The main limitations to this study included a very narrow demographic making the results hard to extrapolate beyond male diabetes patients receiving contrast for angiography. Overall, this study suggests that treatment with sodium bicarbonate or acetylcysteine does not improve the contrast-related morbidity and mortality in patients with CKD III and IV.
Bottom line: Neither intravenous sodium bicarbonate nor acetylcysteine led to improved renal outcomes in predominantly male patients with diabetes and baseline renal dysfunction undergoing angiography.
Citation: Weisbord SD et al. Outcomes after angiography with sodium bicarbonate and acetylcysteine. N Engl J Med. 2017 Nov 12. doi: 10.1056/NEJMal1710933.
Dr. Lusa is assistant professor of medicine, division of hospital medicine, University of Virginia.
Clinical question: Do either intravenous sodium bicarbonate or oral acetylcysteine prevent renal morbidity and mortality in patients with chronic kidney disease (CKD) undergoing angiography?
Background: Both intravenous sodium bicarbonate and acetylcysteine are commonly used therapies aimed at preventing contrast-induced nephropathy. However, data regarding their efficacy are controversial, and prior studies have largely included patients with normal renal function.
Setting: Medical centers (53) throughout the United States, Australia, New Zealand, and Malaysia.
Synopsis: This study included 4,993 patients with CKD, stage III and IV, who were scheduled for angiography. The study population was predominately male (93.6%) and had diabetes (80.9%). Patients were randomized to receive either sodium bicarbonate or normal saline infusion, and oral acetylcysteine or placebo. The primary outcome was a composite of death, dialysis, or a sustained increase in creatinine by 50% at 90 days, and the secondary outcome was contrast-associated acute kidney injury. There was no interaction between sodium bicarbonate and acetylcysteine. Neither therapy prevented the primary or secondary outcome. The main limitations to this study included a very narrow demographic making the results hard to extrapolate beyond male diabetes patients receiving contrast for angiography. Overall, this study suggests that treatment with sodium bicarbonate or acetylcysteine does not improve the contrast-related morbidity and mortality in patients with CKD III and IV.
Bottom line: Neither intravenous sodium bicarbonate nor acetylcysteine led to improved renal outcomes in predominantly male patients with diabetes and baseline renal dysfunction undergoing angiography.
Citation: Weisbord SD et al. Outcomes after angiography with sodium bicarbonate and acetylcysteine. N Engl J Med. 2017 Nov 12. doi: 10.1056/NEJMal1710933.
Dr. Lusa is assistant professor of medicine, division of hospital medicine, University of Virginia.
Clinical question: Do either intravenous sodium bicarbonate or oral acetylcysteine prevent renal morbidity and mortality in patients with chronic kidney disease (CKD) undergoing angiography?
Background: Both intravenous sodium bicarbonate and acetylcysteine are commonly used therapies aimed at preventing contrast-induced nephropathy. However, data regarding their efficacy are controversial, and prior studies have largely included patients with normal renal function.
Setting: Medical centers (53) throughout the United States, Australia, New Zealand, and Malaysia.
Synopsis: This study included 4,993 patients with CKD, stage III and IV, who were scheduled for angiography. The study population was predominately male (93.6%) and had diabetes (80.9%). Patients were randomized to receive either sodium bicarbonate or normal saline infusion, and oral acetylcysteine or placebo. The primary outcome was a composite of death, dialysis, or a sustained increase in creatinine by 50% at 90 days, and the secondary outcome was contrast-associated acute kidney injury. There was no interaction between sodium bicarbonate and acetylcysteine. Neither therapy prevented the primary or secondary outcome. The main limitations to this study included a very narrow demographic making the results hard to extrapolate beyond male diabetes patients receiving contrast for angiography. Overall, this study suggests that treatment with sodium bicarbonate or acetylcysteine does not improve the contrast-related morbidity and mortality in patients with CKD III and IV.
Bottom line: Neither intravenous sodium bicarbonate nor acetylcysteine led to improved renal outcomes in predominantly male patients with diabetes and baseline renal dysfunction undergoing angiography.
Citation: Weisbord SD et al. Outcomes after angiography with sodium bicarbonate and acetylcysteine. N Engl J Med. 2017 Nov 12. doi: 10.1056/NEJMal1710933.
Dr. Lusa is assistant professor of medicine, division of hospital medicine, University of Virginia.
Can African-American Patients Take Metoprolol?
Q) One of the physicians in my practice won't use metoprolol in African-American patients. He says it causes kidney disease. Is it right, or is this an old wives' tale?
There are multiple concerns with the use of metoprolol specifically—this does not apply to all ß-blockers—in the African-American population. The main concerns are
- Lack of effective blood pressure control, compared to angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs)
- No observable reduction in proteinuria
- The possibility of a significant increase in uric acid.
Most of the evidence-based guidelines for care of hypertensive nephrosclerosis in the African-American population were derived from the African-American Study of Kidney Disease and Hypertension (AASK) trial. This large-scale, multicenter, randomized, double-blinded study from the National Institute of Health had multiple arms to compare an ACE inhibitor (ramipril) to a CCB (amlodipine) or a ß-blocker (metoprolol) in the nondiabetic African-American population.1
In a subgroup analysis, more than 1,000 subjects with hypertensive nephrosclerosis were followed for four years, with serial glomerular filtration rate (GFR) measurements taken. Treatment with ACE inhibitors was shown to be superior to CCB and ß-blockers for hypertension and proteinuria control.1
One important take-away from the AASK trial has been that strict blood pressure control is not enough to improve kidney outcomes. Proteinuria (albuminuria) must also be controlled.1
Continue to: In a subsequent secondary analysis
In a subsequent secondary analysis of data from the AASK study, Juraschek et al showed that metoprolol significantly increased serum uric acid in African-American adults.2 It is known that hyperuricemia (> 6 mg/dL) can cause a decline in kidney function.3
Furthermore, uric acid may be a strong prognostic factor for chronic kidney disease (CKD) progression. (This association, however, remains controversial. One recent study showed that, while hyperuricemia is associated with higher risk for kidney failure, the relationship was not parallel in CKD stage 3 or 4 [GFR ≤ 60 mL/min]).4 In fact, taking uric acid–lowering medications did not slow progression of kidney disease.
In other words, your colleague seems to believe that since A (metoprolol) leads to B (hyperuricemia) and B (hyperuricemia) leads to C (kidney disease), then A leads to C. While the theory is undoubtedly logical, we have no proof that metoprolol causes increased kidney disease in African-American patients.
What we do know, thanks to AASK, is that an African-American patient with kidney disease should be treated with a diuretic and/or an ACE inhibitor as initial therapy. Furthermore, we have a blood pressure goal: < 130/80 mm Hg. And we know that CCBs are most effective for African-American patients who do not have kidney disease.5—BWM
Barbara Weis Malone, DNP, FNP-C, FNKF
Assistant Professor
Adult/Gerontology NP Program, College of Nursing
Nurse Practitioner
School of Medicine, University of Colorado Anschutz Medical Campus
1. Toto RD. Lessons from the African-American Study of Kidney Disease and Hypertension: an update. Curr Hypertens Rep. 2006;8(5):409-412.
2. Juraschek SP, Appel LJ, Miller ER III. Metoprolol increases uric acid and risk of gout in African Americans with chronic kidney disease attributed to hypertension. Am J Hypertens. 2017; 30(9):871-875.
3. Tsai C-W, Lin S-Y, Kuo C-C, Huang C-C. Serum uric acid and progression of kidney disease: a longitudinal analysis and mini-review. PLoS One. 2017;12(1):e0170393.
4. Rincon-Choles H, Jolly SE, Arrigain S, et al. Impact of uric acid levels on kidney disease progression. Am J Nephrol. 2017;46(4):315-322.
5. Armstrong C. JNC8 guidelines for the management of hypertension in adults. Am Fam Physician. 2014;90(7):503-504.
Q) One of the physicians in my practice won't use metoprolol in African-American patients. He says it causes kidney disease. Is it right, or is this an old wives' tale?
There are multiple concerns with the use of metoprolol specifically—this does not apply to all ß-blockers—in the African-American population. The main concerns are
- Lack of effective blood pressure control, compared to angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs)
- No observable reduction in proteinuria
- The possibility of a significant increase in uric acid.
Most of the evidence-based guidelines for care of hypertensive nephrosclerosis in the African-American population were derived from the African-American Study of Kidney Disease and Hypertension (AASK) trial. This large-scale, multicenter, randomized, double-blinded study from the National Institute of Health had multiple arms to compare an ACE inhibitor (ramipril) to a CCB (amlodipine) or a ß-blocker (metoprolol) in the nondiabetic African-American population.1
In a subgroup analysis, more than 1,000 subjects with hypertensive nephrosclerosis were followed for four years, with serial glomerular filtration rate (GFR) measurements taken. Treatment with ACE inhibitors was shown to be superior to CCB and ß-blockers for hypertension and proteinuria control.1
One important take-away from the AASK trial has been that strict blood pressure control is not enough to improve kidney outcomes. Proteinuria (albuminuria) must also be controlled.1
Continue to: In a subsequent secondary analysis
In a subsequent secondary analysis of data from the AASK study, Juraschek et al showed that metoprolol significantly increased serum uric acid in African-American adults.2 It is known that hyperuricemia (> 6 mg/dL) can cause a decline in kidney function.3
Furthermore, uric acid may be a strong prognostic factor for chronic kidney disease (CKD) progression. (This association, however, remains controversial. One recent study showed that, while hyperuricemia is associated with higher risk for kidney failure, the relationship was not parallel in CKD stage 3 or 4 [GFR ≤ 60 mL/min]).4 In fact, taking uric acid–lowering medications did not slow progression of kidney disease.
In other words, your colleague seems to believe that since A (metoprolol) leads to B (hyperuricemia) and B (hyperuricemia) leads to C (kidney disease), then A leads to C. While the theory is undoubtedly logical, we have no proof that metoprolol causes increased kidney disease in African-American patients.
What we do know, thanks to AASK, is that an African-American patient with kidney disease should be treated with a diuretic and/or an ACE inhibitor as initial therapy. Furthermore, we have a blood pressure goal: < 130/80 mm Hg. And we know that CCBs are most effective for African-American patients who do not have kidney disease.5—BWM
Barbara Weis Malone, DNP, FNP-C, FNKF
Assistant Professor
Adult/Gerontology NP Program, College of Nursing
Nurse Practitioner
School of Medicine, University of Colorado Anschutz Medical Campus
Q) One of the physicians in my practice won't use metoprolol in African-American patients. He says it causes kidney disease. Is it right, or is this an old wives' tale?
There are multiple concerns with the use of metoprolol specifically—this does not apply to all ß-blockers—in the African-American population. The main concerns are
- Lack of effective blood pressure control, compared to angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs)
- No observable reduction in proteinuria
- The possibility of a significant increase in uric acid.
Most of the evidence-based guidelines for care of hypertensive nephrosclerosis in the African-American population were derived from the African-American Study of Kidney Disease and Hypertension (AASK) trial. This large-scale, multicenter, randomized, double-blinded study from the National Institute of Health had multiple arms to compare an ACE inhibitor (ramipril) to a CCB (amlodipine) or a ß-blocker (metoprolol) in the nondiabetic African-American population.1
In a subgroup analysis, more than 1,000 subjects with hypertensive nephrosclerosis were followed for four years, with serial glomerular filtration rate (GFR) measurements taken. Treatment with ACE inhibitors was shown to be superior to CCB and ß-blockers for hypertension and proteinuria control.1
One important take-away from the AASK trial has been that strict blood pressure control is not enough to improve kidney outcomes. Proteinuria (albuminuria) must also be controlled.1
Continue to: In a subsequent secondary analysis
In a subsequent secondary analysis of data from the AASK study, Juraschek et al showed that metoprolol significantly increased serum uric acid in African-American adults.2 It is known that hyperuricemia (> 6 mg/dL) can cause a decline in kidney function.3
Furthermore, uric acid may be a strong prognostic factor for chronic kidney disease (CKD) progression. (This association, however, remains controversial. One recent study showed that, while hyperuricemia is associated with higher risk for kidney failure, the relationship was not parallel in CKD stage 3 or 4 [GFR ≤ 60 mL/min]).4 In fact, taking uric acid–lowering medications did not slow progression of kidney disease.
In other words, your colleague seems to believe that since A (metoprolol) leads to B (hyperuricemia) and B (hyperuricemia) leads to C (kidney disease), then A leads to C. While the theory is undoubtedly logical, we have no proof that metoprolol causes increased kidney disease in African-American patients.
What we do know, thanks to AASK, is that an African-American patient with kidney disease should be treated with a diuretic and/or an ACE inhibitor as initial therapy. Furthermore, we have a blood pressure goal: < 130/80 mm Hg. And we know that CCBs are most effective for African-American patients who do not have kidney disease.5—BWM
Barbara Weis Malone, DNP, FNP-C, FNKF
Assistant Professor
Adult/Gerontology NP Program, College of Nursing
Nurse Practitioner
School of Medicine, University of Colorado Anschutz Medical Campus
1. Toto RD. Lessons from the African-American Study of Kidney Disease and Hypertension: an update. Curr Hypertens Rep. 2006;8(5):409-412.
2. Juraschek SP, Appel LJ, Miller ER III. Metoprolol increases uric acid and risk of gout in African Americans with chronic kidney disease attributed to hypertension. Am J Hypertens. 2017; 30(9):871-875.
3. Tsai C-W, Lin S-Y, Kuo C-C, Huang C-C. Serum uric acid and progression of kidney disease: a longitudinal analysis and mini-review. PLoS One. 2017;12(1):e0170393.
4. Rincon-Choles H, Jolly SE, Arrigain S, et al. Impact of uric acid levels on kidney disease progression. Am J Nephrol. 2017;46(4):315-322.
5. Armstrong C. JNC8 guidelines for the management of hypertension in adults. Am Fam Physician. 2014;90(7):503-504.
1. Toto RD. Lessons from the African-American Study of Kidney Disease and Hypertension: an update. Curr Hypertens Rep. 2006;8(5):409-412.
2. Juraschek SP, Appel LJ, Miller ER III. Metoprolol increases uric acid and risk of gout in African Americans with chronic kidney disease attributed to hypertension. Am J Hypertens. 2017; 30(9):871-875.
3. Tsai C-W, Lin S-Y, Kuo C-C, Huang C-C. Serum uric acid and progression of kidney disease: a longitudinal analysis and mini-review. PLoS One. 2017;12(1):e0170393.
4. Rincon-Choles H, Jolly SE, Arrigain S, et al. Impact of uric acid levels on kidney disease progression. Am J Nephrol. 2017;46(4):315-322.
5. Armstrong C. JNC8 guidelines for the management of hypertension in adults. Am Fam Physician. 2014;90(7):503-504.
Is “Runner’s Kidney” a Thing?
Q) Many of my patients are athletes. I recall reading something about kidney disease in marathon runners. Am I remembering correctly?
Although data on acute kidney injury (AKI) in marathon runners are limited, two recent studies have added to our knowledge. In 2017, Mansour et al studied 22 marathon runners, collecting urine and blood samples 24 hours before, immediately after, and 24 hours after a race. The results showed that in 82% of the subjects, serum creatinine increased to a level correlated with stage 1 or 2 AKI (as defined by the Acute Kidney Injury Network criteria).1
Based on urine microscopy results, as well as serum creatinine and novel biomarker levels, the researchers concluded that the runners’ AKI was caused by acute tubular injury—likely induced by ischemia. However, the subjects did not show any evidence of chronic kidney disease (CKD), despite years of running and intensive training. One theory: Habitual running might condition the kidneys to transient ischemic conditions—in other words, they build tolerance to repetitive injury over time.1
Continue to: The other recent study
The other recent study examined use of NSAIDs by ultramarathon
In summary: While marathon runners are prone to AKI, the injury seems to be transient and does not progress to CKD. Furthermore, use of NSAIDs during endurance running may contribute to AKI development, so patients should be advised to use caution with these analgesics. Finally, remind your endurance runners to stay hydrated, since it may help to limit kidney damage. As for the casual runner? The impact on the kidney remains unclear and needs further investigation. —DSW
Danielle S. Wentworth, MSN, FNP-BC
Division of Nephrology, University of Viriginia Health System, Charlottesville
1. Mansour SG, Verma G, Pata RW, et al. Kidney injury and repair biomarkers in marathon runners. Am J Kidney Dis. 2017;70(2):252-261.
2. Lipman GS, Shea K, Christensen M, et al. Ibuprofen versus placebo effect on acute kidney injury in ultramarathons: a randomised controlled trial. Emerg Med J. 2017;34(10):637-642.
Q) Many of my patients are athletes. I recall reading something about kidney disease in marathon runners. Am I remembering correctly?
Although data on acute kidney injury (AKI) in marathon runners are limited, two recent studies have added to our knowledge. In 2017, Mansour et al studied 22 marathon runners, collecting urine and blood samples 24 hours before, immediately after, and 24 hours after a race. The results showed that in 82% of the subjects, serum creatinine increased to a level correlated with stage 1 or 2 AKI (as defined by the Acute Kidney Injury Network criteria).1
Based on urine microscopy results, as well as serum creatinine and novel biomarker levels, the researchers concluded that the runners’ AKI was caused by acute tubular injury—likely induced by ischemia. However, the subjects did not show any evidence of chronic kidney disease (CKD), despite years of running and intensive training. One theory: Habitual running might condition the kidneys to transient ischemic conditions—in other words, they build tolerance to repetitive injury over time.1
Continue to: The other recent study
The other recent study examined use of NSAIDs by ultramarathon
In summary: While marathon runners are prone to AKI, the injury seems to be transient and does not progress to CKD. Furthermore, use of NSAIDs during endurance running may contribute to AKI development, so patients should be advised to use caution with these analgesics. Finally, remind your endurance runners to stay hydrated, since it may help to limit kidney damage. As for the casual runner? The impact on the kidney remains unclear and needs further investigation. —DSW
Danielle S. Wentworth, MSN, FNP-BC
Division of Nephrology, University of Viriginia Health System, Charlottesville
Q) Many of my patients are athletes. I recall reading something about kidney disease in marathon runners. Am I remembering correctly?
Although data on acute kidney injury (AKI) in marathon runners are limited, two recent studies have added to our knowledge. In 2017, Mansour et al studied 22 marathon runners, collecting urine and blood samples 24 hours before, immediately after, and 24 hours after a race. The results showed that in 82% of the subjects, serum creatinine increased to a level correlated with stage 1 or 2 AKI (as defined by the Acute Kidney Injury Network criteria).1
Based on urine microscopy results, as well as serum creatinine and novel biomarker levels, the researchers concluded that the runners’ AKI was caused by acute tubular injury—likely induced by ischemia. However, the subjects did not show any evidence of chronic kidney disease (CKD), despite years of running and intensive training. One theory: Habitual running might condition the kidneys to transient ischemic conditions—in other words, they build tolerance to repetitive injury over time.1
Continue to: The other recent study
The other recent study examined use of NSAIDs by ultramarathon
In summary: While marathon runners are prone to AKI, the injury seems to be transient and does not progress to CKD. Furthermore, use of NSAIDs during endurance running may contribute to AKI development, so patients should be advised to use caution with these analgesics. Finally, remind your endurance runners to stay hydrated, since it may help to limit kidney damage. As for the casual runner? The impact on the kidney remains unclear and needs further investigation. —DSW
Danielle S. Wentworth, MSN, FNP-BC
Division of Nephrology, University of Viriginia Health System, Charlottesville
1. Mansour SG, Verma G, Pata RW, et al. Kidney injury and repair biomarkers in marathon runners. Am J Kidney Dis. 2017;70(2):252-261.
2. Lipman GS, Shea K, Christensen M, et al. Ibuprofen versus placebo effect on acute kidney injury in ultramarathons: a randomised controlled trial. Emerg Med J. 2017;34(10):637-642.
1. Mansour SG, Verma G, Pata RW, et al. Kidney injury and repair biomarkers in marathon runners. Am J Kidney Dis. 2017;70(2):252-261.
2. Lipman GS, Shea K, Christensen M, et al. Ibuprofen versus placebo effect on acute kidney injury in ultramarathons: a randomised controlled trial. Emerg Med J. 2017;34(10):637-642.
Clearer picture emerging of renal impact of SGLT2s
LOS ANGELES – Results from recent trials suggest that
“Despite optimal care around blood pressure control, glycemic control, and control of other risk factors, our patients still have a significant risk of both cardiovascular disease progression and renal disease progression,” David Cherney, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “In fact, when we have a narrow focus on glycemia, there is a lot of additional residual risk, and that A1c lowering by itself does not negate that risk and in fact has very little effect on clinical outcomes. That brings us to the newer hyperglycemic therapies, including the SGLT2 inhibitors. While these agents do indeed block the reabsorption of glucose in the kidney, they also have an effect on other nonglycemic risk factors.”
“Inside the kidney, there are direct effects on reducing intraglomerular hypertension, leading to reductions in proteinuria,” he said. “These agents are interesting because of the way that they influence how the kidney handles sodium. As a consequence, they impact on glomerular hypertension.”
Under normal physiological conditions, humans who become volume depleted or hypotensive experience a reduction in sodium delivery to the kidney by the afferent arteriole, he explained. If less sodium is delivered to the afferent arteriole, less is filtered and delivered to the macula densa, which is the sodium-sensing area of the kidney.
“If less sodium is delivered to the macula densa, less sodium will be reabsorbed, which is an energy-requiring process that leads to the breakdown of ATP [adenosine triphosphate],” Dr. Cherney said. “If less ATP is broken down to adenosine, then less adenosine is produced. Adenosine is a vasoconstrictor in this area. So, under conditions of hypervolemia or hypotension, that’s great, because we want to maintain blood flow to the kidney; that’s a protective autoregulatory response that all of us have called tubular glomerular feedback. It’s through sodium delivery to the macula densa.”
He went on to note that hyperglycemic patients who are not taking an SGLT2 inhibitor experience an increase in sodium absorption proximally, which decreases sodium delivery to the macula densa. As a result, this causes afferent dilation, which leads to a rise in glomerular pressure, glomerular hypertension, hyperfiltration, and an increased risk of renal disease progression.
“This leads to all the effects that we see clinically, including the GFR [glomerular filtration rate] dip and the reduction in proteinuria that these agents cause either when used alone or with an ACE or ARB [angiotensin II receptor blocker],” Dr. Cherney said. “SGLT2s constrict the afferent arterial and reduce glomerular hypertension and proteinuria, whereas ACE inhibitors dilate the efferent arterial, which also reduces glomerular hypertension and proteinuria.”
An analysis of renal data from the multicenter EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) found that the use of empagliflozin was associated with slower progression of kidney disease than was placebo when added to standard care. Empagliflozin was also associated with a significantly lower risk of clinically relevant renal events, including a 40%-50% reduction in microalbuminuria in patients with micro- or macroalbuminuria (N Engl J Med. 2016 Jul 28;375:323-34).
In a recent study of EMPA-REG OUTCOME patients, Dr. Cherney and his associates examined the effects of empagliflozin on the urinary albumin to creatinine ratio in patients with type 2 diabetes and established cardiovascular disease (Lancet Diabetes Endocrinol. 2017 Aug;5[8]:610-21). They found that even in patients with normal albuminuria at baseline, by the end of the trial at about 3 years there was a modest but statistically significant 15% reduction in urinary albumin secretion. “That reduction was greater in patients with microalbuminuria at baseline,” Dr. Cherney said. “There was a more than 40% reduction in microalbuminuric patients, and almost a 50% in patients who had macroalbuminuria at baseline, suggesting that the effect is greater in patients with higher levels of albuminuria.”
Meanwhile, results from the CANVAS program, which integrated data from two trials of more than 10,000 patients with type 2 diabetes and high cardiovascular disease risk, showed that those who received canagliflozin had a 14% reduced risk of 3-point major adverse cardiovascular events (3P-MACE), compared with those who received placebo. (N Engl J Med. 2017 Aug;377:644-57). “There was a curious increased risk of amputation and fracture in the canagliflozin group, which has not been seen in other trials,” Dr. Cherney said. “That certainly merits further thought and investigation, to better understand how significant this risk is.”
Upcoming trials of renal endpoints to look out for, he said, include the CREDENCE study (results expected in 2019), DAPA-CKD, which is in the recruitment stage, and a new outcome study to evaluate the effect of empagliflozin for the treatment of people with chronic kidney disease. “This is an expanding area in the renal and cardiovascular world that we will hear a lot more about in the next 3-5 years,” he said.
Dr. Cherney reported consulting fees and/or honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe, and Sanofi.
LOS ANGELES – Results from recent trials suggest that
“Despite optimal care around blood pressure control, glycemic control, and control of other risk factors, our patients still have a significant risk of both cardiovascular disease progression and renal disease progression,” David Cherney, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “In fact, when we have a narrow focus on glycemia, there is a lot of additional residual risk, and that A1c lowering by itself does not negate that risk and in fact has very little effect on clinical outcomes. That brings us to the newer hyperglycemic therapies, including the SGLT2 inhibitors. While these agents do indeed block the reabsorption of glucose in the kidney, they also have an effect on other nonglycemic risk factors.”
“Inside the kidney, there are direct effects on reducing intraglomerular hypertension, leading to reductions in proteinuria,” he said. “These agents are interesting because of the way that they influence how the kidney handles sodium. As a consequence, they impact on glomerular hypertension.”
Under normal physiological conditions, humans who become volume depleted or hypotensive experience a reduction in sodium delivery to the kidney by the afferent arteriole, he explained. If less sodium is delivered to the afferent arteriole, less is filtered and delivered to the macula densa, which is the sodium-sensing area of the kidney.
“If less sodium is delivered to the macula densa, less sodium will be reabsorbed, which is an energy-requiring process that leads to the breakdown of ATP [adenosine triphosphate],” Dr. Cherney said. “If less ATP is broken down to adenosine, then less adenosine is produced. Adenosine is a vasoconstrictor in this area. So, under conditions of hypervolemia or hypotension, that’s great, because we want to maintain blood flow to the kidney; that’s a protective autoregulatory response that all of us have called tubular glomerular feedback. It’s through sodium delivery to the macula densa.”
He went on to note that hyperglycemic patients who are not taking an SGLT2 inhibitor experience an increase in sodium absorption proximally, which decreases sodium delivery to the macula densa. As a result, this causes afferent dilation, which leads to a rise in glomerular pressure, glomerular hypertension, hyperfiltration, and an increased risk of renal disease progression.
“This leads to all the effects that we see clinically, including the GFR [glomerular filtration rate] dip and the reduction in proteinuria that these agents cause either when used alone or with an ACE or ARB [angiotensin II receptor blocker],” Dr. Cherney said. “SGLT2s constrict the afferent arterial and reduce glomerular hypertension and proteinuria, whereas ACE inhibitors dilate the efferent arterial, which also reduces glomerular hypertension and proteinuria.”
An analysis of renal data from the multicenter EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) found that the use of empagliflozin was associated with slower progression of kidney disease than was placebo when added to standard care. Empagliflozin was also associated with a significantly lower risk of clinically relevant renal events, including a 40%-50% reduction in microalbuminuria in patients with micro- or macroalbuminuria (N Engl J Med. 2016 Jul 28;375:323-34).
In a recent study of EMPA-REG OUTCOME patients, Dr. Cherney and his associates examined the effects of empagliflozin on the urinary albumin to creatinine ratio in patients with type 2 diabetes and established cardiovascular disease (Lancet Diabetes Endocrinol. 2017 Aug;5[8]:610-21). They found that even in patients with normal albuminuria at baseline, by the end of the trial at about 3 years there was a modest but statistically significant 15% reduction in urinary albumin secretion. “That reduction was greater in patients with microalbuminuria at baseline,” Dr. Cherney said. “There was a more than 40% reduction in microalbuminuric patients, and almost a 50% in patients who had macroalbuminuria at baseline, suggesting that the effect is greater in patients with higher levels of albuminuria.”
Meanwhile, results from the CANVAS program, which integrated data from two trials of more than 10,000 patients with type 2 diabetes and high cardiovascular disease risk, showed that those who received canagliflozin had a 14% reduced risk of 3-point major adverse cardiovascular events (3P-MACE), compared with those who received placebo. (N Engl J Med. 2017 Aug;377:644-57). “There was a curious increased risk of amputation and fracture in the canagliflozin group, which has not been seen in other trials,” Dr. Cherney said. “That certainly merits further thought and investigation, to better understand how significant this risk is.”
Upcoming trials of renal endpoints to look out for, he said, include the CREDENCE study (results expected in 2019), DAPA-CKD, which is in the recruitment stage, and a new outcome study to evaluate the effect of empagliflozin for the treatment of people with chronic kidney disease. “This is an expanding area in the renal and cardiovascular world that we will hear a lot more about in the next 3-5 years,” he said.
Dr. Cherney reported consulting fees and/or honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe, and Sanofi.
LOS ANGELES – Results from recent trials suggest that
“Despite optimal care around blood pressure control, glycemic control, and control of other risk factors, our patients still have a significant risk of both cardiovascular disease progression and renal disease progression,” David Cherney, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “In fact, when we have a narrow focus on glycemia, there is a lot of additional residual risk, and that A1c lowering by itself does not negate that risk and in fact has very little effect on clinical outcomes. That brings us to the newer hyperglycemic therapies, including the SGLT2 inhibitors. While these agents do indeed block the reabsorption of glucose in the kidney, they also have an effect on other nonglycemic risk factors.”
“Inside the kidney, there are direct effects on reducing intraglomerular hypertension, leading to reductions in proteinuria,” he said. “These agents are interesting because of the way that they influence how the kidney handles sodium. As a consequence, they impact on glomerular hypertension.”
Under normal physiological conditions, humans who become volume depleted or hypotensive experience a reduction in sodium delivery to the kidney by the afferent arteriole, he explained. If less sodium is delivered to the afferent arteriole, less is filtered and delivered to the macula densa, which is the sodium-sensing area of the kidney.
“If less sodium is delivered to the macula densa, less sodium will be reabsorbed, which is an energy-requiring process that leads to the breakdown of ATP [adenosine triphosphate],” Dr. Cherney said. “If less ATP is broken down to adenosine, then less adenosine is produced. Adenosine is a vasoconstrictor in this area. So, under conditions of hypervolemia or hypotension, that’s great, because we want to maintain blood flow to the kidney; that’s a protective autoregulatory response that all of us have called tubular glomerular feedback. It’s through sodium delivery to the macula densa.”
He went on to note that hyperglycemic patients who are not taking an SGLT2 inhibitor experience an increase in sodium absorption proximally, which decreases sodium delivery to the macula densa. As a result, this causes afferent dilation, which leads to a rise in glomerular pressure, glomerular hypertension, hyperfiltration, and an increased risk of renal disease progression.
“This leads to all the effects that we see clinically, including the GFR [glomerular filtration rate] dip and the reduction in proteinuria that these agents cause either when used alone or with an ACE or ARB [angiotensin II receptor blocker],” Dr. Cherney said. “SGLT2s constrict the afferent arterial and reduce glomerular hypertension and proteinuria, whereas ACE inhibitors dilate the efferent arterial, which also reduces glomerular hypertension and proteinuria.”
An analysis of renal data from the multicenter EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) found that the use of empagliflozin was associated with slower progression of kidney disease than was placebo when added to standard care. Empagliflozin was also associated with a significantly lower risk of clinically relevant renal events, including a 40%-50% reduction in microalbuminuria in patients with micro- or macroalbuminuria (N Engl J Med. 2016 Jul 28;375:323-34).
