Nephrology

A  44-year-old woman was admitted to the  hospital for the second time in 2 months with acute onset of severe abdominal pain. She had a history of cervical cancer treated with total hysterectomy with bilateral salpingo-oophorectomy, chemotherapy, and radiotherapy at age 38.

LONG-TERM EFFECTS OF RADIATION ON THE BLADDER

Urinary ascites from intraperitoneal urine leakage is a rare but clinically important sequel to bladder fistula or bladder wall rupture. Fistula or rupture can be caused by pelvic irradiation, blunt trauma, or surgical procedures, but may also be spontaneous.²

When the total radiation dose to the bladder exceeds 60 Gy, radiation cystitis may occur, leading to bladder fistula.³ Effects of radiation on the bladder are usually seen within 2 to 4 years³ but may occur long after the completion of radiation therapy—10 years² or even 30 to 40 years later.⁴ Therefore, ascites of unknown origin in a patient with a history of pelvic radiation therapy should lead to an evaluation for late radiation cystitis and urinary ascites from bladder rupture.

A  44-year-old woman was admitted to the  hospital for the second time in 2 months with acute onset of severe abdominal pain. She had a history of cervical cancer treated with total hysterectomy with bilateral salpingo-oophorectomy, chemotherapy, and radiotherapy at age 38.

LONG-TERM EFFECTS OF RADIATION ON THE BLADDER

Urinary ascites from intraperitoneal urine leakage is a rare but clinically important sequel to bladder fistula or bladder wall rupture. Fistula or rupture can be caused by pelvic irradiation, blunt trauma, or surgical procedures, but may also be spontaneous.²

When the total radiation dose to the bladder exceeds 60 Gy, radiation cystitis may occur, leading to bladder fistula.³ Effects of radiation on the bladder are usually seen within 2 to 4 years³ but may occur long after the completion of radiation therapy—10 years² or even 30 to 40 years later.⁴ Therefore, ascites of unknown origin in a patient with a history of pelvic radiation therapy should lead to an evaluation for late radiation cystitis and urinary ascites from bladder rupture.

A  44-year-old woman was admitted to the  hospital for the second time in 2 months with acute onset of severe abdominal pain. She had a history of cervical cancer treated with total hysterectomy with bilateral salpingo-oophorectomy, chemotherapy, and radiotherapy at age 38.

LONG-TERM EFFECTS OF RADIATION ON THE BLADDER

Urinary ascites from intraperitoneal urine leakage is a rare but clinically important sequel to bladder fistula or bladder wall rupture. Fistula or rupture can be caused by pelvic irradiation, blunt trauma, or surgical procedures, but may also be spontaneous.²

When the total radiation dose to the bladder exceeds 60 Gy, radiation cystitis may occur, leading to bladder fistula.³ Effects of radiation on the bladder are usually seen within 2 to 4 years³ but may occur long after the completion of radiation therapy—10 years² or even 30 to 40 years later.⁴ Therefore, ascites of unknown origin in a patient with a history of pelvic radiation therapy should lead to an evaluation for late radiation cystitis and urinary ascites from bladder rupture.

Case

A 55-year-old woman with diabetes, hypertension, and chronic kidney disease (CKD) stage 4 is admitted to the hospital for treatment of left lower-extremity cellulitis. Laboratory studies on admission show a creatinine level of 2.5 mg/dL (glomerular filtration rate [GFR] is 20 mL/min per 1.73 m²; baseline creatinine is between 2.2 and 2.6 mg/dL), potassium level of 3.0 mEq/L, magnesium level of 1.5 mEq/L, bicarbonate level of 18 mEq/L, phosphate level of 6.5 mg/dL, and calcium level of 7.5 mg/dL.

She is put on renally dosed vancomycin to treat her cellulitis. As the hospitalist, how should you manage her multiple electrolyte abnormalities?
 

Overview of the issue

CKD is also an important risk factor for acute kidney injury. Additionally, rates of readmission for CKD patients are higher than those without CKD. Given that CKD is a “silent disease” that many patients do not realize they have, it is very possible that the first documentation of CKD could happen during an acute hospitalization.

Among the various manifestations of CKD, electrolyte abnormalities are the most likely ones hospitalists will run into.
 

Overview of the data

Hypokalemia and Hypomagnesemia

Hypokalemia (potassium levels less than 3.5 mEq/L) is not as common as hyperkalemia (potassium levels greater than 5.0 mEq/L) in CKD, which is the result of impaired renal excretion of potassium. Hypokalemia can occur as a result of GI losses, urinary losses, or decreased intake and can be worsened by the use of certain drugs, such as non–K-sparing diuretics.

In the setting of diuretic use involving thiazides and loop diuretics, hypokalemia is dose and sodium-intake dependent. Potassium deficiency worsens the effects of detrimental sodium excess, which plays a role in hypertension and its associated complications. Potassium also has a protective vascular effect, which is a major reason why potassium should be kept normal in patients with CKD.

Acutely, hypokalemia can cause arrhythmias, ileus, and paralysis, which are all indications for immediate repletion. In these cases, hypokalemia must be repleted carefully in small increments (some suggest 20 mEq doses), and the patient must be monitored frequently to avoid hyperkalemia. If patients are persistently hypokalemic, several options can be considered based on the underlying cause. Dietary modifications with foods rich in potassium (containing 250mg/100g) can be suggested. Daily potassium chloride supplementation can be used in those on diuretic therapy who have hypokalemia and metabolic alkalosis (bicarbonate levels greater than 30 mEq/L). Alkalinizing salts, containing citrate or bicarbonate, can be used in hypokalemia without metabolic alkalosis. Initiation of angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-adrenergic blockers, and K-sparing diuretics can be used as well.

Potassium supplementation and K-sparing diuretics should be used with extreme caution in CKD 3 and 4 given the risk of overcorrection. If potassium supplements or drugs to raise serum potassium are initiated in house, potassium should be rechecked within a week. These treatments should be avoided in individuals with diabetes, who are at highest risk for hyperkalemia given hyporeninemic hypoaldosteronism (type IV renal tubular acidosis).

Metabolic acidosis

Acid-base balance is maintained by the kidney through urinary excretion of hydrogen ions both as titratable acids and ammonium. In CKD, renal excretion of the daily acid load is impaired, primarily from decreased ammonium excretion caused by there being too few functioning nephrons.

Metabolic acidosis in CKD is defined as a serum bicarbonate concentration of persistently less than 22 mEq/L. The overall prevalence of metabolic acidosis in cases of CKD that don’t require dialysis is about 15% and increases linearly with a decline in GFR. In the Chronic Renal Insufficiency Cohort study, 7%, 13%, and 37% of participants with CKD stages 2, 3, and 4 respectively had metabolic acidosis.

Metabolic acidosis has a variety of adverse outcomes, including bone demineralization, increased protein catabolism and muscle wasting, impaired cardiac function, impaired glucose homeostasis, and systemic inflammation. Additionally, multiple studies have shown an association between metabolic acidosis and progression of CKD and increased mortality.

The 2013 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend maintaining the serum bicarbonate level within the reference range (23-29 mEq/L) with alkali therapy. Options include sodium bicarbonate or sodium citrate (which is rapidly metabolized to bicarbonate) in doses of 0.5-1.0 mEq/kg once per day. Sodium bicarbonate is inexpensive; however, it can lead to gastrointestinal upset as the bicarbonate is converted into CO₂ in the stomach. This side effect is usually self-limited and improves with time. Typical starting doses are 650 mg twice a day if the serum bicarbonate level is 19-21 mEq/L or 1300 mg twice a day if the serum bicarbonate level is less than or equal to 18 mEq/L.

Sodium citrate can be used if gastrointestinal upset occurs, although caution should be used in those on aluminum binders or with liver disease. Alkali treatment should be started when bicarbonate levels are persistently low (for weeks or months) or if very low (less than or equal to 18 mEq/L) without an acute reversible cause. After patients have begun therapy, they should be monitored for the development of worsening hypertension or edema caused by sodium-mediated fluid retention, although this rarely occurs.
 

Hyperphosphatemia and Hypocalcemia

Hyperphosphatemia (phosphate levels greater than 4.6 mg/dL) develops early in CKD because of a reduced filtered-phosphate load. Hypocalcemia and hyperphosphatemia can lead to secondary hyperparathyroidism. Given that hyperphosphatemia has been associated with an increased mortality among patients with CKD, treatment is warranted, but the optimal phosphorus range is unknown. According to the KDIGO guidelines, the goal phosphorus level is less than 4.5 mg/dL in patients with CKD who are not on dialysis.

Treatment includes dietary restriction to 900 mg/day and phosphate binders. There is a high phosphate load in processed foods and colas because of food additives. It is therefore recommended to reduce consumption of these foods while encouraging consumption of meat and eggs, which offer additional nutritional value. Those who have failed dietary restrictions should be put on a phosphate binder, either calcium containing (calcium carbonate, calcium acetate) or non–calcium containing (Sevelamer, lanthanum). Non–calcium-containing binders are recommended for patients with hypercalcemia (levels greater than 9.5 mg/dL). There is some data that suggests that non–calcium-containing binders are superior to calcium-containing binders in terms of vascular disease outcomes, but non–calcium-containing binders are sometimes difficult to obtain because of cost and insurance coverage.

Hypocalcemia (calcium levels below 8.4 mg/dL) occurs in the setting of late stage untreated CKD because of decreased GI uptake of calcium from diet in the context of vitamin D deficiency (less than 30 ng/mL) in addition to hyperphosphatemia. Phosphate and vitamin D correction is preferred to calcium supplementation because hyperphosphatemia and vitamin D deficiency occur earlier in CKD. Phosphate reduction is described above.

Regarding vitamin D deficiency, it is recommended to start supplementation with either vitamin D2 or D3. Doses should be adjusted if GFR is less than 30 mL/min per 1.73 m². It is important to monitor for hypercalcemia, which can also occur in CKD in this context, because it has also been associated with increased morbidity and mortality. If calcium levels are greater than 10.2 mg/dL, all vitamin D supplementation should be discontinued.
 

Back to the case

Our patient who was admitted for cellulitis has concomitant hypokalemia, hypomagnesemia, acidosis, and hyperphosphatemia with related hypocalcemia. She revealed that her diet was poor prior to her admission for her infection. She was given 20 mEq of potassium orally and placed on a potassium rich diet until potassium levels normalized. She was also given magnesium oxide orally on the first and second day of admission, with repeat levels that were normal. Her acidosis was treated with sodium bicarbonate – 1,300 mg orally twice daily. For her hyperphosphatemia and hypocalcemia, she was placed on phosphate restriction with nutritional counseling with plans to follow up as an outpatient to determine need for phosphate binders. In addition, vitamin D levels were checked, and she was started on repletion for vitamin D deficiency (27 ng/mL). Daily BMP, magnesium, and phosphorus were checked while in house until they were normal for 2 days, and follow-up lab work was requested with her nephrology appointment, which was scheduled for within 1 week.

Bottom line

Electrolyte abnormalities in CKD are numerous and have multiple adverse clinical outcomes. Early intervention and management, especially of metabolic acidosis and hyperphosphatemia, can have a significant effect, including prevention of progression of CKD and possibly reduced mortality.

Dr. Daya, Dr. Apgar, and Dr. Eniasivam are assistant clinical professors in the division of hospital medicine at the University of California, San Francisco.

References

1. Coresh J et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007 Nov 7;298(17):2038-47.

2. Dhondup T et al. Electrolyte and acid-base disorders in chronic kidney disease and end-stage kidney failure. Blood Purif. 2017;43(1-3):179-188.

3. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004 May;43(5 Suppl 1):S1-290.

4. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl (2011). 2013 Jan;3(1):1–150.

5. Sakaguchi Y et al. Hypomagnesemia in type 2 diabetic nephropathy: A novel predictor of end-stage renal disease. Diabetes Care. 2012 Jul;35(7):1591-7.

6. Palmer SC et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: A systematic review and meta-analysis. JAMA. 2011 Mar 16;305(11):1119-27.

7. Patel L et al. Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: A meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol. 2016 Feb 5;11(2):232-44.

8. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.

9. Raphael KL et al. Prevalence of and risk factors for reduced serum bicarbonate in chronic kidney disease. Nephrology (Carlton). 2014 Oct;19(10):648-54.

Additional reading

1. Chapter 3: Management of Progression and Complications of CKD. Kidney Int Suppl (2011). 2013 Jan:3(1):73-90.

2. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.

Quiz

A 75-year-old male with hypertension and CKD Stage 4 is admitted to the hospital for a hip fracture following a fall. Laboratory studies on admission show a potassium level of 3.2 mEq/L, vitamin D level of 45 ng/mL, bicarbonate level of 17 mEq/L, phosphate level of 5.0 mg/dL, and calcium level of 10.3 mg/dL.

What electrolyte replacements should be initiated?

A. Dietary restriction of phosphate, sodium bicarbonate, potassium chloride, and vitamin D.

B. Non–calcium-containing phosphate binder, vitamin D, and potassium chloride.

C. Calcium-containing phosphate binder and sodium bicarbonate.

D. Non–calcium-containing phosphate binder, sodium bicarbonate, and potassium chloride.

Answer: D. Given the patient’s hypokalemia, potassium supplementation should be considered. Additionally, given his hyperphosphatemia and hypercalcemia, a non–calcium-containing phosphate binder like Sevelamer should be started. His metabolic acidosis should be corrected with sodium bicarbonate. There is no indication to supplement vitamin D based on his current lab values.
 

Key Points

• Identify and treat underlying causes of hypokalemia and hypomagnesemia.
• Do not hesitate to treat metabolic acidosis in CKD.
• Manage hyperphosphatemia and hypocalcemia by ordering appropriate lab studies and providing nutritional consultation with outpatient nephrology follow-up as indicated.

Case

A 55-year-old woman with diabetes, hypertension, and chronic kidney disease (CKD) stage 4 is admitted to the hospital for treatment of left lower-extremity cellulitis. Laboratory studies on admission show a creatinine level of 2.5 mg/dL (glomerular filtration rate [GFR] is 20 mL/min per 1.73 m²; baseline creatinine is between 2.2 and 2.6 mg/dL), potassium level of 3.0 mEq/L, magnesium level of 1.5 mEq/L, bicarbonate level of 18 mEq/L, phosphate level of 6.5 mg/dL, and calcium level of 7.5 mg/dL.

She is put on renally dosed vancomycin to treat her cellulitis. As the hospitalist, how should you manage her multiple electrolyte abnormalities?
 

Overview of the issue

CKD is also an important risk factor for acute kidney injury. Additionally, rates of readmission for CKD patients are higher than those without CKD. Given that CKD is a “silent disease” that many patients do not realize they have, it is very possible that the first documentation of CKD could happen during an acute hospitalization.

Among the various manifestations of CKD, electrolyte abnormalities are the most likely ones hospitalists will run into.
 

Overview of the data

Hypokalemia and Hypomagnesemia

Hypokalemia (potassium levels less than 3.5 mEq/L) is not as common as hyperkalemia (potassium levels greater than 5.0 mEq/L) in CKD, which is the result of impaired renal excretion of potassium. Hypokalemia can occur as a result of GI losses, urinary losses, or decreased intake and can be worsened by the use of certain drugs, such as non–K-sparing diuretics.

In the setting of diuretic use involving thiazides and loop diuretics, hypokalemia is dose and sodium-intake dependent. Potassium deficiency worsens the effects of detrimental sodium excess, which plays a role in hypertension and its associated complications. Potassium also has a protective vascular effect, which is a major reason why potassium should be kept normal in patients with CKD.

Acutely, hypokalemia can cause arrhythmias, ileus, and paralysis, which are all indications for immediate repletion. In these cases, hypokalemia must be repleted carefully in small increments (some suggest 20 mEq doses), and the patient must be monitored frequently to avoid hyperkalemia. If patients are persistently hypokalemic, several options can be considered based on the underlying cause. Dietary modifications with foods rich in potassium (containing 250mg/100g) can be suggested. Daily potassium chloride supplementation can be used in those on diuretic therapy who have hypokalemia and metabolic alkalosis (bicarbonate levels greater than 30 mEq/L). Alkalinizing salts, containing citrate or bicarbonate, can be used in hypokalemia without metabolic alkalosis. Initiation of angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-adrenergic blockers, and K-sparing diuretics can be used as well.

Potassium supplementation and K-sparing diuretics should be used with extreme caution in CKD 3 and 4 given the risk of overcorrection. If potassium supplements or drugs to raise serum potassium are initiated in house, potassium should be rechecked within a week. These treatments should be avoided in individuals with diabetes, who are at highest risk for hyperkalemia given hyporeninemic hypoaldosteronism (type IV renal tubular acidosis).

Metabolic acidosis

Acid-base balance is maintained by the kidney through urinary excretion of hydrogen ions both as titratable acids and ammonium. In CKD, renal excretion of the daily acid load is impaired, primarily from decreased ammonium excretion caused by there being too few functioning nephrons.

Metabolic acidosis in CKD is defined as a serum bicarbonate concentration of persistently less than 22 mEq/L. The overall prevalence of metabolic acidosis in cases of CKD that don’t require dialysis is about 15% and increases linearly with a decline in GFR. In the Chronic Renal Insufficiency Cohort study, 7%, 13%, and 37% of participants with CKD stages 2, 3, and 4 respectively had metabolic acidosis.

Metabolic acidosis has a variety of adverse outcomes, including bone demineralization, increased protein catabolism and muscle wasting, impaired cardiac function, impaired glucose homeostasis, and systemic inflammation. Additionally, multiple studies have shown an association between metabolic acidosis and progression of CKD and increased mortality.

The 2013 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend maintaining the serum bicarbonate level within the reference range (23-29 mEq/L) with alkali therapy. Options include sodium bicarbonate or sodium citrate (which is rapidly metabolized to bicarbonate) in doses of 0.5-1.0 mEq/kg once per day. Sodium bicarbonate is inexpensive; however, it can lead to gastrointestinal upset as the bicarbonate is converted into CO₂ in the stomach. This side effect is usually self-limited and improves with time. Typical starting doses are 650 mg twice a day if the serum bicarbonate level is 19-21 mEq/L or 1300 mg twice a day if the serum bicarbonate level is less than or equal to 18 mEq/L.

Sodium citrate can be used if gastrointestinal upset occurs, although caution should be used in those on aluminum binders or with liver disease. Alkali treatment should be started when bicarbonate levels are persistently low (for weeks or months) or if very low (less than or equal to 18 mEq/L) without an acute reversible cause. After patients have begun therapy, they should be monitored for the development of worsening hypertension or edema caused by sodium-mediated fluid retention, although this rarely occurs.
 

Hyperphosphatemia and Hypocalcemia

Hyperphosphatemia (phosphate levels greater than 4.6 mg/dL) develops early in CKD because of a reduced filtered-phosphate load. Hypocalcemia and hyperphosphatemia can lead to secondary hyperparathyroidism. Given that hyperphosphatemia has been associated with an increased mortality among patients with CKD, treatment is warranted, but the optimal phosphorus range is unknown. According to the KDIGO guidelines, the goal phosphorus level is less than 4.5 mg/dL in patients with CKD who are not on dialysis.

Treatment includes dietary restriction to 900 mg/day and phosphate binders. There is a high phosphate load in processed foods and colas because of food additives. It is therefore recommended to reduce consumption of these foods while encouraging consumption of meat and eggs, which offer additional nutritional value. Those who have failed dietary restrictions should be put on a phosphate binder, either calcium containing (calcium carbonate, calcium acetate) or non–calcium containing (Sevelamer, lanthanum). Non–calcium-containing binders are recommended for patients with hypercalcemia (levels greater than 9.5 mg/dL). There is some data that suggests that non–calcium-containing binders are superior to calcium-containing binders in terms of vascular disease outcomes, but non–calcium-containing binders are sometimes difficult to obtain because of cost and insurance coverage.

Hypocalcemia (calcium levels below 8.4 mg/dL) occurs in the setting of late stage untreated CKD because of decreased GI uptake of calcium from diet in the context of vitamin D deficiency (less than 30 ng/mL) in addition to hyperphosphatemia. Phosphate and vitamin D correction is preferred to calcium supplementation because hyperphosphatemia and vitamin D deficiency occur earlier in CKD. Phosphate reduction is described above.

Regarding vitamin D deficiency, it is recommended to start supplementation with either vitamin D2 or D3. Doses should be adjusted if GFR is less than 30 mL/min per 1.73 m². It is important to monitor for hypercalcemia, which can also occur in CKD in this context, because it has also been associated with increased morbidity and mortality. If calcium levels are greater than 10.2 mg/dL, all vitamin D supplementation should be discontinued.
 

