FDA adds safety warnings to certain type 2 diabetes medications

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Type 2 diabetes medicines that contain saxagliptin and alogliptin may increase the risk of heart failure, especially in patients who already have heart or kidney disease, according to results from an Food and Drug Administration safety review.

The development, which was announced by MedWatch on April 5, 2016, means that the FDA will add new warnings to the drug labels about this safety issue. “Health care professionals should consider discontinuing medications containing saxagliptin and alogliptin in patients who develop heart failure and monitor their diabetes control,” the communication states. “If a patient’s blood sugar level is not well-controlled with their current treatment, other diabetes medicines may be required.”

The medications of concern include Onglyza (saxagliptin); Kombiglyze XR (saxagliptin and metformin extended release); Nesina (alogliptin); Kazano (alogliptin and metformin), and Oseni (alogliptin and pioglitazone). The move comes after two clinical trials showed that more patients who received saxagliptin- or alogliptin-containing medicines were hospitalized for heart failure, compared with patients who received placebo (for specifics, see the data summary section in the FDA Drug Safety Communication).

The communication noted that patients taking these medicines should contact their health care clinician if they develop signs and symptoms of heart failure such as: unusual shortness of breath during daily activities; trouble breathing when lying down; tiredness, weakness, or fatigue; and weight gain with swelling in the ankles, feet, legs, or stomach.

Clinicians and patients can report adverse events or side effects related to the use of these products at www.accessdata.fda.gov/scripts/medwatch/index.cfm?action=reporting.home.

[email protected]

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Type 2 diabetes medicines that contain saxagliptin and alogliptin may increase the risk of heart failure, especially in patients who already have heart or kidney disease, according to results from an Food and Drug Administration safety review.

The development, which was announced by MedWatch on April 5, 2016, means that the FDA will add new warnings to the drug labels about this safety issue. “Health care professionals should consider discontinuing medications containing saxagliptin and alogliptin in patients who develop heart failure and monitor their diabetes control,” the communication states. “If a patient’s blood sugar level is not well-controlled with their current treatment, other diabetes medicines may be required.”

The medications of concern include Onglyza (saxagliptin); Kombiglyze XR (saxagliptin and metformin extended release); Nesina (alogliptin); Kazano (alogliptin and metformin), and Oseni (alogliptin and pioglitazone). The move comes after two clinical trials showed that more patients who received saxagliptin- or alogliptin-containing medicines were hospitalized for heart failure, compared with patients who received placebo (for specifics, see the data summary section in the FDA Drug Safety Communication).

The communication noted that patients taking these medicines should contact their health care clinician if they develop signs and symptoms of heart failure such as: unusual shortness of breath during daily activities; trouble breathing when lying down; tiredness, weakness, or fatigue; and weight gain with swelling in the ankles, feet, legs, or stomach.

Clinicians and patients can report adverse events or side effects related to the use of these products at www.accessdata.fda.gov/scripts/medwatch/index.cfm?action=reporting.home.

[email protected]

Type 2 diabetes medicines that contain saxagliptin and alogliptin may increase the risk of heart failure, especially in patients who already have heart or kidney disease, according to results from an Food and Drug Administration safety review.

The development, which was announced by MedWatch on April 5, 2016, means that the FDA will add new warnings to the drug labels about this safety issue. “Health care professionals should consider discontinuing medications containing saxagliptin and alogliptin in patients who develop heart failure and monitor their diabetes control,” the communication states. “If a patient’s blood sugar level is not well-controlled with their current treatment, other diabetes medicines may be required.”

The medications of concern include Onglyza (saxagliptin); Kombiglyze XR (saxagliptin and metformin extended release); Nesina (alogliptin); Kazano (alogliptin and metformin), and Oseni (alogliptin and pioglitazone). The move comes after two clinical trials showed that more patients who received saxagliptin- or alogliptin-containing medicines were hospitalized for heart failure, compared with patients who received placebo (for specifics, see the data summary section in the FDA Drug Safety Communication).

The communication noted that patients taking these medicines should contact their health care clinician if they develop signs and symptoms of heart failure such as: unusual shortness of breath during daily activities; trouble breathing when lying down; tiredness, weakness, or fatigue; and weight gain with swelling in the ankles, feet, legs, or stomach.

Clinicians and patients can report adverse events or side effects related to the use of these products at www.accessdata.fda.gov/scripts/medwatch/index.cfm?action=reporting.home.

[email protected]

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Severe Psoriasis, Kidney Disease Linked

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WASHINGTON – Another population-based study has found a link between severe psoriasis and kidney disease – this one discovering almost a fivefold increase in the risk of immunoglobulin A nephropathy (IgAN) and a doubling in the risk of glomerular disease.

The findings suggest yet again that psoriasis is a systemic illness, and not something that affects only the skin, Sungat Grewal said at the annual meeting of the American Academy of Dermatology.

©Waldemarus/Thinkstock

“Numerous case reports have generated a hypothesis that psoriasis may be associated,” with an increased risk of IgAN, said Ms. Grewal, of the department of dermatology at the University of Pennsylvania, Philadelphia. “Our study is the first to test this, and it supports the notion that this is no coincidence. Now we need further research to determine if this association is due to causality or to a shared pathophysiology.”

The link between psoriasis and kidney disease has long been noted, but the first study formally investigating this association was published in 2013 (BMJ. 2013 Oct;347:f5961). The study, also conducted by University of Pennsylvania investigators, used a large patient database in the United Kingdom, matched about 143,000 patients with psoriasis with up to five controls without psoriasis each, and found the risk of chronic kidney disease was nearly doubled for those with severe psoriasis (hazard ratio, 1.93).

A similar finding emerged from Taiwan in 2015. Using the national healthcare database, researchers matched about 4,600 patients with psoriasis with about 923,000 controls. They found that having severe psoriasis was associated with almost a doubling in the risk of chronic kidney disease (HR, 1.90) and almost a tripling in the risk of end stage renal disease (HR, 2.97), after adjusting for age, gender, comorbidities, and use of nonsteroidal anti-inflammatory drugs (J Dermatol Sci. 2015 Jun;78[3]:232-8).

Ms. Grewal and her coinvestigators used data from The Health Improvement Network in the United Kingdom – the same database used in the 2013 study. The study group comprised 206,000 patients with psoriasis and about 1 million controls.

In the overall group of patients, the risk of IgAN was not significantly increased. Nor was there a significant overall association with glomerular disease. And when the group was divided by disease severity, there were no significant associations with either IgAN or glomerular disease in the group with mild psoriasis.

Among those with severe psoriasis, however, the risk of IgAN was almost five times higher (HR, 4.75) and the risk of glomerular disease was doubled (HR, 2.05).

But although the hazard ratios look impressive, the clinical reality shouldn’t spark too much concern, Ms. Grewal said. “To keep things in context, it’s very important to remember that the excess risk of nephropathy attributed to severe psoriasis was still quite small – similar to the chance of a spontaneous pregnancy resulting in triplets.”