In a recent study of EMPA-REG OUTCOME patients, Dr. Cherney and his associates examined the effects of empagliflozin on the urinary albumin to creatinine ratio in patients with type 2 diabetes and established cardiovascular disease (Lancet Diabetes Endocrinol. 2017 Aug;5[8]:610-21). They found that even in patients with normal albuminuria at baseline, by the end of the trial at about 3 years there was a modest but statistically significant 15% reduction in urinary albumin secretion. “That reduction was greater in patients with microalbuminuria at baseline,” Dr. Cherney said. “There was a more than 40% reduction in microalbuminuric patients, and almost a 50% in patients who had macroalbuminuria at baseline, suggesting that the effect is greater in patients with higher levels of albuminuria.”
Meanwhile, results from the CANVAS program, which integrated data from two trials of more than 10,000 patients with type 2 diabetes and high cardiovascular disease risk, showed that those who received canagliflozin had a 14% reduced risk of 3-point major adverse cardiovascular events (3P-MACE), compared with those who received placebo. (N Engl J Med. 2017 Aug;377:644-57). “There was a curious increased risk of amputation and fracture in the canagliflozin group, which has not been seen in other trials,” Dr. Cherney said. “That certainly merits further thought and investigation, to better understand how significant this risk is.”
Upcoming trials of renal endpoints to look out for, he said, include the CREDENCE study (results expected in 2019), DAPA-CKD, which is in the recruitment stage, and a new outcome study to evaluate the effect of empagliflozin for the treatment of people with chronic kidney disease. “This is an expanding area in the renal and cardiovascular world that we will hear a lot more about in the next 3-5 years,” he said.
Dr. Cherney reported consulting fees and/or honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe, and Sanofi.
EXPERT ANALYSIS FROM WCIRDC 2017
Always get culture in symptomatic children with neurogenic bladder
In the symptomatic child with neurogenic bladder at risk for urinary tract infection (UTI), urine culture should be performed regardless of the results of urinalysis, recommended Catherine S. Forster, MD, of Cincinnati Children’s Hospital Medical Center, and her associates.
In a general pediatric population, studies have found that certain uropathogens – such as Enterococcus species, Klebsiella species, and Pseudomonas aeruginosa – are less likely to be associated with pyuria than Escherichia coli.
According to the guidelines of the Infectious Disease Society of America guidelines for the diagnosis of catheter-associated UTI, pyuria is not considered diagnostic of UTI in patients who require CIC.
Children with neurogenic bladder requiring CIC often have bacteriuria and often undergo urinalyses to determine if empirical antibiotics are warranted until urine culture results are available. “Although timely initiation of antibiotics can prevent the progression of infection and decrease the risk of renal scars, unnecessary antimicrobial agents contribute to the emergence of bacterial resistance,” Dr. Forster and her associates said.
So the researchers designed a study to find out if the presence of pyuria was associated with particular uropathogens in children with neurogenic bladders.
In an analysis of 2,420 urinalysis and urine culture results from EHRs between Jan.1, 2008, and Dec. 31, 2014, for patients aged 18 years and younger with neurogenic bladders requiring CIC, the most frequently isolated uropathogen was E. coli (37%), followed by Enterococcus species (14%), Klebsiella species (11%), and various other uropathogen species (38%).
In children needing CIC for neurogenic bladder, growth of Enterococcus species on urine culture was linked with lower odds of both microscopic pyuria (0.44) and leukocyte esterase (0.45).
“With these results, we suggest that the current markers of UTI evidenced on urinalysis and urine microscopy are insufficient for predicting bacteriuria in this population,” Dr. Forster and her colleagues said, leading to their recommendation to perform a culture in symptomatic children with neurogenic bladders irrespective of urinalysis results.
Dr. Forster received a research grant from the National Institutes of Health. The investigators said they had no relevant conflicts of interest.
SOURCE: Forster CS et al. Pediatrics. 2018;141(5):e20173006.
In the symptomatic child with neurogenic bladder at risk for urinary tract infection (UTI), urine culture should be performed regardless of the results of urinalysis, recommended Catherine S. Forster, MD, of Cincinnati Children’s Hospital Medical Center, and her associates.
In a general pediatric population, studies have found that certain uropathogens – such as Enterococcus species, Klebsiella species, and Pseudomonas aeruginosa – are less likely to be associated with pyuria than Escherichia coli.
According to the guidelines of the Infectious Disease Society of America guidelines for the diagnosis of catheter-associated UTI, pyuria is not considered diagnostic of UTI in patients who require CIC.
Children with neurogenic bladder requiring CIC often have bacteriuria and often undergo urinalyses to determine if empirical antibiotics are warranted until urine culture results are available. “Although timely initiation of antibiotics can prevent the progression of infection and decrease the risk of renal scars, unnecessary antimicrobial agents contribute to the emergence of bacterial resistance,” Dr. Forster and her associates said.
So the researchers designed a study to find out if the presence of pyuria was associated with particular uropathogens in children with neurogenic bladders.
In an analysis of 2,420 urinalysis and urine culture results from EHRs between Jan.1, 2008, and Dec. 31, 2014, for patients aged 18 years and younger with neurogenic bladders requiring CIC, the most frequently isolated uropathogen was E. coli (37%), followed by Enterococcus species (14%), Klebsiella species (11%), and various other uropathogen species (38%).
In children needing CIC for neurogenic bladder, growth of Enterococcus species on urine culture was linked with lower odds of both microscopic pyuria (0.44) and leukocyte esterase (0.45).
“With these results, we suggest that the current markers of UTI evidenced on urinalysis and urine microscopy are insufficient for predicting bacteriuria in this population,” Dr. Forster and her colleagues said, leading to their recommendation to perform a culture in symptomatic children with neurogenic bladders irrespective of urinalysis results.
Dr. Forster received a research grant from the National Institutes of Health. The investigators said they had no relevant conflicts of interest.
SOURCE: Forster CS et al. Pediatrics. 2018;141(5):e20173006.
In the symptomatic child with neurogenic bladder at risk for urinary tract infection (UTI), urine culture should be performed regardless of the results of urinalysis, recommended Catherine S. Forster, MD, of Cincinnati Children’s Hospital Medical Center, and her associates.
In a general pediatric population, studies have found that certain uropathogens – such as Enterococcus species, Klebsiella species, and Pseudomonas aeruginosa – are less likely to be associated with pyuria than Escherichia coli.
According to the guidelines of the Infectious Disease Society of America guidelines for the diagnosis of catheter-associated UTI, pyuria is not considered diagnostic of UTI in patients who require CIC.
Children with neurogenic bladder requiring CIC often have bacteriuria and often undergo urinalyses to determine if empirical antibiotics are warranted until urine culture results are available. “Although timely initiation of antibiotics can prevent the progression of infection and decrease the risk of renal scars, unnecessary antimicrobial agents contribute to the emergence of bacterial resistance,” Dr. Forster and her associates said.
So the researchers designed a study to find out if the presence of pyuria was associated with particular uropathogens in children with neurogenic bladders.
In an analysis of 2,420 urinalysis and urine culture results from EHRs between Jan.1, 2008, and Dec. 31, 2014, for patients aged 18 years and younger with neurogenic bladders requiring CIC, the most frequently isolated uropathogen was E. coli (37%), followed by Enterococcus species (14%), Klebsiella species (11%), and various other uropathogen species (38%).
In children needing CIC for neurogenic bladder, growth of Enterococcus species on urine culture was linked with lower odds of both microscopic pyuria (0.44) and leukocyte esterase (0.45).
“With these results, we suggest that the current markers of UTI evidenced on urinalysis and urine microscopy are insufficient for predicting bacteriuria in this population,” Dr. Forster and her colleagues said, leading to their recommendation to perform a culture in symptomatic children with neurogenic bladders irrespective of urinalysis results.
Dr. Forster received a research grant from the National Institutes of Health. The investigators said they had no relevant conflicts of interest.
SOURCE: Forster CS et al. Pediatrics. 2018;141(5):e20173006.
FROM PEDIATRICS
Key clinical point:
Major finding: In children needing CIC for neurogenic bladder, growth of Enterococcus species on urine culture was linked with lower odds of both microscopic pyuria (0.44) and leukocyte esterase (0.45).
Study details: Assessment of 2,420 urinalyses and urine cultures in children with neurogenic bladders.
Disclosures: Dr. Forster received a research grant from the National Institutes of Health. The investigators said they had no relevant conflicts of interest.
Source: Forster CS et al. Pediatrics. 2018;141(5):e20173006.
Acute cardiorenal syndrome: Mechanisms and clinical implications
As the heart goes, so go the kidneys—and vice versa. Cardiac and renal function are intricately interdependent, and failure of either organ causes injury to the other in a vicious circle of worsening function.1
Here, we discuss acute cardiorenal syndrome, ie, acute exacerbation of heart failure leading to acute kidney injury, a common cause of hospitalization and admission to the intensive care unit. We examine its clinical definition, pathophysiology, hemodynamic derangements, clues that help in diagnosing it, and its treatment.
A GROUP OF LINKED DISORDERS
Two types of acute cardiac dysfunction
Although these definitions offer a good general description, further clarification of the nature of organ dysfunction is needed. Acute renal dysfunction can be unambiguously defined using the AKIN (Acute Kidney Injury Network) and RIFLE (risk, injury, failure, loss of kidney function, and end-stage kidney disease) classifications.3 Acute cardiac dysfunction, on the other hand, is an ambiguous term that encompasses 2 clinically and pathophysiologically distinct conditions: cardiogenic shock and acute heart failure.
Cardiogenic shock is characterized by a catastrophic compromise of cardiac pump function leading to global hypoperfusion severe enough to cause systemic organ damage.4 The cardiac index at which organs start to fail varies in different cases, but a value of less than 1.8 L/min/m2 is typically used to define cardiogenic shock.4
Acute heart failure, on the other hand, is defined as gradually or rapidly worsening signs and symptoms of congestive heart failure due to worsening pulmonary or systemic congestion.5 Hypervolemia is the hallmark of acute heart failure, whereas patients with cardiogenic shock may be hypervolemic, normovolemic, or hypovolemic. Although cardiac output may be mildly reduced in some cases of acute heart failure, systemic perfusion is enough to maintain organ function.
These two conditions cause renal injury by distinct mechanisms and have entirely different therapeutic implications. As we discuss later, reduced renal perfusion due to renal venous congestion is now believed to be the major hemodynamic mechanism of renal injury in acute heart failure. On the other hand, in cardiogenic shock, renal perfusion is reduced due to a critical decline of cardiac pump function.
The ideal definition of acute cardiorenal syndrome should describe a distinct pathophysiology of the syndrome and offer distinct therapeutic options that counteract it. Hence, we propose that renal injury from cardiogenic shock should not be included in its definition, an approach that has been adopted in some of the recent reviews as well.6 Our discussion of acute cardiorenal syndrome is restricted to renal injury caused by acute heart failure.
PATHOPHYSIOLOGY OF ACUTE CARDIORENAL SYNDROME
Multiple mechanisms have been implicated in the pathophysiology of cardiorenal syndrome.7,8
Sympathetic hyperactivity is a compensatory mechanism in heart failure and may be aggravated if cardiac output is further reduced. Its effects include constriction of afferent and efferent arterioles, causing reduced renal perfusion and increased tubular sodium and water reabsorption.7
The renin-angiotensin-aldosterone system is activated in patients with stable congestive heart failure and may be further stimulated in a state of reduced renal perfusion, which is a hallmark of acute cardiorenal syndrome. Its activation can cause further salt and water retention.
However, direct hemodynamic mechanisms likely play the most important role and have obvious diagnostic and therapeutic implications.
Elevated venous pressure, not reduced cardiac output, drives kidney injury
The classic view was that renal dysfunction in acute heart failure is caused by reduced renal blood flow due to failing cardiac pump function. Cardiac output may be reduced in acute heart failure for various reasons, such as atrial fibrillation, myocardial infarction, or other processes, but reduced cardiac output has a minimal role, if any, in the pathogenesis of renal injury in acute heart failure.
As evidence of this, acute heart failure is not always associated with reduced cardiac output.5 Even if the cardiac index (cardiac output divided by body surface area) is mildly reduced, renal blood flow is largely unaffected, thanks to effective renal autoregulatory mechanisms. Not until the mean arterial pressure falls below 70 mm Hg do these mechanisms fail and renal blood flow starts to drop.9 Hence, unless cardiac performance is compromised enough to cause cardiogenic shock, renal blood flow usually does not change significantly with mild reduction in cardiac output.
Hanberg et al10 performed a post hoc analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial, in which 525 patients with advanced heart failure underwent pulmonary artery catheterization to measure their cardiac index. The authors found no association between the cardiac index and renal function in these patients.
How venous congestion impairs the kidney
In view of the current clinical evidence, the focus has shifted to renal venous congestion. According to Poiseuille’s law, blood flow through the kidneys depends on the pressure gradient—high pressure on the arterial side, low pressure on the venous side.8 Increased renal venous pressure causes reduced renal perfusion pressure, thereby affecting renal perfusion. This is now recognized as an important hemodynamic mechanism of acute cardiorenal syndrome.
Renal congestion can also affect renal function through indirect mechanisms. For example, it can cause renal interstitial edema that may then increase the intratubular pressure, thereby reducing the transglomerular pressure gradient.11
Firth et al,14 in experiments in animals, found that increasing the renal venous pressure above 18.75 mm Hg significantly reduced the glomerular filtration rate, which completely resolved when renal venous pressure was restored to basal levels.
Mullens et al,15 in a study of 145 patients admitted with acute heart failure, reported that 58 (40%) developed acute kidney injury. Pulmonary artery catheterization revealed that elevated central venous pressure, rather than reduced cardiac index, was the primary hemodynamic factor driving renal dysfunction.
DIAGNOSIS AND CLINICAL ASSESSMENT
Patients with acute cardiorenal syndrome present with clinical features of pulmonary or systemic congestion (or both) and acute kidney injury.
Elevated left-sided pressures are usually but not always associated with elevated right-sided pressures. In a study of 1,000 patients with advanced heart failure, a pulmonary capillary wedge pressure of 22 mm Hg or higher had a positive predictive value of 88% for a right atrial pressure of 10 mm Hg or higher.16 Hence, the clinical presentation may vary depending on the location (pulmonary, systemic, or both) and degree of congestion.
Symptoms of pulmonary congestion include worsening exertional dyspnea and orthopnea; bilateral crackles may be heard on physical examination if pulmonary edema is present.
Systemic congestion can cause significant peripheral edema and weight gain. Jugular venous distention may be noted. Oliguria may be present due to renal dysfunction; patients on maintenance diuretic therapy often note its lack of efficacy.
Signs of acute heart failure
Wang et al,17 in a meta-analysis of 22 studies, concluded that the features that most strongly suggested acute heart failure were:
- History of paroxysmal nocturnal dyspnea
- A third heart sound
- Evidence of pulmonary venous congestion on chest radiography.
Features that most strongly suggested the patient did not have acute heart failure were:
- Absence of exertional dyspnea
- Absence of rales
- Absence of radiographic evidence of cardiomegaly.
Patients may present without some of these classic clinical features, and the diagnosis of acute heart failure may be challenging. For example, even if left-sided pressures are very high, pulmonary edema may be absent because of pulmonary vascular remodeling in chronic heart failure.18 Pulmonary artery catheterization reveals elevated cardiac filling pressures and can be used to guide therapy, but clinical evidence argues against its routine use.19
Urine electrolytes (fractional excretion of sodium < 1% and fractional excretion of urea < 35%) often suggest a prerenal form of acute kidney injury, since the hemodynamic derangements in acute cardiorenal syndrome reduce renal perfusion.
Biomarkers of cell-cycle arrest such as urine insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinase 2 have recently been shown to identify patients with acute heart failure at risk of developing acute cardiorenal syndrome.20
Acute cardiorenal syndrome vs renal injury due to hypovolemia
The major alternative in the differential diagnosis of acute cardiorenal syndrome is renal injury due to hypovolemia. Patients with stable heart failure usually have mild hypervolemia at baseline, but they can become hypovolemic due to overaggressive diuretic therapy, severe diarrhea, or other causes.
Although the fluid status of patients in these 2 conditions is opposite, they can be difficult to distinguish. In both conditions, urine electrolytes suggest a prerenal acute kidney injury. A history of recent fluid losses or diuretic overuse may help identify hypovolemia. If available, analysis of the recent trend in weight can be vital in making the right diagnosis.
Misdiagnosis of acute cardiorenal syndrome as hypovolemia-induced acute kidney injury can be catastrophic. If volume depletion is erroneously judged to be the cause of acute kidney injury, fluid administration can further worsen both cardiac and renal function. This can perpetuate the vicious circle that is already in play. Lack of renal recovery may invite further fluid administration.
TREATMENT
Fluid removal with diuresis or ultrafiltration is the cornerstone of treatment. Other treatments such as inotropes are reserved for patients with resistant disease.
Diuretics
The goal of therapy in acute cardiorenal syndrome is to achieve aggressive diuresis, typically using intravenous diuretics. Loop diuretics are the most potent class of diuretics and are the first-line drugs for this purpose. Other classes of diuretics can be used in conjunction with loop diuretics; however, using them by themselves is neither effective nor recommended.
Resistance to diuretics at usual doses is common in patients with acute cardiorenal syndrome. Several mechanisms contribute to diuretic resistance in these patients.21
Oral bioavailability of diuretics may be reduced due to intestinal edema.
Diuretic pharmacokinetics are significantly deranged in cardiorenal syndrome. All diuretics except mineralocorticoid antagonists (ie, spironolactone and eplerenone) act on targets on the luminal side of renal tubules, but are highly protein-bound and are hence not filtered at the glomerulus. Loop diuretics, thiazides, and carbonic anhydrase inhibitors are secreted in the proximal convoluted tubule via the organic anion transporter,22 whereas epithelial sodium channel inhibitors (amiloride and triamterene) are secreted via the organic cation transporter 2.23 In renal dysfunction, various uremic toxins accumulate in the body and compete with diuretics for secretion into the proximal convoluted tubule via these transporters.24
Finally, activation of the sympathetic nervous system and renin-angiotensin-aldosterone system leads to increased tubular sodium and water retention, thereby also blunting the diuretic response.
Diuretic dosage. In patients whose creatinine clearance is less than 15 mL/min, only 10% to 20% as much loop diuretic is secreted into the renal tubule as in normal individuals.25 This effect warrants dose adjustment of diuretics during uremia.
Continuous infusion or bolus? Continuous infusion of loop diuretics is another strategy to optimize drug delivery. Compared with bolus therapy, continuous infusion provides more sustained and uniform drug delivery and prevents postdiuretic sodium retention.
The Diuretic Optimization Strategies Evaluation (DOSE) trial compared the efficacy and safety of continuous vs bolus furosemide therapy in 308 patients admitted with acute decompensated heart failure.26 There was no difference in symptom control or net fluid loss at 72 hours in either group. Other studies have shown more diuresis with continuous infusion than with a similarly dosed bolus regimen.27 However, definitive clinical evidence is lacking at this point to support routine use of continuous loop diuretic therapy.
Combination diuretic therapy. Sequential nephron blockade with combination diuretic therapy is an important therapeutic strategy against diuretic resistance. Notably, urine output-guided diuretic therapy has been shown to be superior to standard diuretic therapy.28 Such therapeutic protocols may employ combination diuretic therapy as a next step when the desired diuretic response is not obtained with high doses of loop diuretic monotherapy.
The desired diuretic response depends on the clinical situation. For example, in patients with severe congestion, we would like the net fluid output to be at least 2 to 3 L more than the fluid intake after the first 24 hours. Sometimes, patients in the intensive care unit are on several essential drug infusions, so that their net intake amounts to 1 to 2 L. In these patients, the desired urine output would be even more than in patients not on these drug infusions.
Loop diuretics block sodium reabsorption at the thick ascending loop of Henle. This disrupts the countercurrent exchange mechanism and reduces renal medullary interstitial osmolarity; these effects prevent water reabsorption. However, the unresorbed sodium can be taken up by the sodium-chloride cotransporter and the epithelial sodium channel in the distal nephron, thereby blunting the diuretic effect. This is the rationale for combining loop diuretics with thiazides or potassium-sparing diuretics.
Similarly, carbonic anhydrase inhibitors (eg, acetazolamide) reduce sodium reabsorption from the proximal convoluted tubule, but most of this sodium is then reabsorbed distally. Hence, the combination of a loop diuretic and acetazolamide can also have a synergistic diuretic effect.
The most popular combination is a loop diuretic plus a thiazide, although no large-scale placebo-controlled trials have been performed.29 Metolazone (a thiazidelike diuretic) is typically used due to its low cost and availability.30 Metolazone has also been shown to block sodium reabsorption at the proximal tubule, which may contribute to its synergistic effect. Chlorothiazide is available in an intravenous formulation and has a faster onset of action than metolazone. However, studies have failed to detect any benefit of one over the other.31
The potential benefit of combining a loop diuretic with acetazolamide is a lower tendency to develop metabolic alkalosis, a potential side effect of loop diuretics and thiazides. Although data are limited, a recent study showed that adding acetazolamide to bumetanide led to significantly increased natriuresis.32
In the Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) trial, adding spironolactone in high doses to usual therapy was not found to cause any significant change in N-terminal pro-B-type natriuretic peptide level or net urine output.33
Ultrafiltration
Venovenous ultrafiltration (or aquapheresis) employs an extracorporeal circuit, similar to the one used in hemodialysis, which removes iso-osmolar fluid at a fixed rate.34 Newer ultrafiltration systems are more portable, can be used with peripheral venous access, and require minimal nursing supervision.35
Although ultrafiltration seems an attractive alternative to diuresis in acute heart failure, studies have been inconclusive. The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial compared ultrafiltration and diuresis in 188 patients with acute heart failure and acute cardiorenal syndrome.36 Diuresis, performed according to an algorithm, was found to be superior to ultrafiltration in terms of a bivariate end point of change in weight and change in serum creatinine level at 96 hours. However, the level of cystatin C is thought to be a more accurate indicator of renal function, and the change in cystatin C level from baseline did not differ between the two treatment groups. Also, the ultrafiltration rate was 200 mL per hour, which, some argue, may have been excessive and may have caused intravascular depletion.
Although the ideal rate of fluid removal is unknown, it should be individualized and adjusted based on the patient’s renal function, volume status, and hemodynamic status. The initial rate should be based on the degree of fluid overload and the anticipated plasma refill rate from the interstitial fluid.37 For example, a malnourished patient may have low serum oncotic pressure and hence have low plasma refill upon ultrafiltration. Disturbance of this delicate balance between the rates of ultrafiltration and plasma refill may lead to intravascular volume contraction.
In summary, although ultrafiltration is a valuable alternative to diuretics in resistant cases, its use as a primary decongestive therapy cannot be endorsed in view of the current data.
Inotropes
Inotropes such as dobutamine and milrinone are typically used in cases of cardiogenic shock to maintain organ perfusion. There is a physiologic rationale to using inotropes in acute cardiorenal syndrome as well, especially when the aforementioned strategies fail to overcome diuretic resistance.7
Inotropes increase cardiac output, improve renal blood flow, improve right ventricular output, and thereby relieve systemic congestion. These hemodynamic effects may improve renal perfusion and response to diuretics. However, clinical evidence to support this is lacking.
The Renal Optimization Strategies Evaluation (ROSE) trial enrolled 360 patients with acute heart failure and renal dysfunction. Adding dopamine in a low dose (2 μg/kg/min) to diuretic therapy had no significant effect on 72-hour cumulative urine output or renal function as measured by cystatin C levels.38 However, acute kidney injury was not identified in this trial, and the renal function of many of these patients may have been at its baseline when they were admitted. In other words, this trial did not necessarily include patients with acute kidney injury along with acute heart failure. Hence, it did not necessarily include patients with acute cardiorenal syndrome.
Vasodilators
Vasodilators such as nitroglycerin, sodium nitroprusside, and hydralazine are commonly used in patients with acute heart failure, although the clinical evidence supporting their use is weak.
Physiologically, arterial dilation reduces afterload and can help relieve pulmonary congestion, and venodilation increases capacitance and reduces preload. In theory, venodilators such as nitroglycerin can relieve renal venous congestion in patients with acute cardiorenal syndrome, thereby improving renal perfusion.
However, the use of vasodilators is often limited by their adverse effects, the most important being hypotension. This is especially relevant in light of recent data identifying reduction in blood pressure during treatment of acute heart failure as an independent risk factor for worsening renal function.39,40 It is important to note that in these studies, changes in cardiac index did not affect the propensity for developing worsening renal function. The precise mechanism of this finding is unclear but it is plausible that systemic vasodilation redistributes the cardiac output to nonrenal tissues, thereby overriding the renal autoregulatory mechanisms that are normally employed in low output states.
Preventive strategies
Various strategies can be used to prevent acute cardiorenal syndrome. An optimal outpatient diuretic regimen to avoid hypervolemia is essential. Patients with advanced congestive heart failure should be followed up closely in dedicated heart failure clinics until their diuretic regimen is optimized. Patients should be advised to check their weight on a regular basis and seek medical advice if they notice an increase in their weight or a reduction in their urine output.
TAKE-HOME POINTS
- A robust clinical definition of cardiorenal syndrome is lacking. Hence, recognition of this condition can be challenging.
- Volume overload is central to its pathogenesis, and accurate assessment of volume status is critical.
- Renal venous congestion is the major mechanism of type 1 cardiorenal syndrome.
- Misdiagnosis can have devastating consequences, as it may lead to an opposite therapeutic approach.
- Fluid removal by various strategies is the mainstay of treatment.
- Temporary inotropic support should be saved for the last resort.
- Geisberg C, Butler J. Addressing the challenges of cardiorenal syndrome. Cleve Clin J Med 2006; 73:485–491.
- House AA, Anand I, Bellomo R, et al. Definition and classification of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant 2010; 25:1416–1420.
- Chang CH, Lin CY, Tian YC, et al. Acute kidney injury classification: comparison of AKIN and RIFLE criteria. Shock 2010; 33:247-252.
- Reynolds HR, Hochman JS. Cardiogenic shock: current concepts and improving outcomes. Circulation 2008; 117:686–697.
- Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009; 53:557–573.
- ter Maaten JM, Valente MA, Damman K, et al. Diuretic response in acute heart failure—pathophysiology, evaluation, and therapy. Nat Rev Cardiol 2015; 12:184–192.
- Hatamizadeh P, Fonarow GC, Budoff MJ, Darabian S, Kovesdy CP, Kalantar-Zadeh K. Cardiorenal syndrome: pathophysiology and potential targets for clinical management. Nat Rev Nephrol 2013; 9:99–111.
- Bock JS, Gottlieb SS. Cardiorenal syndrome: new perspectives. Circulation 2010; 121:2592–2600.
- Burke M, Pabbidi MR, Farley J, et al. Molecular mechanisms of renal blood flow autoregulation. Curr Vasc Pharmacol 2014; 12:845–858.
- Hanberg JS, Sury K, Wilson FP, et al. Reduced cardiac index is not the dominant driver of renal dysfunction in heart failure. J Am Coll Cardiol 2016; 67:2199–2208.
- Afsar B, Ortiz A, Covic A, et al. Focus on renal congestion in heart failure. Clin Kidney J 2016; 9:39–47.
- Verbrugge FH, Dupont M, Steels P, et al. Abdominal contributions to cardiorenal dysfunction in congestive heart failure. J Am Coll Cardiol 2013; 62:485–495.
- Mullens W, Abrahams Z, Skouri HN, et al. Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function? J Am Coll Cardiol 2008; 51:300–306.
- Firth JD, Raine AE, Ledingham JG. Raised venous pressure: a direct cause of renal sodium retention in oedema? Lancet 1988; 1:1033–1035.
- Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009; 53:589–596.
- Drazner MH, Hamilton MA, Fonarow G, et al. Relationship between right and left-sided filling pressures in 1000 patients with advanced heart failure. J Heart Lung Transplant 1999; 18:1126–1132.
- Wang CS, FitzGerald JM, Schulzer M, et al. Does this dyspneic patient in the emergency department have congestive heart failure? JAMA 2005; 294:1944–1956.
- Gehlbach BK, Geppert E. The pulmonary manifestations of left heart failure. Chest 2004; 125:669–682.
- Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA 2005; 294:1625–1633.
- Schanz M, Shi J , Wasser C , Alscher MD, Kimmel M. Urinary [TIMP-2] × [IGFBP7] for risk prediction of acute kidney injury in decompensated heart failure. Clin Cardiol 2017; doi.org/10.1002/clc.22683.
- Bowman BN, Nawarskas JJ, Anderson JR. Treating diuretic resistance: an overview. Cardiol Rev 2016; 24:256–260.
- Uwai Y, Saito H, Hashimoto Y, Inui KI. Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1. J Pharmacol Exp Ther 2000; 295:261–265.
- Hacker K, Maas R, Kornhuber J, et al. Substrate-dependent inhibition of the human organic cation transporter OCT2: a comparison of metformin with experimental substrates. PLoS One 2015; 10:e0136451.
- Schophuizen CM, Wilmer MJ, Jansen J, et al. Cationic uremic toxins affect human renal proximal tubule cell functioning through interaction with the organic cation transporter. Pflugers Arch 2013; 465:1701–1714.
- Brater DC. Diuretic therapy. N Engl J Med 1998; 339:387–395.
- Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011; 364:797–805.
- Thomson MR, Nappi JM, Dunn SP, Hollis IB, Rodgers JE, Van Bakel AB. Continuous versus intermittent infusion of furosemide in acute decompensated heart failure. J Card Fail 2010; 16:188–193.
- Grodin JL, Stevens SR, de Las Fuentes L, et al. Intensification of medication therapy for cardiorenal syndrome in acute decompensated heart failure. J Card Fail 2016; 22:26–32.
- Ng TM, Konopka E, Hyderi AF, et al. Comparison of bumetanide- and metolazone-based diuretic regimens to furosemide in acute heart failure. J Cardiovasc Pharmacol Ther 2013; 18:345–353.
- Sica DA. Metolazone and its role in edema management. Congest Heart Fail 2003; 9:100–105.
- Moranville MP, Choi S, Hogg J, Anderson AS, Rich JD. Comparison of metolazone versus chlorothiazide in acute decompensated heart failure with diuretic resistance. Cardiovasc Ther 2015; 33:42–49.
- Verbrugge FH, Dupont M, Bertrand PB, et al. Determinants and impact of the natriuretic response to diuretic therapy in heart failure with reduced ejection fraction and volume overload. Acta Cardiol 2015; 70:265–373.
- Butler J, Anstrom KJ, Felker GM, et al. Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF randomized clinical trial. JAMA Cardiol 2017 Jul 12. doi: 10.1001/jamacardio.2017.2198. [Epub ahead of print]
- Pourafshar N, Karimi A, Kazory A. Extracorporeal ultrafiltration therapy for acute decompensated heart failure. Expert Rev Cardiovasc Ther 2016; 14:5–13.
- Jaski BE, Ha J, Denys BG, et al. Peripherally inserted veno-venous ultrafiltration for rapid treatment of volume overloaded patients. J Card Fail 2003; 9:227–231.
- Jaski BE, Ha J, Denys BG, Lamba S, Trupp RJ, Abraham WT. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012; 367:2296–2304.
- Kazory A. Cardiorenal syndrome: ultrafiltration therapy for heart failure—trials and tribulations. Clin J Am Soc Nephrol 2013; 8:1816–1828.
- Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA 2013; 310:2533–2543.
- Testani JM, Coca SG, McCauley BD, et al. Impact of changes in blood pressure during the treatment of acute decompensated heart failure on renal and clinical outcomes. Eur J Heart Fail 2011; 13:877–884.