Back to the case

Our patient who was admitted for cellulitis has concomitant hypokalemia, hypomagnesemia, acidosis, and hyperphosphatemia with related hypocalcemia. She revealed that her diet was poor prior to her admission for her infection. She was given 20 mEq of potassium orally and placed on a potassium rich diet until potassium levels normalized. She was also given magnesium oxide orally on the first and second day of admission, with repeat levels that were normal. Her acidosis was treated with sodium bicarbonate – 1,300 mg orally twice daily. For her hyperphosphatemia and hypocalcemia, she was placed on phosphate restriction with nutritional counseling with plans to follow up as an outpatient to determine need for phosphate binders. In addition, vitamin D levels were checked, and she was started on repletion for vitamin D deficiency (27 ng/mL). Daily BMP, magnesium, and phosphorus were checked while in house until they were normal for 2 days, and follow-up lab work was requested with her nephrology appointment, which was scheduled for within 1 week.

Bottom line

Electrolyte abnormalities in CKD are numerous and have multiple adverse clinical outcomes. Early intervention and management, especially of metabolic acidosis and hyperphosphatemia, can have a significant effect, including prevention of progression of CKD and possibly reduced mortality.

Dr. Daya, Dr. Apgar, and Dr. Eniasivam are assistant clinical professors in the division of hospital medicine at the University of California, San Francisco.

References

1. Coresh J et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007 Nov 7;298(17):2038-47.

2. Dhondup T et al. Electrolyte and acid-base disorders in chronic kidney disease and end-stage kidney failure. Blood Purif. 2017;43(1-3):179-188.

3. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004 May;43(5 Suppl 1):S1-290.

4. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl (2011). 2013 Jan;3(1):1–150.

5. Sakaguchi Y et al. Hypomagnesemia in type 2 diabetic nephropathy: A novel predictor of end-stage renal disease. Diabetes Care. 2012 Jul;35(7):1591-7.

6. Palmer SC et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: A systematic review and meta-analysis. JAMA. 2011 Mar 16;305(11):1119-27.

7. Patel L et al. Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: A meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol. 2016 Feb 5;11(2):232-44.

8. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.

9. Raphael KL et al. Prevalence of and risk factors for reduced serum bicarbonate in chronic kidney disease. Nephrology (Carlton). 2014 Oct;19(10):648-54.

Additional reading

1. Chapter 3: Management of Progression and Complications of CKD. Kidney Int Suppl (2011). 2013 Jan:3(1):73-90.

2. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.

Quiz

A 75-year-old male with hypertension and CKD Stage 4 is admitted to the hospital for a hip fracture following a fall. Laboratory studies on admission show a potassium level of 3.2 mEq/L, vitamin D level of 45 ng/mL, bicarbonate level of 17 mEq/L, phosphate level of 5.0 mg/dL, and calcium level of 10.3 mg/dL.

What electrolyte replacements should be initiated?

A. Dietary restriction of phosphate, sodium bicarbonate, potassium chloride, and vitamin D.

B. Non–calcium-containing phosphate binder, vitamin D, and potassium chloride.

C. Calcium-containing phosphate binder and sodium bicarbonate.

D. Non–calcium-containing phosphate binder, sodium bicarbonate, and potassium chloride.

Answer: D. Given the patient’s hypokalemia, potassium supplementation should be considered. Additionally, given his hyperphosphatemia and hypercalcemia, a non–calcium-containing phosphate binder like Sevelamer should be started. His metabolic acidosis should be corrected with sodium bicarbonate. There is no indication to supplement vitamin D based on his current lab values.
 

Key Points

• Identify and treat underlying causes of hypokalemia and hypomagnesemia.
• Do not hesitate to treat metabolic acidosis in CKD.
• Manage hyperphosphatemia and hypocalcemia by ordering appropriate lab studies and providing nutritional consultation with outpatient nephrology follow-up as indicated.

Case

A 55-year-old woman with diabetes, hypertension, and chronic kidney disease (CKD) stage 4 is admitted to the hospital for treatment of left lower-extremity cellulitis. Laboratory studies on admission show a creatinine level of 2.5 mg/dL (glomerular filtration rate [GFR] is 20 mL/min per 1.73 m²; baseline creatinine is between 2.2 and 2.6 mg/dL), potassium level of 3.0 mEq/L, magnesium level of 1.5 mEq/L, bicarbonate level of 18 mEq/L, phosphate level of 6.5 mg/dL, and calcium level of 7.5 mg/dL.

She is put on renally dosed vancomycin to treat her cellulitis. As the hospitalist, how should you manage her multiple electrolyte abnormalities?
 

Overview of the issue

CKD is also an important risk factor for acute kidney injury. Additionally, rates of readmission for CKD patients are higher than those without CKD. Given that CKD is a “silent disease” that many patients do not realize they have, it is very possible that the first documentation of CKD could happen during an acute hospitalization.

Among the various manifestations of CKD, electrolyte abnormalities are the most likely ones hospitalists will run into.
 

Overview of the data

Hypokalemia and Hypomagnesemia

Hypokalemia (potassium levels less than 3.5 mEq/L) is not as common as hyperkalemia (potassium levels greater than 5.0 mEq/L) in CKD, which is the result of impaired renal excretion of potassium. Hypokalemia can occur as a result of GI losses, urinary losses, or decreased intake and can be worsened by the use of certain drugs, such as non–K-sparing diuretics.

In the setting of diuretic use involving thiazides and loop diuretics, hypokalemia is dose and sodium-intake dependent. Potassium deficiency worsens the effects of detrimental sodium excess, which plays a role in hypertension and its associated complications. Potassium also has a protective vascular effect, which is a major reason why potassium should be kept normal in patients with CKD.

Acutely, hypokalemia can cause arrhythmias, ileus, and paralysis, which are all indications for immediate repletion. In these cases, hypokalemia must be repleted carefully in small increments (some suggest 20 mEq doses), and the patient must be monitored frequently to avoid hyperkalemia. If patients are persistently hypokalemic, several options can be considered based on the underlying cause. Dietary modifications with foods rich in potassium (containing 250mg/100g) can be suggested. Daily potassium chloride supplementation can be used in those on diuretic therapy who have hypokalemia and metabolic alkalosis (bicarbonate levels greater than 30 mEq/L). Alkalinizing salts, containing citrate or bicarbonate, can be used in hypokalemia without metabolic alkalosis. Initiation of angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-adrenergic blockers, and K-sparing diuretics can be used as well.

Potassium supplementation and K-sparing diuretics should be used with extreme caution in CKD 3 and 4 given the risk of overcorrection. If potassium supplements or drugs to raise serum potassium are initiated in house, potassium should be rechecked within a week. These treatments should be avoided in individuals with diabetes, who are at highest risk for hyperkalemia given hyporeninemic hypoaldosteronism (type IV renal tubular acidosis).

Metabolic acidosis

Acid-base balance is maintained by the kidney through urinary excretion of hydrogen ions both as titratable acids and ammonium. In CKD, renal excretion of the daily acid load is impaired, primarily from decreased ammonium excretion caused by there being too few functioning nephrons.

Metabolic acidosis in CKD is defined as a serum bicarbonate concentration of persistently less than 22 mEq/L. The overall prevalence of metabolic acidosis in cases of CKD that don’t require dialysis is about 15% and increases linearly with a decline in GFR. In the Chronic Renal Insufficiency Cohort study, 7%, 13%, and 37% of participants with CKD stages 2, 3, and 4 respectively had metabolic acidosis.

Metabolic acidosis has a variety of adverse outcomes, including bone demineralization, increased protein catabolism and muscle wasting, impaired cardiac function, impaired glucose homeostasis, and systemic inflammation. Additionally, multiple studies have shown an association between metabolic acidosis and progression of CKD and increased mortality.

The 2013 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend maintaining the serum bicarbonate level within the reference range (23-29 mEq/L) with alkali therapy. Options include sodium bicarbonate or sodium citrate (which is rapidly metabolized to bicarbonate) in doses of 0.5-1.0 mEq/kg once per day. Sodium bicarbonate is inexpensive; however, it can lead to gastrointestinal upset as the bicarbonate is converted into CO₂ in the stomach. This side effect is usually self-limited and improves with time. Typical starting doses are 650 mg twice a day if the serum bicarbonate level is 19-21 mEq/L or 1300 mg twice a day if the serum bicarbonate level is less than or equal to 18 mEq/L.

Sodium citrate can be used if gastrointestinal upset occurs, although caution should be used in those on aluminum binders or with liver disease. Alkali treatment should be started when bicarbonate levels are persistently low (for weeks or months) or if very low (less than or equal to 18 mEq/L) without an acute reversible cause. After patients have begun therapy, they should be monitored for the development of worsening hypertension or edema caused by sodium-mediated fluid retention, although this rarely occurs.
 

Hyperphosphatemia and Hypocalcemia

Hyperphosphatemia (phosphate levels greater than 4.6 mg/dL) develops early in CKD because of a reduced filtered-phosphate load. Hypocalcemia and hyperphosphatemia can lead to secondary hyperparathyroidism. Given that hyperphosphatemia has been associated with an increased mortality among patients with CKD, treatment is warranted, but the optimal phosphorus range is unknown. According to the KDIGO guidelines, the goal phosphorus level is less than 4.5 mg/dL in patients with CKD who are not on dialysis.

Treatment includes dietary restriction to 900 mg/day and phosphate binders. There is a high phosphate load in processed foods and colas because of food additives. It is therefore recommended to reduce consumption of these foods while encouraging consumption of meat and eggs, which offer additional nutritional value. Those who have failed dietary restrictions should be put on a phosphate binder, either calcium containing (calcium carbonate, calcium acetate) or non–calcium containing (Sevelamer, lanthanum). Non–calcium-containing binders are recommended for patients with hypercalcemia (levels greater than 9.5 mg/dL). There is some data that suggests that non–calcium-containing binders are superior to calcium-containing binders in terms of vascular disease outcomes, but non–calcium-containing binders are sometimes difficult to obtain because of cost and insurance coverage.

Hypocalcemia (calcium levels below 8.4 mg/dL) occurs in the setting of late stage untreated CKD because of decreased GI uptake of calcium from diet in the context of vitamin D deficiency (less than 30 ng/mL) in addition to hyperphosphatemia. Phosphate and vitamin D correction is preferred to calcium supplementation because hyperphosphatemia and vitamin D deficiency occur earlier in CKD. Phosphate reduction is described above.

Regarding vitamin D deficiency, it is recommended to start supplementation with either vitamin D2 or D3. Doses should be adjusted if GFR is less than 30 mL/min per 1.73 m². It is important to monitor for hypercalcemia, which can also occur in CKD in this context, because it has also been associated with increased morbidity and mortality. If calcium levels are greater than 10.2 mg/dL, all vitamin D supplementation should be discontinued.
 

Back to the case

Our patient who was admitted for cellulitis has concomitant hypokalemia, hypomagnesemia, acidosis, and hyperphosphatemia with related hypocalcemia. She revealed that her diet was poor prior to her admission for her infection. She was given 20 mEq of potassium orally and placed on a potassium rich diet until potassium levels normalized. She was also given magnesium oxide orally on the first and second day of admission, with repeat levels that were normal. Her acidosis was treated with sodium bicarbonate – 1,300 mg orally twice daily. For her hyperphosphatemia and hypocalcemia, she was placed on phosphate restriction with nutritional counseling with plans to follow up as an outpatient to determine need for phosphate binders. In addition, vitamin D levels were checked, and she was started on repletion for vitamin D deficiency (27 ng/mL). Daily BMP, magnesium, and phosphorus were checked while in house until they were normal for 2 days, and follow-up lab work was requested with her nephrology appointment, which was scheduled for within 1 week.

Bottom line

Electrolyte abnormalities in CKD are numerous and have multiple adverse clinical outcomes. Early intervention and management, especially of metabolic acidosis and hyperphosphatemia, can have a significant effect, including prevention of progression of CKD and possibly reduced mortality.

Dr. Daya, Dr. Apgar, and Dr. Eniasivam are assistant clinical professors in the division of hospital medicine at the University of California, San Francisco.

References

1. Coresh J et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007 Nov 7;298(17):2038-47.

2. Dhondup T et al. Electrolyte and acid-base disorders in chronic kidney disease and end-stage kidney failure. Blood Purif. 2017;43(1-3):179-188.

3. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004 May;43(5 Suppl 1):S1-290.

4. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl (2011). 2013 Jan;3(1):1–150.

5. Sakaguchi Y et al. Hypomagnesemia in type 2 diabetic nephropathy: A novel predictor of end-stage renal disease. Diabetes Care. 2012 Jul;35(7):1591-7.

6. Palmer SC et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: A systematic review and meta-analysis. JAMA. 2011 Mar 16;305(11):1119-27.

7. Patel L et al. Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: A meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol. 2016 Feb 5;11(2):232-44.

8. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.

9. Raphael KL et al. Prevalence of and risk factors for reduced serum bicarbonate in chronic kidney disease. Nephrology (Carlton). 2014 Oct;19(10):648-54.

Additional reading

1. Chapter 3: Management of Progression and Complications of CKD. Kidney Int Suppl (2011). 2013 Jan:3(1):73-90.

2. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.

Quiz

A 75-year-old male with hypertension and CKD Stage 4 is admitted to the hospital for a hip fracture following a fall. Laboratory studies on admission show a potassium level of 3.2 mEq/L, vitamin D level of 45 ng/mL, bicarbonate level of 17 mEq/L, phosphate level of 5.0 mg/dL, and calcium level of 10.3 mg/dL.

What electrolyte replacements should be initiated?

A. Dietary restriction of phosphate, sodium bicarbonate, potassium chloride, and vitamin D.

B. Non–calcium-containing phosphate binder, vitamin D, and potassium chloride.

C. Calcium-containing phosphate binder and sodium bicarbonate.

D. Non–calcium-containing phosphate binder, sodium bicarbonate, and potassium chloride.

Answer: D. Given the patient’s hypokalemia, potassium supplementation should be considered. Additionally, given his hyperphosphatemia and hypercalcemia, a non–calcium-containing phosphate binder like Sevelamer should be started. His metabolic acidosis should be corrected with sodium bicarbonate. There is no indication to supplement vitamin D based on his current lab values.
 

Key Points

• Identify and treat underlying causes of hypokalemia and hypomagnesemia.
• Do not hesitate to treat metabolic acidosis in CKD.
• Manage hyperphosphatemia and hypocalcemia by ordering appropriate lab studies and providing nutritional consultation with outpatient nephrology follow-up as indicated.

MONTREAL – A 4% drop in all-cause mortality occurred in case-managed patients with hypertension who received phone calls, care coordination, and coaching from a nurse case manager, according to a retrospective population-based cohort study of almost 85,000 patients with hypertension.

The reduction yielded a hazard ratio for all-cause mortality of 0.504, with a number needed to treat (NNT) of 25 (P less than .05).

Kari Oakes/Frontline Medical News

[email protected]

SOURCE: Yu, Esther et al. NAPCRG 2017, Abstract HY33.

MONTREAL – A 4% drop in all-cause mortality occurred in case-managed patients with hypertension who received phone calls, care coordination, and coaching from a nurse case manager, according to a retrospective population-based cohort study of almost 85,000 patients with hypertension.

The reduction yielded a hazard ratio for all-cause mortality of 0.504, with a number needed to treat (NNT) of 25 (P less than .05).

Kari Oakes/Frontline Medical News

[email protected]

SOURCE: Yu, Esther et al. NAPCRG 2017, Abstract HY33.

MONTREAL – A 4% drop in all-cause mortality occurred in case-managed patients with hypertension who received phone calls, care coordination, and coaching from a nurse case manager, according to a retrospective population-based cohort study of almost 85,000 patients with hypertension.

The reduction yielded a hazard ratio for all-cause mortality of 0.504, with a number needed to treat (NNT) of 25 (P less than .05).

Kari Oakes/Frontline Medical News

[email protected]

SOURCE: Yu, Esther et al. NAPCRG 2017, Abstract HY33.

A 54-year-old man presents to the emergency department (ED) with acute-onset left flank pain that radiates to the groin. CT of the abdomen/pelvis without contrast reveals a 7-mm distal ureteral stone. He is deemed an appropriate candidate for outpatient management. In addition to pain medications, should you prescribe tamsulosin?

According to the most recent National Health and Nutrition Examination Survey, the population prevalence of kidney stones is 8.8%, with a self-reported prevalence of 10.6% in men and 7.1% in women.² Most ureteral stones can be treated in the outpatient setting with oral hydration, antiemetics, and pain control with NSAIDs as firstline treatment and opioids as a second-line option.³

In addition, α-blockers are used for medical expulsive therapy (MET). In fact, the European Association of Urology guideline on urolithiasis states that MET may accelerate passage of ureteral stones.³

Recently, however, uncertainty has surrounded the effectiveness of the α-blocker tamsulosin. Two systematic reviews (limited by heterogeneity because some of the studies lacked a placebo control and blinding) concluded that α-blockers increased stone passage within one to six weeks when compared with placebo or no additional therapy.^4,5 However, a recent large, multicenter RCT revealed no difference between tamsulosin and nifedipine, or either one compared with placebo, at decreasing the need for further treatment to achieve stone passage within four weeks.⁶

STUDY SUMMARY

Results broken down by stone size

This meta-analysis, comprising eight double-blind RCTs, examined the effect of oral tamsulosin (0.4 mg/d; average course, 28 d) on distal ureteral stone passage in adult patients (N = 1,384).¹ A subgroup analysis comparing stone size (< 5 mm and 5-10 mm) was also conducted to determine whether size modified the effect of tamsulosin.

The eight selected studies were published between 2009 and 2015; the trials were conducted in multiple countries, in ED and outpatient urology settings. The main outcome measure was the risk difference (RD) in stone passage between the tamsulosin group and placebo group after follow-up imaging at three weeks with CT or plain film radiographs.

Tamsulosin helps some, but not all. The pooled risk for stone passage was higher in the tamsulosin group than in the placebo group (85% vs 66%; RD, 17%), but significant heterogeneity existed across the trials (I², 80.2%). Subgroup analysis by stone size (< 5 mm vs 5-10 mm) revealed that, compared to placebo, tamsulosin was beneficial for larger stones (6 trials, N = 514; RD, 22%; number needed to treat, 5) but not for smaller stones (4 trials, N = 533; RD, –0.3%). The 5-to-10–mm subgroup had a less heterogeneous population of studies than did the < 5-mm subgroup (I², 33% and 0% respectively).

In terms of adverse events, tamsulosin did not increase the risk for dizziness (RD, 0.2%) or postural hypotension (RD, 0.1%), compared with placebo.

WHAT’S NEW

Increased passage of larger stones

This meta-analysis included only double-blind RCTs; prior meta-analyses did not. Also, this review included the SUSPEND (Spontaneous Urinary Stone Passage Enabled by Drugs) trial, an RCT discussed in a previous PURL (Clinician Reviews. 2016;26[4]:20,44), which recommended against the use of α-blockers tamsulosin and nifedipine for ureteral stones measuring < 10 mm.^6,7

But the subgroup analysis in this review went one step further by examining passage rates by stone size (< 5 mm vs 5-10 mm) and revealing that passage of larger stones increased with tamsulosin use. The different results based on stone size may explain the recent uncertainty as to whether tamsulosin improves the rate of stone passage.

What about proximal or XL stones?

Only distal stones were included in seven of the eight trials in this analysis. Thus, this meta-analysis was unable to determine the effect on more proximal stones. Also, it’s unclear if the drug provides any benefit with stones > 10 mm in size.

CHALLENGES TO IMPLEMENTATION

None worth mentioning

We see no challenges to implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018; 67[1]:37-38).

A 54-year-old man presents to the emergency department (ED) with acute-onset left flank pain that radiates to the groin. CT of the abdomen/pelvis without contrast reveals a 7-mm distal ureteral stone. He is deemed an appropriate candidate for outpatient management. In addition to pain medications, should you prescribe tamsulosin?

According to the most recent National Health and Nutrition Examination Survey, the population prevalence of kidney stones is 8.8%, with a self-reported prevalence of 10.6% in men and 7.1% in women.² Most ureteral stones can be treated in the outpatient setting with oral hydration, antiemetics, and pain control with NSAIDs as firstline treatment and opioids as a second-line option.³

In addition, α-blockers are used for medical expulsive therapy (MET). In fact, the European Association of Urology guideline on urolithiasis states that MET may accelerate passage of ureteral stones.³

Recently, however, uncertainty has surrounded the effectiveness of the α-blocker tamsulosin. Two systematic reviews (limited by heterogeneity because some of the studies lacked a placebo control and blinding) concluded that α-blockers increased stone passage within one to six weeks when compared with placebo or no additional therapy.^4,5 However, a recent large, multicenter RCT revealed no difference between tamsulosin and nifedipine, or either one compared with placebo, at decreasing the need for further treatment to achieve stone passage within four weeks.⁶

STUDY SUMMARY

Results broken down by stone size

This meta-analysis, comprising eight double-blind RCTs, examined the effect of oral tamsulosin (0.4 mg/d; average course, 28 d) on distal ureteral stone passage in adult patients (N = 1,384).¹ A subgroup analysis comparing stone size (< 5 mm and 5-10 mm) was also conducted to determine whether size modified the effect of tamsulosin.