Still, she said, the link is intriguing, and something clinicians should keep in mind when managing patients with severe psoriasis.

Ms. Grewal had no financial disclosures. She is a medical student at the Commonwealth Medical College (Scranton, Pa.), and is currently spending a year at the Gelfand Clinical Research Lab at the University of Pennsylvania, Philadelphia.

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WASHINGTON – Another population-based study has found a link between severe psoriasis and kidney disease – this one discovering almost a fivefold increase in the risk of immunoglobulin A nephropathy (IgAN) and a doubling in the risk of glomerular disease.

The findings suggest yet again that psoriasis is a systemic illness, and not something that affects only the skin, Sungat Grewal said at the annual meeting of the American Academy of Dermatology.

©Waldemarus/Thinkstock

“Numerous case reports have generated a hypothesis that psoriasis may be associated,” with an increased risk of IgAN, said Ms. Grewal, of the department of dermatology at the University of Pennsylvania, Philadelphia. “Our study is the first to test this, and it supports the notion that this is no coincidence. Now we need further research to determine if this association is due to causality or to a shared pathophysiology.”

The link between psoriasis and kidney disease has long been noted, but the first study formally investigating this association was published in 2013 (BMJ. 2013 Oct;347:f5961). The study, also conducted by University of Pennsylvania investigators, used a large patient database in the United Kingdom, matched about 143,000 patients with psoriasis with up to five controls without psoriasis each, and found the risk of chronic kidney disease was nearly doubled for those with severe psoriasis (hazard ratio, 1.93).

A similar finding emerged from Taiwan in 2015. Using the national healthcare database, researchers matched about 4,600 patients with psoriasis with about 923,000 controls. They found that having severe psoriasis was associated with almost a doubling in the risk of chronic kidney disease (HR, 1.90) and almost a tripling in the risk of end stage renal disease (HR, 2.97), after adjusting for age, gender, comorbidities, and use of nonsteroidal anti-inflammatory drugs (J Dermatol Sci. 2015 Jun;78[3]:232-8).

Ms. Grewal and her coinvestigators used data from The Health Improvement Network in the United Kingdom – the same database used in the 2013 study. The study group comprised 206,000 patients with psoriasis and about 1 million controls.

In the overall group of patients, the risk of IgAN was not significantly increased. Nor was there a significant overall association with glomerular disease. And when the group was divided by disease severity, there were no significant associations with either IgAN or glomerular disease in the group with mild psoriasis.

Among those with severe psoriasis, however, the risk of IgAN was almost five times higher (HR, 4.75) and the risk of glomerular disease was doubled (HR, 2.05).

But although the hazard ratios look impressive, the clinical reality shouldn’t spark too much concern, Ms. Grewal said. “To keep things in context, it’s very important to remember that the excess risk of nephropathy attributed to severe psoriasis was still quite small – similar to the chance of a spontaneous pregnancy resulting in triplets.”

Still, she said, the link is intriguing, and something clinicians should keep in mind when managing patients with severe psoriasis.

Ms. Grewal had no financial disclosures. She is a medical student at the Commonwealth Medical College (Scranton, Pa.), and is currently spending a year at the Gelfand Clinical Research Lab at the University of Pennsylvania, Philadelphia.

WASHINGTON – Another population-based study has found a link between severe psoriasis and kidney disease – this one discovering almost a fivefold increase in the risk of immunoglobulin A nephropathy (IgAN) and a doubling in the risk of glomerular disease.

The findings suggest yet again that psoriasis is a systemic illness, and not something that affects only the skin, Sungat Grewal said at the annual meeting of the American Academy of Dermatology.

©Waldemarus/Thinkstock

“Numerous case reports have generated a hypothesis that psoriasis may be associated,” with an increased risk of IgAN, said Ms. Grewal, of the department of dermatology at the University of Pennsylvania, Philadelphia. “Our study is the first to test this, and it supports the notion that this is no coincidence. Now we need further research to determine if this association is due to causality or to a shared pathophysiology.”

The link between psoriasis and kidney disease has long been noted, but the first study formally investigating this association was published in 2013 (BMJ. 2013 Oct;347:f5961). The study, also conducted by University of Pennsylvania investigators, used a large patient database in the United Kingdom, matched about 143,000 patients with psoriasis with up to five controls without psoriasis each, and found the risk of chronic kidney disease was nearly doubled for those with severe psoriasis (hazard ratio, 1.93).

A similar finding emerged from Taiwan in 2015. Using the national healthcare database, researchers matched about 4,600 patients with psoriasis with about 923,000 controls. They found that having severe psoriasis was associated with almost a doubling in the risk of chronic kidney disease (HR, 1.90) and almost a tripling in the risk of end stage renal disease (HR, 2.97), after adjusting for age, gender, comorbidities, and use of nonsteroidal anti-inflammatory drugs (J Dermatol Sci. 2015 Jun;78[3]:232-8).

Ms. Grewal and her coinvestigators used data from The Health Improvement Network in the United Kingdom – the same database used in the 2013 study. The study group comprised 206,000 patients with psoriasis and about 1 million controls.

In the overall group of patients, the risk of IgAN was not significantly increased. Nor was there a significant overall association with glomerular disease. And when the group was divided by disease severity, there were no significant associations with either IgAN or glomerular disease in the group with mild psoriasis.

Among those with severe psoriasis, however, the risk of IgAN was almost five times higher (HR, 4.75) and the risk of glomerular disease was doubled (HR, 2.05).

But although the hazard ratios look impressive, the clinical reality shouldn’t spark too much concern, Ms. Grewal said. “To keep things in context, it’s very important to remember that the excess risk of nephropathy attributed to severe psoriasis was still quite small – similar to the chance of a spontaneous pregnancy resulting in triplets.”

Still, she said, the link is intriguing, and something clinicians should keep in mind when managing patients with severe psoriasis.

Ms. Grewal had no financial disclosures. She is a medical student at the Commonwealth Medical College (Scranton, Pa.), and is currently spending a year at the Gelfand Clinical Research Lab at the University of Pennsylvania, Philadelphia.

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Severe psoriasis, kidney disease linked

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WASHINGTON – Another population-based study has found a link between severe psoriasis and kidney disease – this one discovering almost a fivefold increase in the risk of immunoglobulin A nephropathy (IgAN) and a doubling in the risk of glomerular disease.

The findings suggest yet again that psoriasis is a systemic illness, and not something that affects only the skin, Sungat Grewal said at the annual meeting of the American Academy of Dermatology.

©Waldemarus/Thinkstock

“Numerous case reports have generated a hypothesis that psoriasis may be associated,” with an increased risk of IgAN, said Ms. Grewal, of the department of dermatology at the University of Pennsylvania, Philadelphia. “Our study is the first to test this, and it supports the notion that this is no coincidence. Now we need further research to determine if this association is due to causality or to a shared pathophysiology.”