- Dupont M, Mullens W, Finucan M, et al. Determinants of dynamic changes in serum creatinine in acute decompensated heart failure: the importance of blood pressure reduction during treatment. Eur J Heart Fail 2013; 15:433–440.
As the heart goes, so go the kidneys—and vice versa. Cardiac and renal function are intricately interdependent, and failure of either organ causes injury to the other in a vicious circle of worsening function.1
Here, we discuss acute cardiorenal syndrome, ie, acute exacerbation of heart failure leading to acute kidney injury, a common cause of hospitalization and admission to the intensive care unit. We examine its clinical definition, pathophysiology, hemodynamic derangements, clues that help in diagnosing it, and its treatment.
A GROUP OF LINKED DISORDERS
Two types of acute cardiac dysfunction
Although these definitions offer a good general description, further clarification of the nature of organ dysfunction is needed. Acute renal dysfunction can be unambiguously defined using the AKIN (Acute Kidney Injury Network) and RIFLE (risk, injury, failure, loss of kidney function, and end-stage kidney disease) classifications.3 Acute cardiac dysfunction, on the other hand, is an ambiguous term that encompasses 2 clinically and pathophysiologically distinct conditions: cardiogenic shock and acute heart failure.
Cardiogenic shock is characterized by a catastrophic compromise of cardiac pump function leading to global hypoperfusion severe enough to cause systemic organ damage.4 The cardiac index at which organs start to fail varies in different cases, but a value of less than 1.8 L/min/m2 is typically used to define cardiogenic shock.4
Acute heart failure, on the other hand, is defined as gradually or rapidly worsening signs and symptoms of congestive heart failure due to worsening pulmonary or systemic congestion.5 Hypervolemia is the hallmark of acute heart failure, whereas patients with cardiogenic shock may be hypervolemic, normovolemic, or hypovolemic. Although cardiac output may be mildly reduced in some cases of acute heart failure, systemic perfusion is enough to maintain organ function.
These two conditions cause renal injury by distinct mechanisms and have entirely different therapeutic implications. As we discuss later, reduced renal perfusion due to renal venous congestion is now believed to be the major hemodynamic mechanism of renal injury in acute heart failure. On the other hand, in cardiogenic shock, renal perfusion is reduced due to a critical decline of cardiac pump function.
The ideal definition of acute cardiorenal syndrome should describe a distinct pathophysiology of the syndrome and offer distinct therapeutic options that counteract it. Hence, we propose that renal injury from cardiogenic shock should not be included in its definition, an approach that has been adopted in some of the recent reviews as well.6 Our discussion of acute cardiorenal syndrome is restricted to renal injury caused by acute heart failure.
PATHOPHYSIOLOGY OF ACUTE CARDIORENAL SYNDROME
Multiple mechanisms have been implicated in the pathophysiology of cardiorenal syndrome.7,8
Sympathetic hyperactivity is a compensatory mechanism in heart failure and may be aggravated if cardiac output is further reduced. Its effects include constriction of afferent and efferent arterioles, causing reduced renal perfusion and increased tubular sodium and water reabsorption.7
The renin-angiotensin-aldosterone system is activated in patients with stable congestive heart failure and may be further stimulated in a state of reduced renal perfusion, which is a hallmark of acute cardiorenal syndrome. Its activation can cause further salt and water retention.
However, direct hemodynamic mechanisms likely play the most important role and have obvious diagnostic and therapeutic implications.
Elevated venous pressure, not reduced cardiac output, drives kidney injury
The classic view was that renal dysfunction in acute heart failure is caused by reduced renal blood flow due to failing cardiac pump function. Cardiac output may be reduced in acute heart failure for various reasons, such as atrial fibrillation, myocardial infarction, or other processes, but reduced cardiac output has a minimal role, if any, in the pathogenesis of renal injury in acute heart failure.
As evidence of this, acute heart failure is not always associated with reduced cardiac output.5 Even if the cardiac index (cardiac output divided by body surface area) is mildly reduced, renal blood flow is largely unaffected, thanks to effective renal autoregulatory mechanisms. Not until the mean arterial pressure falls below 70 mm Hg do these mechanisms fail and renal blood flow starts to drop.9 Hence, unless cardiac performance is compromised enough to cause cardiogenic shock, renal blood flow usually does not change significantly with mild reduction in cardiac output.
Hanberg et al10 performed a post hoc analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial, in which 525 patients with advanced heart failure underwent pulmonary artery catheterization to measure their cardiac index. The authors found no association between the cardiac index and renal function in these patients.
How venous congestion impairs the kidney
In view of the current clinical evidence, the focus has shifted to renal venous congestion. According to Poiseuille’s law, blood flow through the kidneys depends on the pressure gradient—high pressure on the arterial side, low pressure on the venous side.8 Increased renal venous pressure causes reduced renal perfusion pressure, thereby affecting renal perfusion. This is now recognized as an important hemodynamic mechanism of acute cardiorenal syndrome.
Renal congestion can also affect renal function through indirect mechanisms. For example, it can cause renal interstitial edema that may then increase the intratubular pressure, thereby reducing the transglomerular pressure gradient.11
Firth et al,14 in experiments in animals, found that increasing the renal venous pressure above 18.75 mm Hg significantly reduced the glomerular filtration rate, which completely resolved when renal venous pressure was restored to basal levels.
Mullens et al,15 in a study of 145 patients admitted with acute heart failure, reported that 58 (40%) developed acute kidney injury. Pulmonary artery catheterization revealed that elevated central venous pressure, rather than reduced cardiac index, was the primary hemodynamic factor driving renal dysfunction.
DIAGNOSIS AND CLINICAL ASSESSMENT
Patients with acute cardiorenal syndrome present with clinical features of pulmonary or systemic congestion (or both) and acute kidney injury.
Elevated left-sided pressures are usually but not always associated with elevated right-sided pressures. In a study of 1,000 patients with advanced heart failure, a pulmonary capillary wedge pressure of 22 mm Hg or higher had a positive predictive value of 88% for a right atrial pressure of 10 mm Hg or higher.16 Hence, the clinical presentation may vary depending on the location (pulmonary, systemic, or both) and degree of congestion.
Symptoms of pulmonary congestion include worsening exertional dyspnea and orthopnea; bilateral crackles may be heard on physical examination if pulmonary edema is present.
Systemic congestion can cause significant peripheral edema and weight gain. Jugular venous distention may be noted. Oliguria may be present due to renal dysfunction; patients on maintenance diuretic therapy often note its lack of efficacy.
Signs of acute heart failure
Wang et al,17 in a meta-analysis of 22 studies, concluded that the features that most strongly suggested acute heart failure were:
- History of paroxysmal nocturnal dyspnea
- A third heart sound
- Evidence of pulmonary venous congestion on chest radiography.
Features that most strongly suggested the patient did not have acute heart failure were:
- Absence of exertional dyspnea
- Absence of rales
- Absence of radiographic evidence of cardiomegaly.
Patients may present without some of these classic clinical features, and the diagnosis of acute heart failure may be challenging. For example, even if left-sided pressures are very high, pulmonary edema may be absent because of pulmonary vascular remodeling in chronic heart failure.18 Pulmonary artery catheterization reveals elevated cardiac filling pressures and can be used to guide therapy, but clinical evidence argues against its routine use.19
Urine electrolytes (fractional excretion of sodium < 1% and fractional excretion of urea < 35%) often suggest a prerenal form of acute kidney injury, since the hemodynamic derangements in acute cardiorenal syndrome reduce renal perfusion.
Biomarkers of cell-cycle arrest such as urine insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinase 2 have recently been shown to identify patients with acute heart failure at risk of developing acute cardiorenal syndrome.20
Acute cardiorenal syndrome vs renal injury due to hypovolemia
The major alternative in the differential diagnosis of acute cardiorenal syndrome is renal injury due to hypovolemia. Patients with stable heart failure usually have mild hypervolemia at baseline, but they can become hypovolemic due to overaggressive diuretic therapy, severe diarrhea, or other causes.
Although the fluid status of patients in these 2 conditions is opposite, they can be difficult to distinguish. In both conditions, urine electrolytes suggest a prerenal acute kidney injury. A history of recent fluid losses or diuretic overuse may help identify hypovolemia. If available, analysis of the recent trend in weight can be vital in making the right diagnosis.
Misdiagnosis of acute cardiorenal syndrome as hypovolemia-induced acute kidney injury can be catastrophic. If volume depletion is erroneously judged to be the cause of acute kidney injury, fluid administration can further worsen both cardiac and renal function. This can perpetuate the vicious circle that is already in play. Lack of renal recovery may invite further fluid administration.
TREATMENT
Fluid removal with diuresis or ultrafiltration is the cornerstone of treatment. Other treatments such as inotropes are reserved for patients with resistant disease.
Diuretics
The goal of therapy in acute cardiorenal syndrome is to achieve aggressive diuresis, typically using intravenous diuretics. Loop diuretics are the most potent class of diuretics and are the first-line drugs for this purpose. Other classes of diuretics can be used in conjunction with loop diuretics; however, using them by themselves is neither effective nor recommended.
Resistance to diuretics at usual doses is common in patients with acute cardiorenal syndrome. Several mechanisms contribute to diuretic resistance in these patients.21
Oral bioavailability of diuretics may be reduced due to intestinal edema.
Diuretic pharmacokinetics are significantly deranged in cardiorenal syndrome. All diuretics except mineralocorticoid antagonists (ie, spironolactone and eplerenone) act on targets on the luminal side of renal tubules, but are highly protein-bound and are hence not filtered at the glomerulus. Loop diuretics, thiazides, and carbonic anhydrase inhibitors are secreted in the proximal convoluted tubule via the organic anion transporter,22 whereas epithelial sodium channel inhibitors (amiloride and triamterene) are secreted via the organic cation transporter 2.23 In renal dysfunction, various uremic toxins accumulate in the body and compete with diuretics for secretion into the proximal convoluted tubule via these transporters.24
Finally, activation of the sympathetic nervous system and renin-angiotensin-aldosterone system leads to increased tubular sodium and water retention, thereby also blunting the diuretic response.
Diuretic dosage. In patients whose creatinine clearance is less than 15 mL/min, only 10% to 20% as much loop diuretic is secreted into the renal tubule as in normal individuals.25 This effect warrants dose adjustment of diuretics during uremia.
Continuous infusion or bolus? Continuous infusion of loop diuretics is another strategy to optimize drug delivery. Compared with bolus therapy, continuous infusion provides more sustained and uniform drug delivery and prevents postdiuretic sodium retention.
The Diuretic Optimization Strategies Evaluation (DOSE) trial compared the efficacy and safety of continuous vs bolus furosemide therapy in 308 patients admitted with acute decompensated heart failure.26 There was no difference in symptom control or net fluid loss at 72 hours in either group. Other studies have shown more diuresis with continuous infusion than with a similarly dosed bolus regimen.27 However, definitive clinical evidence is lacking at this point to support routine use of continuous loop diuretic therapy.
Combination diuretic therapy. Sequential nephron blockade with combination diuretic therapy is an important therapeutic strategy against diuretic resistance. Notably, urine output-guided diuretic therapy has been shown to be superior to standard diuretic therapy.28 Such therapeutic protocols may employ combination diuretic therapy as a next step when the desired diuretic response is not obtained with high doses of loop diuretic monotherapy.
The desired diuretic response depends on the clinical situation. For example, in patients with severe congestion, we would like the net fluid output to be at least 2 to 3 L more than the fluid intake after the first 24 hours. Sometimes, patients in the intensive care unit are on several essential drug infusions, so that their net intake amounts to 1 to 2 L. In these patients, the desired urine output would be even more than in patients not on these drug infusions.
Loop diuretics block sodium reabsorption at the thick ascending loop of Henle. This disrupts the countercurrent exchange mechanism and reduces renal medullary interstitial osmolarity; these effects prevent water reabsorption. However, the unresorbed sodium can be taken up by the sodium-chloride cotransporter and the epithelial sodium channel in the distal nephron, thereby blunting the diuretic effect. This is the rationale for combining loop diuretics with thiazides or potassium-sparing diuretics.
Similarly, carbonic anhydrase inhibitors (eg, acetazolamide) reduce sodium reabsorption from the proximal convoluted tubule, but most of this sodium is then reabsorbed distally. Hence, the combination of a loop diuretic and acetazolamide can also have a synergistic diuretic effect.
The most popular combination is a loop diuretic plus a thiazide, although no large-scale placebo-controlled trials have been performed.29 Metolazone (a thiazidelike diuretic) is typically used due to its low cost and availability.30 Metolazone has also been shown to block sodium reabsorption at the proximal tubule, which may contribute to its synergistic effect. Chlorothiazide is available in an intravenous formulation and has a faster onset of action than metolazone. However, studies have failed to detect any benefit of one over the other.31
The potential benefit of combining a loop diuretic with acetazolamide is a lower tendency to develop metabolic alkalosis, a potential side effect of loop diuretics and thiazides. Although data are limited, a recent study showed that adding acetazolamide to bumetanide led to significantly increased natriuresis.32
In the Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) trial, adding spironolactone in high doses to usual therapy was not found to cause any significant change in N-terminal pro-B-type natriuretic peptide level or net urine output.33
Ultrafiltration
Venovenous ultrafiltration (or aquapheresis) employs an extracorporeal circuit, similar to the one used in hemodialysis, which removes iso-osmolar fluid at a fixed rate.34 Newer ultrafiltration systems are more portable, can be used with peripheral venous access, and require minimal nursing supervision.35
Although ultrafiltration seems an attractive alternative to diuresis in acute heart failure, studies have been inconclusive. The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial compared ultrafiltration and diuresis in 188 patients with acute heart failure and acute cardiorenal syndrome.36 Diuresis, performed according to an algorithm, was found to be superior to ultrafiltration in terms of a bivariate end point of change in weight and change in serum creatinine level at 96 hours. However, the level of cystatin C is thought to be a more accurate indicator of renal function, and the change in cystatin C level from baseline did not differ between the two treatment groups. Also, the ultrafiltration rate was 200 mL per hour, which, some argue, may have been excessive and may have caused intravascular depletion.
Although the ideal rate of fluid removal is unknown, it should be individualized and adjusted based on the patient’s renal function, volume status, and hemodynamic status. The initial rate should be based on the degree of fluid overload and the anticipated plasma refill rate from the interstitial fluid.37 For example, a malnourished patient may have low serum oncotic pressure and hence have low plasma refill upon ultrafiltration. Disturbance of this delicate balance between the rates of ultrafiltration and plasma refill may lead to intravascular volume contraction.
In summary, although ultrafiltration is a valuable alternative to diuretics in resistant cases, its use as a primary decongestive therapy cannot be endorsed in view of the current data.
Inotropes
Inotropes such as dobutamine and milrinone are typically used in cases of cardiogenic shock to maintain organ perfusion. There is a physiologic rationale to using inotropes in acute cardiorenal syndrome as well, especially when the aforementioned strategies fail to overcome diuretic resistance.7
Inotropes increase cardiac output, improve renal blood flow, improve right ventricular output, and thereby relieve systemic congestion. These hemodynamic effects may improve renal perfusion and response to diuretics. However, clinical evidence to support this is lacking.
The Renal Optimization Strategies Evaluation (ROSE) trial enrolled 360 patients with acute heart failure and renal dysfunction. Adding dopamine in a low dose (2 μg/kg/min) to diuretic therapy had no significant effect on 72-hour cumulative urine output or renal function as measured by cystatin C levels.38 However, acute kidney injury was not identified in this trial, and the renal function of many of these patients may have been at its baseline when they were admitted. In other words, this trial did not necessarily include patients with acute kidney injury along with acute heart failure. Hence, it did not necessarily include patients with acute cardiorenal syndrome.
Vasodilators
Vasodilators such as nitroglycerin, sodium nitroprusside, and hydralazine are commonly used in patients with acute heart failure, although the clinical evidence supporting their use is weak.
Physiologically, arterial dilation reduces afterload and can help relieve pulmonary congestion, and venodilation increases capacitance and reduces preload. In theory, venodilators such as nitroglycerin can relieve renal venous congestion in patients with acute cardiorenal syndrome, thereby improving renal perfusion.
However, the use of vasodilators is often limited by their adverse effects, the most important being hypotension. This is especially relevant in light of recent data identifying reduction in blood pressure during treatment of acute heart failure as an independent risk factor for worsening renal function.39,40 It is important to note that in these studies, changes in cardiac index did not affect the propensity for developing worsening renal function. The precise mechanism of this finding is unclear but it is plausible that systemic vasodilation redistributes the cardiac output to nonrenal tissues, thereby overriding the renal autoregulatory mechanisms that are normally employed in low output states.
Preventive strategies
Various strategies can be used to prevent acute cardiorenal syndrome. An optimal outpatient diuretic regimen to avoid hypervolemia is essential. Patients with advanced congestive heart failure should be followed up closely in dedicated heart failure clinics until their diuretic regimen is optimized. Patients should be advised to check their weight on a regular basis and seek medical advice if they notice an increase in their weight or a reduction in their urine output.
TAKE-HOME POINTS
- A robust clinical definition of cardiorenal syndrome is lacking. Hence, recognition of this condition can be challenging.
- Volume overload is central to its pathogenesis, and accurate assessment of volume status is critical.
- Renal venous congestion is the major mechanism of type 1 cardiorenal syndrome.
- Misdiagnosis can have devastating consequences, as it may lead to an opposite therapeutic approach.
- Fluid removal by various strategies is the mainstay of treatment.
- Temporary inotropic support should be saved for the last resort.
As the heart goes, so go the kidneys—and vice versa. Cardiac and renal function are intricately interdependent, and failure of either organ causes injury to the other in a vicious circle of worsening function.1
Here, we discuss acute cardiorenal syndrome, ie, acute exacerbation of heart failure leading to acute kidney injury, a common cause of hospitalization and admission to the intensive care unit. We examine its clinical definition, pathophysiology, hemodynamic derangements, clues that help in diagnosing it, and its treatment.
A GROUP OF LINKED DISORDERS
Two types of acute cardiac dysfunction
Although these definitions offer a good general description, further clarification of the nature of organ dysfunction is needed. Acute renal dysfunction can be unambiguously defined using the AKIN (Acute Kidney Injury Network) and RIFLE (risk, injury, failure, loss of kidney function, and end-stage kidney disease) classifications.3 Acute cardiac dysfunction, on the other hand, is an ambiguous term that encompasses 2 clinically and pathophysiologically distinct conditions: cardiogenic shock and acute heart failure.
Cardiogenic shock is characterized by a catastrophic compromise of cardiac pump function leading to global hypoperfusion severe enough to cause systemic organ damage.4 The cardiac index at which organs start to fail varies in different cases, but a value of less than 1.8 L/min/m2 is typically used to define cardiogenic shock.4
Acute heart failure, on the other hand, is defined as gradually or rapidly worsening signs and symptoms of congestive heart failure due to worsening pulmonary or systemic congestion.5 Hypervolemia is the hallmark of acute heart failure, whereas patients with cardiogenic shock may be hypervolemic, normovolemic, or hypovolemic. Although cardiac output may be mildly reduced in some cases of acute heart failure, systemic perfusion is enough to maintain organ function.
These two conditions cause renal injury by distinct mechanisms and have entirely different therapeutic implications. As we discuss later, reduced renal perfusion due to renal venous congestion is now believed to be the major hemodynamic mechanism of renal injury in acute heart failure. On the other hand, in cardiogenic shock, renal perfusion is reduced due to a critical decline of cardiac pump function.
The ideal definition of acute cardiorenal syndrome should describe a distinct pathophysiology of the syndrome and offer distinct therapeutic options that counteract it. Hence, we propose that renal injury from cardiogenic shock should not be included in its definition, an approach that has been adopted in some of the recent reviews as well.6 Our discussion of acute cardiorenal syndrome is restricted to renal injury caused by acute heart failure.
PATHOPHYSIOLOGY OF ACUTE CARDIORENAL SYNDROME
Multiple mechanisms have been implicated in the pathophysiology of cardiorenal syndrome.7,8
Sympathetic hyperactivity is a compensatory mechanism in heart failure and may be aggravated if cardiac output is further reduced. Its effects include constriction of afferent and efferent arterioles, causing reduced renal perfusion and increased tubular sodium and water reabsorption.7
The renin-angiotensin-aldosterone system is activated in patients with stable congestive heart failure and may be further stimulated in a state of reduced renal perfusion, which is a hallmark of acute cardiorenal syndrome. Its activation can cause further salt and water retention.
However, direct hemodynamic mechanisms likely play the most important role and have obvious diagnostic and therapeutic implications.
Elevated venous pressure, not reduced cardiac output, drives kidney injury
The classic view was that renal dysfunction in acute heart failure is caused by reduced renal blood flow due to failing cardiac pump function. Cardiac output may be reduced in acute heart failure for various reasons, such as atrial fibrillation, myocardial infarction, or other processes, but reduced cardiac output has a minimal role, if any, in the pathogenesis of renal injury in acute heart failure.
As evidence of this, acute heart failure is not always associated with reduced cardiac output.5 Even if the cardiac index (cardiac output divided by body surface area) is mildly reduced, renal blood flow is largely unaffected, thanks to effective renal autoregulatory mechanisms. Not until the mean arterial pressure falls below 70 mm Hg do these mechanisms fail and renal blood flow starts to drop.9 Hence, unless cardiac performance is compromised enough to cause cardiogenic shock, renal blood flow usually does not change significantly with mild reduction in cardiac output.
Hanberg et al10 performed a post hoc analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial, in which 525 patients with advanced heart failure underwent pulmonary artery catheterization to measure their cardiac index. The authors found no association between the cardiac index and renal function in these patients.
How venous congestion impairs the kidney
In view of the current clinical evidence, the focus has shifted to renal venous congestion. According to Poiseuille’s law, blood flow through the kidneys depends on the pressure gradient—high pressure on the arterial side, low pressure on the venous side.8 Increased renal venous pressure causes reduced renal perfusion pressure, thereby affecting renal perfusion. This is now recognized as an important hemodynamic mechanism of acute cardiorenal syndrome.
Renal congestion can also affect renal function through indirect mechanisms. For example, it can cause renal interstitial edema that may then increase the intratubular pressure, thereby reducing the transglomerular pressure gradient.11
Firth et al,14 in experiments in animals, found that increasing the renal venous pressure above 18.75 mm Hg significantly reduced the glomerular filtration rate, which completely resolved when renal venous pressure was restored to basal levels.
Mullens et al,15 in a study of 145 patients admitted with acute heart failure, reported that 58 (40%) developed acute kidney injury. Pulmonary artery catheterization revealed that elevated central venous pressure, rather than reduced cardiac index, was the primary hemodynamic factor driving renal dysfunction.
DIAGNOSIS AND CLINICAL ASSESSMENT
Patients with acute cardiorenal syndrome present with clinical features of pulmonary or systemic congestion (or both) and acute kidney injury.
Elevated left-sided pressures are usually but not always associated with elevated right-sided pressures. In a study of 1,000 patients with advanced heart failure, a pulmonary capillary wedge pressure of 22 mm Hg or higher had a positive predictive value of 88% for a right atrial pressure of 10 mm Hg or higher.16 Hence, the clinical presentation may vary depending on the location (pulmonary, systemic, or both) and degree of congestion.
Symptoms of pulmonary congestion include worsening exertional dyspnea and orthopnea; bilateral crackles may be heard on physical examination if pulmonary edema is present.
Systemic congestion can cause significant peripheral edema and weight gain. Jugular venous distention may be noted. Oliguria may be present due to renal dysfunction; patients on maintenance diuretic therapy often note its lack of efficacy.
Signs of acute heart failure
Wang et al,17 in a meta-analysis of 22 studies, concluded that the features that most strongly suggested acute heart failure were:
- History of paroxysmal nocturnal dyspnea
- A third heart sound
- Evidence of pulmonary venous congestion on chest radiography.
Features that most strongly suggested the patient did not have acute heart failure were:
- Absence of exertional dyspnea
- Absence of rales
- Absence of radiographic evidence of cardiomegaly.
Patients may present without some of these classic clinical features, and the diagnosis of acute heart failure may be challenging. For example, even if left-sided pressures are very high, pulmonary edema may be absent because of pulmonary vascular remodeling in chronic heart failure.18 Pulmonary artery catheterization reveals elevated cardiac filling pressures and can be used to guide therapy, but clinical evidence argues against its routine use.19
Urine electrolytes (fractional excretion of sodium < 1% and fractional excretion of urea < 35%) often suggest a prerenal form of acute kidney injury, since the hemodynamic derangements in acute cardiorenal syndrome reduce renal perfusion.
Biomarkers of cell-cycle arrest such as urine insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinase 2 have recently been shown to identify patients with acute heart failure at risk of developing acute cardiorenal syndrome.20
Acute cardiorenal syndrome vs renal injury due to hypovolemia
The major alternative in the differential diagnosis of acute cardiorenal syndrome is renal injury due to hypovolemia. Patients with stable heart failure usually have mild hypervolemia at baseline, but they can become hypovolemic due to overaggressive diuretic therapy, severe diarrhea, or other causes.
Although the fluid status of patients in these 2 conditions is opposite, they can be difficult to distinguish. In both conditions, urine electrolytes suggest a prerenal acute kidney injury. A history of recent fluid losses or diuretic overuse may help identify hypovolemia. If available, analysis of the recent trend in weight can be vital in making the right diagnosis.
Misdiagnosis of acute cardiorenal syndrome as hypovolemia-induced acute kidney injury can be catastrophic. If volume depletion is erroneously judged to be the cause of acute kidney injury, fluid administration can further worsen both cardiac and renal function. This can perpetuate the vicious circle that is already in play. Lack of renal recovery may invite further fluid administration.
TREATMENT
Fluid removal with diuresis or ultrafiltration is the cornerstone of treatment. Other treatments such as inotropes are reserved for patients with resistant disease.
Diuretics
The goal of therapy in acute cardiorenal syndrome is to achieve aggressive diuresis, typically using intravenous diuretics. Loop diuretics are the most potent class of diuretics and are the first-line drugs for this purpose. Other classes of diuretics can be used in conjunction with loop diuretics; however, using them by themselves is neither effective nor recommended.
Resistance to diuretics at usual doses is common in patients with acute cardiorenal syndrome. Several mechanisms contribute to diuretic resistance in these patients.21
Oral bioavailability of diuretics may be reduced due to intestinal edema.
Diuretic pharmacokinetics are significantly deranged in cardiorenal syndrome. All diuretics except mineralocorticoid antagonists (ie, spironolactone and eplerenone) act on targets on the luminal side of renal tubules, but are highly protein-bound and are hence not filtered at the glomerulus. Loop diuretics, thiazides, and carbonic anhydrase inhibitors are secreted in the proximal convoluted tubule via the organic anion transporter,22 whereas epithelial sodium channel inhibitors (amiloride and triamterene) are secreted via the organic cation transporter 2.23 In renal dysfunction, various uremic toxins accumulate in the body and compete with diuretics for secretion into the proximal convoluted tubule via these transporters.24
Finally, activation of the sympathetic nervous system and renin-angiotensin-aldosterone system leads to increased tubular sodium and water retention, thereby also blunting the diuretic response.
Diuretic dosage. In patients whose creatinine clearance is less than 15 mL/min, only 10% to 20% as much loop diuretic is secreted into the renal tubule as in normal individuals.25 This effect warrants dose adjustment of diuretics during uremia.
Continuous infusion or bolus? Continuous infusion of loop diuretics is another strategy to optimize drug delivery. Compared with bolus therapy, continuous infusion provides more sustained and uniform drug delivery and prevents postdiuretic sodium retention.
The Diuretic Optimization Strategies Evaluation (DOSE) trial compared the efficacy and safety of continuous vs bolus furosemide therapy in 308 patients admitted with acute decompensated heart failure.26 There was no difference in symptom control or net fluid loss at 72 hours in either group. Other studies have shown more diuresis with continuous infusion than with a similarly dosed bolus regimen.27 However, definitive clinical evidence is lacking at this point to support routine use of continuous loop diuretic therapy.
Combination diuretic therapy. Sequential nephron blockade with combination diuretic therapy is an important therapeutic strategy against diuretic resistance. Notably, urine output-guided diuretic therapy has been shown to be superior to standard diuretic therapy.28 Such therapeutic protocols may employ combination diuretic therapy as a next step when the desired diuretic response is not obtained with high doses of loop diuretic monotherapy.
The desired diuretic response depends on the clinical situation. For example, in patients with severe congestion, we would like the net fluid output to be at least 2 to 3 L more than the fluid intake after the first 24 hours. Sometimes, patients in the intensive care unit are on several essential drug infusions, so that their net intake amounts to 1 to 2 L. In these patients, the desired urine output would be even more than in patients not on these drug infusions.
Loop diuretics block sodium reabsorption at the thick ascending loop of Henle. This disrupts the countercurrent exchange mechanism and reduces renal medullary interstitial osmolarity; these effects prevent water reabsorption. However, the unresorbed sodium can be taken up by the sodium-chloride cotransporter and the epithelial sodium channel in the distal nephron, thereby blunting the diuretic effect. This is the rationale for combining loop diuretics with thiazides or potassium-sparing diuretics.
Similarly, carbonic anhydrase inhibitors (eg, acetazolamide) reduce sodium reabsorption from the proximal convoluted tubule, but most of this sodium is then reabsorbed distally. Hence, the combination of a loop diuretic and acetazolamide can also have a synergistic diuretic effect.
The most popular combination is a loop diuretic plus a thiazide, although no large-scale placebo-controlled trials have been performed.29 Metolazone (a thiazidelike diuretic) is typically used due to its low cost and availability.30 Metolazone has also been shown to block sodium reabsorption at the proximal tubule, which may contribute to its synergistic effect. Chlorothiazide is available in an intravenous formulation and has a faster onset of action than metolazone. However, studies have failed to detect any benefit of one over the other.31
The potential benefit of combining a loop diuretic with acetazolamide is a lower tendency to develop metabolic alkalosis, a potential side effect of loop diuretics and thiazides. Although data are limited, a recent study showed that adding acetazolamide to bumetanide led to significantly increased natriuresis.32
In the Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) trial, adding spironolactone in high doses to usual therapy was not found to cause any significant change in N-terminal pro-B-type natriuretic peptide level or net urine output.33
Ultrafiltration
Venovenous ultrafiltration (or aquapheresis) employs an extracorporeal circuit, similar to the one used in hemodialysis, which removes iso-osmolar fluid at a fixed rate.34 Newer ultrafiltration systems are more portable, can be used with peripheral venous access, and require minimal nursing supervision.35
Although ultrafiltration seems an attractive alternative to diuresis in acute heart failure, studies have been inconclusive. The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial compared ultrafiltration and diuresis in 188 patients with acute heart failure and acute cardiorenal syndrome.36 Diuresis, performed according to an algorithm, was found to be superior to ultrafiltration in terms of a bivariate end point of change in weight and change in serum creatinine level at 96 hours. However, the level of cystatin C is thought to be a more accurate indicator of renal function, and the change in cystatin C level from baseline did not differ between the two treatment groups. Also, the ultrafiltration rate was 200 mL per hour, which, some argue, may have been excessive and may have caused intravascular depletion.
Although the ideal rate of fluid removal is unknown, it should be individualized and adjusted based on the patient’s renal function, volume status, and hemodynamic status. The initial rate should be based on the degree of fluid overload and the anticipated plasma refill rate from the interstitial fluid.37 For example, a malnourished patient may have low serum oncotic pressure and hence have low plasma refill upon ultrafiltration. Disturbance of this delicate balance between the rates of ultrafiltration and plasma refill may lead to intravascular volume contraction.