The eight selected studies were published between 2009 and 2015; the trials were conducted in multiple countries, in ED and outpatient urology settings. The main outcome measure was the risk difference (RD) in stone passage between the tamsulosin group and placebo group after follow-up imaging at three weeks with CT or plain film radiographs.

Tamsulosin helps some, but not all. The pooled risk for stone passage was higher in the tamsulosin group than in the placebo group (85% vs 66%; RD, 17%), but significant heterogeneity existed across the trials (I², 80.2%). Subgroup analysis by stone size (< 5 mm vs 5-10 mm) revealed that, compared to placebo, tamsulosin was beneficial for larger stones (6 trials, N = 514; RD, 22%; number needed to treat, 5) but not for smaller stones (4 trials, N = 533; RD, –0.3%). The 5-to-10–mm subgroup had a less heterogeneous population of studies than did the < 5-mm subgroup (I², 33% and 0% respectively).

In terms of adverse events, tamsulosin did not increase the risk for dizziness (RD, 0.2%) or postural hypotension (RD, 0.1%), compared with placebo.

WHAT’S NEW

Increased passage of larger stones

This meta-analysis included only double-blind RCTs; prior meta-analyses did not. Also, this review included the SUSPEND (Spontaneous Urinary Stone Passage Enabled by Drugs) trial, an RCT discussed in a previous PURL (Clinician Reviews. 2016;26[4]:20,44), which recommended against the use of α-blockers tamsulosin and nifedipine for ureteral stones measuring < 10 mm.^6,7

But the subgroup analysis in this review went one step further by examining passage rates by stone size (< 5 mm vs 5-10 mm) and revealing that passage of larger stones increased with tamsulosin use. The different results based on stone size may explain the recent uncertainty as to whether tamsulosin improves the rate of stone passage.

What about proximal or XL stones?

Only distal stones were included in seven of the eight trials in this analysis. Thus, this meta-analysis was unable to determine the effect on more proximal stones. Also, it’s unclear if the drug provides any benefit with stones > 10 mm in size.

CHALLENGES TO IMPLEMENTATION

None worth mentioning

We see no challenges to implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018; 67[1]:37-38).

A 54-year-old man presents to the emergency department (ED) with acute-onset left flank pain that radiates to the groin. CT of the abdomen/pelvis without contrast reveals a 7-mm distal ureteral stone. He is deemed an appropriate candidate for outpatient management. In addition to pain medications, should you prescribe tamsulosin?

According to the most recent National Health and Nutrition Examination Survey, the population prevalence of kidney stones is 8.8%, with a self-reported prevalence of 10.6% in men and 7.1% in women.² Most ureteral stones can be treated in the outpatient setting with oral hydration, antiemetics, and pain control with NSAIDs as firstline treatment and opioids as a second-line option.³

In addition, α-blockers are used for medical expulsive therapy (MET). In fact, the European Association of Urology guideline on urolithiasis states that MET may accelerate passage of ureteral stones.³

Recently, however, uncertainty has surrounded the effectiveness of the α-blocker tamsulosin. Two systematic reviews (limited by heterogeneity because some of the studies lacked a placebo control and blinding) concluded that α-blockers increased stone passage within one to six weeks when compared with placebo or no additional therapy.^4,5 However, a recent large, multicenter RCT revealed no difference between tamsulosin and nifedipine, or either one compared with placebo, at decreasing the need for further treatment to achieve stone passage within four weeks.⁶

STUDY SUMMARY

Results broken down by stone size

This meta-analysis, comprising eight double-blind RCTs, examined the effect of oral tamsulosin (0.4 mg/d; average course, 28 d) on distal ureteral stone passage in adult patients (N = 1,384).¹ A subgroup analysis comparing stone size (< 5 mm and 5-10 mm) was also conducted to determine whether size modified the effect of tamsulosin.

The eight selected studies were published between 2009 and 2015; the trials were conducted in multiple countries, in ED and outpatient urology settings. The main outcome measure was the risk difference (RD) in stone passage between the tamsulosin group and placebo group after follow-up imaging at three weeks with CT or plain film radiographs.

Tamsulosin helps some, but not all. The pooled risk for stone passage was higher in the tamsulosin group than in the placebo group (85% vs 66%; RD, 17%), but significant heterogeneity existed across the trials (I², 80.2%). Subgroup analysis by stone size (< 5 mm vs 5-10 mm) revealed that, compared to placebo, tamsulosin was beneficial for larger stones (6 trials, N = 514; RD, 22%; number needed to treat, 5) but not for smaller stones (4 trials, N = 533; RD, –0.3%). The 5-to-10–mm subgroup had a less heterogeneous population of studies than did the < 5-mm subgroup (I², 33% and 0% respectively).

In terms of adverse events, tamsulosin did not increase the risk for dizziness (RD, 0.2%) or postural hypotension (RD, 0.1%), compared with placebo.

WHAT’S NEW

Increased passage of larger stones

This meta-analysis included only double-blind RCTs; prior meta-analyses did not. Also, this review included the SUSPEND (Spontaneous Urinary Stone Passage Enabled by Drugs) trial, an RCT discussed in a previous PURL (Clinician Reviews. 2016;26[4]:20,44), which recommended against the use of α-blockers tamsulosin and nifedipine for ureteral stones measuring < 10 mm.^6,7

But the subgroup analysis in this review went one step further by examining passage rates by stone size (< 5 mm vs 5-10 mm) and revealing that passage of larger stones increased with tamsulosin use. The different results based on stone size may explain the recent uncertainty as to whether tamsulosin improves the rate of stone passage.

What about proximal or XL stones?

Only distal stones were included in seven of the eight trials in this analysis. Thus, this meta-analysis was unable to determine the effect on more proximal stones. Also, it’s unclear if the drug provides any benefit with stones > 10 mm in size.

CHALLENGES TO IMPLEMENTATION

None worth mentioning

We see no challenges to implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018; 67[1]:37-38).

Much has improved in renal transplantation over the past 20 years. The focus has shifted to using stronger immunotherapy rather than trying to minimize it. There has been increasing recognition of infection and ways to prevent and treat it. Induction therapy now has greater emphasis so that maintenance therapy can be eased, with the aim of reducing long-term toxicity. Perhaps the biggest change is the practice of screening for donor-specific antibodies at the time of transplant so that predictable problems can be prevented or better handled if they occur. Such advances have helped patients directly and by extending the life of their transplanted organs.

LONGER SURVIVAL

As early as the 1990s, it was recognized that kidney transplant offers a survival advantage for patients with end-stage renal disease over maintenance on dialysis.¹ Although the risk of death is higher immediately after transplant, within a few months it becomes much lower than for patients on dialysis. Survival varies according to the health of the patient and the quality of the transplanted organ.

In general, patients who obtain the greatest benefit from transplants in terms of years of life gained are those with diabetes, especially those who are younger. Those ages 20 to 39 live about 8 years on dialysis vs 25 years after transplant.

CONTRAINDICATIONS TO TRANSPLANT

There are multiple contraindications to a solitary kidney transplant (Table 1), including smoking. Most transplant centers require that smokers quit before transplant. Long-standing smokers almost double their risk of a cardiac event after transplant and double their rate of malignancy. Active smoking at the time of transplant is associated with twice the risk of death by 10 years after transplant compared with that of nonsmokers.² Cotinine testing can detect whether a patient is an active smoker.

WAITING-LIST CONSIDERATIONS

Organs are scarce

The number of patients on the kidney waiting list has increased rapidly in the last few decades, while the number of transplants performed each year has remained about the same. In 2016, about 100,000 patients were on the list, but only about 19,000 transplants were performed.³ Wait times, especially for deceased-donor organs, have increased to about 6 years, varying by blood type and geographic region.

Waiting-list placement

Placement on the waiting list for a deceased-donor kidney transplant occurs when a patient has an estimated glomerular filtration rate (GFR) of 20 mL/min/1.73 m² or less, although referral to the list can be made earlier. Early listing remains advantageous, as total time on the list will be counted before starting dialysis. “Preemptive transplant” means the patient had no dialysis before transplant; this applies to about 10% of transplant recipients. These patients tend to fare the best and are usually recipients of a living-donor organ.

Most patients do not receive a transplant until the GFR is less than 15 mL/min/1.73 m².

Since 2014, wait time has been measured from the beginning of dialysis rather than the date of waiting-list placement in patients who are listed after starting dialysis therapy. This approach is more fair but sometimes introduces problems. A patient who did not previously know about the list may suddenly jump to the head of the line after 10 years of dialysis, by which time comorbidities associated with long-term dialysis make the patient less likely to gain as much benefit from a transplant as people lower on the list. Time on dialysis, or “dialysis vintage,” predicts patient and kidney survival after transplant, with reduced survival associated with increasing time on dialysis.⁴

Shorter wait for a suboptimal kidney

The aging population has increased the number of older patients being listed for transplant, presenting multiple challenges. Patients age 65 or older have a 50% chance of dying before they receive a transplant during a 5-year wait.

A patient may shorten the wait by joining the list for a suboptimal organ. All deceased-donor organs are given a Kidney Donor Profile Index score, which predicts the longevity of an organ after transplant. The score is determined by donor age, kidney function based on the serum creatinine at the time of death, and other donor factors.

A kidney with a score higher than 85% is likely to function longer than only 15% of available kidneys. Patients who receive a kidney with that score have a longer period of risk of death soon after transplant and a slightly higher risk of death in the long term than patients who receive a healthier kidney, although on average they still do better than patients on dialysis.⁵

Older patients should be encouraged to sign up for both the regular waiting list and the suboptimal kidney waiting list to reduce the risk of dying before they get a kidney.

Many advantages

Living-donor organ transplant is associated with a better survival rate than deceased-donor organ transplant, and the advantage becomes greater over time. At 1 year, patient survival is more than 90% in both groups, but by 5 years about 80% of patients with a living-donor organ are still alive vs only about 65% of patients with a deceased-donor organ.

The waiting time for a living-donor transplant may be only weeks to months, rather than years. Because increasing time on dialysis predicts worse patient and graft survival after transplant, the shorter wait time is a big advantage. In addition, because the donor and recipient are typically in adjacent operating rooms, the organ sustains less ischemic damage. In general, the kidney quality is better from healthy donors, resulting in superior function early on and longer graft survival by an average of 4 years. If the living donor is related to the recipient, human leukocyte antigen matching also tends to be better and predicts better outcomes.

Special challenges

Opting for a living-donor organ also entails special challenges. In addition to the ethical issues surrounding living-donor organ donation, an appropriate donor must be found. Donors must be highly motivated and pass physical, laboratory, and psychological evaluations.

For older patients, if the donor is a spouse or close friend, he or she is also likely to be older, making the organ less viable than one from a younger person. Even an adult child may not be an ideal donor if there is a family propensity to kidney disease, such as diabetic nephropathy. No test is available to determine the risk for future diabetes, but it is known to run in families.

POTENT IMMUNOSUPPRESSION

Induction therapy

Induction therapy with antithymocyte globulin or basiliximab provides intense immunosuppression to prevent acute rejection during the early posttransplant period.

Antithymocyte globulin is a potent agent that contains antibodies directed at T cells, B cells, neutrophils, platelets, adhesion molecules, and complement. It binds T cells and removes them from circulation by opsonization in splenic and lymphoid tissue. The immunosuppressive effect is sustained for at least 2 to 3 months after a series of injections (dosage 1.5 mg/kg/day, usually for 4 to 10 doses). Antithymocyte globulin is also used to treat acute rejection, especially high-grade rejection for which steroid therapy is likely to be insufficient.

Basiliximab consists of antibodies to the interleukin 2 (IL-2) receptor of T cells. Binding to T cells prevents their activation rather than removing them from circulation. The drug prevents rejection, with 30% relative reduction in early studies compared with placebo. However, it is ineffective in reversing established rejection. Dosage is 20 mg at day 0 and day 4, which provides receptor saturation for 30 to 45 days.

Basiliximab is also sometimes used off-label for patients who need to discontinue a calcineurin inhibitor (ie, tacrolimus or cyclosporine). In such cases, normal therapy is put on hold while basiliximab is given for 1 or 2 doses. Case series have been reported for this use, particularly for patients with a heart and liver transplant who develop acute kidney injury while hospitalized.^6,7

Antithymocyte globulin is more effective but also more risky. Brennan et al⁸ randomized 278 transplant recipients to either antithymocyte globulin or basiliximab. Patients in the antithymocyte globulin group had a 16% rejection rate vs 26% in the basiliximab group.

Antithymocyte globulin therapy is associated with multiple adverse effects, including fever and chills, pulmonary edema, and long-standing immunosuppressive effects such as increased risk of lymphoma and cytomegalovirus (CMV) infection. Basiliximab side-effect profiles are similar to those of placebo.

Maintenance therapy

The calcineurin inhibitors cyclosporine and tacrolimus remain the standard of care in kidney transplant despite multiple drug interactions and side effects that include renal toxicity and fibrosis. Cyclosporine and tacrolimus both bind intracellular immunophilins and thereby prevent transcription of IL-2 and production of T cells. The drugs work similarly but have different binding sites. Cyclosporine has largely been replaced by tacrolimus because its reliability of dosing and higher potency are associated with lower rejection rates.

Tacrolimus is typically given twice daily (1–6 mg/dose). Twelve-hour trough levels are followed (target: 8–12 ng/mL early on, then 5–8 ng/mL after 3 months posttransplant). Side effects include hypertension and hypercholesterolemia, but less so than with cyclosporine. On the other hand, hyperglycemia tends to be worse with tacrolimus than with cyclosporine, and combining tacrolimus with steroids frequently leads to diabetes. Tacrolimus can also cause acute and chronic renal failure, especially at high drug levels, as well as neurotoxicity, tremors, and hair loss.

Cyclosporine, tacrolimus, and sirolimus (not a calcineurin inhibitor) are metabolized through the same cytochrome P450 pathway (CYP3A4), so they have common drug interactions (Table 2).

Mycophenolate mofetil is typically used as an adjunct therapy (500–1,000 mg twice daily). It is also used for other kidney diseases before transplant, including lupus nephritis. Transplanted kidney rejection rates with mycophenolate mofetil with steroids are about 40%, so the drug is not potent enough to be used without a calcineurin inhibitor.

Side effects include gastrointestinal toxicity in up to 20% of patients, and leukopenia, which is associated with viral infections.

CORONARY ARTERY DISEASE IS COMMON WITH DIALYSIS

Coronary artery disease is highly associated with end-stage kidney disease and occurs in as many as 85% of older patients with diabetes on dialysis. Although patients with end-stage kidney disease tend to have more numerous and severe atherosclerotic lesions compared with the general population, justifying aggressive management, cardiac care tends to be conservative in patients on dialysis.⁹

Death from acute myocardial infarction occurs in about 20% to 30% of patients on dialysis vs about 2% of patients with normal renal function. Five years after myocardial infarction, survival is only about 30% in patients on dialysis.⁹

There are many explanations for excess coronary artery disease in patients on dialysis. In addition to the traditional cardiovascular risk factors of diabetes, hypertension, and preexisting coronary artery disease, patients are in a proinflammatory uremic state and have high levels of phosphorus and fibroblast growth factor 23 that contribute to vascular calcification. Almost all patients have high homocysteine levels and hemodynamic instability, particularly if they are on hemodialysis.

Pretransplant evaluation for heart disease

Patients on the kidney transplant waiting list are screened aggressively for heart disease. A history of myocardial infarction usually results in removal from the list. All patients have an initial electrocardiogram and echocardiogram. Thallium or echocardiographic stress testing is used for patients who are age 50 and older, have diabetes, or have had dialysis for many years. Patients with evidence of ischemia undergo catheterization.

Patients are also screened with computed tomography before transplant. Because the kidney is typically anastomosed to the iliac artery and vein, heavy calcification of the iliac artery can make the procedure too difficult to perform.

Kasiske et al¹⁰ analyzed data from more than 50,000 patients from the US Renal Data System and found that, for about the first year after transplant, patients who underwent kidney transplant were more likely to have a myocardial infarction than those on dialysis. After that, they fared better than patients who remained on dialysis. Those with a living-donor transplant were less likely at all times to have a myocardial infarction than those with a deceased-donor transplant. By 3 years after transplant, the relative risk of having a myocardial infarction was 0.89 for deceased-donor organ recipients and 0.69 for living-donor recipients compared with patients on the waiting list.¹⁰

INFECTIOUS COMPLICATIONS IN KIDNEY RECIPIENTS

Kidney recipients are prone to many common and uncommon infections (Table 3). All potential recipients are tested pretransplant for hepatitis B, hepatitis C, human immunodeficiency virus, syphilis, and tuberculosis. A positive result does not necessarily rule out transplant.

The following viral serology tests are also done before transplant:

Epstein-Barr virus (antibodies are positive in about 90% of adults)

CMV (about 70% of adults are seropositive)

Varicella zoster (seronegative patients should be given live-attenuated varicella vaccine).

Risk of transmission of these viruses relates to the serostatus of the donor and recipient before transplant. If a donor is positive for viral antibodies but the recipient is not (a so-called “mismatch”), risk is higher after transplant.

Hepatitis C

Patients with hepatitis C fare better if they get a transplant than if they remain on dialysis, although their posttransplant course is worse compared with transplant patients who do not have hepatitis. Some patients develop accelerated liver disease after kidney transplant. Hepatitis C-related kidney disease—membranous proliferative glomerulonephritis—also occurs, as do comorbidities such as diabetes.

Careful evaluation is warranted before transplant, including liver imaging, alpha-fetoprotein testing, and liver biopsy to evaluate for hepatocellular carcinoma. A patient with advanced fibrosis or cirrhosis may not be a candidate for kidney transplant alone but could possibly receive a combined kidney and liver transplant.

There is a need to determine the best time to treat hepatitis C infection. Patients with advanced liver disease or hepatitis C-related kidney disease would likely benefit from early treatment. However, delaying treatment could shorten the wait time for a deceased-donor organ positive for hepatitis C.  Transplant candidates with active hepatitis C are uniquely considered to accept hepatitis C-positive kidneys, which are often discarded, and may only wait weeks for such a transplant. The shortened kidney survival associated with a hepatitis C-positive kidney may no longer be true with the new antiviral hepatitis C therapy, which has been shown to be effective post-transplant.

Hepatitis B

No cure is available for hepatitis B infection, but it can be well controlled with antiviral therapy. Patients with hepatitis B infection may be candidates for transplant, but they should be stable on antiviral therapy (lamivudine, entecavir, or tenofovir) to eliminate the viral load before transplant, and therapy should be continued afterward. Liver imaging, alpha-fetoprotein levels, and biopsy are recommended for evaluation. All hepatitis B- negative patients should be vaccinated before transplant.

Organs from living or deceased donors that test positive for hepatitis B core antibody, indicating prior exposure, can be considered for transplant in a patient who tests positive for hepatitis B surface antibody, indicating successful vaccination or prior exposure in the recipient. But donors must have negative surface antigen and polymerase chain reaction (PCR) tests that indicate no active hepatitis B infection.

Cytomegalovirus

CMV typically does not appear until prophylactic therapy is stopped. Classic symptoms are fever, leukopenia, and diarrhea. Infection can involve any organ, and patients may present with hepatitis, pancreatitis or, less commonly, pneumonitis.

Patients who are negative for CMV before transplant and receive a donor-positive organ are at the highest risk. Patients who are CMV IgG-positive are considered to be at intermediate risk, regardless of the donor status. Patients who are negative for CMV and receive a donor-negative organ are at the lowest risk and do not need prophylaxis with valganciclovir.

CMV infection is diagnosed by PCR testing of the blood or immunostaining in tissue biopsy. Occasionally, blood testing is negative in the face of tissue-based disease.

BK virus

BK is a polyoma virus and a common virus associated with kidney transplant. Viremia is seen in about 18% of patients, whereas actual kidney disease associated with a higher level of virus is seen in fewer than 10% of patients. Most people are exposed to BK virus, often in childhood, and it can remain indolent in the bladder and uroepithelium.

Patients can develop BK nephropathy after exposure to transplant immunosuppression.¹¹ Posttransplant monitoring protocols typically include PCR testing for BK virus at 1, 3, 6, and 12 months. No agent has been identified to specifically treat BK virus. The general strategy is to minimize immunosuppressive therapy by reducing or eliminating mycophenolate mofetil. Fortunately, BK virus does not tend to recur, and patients can have a low-level viremia (< 10,000 copies/mL) persisting over months or even years but often without clinical consequences.

The appearance of BK virus on biopsy can mimic acute rejection. Before BK viral nephropathy was a recognized entity, patients would have been diagnosed with acute rejection and may have been put on high-dose steroids, which would have worsened the BK infection.

Posttransplant lymphoproliferative disorder

Posttransplant lymphoproliferative disorder is most often associated with Epstein-Barr virus and usually involves a large, diffuse B-cell lymphoma. Burkitt lymphoma and plasma cell neoplasms also can occur less commonly.

The condition is about 30 times more common in patients after transplant than in the general population, and it is the third most common malignancy in transplant patients after skin and cervical cancers. About 80% of the cases occur early after transplant, within the first year.