The link between psoriasis and kidney disease has long been noted, but the first study formally investigating this association was published in 2013 (BMJ. 2013 Oct;347:f5961). The study, also conducted by University of Pennsylvania investigators, used a large patient database in the United Kingdom, matched about 143,000 patients with psoriasis with up to five controls without psoriasis each, and found the risk of chronic kidney disease was nearly doubled for those with severe psoriasis (hazard ratio, 1.93).

A similar finding emerged from Taiwan in 2015. Using the national healthcare database, researchers matched about 4,600 patients with psoriasis with about 923,000 controls. They found that having severe psoriasis was associated with almost a doubling in the risk of chronic kidney disease (HR, 1.90) and almost a tripling in the risk of end stage renal disease (HR, 2.97), after adjusting for age, gender, comorbidities, and use of nonsteroidal anti-inflammatory drugs (J Dermatol Sci. 2015 Jun;78[3]:232-8).

Ms. Grewal and her coinvestigators used data from The Health Improvement Network in the United Kingdom – the same database used in the 2013 study. The study group comprised 206,000 patients with psoriasis and about 1 million controls.

In the overall group of patients, the risk of IgAN was not significantly increased. Nor was there a significant overall association with glomerular disease. And when the group was divided by disease severity, there were no significant associations with either IgAN or glomerular disease in the group with mild psoriasis.

Among those with severe psoriasis, however, the risk of IgAN was almost five times higher (HR, 4.75) and the risk of glomerular disease was doubled (HR, 2.05).

But although the hazard ratios look impressive, the clinical reality shouldn’t spark too much concern, Ms. Grewal said. “To keep things in context, it’s very important to remember that the excess risk of nephropathy attributed to severe psoriasis was still quite small – similar to the chance of a spontaneous pregnancy resulting in triplets.”

Still, she said, the link is intriguing, and something clinicians should keep in mind when managing patients with severe psoriasis.

Ms. Grewal had no financial disclosures. She is a medical student at the Commonwealth Medical College (Scranton, Pa.), and is currently spending a year at the Gelfand Clinical Research Lab at the University of Pennsylvania, Philadelphia.

[email protected]

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WASHINGTON – Another population-based study has found a link between severe psoriasis and kidney disease – this one discovering almost a fivefold increase in the risk of immunoglobulin A nephropathy (IgAN) and a doubling in the risk of glomerular disease.

The findings suggest yet again that psoriasis is a systemic illness, and not something that affects only the skin, Sungat Grewal said at the annual meeting of the American Academy of Dermatology.

©Waldemarus/Thinkstock

“Numerous case reports have generated a hypothesis that psoriasis may be associated,” with an increased risk of IgAN, said Ms. Grewal, of the department of dermatology at the University of Pennsylvania, Philadelphia. “Our study is the first to test this, and it supports the notion that this is no coincidence. Now we need further research to determine if this association is due to causality or to a shared pathophysiology.”

The link between psoriasis and kidney disease has long been noted, but the first study formally investigating this association was published in 2013 (BMJ. 2013 Oct;347:f5961). The study, also conducted by University of Pennsylvania investigators, used a large patient database in the United Kingdom, matched about 143,000 patients with psoriasis with up to five controls without psoriasis each, and found the risk of chronic kidney disease was nearly doubled for those with severe psoriasis (hazard ratio, 1.93).

A similar finding emerged from Taiwan in 2015. Using the national healthcare database, researchers matched about 4,600 patients with psoriasis with about 923,000 controls. They found that having severe psoriasis was associated with almost a doubling in the risk of chronic kidney disease (HR, 1.90) and almost a tripling in the risk of end stage renal disease (HR, 2.97), after adjusting for age, gender, comorbidities, and use of nonsteroidal anti-inflammatory drugs (J Dermatol Sci. 2015 Jun;78[3]:232-8).

Ms. Grewal and her coinvestigators used data from The Health Improvement Network in the United Kingdom – the same database used in the 2013 study. The study group comprised 206,000 patients with psoriasis and about 1 million controls.

In the overall group of patients, the risk of IgAN was not significantly increased. Nor was there a significant overall association with glomerular disease. And when the group was divided by disease severity, there were no significant associations with either IgAN or glomerular disease in the group with mild psoriasis.

Among those with severe psoriasis, however, the risk of IgAN was almost five times higher (HR, 4.75) and the risk of glomerular disease was doubled (HR, 2.05).

But although the hazard ratios look impressive, the clinical reality shouldn’t spark too much concern, Ms. Grewal said. “To keep things in context, it’s very important to remember that the excess risk of nephropathy attributed to severe psoriasis was still quite small – similar to the chance of a spontaneous pregnancy resulting in triplets.”

Still, she said, the link is intriguing, and something clinicians should keep in mind when managing patients with severe psoriasis.

Ms. Grewal had no financial disclosures. She is a medical student at the Commonwealth Medical College (Scranton, Pa.), and is currently spending a year at the Gelfand Clinical Research Lab at the University of Pennsylvania, Philadelphia.

[email protected]

WASHINGTON – Another population-based study has found a link between severe psoriasis and kidney disease – this one discovering almost a fivefold increase in the risk of immunoglobulin A nephropathy (IgAN) and a doubling in the risk of glomerular disease.

The findings suggest yet again that psoriasis is a systemic illness, and not something that affects only the skin, Sungat Grewal said at the annual meeting of the American Academy of Dermatology.

©Waldemarus/Thinkstock

“Numerous case reports have generated a hypothesis that psoriasis may be associated,” with an increased risk of IgAN, said Ms. Grewal, of the department of dermatology at the University of Pennsylvania, Philadelphia. “Our study is the first to test this, and it supports the notion that this is no coincidence. Now we need further research to determine if this association is due to causality or to a shared pathophysiology.”

The link between psoriasis and kidney disease has long been noted, but the first study formally investigating this association was published in 2013 (BMJ. 2013 Oct;347:f5961). The study, also conducted by University of Pennsylvania investigators, used a large patient database in the United Kingdom, matched about 143,000 patients with psoriasis with up to five controls without psoriasis each, and found the risk of chronic kidney disease was nearly doubled for those with severe psoriasis (hazard ratio, 1.93).

A similar finding emerged from Taiwan in 2015. Using the national healthcare database, researchers matched about 4,600 patients with psoriasis with about 923,000 controls. They found that having severe psoriasis was associated with almost a doubling in the risk of chronic kidney disease (HR, 1.90) and almost a tripling in the risk of end stage renal disease (HR, 2.97), after adjusting for age, gender, comorbidities, and use of nonsteroidal anti-inflammatory drugs (J Dermatol Sci. 2015 Jun;78[3]:232-8).

Ms. Grewal and her coinvestigators used data from The Health Improvement Network in the United Kingdom – the same database used in the 2013 study. The study group comprised 206,000 patients with psoriasis and about 1 million controls.

In the overall group of patients, the risk of IgAN was not significantly increased. Nor was there a significant overall association with glomerular disease. And when the group was divided by disease severity, there were no significant associations with either IgAN or glomerular disease in the group with mild psoriasis.