In summary, although ultrafiltration is a valuable alternative to diuretics in resistant cases, its use as a primary decongestive therapy cannot be endorsed in view of the current data.
Inotropes
Inotropes such as dobutamine and milrinone are typically used in cases of cardiogenic shock to maintain organ perfusion. There is a physiologic rationale to using inotropes in acute cardiorenal syndrome as well, especially when the aforementioned strategies fail to overcome diuretic resistance.7
Inotropes increase cardiac output, improve renal blood flow, improve right ventricular output, and thereby relieve systemic congestion. These hemodynamic effects may improve renal perfusion and response to diuretics. However, clinical evidence to support this is lacking.
The Renal Optimization Strategies Evaluation (ROSE) trial enrolled 360 patients with acute heart failure and renal dysfunction. Adding dopamine in a low dose (2 μg/kg/min) to diuretic therapy had no significant effect on 72-hour cumulative urine output or renal function as measured by cystatin C levels.38 However, acute kidney injury was not identified in this trial, and the renal function of many of these patients may have been at its baseline when they were admitted. In other words, this trial did not necessarily include patients with acute kidney injury along with acute heart failure. Hence, it did not necessarily include patients with acute cardiorenal syndrome.
Vasodilators
Vasodilators such as nitroglycerin, sodium nitroprusside, and hydralazine are commonly used in patients with acute heart failure, although the clinical evidence supporting their use is weak.
Physiologically, arterial dilation reduces afterload and can help relieve pulmonary congestion, and venodilation increases capacitance and reduces preload. In theory, venodilators such as nitroglycerin can relieve renal venous congestion in patients with acute cardiorenal syndrome, thereby improving renal perfusion.
However, the use of vasodilators is often limited by their adverse effects, the most important being hypotension. This is especially relevant in light of recent data identifying reduction in blood pressure during treatment of acute heart failure as an independent risk factor for worsening renal function.39,40 It is important to note that in these studies, changes in cardiac index did not affect the propensity for developing worsening renal function. The precise mechanism of this finding is unclear but it is plausible that systemic vasodilation redistributes the cardiac output to nonrenal tissues, thereby overriding the renal autoregulatory mechanisms that are normally employed in low output states.
Preventive strategies
Various strategies can be used to prevent acute cardiorenal syndrome. An optimal outpatient diuretic regimen to avoid hypervolemia is essential. Patients with advanced congestive heart failure should be followed up closely in dedicated heart failure clinics until their diuretic regimen is optimized. Patients should be advised to check their weight on a regular basis and seek medical advice if they notice an increase in their weight or a reduction in their urine output.
TAKE-HOME POINTS
- A robust clinical definition of cardiorenal syndrome is lacking. Hence, recognition of this condition can be challenging.
- Volume overload is central to its pathogenesis, and accurate assessment of volume status is critical.
- Renal venous congestion is the major mechanism of type 1 cardiorenal syndrome.
- Misdiagnosis can have devastating consequences, as it may lead to an opposite therapeutic approach.
- Fluid removal by various strategies is the mainstay of treatment.
- Temporary inotropic support should be saved for the last resort.
- Geisberg C, Butler J. Addressing the challenges of cardiorenal syndrome. Cleve Clin J Med 2006; 73:485–491.
- House AA, Anand I, Bellomo R, et al. Definition and classification of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant 2010; 25:1416–1420.
- Chang CH, Lin CY, Tian YC, et al. Acute kidney injury classification: comparison of AKIN and RIFLE criteria. Shock 2010; 33:247-252.
- Reynolds HR, Hochman JS. Cardiogenic shock: current concepts and improving outcomes. Circulation 2008; 117:686–697.
- Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009; 53:557–573.
- ter Maaten JM, Valente MA, Damman K, et al. Diuretic response in acute heart failure—pathophysiology, evaluation, and therapy. Nat Rev Cardiol 2015; 12:184–192.
- Hatamizadeh P, Fonarow GC, Budoff MJ, Darabian S, Kovesdy CP, Kalantar-Zadeh K. Cardiorenal syndrome: pathophysiology and potential targets for clinical management. Nat Rev Nephrol 2013; 9:99–111.
- Bock JS, Gottlieb SS. Cardiorenal syndrome: new perspectives. Circulation 2010; 121:2592–2600.
- Burke M, Pabbidi MR, Farley J, et al. Molecular mechanisms of renal blood flow autoregulation. Curr Vasc Pharmacol 2014; 12:845–858.
- Hanberg JS, Sury K, Wilson FP, et al. Reduced cardiac index is not the dominant driver of renal dysfunction in heart failure. J Am Coll Cardiol 2016; 67:2199–2208.
- Afsar B, Ortiz A, Covic A, et al. Focus on renal congestion in heart failure. Clin Kidney J 2016; 9:39–47.
- Verbrugge FH, Dupont M, Steels P, et al. Abdominal contributions to cardiorenal dysfunction in congestive heart failure. J Am Coll Cardiol 2013; 62:485–495.
- Mullens W, Abrahams Z, Skouri HN, et al. Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function? J Am Coll Cardiol 2008; 51:300–306.
- Firth JD, Raine AE, Ledingham JG. Raised venous pressure: a direct cause of renal sodium retention in oedema? Lancet 1988; 1:1033–1035.
- Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009; 53:589–596.
- Drazner MH, Hamilton MA, Fonarow G, et al. Relationship between right and left-sided filling pressures in 1000 patients with advanced heart failure. J Heart Lung Transplant 1999; 18:1126–1132.
- Wang CS, FitzGerald JM, Schulzer M, et al. Does this dyspneic patient in the emergency department have congestive heart failure? JAMA 2005; 294:1944–1956.
- Gehlbach BK, Geppert E. The pulmonary manifestations of left heart failure. Chest 2004; 125:669–682.
- Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA 2005; 294:1625–1633.
- Schanz M, Shi J , Wasser C , Alscher MD, Kimmel M. Urinary [TIMP-2] × [IGFBP7] for risk prediction of acute kidney injury in decompensated heart failure. Clin Cardiol 2017; doi.org/10.1002/clc.22683.
- Bowman BN, Nawarskas JJ, Anderson JR. Treating diuretic resistance: an overview. Cardiol Rev 2016; 24:256–260.
- Uwai Y, Saito H, Hashimoto Y, Inui KI. Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1. J Pharmacol Exp Ther 2000; 295:261–265.
- Hacker K, Maas R, Kornhuber J, et al. Substrate-dependent inhibition of the human organic cation transporter OCT2: a comparison of metformin with experimental substrates. PLoS One 2015; 10:e0136451.
- Schophuizen CM, Wilmer MJ, Jansen J, et al. Cationic uremic toxins affect human renal proximal tubule cell functioning through interaction with the organic cation transporter. Pflugers Arch 2013; 465:1701–1714.
- Brater DC. Diuretic therapy. N Engl J Med 1998; 339:387–395.
- Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011; 364:797–805.
- Thomson MR, Nappi JM, Dunn SP, Hollis IB, Rodgers JE, Van Bakel AB. Continuous versus intermittent infusion of furosemide in acute decompensated heart failure. J Card Fail 2010; 16:188–193.
- Grodin JL, Stevens SR, de Las Fuentes L, et al. Intensification of medication therapy for cardiorenal syndrome in acute decompensated heart failure. J Card Fail 2016; 22:26–32.
- Ng TM, Konopka E, Hyderi AF, et al. Comparison of bumetanide- and metolazone-based diuretic regimens to furosemide in acute heart failure. J Cardiovasc Pharmacol Ther 2013; 18:345–353.
- Sica DA. Metolazone and its role in edema management. Congest Heart Fail 2003; 9:100–105.
- Moranville MP, Choi S, Hogg J, Anderson AS, Rich JD. Comparison of metolazone versus chlorothiazide in acute decompensated heart failure with diuretic resistance. Cardiovasc Ther 2015; 33:42–49.
- Verbrugge FH, Dupont M, Bertrand PB, et al. Determinants and impact of the natriuretic response to diuretic therapy in heart failure with reduced ejection fraction and volume overload. Acta Cardiol 2015; 70:265–373.
- Butler J, Anstrom KJ, Felker GM, et al. Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF randomized clinical trial. JAMA Cardiol 2017 Jul 12. doi: 10.1001/jamacardio.2017.2198. [Epub ahead of print]
- Pourafshar N, Karimi A, Kazory A. Extracorporeal ultrafiltration therapy for acute decompensated heart failure. Expert Rev Cardiovasc Ther 2016; 14:5–13.
- Jaski BE, Ha J, Denys BG, et al. Peripherally inserted veno-venous ultrafiltration for rapid treatment of volume overloaded patients. J Card Fail 2003; 9:227–231.
- Jaski BE, Ha J, Denys BG, Lamba S, Trupp RJ, Abraham WT. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012; 367:2296–2304.
- Kazory A. Cardiorenal syndrome: ultrafiltration therapy for heart failure—trials and tribulations. Clin J Am Soc Nephrol 2013; 8:1816–1828.
- Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA 2013; 310:2533–2543.
- Testani JM, Coca SG, McCauley BD, et al. Impact of changes in blood pressure during the treatment of acute decompensated heart failure on renal and clinical outcomes. Eur J Heart Fail 2011; 13:877–884.
- Dupont M, Mullens W, Finucan M, et al. Determinants of dynamic changes in serum creatinine in acute decompensated heart failure: the importance of blood pressure reduction during treatment. Eur J Heart Fail 2013; 15:433–440.
- Geisberg C, Butler J. Addressing the challenges of cardiorenal syndrome. Cleve Clin J Med 2006; 73:485–491.
- House AA, Anand I, Bellomo R, et al. Definition and classification of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant 2010; 25:1416–1420.
- Chang CH, Lin CY, Tian YC, et al. Acute kidney injury classification: comparison of AKIN and RIFLE criteria. Shock 2010; 33:247-252.
- Reynolds HR, Hochman JS. Cardiogenic shock: current concepts and improving outcomes. Circulation 2008; 117:686–697.
- Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009; 53:557–573.
- ter Maaten JM, Valente MA, Damman K, et al. Diuretic response in acute heart failure—pathophysiology, evaluation, and therapy. Nat Rev Cardiol 2015; 12:184–192.
- Hatamizadeh P, Fonarow GC, Budoff MJ, Darabian S, Kovesdy CP, Kalantar-Zadeh K. Cardiorenal syndrome: pathophysiology and potential targets for clinical management. Nat Rev Nephrol 2013; 9:99–111.
- Bock JS, Gottlieb SS. Cardiorenal syndrome: new perspectives. Circulation 2010; 121:2592–2600.
- Burke M, Pabbidi MR, Farley J, et al. Molecular mechanisms of renal blood flow autoregulation. Curr Vasc Pharmacol 2014; 12:845–858.
- Hanberg JS, Sury K, Wilson FP, et al. Reduced cardiac index is not the dominant driver of renal dysfunction in heart failure. J Am Coll Cardiol 2016; 67:2199–2208.
- Afsar B, Ortiz A, Covic A, et al. Focus on renal congestion in heart failure. Clin Kidney J 2016; 9:39–47.
- Verbrugge FH, Dupont M, Steels P, et al. Abdominal contributions to cardiorenal dysfunction in congestive heart failure. J Am Coll Cardiol 2013; 62:485–495.
- Mullens W, Abrahams Z, Skouri HN, et al. Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function? J Am Coll Cardiol 2008; 51:300–306.
- Firth JD, Raine AE, Ledingham JG. Raised venous pressure: a direct cause of renal sodium retention in oedema? Lancet 1988; 1:1033–1035.
- Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009; 53:589–596.
- Drazner MH, Hamilton MA, Fonarow G, et al. Relationship between right and left-sided filling pressures in 1000 patients with advanced heart failure. J Heart Lung Transplant 1999; 18:1126–1132.
- Wang CS, FitzGerald JM, Schulzer M, et al. Does this dyspneic patient in the emergency department have congestive heart failure? JAMA 2005; 294:1944–1956.
- Gehlbach BK, Geppert E. The pulmonary manifestations of left heart failure. Chest 2004; 125:669–682.
- Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA 2005; 294:1625–1633.
- Schanz M, Shi J , Wasser C , Alscher MD, Kimmel M. Urinary [TIMP-2] × [IGFBP7] for risk prediction of acute kidney injury in decompensated heart failure. Clin Cardiol 2017; doi.org/10.1002/clc.22683.
- Bowman BN, Nawarskas JJ, Anderson JR. Treating diuretic resistance: an overview. Cardiol Rev 2016; 24:256–260.
- Uwai Y, Saito H, Hashimoto Y, Inui KI. Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1. J Pharmacol Exp Ther 2000; 295:261–265.
- Hacker K, Maas R, Kornhuber J, et al. Substrate-dependent inhibition of the human organic cation transporter OCT2: a comparison of metformin with experimental substrates. PLoS One 2015; 10:e0136451.
- Schophuizen CM, Wilmer MJ, Jansen J, et al. Cationic uremic toxins affect human renal proximal tubule cell functioning through interaction with the organic cation transporter. Pflugers Arch 2013; 465:1701–1714.
- Brater DC. Diuretic therapy. N Engl J Med 1998; 339:387–395.
- Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011; 364:797–805.
- Thomson MR, Nappi JM, Dunn SP, Hollis IB, Rodgers JE, Van Bakel AB. Continuous versus intermittent infusion of furosemide in acute decompensated heart failure. J Card Fail 2010; 16:188–193.
- Grodin JL, Stevens SR, de Las Fuentes L, et al. Intensification of medication therapy for cardiorenal syndrome in acute decompensated heart failure. J Card Fail 2016; 22:26–32.
- Ng TM, Konopka E, Hyderi AF, et al. Comparison of bumetanide- and metolazone-based diuretic regimens to furosemide in acute heart failure. J Cardiovasc Pharmacol Ther 2013; 18:345–353.
- Sica DA. Metolazone and its role in edema management. Congest Heart Fail 2003; 9:100–105.
- Moranville MP, Choi S, Hogg J, Anderson AS, Rich JD. Comparison of metolazone versus chlorothiazide in acute decompensated heart failure with diuretic resistance. Cardiovasc Ther 2015; 33:42–49.
- Verbrugge FH, Dupont M, Bertrand PB, et al. Determinants and impact of the natriuretic response to diuretic therapy in heart failure with reduced ejection fraction and volume overload. Acta Cardiol 2015; 70:265–373.
- Butler J, Anstrom KJ, Felker GM, et al. Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF randomized clinical trial. JAMA Cardiol 2017 Jul 12. doi: 10.1001/jamacardio.2017.2198. [Epub ahead of print]
- Pourafshar N, Karimi A, Kazory A. Extracorporeal ultrafiltration therapy for acute decompensated heart failure. Expert Rev Cardiovasc Ther 2016; 14:5–13.
- Jaski BE, Ha J, Denys BG, et al. Peripherally inserted veno-venous ultrafiltration for rapid treatment of volume overloaded patients. J Card Fail 2003; 9:227–231.
- Jaski BE, Ha J, Denys BG, Lamba S, Trupp RJ, Abraham WT. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012; 367:2296–2304.
- Kazory A. Cardiorenal syndrome: ultrafiltration therapy for heart failure—trials and tribulations. Clin J Am Soc Nephrol 2013; 8:1816–1828.
- Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA 2013; 310:2533–2543.
- Testani JM, Coca SG, McCauley BD, et al. Impact of changes in blood pressure during the treatment of acute decompensated heart failure on renal and clinical outcomes. Eur J Heart Fail 2011; 13:877–884.
- Dupont M, Mullens W, Finucan M, et al. Determinants of dynamic changes in serum creatinine in acute decompensated heart failure: the importance of blood pressure reduction during treatment. Eur J Heart Fail 2013; 15:433–440.
KEY POINTS
- Acute cardiorenal syndrome is the acute worsening of renal function due to acute decompensated heart failure.
- The most important mechanism of acute cardiorenal syndrome is now believed to be systemic congestion leading to increased renal venous pressure, which in turn reduces renal perfusion.
- The major alternative in the differential diagnosis of acute cardiorenal syndrome is renal injury due to hypovolemia. Differentiating the 2 may be challenging if signs of systemic and pulmonary congestion are not obvious.
- Diuretic resistance is common in acute cardiorenal syndrome but may be overcome by using higher doses of diuretics and combinations of diuretics that block reabsorption at different segments of the renal tubules.
Hemodynamically, the kidney is at the heart of cardiorenal syndrome
In heart failure, the heart and the kidneys share a rocky relationship. Cardiac dysfunction can heighten renal dysfunction and vice versa—appropriately dubbed “cardiorenal syndrome.”
Although classically defined by a reduction in the glomerular filtration rate (GFR),1 cardiorenal syndrome also encompasses complex neurohormonal, pharmacologic, and metabolic interactions affecting or affected by both glomerular and tubular function. Unfortunately, all of these maladaptive processes occur in heart failure and perpetuate a vicious circle of continued dual-organ dysfunction.
The central insult here is hemodynamic disarray from acute or chronic cardiac dysfunction, which can directly influence glomerular function. However, to understand the hemodynamic ramifications for glomerular function, we focus on the determinants of glomerular filtration.
DETERMINANTS OF GFR
The GFR is the rate of fluid flow between the glomerular capillaries and the Bowman capsule and is classically represented by the following equations2:
GFR = Kf × (PG – PB – πG + πB)
Kf = N × Lp × S
Kf is the filtration constant, N the number of functional nephrons, Lp the hydraulic conductivity of the glomerular capillary, S the filtration area, PG the hydrostatic pressure in the glomerular capillaries, PB the hydrostatic pressure in the Bowman capsule, and πG and πB the colloid osmotic pressures within the glomerular capillaries and Bowman space, respectively.
Based on this relationship, the GFR is reduced when PG is reduced in the setting of hypovolemia, hypotension, or renin-angiotensin system antagonist use or when PB is increased in the setting of elevated central venous pressure or elevated abdominal pressure—all common in heart failure. With this understanding, one would assume that strategies to increase PG (improve perfusion) and reduce PB (reduce congestion) might ameliorate ongoing renal dysfunction and improve the GFR in heart failure.
In this issue, Thind et al3 highlight the impact of hemodynamic derangements in heart failure with acute cardiorenal syndrome and provide an overview of its treatment. They review the complex relationship between progressive cardiac failure translating into accelerated neurohormonal responses (increases in sympathetic nervous system and renin-angiotensin-aldosterone system activation) and the impact of increased central venous pressure on progressive renal dysfunction. They also provide an overview of efforts to mitigate cardiorenal syndrome, after careful appraisal of volume status, through diuretic-mediated decongestion with aggressive use of loop diuretics (either in isolation or in the form of sequential nephron blockade with a thiazide or acetazolamide), and they highlight the lingering uncertainty regarding inotrope use.
VENOUS CONGESTION VS DECREASED CARDIAC OUTPUT
Returning to the GFR equation, it is clear that an imbalance in PG and PB can worsen glomerular function. Because cardiac dysfunction can lead to both venous congestion and decreased cardiac output, this leads to the question, “Of these, which is the more important driver of this imbalance and its effects on renal function?”
A compelling argument can be made for each side. On one hand, experiments over a half-century old in human models of venous congestion highlighted the profound impact of elevated venous pressure, which decreases electrolyte excretion (sodium included) and diminishes urine flow.4,5 This has been replicated in more-contemporary decompensated heart failure cohorts in which worsening renal function was more closely associated with elevated central venous pressure rather than cardiac output.6,7 On the other hand, early landmark experiments and more recent cohorts with heart failure have also shown that reductions in effective arterial blood volume, renal blood flow, and cardiac output are also associated with reductions in GFR.5,8,9
How then shall we reconcile whether cardiorenal syndrome is a “backward failure” (from central venous pressure) or a “forward failure” (from decreased perfusion) phenomenon?
The answer is complicated and is likely “both,” with the major component being increased central venous pressure. To understand this construct, we must first exclude frank cardiogenic shock—when the hydraulic function of the heart fails to provide enough flow, leading to a catastrophic drop in mean arterial pressure that supersedes the kidney’s ability to autoregulate renal blood flow.10,11
In patients with chronic heart failure and congestion who are not in shock, historical observations suggest that both intra-abdominal pressure (which increases renal venous pressure) and central venous pressure lead to reduced renal blood flow and increased renal vasomotor resistance (increase in afferent, intrarenal, and efferent vascular tone).12–14 More recent observations from epidemiologic studies have largely replicated these findings. Central venous pressure remains essential to impacting renal function in heart failure,6,15 and the impact of cardiac output on renal function remains uncertain.16
The relationship of intracardiac hemodynamics may also play a role in modifying renal function. Several reports recently described the relationship between both right- and left-sided filling pressures as being associated with worse renal function in heart failure.17–19 Patients with a disproportionately higher right atrial pressure to pulmonary capillary wedge pressure have higher serum creatinine during and after decongestive therapies. Therefore, the concept of “right-sided heart failure” expands beyond the simple representation of “backward congestion” at the level of venous return. In fact, a higher ratio of right atrial pressure to pulmonary capillary wedge pressure may point to an inability of the venous and pulmonary circulations to provide adequate left ventricular preload. Therefore, a relatively underfilled left ventricle in the face of biventricular dysfunction may result in worsening renal function.
TREATMENT IS CHALLENGING
The treatment of cardiorenal syndrome is challenging. It is often accompanied by heightened azotemia, diuretic resistance, electrolyte abnormalities, and a spectrum of hemodynamic disarray. As Thind et al point out, there is, unfortunately, no firmly established treatment. While “sequential nephron blockade” (pharmacologically blocking multiple sites on the nephron simultaneously) is theoretically promising, there are no rigorously studied therapeutic strategies with proven efficacy.
On the other hand, mechanical removal of isotonic fluid with ultrafiltration showed early promise in decompensated heart failure, but enthusiasm diminished with results from the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial.20 Ultrafiltration was roughly equivalent to aggressive pharmacologic therapy for fluid loss, was associated with higher serum creatinine levels, and was more challenging to administer.
Equally uncertain is the benefit of inotropic or vasoactive therapy, which directly alters cardiac hemodynamics. Low-dose dopamine or low-dose nesiritide is of no benefit toward enhancement of decongestion or renal protection when added to standard diuretic therapy.21 Furthermore, routine use of inotropes is fraught with more arrhythmias and hypotension and is associated with dismal long-term outcomes.22,23
Alternative therapies that act directly on renal physiology—eg, rolofylline, a selective adenosine A1 receptor antagonist that may enhance renal blood flow, augment natriuresis, and break diuretic resistance—have been similarly disappointing.24
With so much uncertainty, more investigation into novel treatments for cardiorenal syndrome is clearly warranted.
However, because venous congestion is the hemodynamic hallmark of acute cardiorenal syndrome (increasing PB), reducing central venous pressure remains the cornerstone treatment for cardiorenal syndrome. Additionally, efforts to preserve renal perfusion and avoid hypotension are prudent to maintain glomerular capillary hydrostatic pressure (PG).
In light of these considerations, there is no “one size fits all” for the treatment of cardiorenal syndrome. Treatment should be based on thoughtful individualized strategies tailored to the underlying cardiorenal pathophysiology, and with the understanding that the kidney is at the heart of the matter.
- House AA, Anand I, Bellomo R, et al; Acute Dialysis Quality Initiative Consensus Group. Definition and classification of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant 2010; 25:1416–1420.
- Tucker BJ, Blantz RC. An analysis of the determinants of nephron filtration rate. Am J Physiol 1977; 232:F477–F483.
- Thind GS, Loehrke M, Wilt JL. Acute cardiorenal syndrome: mechanisms and clinical implications. Cleve Clin J Med 2018; 85:231–239.
- Wilkins RW, Tinsley CM, Culbertson JW, et al. The effects of venous congestion of the limbs upon renal clearances and the excretion of water and salt. I. Studies in normal subjects and in hypertensive patients before and after splanchnicectomy. J Clin Invest 1953; 32:1101–1116.
- Judson WE, Hatcher JD, Hollander W, Halperin MH, Wilkins RW. The effects of venous congestion of the limbs and phlebotomy upon renal clearances and the excretion of water and salt. II. Studies in patients with congestive failure. J Clin Invest 1955; 34:1591–1599.
- Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009; 53:589–596.
- Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol 2009; 53:582–588.
- Ljungman S, Laragh JH, Cody RJ. Role of the kidney in congestive heart failure. Relationship of cardiac index to kidney function. Drugs 1990; 39(suppl 4):10–21; discussion 22–24.
- Damman K, Navis G, Smilde TD, et al. Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction. Eur J Heart Fail 2007; 9:872–878.
- Fincke R, Hochman JS, Lowe AM, et al. Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry. J Am Coll Cardiol 2004; 44:340–348.
- Adams PL, Adams FF, Bell PD, Navar LG. Impaired renal blood flow autoregulation in ischemic acute renal failure. Kidney Int 1980; 18:68–76.
- Maxwell MH, Breed ES, Schwartz IL. Renal venous pressure in chronic congestive heart failure. J Clin Invest 1950; 29:342–348.
- Blake WD, Wégria R, Keating RP, Ward HP. Effect of increased renal venous pressure on renal function. Am J Physiol 1949; 157:1–13.
- Bradley SE, Bradley GP. The effect of increased intra-abdominal pressure on renal function in man. J Clin Invest 1947; 26:1010–1022.
- Mullens W, Abrahams Z, Skouri HN, et al. Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function? J Am Coll Cardiol 2008; 51:300–306.
- Hanberg JS, Sury K, Wilson FP, et al. Reduced cardiac index is not the dominant driver of renal dysfunction in heart failure. J Am Coll Cardiol 2016; 67:2199–2208.
- Drazner MH, Brown RN, Kaiser PA, et al. Relationship of right- and left-sided filling pressures in patients with advanced heart failure: a 14-year multi-institutional analysis. J Heart Lung Transplant 2012; 31:67–72.
- Drazner MH, Velez-Martinez M, Ayers CR, et al. Relationship of right- to left-sided ventricular filling pressures in advanced heart failure: insights from the ESCAPE trial. Circ Heart Fail 2013; 6:264–270.
- Grodin JL, Drazner MH, Dupont M, et al. A disproportionate elevation in right ventricular filling pressure, in relation to left ventricular filling pressure, is associated with renal impairment and increased mortality in advanced decompensated heart failure. Am Heart J 2015; 169:806–812.
- Bart BA, Goldsmith SR, Lee KL, et al, for the Heart Failure Clinical Research Network. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012; 367:2296–2304.
- Chen HH, Anstrom KJ, Givertz MM, et al; NHLBI Heart Failure Clinical Research Network. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA 2013; 310:2533–2543.
- Gorodeski EZ, Chu EC, Reese JR, Shishehbor MH, Hsich E, Starling RC. Prognosis on chronic dobutamine or milrinone infusions for stage D heart failure. Circ Heart Fail 2009; 2:320–324.
- Cuffe MS, Califf RM, Adams KF Jr, et al, for the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Investigators. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA 2002; 287:1541–1547.
- Massie BM, O’Connor CM, Metra M, et al, for the PROTECT Investigators and Committees. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010; 363:1419–1428.
In heart failure, the heart and the kidneys share a rocky relationship. Cardiac dysfunction can heighten renal dysfunction and vice versa—appropriately dubbed “cardiorenal syndrome.”
Although classically defined by a reduction in the glomerular filtration rate (GFR),1 cardiorenal syndrome also encompasses complex neurohormonal, pharmacologic, and metabolic interactions affecting or affected by both glomerular and tubular function. Unfortunately, all of these maladaptive processes occur in heart failure and perpetuate a vicious circle of continued dual-organ dysfunction.
The central insult here is hemodynamic disarray from acute or chronic cardiac dysfunction, which can directly influence glomerular function. However, to understand the hemodynamic ramifications for glomerular function, we focus on the determinants of glomerular filtration.
DETERMINANTS OF GFR
The GFR is the rate of fluid flow between the glomerular capillaries and the Bowman capsule and is classically represented by the following equations2:
GFR = Kf × (PG – PB – πG + πB)
Kf = N × Lp × S
Kf is the filtration constant, N the number of functional nephrons, Lp the hydraulic conductivity of the glomerular capillary, S the filtration area, PG the hydrostatic pressure in the glomerular capillaries, PB the hydrostatic pressure in the Bowman capsule, and πG and πB the colloid osmotic pressures within the glomerular capillaries and Bowman space, respectively.
Based on this relationship, the GFR is reduced when PG is reduced in the setting of hypovolemia, hypotension, or renin-angiotensin system antagonist use or when PB is increased in the setting of elevated central venous pressure or elevated abdominal pressure—all common in heart failure. With this understanding, one would assume that strategies to increase PG (improve perfusion) and reduce PB (reduce congestion) might ameliorate ongoing renal dysfunction and improve the GFR in heart failure.
In this issue, Thind et al3 highlight the impact of hemodynamic derangements in heart failure with acute cardiorenal syndrome and provide an overview of its treatment. They review the complex relationship between progressive cardiac failure translating into accelerated neurohormonal responses (increases in sympathetic nervous system and renin-angiotensin-aldosterone system activation) and the impact of increased central venous pressure on progressive renal dysfunction. They also provide an overview of efforts to mitigate cardiorenal syndrome, after careful appraisal of volume status, through diuretic-mediated decongestion with aggressive use of loop diuretics (either in isolation or in the form of sequential nephron blockade with a thiazide or acetazolamide), and they highlight the lingering uncertainty regarding inotrope use.
VENOUS CONGESTION VS DECREASED CARDIAC OUTPUT
Returning to the GFR equation, it is clear that an imbalance in PG and PB can worsen glomerular function. Because cardiac dysfunction can lead to both venous congestion and decreased cardiac output, this leads to the question, “Of these, which is the more important driver of this imbalance and its effects on renal function?”
A compelling argument can be made for each side. On one hand, experiments over a half-century old in human models of venous congestion highlighted the profound impact of elevated venous pressure, which decreases electrolyte excretion (sodium included) and diminishes urine flow.4,5 This has been replicated in more-contemporary decompensated heart failure cohorts in which worsening renal function was more closely associated with elevated central venous pressure rather than cardiac output.6,7 On the other hand, early landmark experiments and more recent cohorts with heart failure have also shown that reductions in effective arterial blood volume, renal blood flow, and cardiac output are also associated with reductions in GFR.5,8,9
How then shall we reconcile whether cardiorenal syndrome is a “backward failure” (from central venous pressure) or a “forward failure” (from decreased perfusion) phenomenon?
The answer is complicated and is likely “both,” with the major component being increased central venous pressure. To understand this construct, we must first exclude frank cardiogenic shock—when the hydraulic function of the heart fails to provide enough flow, leading to a catastrophic drop in mean arterial pressure that supersedes the kidney’s ability to autoregulate renal blood flow.10,11
In patients with chronic heart failure and congestion who are not in shock, historical observations suggest that both intra-abdominal pressure (which increases renal venous pressure) and central venous pressure lead to reduced renal blood flow and increased renal vasomotor resistance (increase in afferent, intrarenal, and efferent vascular tone).12–14 More recent observations from epidemiologic studies have largely replicated these findings. Central venous pressure remains essential to impacting renal function in heart failure,6,15 and the impact of cardiac output on renal function remains uncertain.16
The relationship of intracardiac hemodynamics may also play a role in modifying renal function. Several reports recently described the relationship between both right- and left-sided filling pressures as being associated with worse renal function in heart failure.17–19 Patients with a disproportionately higher right atrial pressure to pulmonary capillary wedge pressure have higher serum creatinine during and after decongestive therapies. Therefore, the concept of “right-sided heart failure” expands beyond the simple representation of “backward congestion” at the level of venous return. In fact, a higher ratio of right atrial pressure to pulmonary capillary wedge pressure may point to an inability of the venous and pulmonary circulations to provide adequate left ventricular preload. Therefore, a relatively underfilled left ventricle in the face of biventricular dysfunction may result in worsening renal function.