Patients typically have a marked elevation in viral load of Epstein-Barr virus, although a negative viral load does not rule it out. A patient who is serologically negative for Epstein-Barr virus receiving a donor-positive kidney is at highest risk; this situation is most often seen in the pediatric population. Potent induction therapies (eg, antilymphocyte antibody therapy) are also associated with posttransplant lymphoproliferative disorder.

Patients typically present with fever of unknown origin with no localizing signs or symptoms. Mass lesions can be challenging to find; positron emission tomography may be helpful. The culprit is usually a focal mass, ulcer (especially in the gastrointestinal tract), or infiltrate (commonly localized to the allograft). Multifocal or disseminated disease can also occur, including lymphoma or with central nervous system, gastrointestinal, or pulmonary involvement.

Biopsy of the affected site is required for histopathology and Epstein-Barr virus markers. PCR blood testing is often positive for Epstein-Barr virus.

Typical antiviral therapy does not eliminate Epstein-Barr virus. In early polyclonal viral proliferation, the first goal is to reduce immunosuppressive therapy. Rituximab alone may also help in polymorphic cases. With disease that is clearly monomorphic and has transformed to a true malignancy, cytotoxic chemotherapy is also required. “R-CHOP,” a combination therapy consisting of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone, is usually used. Radiation therapy may help in some cases.

Cryptococcal infection

Previously seen in patients with acquired immune deficiency syndrome, cryptococcal infection is now most commonly encountered in patients with solid-organ transplants. Vilchez et al¹² found a 1% incidence in a series of more than 5,000 patients who had received an organ transplant.

Immunosuppression likely conveys risk, but because cryptococcal infection is acquired, environmental exposure also plays a role. It tends to appear more than 6 months after transplant, indicating that its cause is a primary infection by spore inhalation rather than by reactivation or transmission from the donor organ.¹³ Bird exposure is a risk factor for cryptococcal infection. One case identified the same strain of Cryptococcus in a kidney transplant recipient and the family’s pet cockatoo.¹⁴

Cryptococcal infection typically starts as pneumonia, which may be subclinical. The infection can then disseminate, with meningitis presenting with headache and mental status changes being the most concerning complication. The death rate is about 50% in most series of patients with meningitis. Skin and soft-tissue manifestations may also occur in 10% to 15% of cases and can be nodular, ulcerative, or cellulitic.

More than 75% of fungal infections requiring hospitalization in US patients who have undergone transplant are attributed to either Candida, Aspergillus, or Cryptococcus species.¹⁵ Risk of fungal infection is increased with diabetes, duration of pretransplant dialysis, tacrolimus therapy, or rejection treatment.

Much has improved in renal transplantation over the past 20 years. The focus has shifted to using stronger immunotherapy rather than trying to minimize it. There has been increasing recognition of infection and ways to prevent and treat it. Induction therapy now has greater emphasis so that maintenance therapy can be eased, with the aim of reducing long-term toxicity. Perhaps the biggest change is the practice of screening for donor-specific antibodies at the time of transplant so that predictable problems can be prevented or better handled if they occur. Such advances have helped patients directly and by extending the life of their transplanted organs.

LONGER SURVIVAL

As early as the 1990s, it was recognized that kidney transplant offers a survival advantage for patients with end-stage renal disease over maintenance on dialysis.¹ Although the risk of death is higher immediately after transplant, within a few months it becomes much lower than for patients on dialysis. Survival varies according to the health of the patient and the quality of the transplanted organ.

In general, patients who obtain the greatest benefit from transplants in terms of years of life gained are those with diabetes, especially those who are younger. Those ages 20 to 39 live about 8 years on dialysis vs 25 years after transplant.

CONTRAINDICATIONS TO TRANSPLANT

There are multiple contraindications to a solitary kidney transplant (Table 1), including smoking. Most transplant centers require that smokers quit before transplant. Long-standing smokers almost double their risk of a cardiac event after transplant and double their rate of malignancy. Active smoking at the time of transplant is associated with twice the risk of death by 10 years after transplant compared with that of nonsmokers.² Cotinine testing can detect whether a patient is an active smoker.

WAITING-LIST CONSIDERATIONS

Organs are scarce

The number of patients on the kidney waiting list has increased rapidly in the last few decades, while the number of transplants performed each year has remained about the same. In 2016, about 100,000 patients were on the list, but only about 19,000 transplants were performed.³ Wait times, especially for deceased-donor organs, have increased to about 6 years, varying by blood type and geographic region.

Waiting-list placement

Placement on the waiting list for a deceased-donor kidney transplant occurs when a patient has an estimated glomerular filtration rate (GFR) of 20 mL/min/1.73 m² or less, although referral to the list can be made earlier. Early listing remains advantageous, as total time on the list will be counted before starting dialysis. “Preemptive transplant” means the patient had no dialysis before transplant; this applies to about 10% of transplant recipients. These patients tend to fare the best and are usually recipients of a living-donor organ.

Most patients do not receive a transplant until the GFR is less than 15 mL/min/1.73 m².

Since 2014, wait time has been measured from the beginning of dialysis rather than the date of waiting-list placement in patients who are listed after starting dialysis therapy. This approach is more fair but sometimes introduces problems. A patient who did not previously know about the list may suddenly jump to the head of the line after 10 years of dialysis, by which time comorbidities associated with long-term dialysis make the patient less likely to gain as much benefit from a transplant as people lower on the list. Time on dialysis, or “dialysis vintage,” predicts patient and kidney survival after transplant, with reduced survival associated with increasing time on dialysis.⁴

Shorter wait for a suboptimal kidney

The aging population has increased the number of older patients being listed for transplant, presenting multiple challenges. Patients age 65 or older have a 50% chance of dying before they receive a transplant during a 5-year wait.

A patient may shorten the wait by joining the list for a suboptimal organ. All deceased-donor organs are given a Kidney Donor Profile Index score, which predicts the longevity of an organ after transplant. The score is determined by donor age, kidney function based on the serum creatinine at the time of death, and other donor factors.

A kidney with a score higher than 85% is likely to function longer than only 15% of available kidneys. Patients who receive a kidney with that score have a longer period of risk of death soon after transplant and a slightly higher risk of death in the long term than patients who receive a healthier kidney, although on average they still do better than patients on dialysis.⁵

Older patients should be encouraged to sign up for both the regular waiting list and the suboptimal kidney waiting list to reduce the risk of dying before they get a kidney.

Many advantages

Living-donor organ transplant is associated with a better survival rate than deceased-donor organ transplant, and the advantage becomes greater over time. At 1 year, patient survival is more than 90% in both groups, but by 5 years about 80% of patients with a living-donor organ are still alive vs only about 65% of patients with a deceased-donor organ.

The waiting time for a living-donor transplant may be only weeks to months, rather than years. Because increasing time on dialysis predicts worse patient and graft survival after transplant, the shorter wait time is a big advantage. In addition, because the donor and recipient are typically in adjacent operating rooms, the organ sustains less ischemic damage. In general, the kidney quality is better from healthy donors, resulting in superior function early on and longer graft survival by an average of 4 years. If the living donor is related to the recipient, human leukocyte antigen matching also tends to be better and predicts better outcomes.

Special challenges

Opting for a living-donor organ also entails special challenges. In addition to the ethical issues surrounding living-donor organ donation, an appropriate donor must be found. Donors must be highly motivated and pass physical, laboratory, and psychological evaluations.

For older patients, if the donor is a spouse or close friend, he or she is also likely to be older, making the organ less viable than one from a younger person. Even an adult child may not be an ideal donor if there is a family propensity to kidney disease, such as diabetic nephropathy. No test is available to determine the risk for future diabetes, but it is known to run in families.

POTENT IMMUNOSUPPRESSION

Induction therapy

Induction therapy with antithymocyte globulin or basiliximab provides intense immunosuppression to prevent acute rejection during the early posttransplant period.

Antithymocyte globulin is a potent agent that contains antibodies directed at T cells, B cells, neutrophils, platelets, adhesion molecules, and complement. It binds T cells and removes them from circulation by opsonization in splenic and lymphoid tissue. The immunosuppressive effect is sustained for at least 2 to 3 months after a series of injections (dosage 1.5 mg/kg/day, usually for 4 to 10 doses). Antithymocyte globulin is also used to treat acute rejection, especially high-grade rejection for which steroid therapy is likely to be insufficient.

Basiliximab consists of antibodies to the interleukin 2 (IL-2) receptor of T cells. Binding to T cells prevents their activation rather than removing them from circulation. The drug prevents rejection, with 30% relative reduction in early studies compared with placebo. However, it is ineffective in reversing established rejection. Dosage is 20 mg at day 0 and day 4, which provides receptor saturation for 30 to 45 days.

Basiliximab is also sometimes used off-label for patients who need to discontinue a calcineurin inhibitor (ie, tacrolimus or cyclosporine). In such cases, normal therapy is put on hold while basiliximab is given for 1 or 2 doses. Case series have been reported for this use, particularly for patients with a heart and liver transplant who develop acute kidney injury while hospitalized.^6,7

Antithymocyte globulin is more effective but also more risky. Brennan et al⁸ randomized 278 transplant recipients to either antithymocyte globulin or basiliximab. Patients in the antithymocyte globulin group had a 16% rejection rate vs 26% in the basiliximab group.

Antithymocyte globulin therapy is associated with multiple adverse effects, including fever and chills, pulmonary edema, and long-standing immunosuppressive effects such as increased risk of lymphoma and cytomegalovirus (CMV) infection. Basiliximab side-effect profiles are similar to those of placebo.

Maintenance therapy

The calcineurin inhibitors cyclosporine and tacrolimus remain the standard of care in kidney transplant despite multiple drug interactions and side effects that include renal toxicity and fibrosis. Cyclosporine and tacrolimus both bind intracellular immunophilins and thereby prevent transcription of IL-2 and production of T cells. The drugs work similarly but have different binding sites. Cyclosporine has largely been replaced by tacrolimus because its reliability of dosing and higher potency are associated with lower rejection rates.

Tacrolimus is typically given twice daily (1–6 mg/dose). Twelve-hour trough levels are followed (target: 8–12 ng/mL early on, then 5–8 ng/mL after 3 months posttransplant). Side effects include hypertension and hypercholesterolemia, but less so than with cyclosporine. On the other hand, hyperglycemia tends to be worse with tacrolimus than with cyclosporine, and combining tacrolimus with steroids frequently leads to diabetes. Tacrolimus can also cause acute and chronic renal failure, especially at high drug levels, as well as neurotoxicity, tremors, and hair loss.

Cyclosporine, tacrolimus, and sirolimus (not a calcineurin inhibitor) are metabolized through the same cytochrome P450 pathway (CYP3A4), so they have common drug interactions (Table 2).

Mycophenolate mofetil is typically used as an adjunct therapy (500–1,000 mg twice daily). It is also used for other kidney diseases before transplant, including lupus nephritis. Transplanted kidney rejection rates with mycophenolate mofetil with steroids are about 40%, so the drug is not potent enough to be used without a calcineurin inhibitor.

Side effects include gastrointestinal toxicity in up to 20% of patients, and leukopenia, which is associated with viral infections.

CORONARY ARTERY DISEASE IS COMMON WITH DIALYSIS

Coronary artery disease is highly associated with end-stage kidney disease and occurs in as many as 85% of older patients with diabetes on dialysis. Although patients with end-stage kidney disease tend to have more numerous and severe atherosclerotic lesions compared with the general population, justifying aggressive management, cardiac care tends to be conservative in patients on dialysis.⁹

Death from acute myocardial infarction occurs in about 20% to 30% of patients on dialysis vs about 2% of patients with normal renal function. Five years after myocardial infarction, survival is only about 30% in patients on dialysis.⁹

There are many explanations for excess coronary artery disease in patients on dialysis. In addition to the traditional cardiovascular risk factors of diabetes, hypertension, and preexisting coronary artery disease, patients are in a proinflammatory uremic state and have high levels of phosphorus and fibroblast growth factor 23 that contribute to vascular calcification. Almost all patients have high homocysteine levels and hemodynamic instability, particularly if they are on hemodialysis.

Pretransplant evaluation for heart disease

Patients on the kidney transplant waiting list are screened aggressively for heart disease. A history of myocardial infarction usually results in removal from the list. All patients have an initial electrocardiogram and echocardiogram. Thallium or echocardiographic stress testing is used for patients who are age 50 and older, have diabetes, or have had dialysis for many years. Patients with evidence of ischemia undergo catheterization.

Patients are also screened with computed tomography before transplant. Because the kidney is typically anastomosed to the iliac artery and vein, heavy calcification of the iliac artery can make the procedure too difficult to perform.

Kasiske et al¹⁰ analyzed data from more than 50,000 patients from the US Renal Data System and found that, for about the first year after transplant, patients who underwent kidney transplant were more likely to have a myocardial infarction than those on dialysis. After that, they fared better than patients who remained on dialysis. Those with a living-donor transplant were less likely at all times to have a myocardial infarction than those with a deceased-donor transplant. By 3 years after transplant, the relative risk of having a myocardial infarction was 0.89 for deceased-donor organ recipients and 0.69 for living-donor recipients compared with patients on the waiting list.¹⁰

INFECTIOUS COMPLICATIONS IN KIDNEY RECIPIENTS

Kidney recipients are prone to many common and uncommon infections (Table 3). All potential recipients are tested pretransplant for hepatitis B, hepatitis C, human immunodeficiency virus, syphilis, and tuberculosis. A positive result does not necessarily rule out transplant.

The following viral serology tests are also done before transplant:

Epstein-Barr virus (antibodies are positive in about 90% of adults)

CMV (about 70% of adults are seropositive)

Varicella zoster (seronegative patients should be given live-attenuated varicella vaccine).

Risk of transmission of these viruses relates to the serostatus of the donor and recipient before transplant. If a donor is positive for viral antibodies but the recipient is not (a so-called “mismatch”), risk is higher after transplant.

Hepatitis C

Patients with hepatitis C fare better if they get a transplant than if they remain on dialysis, although their posttransplant course is worse compared with transplant patients who do not have hepatitis. Some patients develop accelerated liver disease after kidney transplant. Hepatitis C-related kidney disease—membranous proliferative glomerulonephritis—also occurs, as do comorbidities such as diabetes.

Careful evaluation is warranted before transplant, including liver imaging, alpha-fetoprotein testing, and liver biopsy to evaluate for hepatocellular carcinoma. A patient with advanced fibrosis or cirrhosis may not be a candidate for kidney transplant alone but could possibly receive a combined kidney and liver transplant.

There is a need to determine the best time to treat hepatitis C infection. Patients with advanced liver disease or hepatitis C-related kidney disease would likely benefit from early treatment. However, delaying treatment could shorten the wait time for a deceased-donor organ positive for hepatitis C.  Transplant candidates with active hepatitis C are uniquely considered to accept hepatitis C-positive kidneys, which are often discarded, and may only wait weeks for such a transplant. The shortened kidney survival associated with a hepatitis C-positive kidney may no longer be true with the new antiviral hepatitis C therapy, which has been shown to be effective post-transplant.

Hepatitis B

No cure is available for hepatitis B infection, but it can be well controlled with antiviral therapy. Patients with hepatitis B infection may be candidates for transplant, but they should be stable on antiviral therapy (lamivudine, entecavir, or tenofovir) to eliminate the viral load before transplant, and therapy should be continued afterward. Liver imaging, alpha-fetoprotein levels, and biopsy are recommended for evaluation. All hepatitis B- negative patients should be vaccinated before transplant.

Organs from living or deceased donors that test positive for hepatitis B core antibody, indicating prior exposure, can be considered for transplant in a patient who tests positive for hepatitis B surface antibody, indicating successful vaccination or prior exposure in the recipient. But donors must have negative surface antigen and polymerase chain reaction (PCR) tests that indicate no active hepatitis B infection.

Cytomegalovirus

CMV typically does not appear until prophylactic therapy is stopped. Classic symptoms are fever, leukopenia, and diarrhea. Infection can involve any organ, and patients may present with hepatitis, pancreatitis or, less commonly, pneumonitis.

Patients who are negative for CMV before transplant and receive a donor-positive organ are at the highest risk. Patients who are CMV IgG-positive are considered to be at intermediate risk, regardless of the donor status. Patients who are negative for CMV and receive a donor-negative organ are at the lowest risk and do not need prophylaxis with valganciclovir.

CMV infection is diagnosed by PCR testing of the blood or immunostaining in tissue biopsy. Occasionally, blood testing is negative in the face of tissue-based disease.

BK virus

BK is a polyoma virus and a common virus associated with kidney transplant. Viremia is seen in about 18% of patients, whereas actual kidney disease associated with a higher level of virus is seen in fewer than 10% of patients. Most people are exposed to BK virus, often in childhood, and it can remain indolent in the bladder and uroepithelium.

Patients can develop BK nephropathy after exposure to transplant immunosuppression.¹¹ Posttransplant monitoring protocols typically include PCR testing for BK virus at 1, 3, 6, and 12 months. No agent has been identified to specifically treat BK virus. The general strategy is to minimize immunosuppressive therapy by reducing or eliminating mycophenolate mofetil. Fortunately, BK virus does not tend to recur, and patients can have a low-level viremia (< 10,000 copies/mL) persisting over months or even years but often without clinical consequences.

The appearance of BK virus on biopsy can mimic acute rejection. Before BK viral nephropathy was a recognized entity, patients would have been diagnosed with acute rejection and may have been put on high-dose steroids, which would have worsened the BK infection.

Posttransplant lymphoproliferative disorder

Posttransplant lymphoproliferative disorder is most often associated with Epstein-Barr virus and usually involves a large, diffuse B-cell lymphoma. Burkitt lymphoma and plasma cell neoplasms also can occur less commonly.

The condition is about 30 times more common in patients after transplant than in the general population, and it is the third most common malignancy in transplant patients after skin and cervical cancers. About 80% of the cases occur early after transplant, within the first year.

Patients typically have a marked elevation in viral load of Epstein-Barr virus, although a negative viral load does not rule it out. A patient who is serologically negative for Epstein-Barr virus receiving a donor-positive kidney is at highest risk; this situation is most often seen in the pediatric population. Potent induction therapies (eg, antilymphocyte antibody therapy) are also associated with posttransplant lymphoproliferative disorder.

Patients typically present with fever of unknown origin with no localizing signs or symptoms. Mass lesions can be challenging to find; positron emission tomography may be helpful. The culprit is usually a focal mass, ulcer (especially in the gastrointestinal tract), or infiltrate (commonly localized to the allograft). Multifocal or disseminated disease can also occur, including lymphoma or with central nervous system, gastrointestinal, or pulmonary involvement.

Biopsy of the affected site is required for histopathology and Epstein-Barr virus markers. PCR blood testing is often positive for Epstein-Barr virus.

Typical antiviral therapy does not eliminate Epstein-Barr virus. In early polyclonal viral proliferation, the first goal is to reduce immunosuppressive therapy. Rituximab alone may also help in polymorphic cases. With disease that is clearly monomorphic and has transformed to a true malignancy, cytotoxic chemotherapy is also required. “R-CHOP,” a combination therapy consisting of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone, is usually used. Radiation therapy may help in some cases.

Cryptococcal infection

Previously seen in patients with acquired immune deficiency syndrome, cryptococcal infection is now most commonly encountered in patients with solid-organ transplants. Vilchez et al¹² found a 1% incidence in a series of more than 5,000 patients who had received an organ transplant.

Immunosuppression likely conveys risk, but because cryptococcal infection is acquired, environmental exposure also plays a role. It tends to appear more than 6 months after transplant, indicating that its cause is a primary infection by spore inhalation rather than by reactivation or transmission from the donor organ.¹³ Bird exposure is a risk factor for cryptococcal infection. One case identified the same strain of Cryptococcus in a kidney transplant recipient and the family’s pet cockatoo.¹⁴

Cryptococcal infection typically starts as pneumonia, which may be subclinical. The infection can then disseminate, with meningitis presenting with headache and mental status changes being the most concerning complication. The death rate is about 50% in most series of patients with meningitis. Skin and soft-tissue manifestations may also occur in 10% to 15% of cases and can be nodular, ulcerative, or cellulitic.

More than 75% of fungal infections requiring hospitalization in US patients who have undergone transplant are attributed to either Candida, Aspergillus, or Cryptococcus species.¹⁵ Risk of fungal infection is increased with diabetes, duration of pretransplant dialysis, tacrolimus therapy, or rejection treatment.

Much has improved in renal transplantation over the past 20 years. The focus has shifted to using stronger immunotherapy rather than trying to minimize it. There has been increasing recognition of infection and ways to prevent and treat it. Induction therapy now has greater emphasis so that maintenance therapy can be eased, with the aim of reducing long-term toxicity. Perhaps the biggest change is the practice of screening for donor-specific antibodies at the time of transplant so that predictable problems can be prevented or better handled if they occur. Such advances have helped patients directly and by extending the life of their transplanted organs.