Among those with severe psoriasis, however, the risk of IgAN was almost five times higher (HR, 4.75) and the risk of glomerular disease was doubled (HR, 2.05).

But although the hazard ratios look impressive, the clinical reality shouldn’t spark too much concern, Ms. Grewal said. “To keep things in context, it’s very important to remember that the excess risk of nephropathy attributed to severe psoriasis was still quite small – similar to the chance of a spontaneous pregnancy resulting in triplets.”

Still, she said, the link is intriguing, and something clinicians should keep in mind when managing patients with severe psoriasis.

Ms. Grewal had no financial disclosures. She is a medical student at the Commonwealth Medical College (Scranton, Pa.), and is currently spending a year at the Gelfand Clinical Research Lab at the University of Pennsylvania, Philadelphia.

[email protected]

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Key clinical point: Severe psoriasis appears to increase the risk of both immunoglobulin A glomerulonephritis and glomerular disease.

Major finding: The risk of glomerulonephritis was five-fold higher and the risk of glomerular disease doubled in those with severe psoriasis.

Data source: A population based cohort study comprised about 1.2 million subjects.

Disclosures: Ms. Sungat Grewal had no financial disclosures.

Kidney Stones? It’s Time to Rethink Those Meds

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Despite being recommended for ureteral stone expulsion, tamsulosin or nifedipine is no more effective than placebo.

PRACTICE CHANGER
Do not prescribe tamsulosin or nifedipine for stone expulsion in patients with ureteral stones that are ≤ 10 mm.1

Strength of recommendation
A:
 Based on a high-quality randomized controlled trial (RCT).1

Bob Z, age 48, presents to the emergency department (ED) with unspecified groin pain. CT of the kidney, ureter, and bladder (CT KUB) finds evidence of a single ureteral stone measuring 8 mm. He’s prescribed medication for the pain and discharged. The day after his ED visit, he comes to your office to discuss further treatment options. Should you prescribe tamsulosin or nifedipine to help him pass the stone?

The most recent National Health and Nutrition Examination Survey found kidney stones affect 8.8% of the population.2 Outpatient therapy is indicated for patients with ureteric colic secondary to stones ≤ 10 mm who do not have uncontrolled pain, impaired kidney function, or severe infection. Routine out­patient care includes oral hydration, antiemetics, and pain medications.

Medical expulsive therapy (MET) is also used to facilitate stone passage. MET is increasingly becoming part of routine care; use of MET in kidney stone patients in the United States has grown from 14% in 2009 to 64% in 2012.3,4

The joint European Association of Urology/American Urological Association Nephrolithiasis Guideline Panel supports the use of MET.5 Meta-analyses of multiple RCTs suggest that an α-blocker (tamsulosin) or a calcium channel blocker (nifedipine) can reduce pain and lead to quicker stone passage and a higher rate of eventual stone passage when compared to placebo or observation.6,7 However, these reviews included small, heterogeneous studies with a high or unclear risk for bias.

Continue for the study summary >>

 

 


STUDY SUMMARY
MET doesn’t increase the rate of stone passage
The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial1 was a multicenter RCT designed to determine the effectiveness of tamsulosin or nifedipine as MET for patients ages 18 to 65 with a single ureteric stone measuring ≤ 10 mm on CT KUB, which has 98% diagnostic accuracy.8 (Stones > 10 mm typically require surgery or lithotripsy.)

In this RCT, 1,167 adults were randomized to take tamsulosin (0.4 mg/d), nifedipine (30 mg/d), or placebo for four weeks or until the stone spontaneously passed, whichever came first. The participants, clinicians, and research staff were blinded to treatment assignment. The primary outcome was the proportion of participants who spontaneously passed their stone, as indicated in patient self-reported questionnaires and case-report forms completed by researchers. Secondary outcomes were time to stone passage and pain as assessed by analgesic use and a visual analogue scale (VAS).

At four weeks, 1,136 (97%) of the randomized participants had data available for analysis. The proportion of participants who passed their stone did not differ between MET and placebo; 80% of the placebo group (303 of 379 participants) passed the stone, compared with 81% (307 of 378) of the tamsulosin group and 80% (304 of 379) of the nifedipine group. The odds ratio (OR) for MET vs placebo was 1.04 (95% confidence interval [CI], 0.77 to 1.43) and the OR for tamsulosin vs nifedipine was 1.07 (95% CI, 0.74 to 1.53). These findings did not change with further subgroup analysis, including by sex, stone size (≤ 5 mm vs > 5 mm), or stone location.

There were no differences between groups in time to stone passage as measured by clinical report and confirmed by imaging. Time to passage of stone was available for 237 (21% of) participants. The mean days to stone passage was 15.9 (n = 84) for placebo, 16.5 (n = 79) for tamsulosin, and 16.2 (n = 74) for nifedipine, with a MET vs placebo difference of 0.5 days (95% CI, –2.9 to 3.9; P = .78). Sensitivity analysis accounting for bias from missing data did not change this outcome.

No differences in analgesic use or pain. Self-reported use of pain medication during the first four weeks was similar between groups: 59% (placebo patients), 56% (tamsulosin), and 56% (nifedipine). The mean days of pain medication use was 10.5 for placebo, 11.6 for tamsulosin, and 10.7 for nifedipine, with a MET vs placebo difference of 0.6 days (95% CI, –1.6 to 2.8; P = .45).

There was no difference between groups in the VAS pain score at four weeks. The MET vs placebo difference was 0.0 (95% CI, –0.4 to 0.4; P = .96) and the mean VAS pain score was 1.2 for placebo, 1.0 for tamsulosin, and 1.3 for nifedipine.

WHAT’S NEW
This large RCT contradicts results from previous meta-analyses
The SUSPEND study is the first large, multicenter RCT of MET with tamsulosin or nifedipine for kidney stones that used patient-oriented outcomes to find no benefit for stone expulsion, analgesic use, or reported pain compared to placebo. The discrepancy with prior meta-analyses is not unusual. Up to one-third of meta-analyses that show positive outcomes of a therapy are subsequently altered by the inclusion of results from a single, large, well-designed, multicenter RCT.9

Continue for caveats >>

 

 


CAVEATS
This trial included fewer women than previous studies
The SUSPEND study included a smaller proportion of women than previously published case series due to a need for a diagnostic CT KUB, which excluded more women than men due to radiation concerns. However, the proportion of women was balanced across all groups in this trial, and there was no evidence that sex impacted the efficacy of treatment for the primary outcome.1

CHALLENGES TO IMPLEMENTATION
We see no challenges to the implementation of this recommendation.