TREATMENT IS CHALLENGING
The treatment of cardiorenal syndrome is challenging. It is often accompanied by heightened azotemia, diuretic resistance, electrolyte abnormalities, and a spectrum of hemodynamic disarray. As Thind et al point out, there is, unfortunately, no firmly established treatment. While “sequential nephron blockade” (pharmacologically blocking multiple sites on the nephron simultaneously) is theoretically promising, there are no rigorously studied therapeutic strategies with proven efficacy.
On the other hand, mechanical removal of isotonic fluid with ultrafiltration showed early promise in decompensated heart failure, but enthusiasm diminished with results from the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial.20 Ultrafiltration was roughly equivalent to aggressive pharmacologic therapy for fluid loss, was associated with higher serum creatinine levels, and was more challenging to administer.
Equally uncertain is the benefit of inotropic or vasoactive therapy, which directly alters cardiac hemodynamics. Low-dose dopamine or low-dose nesiritide is of no benefit toward enhancement of decongestion or renal protection when added to standard diuretic therapy.21 Furthermore, routine use of inotropes is fraught with more arrhythmias and hypotension and is associated with dismal long-term outcomes.22,23
Alternative therapies that act directly on renal physiology—eg, rolofylline, a selective adenosine A1 receptor antagonist that may enhance renal blood flow, augment natriuresis, and break diuretic resistance—have been similarly disappointing.24
With so much uncertainty, more investigation into novel treatments for cardiorenal syndrome is clearly warranted.
However, because venous congestion is the hemodynamic hallmark of acute cardiorenal syndrome (increasing PB), reducing central venous pressure remains the cornerstone treatment for cardiorenal syndrome. Additionally, efforts to preserve renal perfusion and avoid hypotension are prudent to maintain glomerular capillary hydrostatic pressure (PG).
In light of these considerations, there is no “one size fits all” for the treatment of cardiorenal syndrome. Treatment should be based on thoughtful individualized strategies tailored to the underlying cardiorenal pathophysiology, and with the understanding that the kidney is at the heart of the matter.
In heart failure, the heart and the kidneys share a rocky relationship. Cardiac dysfunction can heighten renal dysfunction and vice versa—appropriately dubbed “cardiorenal syndrome.”
Although classically defined by a reduction in the glomerular filtration rate (GFR),1 cardiorenal syndrome also encompasses complex neurohormonal, pharmacologic, and metabolic interactions affecting or affected by both glomerular and tubular function. Unfortunately, all of these maladaptive processes occur in heart failure and perpetuate a vicious circle of continued dual-organ dysfunction.
The central insult here is hemodynamic disarray from acute or chronic cardiac dysfunction, which can directly influence glomerular function. However, to understand the hemodynamic ramifications for glomerular function, we focus on the determinants of glomerular filtration.
DETERMINANTS OF GFR
The GFR is the rate of fluid flow between the glomerular capillaries and the Bowman capsule and is classically represented by the following equations2:
GFR = Kf × (PG – PB – πG + πB)
Kf = N × Lp × S
Kf is the filtration constant, N the number of functional nephrons, Lp the hydraulic conductivity of the glomerular capillary, S the filtration area, PG the hydrostatic pressure in the glomerular capillaries, PB the hydrostatic pressure in the Bowman capsule, and πG and πB the colloid osmotic pressures within the glomerular capillaries and Bowman space, respectively.
Based on this relationship, the GFR is reduced when PG is reduced in the setting of hypovolemia, hypotension, or renin-angiotensin system antagonist use or when PB is increased in the setting of elevated central venous pressure or elevated abdominal pressure—all common in heart failure. With this understanding, one would assume that strategies to increase PG (improve perfusion) and reduce PB (reduce congestion) might ameliorate ongoing renal dysfunction and improve the GFR in heart failure.
In this issue, Thind et al3 highlight the impact of hemodynamic derangements in heart failure with acute cardiorenal syndrome and provide an overview of its treatment. They review the complex relationship between progressive cardiac failure translating into accelerated neurohormonal responses (increases in sympathetic nervous system and renin-angiotensin-aldosterone system activation) and the impact of increased central venous pressure on progressive renal dysfunction. They also provide an overview of efforts to mitigate cardiorenal syndrome, after careful appraisal of volume status, through diuretic-mediated decongestion with aggressive use of loop diuretics (either in isolation or in the form of sequential nephron blockade with a thiazide or acetazolamide), and they highlight the lingering uncertainty regarding inotrope use.
VENOUS CONGESTION VS DECREASED CARDIAC OUTPUT
Returning to the GFR equation, it is clear that an imbalance in PG and PB can worsen glomerular function. Because cardiac dysfunction can lead to both venous congestion and decreased cardiac output, this leads to the question, “Of these, which is the more important driver of this imbalance and its effects on renal function?”
A compelling argument can be made for each side. On one hand, experiments over a half-century old in human models of venous congestion highlighted the profound impact of elevated venous pressure, which decreases electrolyte excretion (sodium included) and diminishes urine flow.4,5 This has been replicated in more-contemporary decompensated heart failure cohorts in which worsening renal function was more closely associated with elevated central venous pressure rather than cardiac output.6,7 On the other hand, early landmark experiments and more recent cohorts with heart failure have also shown that reductions in effective arterial blood volume, renal blood flow, and cardiac output are also associated with reductions in GFR.5,8,9
How then shall we reconcile whether cardiorenal syndrome is a “backward failure” (from central venous pressure) or a “forward failure” (from decreased perfusion) phenomenon?
The answer is complicated and is likely “both,” with the major component being increased central venous pressure. To understand this construct, we must first exclude frank cardiogenic shock—when the hydraulic function of the heart fails to provide enough flow, leading to a catastrophic drop in mean arterial pressure that supersedes the kidney’s ability to autoregulate renal blood flow.10,11
In patients with chronic heart failure and congestion who are not in shock, historical observations suggest that both intra-abdominal pressure (which increases renal venous pressure) and central venous pressure lead to reduced renal blood flow and increased renal vasomotor resistance (increase in afferent, intrarenal, and efferent vascular tone).12–14 More recent observations from epidemiologic studies have largely replicated these findings. Central venous pressure remains essential to impacting renal function in heart failure,6,15 and the impact of cardiac output on renal function remains uncertain.16
The relationship of intracardiac hemodynamics may also play a role in modifying renal function. Several reports recently described the relationship between both right- and left-sided filling pressures as being associated with worse renal function in heart failure.17–19 Patients with a disproportionately higher right atrial pressure to pulmonary capillary wedge pressure have higher serum creatinine during and after decongestive therapies. Therefore, the concept of “right-sided heart failure” expands beyond the simple representation of “backward congestion” at the level of venous return. In fact, a higher ratio of right atrial pressure to pulmonary capillary wedge pressure may point to an inability of the venous and pulmonary circulations to provide adequate left ventricular preload. Therefore, a relatively underfilled left ventricle in the face of biventricular dysfunction may result in worsening renal function.
TREATMENT IS CHALLENGING
The treatment of cardiorenal syndrome is challenging. It is often accompanied by heightened azotemia, diuretic resistance, electrolyte abnormalities, and a spectrum of hemodynamic disarray. As Thind et al point out, there is, unfortunately, no firmly established treatment. While “sequential nephron blockade” (pharmacologically blocking multiple sites on the nephron simultaneously) is theoretically promising, there are no rigorously studied therapeutic strategies with proven efficacy.
On the other hand, mechanical removal of isotonic fluid with ultrafiltration showed early promise in decompensated heart failure, but enthusiasm diminished with results from the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial.20 Ultrafiltration was roughly equivalent to aggressive pharmacologic therapy for fluid loss, was associated with higher serum creatinine levels, and was more challenging to administer.
Equally uncertain is the benefit of inotropic or vasoactive therapy, which directly alters cardiac hemodynamics. Low-dose dopamine or low-dose nesiritide is of no benefit toward enhancement of decongestion or renal protection when added to standard diuretic therapy.21 Furthermore, routine use of inotropes is fraught with more arrhythmias and hypotension and is associated with dismal long-term outcomes.22,23
Alternative therapies that act directly on renal physiology—eg, rolofylline, a selective adenosine A1 receptor antagonist that may enhance renal blood flow, augment natriuresis, and break diuretic resistance—have been similarly disappointing.24
With so much uncertainty, more investigation into novel treatments for cardiorenal syndrome is clearly warranted.
However, because venous congestion is the hemodynamic hallmark of acute cardiorenal syndrome (increasing PB), reducing central venous pressure remains the cornerstone treatment for cardiorenal syndrome. Additionally, efforts to preserve renal perfusion and avoid hypotension are prudent to maintain glomerular capillary hydrostatic pressure (PG).
In light of these considerations, there is no “one size fits all” for the treatment of cardiorenal syndrome. Treatment should be based on thoughtful individualized strategies tailored to the underlying cardiorenal pathophysiology, and with the understanding that the kidney is at the heart of the matter.
- House AA, Anand I, Bellomo R, et al; Acute Dialysis Quality Initiative Consensus Group. Definition and classification of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant 2010; 25:1416–1420.
- Tucker BJ, Blantz RC. An analysis of the determinants of nephron filtration rate. Am J Physiol 1977; 232:F477–F483.
- Thind GS, Loehrke M, Wilt JL. Acute cardiorenal syndrome: mechanisms and clinical implications. Cleve Clin J Med 2018; 85:231–239.
- Wilkins RW, Tinsley CM, Culbertson JW, et al. The effects of venous congestion of the limbs upon renal clearances and the excretion of water and salt. I. Studies in normal subjects and in hypertensive patients before and after splanchnicectomy. J Clin Invest 1953; 32:1101–1116.
- Judson WE, Hatcher JD, Hollander W, Halperin MH, Wilkins RW. The effects of venous congestion of the limbs and phlebotomy upon renal clearances and the excretion of water and salt. II. Studies in patients with congestive failure. J Clin Invest 1955; 34:1591–1599.
- Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009; 53:589–596.
- Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol 2009; 53:582–588.
- Ljungman S, Laragh JH, Cody RJ. Role of the kidney in congestive heart failure. Relationship of cardiac index to kidney function. Drugs 1990; 39(suppl 4):10–21; discussion 22–24.
- Damman K, Navis G, Smilde TD, et al. Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction. Eur J Heart Fail 2007; 9:872–878.
- Fincke R, Hochman JS, Lowe AM, et al. Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry. J Am Coll Cardiol 2004; 44:340–348.
- Adams PL, Adams FF, Bell PD, Navar LG. Impaired renal blood flow autoregulation in ischemic acute renal failure. Kidney Int 1980; 18:68–76.
- Maxwell MH, Breed ES, Schwartz IL. Renal venous pressure in chronic congestive heart failure. J Clin Invest 1950; 29:342–348.
- Blake WD, Wégria R, Keating RP, Ward HP. Effect of increased renal venous pressure on renal function. Am J Physiol 1949; 157:1–13.
- Bradley SE, Bradley GP. The effect of increased intra-abdominal pressure on renal function in man. J Clin Invest 1947; 26:1010–1022.
- Mullens W, Abrahams Z, Skouri HN, et al. Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function? J Am Coll Cardiol 2008; 51:300–306.
- Hanberg JS, Sury K, Wilson FP, et al. Reduced cardiac index is not the dominant driver of renal dysfunction in heart failure. J Am Coll Cardiol 2016; 67:2199–2208.
- Drazner MH, Brown RN, Kaiser PA, et al. Relationship of right- and left-sided filling pressures in patients with advanced heart failure: a 14-year multi-institutional analysis. J Heart Lung Transplant 2012; 31:67–72.
- Drazner MH, Velez-Martinez M, Ayers CR, et al. Relationship of right- to left-sided ventricular filling pressures in advanced heart failure: insights from the ESCAPE trial. Circ Heart Fail 2013; 6:264–270.
- Grodin JL, Drazner MH, Dupont M, et al. A disproportionate elevation in right ventricular filling pressure, in relation to left ventricular filling pressure, is associated with renal impairment and increased mortality in advanced decompensated heart failure. Am Heart J 2015; 169:806–812.
- Bart BA, Goldsmith SR, Lee KL, et al, for the Heart Failure Clinical Research Network. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012; 367:2296–2304.
- Chen HH, Anstrom KJ, Givertz MM, et al; NHLBI Heart Failure Clinical Research Network. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA 2013; 310:2533–2543.
- Gorodeski EZ, Chu EC, Reese JR, Shishehbor MH, Hsich E, Starling RC. Prognosis on chronic dobutamine or milrinone infusions for stage D heart failure. Circ Heart Fail 2009; 2:320–324.
- Cuffe MS, Califf RM, Adams KF Jr, et al, for the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Investigators. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA 2002; 287:1541–1547.
- Massie BM, O’Connor CM, Metra M, et al, for the PROTECT Investigators and Committees. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010; 363:1419–1428.
- House AA, Anand I, Bellomo R, et al; Acute Dialysis Quality Initiative Consensus Group. Definition and classification of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant 2010; 25:1416–1420.
- Tucker BJ, Blantz RC. An analysis of the determinants of nephron filtration rate. Am J Physiol 1977; 232:F477–F483.
- Thind GS, Loehrke M, Wilt JL. Acute cardiorenal syndrome: mechanisms and clinical implications. Cleve Clin J Med 2018; 85:231–239.
- Wilkins RW, Tinsley CM, Culbertson JW, et al. The effects of venous congestion of the limbs upon renal clearances and the excretion of water and salt. I. Studies in normal subjects and in hypertensive patients before and after splanchnicectomy. J Clin Invest 1953; 32:1101–1116.
- Judson WE, Hatcher JD, Hollander W, Halperin MH, Wilkins RW. The effects of venous congestion of the limbs and phlebotomy upon renal clearances and the excretion of water and salt. II. Studies in patients with congestive failure. J Clin Invest 1955; 34:1591–1599.
- Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009; 53:589–596.
- Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol 2009; 53:582–588.
- Ljungman S, Laragh JH, Cody RJ. Role of the kidney in congestive heart failure. Relationship of cardiac index to kidney function. Drugs 1990; 39(suppl 4):10–21; discussion 22–24.
- Damman K, Navis G, Smilde TD, et al. Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction. Eur J Heart Fail 2007; 9:872–878.
- Fincke R, Hochman JS, Lowe AM, et al. Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry. J Am Coll Cardiol 2004; 44:340–348.
- Adams PL, Adams FF, Bell PD, Navar LG. Impaired renal blood flow autoregulation in ischemic acute renal failure. Kidney Int 1980; 18:68–76.
- Maxwell MH, Breed ES, Schwartz IL. Renal venous pressure in chronic congestive heart failure. J Clin Invest 1950; 29:342–348.
- Blake WD, Wégria R, Keating RP, Ward HP. Effect of increased renal venous pressure on renal function. Am J Physiol 1949; 157:1–13.
- Bradley SE, Bradley GP. The effect of increased intra-abdominal pressure on renal function in man. J Clin Invest 1947; 26:1010–1022.
- Mullens W, Abrahams Z, Skouri HN, et al. Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function? J Am Coll Cardiol 2008; 51:300–306.
- Hanberg JS, Sury K, Wilson FP, et al. Reduced cardiac index is not the dominant driver of renal dysfunction in heart failure. J Am Coll Cardiol 2016; 67:2199–2208.
- Drazner MH, Brown RN, Kaiser PA, et al. Relationship of right- and left-sided filling pressures in patients with advanced heart failure: a 14-year multi-institutional analysis. J Heart Lung Transplant 2012; 31:67–72.
- Drazner MH, Velez-Martinez M, Ayers CR, et al. Relationship of right- to left-sided ventricular filling pressures in advanced heart failure: insights from the ESCAPE trial. Circ Heart Fail 2013; 6:264–270.
- Grodin JL, Drazner MH, Dupont M, et al. A disproportionate elevation in right ventricular filling pressure, in relation to left ventricular filling pressure, is associated with renal impairment and increased mortality in advanced decompensated heart failure. Am Heart J 2015; 169:806–812.
- Bart BA, Goldsmith SR, Lee KL, et al, for the Heart Failure Clinical Research Network. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012; 367:2296–2304.
- Chen HH, Anstrom KJ, Givertz MM, et al; NHLBI Heart Failure Clinical Research Network. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA 2013; 310:2533–2543.
- Gorodeski EZ, Chu EC, Reese JR, Shishehbor MH, Hsich E, Starling RC. Prognosis on chronic dobutamine or milrinone infusions for stage D heart failure. Circ Heart Fail 2009; 2:320–324.
- Cuffe MS, Califf RM, Adams KF Jr, et al, for the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Investigators. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA 2002; 287:1541–1547.
- Massie BM, O’Connor CM, Metra M, et al, for the PROTECT Investigators and Committees. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010; 363:1419–1428.
Hypertension in older adults: What is the target blood pressure?
We should aim for a standard office systolic pressure lower than 130 mm Hg in most adults age 65 and older if the patient can take multiple antihypertensive medications and be followed closely for adverse effects.
This recommendation is part of the 2017 hypertension guideline from the American College of Cardiology and American Heart Association.1 This new guideline advocates drug treatment of hypertension to a target less than 130/80 mm Hg for patients of all ages for secondary prevention of cardiovascular disease, and for primary prevention in those at high risk (ie, an estimated 10-year risk of atherosclerotic cardiovascular disease of 10% or higher). The target blood pressure for those at lower risk is less than 140/90 mm Hg.
There are multiple tools to estimate the 10-year risk. All tools incorporate major predictors such as age, blood pressure, cholesterol profile, and other markers, depending on the tool. Although risk increases with age, the tools are inaccurate once the patient is approximately 80 years of age.
The recommendation for older adults omits a target diastolic pressure, since treating elevated systolic pressure has more data supporting it than treating elevated diastolic blood pressure in older people. These recommendations apply only to older adults who can walk and are living in the community, not in an institution, and includes the subset of older adults who have mild cognitive impairment and frailty. The goals of treatment should be patient-centered.
DATA BEHIND THE GUIDELINE: THE SPRINT TRIAL
The Systolic Blood Pressure Intervention Trial (SPRINT)2 enrolled 9,361 patients who, to enter, had to be at least 50 years old (the mean age was 67.9), have a systolic blood pressure of 130 to 180 mm Hg (the mean was 139.7 mm Hg), and be at risk of cardiovascular disease due to chronic kidney disease, clinical or subclinical cardiovascular disease, a 10-year Framingham risk score of at least 15%, or age 75 or older. They had few comorbidities, and patients with diabetes mellitus or prior stroke were excluded. The objective was to see if intensive blood pressure treatment reduced the incidence of adverse cardiovascular outcomes compared with standard control.
The participants were randomized to either an intensive treatment goal of systolic pressure less than 120 mm Hg or a standard treatment goal of less than 140 mm Hg. Investigators chose drugs and doses according to their clinical judgment. The study protocol called for blood pressure measurement using an untended automated cuff, which probably resulted in systolic pressure readings 5 to 10 mm Hg lower than with typical methods used in the office.3
The intensive treatment group achieved a mean systolic pressure of 121.5 mm Hg, which required an average of 3 drugs. In contrast, the standard treatment group achieved a systolic pressure of 136.2 mm Hg, which required an average of 1.9 drugs.
Due to an absolute risk reduction in cardiovascular events and mortality, SPRINT was discontinued early after a median follow-up of 3.3 years. In the entire cohort, 61 patients needed to be treated intensively to prevent 1 cardiovascular event, and 90 needed to be treated intensively to prevent 1 death.2
Favorable outcomes in the oldest subgroup
The oldest patients in the SPRINT trial tolerated the intensive treatment as well as the youngest.2,4
Exploratory analysis of the subgroup of patients age 75 and older, who constituted 28% of the patients in the trial, demonstrated significant benefit from intensive treatment. In this subgroup, 27 patients needed to be treated aggressively (compared with standard treatment) to prevent 1 cardiovascular event, and 41 needed to be treated intensively to prevent 1 death.4 The lower numbers needing to be treated in the older subgroup than in the overall trial reflect the higher absolute risk in this older population.
Serious adverse events were more common with intensive treatment than with standard treatment in the subgroup of older patients who were frail.4 Emergency department visits or serious adverse events were more likely when gait speed (a measure of frailty) was missing from the medical record in the intensive treatment group compared with the standard treatment group. Hyponatremia (serum sodium level < 130 mmol/L) was more likely in the intensively treated group than in the standard treatment group. Although the rate of falls was higher in the oldest subgroup than in the overall SPRINT population, within this subgroup the rate of injurious falls resulting in an emergency department visit was lower with intensive treatment than with standard treatment (11.6% vs 14.1%, P = .04).4
Most of the oldest patients scored below the nominal cutoff for normal (26 points)5 on the 30-point Montreal Cognitive Assessment, and about one-quarter scored below 19, which may be consistent with a major neurocognitive disorder.6
The SPRINT investigators validated a frailty scale in the study patients and found that the most frail benefited from intensive blood pressure control, as did the slowest walkers.
SPRINT results do not apply to very frail, sick patients
For older patients with hypertension, a high burden of comorbidity, and a limited life expectancy, the 2017 guidelines defer treatment decisions to clinical judgment and patient preference.
There have been no randomized trials of blood pressure management for older adults with substantial comorbidities or dementia. The “frail” older adults in the SPRINT trial were still living in the community, without dementia. The intensively treated frail older adults had more serious adverse events than with standard treatment. Those who were documented as being unable to walk at the time of enrollment also had more serious adverse events. Institutionalized older adults and nonambulatory adults in the community would likely have even higher rates of serious adverse events with intensive treatment than the SPRINT patients, and there is concern for excessive adverse effects from intensive blood pressure control in more debilitated older patients.
DOES TREATING HIGH BLOOD PRESSURE PREVENT FRAILTY OR DEMENTIA?
Aging without frailty is an important goal of geriatric care and is likely related to cardiovascular health.7 An older adult who becomes slower physically or mentally, with diminished strength and energy, is less likely to be able to live independently.
Would treating systolic blood pressure to a target of 120 to 130 mm Hg reduce the risk of prefrailty or frailty? Unfortunately, the 3-year SPRINT follow-up of the adults age 75 and older did not show any effect of intensive treatment on gait speed or mobility limitation.8 It is possible that the early termination of the study limited outcomes.
Regarding cognition, the new guidelines say that lowering blood pressure in adults with hypertension to prevent cognitive decline and dementia is reasonable, giving it a class IIa (moderate) recommendation, but they do not offer a particular blood pressure target.
Two systematic reviews of randomized placebo-controlled trials9,10 suggested that pharmacologic treatment of hypertension reduces the progression of cognitive impairment. The trials did not use an intensive treatment goal.
The impact of intensive treatment of hypertension (to a target of 120–130 mm Hg) on the development or progression of cognitive impairment is not known at this time. The SPRINT Memory and Cognition in Decreased Hypertension analysis may shed light on the effect of intensive treatment of blood pressure on the incidence of dementia, although the early termination of SPRINT may limit its conclusions as well.
GOALS SHOULD BE PATIENT-CENTERED
The new hypertension guideline gives clinicians 2 things to think about when treating hypertensive, ambulatory, noninstitutionalized, nondemented older adults, including those age 75 and older:
- Older adults tolerate intensive blood pressure treatment as well as standard treatment. In particular, the fall rate is not increased and may even be less with intensive treatment.
- Older adults have better cardiovascular outcomes with blood pressure less than 130 mm Hg than with higher levels.
Adherence to the new guidelines would require many older adults without significant multimorbidity to take 3 drugs and undergo more frequent monitoring. This burden may align with the goals of care for many older adults. However, data do not exist to prove a benefit from intensive blood pressure control in debilitated elderly patients, and there may be harm. Lowering the medication burden may be a more important goal than lowering the pressure for this population. Blood pressure targets and hypertension management should reflect patient-centered goals of care.
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2017. Epub ahead of print.
- SPRINT Research Group; Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015; 373:2103–2116.
- Bakris GL. The implications of blood pressure measurement methods on treatment targets for blood pressure. Circulation 2016; 134:904–905.
- Williamson JD, Supiano MA, Applegate WB, et al; SPRINT Research Group. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥ 75 years: a randomized clinical trial. JAMA 2016; 315:2673–2682.
- Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005; 53:695–699.
- Borland E, Nagga K, Nilsson PM, Minthon L, Nilsson ED, Palmqvist S. The Montreal Cognitive Assessment: normative data from a large Swedish population-based cohort. J Alzheimers Dis 2017; 59:893–901.
- Graciani A, Garcia-Esquinas E, Lopez-Garcia E, Banegas JR, Rodriguez-Artalejo F. Ideal cardiovascular health and risk of frailty in older adults. Circ Cardiovasc Qual Outcomes 2016; 9:239–245.
- Odden MC, Peralta CA, Berlowitz DR, et al; Systolic Blood Pressure Intervention Trial (SPRINT) Research Group. Effect of intensive blood pressure control on gait speed and mobility limitation in adults 75 years or older: a randomized clinical trial. JAMA Intern Med 2017; 177:500–507.
- Tully PJ, Hanon O, Cosh S, Tzourio C. Diuretic antihypertensive drugs and incident dementia risk: a systematic review, meta-analysis and meta-regression of prospective studies. J Hypertens 2016; 34:1027–1035.
- Rouch L, Cestac P, Hanon O, et al. Antihypertensive drugs, prevention of cognitive decline and dementia: a systematic review of observational studies, randomized controlled trials and meta-analyses, with discussion of potential mechanisms. CNS Drugs 2015; 29:113–130.
We should aim for a standard office systolic pressure lower than 130 mm Hg in most adults age 65 and older if the patient can take multiple antihypertensive medications and be followed closely for adverse effects.
This recommendation is part of the 2017 hypertension guideline from the American College of Cardiology and American Heart Association.1 This new guideline advocates drug treatment of hypertension to a target less than 130/80 mm Hg for patients of all ages for secondary prevention of cardiovascular disease, and for primary prevention in those at high risk (ie, an estimated 10-year risk of atherosclerotic cardiovascular disease of 10% or higher). The target blood pressure for those at lower risk is less than 140/90 mm Hg.
There are multiple tools to estimate the 10-year risk. All tools incorporate major predictors such as age, blood pressure, cholesterol profile, and other markers, depending on the tool. Although risk increases with age, the tools are inaccurate once the patient is approximately 80 years of age.
The recommendation for older adults omits a target diastolic pressure, since treating elevated systolic pressure has more data supporting it than treating elevated diastolic blood pressure in older people. These recommendations apply only to older adults who can walk and are living in the community, not in an institution, and includes the subset of older adults who have mild cognitive impairment and frailty. The goals of treatment should be patient-centered.
DATA BEHIND THE GUIDELINE: THE SPRINT TRIAL
The Systolic Blood Pressure Intervention Trial (SPRINT)2 enrolled 9,361 patients who, to enter, had to be at least 50 years old (the mean age was 67.9), have a systolic blood pressure of 130 to 180 mm Hg (the mean was 139.7 mm Hg), and be at risk of cardiovascular disease due to chronic kidney disease, clinical or subclinical cardiovascular disease, a 10-year Framingham risk score of at least 15%, or age 75 or older. They had few comorbidities, and patients with diabetes mellitus or prior stroke were excluded. The objective was to see if intensive blood pressure treatment reduced the incidence of adverse cardiovascular outcomes compared with standard control.
The participants were randomized to either an intensive treatment goal of systolic pressure less than 120 mm Hg or a standard treatment goal of less than 140 mm Hg. Investigators chose drugs and doses according to their clinical judgment. The study protocol called for blood pressure measurement using an untended automated cuff, which probably resulted in systolic pressure readings 5 to 10 mm Hg lower than with typical methods used in the office.3
The intensive treatment group achieved a mean systolic pressure of 121.5 mm Hg, which required an average of 3 drugs. In contrast, the standard treatment group achieved a systolic pressure of 136.2 mm Hg, which required an average of 1.9 drugs.
Due to an absolute risk reduction in cardiovascular events and mortality, SPRINT was discontinued early after a median follow-up of 3.3 years. In the entire cohort, 61 patients needed to be treated intensively to prevent 1 cardiovascular event, and 90 needed to be treated intensively to prevent 1 death.2
Favorable outcomes in the oldest subgroup
The oldest patients in the SPRINT trial tolerated the intensive treatment as well as the youngest.2,4
Exploratory analysis of the subgroup of patients age 75 and older, who constituted 28% of the patients in the trial, demonstrated significant benefit from intensive treatment. In this subgroup, 27 patients needed to be treated aggressively (compared with standard treatment) to prevent 1 cardiovascular event, and 41 needed to be treated intensively to prevent 1 death.4 The lower numbers needing to be treated in the older subgroup than in the overall trial reflect the higher absolute risk in this older population.
Serious adverse events were more common with intensive treatment than with standard treatment in the subgroup of older patients who were frail.4 Emergency department visits or serious adverse events were more likely when gait speed (a measure of frailty) was missing from the medical record in the intensive treatment group compared with the standard treatment group. Hyponatremia (serum sodium level < 130 mmol/L) was more likely in the intensively treated group than in the standard treatment group. Although the rate of falls was higher in the oldest subgroup than in the overall SPRINT population, within this subgroup the rate of injurious falls resulting in an emergency department visit was lower with intensive treatment than with standard treatment (11.6% vs 14.1%, P = .04).4
Most of the oldest patients scored below the nominal cutoff for normal (26 points)5 on the 30-point Montreal Cognitive Assessment, and about one-quarter scored below 19, which may be consistent with a major neurocognitive disorder.6
The SPRINT investigators validated a frailty scale in the study patients and found that the most frail benefited from intensive blood pressure control, as did the slowest walkers.
SPRINT results do not apply to very frail, sick patients
For older patients with hypertension, a high burden of comorbidity, and a limited life expectancy, the 2017 guidelines defer treatment decisions to clinical judgment and patient preference.
There have been no randomized trials of blood pressure management for older adults with substantial comorbidities or dementia. The “frail” older adults in the SPRINT trial were still living in the community, without dementia. The intensively treated frail older adults had more serious adverse events than with standard treatment. Those who were documented as being unable to walk at the time of enrollment also had more serious adverse events. Institutionalized older adults and nonambulatory adults in the community would likely have even higher rates of serious adverse events with intensive treatment than the SPRINT patients, and there is concern for excessive adverse effects from intensive blood pressure control in more debilitated older patients.
DOES TREATING HIGH BLOOD PRESSURE PREVENT FRAILTY OR DEMENTIA?
Aging without frailty is an important goal of geriatric care and is likely related to cardiovascular health.7 An older adult who becomes slower physically or mentally, with diminished strength and energy, is less likely to be able to live independently.
Would treating systolic blood pressure to a target of 120 to 130 mm Hg reduce the risk of prefrailty or frailty? Unfortunately, the 3-year SPRINT follow-up of the adults age 75 and older did not show any effect of intensive treatment on gait speed or mobility limitation.8 It is possible that the early termination of the study limited outcomes.
Regarding cognition, the new guidelines say that lowering blood pressure in adults with hypertension to prevent cognitive decline and dementia is reasonable, giving it a class IIa (moderate) recommendation, but they do not offer a particular blood pressure target.
Two systematic reviews of randomized placebo-controlled trials9,10 suggested that pharmacologic treatment of hypertension reduces the progression of cognitive impairment. The trials did not use an intensive treatment goal.
The impact of intensive treatment of hypertension (to a target of 120–130 mm Hg) on the development or progression of cognitive impairment is not known at this time. The SPRINT Memory and Cognition in Decreased Hypertension analysis may shed light on the effect of intensive treatment of blood pressure on the incidence of dementia, although the early termination of SPRINT may limit its conclusions as well.