LONGER SURVIVAL

As early as the 1990s, it was recognized that kidney transplant offers a survival advantage for patients with end-stage renal disease over maintenance on dialysis.¹ Although the risk of death is higher immediately after transplant, within a few months it becomes much lower than for patients on dialysis. Survival varies according to the health of the patient and the quality of the transplanted organ.

In general, patients who obtain the greatest benefit from transplants in terms of years of life gained are those with diabetes, especially those who are younger. Those ages 20 to 39 live about 8 years on dialysis vs 25 years after transplant.

CONTRAINDICATIONS TO TRANSPLANT

There are multiple contraindications to a solitary kidney transplant (Table 1), including smoking. Most transplant centers require that smokers quit before transplant. Long-standing smokers almost double their risk of a cardiac event after transplant and double their rate of malignancy. Active smoking at the time of transplant is associated with twice the risk of death by 10 years after transplant compared with that of nonsmokers.² Cotinine testing can detect whether a patient is an active smoker.

WAITING-LIST CONSIDERATIONS

Organs are scarce

The number of patients on the kidney waiting list has increased rapidly in the last few decades, while the number of transplants performed each year has remained about the same. In 2016, about 100,000 patients were on the list, but only about 19,000 transplants were performed.³ Wait times, especially for deceased-donor organs, have increased to about 6 years, varying by blood type and geographic region.

Waiting-list placement

Placement on the waiting list for a deceased-donor kidney transplant occurs when a patient has an estimated glomerular filtration rate (GFR) of 20 mL/min/1.73 m² or less, although referral to the list can be made earlier. Early listing remains advantageous, as total time on the list will be counted before starting dialysis. “Preemptive transplant” means the patient had no dialysis before transplant; this applies to about 10% of transplant recipients. These patients tend to fare the best and are usually recipients of a living-donor organ.

Most patients do not receive a transplant until the GFR is less than 15 mL/min/1.73 m².

Since 2014, wait time has been measured from the beginning of dialysis rather than the date of waiting-list placement in patients who are listed after starting dialysis therapy. This approach is more fair but sometimes introduces problems. A patient who did not previously know about the list may suddenly jump to the head of the line after 10 years of dialysis, by which time comorbidities associated with long-term dialysis make the patient less likely to gain as much benefit from a transplant as people lower on the list. Time on dialysis, or “dialysis vintage,” predicts patient and kidney survival after transplant, with reduced survival associated with increasing time on dialysis.⁴

Shorter wait for a suboptimal kidney

The aging population has increased the number of older patients being listed for transplant, presenting multiple challenges. Patients age 65 or older have a 50% chance of dying before they receive a transplant during a 5-year wait.

A patient may shorten the wait by joining the list for a suboptimal organ. All deceased-donor organs are given a Kidney Donor Profile Index score, which predicts the longevity of an organ after transplant. The score is determined by donor age, kidney function based on the serum creatinine at the time of death, and other donor factors.

A kidney with a score higher than 85% is likely to function longer than only 15% of available kidneys. Patients who receive a kidney with that score have a longer period of risk of death soon after transplant and a slightly higher risk of death in the long term than patients who receive a healthier kidney, although on average they still do better than patients on dialysis.⁵

Older patients should be encouraged to sign up for both the regular waiting list and the suboptimal kidney waiting list to reduce the risk of dying before they get a kidney.

Many advantages

Living-donor organ transplant is associated with a better survival rate than deceased-donor organ transplant, and the advantage becomes greater over time. At 1 year, patient survival is more than 90% in both groups, but by 5 years about 80% of patients with a living-donor organ are still alive vs only about 65% of patients with a deceased-donor organ.

The waiting time for a living-donor transplant may be only weeks to months, rather than years. Because increasing time on dialysis predicts worse patient and graft survival after transplant, the shorter wait time is a big advantage. In addition, because the donor and recipient are typically in adjacent operating rooms, the organ sustains less ischemic damage. In general, the kidney quality is better from healthy donors, resulting in superior function early on and longer graft survival by an average of 4 years. If the living donor is related to the recipient, human leukocyte antigen matching also tends to be better and predicts better outcomes.

Special challenges

Opting for a living-donor organ also entails special challenges. In addition to the ethical issues surrounding living-donor organ donation, an appropriate donor must be found. Donors must be highly motivated and pass physical, laboratory, and psychological evaluations.

For older patients, if the donor is a spouse or close friend, he or she is also likely to be older, making the organ less viable than one from a younger person. Even an adult child may not be an ideal donor if there is a family propensity to kidney disease, such as diabetic nephropathy. No test is available to determine the risk for future diabetes, but it is known to run in families.

POTENT IMMUNOSUPPRESSION

Induction therapy

Induction therapy with antithymocyte globulin or basiliximab provides intense immunosuppression to prevent acute rejection during the early posttransplant period.

Antithymocyte globulin is a potent agent that contains antibodies directed at T cells, B cells, neutrophils, platelets, adhesion molecules, and complement. It binds T cells and removes them from circulation by opsonization in splenic and lymphoid tissue. The immunosuppressive effect is sustained for at least 2 to 3 months after a series of injections (dosage 1.5 mg/kg/day, usually for 4 to 10 doses). Antithymocyte globulin is also used to treat acute rejection, especially high-grade rejection for which steroid therapy is likely to be insufficient.

Basiliximab consists of antibodies to the interleukin 2 (IL-2) receptor of T cells. Binding to T cells prevents their activation rather than removing them from circulation. The drug prevents rejection, with 30% relative reduction in early studies compared with placebo. However, it is ineffective in reversing established rejection. Dosage is 20 mg at day 0 and day 4, which provides receptor saturation for 30 to 45 days.

Basiliximab is also sometimes used off-label for patients who need to discontinue a calcineurin inhibitor (ie, tacrolimus or cyclosporine). In such cases, normal therapy is put on hold while basiliximab is given for 1 or 2 doses. Case series have been reported for this use, particularly for patients with a heart and liver transplant who develop acute kidney injury while hospitalized.^6,7

Antithymocyte globulin is more effective but also more risky. Brennan et al⁸ randomized 278 transplant recipients to either antithymocyte globulin or basiliximab. Patients in the antithymocyte globulin group had a 16% rejection rate vs 26% in the basiliximab group.

Antithymocyte globulin therapy is associated with multiple adverse effects, including fever and chills, pulmonary edema, and long-standing immunosuppressive effects such as increased risk of lymphoma and cytomegalovirus (CMV) infection. Basiliximab side-effect profiles are similar to those of placebo.

Maintenance therapy

The calcineurin inhibitors cyclosporine and tacrolimus remain the standard of care in kidney transplant despite multiple drug interactions and side effects that include renal toxicity and fibrosis. Cyclosporine and tacrolimus both bind intracellular immunophilins and thereby prevent transcription of IL-2 and production of T cells. The drugs work similarly but have different binding sites. Cyclosporine has largely been replaced by tacrolimus because its reliability of dosing and higher potency are associated with lower rejection rates.

Tacrolimus is typically given twice daily (1–6 mg/dose). Twelve-hour trough levels are followed (target: 8–12 ng/mL early on, then 5–8 ng/mL after 3 months posttransplant). Side effects include hypertension and hypercholesterolemia, but less so than with cyclosporine. On the other hand, hyperglycemia tends to be worse with tacrolimus than with cyclosporine, and combining tacrolimus with steroids frequently leads to diabetes. Tacrolimus can also cause acute and chronic renal failure, especially at high drug levels, as well as neurotoxicity, tremors, and hair loss.

Cyclosporine, tacrolimus, and sirolimus (not a calcineurin inhibitor) are metabolized through the same cytochrome P450 pathway (CYP3A4), so they have common drug interactions (Table 2).

Mycophenolate mofetil is typically used as an adjunct therapy (500–1,000 mg twice daily). It is also used for other kidney diseases before transplant, including lupus nephritis. Transplanted kidney rejection rates with mycophenolate mofetil with steroids are about 40%, so the drug is not potent enough to be used without a calcineurin inhibitor.

Side effects include gastrointestinal toxicity in up to 20% of patients, and leukopenia, which is associated with viral infections.

CORONARY ARTERY DISEASE IS COMMON WITH DIALYSIS

Coronary artery disease is highly associated with end-stage kidney disease and occurs in as many as 85% of older patients with diabetes on dialysis. Although patients with end-stage kidney disease tend to have more numerous and severe atherosclerotic lesions compared with the general population, justifying aggressive management, cardiac care tends to be conservative in patients on dialysis.⁹

Death from acute myocardial infarction occurs in about 20% to 30% of patients on dialysis vs about 2% of patients with normal renal function. Five years after myocardial infarction, survival is only about 30% in patients on dialysis.⁹

There are many explanations for excess coronary artery disease in patients on dialysis. In addition to the traditional cardiovascular risk factors of diabetes, hypertension, and preexisting coronary artery disease, patients are in a proinflammatory uremic state and have high levels of phosphorus and fibroblast growth factor 23 that contribute to vascular calcification. Almost all patients have high homocysteine levels and hemodynamic instability, particularly if they are on hemodialysis.

Pretransplant evaluation for heart disease

Patients on the kidney transplant waiting list are screened aggressively for heart disease. A history of myocardial infarction usually results in removal from the list. All patients have an initial electrocardiogram and echocardiogram. Thallium or echocardiographic stress testing is used for patients who are age 50 and older, have diabetes, or have had dialysis for many years. Patients with evidence of ischemia undergo catheterization.

Patients are also screened with computed tomography before transplant. Because the kidney is typically anastomosed to the iliac artery and vein, heavy calcification of the iliac artery can make the procedure too difficult to perform.

Kasiske et al¹⁰ analyzed data from more than 50,000 patients from the US Renal Data System and found that, for about the first year after transplant, patients who underwent kidney transplant were more likely to have a myocardial infarction than those on dialysis. After that, they fared better than patients who remained on dialysis. Those with a living-donor transplant were less likely at all times to have a myocardial infarction than those with a deceased-donor transplant. By 3 years after transplant, the relative risk of having a myocardial infarction was 0.89 for deceased-donor organ recipients and 0.69 for living-donor recipients compared with patients on the waiting list.¹⁰

INFECTIOUS COMPLICATIONS IN KIDNEY RECIPIENTS

Kidney recipients are prone to many common and uncommon infections (Table 3). All potential recipients are tested pretransplant for hepatitis B, hepatitis C, human immunodeficiency virus, syphilis, and tuberculosis. A positive result does not necessarily rule out transplant.

The following viral serology tests are also done before transplant:

Epstein-Barr virus (antibodies are positive in about 90% of adults)

CMV (about 70% of adults are seropositive)

Varicella zoster (seronegative patients should be given live-attenuated varicella vaccine).

Risk of transmission of these viruses relates to the serostatus of the donor and recipient before transplant. If a donor is positive for viral antibodies but the recipient is not (a so-called “mismatch”), risk is higher after transplant.

Hepatitis C

Patients with hepatitis C fare better if they get a transplant than if they remain on dialysis, although their posttransplant course is worse compared with transplant patients who do not have hepatitis. Some patients develop accelerated liver disease after kidney transplant. Hepatitis C-related kidney disease—membranous proliferative glomerulonephritis—also occurs, as do comorbidities such as diabetes.

Careful evaluation is warranted before transplant, including liver imaging, alpha-fetoprotein testing, and liver biopsy to evaluate for hepatocellular carcinoma. A patient with advanced fibrosis or cirrhosis may not be a candidate for kidney transplant alone but could possibly receive a combined kidney and liver transplant.

There is a need to determine the best time to treat hepatitis C infection. Patients with advanced liver disease or hepatitis C-related kidney disease would likely benefit from early treatment. However, delaying treatment could shorten the wait time for a deceased-donor organ positive for hepatitis C.  Transplant candidates with active hepatitis C are uniquely considered to accept hepatitis C-positive kidneys, which are often discarded, and may only wait weeks for such a transplant. The shortened kidney survival associated with a hepatitis C-positive kidney may no longer be true with the new antiviral hepatitis C therapy, which has been shown to be effective post-transplant.

Hepatitis B

No cure is available for hepatitis B infection, but it can be well controlled with antiviral therapy. Patients with hepatitis B infection may be candidates for transplant, but they should be stable on antiviral therapy (lamivudine, entecavir, or tenofovir) to eliminate the viral load before transplant, and therapy should be continued afterward. Liver imaging, alpha-fetoprotein levels, and biopsy are recommended for evaluation. All hepatitis B- negative patients should be vaccinated before transplant.

Organs from living or deceased donors that test positive for hepatitis B core antibody, indicating prior exposure, can be considered for transplant in a patient who tests positive for hepatitis B surface antibody, indicating successful vaccination or prior exposure in the recipient. But donors must have negative surface antigen and polymerase chain reaction (PCR) tests that indicate no active hepatitis B infection.

Cytomegalovirus

CMV typically does not appear until prophylactic therapy is stopped. Classic symptoms are fever, leukopenia, and diarrhea. Infection can involve any organ, and patients may present with hepatitis, pancreatitis or, less commonly, pneumonitis.

Patients who are negative for CMV before transplant and receive a donor-positive organ are at the highest risk. Patients who are CMV IgG-positive are considered to be at intermediate risk, regardless of the donor status. Patients who are negative for CMV and receive a donor-negative organ are at the lowest risk and do not need prophylaxis with valganciclovir.

CMV infection is diagnosed by PCR testing of the blood or immunostaining in tissue biopsy. Occasionally, blood testing is negative in the face of tissue-based disease.

BK virus

BK is a polyoma virus and a common virus associated with kidney transplant. Viremia is seen in about 18% of patients, whereas actual kidney disease associated with a higher level of virus is seen in fewer than 10% of patients. Most people are exposed to BK virus, often in childhood, and it can remain indolent in the bladder and uroepithelium.

Patients can develop BK nephropathy after exposure to transplant immunosuppression.¹¹ Posttransplant monitoring protocols typically include PCR testing for BK virus at 1, 3, 6, and 12 months. No agent has been identified to specifically treat BK virus. The general strategy is to minimize immunosuppressive therapy by reducing or eliminating mycophenolate mofetil. Fortunately, BK virus does not tend to recur, and patients can have a low-level viremia (< 10,000 copies/mL) persisting over months or even years but often without clinical consequences.

The appearance of BK virus on biopsy can mimic acute rejection. Before BK viral nephropathy was a recognized entity, patients would have been diagnosed with acute rejection and may have been put on high-dose steroids, which would have worsened the BK infection.

Posttransplant lymphoproliferative disorder

Posttransplant lymphoproliferative disorder is most often associated with Epstein-Barr virus and usually involves a large, diffuse B-cell lymphoma. Burkitt lymphoma and plasma cell neoplasms also can occur less commonly.

The condition is about 30 times more common in patients after transplant than in the general population, and it is the third most common malignancy in transplant patients after skin and cervical cancers. About 80% of the cases occur early after transplant, within the first year.

Patients typically have a marked elevation in viral load of Epstein-Barr virus, although a negative viral load does not rule it out. A patient who is serologically negative for Epstein-Barr virus receiving a donor-positive kidney is at highest risk; this situation is most often seen in the pediatric population. Potent induction therapies (eg, antilymphocyte antibody therapy) are also associated with posttransplant lymphoproliferative disorder.

Patients typically present with fever of unknown origin with no localizing signs or symptoms. Mass lesions can be challenging to find; positron emission tomography may be helpful. The culprit is usually a focal mass, ulcer (especially in the gastrointestinal tract), or infiltrate (commonly localized to the allograft). Multifocal or disseminated disease can also occur, including lymphoma or with central nervous system, gastrointestinal, or pulmonary involvement.

Biopsy of the affected site is required for histopathology and Epstein-Barr virus markers. PCR blood testing is often positive for Epstein-Barr virus.

Typical antiviral therapy does not eliminate Epstein-Barr virus. In early polyclonal viral proliferation, the first goal is to reduce immunosuppressive therapy. Rituximab alone may also help in polymorphic cases. With disease that is clearly monomorphic and has transformed to a true malignancy, cytotoxic chemotherapy is also required. “R-CHOP,” a combination therapy consisting of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone, is usually used. Radiation therapy may help in some cases.

Cryptococcal infection

Previously seen in patients with acquired immune deficiency syndrome, cryptococcal infection is now most commonly encountered in patients with solid-organ transplants. Vilchez et al¹² found a 1% incidence in a series of more than 5,000 patients who had received an organ transplant.

Immunosuppression likely conveys risk, but because cryptococcal infection is acquired, environmental exposure also plays a role. It tends to appear more than 6 months after transplant, indicating that its cause is a primary infection by spore inhalation rather than by reactivation or transmission from the donor organ.¹³ Bird exposure is a risk factor for cryptococcal infection. One case identified the same strain of Cryptococcus in a kidney transplant recipient and the family’s pet cockatoo.¹⁴

Cryptococcal infection typically starts as pneumonia, which may be subclinical. The infection can then disseminate, with meningitis presenting with headache and mental status changes being the most concerning complication. The death rate is about 50% in most series of patients with meningitis. Skin and soft-tissue manifestations may also occur in 10% to 15% of cases and can be nodular, ulcerative, or cellulitic.

More than 75% of fungal infections requiring hospitalization in US patients who have undergone transplant are attributed to either Candida, Aspergillus, or Cryptococcus species.¹⁵ Risk of fungal infection is increased with diabetes, duration of pretransplant dialysis, tacrolimus therapy, or rejection treatment.

A 75-year-old man presented to the emergency department for evaluation of abdominal pain. He had stage 3 chronic obstructive pulmonary disease (COPD), with a forced expiratory volume in 1 second of 33%.

PREVIOUS HOSPITALIZATION

Aside from his COPD, he had been healthy until 1 month earlier, when he had been hospitalized because of shortness of breath and chest pressure with exertion. His troponin T level had been elevated, peaking at 0.117 ng/mL (reference range 0–0.029).

Left heart catheterization had shown no significant coronary artery disease. A myocardial bridge of the distal left anterior descending coronary artery had been seen, so that the artery appeared to be narrowed by 50% to 60% with ventricular contraction. But this was not thought to have been the cause of his presentation.

On discharge, he required oxygen 4 L/min by nasal cannula. Previously, he had not needed supplemental oxygen.

CURRENT PRESENTATION

The patient described persistent and severe periumbilical abdominal pain during the previous day. It was not associated with eating, and he denied diarrhea, constipation, hematemesis, hematochezia, bright red blood per rectum, or melena. He continued to describe persistent shortness of breath and pleuritic chest pain. His vital signs were as follows:

• Heart rate 104 beats per minute
• Respiratory rate 16 to 20 breaths per minute
• Blood pressure 101–142/62–84 mm Hg
• Oxygen saturation 78% on room air.

His laboratory findings on presentation are shown in Table 1, and his electrocardiogram is shown in Figure 1.

WHAT DOES HIS ELECTROCARDIOGRAM SHOW?

1. Which of the following is the most accurate description of this patient’s electrocardiogram?

• Sinus tachycardia, peaked P waves (P pulmonale) in lead II, and T-wave inversions in the right precordial leads
• Sinus tachycardia and left bundle branch block
• Sinus tachycardia and poor R-wave progression
• Sinus tachycardia and ST elevation in the precordial leads

Our patient’s electrocardiogram shows sinus tachycardia, P pulmonale, T-wave inversion in the right precordial leads (V₁–V₃), and biphasic T waves in lead V_4,, which suggest right ventricular strain.

The rhythm most commonly seen in patients with pulmonary embolism is sinus tachycardia, followed by nonspecific ST-segment or T-wave abnormalities. In one series of patients with acute pulmonary embolism, the classic findings of P pulmonale, right ventricular hypertrophy, right axis deviation, and right bundle branch block were rare (< 6%).¹ Thus, these classic findings are not sensitive for the diagnosis of pulmonary embolism, and their absence does not rule it out.

Further studies for our patient

Transthoracic echocardiography was performed to look for evidence of right ventricular strain secondary to the pulmonary embolism.

2. Which of the following findings on transthoracic echocardiography would not suggest acute pulmonary embolism?

• Midright ventricular wall hypokinesis with apical sparing
• Severe tricuspid regurgitation
• Left ventricular dilation
• Lack of respiratory variation of the inferior vena cava
• Septal wall motion toward the left ventricle

Left ventricular dilation does not suggest acute pulmonary embolism. Echocardiograms of patients with acute submassive pulmonary embolism typically show evidence of right ventricular strain, such as the other entities listed above (midright ventricular hypokinesis with apical sparing, severe tricuspid regurgitation, lack of respiratory variation of the inferior vena cava, and septal wall motion toward the left ventricle).

The degree of right ventricular dysfunction is related to the extent of acute pulmonary vascular occlusion and aids in risk-stratification of patients with acute pulmonary embolism. Midright ventricular wall hypokinesis with apical sparing has been termed the McConnell sign.²

In our patient, transthoracic echocardiography showed:

• Normal left ventricular ejection fraction
• Mild diastolic dysfunction
• Right ventricular dilation with moderately decreased right ventricular systolic function and apical sparing
• Right ventricular systolic pressure 54 mm Hg, consistent with moderate pulmonary hypertension
• Right atrial pressure 10 mm Hg
• No inspiratory collapse of a dilated inferior vena cava
• Mild tricuspid valve regurgitation.