References
1. Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015;386:341-349.
2. Scales CD Jr, Smith AC, Hanley JM, et al. Prevalence of kidney stones in the United States. Eur Urol. 2012;62:160-165.
3. Fwu CW, Eggers PW, Kimmel PL, et al. Emergency department visits, use of imaging, and drugs for urolithiasis have increased in the United States. Kidney Int. 2013;89:479-486.
4. Bagga H, Appa A, Wang R, et al. 2257 medical expulsion therapy is underutilized in women presenting to an emergency department with acute urinary stone disease. J Urol. 2013; 189:e925-e926.
5. Preminger GM, Tiselius HG, Assimos DG, et al; American Urological Association Education and Research, Inc; European Association of Urology. 2007 Guideline for the management of ureteral calculi. Eur Urol. 2007;52:1610-1631.
6. Campschroer T, Zhu Y, Duijvesz D, et al. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev. 2014;4:CD008509.
7. Seitz C, Liatsikos E, Porpiglia F, et al. Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol. 2009;56:455-471.
8. Worster A, Preyra I, Weaver B, et al. The accuracy of noncontrast helical computed tomography versus intravenous pyelography in the diagnosis of suspected acute urolithiasis: a meta-analysis. Ann Emerg Med. 2002;40: 280-286.
9. LeLorier J, Gregoire G, Benhaddad A, et al. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997;337:536-542.

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 © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(2):118-120.

References

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Andrew H. Slattengren and Shailendra Prasad are with the North Memorial Family Medicine Residency at the University of Minnesota, Minneapolis. Jennie B. Jarrett is with the Family Medicine Residency Program at the University of Pittsburgh Medical Center in St. Margaret, Pennsylvania.

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Despite being recommended for ureteral stone expulsion, tamsulosin or nifedipine is no more effective than placebo.
Despite being recommended for ureteral stone expulsion, tamsulosin or nifedipine is no more effective than placebo.

PRACTICE CHANGER
Do not prescribe tamsulosin or nifedipine for stone expulsion in patients with ureteral stones that are ≤ 10 mm.1

Strength of recommendation
A:
 Based on a high-quality randomized controlled trial (RCT).1

Bob Z, age 48, presents to the emergency department (ED) with unspecified groin pain. CT of the kidney, ureter, and bladder (CT KUB) finds evidence of a single ureteral stone measuring 8 mm. He’s prescribed medication for the pain and discharged. The day after his ED visit, he comes to your office to discuss further treatment options. Should you prescribe tamsulosin or nifedipine to help him pass the stone?

The most recent National Health and Nutrition Examination Survey found kidney stones affect 8.8% of the population.2 Outpatient therapy is indicated for patients with ureteric colic secondary to stones ≤ 10 mm who do not have uncontrolled pain, impaired kidney function, or severe infection. Routine out­patient care includes oral hydration, antiemetics, and pain medications.

Medical expulsive therapy (MET) is also used to facilitate stone passage. MET is increasingly becoming part of routine care; use of MET in kidney stone patients in the United States has grown from 14% in 2009 to 64% in 2012.3,4

The joint European Association of Urology/American Urological Association Nephrolithiasis Guideline Panel supports the use of MET.5 Meta-analyses of multiple RCTs suggest that an α-blocker (tamsulosin) or a calcium channel blocker (nifedipine) can reduce pain and lead to quicker stone passage and a higher rate of eventual stone passage when compared to placebo or observation.6,7 However, these reviews included small, heterogeneous studies with a high or unclear risk for bias.

Continue for the study summary >>

 

 


STUDY SUMMARY
MET doesn’t increase the rate of stone passage
The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial1 was a multicenter RCT designed to determine the effectiveness of tamsulosin or nifedipine as MET for patients ages 18 to 65 with a single ureteric stone measuring ≤ 10 mm on CT KUB, which has 98% diagnostic accuracy.8 (Stones > 10 mm typically require surgery or lithotripsy.)

In this RCT, 1,167 adults were randomized to take tamsulosin (0.4 mg/d), nifedipine (30 mg/d), or placebo for four weeks or until the stone spontaneously passed, whichever came first. The participants, clinicians, and research staff were blinded to treatment assignment. The primary outcome was the proportion of participants who spontaneously passed their stone, as indicated in patient self-reported questionnaires and case-report forms completed by researchers. Secondary outcomes were time to stone passage and pain as assessed by analgesic use and a visual analogue scale (VAS).

At four weeks, 1,136 (97%) of the randomized participants had data available for analysis. The proportion of participants who passed their stone did not differ between MET and placebo; 80% of the placebo group (303 of 379 participants) passed the stone, compared with 81% (307 of 378) of the tamsulosin group and 80% (304 of 379) of the nifedipine group. The odds ratio (OR) for MET vs placebo was 1.04 (95% confidence interval [CI], 0.77 to 1.43) and the OR for tamsulosin vs nifedipine was 1.07 (95% CI, 0.74 to 1.53). These findings did not change with further subgroup analysis, including by sex, stone size (≤ 5 mm vs > 5 mm), or stone location.

There were no differences between groups in time to stone passage as measured by clinical report and confirmed by imaging. Time to passage of stone was available for 237 (21% of) participants. The mean days to stone passage was 15.9 (n = 84) for placebo, 16.5 (n = 79) for tamsulosin, and 16.2 (n = 74) for nifedipine, with a MET vs placebo difference of 0.5 days (95% CI, –2.9 to 3.9; P = .78). Sensitivity analysis accounting for bias from missing data did not change this outcome.

No differences in analgesic use or pain. Self-reported use of pain medication during the first four weeks was similar between groups: 59% (placebo patients), 56% (tamsulosin), and 56% (nifedipine). The mean days of pain medication use was 10.5 for placebo, 11.6 for tamsulosin, and 10.7 for nifedipine, with a MET vs placebo difference of 0.6 days (95% CI, –1.6 to 2.8; P = .45).

There was no difference between groups in the VAS pain score at four weeks. The MET vs placebo difference was 0.0 (95% CI, –0.4 to 0.4; P = .96) and the mean VAS pain score was 1.2 for placebo, 1.0 for tamsulosin, and 1.3 for nifedipine.

WHAT’S NEW
This large RCT contradicts results from previous meta-analyses
The SUSPEND study is the first large, multicenter RCT of MET with tamsulosin or nifedipine for kidney stones that used patient-oriented outcomes to find no benefit for stone expulsion, analgesic use, or reported pain compared to placebo. The discrepancy with prior meta-analyses is not unusual. Up to one-third of meta-analyses that show positive outcomes of a therapy are subsequently altered by the inclusion of results from a single, large, well-designed, multicenter RCT.9

Continue for caveats >>

 

 


CAVEATS
This trial included fewer women than previous studies
The SUSPEND study included a smaller proportion of women than previously published case series due to a need for a diagnostic CT KUB, which excluded more women than men due to radiation concerns. However, the proportion of women was balanced across all groups in this trial, and there was no evidence that sex impacted the efficacy of treatment for the primary outcome.1

CHALLENGES TO IMPLEMENTATION
We see no challenges to the implementation of this recommendation.