GOALS SHOULD BE PATIENT-CENTERED
The new hypertension guideline gives clinicians 2 things to think about when treating hypertensive, ambulatory, noninstitutionalized, nondemented older adults, including those age 75 and older:
- Older adults tolerate intensive blood pressure treatment as well as standard treatment. In particular, the fall rate is not increased and may even be less with intensive treatment.
- Older adults have better cardiovascular outcomes with blood pressure less than 130 mm Hg than with higher levels.
Adherence to the new guidelines would require many older adults without significant multimorbidity to take 3 drugs and undergo more frequent monitoring. This burden may align with the goals of care for many older adults. However, data do not exist to prove a benefit from intensive blood pressure control in debilitated elderly patients, and there may be harm. Lowering the medication burden may be a more important goal than lowering the pressure for this population. Blood pressure targets and hypertension management should reflect patient-centered goals of care.
We should aim for a standard office systolic pressure lower than 130 mm Hg in most adults age 65 and older if the patient can take multiple antihypertensive medications and be followed closely for adverse effects.
This recommendation is part of the 2017 hypertension guideline from the American College of Cardiology and American Heart Association.1 This new guideline advocates drug treatment of hypertension to a target less than 130/80 mm Hg for patients of all ages for secondary prevention of cardiovascular disease, and for primary prevention in those at high risk (ie, an estimated 10-year risk of atherosclerotic cardiovascular disease of 10% or higher). The target blood pressure for those at lower risk is less than 140/90 mm Hg.
There are multiple tools to estimate the 10-year risk. All tools incorporate major predictors such as age, blood pressure, cholesterol profile, and other markers, depending on the tool. Although risk increases with age, the tools are inaccurate once the patient is approximately 80 years of age.
The recommendation for older adults omits a target diastolic pressure, since treating elevated systolic pressure has more data supporting it than treating elevated diastolic blood pressure in older people. These recommendations apply only to older adults who can walk and are living in the community, not in an institution, and includes the subset of older adults who have mild cognitive impairment and frailty. The goals of treatment should be patient-centered.
DATA BEHIND THE GUIDELINE: THE SPRINT TRIAL
The Systolic Blood Pressure Intervention Trial (SPRINT)2 enrolled 9,361 patients who, to enter, had to be at least 50 years old (the mean age was 67.9), have a systolic blood pressure of 130 to 180 mm Hg (the mean was 139.7 mm Hg), and be at risk of cardiovascular disease due to chronic kidney disease, clinical or subclinical cardiovascular disease, a 10-year Framingham risk score of at least 15%, or age 75 or older. They had few comorbidities, and patients with diabetes mellitus or prior stroke were excluded. The objective was to see if intensive blood pressure treatment reduced the incidence of adverse cardiovascular outcomes compared with standard control.
The participants were randomized to either an intensive treatment goal of systolic pressure less than 120 mm Hg or a standard treatment goal of less than 140 mm Hg. Investigators chose drugs and doses according to their clinical judgment. The study protocol called for blood pressure measurement using an untended automated cuff, which probably resulted in systolic pressure readings 5 to 10 mm Hg lower than with typical methods used in the office.3
The intensive treatment group achieved a mean systolic pressure of 121.5 mm Hg, which required an average of 3 drugs. In contrast, the standard treatment group achieved a systolic pressure of 136.2 mm Hg, which required an average of 1.9 drugs.
Due to an absolute risk reduction in cardiovascular events and mortality, SPRINT was discontinued early after a median follow-up of 3.3 years. In the entire cohort, 61 patients needed to be treated intensively to prevent 1 cardiovascular event, and 90 needed to be treated intensively to prevent 1 death.2
Favorable outcomes in the oldest subgroup
The oldest patients in the SPRINT trial tolerated the intensive treatment as well as the youngest.2,4
Exploratory analysis of the subgroup of patients age 75 and older, who constituted 28% of the patients in the trial, demonstrated significant benefit from intensive treatment. In this subgroup, 27 patients needed to be treated aggressively (compared with standard treatment) to prevent 1 cardiovascular event, and 41 needed to be treated intensively to prevent 1 death.4 The lower numbers needing to be treated in the older subgroup than in the overall trial reflect the higher absolute risk in this older population.
Serious adverse events were more common with intensive treatment than with standard treatment in the subgroup of older patients who were frail.4 Emergency department visits or serious adverse events were more likely when gait speed (a measure of frailty) was missing from the medical record in the intensive treatment group compared with the standard treatment group. Hyponatremia (serum sodium level < 130 mmol/L) was more likely in the intensively treated group than in the standard treatment group. Although the rate of falls was higher in the oldest subgroup than in the overall SPRINT population, within this subgroup the rate of injurious falls resulting in an emergency department visit was lower with intensive treatment than with standard treatment (11.6% vs 14.1%, P = .04).4
Most of the oldest patients scored below the nominal cutoff for normal (26 points)5 on the 30-point Montreal Cognitive Assessment, and about one-quarter scored below 19, which may be consistent with a major neurocognitive disorder.6
The SPRINT investigators validated a frailty scale in the study patients and found that the most frail benefited from intensive blood pressure control, as did the slowest walkers.
SPRINT results do not apply to very frail, sick patients
For older patients with hypertension, a high burden of comorbidity, and a limited life expectancy, the 2017 guidelines defer treatment decisions to clinical judgment and patient preference.
There have been no randomized trials of blood pressure management for older adults with substantial comorbidities or dementia. The “frail” older adults in the SPRINT trial were still living in the community, without dementia. The intensively treated frail older adults had more serious adverse events than with standard treatment. Those who were documented as being unable to walk at the time of enrollment also had more serious adverse events. Institutionalized older adults and nonambulatory adults in the community would likely have even higher rates of serious adverse events with intensive treatment than the SPRINT patients, and there is concern for excessive adverse effects from intensive blood pressure control in more debilitated older patients.
DOES TREATING HIGH BLOOD PRESSURE PREVENT FRAILTY OR DEMENTIA?
Aging without frailty is an important goal of geriatric care and is likely related to cardiovascular health.7 An older adult who becomes slower physically or mentally, with diminished strength and energy, is less likely to be able to live independently.
Would treating systolic blood pressure to a target of 120 to 130 mm Hg reduce the risk of prefrailty or frailty? Unfortunately, the 3-year SPRINT follow-up of the adults age 75 and older did not show any effect of intensive treatment on gait speed or mobility limitation.8 It is possible that the early termination of the study limited outcomes.
Regarding cognition, the new guidelines say that lowering blood pressure in adults with hypertension to prevent cognitive decline and dementia is reasonable, giving it a class IIa (moderate) recommendation, but they do not offer a particular blood pressure target.
Two systematic reviews of randomized placebo-controlled trials9,10 suggested that pharmacologic treatment of hypertension reduces the progression of cognitive impairment. The trials did not use an intensive treatment goal.
The impact of intensive treatment of hypertension (to a target of 120–130 mm Hg) on the development or progression of cognitive impairment is not known at this time. The SPRINT Memory and Cognition in Decreased Hypertension analysis may shed light on the effect of intensive treatment of blood pressure on the incidence of dementia, although the early termination of SPRINT may limit its conclusions as well.
GOALS SHOULD BE PATIENT-CENTERED
The new hypertension guideline gives clinicians 2 things to think about when treating hypertensive, ambulatory, noninstitutionalized, nondemented older adults, including those age 75 and older:
- Older adults tolerate intensive blood pressure treatment as well as standard treatment. In particular, the fall rate is not increased and may even be less with intensive treatment.
- Older adults have better cardiovascular outcomes with blood pressure less than 130 mm Hg than with higher levels.
Adherence to the new guidelines would require many older adults without significant multimorbidity to take 3 drugs and undergo more frequent monitoring. This burden may align with the goals of care for many older adults. However, data do not exist to prove a benefit from intensive blood pressure control in debilitated elderly patients, and there may be harm. Lowering the medication burden may be a more important goal than lowering the pressure for this population. Blood pressure targets and hypertension management should reflect patient-centered goals of care.
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2017. Epub ahead of print.
- SPRINT Research Group; Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015; 373:2103–2116.
- Bakris GL. The implications of blood pressure measurement methods on treatment targets for blood pressure. Circulation 2016; 134:904–905.
- Williamson JD, Supiano MA, Applegate WB, et al; SPRINT Research Group. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥ 75 years: a randomized clinical trial. JAMA 2016; 315:2673–2682.
- Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005; 53:695–699.
- Borland E, Nagga K, Nilsson PM, Minthon L, Nilsson ED, Palmqvist S. The Montreal Cognitive Assessment: normative data from a large Swedish population-based cohort. J Alzheimers Dis 2017; 59:893–901.
- Graciani A, Garcia-Esquinas E, Lopez-Garcia E, Banegas JR, Rodriguez-Artalejo F. Ideal cardiovascular health and risk of frailty in older adults. Circ Cardiovasc Qual Outcomes 2016; 9:239–245.
- Odden MC, Peralta CA, Berlowitz DR, et al; Systolic Blood Pressure Intervention Trial (SPRINT) Research Group. Effect of intensive blood pressure control on gait speed and mobility limitation in adults 75 years or older: a randomized clinical trial. JAMA Intern Med 2017; 177:500–507.
- Tully PJ, Hanon O, Cosh S, Tzourio C. Diuretic antihypertensive drugs and incident dementia risk: a systematic review, meta-analysis and meta-regression of prospective studies. J Hypertens 2016; 34:1027–1035.
- Rouch L, Cestac P, Hanon O, et al. Antihypertensive drugs, prevention of cognitive decline and dementia: a systematic review of observational studies, randomized controlled trials and meta-analyses, with discussion of potential mechanisms. CNS Drugs 2015; 29:113–130.
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2017. Epub ahead of print.
- SPRINT Research Group; Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015; 373:2103–2116.
- Bakris GL. The implications of blood pressure measurement methods on treatment targets for blood pressure. Circulation 2016; 134:904–905.
- Williamson JD, Supiano MA, Applegate WB, et al; SPRINT Research Group. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥ 75 years: a randomized clinical trial. JAMA 2016; 315:2673–2682.
- Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005; 53:695–699.
- Borland E, Nagga K, Nilsson PM, Minthon L, Nilsson ED, Palmqvist S. The Montreal Cognitive Assessment: normative data from a large Swedish population-based cohort. J Alzheimers Dis 2017; 59:893–901.
- Graciani A, Garcia-Esquinas E, Lopez-Garcia E, Banegas JR, Rodriguez-Artalejo F. Ideal cardiovascular health and risk of frailty in older adults. Circ Cardiovasc Qual Outcomes 2016; 9:239–245.
- Odden MC, Peralta CA, Berlowitz DR, et al; Systolic Blood Pressure Intervention Trial (SPRINT) Research Group. Effect of intensive blood pressure control on gait speed and mobility limitation in adults 75 years or older: a randomized clinical trial. JAMA Intern Med 2017; 177:500–507.
- Tully PJ, Hanon O, Cosh S, Tzourio C. Diuretic antihypertensive drugs and incident dementia risk: a systematic review, meta-analysis and meta-regression of prospective studies. J Hypertens 2016; 34:1027–1035.
- Rouch L, Cestac P, Hanon O, et al. Antihypertensive drugs, prevention of cognitive decline and dementia: a systematic review of observational studies, randomized controlled trials and meta-analyses, with discussion of potential mechanisms. CNS Drugs 2015; 29:113–130.
A 67-year-old woman with bilateral hand numbness
A 67-year-old woman presents to the emergency department after 8 weeks of progressive numbness and tingling in both hands, involving all fingers. The numbness has increased in severity in the last 3 days. She also has occasional numbness around her mouth. She reports no numbness in her feet.
She says she underwent thyroid surgery twice for thyroid cancer 10 years ago. Her medical history also includes type 2 diabetes mellitus (diagnosed 1 year ago), hypertension, dyslipidemia, and diastolic heart failure (diagnosed 5 years ago).
Her current medications are:
- Metformin 1 g twice a day
- Candesartan 16 mg once a day
- Atorvastatin 20 mg once a day
- Furosemide 40 mg twice a day
- Levothyroxine 100 μg per day
- Calcium carbonate 1,500 mg twice a day
- A vitamin D tablet twice a day, which she has not taken for the last 2 months.
She admits she has not been taking her medications regularly because she has been feeling depressed.
On physical examination, she is alert and oriented but appears anxious. She is not in respiratory distress. Her blood pressure is 150/90 mm Hg and her pulse is 92 beats per minute and regular. There is a thyroidectomy scar on the anterior neck. Her jugular venous pressure is not elevated. Her heart sounds are normal without extra sounds. She has no pulmonary rales and no lower-extremity edema.
The Phalen test and Tinel test for carpal tunnel syndrome are negative in both hands. Using a Katz hand diagram, the patient reports tingling and numbness in all fingers, both palms, and the dorsum of both hands. Tapping the area over the facial nerve does not elicit twitching of the facial muscles (ie, no Chvostek sign), but compression of the upper arm elicits carpal spasm (ie, positive Trousseau sign). There is no evidence of motor weakness in her hands. The rest of the physical examination is unremarkable.
POSSIBLE CAUSES OF NUMBNESS
1. Based on the initial evaluation, which of the following is the most likely cause of our patient’s bilateral hand numbness?
- Hypocalcemia due to primary hypoparathyroidism
- Carpal tunnel syndrome due to primary hypothyroidism
- Diabetic peripheral neuropathy
- Vitamin B12 deficiency due to metformin
- Hypocalcemia due to low serum calcitonin
All the conditions above except low serum calcitonin can cause bilateral hand paresthesia. Our patient most likely has hypocalcemia due to primary hypoparathyroidism.
Hypocalcemia
In our patient, bilateral hand numbness and perioral numbness after stopping vitamin D and a positive Trousseau sign strongly suggest hypocalcemia. The classic physical findings in patients with hypocalcemia are the Trousseau sign and the Chvostek sign. The Trousseau sign is elicited by inflating a blood pressure cuff above the systolic blood pressure for 3 minutes and observing for ischemia-induced carpopedal spasm, wrist and metacarpophalangeal joint flexion, thumb adduction, and interphalangeal joint extension. The Chvostek sign is elicited by tapping over the area of the facial nerve below the zygoma in front of the tragus, resulting in ipsilateral twitching of facial muscles.
Although the Trousseau sign is more sensitive and specific than the Chvostek sign, neither is pathognomonic for hypocalcemia.1 The Chvostek sign has been reported to be negative in 30% of patients with hypocalcemia and positive in 10% of normocalcemic individuals.1 The Trousseau sign, however, is present in 94% of hypocalcemic patients vs 1% of normocalcemic individuals.2
Primary hypoparathyroidism secondary to thyroidectomy. Postsurgical hypoparathyroidism is the most common cause of primary hypoparathyroidism. It results from ischemic injury or accidental removal of the parathyroid glands during anterior neck surgery.3,4 The consequent hypocalcemia can be transient, intermittent, or permanent. Permanent postsurgical hypoparathyroidism is defined as persistent hypocalcemia with insufficient parathyroid hormone (PTH) for more than 12 months after neck surgery; however, some consider 6 months to be enough to define the condition.5–7
The incidence of postsurgical hypoparathyroidism varies considerably with the extent of thyroid surgery and the experience of the surgeon.6,8 In the hands of experienced surgeons, permanent hypoparathyroidism occurs in fewer than 1% of patients after total thyroidectomy, whereas the rate may be higher than 6% with less-experienced surgeons.5,9 Other risk factors for postsurgical hypoparathyroidism include female sex, autoimmune thyroid disease, pregnancy, and lactation.5
Pseudohypoparathyroidism is a group of disorders characterized by renal resistance to PTH, leading to hypocalcemia, hyperphosphatemia, and elevated serum PTH. It is also associated with phenotypic features such as short stature and short fourth metacarpal bones.
Calcitonin deficiency. Calcitonin is a polypeptide hormone secreted from the parafollicular (C) cells of the thyroid gland. After total thyroidectomy, calcitonin levels are expected to be reduced. However, the role of calcitonin in humans is unclear. One study has shown that calcitonin is possibly a vestigial hormone, given that no calcitonin-related disorders (excess or deficiency) have been reported in humans.10
Carpal tunnel syndrome due to hypothyroidism
Our patient also could have primary hypothyroidism as a result of thyroidectomy. Hypothyroidism can cause bilateral hand numbness due to carpal tunnel syndrome, which is mediated by mucopolysaccharide deposition and synovial membrane swelling.11 One study reported that 29% of patients with hypothyroidism had carpal tunnel syndrome.12 Symptoms of carpal tunnel syndrome in hypothyroid patients may occur despite thyroid replacement therapy.13
Carpal tunnel syndrome is a clinical diagnosis. Patients usually experience hand paresthesia in the distribution of the median nerve. Provocative physical tests for carpal tunnel syndrome include the Tinel test, the Phalen test, and the Katz hand diagram, which is considered the best of the 3 tests.14,15 Based on how the patient marks the location and type of symptoms on the diagram, carpal tunnel syndrome is rated as classic, probable, possible, or unlikely (Table 1).14,16,17 The sensitivity of a classic or probable diagram ranges from 64% to 80%, while the specificity ranges from 73% to 90%.14,15
Carpal tunnel syndrome is less likely to be the cause of our patient’s symptoms, as her Katz hand diagram indicates only “possible” carpal tunnel syndrome. Her perioral numbness and positive Trousseau sign make hypocalcemia a more likely cause.
Diabetic peripheral neuropathy
Sensory peripheral neuropathy is a recognized complication of diabetes mellitus. However, neuropathy in diabetic patients most commonly manifests initially as distal symmetrical ascending neuropathy starting in the lower extremities.18 Therefore, diabetic peripheral neuropathy is less likely in this patient since her symptoms are limited to her hands.
Vitamin B12 deficiency
Metformin-induced vitamin B12 deficiency is another possible cause of peripheral neuropathy. It might be secondary to metformin-induced changes in intrinsic factor levels and small-intestine motility with resultant bacterial overgrowth, as well as inhibition of vitamin B12 absorption in the terminal ileum.19
However, metformin-induced vitamin B12 deficiency is not the most likely cause of our patient’s neuropathy, since she has been taking this drug for only 1 year. Vitamin B12 deficiency with consequent peripheral neuropathy is more likely in patients taking metformin in high doses for 10 or more years.20
Laboratory results and electrocardiography
Table 2 shows the patient’s initial laboratory results. Of note, her serum calcium level is 5.7 mg/dL (reference range 8.9–10.1). Electrocardiography in the emergency department shows:
- Prolonged PR interval (23 msec)
- Wide QRS complexes (13 msec)
- Flat T waves
- Prolonged corrected QT interval (475 msec)
- Occasional premature ventricular complexes.
CLINICAL MANIFESTATIONS OF HYPOCALCEMIA
2. Which of the following is not a manifestation of hypocalcemia?
- Tonic-clonic seizures
- Cyanosis
- Cardiac ventricular arrhythmias
- Acute pancreatitis
- Depression
Hypocalcemia can cause a wide range of clinical manifestations (Table 3), the extent and severity of which depend on the severity of hypocalcemia and how quickly it develops. The more acute the hypocalcemia, the more severe the manifestations.21
Tetany can cause seizures
Hypocalcemia is characterized by neuromuscular hyperexcitability, manifested clinically by tetany.22 Manifestations of tetany are numerous and include acral paresthesia, perioral numbness, muscle cramps, carpopedal spasm, and seizures. Tetany is the hallmark of hypocalcemia regardless of etiology. However, certain causes are associated with peculiar clinical manifestations. For example, chronic primary hypoparathyroidism may be associated with basal ganglia calcifications that can result in parkinsonism, other extrapyramidal disorders, and dementia (Table 4).6
Airway spasm can be fatal
A serious manifestation of acute severe hypocalcemia is spasm of the glottis muscles, which may cause cyanosis and, if untreated, death.21
Ventricular arrhythmias
Another potential fatal complication of acute severe hypocalcemia is polymorphic ventricular tachycardia due to prolongation of the QT interval, which is readily identified with electrocardiography.23
Hypocalcemia does not cause pancreatitis
Hypercalcemia, rather than hypocalcemia, may cause acute pancreatitis.24 Conversely, acute pancreatitis may cause hypocalcemia due to precipitation of calcium in the abdominal cavity.25
Psychiatric manifestations
In addition to depression, hypocalcemia is associated with psychiatric manifestations including anxiety, confusion, and emotional instability.
STEPS TO DIAGNOSIS OF HYPOCALCEMIA
First step: Confirm true hypocalcemia
Calcium circulates in the blood in 3 forms: bound to albumin (40% to 45%), bound to anions (10% to 15%), and free (ionized) (45%). Although ionized calcium is the active form, most laboratories report total serum calcium.
Since changes in serum albumin concentration affect the total serum calcium level, it is imperative to correct the measured serum calcium to the serum albumin concentration. Each 1-g/dL decrease in serum albumin lowers the total serum calcium by 0.8 mg/dL. Thus:
Corrected serum calcium (mg/dL) =
measured total serum calcium (mg/dL) +
0.8 (4 − serum albumin [g/dL]).
If the patient’s serum calcium level remains low when corrected for serum albumin, he or she has true hypocalcemia, which implies a low ionized serum calcium. Conversely, pseudohypocalcemia means that the measured calcium level is low but the corrected serum calcium is normal.
Using this formula, our patient’s corrected calcium level is calculated as 5.7 + 0.8 (4 – 3.2) = 6.3 mg/dL, indicating true hypocalcemia.
PHOSPHATE IS OFTEN HIGH WHEN CALCIUM IS LOW
In addition to hypocalcemia, our patient has an elevated phosphate level (Table 2).
3. Which of the following hypocalcemic disorders is not associated with hyperphosphatemia?
- End-stage renal disease
- Primary hypoparathyroidism
- Pseudohypoparathyroidism
- Vitamin D3 deficiency
- Rhabdomyolysis
Vitamin D deficiency is not associated with hyperphosphatemia.
Second step in evaluating hypocalcemia: Check phosphate, magnesium, creatinine
The major causes of hypocalcemia can be categorized according to the serum phosphate level: high vs normal or low (Table 5).
High-phosphate, low-calcium states. In the absence of concurrent end-stage renal disease and an excessive phosphate load, primary hypoparathyroidism is the most likely cause of hypocalcemia associated with hyperphosphatemia.
PTH increases serum ionized calcium by26,27:
- Increasing bone resorption
- Increasing reabsorption of calcium from the distal renal tubules
- Increasing the activity of 1-alpha-hydroxylase, responsible for conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 (the most biologically active vitamin D metabolite); 1,25-dihydroxyvitamin D increases the absorption of calcium and phosphate from the intestine.
Conversely, PTH decreases reabsorption of phosphate from proximal renal tubules, resulting in hypophosphatemia. Therefore, low serum PTH (primary hypoparathyroidism) or a PTH-resistant state (pseudohypoparathyroidism) results in hypocalcemia and hyperphosphatemia.26,27
Both end-stage renal disease and rhabdomyolysis are associated with high serum phosphate levels. The kidney normally excretes excess dietary phosphate to maintain phosphate homeostasis; however, this is impaired in end-stage renal disease, leading to hyperphosphatemia. In rhabdomyolysis, it is mainly the transcellular shift of phosphate into the extracellular space from myocyte injury that raises phosphate levels.
Normal- or low-phosphate, low calcium states. Hypocalcemia can also result from vitamin D deficiency, but this cause is associated with a low or normal serum phosphate level. In such cases, hypocalcemia causes secondary hyperparathyroidism with consequent renal phosphate loss and, thus, hypophosphatemia.27
Third step: Check serum intact PTH and 25-hydroxyvitamin D levels
Hypocalcemia stimulates secretion of PTH. Therefore, hypocalcemia with elevated serum PTH is caused by disorders that do not impair PTH secretion, including chronic renal failure and vitamin D deficiency (Table 5). Conversely, hypocalcemia with low or normal serum PTH levels suggests primary hypoparathyroidism.
Our patient’s serum PTH level is 20 ng/mL, which is within the reference range. This does not discount the diagnosis of primary hypoparathyroidism. Although most patients with primary hypoparathyroidism have low or undetectable serum PTH levels, some have normal PTH levels if some degree of PTH production is preserved.5,7,28–30 In these patients, the remaining functioning parathyroid tissue is not enough to maintain a normal serum calcium level, resulting in hypocalcemia. As a result, hypocalcemia stimulates the remaining parathyroid tissue to its maximum output, producing PTH levels usually within the lower or middle-normal range.30 In such patients, the terms parathyroid insufficiency and relative primary hypoparathyroidism are more precise than primary hypoparathyroidism.
Postsurgical hypoparathyroidism with an inappropriately normal PTH level is usually seen in patients with disorders that impair intestinal calcium absorption or bone resorption.31 In our patient’s case, the “normal” serum PTH level is likely due to maximal stimulation of remaining functioning parathyroid tissue by severe hypocalcemia, which is a result of her discontinuation of calcium and calcitriol therapy and her vitamin D deficiency.
CASE RESUMED: NO RESPONSE TO INTRAVENOUS CALCIUM GLUCONATE
The patient is given 2 10-mL ampules of 10% calcium gluconate diluted in 100 mL of 5% dextrose in water over 20 minutes intravenously. Electrocardiographic monitoring is continued. Two hours later, her measured serum calcium is only 5.8 mg/dL, with no improvement in her symptoms.
A continuous infusion of calcium gluconate is started: 12 ampules of calcium gluconate are added to 380 mL of 5% dextrose in water and infused at 40 mL/hour (infused rate of elemental calcium = 1.3 mg/kg/hour); 3 hours later, her measured serum calcium level is still only 5.8 mg//dL; at 6 hours it is 5.9 mg/dL, and her symptoms have not improved.
4. Which of the following is the most appropriate next step?
- Change the calcium gluconate to calcium chloride
- Increase the infusion rate to 1.5 mg of elemental calcium/kg/hour
- Give a bolus of 2 10-mL ampules of 10% calcium gluconate intravenously over 1 minute
- Give additional oral calcium tablets
- Check the serum magnesium level
Treatment of hypocalcemia can involve intravenous or oral calcium therapy.
Intravenous calcium is indicated for patients with any of the following6,32:
- Moderate to severe neuromuscular irritability (eg, acral paresthesia, carpopedal spasm, prolonged QT interval, seizures, laryngospasm, bronchospasm)
- Acute hypocalcemia with corrected serum calcium level less than 7.6 mg/dL, even if the patient is asymptomatic
- Cardiac failure.
One 10-mL ampule of 10% calcium gluconate contains 93 mg of elemental calcium; 1 or 2 ampules are typically diluted in 50 to 100 mL of 5% dextrose in water and infused slowly over 15 to 20 minutes. Rapid administration of intravenous calcium is contraindicated, as it may produce cardiac arrhythmias and possibly cardiac arrest. Therefore, intravenous calcium should be given slowly while continuing electrocardiographic monitoring.33
Since the effect of 1 ampule of calcium gluconate lasts only 2 to 3 hours, most patients with symptomatic hypocalcemia require continuous intravenous calcium infusion. The recommended dose of infused elemental calcium is 0.5 to 1.5 mg/kg/hour.34 Several ampules are added to 500 to 1,000 mL of 5% dextrose in water or 0.9% normal saline and infused at a rate appropriate for the patient’s corrected calcium and symptoms.
Oral calcium and vitamin D supplements can be given initially to patients with a corrected serum calcium level of 7.6 mg/dL or greater, with or without mild symptoms, if they can tolerate oral intake. However, this is not the treatment of choice for resistant acute hypocalcemia, as in this case.
Calcium chloride has no advantages over calcium gluconate. Further, it can be associated with local irritation and may result in tissue necrosis if extravasation occurs.35
Increasing the infusion rate of calcium gluconate to the maximum recommended dose may improve the patient’s ionized calcium level and symptoms somewhat. However, it is not the best option for this patient, given that she did not respond to 2 ampules of calcium gluconate followed by continuous infusion of 1.3 mg/kg/hour for 6 hours.
Calcium gluconate bolus. Similarly, giving the patient an additional 2 ampules of calcium gluconate over 1 minute would not be recommended, as rapid administration of intravenous calcium gluconate (eg, over 1 minute) is contraindicated.
Check magnesium
If hypocalcemia persists despite intravenous calcium therapy, as in our patient, further investigation or action is required. An important cause of persistent hypocalcemia is severe hypomagnesemia. Severe hypomagnesemia (serum magnesium < 0.8 mg/dL) causes resistant hypocalcemia by several mechanisms:
- Inducing PTH resistance32,36,37
- Decreasing PTH secretion32,36
- Decreasing calcitriol production.
The decrease in calcitriol production is a direct effect of hypomagnesemia, but it is also an indirect effect of low PTH secretion, which inhibits the enzyme 1-alpha-hydroxylase. Thus, conversion of 25-hydroxyvitamin D3 to calcitriol is impaired, leading to low calcitriol production.
Our patient could have hypomagnesemia due to furosemide use and uncontrolled diabetes mellitus. Hypocalcemia resistant to calcium therapy may occasionally respond to magnesium therapy even if the serum magnesium level is normal. This may be due to depleted intracellular magnesium salt levels.6,38 Rarely, severe hypermagnesemia can also be associated with hypocalcemia due to inhibition of PTH secretion.37,39
CASE RESUMED
Our patient’s serum magnesium level is 0.6 mg/dL (reference range 1.7–2.4 mg/dL). She is given 2 g of magnesium sulfate in 60 mL of 0.9% normal saline infused over 1 hour, followed by a continuous infusion of magnesium sulfate (12 g diluted in 250 mL of 0.9% normal saline, infused over 24 hours). On repeat testing 4 hours later, her serum magnesium level is 0.7 mg/dL, and at 8 hours later it is 0.9 mg/dL. She is subsequently started on oral magnesium oxide 600 mg per day. The magnesium sulfate infusion is continued for another 24 hours.
PREVENTING HYPERCALCIURIA
Patients with low PTH (primary hypoparathyroidism) may have hypercalciuria due to decreased renal tubular calcium reabsorption. Two important measures can minimize hypercalciuria in such patients:
- Keeping the serum calcium level in the low-normal range4,5,40
- Giving a thiazide diuretic (eg, hydrochlorothiazide 12.5–50 mg daily) with a low-salt diet.41,42
A thiazide diuretic is usually started once the 24-hour urine calcium reaches 250 mg.6 Thiazides are thought to enhance both proximal and distal renal tubular calcium reabsorption.43,44
PRIMARY HYPOPARATHYROIDISM: LONG-TERM MANAGEMENT
Long-term management of primary hypoparathyroidism requires calcium and vitamin D supplementation.
Calcium supplements. The most commonly prescribed calcium preparations are calcium carbonate and calcium citrate (containing 40% and 20% elemental calcium, respectively). Calcium carbonate, which is less expensive than calcium citrate, binds with phosphate intake and requires an acidic environment for absorption, and so it is better absorbed when taken with meals. Because calcium citrate does not require an acidic environment for absorption, it is the calcium preparation of choice for patients on proton pump inhibitors, or patients with achlorhydria or constipation.45 Calcium doses vary widely, with most hypoparathyroid patients requiring 1 to 2 g of elemental calcium daily.6
Vitamin D supplements. To promote intestinal absorption, calcium is combined with vitamin D in a fixed-dose preparation given in divided doses.46 Calcitriol (1,25-dihydroxyvitamin D3) is the most active metabolite of vitamin D, with rapid onset and offset of action, and it is the preferred form of vitamin D therapy for patients with hypoparathyroidism. If calcitriol is not available or is not affordable, alphacalcidol (1-alpha-hydroxyvitamin D3) is another option. This is a synthetic analogue of vitamin D that is already hyroxylated at the C1 position. After oral intake, it is hydroxylated in the liver to form calcitriol.