CLASSIFICATION OF ACUTE PULMONARY EMBOLISM

3. Given the above information, how would you classify the patient’s pulmonary embolism?

• Massive
• Submassive
• Low-risk
• Clinically stable

The patient’s pulmonary embolism is submassive.

Historically, the classification of pulmonary embolism was determined by the angiographic thrombus burden. However, this has limited utility because clinical factors (eg, hypotension on initial presentation) have been shown to be better predictors of short-term mortality risk.³

Our patient is characterized as having a submassive pulmonary embolism based on elevated biomarkers (troponin T, N-terminal pro-B-type natriuretic peptide) and right ventricular dysfunction in the absence of hypotension.

ULTRASONOGRAPHY FOR DIAGNOSIS OF DEEP VEIN THROMBOSIS

Venous duplex ultrasonography has become the standard for diagnosis of lower extremity deep vein thrombosis. However, its quality and diagnostic accuracy depend on the skill of the person performing the examination. It is further limited by certain patient characteristics, including severe obesity, edema, and wounds and dressings at the site being examined.⁵

Our patient underwent duplex ultrasonography of the lower extremities, which demonstrated acute proximal and calf deep vein thrombosis in the right femoral, popliteal, and peroneal veins and no deep vein thrombosis in the left leg.

Multiple models exist to estimate the risk of complications in patients with acute pulmonary embolism.

The Bova score⁶ is based on the following factors:

• Systolic blood pressure 90–100 mm Hg (2 points) (patients with systolic blood pressure lower than 90 mm Hg were excluded from the study from which this score was derived)
• Cardiac troponin elevation (2 points)
• Right ventricular dysfunction on echocardiography or computed tomography (2 points)
• Heart rate 100 beats/min or greater (1 point).

A total score of 0, 1, or 2 (stage I) denotes low risk, 3 or 4 points (stage II) intermediate risk, and more than 4 points (stage III) high risk.

The PESI score (Pulmonary Embolism Severity Index)⁷ is based on:

• Age (1 point per year)
• Sex (10 points for being male)
• Heart rate 110 per minute or greater (20 points)
• Cancer (30 points)
• Heart failure (10 points)
• Chronic lung disease (10 points)
• Systolic blood pressure less than 100 mm Hg (30 points)
• Respiratory rate at least 30 per minute (20 points)
• Temperature less than 36ºC (20 points)
• Altered mental status (60 points)
• Arterial oxygen saturation less than 90% (20 points).

The total score is broken down into 5 classes: I (< 65 points), II (65–85), III (86–105), IV (106–125), and V (> 126). Classes I and II are low risk, and the higher ones are high risk.

The simplified PESI score⁸ was developed to more rapidly risk-stratify patients and has been found to be similar to the PESI score in prognostic accuracy. Patients get 1 point for each of the following:

• Age over 80
• Cancer
• Chronic cardiopulmonary disease (heart failure or chronic lung disease)
• Heart rate 110 per minute or greater
• Systolic blood pressure less than 100 mm Hg
• Arterial oxygen saturation less than 90%.

A total score of 0 is low risk; anything higher is high risk.

Back to our patient

Our patient had proximal and calf deep vein thrombosis of the right leg, bilateral submassive pulmonary emboli with associated biomarker elevation and right ventricular dysfunction, and left renal artery thrombosis with infarction. Using the PESI score, his risk of death in the next 30 days was 13.7% and his 30-day risk of a complicated course was 27%. Using the Bova score, his 30-day risk of death was 15.5% and his 30-day risk of a complicated course was 29.2%.^6,7

Notably, the patient’s right ventricular function had also been impaired on the echocardiogram performed during his admission 1 month previously. On transthoracic echocardiography during the current admission, the patient was found to have a similar degree of right ventricular dysfunction. This finding, along with the oxygen requirement that developed during the earlier admission, suggested that his pulmonary embolism may have been subacute and that the diagnosis may have been missed during the earlier hospital stay.

The patient was treated with unfractionated heparin. After the hospital’s multidisciplinary pulmonary embolism response team discussed and weighed the above factors, they recommended to not pursue thrombolytic therapy or inferior vena cava filter placement.

Of note, the patient’s pulses in the left lower extremity continued to be weak but palpable, and the left leg was cooler to touch than the right leg.

ASSESSING PERIPHERAL ARTERY DISEASE

4. How should the finding of weak pulses in this patient’s left leg be initially investigated?

• Computed tomographic angiography with runoff
• Ankle-brachial indices with pulse-volume recordings
• Arterial duplex ultrasonography
• Magnetic resonance angiography of the lower extremities

The ankle-brachial index is the initial diagnostic test for assessment of pulse abnormalities and for diagnosis of lower-extremity peripheral artery disease. It is calculated by dividing the higher of the ankle systolic pressures (posterior tibial or dorsalis pedis) by the higher of the 2 brachial pressures (left or right).⁹ Normal values are between 1.00 and 1.40.

Ankle-brachial indices in our patient

Our patient underwent measurement of his brachial, dorsalis pedis, and posterior tibial artery systolic pressures using blood pressure cuffs and continuous-wave Doppler. Ankle pulse-volume recordings were also obtained.

Given the patient’s poor renal function and concern for acute renal infarction, we thought it best to avoid iodinated or gadolinium contrast, such as with magnetic resonance or computed tomographic angiography.

Segmental leg pressures and pulse-volume recordings can be performed to help localize the level of arterial disease in the extremities, but were not done in this case because of the extensive deep vein thrombosis in the right leg.^10,11

Arterial ultrasonography in our patient

Arterial duplex ultrasonography was performed to help determine the location of arterial disease. It showed patent arteries in the right leg. In the left lower extremity there was slow, monophasic blood flow in the distal superficial femoral artery. The popliteal artery was occluded. The posterior tibial artery was occluded at the origin, with reconstitution distally. The peroneal artery was occluded throughout. The anterior tibial artery was patent throughout. The ultrasonographic findings were thought to be suspicious for arterial thromboembolism.

5. Given that the patient had both arterial thrombosis (renal artery, lower-extremity arteries) and venous thromboembolism (deep vein thrombosis and pulmonary embolism), which of the following would be included in the differential diagnosis?

• Antiphospholipid antibody syndrome
• Protein C or protein S deficiency
• Malignancy
• Paradoxical embolization
• Factor V Leiden mutation

Correct answers include antiphospholipid antibody syndrome, malignancy, and paradoxical embolization.

The differential diagnosis for concomitant venous and arterial thrombosis is broad,¹² and includes the following:

• Structural factors: patent foramen ovale, popliteal artery aneurysm
• Malignancy
• Inflammatory diseases: Behçet disease, Buerger disease, inflammatory bowel disease, antiphospholipid antibody syndrome, elevated lipoprotein(a), elevated homocysteine
• Hematologic diseases: myelodysplastic syndrome, disseminated intravascular coagulation, paroxysmal nocturnal hemoglobinuria, heparin-induced thrombocytopenia.

Traditional risk factors for venous thromboembolism include protein C deficiency, protein S deficiency, factor V Leiden mutation, the prothrombin G20210A gene mutation, and others. These are relatively minor risk factors for venous thrombosis and do not pose a risk for arterial thrombosis.¹² In contrast, antiphospholipid antibody syndrome and malignancy pose a risk for both venous and arterial thrombosis. Paradoxical embolism is a mechanism by which arterial thrombosis (emboli) can develop in the setting of existing venous thrombosis.¹²

Our patient underwent testing for antiphospholipid antibodies and lupus anticoagulant, and he was encouraged to undergo age-appropriate cancer screening as an outpatient.¹²

ANTIPHOSPHOLIPID ANTIBODY SYNDROME

Antiphospholipid antibody syndrome is defined by both clinical and laboratory criteria. Clinical symptoms include vascular thrombosis (arterial, venous, or both) and pregnancy-related complications.¹³

Laboratory criteria require the presence of antiphospholipid antibodies or lupus anticoagulant. These must be confirmed with repeat testing in 12 weeks. Antiphospholipid antibodies are detected by an enzyme-linked immunosorbent assay; laboratory assessment for the presence of lupus anticoagulant is a stepwise process and relies on 4 criteria:

• There should be prolongation of a phospholipid-dependent clotting test (eg, activated partial thromboplastin time, dilute Russell viper venom time test).
• There must be evidence of an inhibitory activity with mixing study.
• The inhibitor must exhibit phospholipid dependence; that is, with more phospholipid there is shortening of clotting time.
• Specific inhibitors must be excluded, including factor VIII and anticoagulant drugs such as heparin.^14–17

From Houghton DE, Moll S. Antiphospholipid antibodies. Vasc Med 2017; 22:545–550.

Clinically, one should consider antiphospholipid antibody syndrome in patients who have arterial thrombosis, a history of pregnancy morbidity, or unexplained prolongation of activated partial thromboplastin time.¹³

Antiphospholipid antibodies may be present in up to a quarter of patients with venous thromboembolism, but it is persistent positivity of antibody assays that is associated with increased future risk of venous thromboembolism.¹⁹ Of note, the risk of venous thromboembolism in patients with confirmed antiphospholipid antibody syndrome is 10 times higher than in the general population.²⁰

ANTIPHOSPHOLIPID ANTIBODIES ARE NOT ALL THE SAME

6. Which of the following antiphospholipid antibodies have not been associated with an increased thrombotic risk?

• Anti-beta-2-glycoprotein I IgG
• Lupus anticoagulant
• Antiphosphatidylserine
• Anticardiolipin IgM
• Anticardiolipin IgG

The correct answer is antiphosphatidylserine.¹⁵

Antiphospholipid antibodies are directed against a portion of select plasma proteins that are uncovered upon phospholipid binding. While lupus anticoagulant, anti-beta-2-glycoprotein I, and anticardiolipin antibodies are associated with thrombosis, antiprothrombin antibodies (including antiprothrombin and antiphosphatidylserine antibodies) are not.^15,21

Patent foramen ovale, a communication between the right and left atrium in the interatrial septum, is associated with an increased risk of paradoxical embolization. The prevalence of patent foramen ovale is estimated to be 27% to 29% in the general population.²² Noncerebral systemic paradoxical embolism occurs less frequently than cerebral embolism, accounting for approximately 5% to 10% of paradoxical emboli.²²

To evaluate for patent foramen ovale, transthoracic echocardiography is performed with a bubble (agitated saline contrast) study to assess for interatrial shunting. Transesophageal echocardiography or transcranial Doppler bubble studies may also be performed.

Although patent foramen ovale is most commonly associated with cerebral embolism, peripheral emboli can occur. Some research suggests that this may be a more common cause of arterial thromboembolism in younger patients. There have also been reports of other sites of systemic embolization, including the renal artery.¹²

Back to our patient

Initial antiphospholipid antibody testing was positive for lupus anticoagulant. Anticardiolipin and anti-beta-2-glycoprotein I antibodies were not detected.

Transesophageal echocardiography revealed a patent foramen ovale with a highly mobile atrial septum (atrial septal aneurysm).

The patient was treated with intravenous unfractionated heparin with bridging to warfarin with a target international normalized ratio (INR) of 2 to 3. His renal artery infarction and his lower-extremity arterial thromboembolic event were conservatively managed. His respiratory status improved, and he no longer required supplemental oxygen. His creatinine peaked at 1.7 mg/dL during his admission and improved to 1.2 mg/dL before he was discharged.

At follow-up, repeat echocardiography showed that his right ventricular systolic pressure had improved (decreased) to 37 mm Hg from 54 mm Hg. Repeat confirmatory testing was positive for lupus anticoagulant 12 weeks later. He has been maintained on warfarin with an INR goal of 2 to 3 as well as low-dose aspirin with plans for long-term anticoagulation. We decided to keep the patient on anticoagulation indefinitely with warfarin; he was not a candidate for a direct oral anticoagulant, given limited data on the use of these agents in the setting of lupus anticoagulant and antiphospholipid antibody syndrome.

SUMMARY OF CASE

In summary, this patient was a 75-year-old man with COPD who presented with abdominal pain. He was noted to have a left renal infarction, extensive unprovoked lower-extremity deep vein thrombosis with pulmonary emboli, and lower limb arterial thromboembolism.

He also had an underlying hypercoagulable state—antiphospholipid antibody syndrome—that predisposed him to both arterial and venous thrombosis. He was ultimately found to have a patent foramen ovale, which further increased the risk of arterial thrombosis by facilitating paradoxical embolization of venous thrombi. It is not certain whether the renal infarction and leg artery thrombi were due to paradoxical embolism or to in situ thrombosis, but we believe that it was most likely paradoxical embolization.        

A 75-year-old man presented to the emergency department for evaluation of abdominal pain. He had stage 3 chronic obstructive pulmonary disease (COPD), with a forced expiratory volume in 1 second of 33%.

PREVIOUS HOSPITALIZATION

Aside from his COPD, he had been healthy until 1 month earlier, when he had been hospitalized because of shortness of breath and chest pressure with exertion. His troponin T level had been elevated, peaking at 0.117 ng/mL (reference range 0–0.029).

Left heart catheterization had shown no significant coronary artery disease. A myocardial bridge of the distal left anterior descending coronary artery had been seen, so that the artery appeared to be narrowed by 50% to 60% with ventricular contraction. But this was not thought to have been the cause of his presentation.

On discharge, he required oxygen 4 L/min by nasal cannula. Previously, he had not needed supplemental oxygen.

CURRENT PRESENTATION

The patient described persistent and severe periumbilical abdominal pain during the previous day. It was not associated with eating, and he denied diarrhea, constipation, hematemesis, hematochezia, bright red blood per rectum, or melena. He continued to describe persistent shortness of breath and pleuritic chest pain. His vital signs were as follows:

• Heart rate 104 beats per minute
• Respiratory rate 16 to 20 breaths per minute
• Blood pressure 101–142/62–84 mm Hg
• Oxygen saturation 78% on room air.

His laboratory findings on presentation are shown in Table 1, and his electrocardiogram is shown in Figure 1.

WHAT DOES HIS ELECTROCARDIOGRAM SHOW?

1. Which of the following is the most accurate description of this patient’s electrocardiogram?

• Sinus tachycardia, peaked P waves (P pulmonale) in lead II, and T-wave inversions in the right precordial leads
• Sinus tachycardia and left bundle branch block
• Sinus tachycardia and poor R-wave progression
• Sinus tachycardia and ST elevation in the precordial leads

Our patient’s electrocardiogram shows sinus tachycardia, P pulmonale, T-wave inversion in the right precordial leads (V₁–V₃), and biphasic T waves in lead V_4,, which suggest right ventricular strain.

The rhythm most commonly seen in patients with pulmonary embolism is sinus tachycardia, followed by nonspecific ST-segment or T-wave abnormalities. In one series of patients with acute pulmonary embolism, the classic findings of P pulmonale, right ventricular hypertrophy, right axis deviation, and right bundle branch block were rare (< 6%).¹ Thus, these classic findings are not sensitive for the diagnosis of pulmonary embolism, and their absence does not rule it out.

Further studies for our patient

Transthoracic echocardiography was performed to look for evidence of right ventricular strain secondary to the pulmonary embolism.

2. Which of the following findings on transthoracic echocardiography would not suggest acute pulmonary embolism?

• Midright ventricular wall hypokinesis with apical sparing
• Severe tricuspid regurgitation
• Left ventricular dilation
• Lack of respiratory variation of the inferior vena cava
• Septal wall motion toward the left ventricle

Left ventricular dilation does not suggest acute pulmonary embolism. Echocardiograms of patients with acute submassive pulmonary embolism typically show evidence of right ventricular strain, such as the other entities listed above (midright ventricular hypokinesis with apical sparing, severe tricuspid regurgitation, lack of respiratory variation of the inferior vena cava, and septal wall motion toward the left ventricle).

The degree of right ventricular dysfunction is related to the extent of acute pulmonary vascular occlusion and aids in risk-stratification of patients with acute pulmonary embolism. Midright ventricular wall hypokinesis with apical sparing has been termed the McConnell sign.²

In our patient, transthoracic echocardiography showed:

• Normal left ventricular ejection fraction
• Mild diastolic dysfunction
• Right ventricular dilation with moderately decreased right ventricular systolic function and apical sparing
• Right ventricular systolic pressure 54 mm Hg, consistent with moderate pulmonary hypertension
• Right atrial pressure 10 mm Hg
• No inspiratory collapse of a dilated inferior vena cava
• Mild tricuspid valve regurgitation.

CLASSIFICATION OF ACUTE PULMONARY EMBOLISM

3. Given the above information, how would you classify the patient’s pulmonary embolism?

• Massive
• Submassive
• Low-risk
• Clinically stable

The patient’s pulmonary embolism is submassive.

Historically, the classification of pulmonary embolism was determined by the angiographic thrombus burden. However, this has limited utility because clinical factors (eg, hypotension on initial presentation) have been shown to be better predictors of short-term mortality risk.³

Our patient is characterized as having a submassive pulmonary embolism based on elevated biomarkers (troponin T, N-terminal pro-B-type natriuretic peptide) and right ventricular dysfunction in the absence of hypotension.

ULTRASONOGRAPHY FOR DIAGNOSIS OF DEEP VEIN THROMBOSIS

Venous duplex ultrasonography has become the standard for diagnosis of lower extremity deep vein thrombosis. However, its quality and diagnostic accuracy depend on the skill of the person performing the examination. It is further limited by certain patient characteristics, including severe obesity, edema, and wounds and dressings at the site being examined.⁵

Our patient underwent duplex ultrasonography of the lower extremities, which demonstrated acute proximal and calf deep vein thrombosis in the right femoral, popliteal, and peroneal veins and no deep vein thrombosis in the left leg.

Multiple models exist to estimate the risk of complications in patients with acute pulmonary embolism.

The Bova score⁶ is based on the following factors:

• Systolic blood pressure 90–100 mm Hg (2 points) (patients with systolic blood pressure lower than 90 mm Hg were excluded from the study from which this score was derived)
• Cardiac troponin elevation (2 points)
• Right ventricular dysfunction on echocardiography or computed tomography (2 points)
• Heart rate 100 beats/min or greater (1 point).

A total score of 0, 1, or 2 (stage I) denotes low risk, 3 or 4 points (stage II) intermediate risk, and more than 4 points (stage III) high risk.

The PESI score (Pulmonary Embolism Severity Index)⁷ is based on:

• Age (1 point per year)
• Sex (10 points for being male)
• Heart rate 110 per minute or greater (20 points)
• Cancer (30 points)
• Heart failure (10 points)
• Chronic lung disease (10 points)
• Systolic blood pressure less than 100 mm Hg (30 points)
• Respiratory rate at least 30 per minute (20 points)
• Temperature less than 36ºC (20 points)
• Altered mental status (60 points)
• Arterial oxygen saturation less than 90% (20 points).

The total score is broken down into 5 classes: I (< 65 points), II (65–85), III (86–105), IV (106–125), and V (> 126). Classes I and II are low risk, and the higher ones are high risk.

The simplified PESI score⁸ was developed to more rapidly risk-stratify patients and has been found to be similar to the PESI score in prognostic accuracy. Patients get 1 point for each of the following:

• Age over 80
• Cancer
• Chronic cardiopulmonary disease (heart failure or chronic lung disease)
• Heart rate 110 per minute or greater
• Systolic blood pressure less than 100 mm Hg
• Arterial oxygen saturation less than 90%.

A total score of 0 is low risk; anything higher is high risk.

Back to our patient

Our patient had proximal and calf deep vein thrombosis of the right leg, bilateral submassive pulmonary emboli with associated biomarker elevation and right ventricular dysfunction, and left renal artery thrombosis with infarction. Using the PESI score, his risk of death in the next 30 days was 13.7% and his 30-day risk of a complicated course was 27%. Using the Bova score, his 30-day risk of death was 15.5% and his 30-day risk of a complicated course was 29.2%.^6,7

Notably, the patient’s right ventricular function had also been impaired on the echocardiogram performed during his admission 1 month previously. On transthoracic echocardiography during the current admission, the patient was found to have a similar degree of right ventricular dysfunction. This finding, along with the oxygen requirement that developed during the earlier admission, suggested that his pulmonary embolism may have been subacute and that the diagnosis may have been missed during the earlier hospital stay.

The patient was treated with unfractionated heparin. After the hospital’s multidisciplinary pulmonary embolism response team discussed and weighed the above factors, they recommended to not pursue thrombolytic therapy or inferior vena cava filter placement.

Of note, the patient’s pulses in the left lower extremity continued to be weak but palpable, and the left leg was cooler to touch than the right leg.