References
1. Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015;386:341-349.
2. Scales CD Jr, Smith AC, Hanley JM, et al. Prevalence of kidney stones in the United States. Eur Urol. 2012;62:160-165.
3. Fwu CW, Eggers PW, Kimmel PL, et al. Emergency department visits, use of imaging, and drugs for urolithiasis have increased in the United States. Kidney Int. 2013;89:479-486.
4. Bagga H, Appa A, Wang R, et al. 2257 medical expulsion therapy is underutilized in women presenting to an emergency department with acute urinary stone disease. J Urol. 2013; 189:e925-e926.
5. Preminger GM, Tiselius HG, Assimos DG, et al; American Urological Association Education and Research, Inc; European Association of Urology. 2007 Guideline for the management of ureteral calculi. Eur Urol. 2007;52:1610-1631.
6. Campschroer T, Zhu Y, Duijvesz D, et al. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev. 2014;4:CD008509.
7. Seitz C, Liatsikos E, Porpiglia F, et al. Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol. 2009;56:455-471.
8. Worster A, Preyra I, Weaver B, et al. The accuracy of noncontrast helical computed tomography versus intravenous pyelography in the diagnosis of suspected acute urolithiasis: a meta-analysis. Ann Emerg Med. 2002;40: 280-286.
9. LeLorier J, Gregoire G, Benhaddad A, et al. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997;337:536-542.

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 © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(2):118-120.

PRACTICE CHANGER
Do not prescribe tamsulosin or nifedipine for stone expulsion in patients with ureteral stones that are ≤ 10 mm.1

Strength of recommendation
A:
 Based on a high-quality randomized controlled trial (RCT).1

Bob Z, age 48, presents to the emergency department (ED) with unspecified groin pain. CT of the kidney, ureter, and bladder (CT KUB) finds evidence of a single ureteral stone measuring 8 mm. He’s prescribed medication for the pain and discharged. The day after his ED visit, he comes to your office to discuss further treatment options. Should you prescribe tamsulosin or nifedipine to help him pass the stone?

The most recent National Health and Nutrition Examination Survey found kidney stones affect 8.8% of the population.2 Outpatient therapy is indicated for patients with ureteric colic secondary to stones ≤ 10 mm who do not have uncontrolled pain, impaired kidney function, or severe infection. Routine out­patient care includes oral hydration, antiemetics, and pain medications.

Medical expulsive therapy (MET) is also used to facilitate stone passage. MET is increasingly becoming part of routine care; use of MET in kidney stone patients in the United States has grown from 14% in 2009 to 64% in 2012.3,4

The joint European Association of Urology/American Urological Association Nephrolithiasis Guideline Panel supports the use of MET.5 Meta-analyses of multiple RCTs suggest that an α-blocker (tamsulosin) or a calcium channel blocker (nifedipine) can reduce pain and lead to quicker stone passage and a higher rate of eventual stone passage when compared to placebo or observation.6,7 However, these reviews included small, heterogeneous studies with a high or unclear risk for bias.

Continue for the study summary >>

 

 


STUDY SUMMARY
MET doesn’t increase the rate of stone passage
The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial1 was a multicenter RCT designed to determine the effectiveness of tamsulosin or nifedipine as MET for patients ages 18 to 65 with a single ureteric stone measuring ≤ 10 mm on CT KUB, which has 98% diagnostic accuracy.8 (Stones > 10 mm typically require surgery or lithotripsy.)

In this RCT, 1,167 adults were randomized to take tamsulosin (0.4 mg/d), nifedipine (30 mg/d), or placebo for four weeks or until the stone spontaneously passed, whichever came first. The participants, clinicians, and research staff were blinded to treatment assignment. The primary outcome was the proportion of participants who spontaneously passed their stone, as indicated in patient self-reported questionnaires and case-report forms completed by researchers. Secondary outcomes were time to stone passage and pain as assessed by analgesic use and a visual analogue scale (VAS).

At four weeks, 1,136 (97%) of the randomized participants had data available for analysis. The proportion of participants who passed their stone did not differ between MET and placebo; 80% of the placebo group (303 of 379 participants) passed the stone, compared with 81% (307 of 378) of the tamsulosin group and 80% (304 of 379) of the nifedipine group. The odds ratio (OR) for MET vs placebo was 1.04 (95% confidence interval [CI], 0.77 to 1.43) and the OR for tamsulosin vs nifedipine was 1.07 (95% CI, 0.74 to 1.53). These findings did not change with further subgroup analysis, including by sex, stone size (≤ 5 mm vs > 5 mm), or stone location.

There were no differences between groups in time to stone passage as measured by clinical report and confirmed by imaging. Time to passage of stone was available for 237 (21% of) participants. The mean days to stone passage was 15.9 (n = 84) for placebo, 16.5 (n = 79) for tamsulosin, and 16.2 (n = 74) for nifedipine, with a MET vs placebo difference of 0.5 days (95% CI, –2.9 to 3.9; P = .78). Sensitivity analysis accounting for bias from missing data did not change this outcome.

No differences in analgesic use or pain. Self-reported use of pain medication during the first four weeks was similar between groups: 59% (placebo patients), 56% (tamsulosin), and 56% (nifedipine). The mean days of pain medication use was 10.5 for placebo, 11.6 for tamsulosin, and 10.7 for nifedipine, with a MET vs placebo difference of 0.6 days (95% CI, –1.6 to 2.8; P = .45).

There was no difference between groups in the VAS pain score at four weeks. The MET vs placebo difference was 0.0 (95% CI, –0.4 to 0.4; P = .96) and the mean VAS pain score was 1.2 for placebo, 1.0 for tamsulosin, and 1.3 for nifedipine.

WHAT’S NEW
This large RCT contradicts results from previous meta-analyses
The SUSPEND study is the first large, multicenter RCT of MET with tamsulosin or nifedipine for kidney stones that used patient-oriented outcomes to find no benefit for stone expulsion, analgesic use, or reported pain compared to placebo. The discrepancy with prior meta-analyses is not unusual. Up to one-third of meta-analyses that show positive outcomes of a therapy are subsequently altered by the inclusion of results from a single, large, well-designed, multicenter RCT.9

Continue for caveats >>

 

 


CAVEATS
This trial included fewer women than previous studies
The SUSPEND study included a smaller proportion of women than previously published case series due to a need for a diagnostic CT KUB, which excluded more women than men due to radiation concerns. However, the proportion of women was balanced across all groups in this trial, and there was no evidence that sex impacted the efficacy of treatment for the primary outcome.1

CHALLENGES TO IMPLEMENTATION
We see no challenges to the implementation of this recommendation.