Since renal production of calcitriol is PTH-dependent, in hypoparathyroidism the conversion of 25-hydroxyvitamin D3 to calcitriol is limited. Therefore, vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol) are not the preferred forms of vitamin D for such patients. However, either can be added to calcitriol, as they may have extraskeletal benefits.7
CASE CONCLUDED
Our patient presented with primary parathyroid insufficiency associated with vitamin D deficiency. Therefore, in addition to calcitriol and calcium combined with vitamin D in a fixed-dose preparation, her management included vitamin D3 for her vitamin D deficiency.
She was discharged on these medications. At a follow-up visit 3 weeks later, her measured serum calcium level was 8.6 mg/dL. She reported gradual resolution of her symptoms. She was also referred to a psychiatrist for her depression.
TAKE-HOME POINTS
- Hypocalcemia causes neuromuscular excitability, manifested clinically by tetany.
- Common causes of hypocalcemia include vitamin D deficiency, hypomagnesemia, renal failure, and primary hypoparathyroidism.
- The first step in evaluating hypocalcemia is to correct the measured serum calcium to the serum albumin concentration.
- Laboratory testing for hypocalcemia should include serum phosphorus, magnesium, creatinine, PTH, and 25-hydroxyvitamin D3.
- Primary hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, and low serum PTH.
- Moderate to severe manifestations of hypo-
calcemia and acute hypocalcemia (< 7.6 mg/dL), even if asymptomatic, warrant intravenous calcium therapy. - Correction of hypomagnesemia is essential to treat hypocalcemia, especially if resistant to intravenous calcium therapy.
- The goal of chronic management of primary hypoparathyroidism includes correcting the serum calcium level to a low-normal range, the serum phosphorus level to an upper-normal range, and prevention of hypercalciuria.
Acknowledgments: The authors wish to thank Mr. Michael Edward Tierney of the School of Medicine, University of Sydney, Australia, for his linguistic editing of the manuscript.
- Jesus JE, Landry A. Images in clinical medicine. Chvostek’s and Trousseau’s signs. N Engl J Med 2012; 367:e15.
- Urbano FL. Signs of hypocalcemia: Chvostek’s and Trousseau’s. Hosp Physician 2000; 36:43–45.
- Chisthi MM, Nair RS, Kuttanchettiyar KG, Yadev I. Mechanisms behind post-thyroidectomy hypocalcemia: interplay of calcitonin, parathormone, and albumin—a prospective study. J Invest Surg 2017; 30:217–225.
- Shoback DM, Bilezikian JP, Costa AG, et al. Presentation of hypoparathyroidism: etiologies and clinical features. J Clin Endocrinol Metab 2016; 101:2300–2312.
- Stack BC Jr, Bimston DN, Bodenner DL, et al. American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review: postoperative hypoparathyroidism—definitions and management. Endocr Pract 2015; 21:674–685.
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- Coimbra C, Monteiro F, Oliveira P, Ribeiro L, de Almeida MG, Condé A. Hypoparathyroidism following thyroidectomy: predictive factors. Acta Otorrinolaringol Esp 2017; 68:106–111.
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A 67-year-old woman presents to the emergency department after 8 weeks of progressive numbness and tingling in both hands, involving all fingers. The numbness has increased in severity in the last 3 days. She also has occasional numbness around her mouth. She reports no numbness in her feet.
She says she underwent thyroid surgery twice for thyroid cancer 10 years ago. Her medical history also includes type 2 diabetes mellitus (diagnosed 1 year ago), hypertension, dyslipidemia, and diastolic heart failure (diagnosed 5 years ago).
Her current medications are:
- Metformin 1 g twice a day
- Candesartan 16 mg once a day
- Atorvastatin 20 mg once a day
- Furosemide 40 mg twice a day
- Levothyroxine 100 μg per day
- Calcium carbonate 1,500 mg twice a day
- A vitamin D tablet twice a day, which she has not taken for the last 2 months.
She admits she has not been taking her medications regularly because she has been feeling depressed.
On physical examination, she is alert and oriented but appears anxious. She is not in respiratory distress. Her blood pressure is 150/90 mm Hg and her pulse is 92 beats per minute and regular. There is a thyroidectomy scar on the anterior neck. Her jugular venous pressure is not elevated. Her heart sounds are normal without extra sounds. She has no pulmonary rales and no lower-extremity edema.
The Phalen test and Tinel test for carpal tunnel syndrome are negative in both hands. Using a Katz hand diagram, the patient reports tingling and numbness in all fingers, both palms, and the dorsum of both hands. Tapping the area over the facial nerve does not elicit twitching of the facial muscles (ie, no Chvostek sign), but compression of the upper arm elicits carpal spasm (ie, positive Trousseau sign). There is no evidence of motor weakness in her hands. The rest of the physical examination is unremarkable.
POSSIBLE CAUSES OF NUMBNESS
1. Based on the initial evaluation, which of the following is the most likely cause of our patient’s bilateral hand numbness?
- Hypocalcemia due to primary hypoparathyroidism
- Carpal tunnel syndrome due to primary hypothyroidism
- Diabetic peripheral neuropathy
- Vitamin B12 deficiency due to metformin
- Hypocalcemia due to low serum calcitonin
All the conditions above except low serum calcitonin can cause bilateral hand paresthesia. Our patient most likely has hypocalcemia due to primary hypoparathyroidism.
Hypocalcemia
In our patient, bilateral hand numbness and perioral numbness after stopping vitamin D and a positive Trousseau sign strongly suggest hypocalcemia. The classic physical findings in patients with hypocalcemia are the Trousseau sign and the Chvostek sign. The Trousseau sign is elicited by inflating a blood pressure cuff above the systolic blood pressure for 3 minutes and observing for ischemia-induced carpopedal spasm, wrist and metacarpophalangeal joint flexion, thumb adduction, and interphalangeal joint extension. The Chvostek sign is elicited by tapping over the area of the facial nerve below the zygoma in front of the tragus, resulting in ipsilateral twitching of facial muscles.
Although the Trousseau sign is more sensitive and specific than the Chvostek sign, neither is pathognomonic for hypocalcemia.1 The Chvostek sign has been reported to be negative in 30% of patients with hypocalcemia and positive in 10% of normocalcemic individuals.1 The Trousseau sign, however, is present in 94% of hypocalcemic patients vs 1% of normocalcemic individuals.2
Primary hypoparathyroidism secondary to thyroidectomy. Postsurgical hypoparathyroidism is the most common cause of primary hypoparathyroidism. It results from ischemic injury or accidental removal of the parathyroid glands during anterior neck surgery.3,4 The consequent hypocalcemia can be transient, intermittent, or permanent. Permanent postsurgical hypoparathyroidism is defined as persistent hypocalcemia with insufficient parathyroid hormone (PTH) for more than 12 months after neck surgery; however, some consider 6 months to be enough to define the condition.5–7
The incidence of postsurgical hypoparathyroidism varies considerably with the extent of thyroid surgery and the experience of the surgeon.6,8 In the hands of experienced surgeons, permanent hypoparathyroidism occurs in fewer than 1% of patients after total thyroidectomy, whereas the rate may be higher than 6% with less-experienced surgeons.5,9 Other risk factors for postsurgical hypoparathyroidism include female sex, autoimmune thyroid disease, pregnancy, and lactation.5
Pseudohypoparathyroidism is a group of disorders characterized by renal resistance to PTH, leading to hypocalcemia, hyperphosphatemia, and elevated serum PTH. It is also associated with phenotypic features such as short stature and short fourth metacarpal bones.
Calcitonin deficiency. Calcitonin is a polypeptide hormone secreted from the parafollicular (C) cells of the thyroid gland. After total thyroidectomy, calcitonin levels are expected to be reduced. However, the role of calcitonin in humans is unclear. One study has shown that calcitonin is possibly a vestigial hormone, given that no calcitonin-related disorders (excess or deficiency) have been reported in humans.10
Carpal tunnel syndrome due to hypothyroidism
Our patient also could have primary hypothyroidism as a result of thyroidectomy. Hypothyroidism can cause bilateral hand numbness due to carpal tunnel syndrome, which is mediated by mucopolysaccharide deposition and synovial membrane swelling.11 One study reported that 29% of patients with hypothyroidism had carpal tunnel syndrome.12 Symptoms of carpal tunnel syndrome in hypothyroid patients may occur despite thyroid replacement therapy.13
Carpal tunnel syndrome is a clinical diagnosis. Patients usually experience hand paresthesia in the distribution of the median nerve. Provocative physical tests for carpal tunnel syndrome include the Tinel test, the Phalen test, and the Katz hand diagram, which is considered the best of the 3 tests.14,15 Based on how the patient marks the location and type of symptoms on the diagram, carpal tunnel syndrome is rated as classic, probable, possible, or unlikely (Table 1).14,16,17 The sensitivity of a classic or probable diagram ranges from 64% to 80%, while the specificity ranges from 73% to 90%.14,15
Carpal tunnel syndrome is less likely to be the cause of our patient’s symptoms, as her Katz hand diagram indicates only “possible” carpal tunnel syndrome. Her perioral numbness and positive Trousseau sign make hypocalcemia a more likely cause.
Diabetic peripheral neuropathy
Sensory peripheral neuropathy is a recognized complication of diabetes mellitus. However, neuropathy in diabetic patients most commonly manifests initially as distal symmetrical ascending neuropathy starting in the lower extremities.18 Therefore, diabetic peripheral neuropathy is less likely in this patient since her symptoms are limited to her hands.
Vitamin B12 deficiency
Metformin-induced vitamin B12 deficiency is another possible cause of peripheral neuropathy. It might be secondary to metformin-induced changes in intrinsic factor levels and small-intestine motility with resultant bacterial overgrowth, as well as inhibition of vitamin B12 absorption in the terminal ileum.19
However, metformin-induced vitamin B12 deficiency is not the most likely cause of our patient’s neuropathy, since she has been taking this drug for only 1 year. Vitamin B12 deficiency with consequent peripheral neuropathy is more likely in patients taking metformin in high doses for 10 or more years.20
Laboratory results and electrocardiography
Table 2 shows the patient’s initial laboratory results. Of note, her serum calcium level is 5.7 mg/dL (reference range 8.9–10.1). Electrocardiography in the emergency department shows:
- Prolonged PR interval (23 msec)
- Wide QRS complexes (13 msec)
- Flat T waves
- Prolonged corrected QT interval (475 msec)
- Occasional premature ventricular complexes.
CLINICAL MANIFESTATIONS OF HYPOCALCEMIA
2. Which of the following is not a manifestation of hypocalcemia?
- Tonic-clonic seizures
- Cyanosis
- Cardiac ventricular arrhythmias
- Acute pancreatitis
- Depression
Hypocalcemia can cause a wide range of clinical manifestations (Table 3), the extent and severity of which depend on the severity of hypocalcemia and how quickly it develops. The more acute the hypocalcemia, the more severe the manifestations.21
Tetany can cause seizures
Hypocalcemia is characterized by neuromuscular hyperexcitability, manifested clinically by tetany.22 Manifestations of tetany are numerous and include acral paresthesia, perioral numbness, muscle cramps, carpopedal spasm, and seizures. Tetany is the hallmark of hypocalcemia regardless of etiology. However, certain causes are associated with peculiar clinical manifestations. For example, chronic primary hypoparathyroidism may be associated with basal ganglia calcifications that can result in parkinsonism, other extrapyramidal disorders, and dementia (Table 4).6
Airway spasm can be fatal
A serious manifestation of acute severe hypocalcemia is spasm of the glottis muscles, which may cause cyanosis and, if untreated, death.21
Ventricular arrhythmias
Another potential fatal complication of acute severe hypocalcemia is polymorphic ventricular tachycardia due to prolongation of the QT interval, which is readily identified with electrocardiography.23
Hypocalcemia does not cause pancreatitis
Hypercalcemia, rather than hypocalcemia, may cause acute pancreatitis.24 Conversely, acute pancreatitis may cause hypocalcemia due to precipitation of calcium in the abdominal cavity.25
Psychiatric manifestations
In addition to depression, hypocalcemia is associated with psychiatric manifestations including anxiety, confusion, and emotional instability.
STEPS TO DIAGNOSIS OF HYPOCALCEMIA
First step: Confirm true hypocalcemia
Calcium circulates in the blood in 3 forms: bound to albumin (40% to 45%), bound to anions (10% to 15%), and free (ionized) (45%). Although ionized calcium is the active form, most laboratories report total serum calcium.
Since changes in serum albumin concentration affect the total serum calcium level, it is imperative to correct the measured serum calcium to the serum albumin concentration. Each 1-g/dL decrease in serum albumin lowers the total serum calcium by 0.8 mg/dL. Thus:
Corrected serum calcium (mg/dL) =
measured total serum calcium (mg/dL) +
0.8 (4 − serum albumin [g/dL]).
If the patient’s serum calcium level remains low when corrected for serum albumin, he or she has true hypocalcemia, which implies a low ionized serum calcium. Conversely, pseudohypocalcemia means that the measured calcium level is low but the corrected serum calcium is normal.
Using this formula, our patient’s corrected calcium level is calculated as 5.7 + 0.8 (4 – 3.2) = 6.3 mg/dL, indicating true hypocalcemia.
PHOSPHATE IS OFTEN HIGH WHEN CALCIUM IS LOW
In addition to hypocalcemia, our patient has an elevated phosphate level (Table 2).
3. Which of the following hypocalcemic disorders is not associated with hyperphosphatemia?
- End-stage renal disease
- Primary hypoparathyroidism
- Pseudohypoparathyroidism
- Vitamin D3 deficiency
- Rhabdomyolysis
Vitamin D deficiency is not associated with hyperphosphatemia.
Second step in evaluating hypocalcemia: Check phosphate, magnesium, creatinine
The major causes of hypocalcemia can be categorized according to the serum phosphate level: high vs normal or low (Table 5).
High-phosphate, low-calcium states. In the absence of concurrent end-stage renal disease and an excessive phosphate load, primary hypoparathyroidism is the most likely cause of hypocalcemia associated with hyperphosphatemia.
PTH increases serum ionized calcium by26,27:
- Increasing bone resorption
- Increasing reabsorption of calcium from the distal renal tubules
- Increasing the activity of 1-alpha-hydroxylase, responsible for conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 (the most biologically active vitamin D metabolite); 1,25-dihydroxyvitamin D increases the absorption of calcium and phosphate from the intestine.
Conversely, PTH decreases reabsorption of phosphate from proximal renal tubules, resulting in hypophosphatemia. Therefore, low serum PTH (primary hypoparathyroidism) or a PTH-resistant state (pseudohypoparathyroidism) results in hypocalcemia and hyperphosphatemia.26,27
Both end-stage renal disease and rhabdomyolysis are associated with high serum phosphate levels. The kidney normally excretes excess dietary phosphate to maintain phosphate homeostasis; however, this is impaired in end-stage renal disease, leading to hyperphosphatemia. In rhabdomyolysis, it is mainly the transcellular shift of phosphate into the extracellular space from myocyte injury that raises phosphate levels.
Normal- or low-phosphate, low calcium states. Hypocalcemia can also result from vitamin D deficiency, but this cause is associated with a low or normal serum phosphate level. In such cases, hypocalcemia causes secondary hyperparathyroidism with consequent renal phosphate loss and, thus, hypophosphatemia.27
Third step: Check serum intact PTH and 25-hydroxyvitamin D levels
Hypocalcemia stimulates secretion of PTH. Therefore, hypocalcemia with elevated serum PTH is caused by disorders that do not impair PTH secretion, including chronic renal failure and vitamin D deficiency (Table 5). Conversely, hypocalcemia with low or normal serum PTH levels suggests primary hypoparathyroidism.
Our patient’s serum PTH level is 20 ng/mL, which is within the reference range. This does not discount the diagnosis of primary hypoparathyroidism. Although most patients with primary hypoparathyroidism have low or undetectable serum PTH levels, some have normal PTH levels if some degree of PTH production is preserved.5,7,28–30 In these patients, the remaining functioning parathyroid tissue is not enough to maintain a normal serum calcium level, resulting in hypocalcemia. As a result, hypocalcemia stimulates the remaining parathyroid tissue to its maximum output, producing PTH levels usually within the lower or middle-normal range.30 In such patients, the terms parathyroid insufficiency and relative primary hypoparathyroidism are more precise than primary hypoparathyroidism.
Postsurgical hypoparathyroidism with an inappropriately normal PTH level is usually seen in patients with disorders that impair intestinal calcium absorption or bone resorption.31 In our patient’s case, the “normal” serum PTH level is likely due to maximal stimulation of remaining functioning parathyroid tissue by severe hypocalcemia, which is a result of her discontinuation of calcium and calcitriol therapy and her vitamin D deficiency.
CASE RESUMED: NO RESPONSE TO INTRAVENOUS CALCIUM GLUCONATE
The patient is given 2 10-mL ampules of 10% calcium gluconate diluted in 100 mL of 5% dextrose in water over 20 minutes intravenously. Electrocardiographic monitoring is continued. Two hours later, her measured serum calcium is only 5.8 mg/dL, with no improvement in her symptoms.
A continuous infusion of calcium gluconate is started: 12 ampules of calcium gluconate are added to 380 mL of 5% dextrose in water and infused at 40 mL/hour (infused rate of elemental calcium = 1.3 mg/kg/hour); 3 hours later, her measured serum calcium level is still only 5.8 mg//dL; at 6 hours it is 5.9 mg/dL, and her symptoms have not improved.
4. Which of the following is the most appropriate next step?
- Change the calcium gluconate to calcium chloride
- Increase the infusion rate to 1.5 mg of elemental calcium/kg/hour
- Give a bolus of 2 10-mL ampules of 10% calcium gluconate intravenously over 1 minute
- Give additional oral calcium tablets
- Check the serum magnesium level
Treatment of hypocalcemia can involve intravenous or oral calcium therapy.
Intravenous calcium is indicated for patients with any of the following6,32:
- Moderate to severe neuromuscular irritability (eg, acral paresthesia, carpopedal spasm, prolonged QT interval, seizures, laryngospasm, bronchospasm)
- Acute hypocalcemia with corrected serum calcium level less than 7.6 mg/dL, even if the patient is asymptomatic
- Cardiac failure.
One 10-mL ampule of 10% calcium gluconate contains 93 mg of elemental calcium; 1 or 2 ampules are typically diluted in 50 to 100 mL of 5% dextrose in water and infused slowly over 15 to 20 minutes. Rapid administration of intravenous calcium is contraindicated, as it may produce cardiac arrhythmias and possibly cardiac arrest. Therefore, intravenous calcium should be given slowly while continuing electrocardiographic monitoring.33
Since the effect of 1 ampule of calcium gluconate lasts only 2 to 3 hours, most patients with symptomatic hypocalcemia require continuous intravenous calcium infusion. The recommended dose of infused elemental calcium is 0.5 to 1.5 mg/kg/hour.34 Several ampules are added to 500 to 1,000 mL of 5% dextrose in water or 0.9% normal saline and infused at a rate appropriate for the patient’s corrected calcium and symptoms.
Oral calcium and vitamin D supplements can be given initially to patients with a corrected serum calcium level of 7.6 mg/dL or greater, with or without mild symptoms, if they can tolerate oral intake. However, this is not the treatment of choice for resistant acute hypocalcemia, as in this case.
Calcium chloride has no advantages over calcium gluconate. Further, it can be associated with local irritation and may result in tissue necrosis if extravasation occurs.35
Increasing the infusion rate of calcium gluconate to the maximum recommended dose may improve the patient’s ionized calcium level and symptoms somewhat. However, it is not the best option for this patient, given that she did not respond to 2 ampules of calcium gluconate followed by continuous infusion of 1.3 mg/kg/hour for 6 hours.
Calcium gluconate bolus. Similarly, giving the patient an additional 2 ampules of calcium gluconate over 1 minute would not be recommended, as rapid administration of intravenous calcium gluconate (eg, over 1 minute) is contraindicated.
Check magnesium
If hypocalcemia persists despite intravenous calcium therapy, as in our patient, further investigation or action is required. An important cause of persistent hypocalcemia is severe hypomagnesemia. Severe hypomagnesemia (serum magnesium < 0.8 mg/dL) causes resistant hypocalcemia by several mechanisms:
- Inducing PTH resistance32,36,37
- Decreasing PTH secretion32,36
- Decreasing calcitriol production.
The decrease in calcitriol production is a direct effect of hypomagnesemia, but it is also an indirect effect of low PTH secretion, which inhibits the enzyme 1-alpha-hydroxylase. Thus, conversion of 25-hydroxyvitamin D3 to calcitriol is impaired, leading to low calcitriol production.
Our patient could have hypomagnesemia due to furosemide use and uncontrolled diabetes mellitus. Hypocalcemia resistant to calcium therapy may occasionally respond to magnesium therapy even if the serum magnesium level is normal. This may be due to depleted intracellular magnesium salt levels.6,38 Rarely, severe hypermagnesemia can also be associated with hypocalcemia due to inhibition of PTH secretion.37,39
CASE RESUMED
Our patient’s serum magnesium level is 0.6 mg/dL (reference range 1.7–2.4 mg/dL). She is given 2 g of magnesium sulfate in 60 mL of 0.9% normal saline infused over 1 hour, followed by a continuous infusion of magnesium sulfate (12 g diluted in 250 mL of 0.9% normal saline, infused over 24 hours). On repeat testing 4 hours later, her serum magnesium level is 0.7 mg/dL, and at 8 hours later it is 0.9 mg/dL. She is subsequently started on oral magnesium oxide 600 mg per day. The magnesium sulfate infusion is continued for another 24 hours.
PREVENTING HYPERCALCIURIA
Patients with low PTH (primary hypoparathyroidism) may have hypercalciuria due to decreased renal tubular calcium reabsorption. Two important measures can minimize hypercalciuria in such patients:
- Keeping the serum calcium level in the low-normal range4,5,40
- Giving a thiazide diuretic (eg, hydrochlorothiazide 12.5–50 mg daily) with a low-salt diet.41,42
A thiazide diuretic is usually started once the 24-hour urine calcium reaches 250 mg.6 Thiazides are thought to enhance both proximal and distal renal tubular calcium reabsorption.43,44
PRIMARY HYPOPARATHYROIDISM: LONG-TERM MANAGEMENT
Long-term management of primary hypoparathyroidism requires calcium and vitamin D supplementation.
Calcium supplements. The most commonly prescribed calcium preparations are calcium carbonate and calcium citrate (containing 40% and 20% elemental calcium, respectively). Calcium carbonate, which is less expensive than calcium citrate, binds with phosphate intake and requires an acidic environment for absorption, and so it is better absorbed when taken with meals. Because calcium citrate does not require an acidic environment for absorption, it is the calcium preparation of choice for patients on proton pump inhibitors, or patients with achlorhydria or constipation.45 Calcium doses vary widely, with most hypoparathyroid patients requiring 1 to 2 g of elemental calcium daily.6
Vitamin D supplements. To promote intestinal absorption, calcium is combined with vitamin D in a fixed-dose preparation given in divided doses.46 Calcitriol (1,25-dihydroxyvitamin D3) is the most active metabolite of vitamin D, with rapid onset and offset of action, and it is the preferred form of vitamin D therapy for patients with hypoparathyroidism. If calcitriol is not available or is not affordable, alphacalcidol (1-alpha-hydroxyvitamin D3) is another option. This is a synthetic analogue of vitamin D that is already hyroxylated at the C1 position. After oral intake, it is hydroxylated in the liver to form calcitriol.
Since renal production of calcitriol is PTH-dependent, in hypoparathyroidism the conversion of 25-hydroxyvitamin D3 to calcitriol is limited. Therefore, vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol) are not the preferred forms of vitamin D for such patients. However, either can be added to calcitriol, as they may have extraskeletal benefits.7
CASE CONCLUDED
Our patient presented with primary parathyroid insufficiency associated with vitamin D deficiency. Therefore, in addition to calcitriol and calcium combined with vitamin D in a fixed-dose preparation, her management included vitamin D3 for her vitamin D deficiency.
She was discharged on these medications. At a follow-up visit 3 weeks later, her measured serum calcium level was 8.6 mg/dL. She reported gradual resolution of her symptoms. She was also referred to a psychiatrist for her depression.
TAKE-HOME POINTS
- Hypocalcemia causes neuromuscular excitability, manifested clinically by tetany.
- Common causes of hypocalcemia include vitamin D deficiency, hypomagnesemia, renal failure, and primary hypoparathyroidism.
- The first step in evaluating hypocalcemia is to correct the measured serum calcium to the serum albumin concentration.
- Laboratory testing for hypocalcemia should include serum phosphorus, magnesium, creatinine, PTH, and 25-hydroxyvitamin D3.
- Primary hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, and low serum PTH.
- Moderate to severe manifestations of hypo-
calcemia and acute hypocalcemia (< 7.6 mg/dL), even if asymptomatic, warrant intravenous calcium therapy. - Correction of hypomagnesemia is essential to treat hypocalcemia, especially if resistant to intravenous calcium therapy.
- The goal of chronic management of primary hypoparathyroidism includes correcting the serum calcium level to a low-normal range, the serum phosphorus level to an upper-normal range, and prevention of hypercalciuria.
Acknowledgments: The authors wish to thank Mr. Michael Edward Tierney of the School of Medicine, University of Sydney, Australia, for his linguistic editing of the manuscript.
A 67-year-old woman presents to the emergency department after 8 weeks of progressive numbness and tingling in both hands, involving all fingers. The numbness has increased in severity in the last 3 days. She also has occasional numbness around her mouth. She reports no numbness in her feet.
She says she underwent thyroid surgery twice for thyroid cancer 10 years ago. Her medical history also includes type 2 diabetes mellitus (diagnosed 1 year ago), hypertension, dyslipidemia, and diastolic heart failure (diagnosed 5 years ago).
Her current medications are:
- Metformin 1 g twice a day
- Candesartan 16 mg once a day
- Atorvastatin 20 mg once a day
- Furosemide 40 mg twice a day
- Levothyroxine 100 μg per day
- Calcium carbonate 1,500 mg twice a day
- A vitamin D tablet twice a day, which she has not taken for the last 2 months.
She admits she has not been taking her medications regularly because she has been feeling depressed.
On physical examination, she is alert and oriented but appears anxious. She is not in respiratory distress. Her blood pressure is 150/90 mm Hg and her pulse is 92 beats per minute and regular. There is a thyroidectomy scar on the anterior neck. Her jugular venous pressure is not elevated. Her heart sounds are normal without extra sounds. She has no pulmonary rales and no lower-extremity edema.
The Phalen test and Tinel test for carpal tunnel syndrome are negative in both hands. Using a Katz hand diagram, the patient reports tingling and numbness in all fingers, both palms, and the dorsum of both hands. Tapping the area over the facial nerve does not elicit twitching of the facial muscles (ie, no Chvostek sign), but compression of the upper arm elicits carpal spasm (ie, positive Trousseau sign). There is no evidence of motor weakness in her hands. The rest of the physical examination is unremarkable.
POSSIBLE CAUSES OF NUMBNESS
1. Based on the initial evaluation, which of the following is the most likely cause of our patient’s bilateral hand numbness?
- Hypocalcemia due to primary hypoparathyroidism
- Carpal tunnel syndrome due to primary hypothyroidism
- Diabetic peripheral neuropathy
- Vitamin B12 deficiency due to metformin
- Hypocalcemia due to low serum calcitonin
All the conditions above except low serum calcitonin can cause bilateral hand paresthesia. Our patient most likely has hypocalcemia due to primary hypoparathyroidism.
Hypocalcemia
In our patient, bilateral hand numbness and perioral numbness after stopping vitamin D and a positive Trousseau sign strongly suggest hypocalcemia. The classic physical findings in patients with hypocalcemia are the Trousseau sign and the Chvostek sign. The Trousseau sign is elicited by inflating a blood pressure cuff above the systolic blood pressure for 3 minutes and observing for ischemia-induced carpopedal spasm, wrist and metacarpophalangeal joint flexion, thumb adduction, and interphalangeal joint extension. The Chvostek sign is elicited by tapping over the area of the facial nerve below the zygoma in front of the tragus, resulting in ipsilateral twitching of facial muscles.
Although the Trousseau sign is more sensitive and specific than the Chvostek sign, neither is pathognomonic for hypocalcemia.1 The Chvostek sign has been reported to be negative in 30% of patients with hypocalcemia and positive in 10% of normocalcemic individuals.1 The Trousseau sign, however, is present in 94% of hypocalcemic patients vs 1% of normocalcemic individuals.2
Primary hypoparathyroidism secondary to thyroidectomy. Postsurgical hypoparathyroidism is the most common cause of primary hypoparathyroidism. It results from ischemic injury or accidental removal of the parathyroid glands during anterior neck surgery.3,4 The consequent hypocalcemia can be transient, intermittent, or permanent. Permanent postsurgical hypoparathyroidism is defined as persistent hypocalcemia with insufficient parathyroid hormone (PTH) for more than 12 months after neck surgery; however, some consider 6 months to be enough to define the condition.5–7
The incidence of postsurgical hypoparathyroidism varies considerably with the extent of thyroid surgery and the experience of the surgeon.6,8 In the hands of experienced surgeons, permanent hypoparathyroidism occurs in fewer than 1% of patients after total thyroidectomy, whereas the rate may be higher than 6% with less-experienced surgeons.5,9 Other risk factors for postsurgical hypoparathyroidism include female sex, autoimmune thyroid disease, pregnancy, and lactation.5
Pseudohypoparathyroidism is a group of disorders characterized by renal resistance to PTH, leading to hypocalcemia, hyperphosphatemia, and elevated serum PTH. It is also associated with phenotypic features such as short stature and short fourth metacarpal bones.
Calcitonin deficiency. Calcitonin is a polypeptide hormone secreted from the parafollicular (C) cells of the thyroid gland. After total thyroidectomy, calcitonin levels are expected to be reduced. However, the role of calcitonin in humans is unclear. One study has shown that calcitonin is possibly a vestigial hormone, given that no calcitonin-related disorders (excess or deficiency) have been reported in humans.10
Carpal tunnel syndrome due to hypothyroidism
Our patient also could have primary hypothyroidism as a result of thyroidectomy. Hypothyroidism can cause bilateral hand numbness due to carpal tunnel syndrome, which is mediated by mucopolysaccharide deposition and synovial membrane swelling.11 One study reported that 29% of patients with hypothyroidism had carpal tunnel syndrome.12 Symptoms of carpal tunnel syndrome in hypothyroid patients may occur despite thyroid replacement therapy.13
Carpal tunnel syndrome is a clinical diagnosis. Patients usually experience hand paresthesia in the distribution of the median nerve. Provocative physical tests for carpal tunnel syndrome include the Tinel test, the Phalen test, and the Katz hand diagram, which is considered the best of the 3 tests.14,15 Based on how the patient marks the location and type of symptoms on the diagram, carpal tunnel syndrome is rated as classic, probable, possible, or unlikely (Table 1).14,16,17 The sensitivity of a classic or probable diagram ranges from 64% to 80%, while the specificity ranges from 73% to 90%.14,15
Carpal tunnel syndrome is less likely to be the cause of our patient’s symptoms, as her Katz hand diagram indicates only “possible” carpal tunnel syndrome. Her perioral numbness and positive Trousseau sign make hypocalcemia a more likely cause.
Diabetic peripheral neuropathy
Sensory peripheral neuropathy is a recognized complication of diabetes mellitus. However, neuropathy in diabetic patients most commonly manifests initially as distal symmetrical ascending neuropathy starting in the lower extremities.18 Therefore, diabetic peripheral neuropathy is less likely in this patient since her symptoms are limited to her hands.