ASSESSING PERIPHERAL ARTERY DISEASE

4. How should the finding of weak pulses in this patient’s left leg be initially investigated?

• Computed tomographic angiography with runoff
• Ankle-brachial indices with pulse-volume recordings
• Arterial duplex ultrasonography
• Magnetic resonance angiography of the lower extremities

The ankle-brachial index is the initial diagnostic test for assessment of pulse abnormalities and for diagnosis of lower-extremity peripheral artery disease. It is calculated by dividing the higher of the ankle systolic pressures (posterior tibial or dorsalis pedis) by the higher of the 2 brachial pressures (left or right).⁹ Normal values are between 1.00 and 1.40.

Ankle-brachial indices in our patient

Our patient underwent measurement of his brachial, dorsalis pedis, and posterior tibial artery systolic pressures using blood pressure cuffs and continuous-wave Doppler. Ankle pulse-volume recordings were also obtained.

Given the patient’s poor renal function and concern for acute renal infarction, we thought it best to avoid iodinated or gadolinium contrast, such as with magnetic resonance or computed tomographic angiography.

Segmental leg pressures and pulse-volume recordings can be performed to help localize the level of arterial disease in the extremities, but were not done in this case because of the extensive deep vein thrombosis in the right leg.^10,11

Arterial ultrasonography in our patient

Arterial duplex ultrasonography was performed to help determine the location of arterial disease. It showed patent arteries in the right leg. In the left lower extremity there was slow, monophasic blood flow in the distal superficial femoral artery. The popliteal artery was occluded. The posterior tibial artery was occluded at the origin, with reconstitution distally. The peroneal artery was occluded throughout. The anterior tibial artery was patent throughout. The ultrasonographic findings were thought to be suspicious for arterial thromboembolism.

5. Given that the patient had both arterial thrombosis (renal artery, lower-extremity arteries) and venous thromboembolism (deep vein thrombosis and pulmonary embolism), which of the following would be included in the differential diagnosis?

• Antiphospholipid antibody syndrome
• Protein C or protein S deficiency
• Malignancy
• Paradoxical embolization
• Factor V Leiden mutation

Correct answers include antiphospholipid antibody syndrome, malignancy, and paradoxical embolization.

The differential diagnosis for concomitant venous and arterial thrombosis is broad,¹² and includes the following:

• Structural factors: patent foramen ovale, popliteal artery aneurysm
• Malignancy
• Inflammatory diseases: Behçet disease, Buerger disease, inflammatory bowel disease, antiphospholipid antibody syndrome, elevated lipoprotein(a), elevated homocysteine
• Hematologic diseases: myelodysplastic syndrome, disseminated intravascular coagulation, paroxysmal nocturnal hemoglobinuria, heparin-induced thrombocytopenia.

Traditional risk factors for venous thromboembolism include protein C deficiency, protein S deficiency, factor V Leiden mutation, the prothrombin G20210A gene mutation, and others. These are relatively minor risk factors for venous thrombosis and do not pose a risk for arterial thrombosis.¹² In contrast, antiphospholipid antibody syndrome and malignancy pose a risk for both venous and arterial thrombosis. Paradoxical embolism is a mechanism by which arterial thrombosis (emboli) can develop in the setting of existing venous thrombosis.¹²

Our patient underwent testing for antiphospholipid antibodies and lupus anticoagulant, and he was encouraged to undergo age-appropriate cancer screening as an outpatient.¹²

ANTIPHOSPHOLIPID ANTIBODY SYNDROME

Antiphospholipid antibody syndrome is defined by both clinical and laboratory criteria. Clinical symptoms include vascular thrombosis (arterial, venous, or both) and pregnancy-related complications.¹³

Laboratory criteria require the presence of antiphospholipid antibodies or lupus anticoagulant. These must be confirmed with repeat testing in 12 weeks. Antiphospholipid antibodies are detected by an enzyme-linked immunosorbent assay; laboratory assessment for the presence of lupus anticoagulant is a stepwise process and relies on 4 criteria:

• There should be prolongation of a phospholipid-dependent clotting test (eg, activated partial thromboplastin time, dilute Russell viper venom time test).
• There must be evidence of an inhibitory activity with mixing study.
• The inhibitor must exhibit phospholipid dependence; that is, with more phospholipid there is shortening of clotting time.
• Specific inhibitors must be excluded, including factor VIII and anticoagulant drugs such as heparin.^14–17

From Houghton DE, Moll S. Antiphospholipid antibodies. Vasc Med 2017; 22:545–550.

Clinically, one should consider antiphospholipid antibody syndrome in patients who have arterial thrombosis, a history of pregnancy morbidity, or unexplained prolongation of activated partial thromboplastin time.¹³

Antiphospholipid antibodies may be present in up to a quarter of patients with venous thromboembolism, but it is persistent positivity of antibody assays that is associated with increased future risk of venous thromboembolism.¹⁹ Of note, the risk of venous thromboembolism in patients with confirmed antiphospholipid antibody syndrome is 10 times higher than in the general population.²⁰

ANTIPHOSPHOLIPID ANTIBODIES ARE NOT ALL THE SAME

6. Which of the following antiphospholipid antibodies have not been associated with an increased thrombotic risk?

• Anti-beta-2-glycoprotein I IgG
• Lupus anticoagulant
• Antiphosphatidylserine
• Anticardiolipin IgM
• Anticardiolipin IgG

The correct answer is antiphosphatidylserine.¹⁵

Antiphospholipid antibodies are directed against a portion of select plasma proteins that are uncovered upon phospholipid binding. While lupus anticoagulant, anti-beta-2-glycoprotein I, and anticardiolipin antibodies are associated with thrombosis, antiprothrombin antibodies (including antiprothrombin and antiphosphatidylserine antibodies) are not.^15,21

Patent foramen ovale, a communication between the right and left atrium in the interatrial septum, is associated with an increased risk of paradoxical embolization. The prevalence of patent foramen ovale is estimated to be 27% to 29% in the general population.²² Noncerebral systemic paradoxical embolism occurs less frequently than cerebral embolism, accounting for approximately 5% to 10% of paradoxical emboli.²²

To evaluate for patent foramen ovale, transthoracic echocardiography is performed with a bubble (agitated saline contrast) study to assess for interatrial shunting. Transesophageal echocardiography or transcranial Doppler bubble studies may also be performed.

Although patent foramen ovale is most commonly associated with cerebral embolism, peripheral emboli can occur. Some research suggests that this may be a more common cause of arterial thromboembolism in younger patients. There have also been reports of other sites of systemic embolization, including the renal artery.¹²

Back to our patient

Initial antiphospholipid antibody testing was positive for lupus anticoagulant. Anticardiolipin and anti-beta-2-glycoprotein I antibodies were not detected.

Transesophageal echocardiography revealed a patent foramen ovale with a highly mobile atrial septum (atrial septal aneurysm).

The patient was treated with intravenous unfractionated heparin with bridging to warfarin with a target international normalized ratio (INR) of 2 to 3. His renal artery infarction and his lower-extremity arterial thromboembolic event were conservatively managed. His respiratory status improved, and he no longer required supplemental oxygen. His creatinine peaked at 1.7 mg/dL during his admission and improved to 1.2 mg/dL before he was discharged.

At follow-up, repeat echocardiography showed that his right ventricular systolic pressure had improved (decreased) to 37 mm Hg from 54 mm Hg. Repeat confirmatory testing was positive for lupus anticoagulant 12 weeks later. He has been maintained on warfarin with an INR goal of 2 to 3 as well as low-dose aspirin with plans for long-term anticoagulation. We decided to keep the patient on anticoagulation indefinitely with warfarin; he was not a candidate for a direct oral anticoagulant, given limited data on the use of these agents in the setting of lupus anticoagulant and antiphospholipid antibody syndrome.

SUMMARY OF CASE

In summary, this patient was a 75-year-old man with COPD who presented with abdominal pain. He was noted to have a left renal infarction, extensive unprovoked lower-extremity deep vein thrombosis with pulmonary emboli, and lower limb arterial thromboembolism.

He also had an underlying hypercoagulable state—antiphospholipid antibody syndrome—that predisposed him to both arterial and venous thrombosis. He was ultimately found to have a patent foramen ovale, which further increased the risk of arterial thrombosis by facilitating paradoxical embolization of venous thrombi. It is not certain whether the renal infarction and leg artery thrombi were due to paradoxical embolism or to in situ thrombosis, but we believe that it was most likely paradoxical embolization.        

A 75-year-old man presented to the emergency department for evaluation of abdominal pain. He had stage 3 chronic obstructive pulmonary disease (COPD), with a forced expiratory volume in 1 second of 33%.

PREVIOUS HOSPITALIZATION

Aside from his COPD, he had been healthy until 1 month earlier, when he had been hospitalized because of shortness of breath and chest pressure with exertion. His troponin T level had been elevated, peaking at 0.117 ng/mL (reference range 0–0.029).

Left heart catheterization had shown no significant coronary artery disease. A myocardial bridge of the distal left anterior descending coronary artery had been seen, so that the artery appeared to be narrowed by 50% to 60% with ventricular contraction. But this was not thought to have been the cause of his presentation.

On discharge, he required oxygen 4 L/min by nasal cannula. Previously, he had not needed supplemental oxygen.

CURRENT PRESENTATION

The patient described persistent and severe periumbilical abdominal pain during the previous day. It was not associated with eating, and he denied diarrhea, constipation, hematemesis, hematochezia, bright red blood per rectum, or melena. He continued to describe persistent shortness of breath and pleuritic chest pain. His vital signs were as follows:

• Heart rate 104 beats per minute
• Respiratory rate 16 to 20 breaths per minute
• Blood pressure 101–142/62–84 mm Hg
• Oxygen saturation 78% on room air.

His laboratory findings on presentation are shown in Table 1, and his electrocardiogram is shown in Figure 1.

WHAT DOES HIS ELECTROCARDIOGRAM SHOW?

1. Which of the following is the most accurate description of this patient’s electrocardiogram?

• Sinus tachycardia, peaked P waves (P pulmonale) in lead II, and T-wave inversions in the right precordial leads
• Sinus tachycardia and left bundle branch block
• Sinus tachycardia and poor R-wave progression
• Sinus tachycardia and ST elevation in the precordial leads

Our patient’s electrocardiogram shows sinus tachycardia, P pulmonale, T-wave inversion in the right precordial leads (V₁–V₃), and biphasic T waves in lead V_4,, which suggest right ventricular strain.

The rhythm most commonly seen in patients with pulmonary embolism is sinus tachycardia, followed by nonspecific ST-segment or T-wave abnormalities. In one series of patients with acute pulmonary embolism, the classic findings of P pulmonale, right ventricular hypertrophy, right axis deviation, and right bundle branch block were rare (< 6%).¹ Thus, these classic findings are not sensitive for the diagnosis of pulmonary embolism, and their absence does not rule it out.

Further studies for our patient

Transthoracic echocardiography was performed to look for evidence of right ventricular strain secondary to the pulmonary embolism.

2. Which of the following findings on transthoracic echocardiography would not suggest acute pulmonary embolism?

• Midright ventricular wall hypokinesis with apical sparing
• Severe tricuspid regurgitation
• Left ventricular dilation
• Lack of respiratory variation of the inferior vena cava
• Septal wall motion toward the left ventricle

Left ventricular dilation does not suggest acute pulmonary embolism. Echocardiograms of patients with acute submassive pulmonary embolism typically show evidence of right ventricular strain, such as the other entities listed above (midright ventricular hypokinesis with apical sparing, severe tricuspid regurgitation, lack of respiratory variation of the inferior vena cava, and septal wall motion toward the left ventricle).

The degree of right ventricular dysfunction is related to the extent of acute pulmonary vascular occlusion and aids in risk-stratification of patients with acute pulmonary embolism. Midright ventricular wall hypokinesis with apical sparing has been termed the McConnell sign.²

In our patient, transthoracic echocardiography showed:

• Normal left ventricular ejection fraction
• Mild diastolic dysfunction
• Right ventricular dilation with moderately decreased right ventricular systolic function and apical sparing
• Right ventricular systolic pressure 54 mm Hg, consistent with moderate pulmonary hypertension
• Right atrial pressure 10 mm Hg
• No inspiratory collapse of a dilated inferior vena cava
• Mild tricuspid valve regurgitation.

CLASSIFICATION OF ACUTE PULMONARY EMBOLISM

3. Given the above information, how would you classify the patient’s pulmonary embolism?

• Massive
• Submassive
• Low-risk
• Clinically stable

The patient’s pulmonary embolism is submassive.

Historically, the classification of pulmonary embolism was determined by the angiographic thrombus burden. However, this has limited utility because clinical factors (eg, hypotension on initial presentation) have been shown to be better predictors of short-term mortality risk.³

Our patient is characterized as having a submassive pulmonary embolism based on elevated biomarkers (troponin T, N-terminal pro-B-type natriuretic peptide) and right ventricular dysfunction in the absence of hypotension.

ULTRASONOGRAPHY FOR DIAGNOSIS OF DEEP VEIN THROMBOSIS

Venous duplex ultrasonography has become the standard for diagnosis of lower extremity deep vein thrombosis. However, its quality and diagnostic accuracy depend on the skill of the person performing the examination. It is further limited by certain patient characteristics, including severe obesity, edema, and wounds and dressings at the site being examined.⁵

Our patient underwent duplex ultrasonography of the lower extremities, which demonstrated acute proximal and calf deep vein thrombosis in the right femoral, popliteal, and peroneal veins and no deep vein thrombosis in the left leg.

Multiple models exist to estimate the risk of complications in patients with acute pulmonary embolism.

The Bova score⁶ is based on the following factors:

• Systolic blood pressure 90–100 mm Hg (2 points) (patients with systolic blood pressure lower than 90 mm Hg were excluded from the study from which this score was derived)
• Cardiac troponin elevation (2 points)
• Right ventricular dysfunction on echocardiography or computed tomography (2 points)
• Heart rate 100 beats/min or greater (1 point).

A total score of 0, 1, or 2 (stage I) denotes low risk, 3 or 4 points (stage II) intermediate risk, and more than 4 points (stage III) high risk.

The PESI score (Pulmonary Embolism Severity Index)⁷ is based on:

• Age (1 point per year)
• Sex (10 points for being male)
• Heart rate 110 per minute or greater (20 points)
• Cancer (30 points)
• Heart failure (10 points)
• Chronic lung disease (10 points)
• Systolic blood pressure less than 100 mm Hg (30 points)
• Respiratory rate at least 30 per minute (20 points)
• Temperature less than 36ºC (20 points)
• Altered mental status (60 points)
• Arterial oxygen saturation less than 90% (20 points).

The total score is broken down into 5 classes: I (< 65 points), II (65–85), III (86–105), IV (106–125), and V (> 126). Classes I and II are low risk, and the higher ones are high risk.

The simplified PESI score⁸ was developed to more rapidly risk-stratify patients and has been found to be similar to the PESI score in prognostic accuracy. Patients get 1 point for each of the following:

• Age over 80
• Cancer
• Chronic cardiopulmonary disease (heart failure or chronic lung disease)
• Heart rate 110 per minute or greater
• Systolic blood pressure less than 100 mm Hg
• Arterial oxygen saturation less than 90%.

A total score of 0 is low risk; anything higher is high risk.

Back to our patient

Our patient had proximal and calf deep vein thrombosis of the right leg, bilateral submassive pulmonary emboli with associated biomarker elevation and right ventricular dysfunction, and left renal artery thrombosis with infarction. Using the PESI score, his risk of death in the next 30 days was 13.7% and his 30-day risk of a complicated course was 27%. Using the Bova score, his 30-day risk of death was 15.5% and his 30-day risk of a complicated course was 29.2%.^6,7

Notably, the patient’s right ventricular function had also been impaired on the echocardiogram performed during his admission 1 month previously. On transthoracic echocardiography during the current admission, the patient was found to have a similar degree of right ventricular dysfunction. This finding, along with the oxygen requirement that developed during the earlier admission, suggested that his pulmonary embolism may have been subacute and that the diagnosis may have been missed during the earlier hospital stay.

The patient was treated with unfractionated heparin. After the hospital’s multidisciplinary pulmonary embolism response team discussed and weighed the above factors, they recommended to not pursue thrombolytic therapy or inferior vena cava filter placement.

Of note, the patient’s pulses in the left lower extremity continued to be weak but palpable, and the left leg was cooler to touch than the right leg.

ASSESSING PERIPHERAL ARTERY DISEASE

4. How should the finding of weak pulses in this patient’s left leg be initially investigated?

• Computed tomographic angiography with runoff
• Ankle-brachial indices with pulse-volume recordings
• Arterial duplex ultrasonography
• Magnetic resonance angiography of the lower extremities

The ankle-brachial index is the initial diagnostic test for assessment of pulse abnormalities and for diagnosis of lower-extremity peripheral artery disease. It is calculated by dividing the higher of the ankle systolic pressures (posterior tibial or dorsalis pedis) by the higher of the 2 brachial pressures (left or right).⁹ Normal values are between 1.00 and 1.40.

Ankle-brachial indices in our patient

Our patient underwent measurement of his brachial, dorsalis pedis, and posterior tibial artery systolic pressures using blood pressure cuffs and continuous-wave Doppler. Ankle pulse-volume recordings were also obtained.

Given the patient’s poor renal function and concern for acute renal infarction, we thought it best to avoid iodinated or gadolinium contrast, such as with magnetic resonance or computed tomographic angiography.

Segmental leg pressures and pulse-volume recordings can be performed to help localize the level of arterial disease in the extremities, but were not done in this case because of the extensive deep vein thrombosis in the right leg.^10,11

Arterial ultrasonography in our patient

Arterial duplex ultrasonography was performed to help determine the location of arterial disease. It showed patent arteries in the right leg. In the left lower extremity there was slow, monophasic blood flow in the distal superficial femoral artery. The popliteal artery was occluded. The posterior tibial artery was occluded at the origin, with reconstitution distally. The peroneal artery was occluded throughout. The anterior tibial artery was patent throughout. The ultrasonographic findings were thought to be suspicious for arterial thromboembolism.

5. Given that the patient had both arterial thrombosis (renal artery, lower-extremity arteries) and venous thromboembolism (deep vein thrombosis and pulmonary embolism), which of the following would be included in the differential diagnosis?

• Antiphospholipid antibody syndrome
• Protein C or protein S deficiency
• Malignancy
• Paradoxical embolization
• Factor V Leiden mutation

Correct answers include antiphospholipid antibody syndrome, malignancy, and paradoxical embolization.

The differential diagnosis for concomitant venous and arterial thrombosis is broad,¹² and includes the following:

• Structural factors: patent foramen ovale, popliteal artery aneurysm
• Malignancy
• Inflammatory diseases: Behçet disease, Buerger disease, inflammatory bowel disease, antiphospholipid antibody syndrome, elevated lipoprotein(a), elevated homocysteine
• Hematologic diseases: myelodysplastic syndrome, disseminated intravascular coagulation, paroxysmal nocturnal hemoglobinuria, heparin-induced thrombocytopenia.

Traditional risk factors for venous thromboembolism include protein C deficiency, protein S deficiency, factor V Leiden mutation, the prothrombin G20210A gene mutation, and others. These are relatively minor risk factors for venous thrombosis and do not pose a risk for arterial thrombosis.¹² In contrast, antiphospholipid antibody syndrome and malignancy pose a risk for both venous and arterial thrombosis. Paradoxical embolism is a mechanism by which arterial thrombosis (emboli) can develop in the setting of existing venous thrombosis.¹²

Our patient underwent testing for antiphospholipid antibodies and lupus anticoagulant, and he was encouraged to undergo age-appropriate cancer screening as an outpatient.¹²

ANTIPHOSPHOLIPID ANTIBODY SYNDROME

Antiphospholipid antibody syndrome is defined by both clinical and laboratory criteria. Clinical symptoms include vascular thrombosis (arterial, venous, or both) and pregnancy-related complications.¹³

Laboratory criteria require the presence of antiphospholipid antibodies or lupus anticoagulant. These must be confirmed with repeat testing in 12 weeks. Antiphospholipid antibodies are detected by an enzyme-linked immunosorbent assay; laboratory assessment for the presence of lupus anticoagulant is a stepwise process and relies on 4 criteria:

• There should be prolongation of a phospholipid-dependent clotting test (eg, activated partial thromboplastin time, dilute Russell viper venom time test).
• There must be evidence of an inhibitory activity with mixing study.
• The inhibitor must exhibit phospholipid dependence; that is, with more phospholipid there is shortening of clotting time.
• Specific inhibitors must be excluded, including factor VIII and anticoagulant drugs such as heparin.^14–17

From Houghton DE, Moll S. Antiphospholipid antibodies. Vasc Med 2017; 22:545–550.