References
1. Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015;386:341-349.
2. Scales CD Jr, Smith AC, Hanley JM, et al. Prevalence of kidney stones in the United States. Eur Urol. 2012;62:160-165.
3. Fwu CW, Eggers PW, Kimmel PL, et al. Emergency department visits, use of imaging, and drugs for urolithiasis have increased in the United States. Kidney Int. 2013;89:479-486.
4. Bagga H, Appa A, Wang R, et al. 2257 medical expulsion therapy is underutilized in women presenting to an emergency department with acute urinary stone disease. J Urol. 2013; 189:e925-e926.
5. Preminger GM, Tiselius HG, Assimos DG, et al; American Urological Association Education and Research, Inc; European Association of Urology. 2007 Guideline for the management of ureteral calculi. Eur Urol. 2007;52:1610-1631.
6. Campschroer T, Zhu Y, Duijvesz D, et al. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev. 2014;4:CD008509.
7. Seitz C, Liatsikos E, Porpiglia F, et al. Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol. 2009;56:455-471.
8. Worster A, Preyra I, Weaver B, et al. The accuracy of noncontrast helical computed tomography versus intravenous pyelography in the diagnosis of suspected acute urolithiasis: a meta-analysis. Ann Emerg Med. 2002;40: 280-286.
9. LeLorier J, Gregoire G, Benhaddad A, et al. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997;337:536-542.

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 © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(2):118-120.

References

References

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Kidney Stones? It’s Time to Rethink Those Meds
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Managing diabetes in hospitalized patients with chronic kidney disease

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Managing diabetes in hospitalized patients with chronic kidney disease

Managing glycemic control in hospitalized patients with chronic kidney disease (CKD) and diabetes mellitus is a challenge, with no published guidelines. In this setting, avoiding hypoglycemia takes precedence over meeting strict blood glucose targets. Optimal management is essential to reduce hypoglycemia and the risk of death from cardiovascular disease.1

This article reviews the evidence to guide diabetes management in hospitalized patients with CKD, focusing on blood glucose monitoring, insulin dosing, and concerns about other diabetic agents.

FOCUS ON AVOIDING HYPOGLYCEMIA

CKD is common, estimated to affect more than 50 million people worldwide.2 Diabetes mellitus is the primary cause of kidney failure in 45% of dialysis patients with CKD.

Tight control comes with a cost

Hyperglycemia in hospitalized patients is associated with a higher risk of death, a higher risk of infections, and a longer hospital stay.3,4 In 2001, Van den Berghe et al5 found that intensive insulin therapy reduced the mortality rate in critically ill patients in the surgical intensive care unit. But subsequent studies6,7 found that intensive insulin therapy to achieve tight glycemic control increased rates of morbidity and mortality without adding clinical benefit.

Randomized clinical trials in outpatients have shown that tight control of blood glucose levels reduces microvascular and macrovascular complications in patients with type 1 diabetes.8–10 In the Diabetes Control and Complications Trial,9 compared with conventional therapy, intensive insulin therapy reduced the incidence of retinopathy progression (4.7 vs 1.2 cases per 100 patient-years, number needed to treat [NNT] = 3 for 10 years) and clinical neuropathy (9.8 vs 3.1 per 100 patient-years, NNT = 1.5 for 10 years). The long-term likelihood of a cardiovascular event was also significantly lower in the intensive treatment group (0.38 vs 0.80 events per 100 patient-years).9

Similarly, in the Epidemiology of Diabetes Interventions and Complications follow-up study, the intensive therapy group had fewer cardiovascular deaths.11 On the other hand, the risk of severe hypoglycemia and subsequent coma or seizure was significantly higher in the intensive therapy group than in the conventional therapy group (16.3 vs 5.4 per 100 patient-years).8

CKD increases hypoglycemia risk

Chronic kidney disease is a risk factor for hypoglycemia in hospitalized patients
Figure 1. Incidence of hypoglycemic episodes in hospitalized patients with or without chronic kidney disease (CKD) and diabetes in a Veterans Administration study.12 All differences compared with the reference group (no CKD, no diabetes) were statistically significant (P < .0001).

Moen et al12 found that the incidence of hypoglycemia was significantly higher in patients with CKD (estimated glomerular filtration rate [GFR] < 60 mL/min) with or without diabetes, and that patients with both conditions were at greatest risk (Figure 1). Multiple factors contribute to the increased risk of hypoglycemia: patients with advanced CKD tend to have poor nutrition, resulting in reduced glycogen stores, and a smaller renal mass reduces renal gluconeogenesis and decreases the elimination of insulin and oral antidiabetic agents.

After the onset of diabetic nephropathy, progression of renal complications and overall life expectancy are influenced by earlier glycemic control.8 Development of diabetic nephropathy is commonly accompanied by changes in metabolic control, particularly an increased risk of hypoglycemia.13 In addition, episodes of severe hypoglycemia constitute an independent cardiovascular risk factor.14

Aggressive glycemic control in hospitalized patients, particularly those with advanced CKD, is associated with a risk of hypoglycemia without overall improvement in outcomes.15 Elderly patients with type 2 diabetes are similar to patients with CKD in that they have a reduced GFR and are thus more sensitive to insulin. In both groups, intensifying glycemic control, especially in the hospital, is associated with more frequent episodes of severe hypoglycemia.16 The focus should be not only on maintaining optimal blood glucose concentration, but also on preventing hypoglycemia.

‘Burnt-out’ diabetes

Paradoxically, patients with end-stage renal disease and type 2 diabetes often experience altered glucose homeostasis with markedly improved glycemic control. They may attain normoglycemia and normalization of hemoglobin A1c, a condition known as “burnt-out” diabetes. Its precise mechanism is not understood and its significance remains unclear (Table 1).17

HEMOGLOBIN A1c CAN BE FALSELY HIGH OR FALSELY LOW

Hemoglobin A1c measurement is used to diagnose diabetes and to assess long-term glycemic control. It is a measure of the fraction of hemoglobin that has been glycated by exposure to glucose. Because the average lifespan of a red cell is 120 days, the hemoglobin A1c value reflects the mean blood glucose concentration over the preceding 3 months.

But hemoglobin A1c measurement has limitations: any condition that alters the lifespan of erythrocytes leads to higher or lower hemoglobin A1c levels. Hemoglobin A1c levels are also affected by kidney dysfunction, hemolysis, and acidosis.18

Falsely high hemoglobin A1c levels are associated with conditions that prolong the lifespan of erythrocytes, such as asplenia. Iron deficiency also increases the average age of circulating red cells because of reduced red cell production. For patients in whom blood glucose measurements do not correlate with hemoglobin A1c measurements, iron deficiency anemia should be considered before altering a treatment regimen.

Falsely low hemoglobin A1c levels are associated with conditions of more rapid erythrocyte turnover, such as autoimmune hemolytic anemia, hereditary spherocytosis, and acute blood loss anemia. In patients with CKD, recombinant erythropoietin treatment lowers hemoglobin A1c levels by increasing the number of immature red cells, which are less likely to glycosylate.19

Morgan et al20 compared the association between hemoglobin A1c and blood glucose levels in diabetic patients with moderate to severe CKD not requiring dialysis and in diabetic patients with normal renal function and found no difference between these two groups, suggesting that hemoglobin A1c is reliable in this setting. But study results conflict for patients on dialysis, making the usefulness of hemoglobin A1c testing for those patients less clear. In one study, hemoglobin A1c testing underestimated glycemic control,20 but other studies found that glycemic control was overestimated.21,22

Alternatives to hemoglobin A1c

Other measures of long-term glycemic control such as fructosamine and glycated albumin levels are sometimes used in conditions in which hemoglobin A1c may not be reliable.