Vitamin B12 deficiency
Metformin-induced vitamin B12 deficiency is another possible cause of peripheral neuropathy. It might be secondary to metformin-induced changes in intrinsic factor levels and small-intestine motility with resultant bacterial overgrowth, as well as inhibition of vitamin B12 absorption in the terminal ileum.19
However, metformin-induced vitamin B12 deficiency is not the most likely cause of our patient’s neuropathy, since she has been taking this drug for only 1 year. Vitamin B12 deficiency with consequent peripheral neuropathy is more likely in patients taking metformin in high doses for 10 or more years.20
Laboratory results and electrocardiography
Table 2 shows the patient’s initial laboratory results. Of note, her serum calcium level is 5.7 mg/dL (reference range 8.9–10.1). Electrocardiography in the emergency department shows:
- Prolonged PR interval (23 msec)
- Wide QRS complexes (13 msec)
- Flat T waves
- Prolonged corrected QT interval (475 msec)
- Occasional premature ventricular complexes.
CLINICAL MANIFESTATIONS OF HYPOCALCEMIA
2. Which of the following is not a manifestation of hypocalcemia?
- Tonic-clonic seizures
- Cyanosis
- Cardiac ventricular arrhythmias
- Acute pancreatitis
- Depression
Hypocalcemia can cause a wide range of clinical manifestations (Table 3), the extent and severity of which depend on the severity of hypocalcemia and how quickly it develops. The more acute the hypocalcemia, the more severe the manifestations.21
Tetany can cause seizures
Hypocalcemia is characterized by neuromuscular hyperexcitability, manifested clinically by tetany.22 Manifestations of tetany are numerous and include acral paresthesia, perioral numbness, muscle cramps, carpopedal spasm, and seizures. Tetany is the hallmark of hypocalcemia regardless of etiology. However, certain causes are associated with peculiar clinical manifestations. For example, chronic primary hypoparathyroidism may be associated with basal ganglia calcifications that can result in parkinsonism, other extrapyramidal disorders, and dementia (Table 4).6
Airway spasm can be fatal
A serious manifestation of acute severe hypocalcemia is spasm of the glottis muscles, which may cause cyanosis and, if untreated, death.21
Ventricular arrhythmias
Another potential fatal complication of acute severe hypocalcemia is polymorphic ventricular tachycardia due to prolongation of the QT interval, which is readily identified with electrocardiography.23
Hypocalcemia does not cause pancreatitis
Hypercalcemia, rather than hypocalcemia, may cause acute pancreatitis.24 Conversely, acute pancreatitis may cause hypocalcemia due to precipitation of calcium in the abdominal cavity.25
Psychiatric manifestations
In addition to depression, hypocalcemia is associated with psychiatric manifestations including anxiety, confusion, and emotional instability.
STEPS TO DIAGNOSIS OF HYPOCALCEMIA
First step: Confirm true hypocalcemia
Calcium circulates in the blood in 3 forms: bound to albumin (40% to 45%), bound to anions (10% to 15%), and free (ionized) (45%). Although ionized calcium is the active form, most laboratories report total serum calcium.
Since changes in serum albumin concentration affect the total serum calcium level, it is imperative to correct the measured serum calcium to the serum albumin concentration. Each 1-g/dL decrease in serum albumin lowers the total serum calcium by 0.8 mg/dL. Thus:
Corrected serum calcium (mg/dL) =
measured total serum calcium (mg/dL) +
0.8 (4 − serum albumin [g/dL]).
If the patient’s serum calcium level remains low when corrected for serum albumin, he or she has true hypocalcemia, which implies a low ionized serum calcium. Conversely, pseudohypocalcemia means that the measured calcium level is low but the corrected serum calcium is normal.
Using this formula, our patient’s corrected calcium level is calculated as 5.7 + 0.8 (4 – 3.2) = 6.3 mg/dL, indicating true hypocalcemia.
PHOSPHATE IS OFTEN HIGH WHEN CALCIUM IS LOW
In addition to hypocalcemia, our patient has an elevated phosphate level (Table 2).
3. Which of the following hypocalcemic disorders is not associated with hyperphosphatemia?
- End-stage renal disease
- Primary hypoparathyroidism
- Pseudohypoparathyroidism
- Vitamin D3 deficiency
- Rhabdomyolysis
Vitamin D deficiency is not associated with hyperphosphatemia.
Second step in evaluating hypocalcemia: Check phosphate, magnesium, creatinine
The major causes of hypocalcemia can be categorized according to the serum phosphate level: high vs normal or low (Table 5).
High-phosphate, low-calcium states. In the absence of concurrent end-stage renal disease and an excessive phosphate load, primary hypoparathyroidism is the most likely cause of hypocalcemia associated with hyperphosphatemia.
PTH increases serum ionized calcium by26,27:
- Increasing bone resorption
- Increasing reabsorption of calcium from the distal renal tubules
- Increasing the activity of 1-alpha-hydroxylase, responsible for conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 (the most biologically active vitamin D metabolite); 1,25-dihydroxyvitamin D increases the absorption of calcium and phosphate from the intestine.
Conversely, PTH decreases reabsorption of phosphate from proximal renal tubules, resulting in hypophosphatemia. Therefore, low serum PTH (primary hypoparathyroidism) or a PTH-resistant state (pseudohypoparathyroidism) results in hypocalcemia and hyperphosphatemia.26,27
Both end-stage renal disease and rhabdomyolysis are associated with high serum phosphate levels. The kidney normally excretes excess dietary phosphate to maintain phosphate homeostasis; however, this is impaired in end-stage renal disease, leading to hyperphosphatemia. In rhabdomyolysis, it is mainly the transcellular shift of phosphate into the extracellular space from myocyte injury that raises phosphate levels.
Normal- or low-phosphate, low calcium states. Hypocalcemia can also result from vitamin D deficiency, but this cause is associated with a low or normal serum phosphate level. In such cases, hypocalcemia causes secondary hyperparathyroidism with consequent renal phosphate loss and, thus, hypophosphatemia.27
Third step: Check serum intact PTH and 25-hydroxyvitamin D levels
Hypocalcemia stimulates secretion of PTH. Therefore, hypocalcemia with elevated serum PTH is caused by disorders that do not impair PTH secretion, including chronic renal failure and vitamin D deficiency (Table 5). Conversely, hypocalcemia with low or normal serum PTH levels suggests primary hypoparathyroidism.
Our patient’s serum PTH level is 20 ng/mL, which is within the reference range. This does not discount the diagnosis of primary hypoparathyroidism. Although most patients with primary hypoparathyroidism have low or undetectable serum PTH levels, some have normal PTH levels if some degree of PTH production is preserved.5,7,28–30 In these patients, the remaining functioning parathyroid tissue is not enough to maintain a normal serum calcium level, resulting in hypocalcemia. As a result, hypocalcemia stimulates the remaining parathyroid tissue to its maximum output, producing PTH levels usually within the lower or middle-normal range.30 In such patients, the terms parathyroid insufficiency and relative primary hypoparathyroidism are more precise than primary hypoparathyroidism.
Postsurgical hypoparathyroidism with an inappropriately normal PTH level is usually seen in patients with disorders that impair intestinal calcium absorption or bone resorption.31 In our patient’s case, the “normal” serum PTH level is likely due to maximal stimulation of remaining functioning parathyroid tissue by severe hypocalcemia, which is a result of her discontinuation of calcium and calcitriol therapy and her vitamin D deficiency.
CASE RESUMED: NO RESPONSE TO INTRAVENOUS CALCIUM GLUCONATE
The patient is given 2 10-mL ampules of 10% calcium gluconate diluted in 100 mL of 5% dextrose in water over 20 minutes intravenously. Electrocardiographic monitoring is continued. Two hours later, her measured serum calcium is only 5.8 mg/dL, with no improvement in her symptoms.
A continuous infusion of calcium gluconate is started: 12 ampules of calcium gluconate are added to 380 mL of 5% dextrose in water and infused at 40 mL/hour (infused rate of elemental calcium = 1.3 mg/kg/hour); 3 hours later, her measured serum calcium level is still only 5.8 mg//dL; at 6 hours it is 5.9 mg/dL, and her symptoms have not improved.
4. Which of the following is the most appropriate next step?
- Change the calcium gluconate to calcium chloride
- Increase the infusion rate to 1.5 mg of elemental calcium/kg/hour
- Give a bolus of 2 10-mL ampules of 10% calcium gluconate intravenously over 1 minute
- Give additional oral calcium tablets
- Check the serum magnesium level
Treatment of hypocalcemia can involve intravenous or oral calcium therapy.
Intravenous calcium is indicated for patients with any of the following6,32:
- Moderate to severe neuromuscular irritability (eg, acral paresthesia, carpopedal spasm, prolonged QT interval, seizures, laryngospasm, bronchospasm)
- Acute hypocalcemia with corrected serum calcium level less than 7.6 mg/dL, even if the patient is asymptomatic
- Cardiac failure.
One 10-mL ampule of 10% calcium gluconate contains 93 mg of elemental calcium; 1 or 2 ampules are typically diluted in 50 to 100 mL of 5% dextrose in water and infused slowly over 15 to 20 minutes. Rapid administration of intravenous calcium is contraindicated, as it may produce cardiac arrhythmias and possibly cardiac arrest. Therefore, intravenous calcium should be given slowly while continuing electrocardiographic monitoring.33
Since the effect of 1 ampule of calcium gluconate lasts only 2 to 3 hours, most patients with symptomatic hypocalcemia require continuous intravenous calcium infusion. The recommended dose of infused elemental calcium is 0.5 to 1.5 mg/kg/hour.34 Several ampules are added to 500 to 1,000 mL of 5% dextrose in water or 0.9% normal saline and infused at a rate appropriate for the patient’s corrected calcium and symptoms.
Oral calcium and vitamin D supplements can be given initially to patients with a corrected serum calcium level of 7.6 mg/dL or greater, with or without mild symptoms, if they can tolerate oral intake. However, this is not the treatment of choice for resistant acute hypocalcemia, as in this case.
Calcium chloride has no advantages over calcium gluconate. Further, it can be associated with local irritation and may result in tissue necrosis if extravasation occurs.35
Increasing the infusion rate of calcium gluconate to the maximum recommended dose may improve the patient’s ionized calcium level and symptoms somewhat. However, it is not the best option for this patient, given that she did not respond to 2 ampules of calcium gluconate followed by continuous infusion of 1.3 mg/kg/hour for 6 hours.
Calcium gluconate bolus. Similarly, giving the patient an additional 2 ampules of calcium gluconate over 1 minute would not be recommended, as rapid administration of intravenous calcium gluconate (eg, over 1 minute) is contraindicated.
Check magnesium
If hypocalcemia persists despite intravenous calcium therapy, as in our patient, further investigation or action is required. An important cause of persistent hypocalcemia is severe hypomagnesemia. Severe hypomagnesemia (serum magnesium < 0.8 mg/dL) causes resistant hypocalcemia by several mechanisms:
- Inducing PTH resistance32,36,37
- Decreasing PTH secretion32,36
- Decreasing calcitriol production.
The decrease in calcitriol production is a direct effect of hypomagnesemia, but it is also an indirect effect of low PTH secretion, which inhibits the enzyme 1-alpha-hydroxylase. Thus, conversion of 25-hydroxyvitamin D3 to calcitriol is impaired, leading to low calcitriol production.
Our patient could have hypomagnesemia due to furosemide use and uncontrolled diabetes mellitus. Hypocalcemia resistant to calcium therapy may occasionally respond to magnesium therapy even if the serum magnesium level is normal. This may be due to depleted intracellular magnesium salt levels.6,38 Rarely, severe hypermagnesemia can also be associated with hypocalcemia due to inhibition of PTH secretion.37,39
CASE RESUMED
Our patient’s serum magnesium level is 0.6 mg/dL (reference range 1.7–2.4 mg/dL). She is given 2 g of magnesium sulfate in 60 mL of 0.9% normal saline infused over 1 hour, followed by a continuous infusion of magnesium sulfate (12 g diluted in 250 mL of 0.9% normal saline, infused over 24 hours). On repeat testing 4 hours later, her serum magnesium level is 0.7 mg/dL, and at 8 hours later it is 0.9 mg/dL. She is subsequently started on oral magnesium oxide 600 mg per day. The magnesium sulfate infusion is continued for another 24 hours.
PREVENTING HYPERCALCIURIA
Patients with low PTH (primary hypoparathyroidism) may have hypercalciuria due to decreased renal tubular calcium reabsorption. Two important measures can minimize hypercalciuria in such patients:
- Keeping the serum calcium level in the low-normal range4,5,40
- Giving a thiazide diuretic (eg, hydrochlorothiazide 12.5–50 mg daily) with a low-salt diet.41,42
A thiazide diuretic is usually started once the 24-hour urine calcium reaches 250 mg.6 Thiazides are thought to enhance both proximal and distal renal tubular calcium reabsorption.43,44
PRIMARY HYPOPARATHYROIDISM: LONG-TERM MANAGEMENT
Long-term management of primary hypoparathyroidism requires calcium and vitamin D supplementation.
Calcium supplements. The most commonly prescribed calcium preparations are calcium carbonate and calcium citrate (containing 40% and 20% elemental calcium, respectively). Calcium carbonate, which is less expensive than calcium citrate, binds with phosphate intake and requires an acidic environment for absorption, and so it is better absorbed when taken with meals. Because calcium citrate does not require an acidic environment for absorption, it is the calcium preparation of choice for patients on proton pump inhibitors, or patients with achlorhydria or constipation.45 Calcium doses vary widely, with most hypoparathyroid patients requiring 1 to 2 g of elemental calcium daily.6
Vitamin D supplements. To promote intestinal absorption, calcium is combined with vitamin D in a fixed-dose preparation given in divided doses.46 Calcitriol (1,25-dihydroxyvitamin D3) is the most active metabolite of vitamin D, with rapid onset and offset of action, and it is the preferred form of vitamin D therapy for patients with hypoparathyroidism. If calcitriol is not available or is not affordable, alphacalcidol (1-alpha-hydroxyvitamin D3) is another option. This is a synthetic analogue of vitamin D that is already hyroxylated at the C1 position. After oral intake, it is hydroxylated in the liver to form calcitriol.
Since renal production of calcitriol is PTH-dependent, in hypoparathyroidism the conversion of 25-hydroxyvitamin D3 to calcitriol is limited. Therefore, vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol) are not the preferred forms of vitamin D for such patients. However, either can be added to calcitriol, as they may have extraskeletal benefits.7
CASE CONCLUDED
Our patient presented with primary parathyroid insufficiency associated with vitamin D deficiency. Therefore, in addition to calcitriol and calcium combined with vitamin D in a fixed-dose preparation, her management included vitamin D3 for her vitamin D deficiency.
She was discharged on these medications. At a follow-up visit 3 weeks later, her measured serum calcium level was 8.6 mg/dL. She reported gradual resolution of her symptoms. She was also referred to a psychiatrist for her depression.
TAKE-HOME POINTS
- Hypocalcemia causes neuromuscular excitability, manifested clinically by tetany.
- Common causes of hypocalcemia include vitamin D deficiency, hypomagnesemia, renal failure, and primary hypoparathyroidism.
- The first step in evaluating hypocalcemia is to correct the measured serum calcium to the serum albumin concentration.
- Laboratory testing for hypocalcemia should include serum phosphorus, magnesium, creatinine, PTH, and 25-hydroxyvitamin D3.
- Primary hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, and low serum PTH.
- Moderate to severe manifestations of hypo-
calcemia and acute hypocalcemia (< 7.6 mg/dL), even if asymptomatic, warrant intravenous calcium therapy. - Correction of hypomagnesemia is essential to treat hypocalcemia, especially if resistant to intravenous calcium therapy.
- The goal of chronic management of primary hypoparathyroidism includes correcting the serum calcium level to a low-normal range, the serum phosphorus level to an upper-normal range, and prevention of hypercalciuria.
Acknowledgments: The authors wish to thank Mr. Michael Edward Tierney of the School of Medicine, University of Sydney, Australia, for his linguistic editing of the manuscript.
- Jesus JE, Landry A. Images in clinical medicine. Chvostek’s and Trousseau’s signs. N Engl J Med 2012; 367:e15.
- Urbano FL. Signs of hypocalcemia: Chvostek’s and Trousseau’s. Hosp Physician 2000; 36:43–45.
- Chisthi MM, Nair RS, Kuttanchettiyar KG, Yadev I. Mechanisms behind post-thyroidectomy hypocalcemia: interplay of calcitonin, parathormone, and albumin—a prospective study. J Invest Surg 2017; 30:217–225.
- Shoback DM, Bilezikian JP, Costa AG, et al. Presentation of hypoparathyroidism: etiologies and clinical features. J Clin Endocrinol Metab 2016; 101:2300–2312.
- Stack BC Jr, Bimston DN, Bodenner DL, et al. American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review: postoperative hypoparathyroidism—definitions and management. Endocr Pract 2015; 21:674–685.
- Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med 2008; 359:391–403.
- Abate EG, Clarke BL. Review of hypoparathyroidism. Front Endocrinol (Lausanne) 2017; 7:172.
- Coimbra C, Monteiro F, Oliveira P, Ribeiro L, de Almeida MG, Condé A. Hypoparathyroidism following thyroidectomy: predictive factors. Acta Otorrinolaringol Esp 2017; 68:106–111.
- Thomusch O, Machens A, Sekulla C, Ukkat J, Brauckhoff M, Dralle H. The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: a multivariate analysis of 5846 consecutive patients. Surgery 2003; 133:180–185.
- Hirsch PF, Lester GE, Talmage RV. Calcitonin, an enigmatic hormone: does it have a function? J Musculoskelet Neuronal Interact 2001; 1:299–305.
- Karne SS, Bhalerao NS. Carpal tunnel syndrome in hypothyroidism. J Clin Diagn Res 2016; 10:OC36–OC38.
- Duyff RF, Van den Bosch J, Laman DM, van Loon BJ, Linssen WH. Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry 2000; 68:750–755.
- Palumbo CF, Szabo RM, Olmsted SL. The effects of hypothyroidism and thyroid replacement on the development of carpal tunnel syndrome. J Hand Surg Am 2000; 25:734–739.
- Katz JN, Stirrat CR, Larson MG, Fossel AH, Eaton HM, Liang MH. A self-administered hand symptom diagram for the diagnosis and epidemiologic study of carpal tunnel syndrome. J Rheumatol 1990; 17:1495–1498.
- Katz JN, Stirrat CR. A self-administered hand diagram for the diagnosis of carpal tunnel syndrome. J Hand Surg Am 1990; 15:360–363.
- Calfee RP, Dale AM, Ryan D, Descatha A, Franzblau A, Evanoff B. Performance of simplified scoring systems for hand diagrams in carpal tunnel syndrome screening. J Hand Surg Am 2012; 37:10–17.
- D’Arcy CA, McGee S. The rational clinical examination. Does this patient have carpal tunnel syndrome? JAMA 2000; 283:3110–3117.
- Marchettini P, Lacerenza M, Mauri E, Marangoni C. Painful peripheral neuropathies. Curr Neuropharmacol 2006; 4:175–181.
- Kibirige D, Mwebaze R. Vitamin B12 deficiency among patients with diabetes mellitus: is routine screening and supplementation justified? J Diabetes Metab Disord 2013;12:17.
- Akinlade KS, Agbebaku SO, Rahamon SK, Balogun WO. Vitamin B12 levels in patients with type 2 diabetes mellitus on metformin. Ann Ib Postgrad Med 2015; 13:79–83.
- Tohme JF, Bilezikian JP. Hypocalcemic emergencies. Endocrinol Metab Clin North Am 1993; 22:363–375.
- Macefield G, Burke D. Paraesthesiae and tetany induced by voluntary hyperventilation. Increased excitability of human cutaneous and motor axons. Brain 1991; 114:527–540.
- Benoit SR, Mendelsohn AB, Nourjah P, Staffa JA, Graham DJ. Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey. Eur J Cardiovasc Prev Rehabil 2005; 12:363–368.
- Khoo TK, Vege SS, Abu-Lebdeh HS, Ryu E, Nadeem S, Wermers RA. Acute pancreatitis in primary hyperparathyroidism: a population-based study. J Clin Endocrinol Metab 2009; 94:2115–2118.
- McKay C, Beastall GH, Imrie CW, Baxter JN. Circulating intact parathyroid hormone levels in acute pancreatitis. Br J Surg 1994; 81:357–360.
- Talmage RV, Mobley HT. Calcium homeostasis: reassessment of the actions of parathyroid hormone. Gen Comp Endocrinol 2008; 156:1–8.
- Friedman PA, Gesek FA. Calcium transport in renal epithelial cells. Am J Physiol 1993; 264:F181–F198.
- Jensen PV, Jelstrup SM, Homøe P. Long-term outcomes after total thyroidectomy. Dan Med J 2015; 62:A5156.
- Ritter K, Elfenbein D, Schneider DF, Chen H, Sippel RS. Hypoparathyroidism after total thyroidectomy: incidence and resolution. J Surg Res 2015; 197:348–353.
- Promberger R, Ott J, Kober F, Karik M, Freissmuth M, Hermann M. Normal parathyroid hormone levels do not exclude permanent hypoparathyroidism after thyroidectomy. Thyroid 2011; 21:145–150.
- Lorente-Poch L, Sancho JJ, Muñoz-Nova JL, Sánchez-Velázquez P, Sitges-Serra A. Defining the syndromes of parathyroid failure after total thyroidectomy. Gland Surgery 2015; 4:82–90.
- Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ 2008; 336:1298–1302.
- Tohme JF, Bilezikian JP. Diagnosis and treatment of hypocalcemic emergencies. Endocrinologist 1996; 6:10–18.
- Carroll R, Matfin G. Endocrine and metabolic emergencies: hypocalcaemia. Ther Adv Endocrinol Metab 2010; 1:29–33.
- Kim MP, Raho VJ, Mak J, Kaynar AM. Skin and soft tissue necrosis from calcium chloride in a deicer. J Emerg Med 2007; 32:41–44.
- Tong GM, Rude RK. Magnesium deficiency in critical illness. J Intensive Care Med 2005; 20:3–17.
- Cholst IN, Steinberg SF, Tropper PJ, Fox HE, Segre GV, Bilezikian JP. The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 1984; 310:1221–1225.
- Ryzen E, Nelson TA, Rude RK. Low blood mononuclear cell magnesium content and hypocalcemia in normomagnesemic patients. West J Med 1987; 147:549–553.
- Koontz SL, Friedman SA, Schwartz ML. Symptomatic hypocalcemia after tocolytic therapy with magnesium sulfate and nifedipine. Am J Obstet Gynecol 2004; 190:1773–1776.
- Brandi ML, Bilezikian JP, Shoback D, et al. Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab 2016; 101:2273–2283.
- Porter RH, Cox BG, Heaney D, Hostetter TH, Stinebaugh BJ, Suki WN. Treatment of hypoparathyroid patients with chlorthalidone. N Engl J Med 1978; 298:577–581.
- Clarke BL, Brown EM, Collins MT, et al. Epidemiology and diagnosis of hypoparathyroidism. J Clin Endocrinol Metab 2016; 101:2284–2299.
- Nijenhuis T, Vallon V, van der Kemp AW, Loffing J, Hoenderop JG, Bindels RJ. Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest 2005; 115:1651–1658.
- Costanzo LS. Localization of diuretic action in microperfused rat distal tubules: Ca and Na transport. Am J Physiol 1985; 248:F527–F535.
- Brandi ML, Bilezikian JP, Shoback D, et al. Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab 2016; 101:2273–2283.
- Scotti A, Bianchini C, Abbiati G, Marzo A. Absorption of calcium administered alone or in fixed combination with vitamin D to healthy volunteers. Arzneimittelforschung 2001; 51:493–500.
- Jesus JE, Landry A. Images in clinical medicine. Chvostek’s and Trousseau’s signs. N Engl J Med 2012; 367:e15.
- Urbano FL. Signs of hypocalcemia: Chvostek’s and Trousseau’s. Hosp Physician 2000; 36:43–45.
- Chisthi MM, Nair RS, Kuttanchettiyar KG, Yadev I. Mechanisms behind post-thyroidectomy hypocalcemia: interplay of calcitonin, parathormone, and albumin—a prospective study. J Invest Surg 2017; 30:217–225.
- Shoback DM, Bilezikian JP, Costa AG, et al. Presentation of hypoparathyroidism: etiologies and clinical features. J Clin Endocrinol Metab 2016; 101:2300–2312.
- Stack BC Jr, Bimston DN, Bodenner DL, et al. American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review: postoperative hypoparathyroidism—definitions and management. Endocr Pract 2015; 21:674–685.
- Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med 2008; 359:391–403.
- Abate EG, Clarke BL. Review of hypoparathyroidism. Front Endocrinol (Lausanne) 2017; 7:172.
- Coimbra C, Monteiro F, Oliveira P, Ribeiro L, de Almeida MG, Condé A. Hypoparathyroidism following thyroidectomy: predictive factors. Acta Otorrinolaringol Esp 2017; 68:106–111.
- Thomusch O, Machens A, Sekulla C, Ukkat J, Brauckhoff M, Dralle H. The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: a multivariate analysis of 5846 consecutive patients. Surgery 2003; 133:180–185.
- Hirsch PF, Lester GE, Talmage RV. Calcitonin, an enigmatic hormone: does it have a function? J Musculoskelet Neuronal Interact 2001; 1:299–305.
- Karne SS, Bhalerao NS. Carpal tunnel syndrome in hypothyroidism. J Clin Diagn Res 2016; 10:OC36–OC38.
- Duyff RF, Van den Bosch J, Laman DM, van Loon BJ, Linssen WH. Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry 2000; 68:750–755.
- Palumbo CF, Szabo RM, Olmsted SL. The effects of hypothyroidism and thyroid replacement on the development of carpal tunnel syndrome. J Hand Surg Am 2000; 25:734–739.
- Katz JN, Stirrat CR, Larson MG, Fossel AH, Eaton HM, Liang MH. A self-administered hand symptom diagram for the diagnosis and epidemiologic study of carpal tunnel syndrome. J Rheumatol 1990; 17:1495–1498.
- Katz JN, Stirrat CR. A self-administered hand diagram for the diagnosis of carpal tunnel syndrome. J Hand Surg Am 1990; 15:360–363.
- Calfee RP, Dale AM, Ryan D, Descatha A, Franzblau A, Evanoff B. Performance of simplified scoring systems for hand diagrams in carpal tunnel syndrome screening. J Hand Surg Am 2012; 37:10–17.
- D’Arcy CA, McGee S. The rational clinical examination. Does this patient have carpal tunnel syndrome? JAMA 2000; 283:3110–3117.
- Marchettini P, Lacerenza M, Mauri E, Marangoni C. Painful peripheral neuropathies. Curr Neuropharmacol 2006; 4:175–181.
- Kibirige D, Mwebaze R. Vitamin B12 deficiency among patients with diabetes mellitus: is routine screening and supplementation justified? J Diabetes Metab Disord 2013;12:17.
- Akinlade KS, Agbebaku SO, Rahamon SK, Balogun WO. Vitamin B12 levels in patients with type 2 diabetes mellitus on metformin. Ann Ib Postgrad Med 2015; 13:79–83.
- Tohme JF, Bilezikian JP. Hypocalcemic emergencies. Endocrinol Metab Clin North Am 1993; 22:363–375.
- Macefield G, Burke D. Paraesthesiae and tetany induced by voluntary hyperventilation. Increased excitability of human cutaneous and motor axons. Brain 1991; 114:527–540.
- Benoit SR, Mendelsohn AB, Nourjah P, Staffa JA, Graham DJ. Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey. Eur J Cardiovasc Prev Rehabil 2005; 12:363–368.
- Khoo TK, Vege SS, Abu-Lebdeh HS, Ryu E, Nadeem S, Wermers RA. Acute pancreatitis in primary hyperparathyroidism: a population-based study. J Clin Endocrinol Metab 2009; 94:2115–2118.
- McKay C, Beastall GH, Imrie CW, Baxter JN. Circulating intact parathyroid hormone levels in acute pancreatitis. Br J Surg 1994; 81:357–360.
- Talmage RV, Mobley HT. Calcium homeostasis: reassessment of the actions of parathyroid hormone. Gen Comp Endocrinol 2008; 156:1–8.
- Friedman PA, Gesek FA. Calcium transport in renal epithelial cells. Am J Physiol 1993; 264:F181–F198.
- Jensen PV, Jelstrup SM, Homøe P. Long-term outcomes after total thyroidectomy. Dan Med J 2015; 62:A5156.
- Ritter K, Elfenbein D, Schneider DF, Chen H, Sippel RS. Hypoparathyroidism after total thyroidectomy: incidence and resolution. J Surg Res 2015; 197:348–353.
- Promberger R, Ott J, Kober F, Karik M, Freissmuth M, Hermann M. Normal parathyroid hormone levels do not exclude permanent hypoparathyroidism after thyroidectomy. Thyroid 2011; 21:145–150.
- Lorente-Poch L, Sancho JJ, Muñoz-Nova JL, Sánchez-Velázquez P, Sitges-Serra A. Defining the syndromes of parathyroid failure after total thyroidectomy. Gland Surgery 2015; 4:82–90.
- Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ 2008; 336:1298–1302.
- Tohme JF, Bilezikian JP. Diagnosis and treatment of hypocalcemic emergencies. Endocrinologist 1996; 6:10–18.
- Carroll R, Matfin G. Endocrine and metabolic emergencies: hypocalcaemia. Ther Adv Endocrinol Metab 2010; 1:29–33.
- Kim MP, Raho VJ, Mak J, Kaynar AM. Skin and soft tissue necrosis from calcium chloride in a deicer. J Emerg Med 2007; 32:41–44.
- Tong GM, Rude RK. Magnesium deficiency in critical illness. J Intensive Care Med 2005; 20:3–17.
- Cholst IN, Steinberg SF, Tropper PJ, Fox HE, Segre GV, Bilezikian JP. The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 1984; 310:1221–1225.
- Ryzen E, Nelson TA, Rude RK. Low blood mononuclear cell magnesium content and hypocalcemia in normomagnesemic patients. West J Med 1987; 147:549–553.
- Koontz SL, Friedman SA, Schwartz ML. Symptomatic hypocalcemia after tocolytic therapy with magnesium sulfate and nifedipine. Am J Obstet Gynecol 2004; 190:1773–1776.
- Brandi ML, Bilezikian JP, Shoback D, et al. Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab 2016; 101:2273–2283.
- Porter RH, Cox BG, Heaney D, Hostetter TH, Stinebaugh BJ, Suki WN. Treatment of hypoparathyroid patients with chlorthalidone. N Engl J Med 1978; 298:577–581.
- Clarke BL, Brown EM, Collins MT, et al. Epidemiology and diagnosis of hypoparathyroidism. J Clin Endocrinol Metab 2016; 101:2284–2299.
- Nijenhuis T, Vallon V, van der Kemp AW, Loffing J, Hoenderop JG, Bindels RJ. Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest 2005; 115:1651–1658.
- Costanzo LS. Localization of diuretic action in microperfused rat distal tubules: Ca and Na transport. Am J Physiol 1985; 248:F527–F535.
- Brandi ML, Bilezikian JP, Shoback D, et al. Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab 2016; 101:2273–2283.
- Scotti A, Bianchini C, Abbiati G, Marzo A. Absorption of calcium administered alone or in fixed combination with vitamin D to healthy volunteers. Arzneimittelforschung 2001; 51:493–500.