Clinically, one should consider antiphospholipid antibody syndrome in patients who have arterial thrombosis, a history of pregnancy morbidity, or unexplained prolongation of activated partial thromboplastin time.¹³

Antiphospholipid antibodies may be present in up to a quarter of patients with venous thromboembolism, but it is persistent positivity of antibody assays that is associated with increased future risk of venous thromboembolism.¹⁹ Of note, the risk of venous thromboembolism in patients with confirmed antiphospholipid antibody syndrome is 10 times higher than in the general population.²⁰

ANTIPHOSPHOLIPID ANTIBODIES ARE NOT ALL THE SAME

6. Which of the following antiphospholipid antibodies have not been associated with an increased thrombotic risk?

• Anti-beta-2-glycoprotein I IgG
• Lupus anticoagulant
• Antiphosphatidylserine
• Anticardiolipin IgM
• Anticardiolipin IgG

The correct answer is antiphosphatidylserine.¹⁵

Antiphospholipid antibodies are directed against a portion of select plasma proteins that are uncovered upon phospholipid binding. While lupus anticoagulant, anti-beta-2-glycoprotein I, and anticardiolipin antibodies are associated with thrombosis, antiprothrombin antibodies (including antiprothrombin and antiphosphatidylserine antibodies) are not.^15,21

Patent foramen ovale, a communication between the right and left atrium in the interatrial septum, is associated with an increased risk of paradoxical embolization. The prevalence of patent foramen ovale is estimated to be 27% to 29% in the general population.²² Noncerebral systemic paradoxical embolism occurs less frequently than cerebral embolism, accounting for approximately 5% to 10% of paradoxical emboli.²²

To evaluate for patent foramen ovale, transthoracic echocardiography is performed with a bubble (agitated saline contrast) study to assess for interatrial shunting. Transesophageal echocardiography or transcranial Doppler bubble studies may also be performed.

Although patent foramen ovale is most commonly associated with cerebral embolism, peripheral emboli can occur. Some research suggests that this may be a more common cause of arterial thromboembolism in younger patients. There have also been reports of other sites of systemic embolization, including the renal artery.¹²

Back to our patient

Initial antiphospholipid antibody testing was positive for lupus anticoagulant. Anticardiolipin and anti-beta-2-glycoprotein I antibodies were not detected.

Transesophageal echocardiography revealed a patent foramen ovale with a highly mobile atrial septum (atrial septal aneurysm).

The patient was treated with intravenous unfractionated heparin with bridging to warfarin with a target international normalized ratio (INR) of 2 to 3. His renal artery infarction and his lower-extremity arterial thromboembolic event were conservatively managed. His respiratory status improved, and he no longer required supplemental oxygen. His creatinine peaked at 1.7 mg/dL during his admission and improved to 1.2 mg/dL before he was discharged.

At follow-up, repeat echocardiography showed that his right ventricular systolic pressure had improved (decreased) to 37 mm Hg from 54 mm Hg. Repeat confirmatory testing was positive for lupus anticoagulant 12 weeks later. He has been maintained on warfarin with an INR goal of 2 to 3 as well as low-dose aspirin with plans for long-term anticoagulation. We decided to keep the patient on anticoagulation indefinitely with warfarin; he was not a candidate for a direct oral anticoagulant, given limited data on the use of these agents in the setting of lupus anticoagulant and antiphospholipid antibody syndrome.

SUMMARY OF CASE

In summary, this patient was a 75-year-old man with COPD who presented with abdominal pain. He was noted to have a left renal infarction, extensive unprovoked lower-extremity deep vein thrombosis with pulmonary emboli, and lower limb arterial thromboembolism.

He also had an underlying hypercoagulable state—antiphospholipid antibody syndrome—that predisposed him to both arterial and venous thrombosis. He was ultimately found to have a patent foramen ovale, which further increased the risk of arterial thrombosis by facilitating paradoxical embolization of venous thrombi. It is not certain whether the renal infarction and leg artery thrombi were due to paradoxical embolism or to in situ thrombosis, but we believe that it was most likely paradoxical embolization.        

Clinical question: Do rates of acute kidney injury (AKI), renal replacement therapy (RRT), or mortality differ between adults receiving contrast-enhanced computed tomography (CT) versus those receiving noncontrast CT?

Background: Published estimates regarding the risk of postcontrast complications are highly variable and recent data show that the risk of postcontrast AKI may be lower than previously suggested.

Study design: Systematic review and meta-analysis..

Setting: Noninterventional studies assessing differences in AKI, new RRT, or mortality among adults who received contrast-enhanced CT, compared with those receiving noncontrast CT.

Synopsis: A search among six databases and Google Scholar from inception through 2016 yielded 28 observational studies meeting inclusion criteria that included 107,335 participants. Twenty-six assessed AKI, 13 assessed need for RRT, and 9 assessed all-cause mortality. Compared with noncontrast CT, contrast-enhanced CT was not significantly associated with AKI (odds ratio, 0.94; 95% confidence interval, 0.83-1.07), RRT (OR, 0.83; 95% CI 0.59-1.16), or all-cause mortality (OR, 1.0; 95% CI 0.73-1.36). The overall risk of bias ranged from low to serious among the included studies. Studies were observational in nature, they were conducted in multiple settings (for example, ICU, emergency department), and the baseline characteristics of included patients were highly variable.

Bottom line: This meta-analysis observed no difference in adverse events between patients receiving contrast-enhanced CT versus those receiving noncontrast CT but should be interpreted with caution given the observational nature of the studies and differing characteristics of the included patients and study settings.

Citation: Aycock RD et al. Acute kidney injury after computed tomography: a meta-analysis. Ann Emerg Med. 2017 Aug 12. doi: 10.1016/j.annemergmed.2017.06.041

Dr. Simonetti is a hospitalist at the University of Colorado School of Medicine.

Clinical question: Do rates of acute kidney injury (AKI), renal replacement therapy (RRT), or mortality differ between adults receiving contrast-enhanced computed tomography (CT) versus those receiving noncontrast CT?

Background: Published estimates regarding the risk of postcontrast complications are highly variable and recent data show that the risk of postcontrast AKI may be lower than previously suggested.

Study design: Systematic review and meta-analysis..

Setting: Noninterventional studies assessing differences in AKI, new RRT, or mortality among adults who received contrast-enhanced CT, compared with those receiving noncontrast CT.

Synopsis: A search among six databases and Google Scholar from inception through 2016 yielded 28 observational studies meeting inclusion criteria that included 107,335 participants. Twenty-six assessed AKI, 13 assessed need for RRT, and 9 assessed all-cause mortality. Compared with noncontrast CT, contrast-enhanced CT was not significantly associated with AKI (odds ratio, 0.94; 95% confidence interval, 0.83-1.07), RRT (OR, 0.83; 95% CI 0.59-1.16), or all-cause mortality (OR, 1.0; 95% CI 0.73-1.36). The overall risk of bias ranged from low to serious among the included studies. Studies were observational in nature, they were conducted in multiple settings (for example, ICU, emergency department), and the baseline characteristics of included patients were highly variable.

Bottom line: This meta-analysis observed no difference in adverse events between patients receiving contrast-enhanced CT versus those receiving noncontrast CT but should be interpreted with caution given the observational nature of the studies and differing characteristics of the included patients and study settings.

Citation: Aycock RD et al. Acute kidney injury after computed tomography: a meta-analysis. Ann Emerg Med. 2017 Aug 12. doi: 10.1016/j.annemergmed.2017.06.041

Dr. Simonetti is a hospitalist at the University of Colorado School of Medicine.

Clinical question: Do rates of acute kidney injury (AKI), renal replacement therapy (RRT), or mortality differ between adults receiving contrast-enhanced computed tomography (CT) versus those receiving noncontrast CT?

Background: Published estimates regarding the risk of postcontrast complications are highly variable and recent data show that the risk of postcontrast AKI may be lower than previously suggested.

Study design: Systematic review and meta-analysis..

Setting: Noninterventional studies assessing differences in AKI, new RRT, or mortality among adults who received contrast-enhanced CT, compared with those receiving noncontrast CT.

Synopsis: A search among six databases and Google Scholar from inception through 2016 yielded 28 observational studies meeting inclusion criteria that included 107,335 participants. Twenty-six assessed AKI, 13 assessed need for RRT, and 9 assessed all-cause mortality. Compared with noncontrast CT, contrast-enhanced CT was not significantly associated with AKI (odds ratio, 0.94; 95% confidence interval, 0.83-1.07), RRT (OR, 0.83; 95% CI 0.59-1.16), or all-cause mortality (OR, 1.0; 95% CI 0.73-1.36). The overall risk of bias ranged from low to serious among the included studies. Studies were observational in nature, they were conducted in multiple settings (for example, ICU, emergency department), and the baseline characteristics of included patients were highly variable.

Bottom line: This meta-analysis observed no difference in adverse events between patients receiving contrast-enhanced CT versus those receiving noncontrast CT but should be interpreted with caution given the observational nature of the studies and differing characteristics of the included patients and study settings.

Citation: Aycock RD et al. Acute kidney injury after computed tomography: a meta-analysis. Ann Emerg Med. 2017 Aug 12. doi: 10.1016/j.annemergmed.2017.06.041

Dr. Simonetti is a hospitalist at the University of Colorado School of Medicine.

Hypertension discovery in pediatric patients more than doubled for physicians using a clinical decision support (CDS) tool connected to the EHR, results of a study found.

Elyse O. Kharbanda, MD, MPH, a researcher at the HealthPartners Institute, Minneapolis, and her fellow investigators assert that using such a tool will help rectify the trend of underreported hypertension in adolescents, which remains a serious concern despite providers’ routinely taking blood pressure measurements during outpatient visits.

Vishnu Kumar/Thinkstock

[email protected]

Source: Kharbanda EO et al. Pediatrics. 2018. doi: 10.1542/peds.2017- 2954.

Hypertension discovery in pediatric patients more than doubled for physicians using a clinical decision support (CDS) tool connected to the EHR, results of a study found.

Elyse O. Kharbanda, MD, MPH, a researcher at the HealthPartners Institute, Minneapolis, and her fellow investigators assert that using such a tool will help rectify the trend of underreported hypertension in adolescents, which remains a serious concern despite providers’ routinely taking blood pressure measurements during outpatient visits.

Vishnu Kumar/Thinkstock

[email protected]

Source: Kharbanda EO et al. Pediatrics. 2018. doi: 10.1542/peds.2017- 2954.

Hypertension discovery in pediatric patients more than doubled for physicians using a clinical decision support (CDS) tool connected to the EHR, results of a study found.

Elyse O. Kharbanda, MD, MPH, a researcher at the HealthPartners Institute, Minneapolis, and her fellow investigators assert that using such a tool will help rectify the trend of underreported hypertension in adolescents, which remains a serious concern despite providers’ routinely taking blood pressure measurements during outpatient visits.

Vishnu Kumar/Thinkstock

[email protected]

Source: Kharbanda EO et al. Pediatrics. 2018. doi: 10.1542/peds.2017- 2954.

Q) I teach nephrology at a local PA program, and they want us to integrate dental care into each module. What’s the connection between the two?

Dental health is frequently overlooked in the medical realm, as many clinicians feel that dental issues are out of our purview. Hematuria worries us, but bleeding gums and other signs of periodontal disease are often ignored. Surprisingly, many patients don’t seem to mind when their gums bleed every time they brush; they believe that this is normal, when really, it’s not.

Growing evidence supports associations between dental health and multiple medical issues—chronic kidney disease (CKD) among them. Periodontal disease is one of several inflammatory diseases caused by an interaction between gram-negative periodontal bacterial species and the immune system. It manifests with sore, red, bleeding gums and can lead to tooth loss if left untreated.

Chronic inflammation in the gums is a good indicator of inflammation elsewhere in the body. In and of itself, periodontitis can set off an inflammatory cascade in the body. Poor dentition can also lead to poor nutrition, which then causes a feedback loop, leading to even more inflammation.

Patients with periodontal disease have higher levels of C-reactive protein and a higher erythrocyte sedimentation rate than those without the disease.¹ And a recent study by Zhang et al showed that periodontal disease increased risk for all-cause mortality in patients with CKD.²

The high cost of CKD from both a financial and personal view makes any intervention worth exploring, as the risk factors are difficult to modify and the CKD population is growing worldwide. We, as medical providers, should reiterate what our dental colleagues have been saying for years: Encourage patients with CKD to practice good dental hygiene by brushing twice a day and flossing daily, in an attempt to improve their overall outcomes. —JT

LCDR Julie Taylor, PA-C
United States Public Health Service, Boston

Q) I teach nephrology at a local PA program, and they want us to integrate dental care into each module. What’s the connection between the two?

Dental health is frequently overlooked in the medical realm, as many clinicians feel that dental issues are out of our purview. Hematuria worries us, but bleeding gums and other signs of periodontal disease are often ignored. Surprisingly, many patients don’t seem to mind when their gums bleed every time they brush; they believe that this is normal, when really, it’s not.

Growing evidence supports associations between dental health and multiple medical issues—chronic kidney disease (CKD) among them. Periodontal disease is one of several inflammatory diseases caused by an interaction between gram-negative periodontal bacterial species and the immune system. It manifests with sore, red, bleeding gums and can lead to tooth loss if left untreated.

Chronic inflammation in the gums is a good indicator of inflammation elsewhere in the body. In and of itself, periodontitis can set off an inflammatory cascade in the body. Poor dentition can also lead to poor nutrition, which then causes a feedback loop, leading to even more inflammation.

Patients with periodontal disease have higher levels of C-reactive protein and a higher erythrocyte sedimentation rate than those without the disease.¹ And a recent study by Zhang et al showed that periodontal disease increased risk for all-cause mortality in patients with CKD.²

The high cost of CKD from both a financial and personal view makes any intervention worth exploring, as the risk factors are difficult to modify and the CKD population is growing worldwide. We, as medical providers, should reiterate what our dental colleagues have been saying for years: Encourage patients with CKD to practice good dental hygiene by brushing twice a day and flossing daily, in an attempt to improve their overall outcomes. —JT

LCDR Julie Taylor, PA-C
United States Public Health Service, Boston

Q) I teach nephrology at a local PA program, and they want us to integrate dental care into each module. What’s the connection between the two?

Dental health is frequently overlooked in the medical realm, as many clinicians feel that dental issues are out of our purview. Hematuria worries us, but bleeding gums and other signs of periodontal disease are often ignored. Surprisingly, many patients don’t seem to mind when their gums bleed every time they brush; they believe that this is normal, when really, it’s not.

Growing evidence supports associations between dental health and multiple medical issues—chronic kidney disease (CKD) among them. Periodontal disease is one of several inflammatory diseases caused by an interaction between gram-negative periodontal bacterial species and the immune system. It manifests with sore, red, bleeding gums and can lead to tooth loss if left untreated.

Chronic inflammation in the gums is a good indicator of inflammation elsewhere in the body. In and of itself, periodontitis can set off an inflammatory cascade in the body. Poor dentition can also lead to poor nutrition, which then causes a feedback loop, leading to even more inflammation.

Patients with periodontal disease have higher levels of C-reactive protein and a higher erythrocyte sedimentation rate than those without the disease.¹ And a recent study by Zhang et al showed that periodontal disease increased risk for all-cause mortality in patients with CKD.²

The high cost of CKD from both a financial and personal view makes any intervention worth exploring, as the risk factors are difficult to modify and the CKD population is growing worldwide. We, as medical providers, should reiterate what our dental colleagues have been saying for years: Encourage patients with CKD to practice good dental hygiene by brushing twice a day and flossing daily, in an attempt to improve their overall outcomes. —JT

LCDR Julie Taylor, PA-C
United States Public Health Service, Boston

Q) What can I tell my kidney patients to increase acceptance of the influenza and pneumonia vaccines during cold and flu season?

The CDC recommends that everyone ages 6 months and older receive an annual flu vaccination, unless contraindicated.¹ Additionally, administration of either the 13-valent pneumococcal conjugate vaccine (PCV13) or the 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for all adults ages 65 and older and for younger adults (ages 19 to 64) with diabetes, chronic kidney disease (CKD), chronic heart disease, and/or solid organ transplant.¹ Despite these recommendations, patients often decline vaccination. What they may not realize is that CKD increases their risk for infection.

In a cohort of more than 1 million Swedish patients, researchers found that any stage of CKD increased risk for community-acquired infection and that the risk for lower respiratory tract infection increased as glomerular filtration rate declined.² Patients on hemodialysis have an increased risk for pneumonia and an incidence of pneumonia-related mortality that is up to 16 times higher than that of the general population.³ Pneumonia also increases the risk for cardiovascular events among all patients with CKD, regardless of stage.⁴

So, can vaccines reduce these risks in our kidney patients? McGrath and colleagues found that patients with end-stage renal disease (ESRD) who were vaccinated against the flu had lower mortality rates than those who were not vaccinated—even when the vaccine was poorly matched to the circulating virus strain.⁵ Additional research has demonstrated that for patients with any stage of CKD, including those on dialysis, the flu vaccine is safe and effective, and its protection may be durable over time.⁶

For pneumonia vaccines, antibody response in patients with CKD may be suboptimal; however, Medicare data have demonstrated that patients with ESRD who are vaccinated against pneumonia have lower rates of all-cause and cardiovascular mortality than unvaccinated patients do.⁵ Given their increased vulnerability to vaccine-preventable respiratory illnesses, it is imperative that our kidney patients receive both the flu and pneumonia vaccines. —NDM

Nicole DeFeo McCormick, DNP, MBA, NP-C, CCTC
Assistant Professor
School of Medicine at the University of Colorado

Q) What can I tell my kidney patients to increase acceptance of the influenza and pneumonia vaccines during cold and flu season?

The CDC recommends that everyone ages 6 months and older receive an annual flu vaccination, unless contraindicated.¹ Additionally, administration of either the 13-valent pneumococcal conjugate vaccine (PCV13) or the 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for all adults ages 65 and older and for younger adults (ages 19 to 64) with diabetes, chronic kidney disease (CKD), chronic heart disease, and/or solid organ transplant.¹ Despite these recommendations, patients often decline vaccination. What they may not realize is that CKD increases their risk for infection.

In a cohort of more than 1 million Swedish patients, researchers found that any stage of CKD increased risk for community-acquired infection and that the risk for lower respiratory tract infection increased as glomerular filtration rate declined.² Patients on hemodialysis have an increased risk for pneumonia and an incidence of pneumonia-related mortality that is up to 16 times higher than that of the general population.³ Pneumonia also increases the risk for cardiovascular events among all patients with CKD, regardless of stage.⁴

So, can vaccines reduce these risks in our kidney patients? McGrath and colleagues found that patients with end-stage renal disease (ESRD) who were vaccinated against the flu had lower mortality rates than those who were not vaccinated—even when the vaccine was poorly matched to the circulating virus strain.⁵ Additional research has demonstrated that for patients with any stage of CKD, including those on dialysis, the flu vaccine is safe and effective, and its protection may be durable over time.⁶

For pneumonia vaccines, antibody response in patients with CKD may be suboptimal; however, Medicare data have demonstrated that patients with ESRD who are vaccinated against pneumonia have lower rates of all-cause and cardiovascular mortality than unvaccinated patients do.⁵ Given their increased vulnerability to vaccine-preventable respiratory illnesses, it is imperative that our kidney patients receive both the flu and pneumonia vaccines. —NDM

Nicole DeFeo McCormick, DNP, MBA, NP-C, CCTC
Assistant Professor
School of Medicine at the University of Colorado

Q) What can I tell my kidney patients to increase acceptance of the influenza and pneumonia vaccines during cold and flu season?

The CDC recommends that everyone ages 6 months and older receive an annual flu vaccination, unless contraindicated.¹ Additionally, administration of either the 13-valent pneumococcal conjugate vaccine (PCV13) or the 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for all adults ages 65 and older and for younger adults (ages 19 to 64) with diabetes, chronic kidney disease (CKD), chronic heart disease, and/or solid organ transplant.¹ Despite these recommendations, patients often decline vaccination. What they may not realize is that CKD increases their risk for infection.

In a cohort of more than 1 million Swedish patients, researchers found that any stage of CKD increased risk for community-acquired infection and that the risk for lower respiratory tract infection increased as glomerular filtration rate declined.² Patients on hemodialysis have an increased risk for pneumonia and an incidence of pneumonia-related mortality that is up to 16 times higher than that of the general population.³ Pneumonia also increases the risk for cardiovascular events among all patients with CKD, regardless of stage.⁴

So, can vaccines reduce these risks in our kidney patients? McGrath and colleagues found that patients with end-stage renal disease (ESRD) who were vaccinated against the flu had lower mortality rates than those who were not vaccinated—even when the vaccine was poorly matched to the circulating virus strain.⁵ Additional research has demonstrated that for patients with any stage of CKD, including those on dialysis, the flu vaccine is safe and effective, and its protection may be durable over time.⁶

For pneumonia vaccines, antibody response in patients with CKD may be suboptimal; however, Medicare data have demonstrated that patients with ESRD who are vaccinated against pneumonia have lower rates of all-cause and cardiovascular mortality than unvaccinated patients do.⁵ Given their increased vulnerability to vaccine-preventable respiratory illnesses, it is imperative that our kidney patients receive both the flu and pneumonia vaccines. —NDM

Nicole DeFeo McCormick, DNP, MBA, NP-C, CCTC
Assistant Professor
School of Medicine at the University of Colorado