Albumin also undergoes glycation when exposed to glucose. Glycated albumin appears to be a better measure of glycemic control in patients with CKD and diabetes than serum fructosamine,23 which has failed to show a significant correlation with blood glucose levels in patients with CKD.24 However, because serum albumin has a short half-life, glycated albumin reflects glycemic control in only the approximately 1 to 2 weeks before sampling,25 so monthly monitoring is required.

Glycated albumin levels may be reduced due to increased albumin turnover in patients with nephrotic-range proteinuria and in diabetic patients on peritoneal dialysis. Several issues remain unclear, such as the appropriate target level of glycated albumin and at what stage of CKD it should replace hemoglobin A1c testing. If an improved assay that is unaffected by changes in serum albumin becomes available, it may be appropriate to use glycated albumin measurements to assess long-term glycemic control for patients with CKD.

In general, therapeutic decisions to achieve optimum glycemic control in patients with diabetes and CKD should be based on hemoglobin A1c testing, multiple glucose measurements, and patient symptoms of hypoglycemia or hyperglycemia. The best measure for assessing glycemic control in hospitalized patients with CKD remains multiple blood glucose testing daily.

INSULIN THERAPY PREFERRED

Although several studies have evaluated inpatient glycemic control,26–29 no guidelines have been published for hospitalized patients with diabetes and CKD. Insulin therapy is preferred for achieving glycemic control in acutely ill or hospitalized patients with diabetes. Oral hypoglycemic agents should be discontinued.

Regardless of the form of insulin chosen to treat diabetes, caution is needed for patients with kidney disease. During hospitalization, clinical changes are expected owing to illness and differences in caloric intake and physical activity, resulting in altered insulin sensitivity. Insulin-treated hospitalized patients require individualized care, including multiple daily blood glucose tests and insulin therapy modifications for ideal glycemic control.

For surgical or medical intensive care patients on insulin therapy, the target blood glucose level before meals should be 140 mg/dL, and the target random level should be less than 180 mg/dL.15,26–29

Basal-bolus insulin

Sliding-scale therapy should be avoided as the only method for glycemic control. Instead, scheduled subcutaneous basal insulin once or twice daily combined with rapid- or short-acting insulin with meals is recommended.

Basal-bolus insulin therapy, one of the most advanced and flexible insulin replacement therapies, mimics endogenous insulin release and offers great advantages in diabetes care. Using mealtime bolus insulin permits variation in the amount of food eaten; more insulin can be taken with a larger meal and less with smaller meals. A bolus approach offers the flexibility of administering rapid-acting insulin immediately after meals when oral intake is variable.

Individualize insulin therapy

Optimizing glycemic control requires an understanding of the altered pharmacokinetics and pharmacodynamics of insulin in patients with diabetic nephropathy. Table 2 shows the pharmacokinetic profiles of insulin preparations in healthy people. Analogue insulins, which are manufactured by recombinant DNA technology, have conformational changes in the insulin molecule that alter their pharmacokinetics and pharmacodynamics. The rapid-acting analogue insulins are absorbed quickly, making them suitable for postprandial glucose control.

Changes in GFR are associated with altered pharmacokinetics and pharmacodynamics of insulin,30,31 but unlike for oral antidiabetic agents, these properties are not well characterized for insulin preparations in patients with renal insufficiency.13,32–36

CKD may reduce insulin clearance. Rave et al32 reported that the clearance of regular human insulin was reduced by 30% to 40% in patients with type 1 diabetes and a mean estimated GFR of 54 mL/min. They found that the metabolic activity of insulin lispro was more robust than that of short-acting regular human insulin in patients with diabetic nephropathy. In another study, patients with diabetes treated with insulin aspart did not show any significant change in the required insulin dosage in relation to the renal filtration rate.34 Biesenbach et al33 found a 38% reduction in insulin requirements in patients with type 1 diabetes as estimated GFR decreased from 80 mL/min to 10 mL/min. Further studies are required to better understand the safety of insulin in treating hospitalized patients with diabetes and renal insufficiency.

Few studies have compared the pharmacodynamics of long-acting insulins in relation to declining renal function. The long-acting analogue insulins have less of a peak than human insulin and thus better mimic endogenous insulin secretion. For insulin detemir, Lindholm and Jacobsen found no significant differences in the pharmacokinetics related to the stages of CKD.35 When using the long-acting insulins glargine or detemir, one should consider giving much lower doses (half the initial starting dosage) and titrating the dosage until target fasting glucose concentrations are reached to prevent hypoglycemia.

Table 3 summarizes recommended insulin dosage adjustments in CKD based on the literature and our clinical experience.

 

 

Considerations for dialysis patients

Subcutaneously administered insulin is eliminated renally, unlike endogenous insulin, which undergoes first-pass metabolism in the liver.13,37 As renal function declines, insulin clearance decreases and the insulin dosage must be reduced to prevent hypoglycemia.

Patients on hemodialysis or peritoneal dialysis pose a challenge for insulin dosing. Hemodialysis improves insulin sensitivity but also increases insulin clearance, making it difficult to determine insulin requirements. Sobngwi et al38 conducted a study in diabetic patients with end-stage renal disease on hemodialysis, using a 24-hour euglycemic clamp. They found that exogenous basal insulin requirements were 25% lower on the day after hemodialysis compared with the day before, but premeal insulin requirements stayed the same.

Peritoneal dialysis exposes patients to a high glucose load via the peritoneum, which can worsen insulin resistance. Intraperitoneal administration of insulin during peritoneal dialysis provides a more physiologic effect than subcutaneous administration: it prevents fluctuations of blood glucose and the formation of insulin antibodies. But insulin requirements are higher owing to a dilutional effect and to insulin binding to the plastic surface of the dialysis fluid reservoir.39

GLYCEMIC CONTROL FOR PROCEDURES

No guidelines have been established regarding the optimal blood glucose range for diabetic patients with CKD undergoing diagnostic or surgical procedures. Given the risk of hypoglycemia in such settings, less-stringent targets are reasonable, ie, premeal blood glucose levels of 140 mg/dL and random blood glucose levels of less than 180 mg/dL.

Before surgery, consideration should be given to the type of diabetes, surgical procedure, and metabolic control. Patients on insulin detemir or glargine as part of a basal-bolus regimen with rapid-acting insulin may safely be given the full dose of their basal insulin the night before or the morning of their procedure. However, patients on neutral protamine Hagedorn (NPH) insulin as a part of their basal-bolus regimen should receive half of their usual dose due to a difference in pharmacokinetic profile compared with insulin glargine or detemir.

In insulin-treated patients undergoing prolonged procedures (eg, coronary artery bypass grafting, transplant):

  • Discontinue subcutaneous insulin and start an intravenous insulin infusion, titrated to maintain a blood glucose range of 140 to 180 mg/dL
  • Subcutaneous insulin management may be acceptable for patients undergoing shorter outpatient procedures
  • Supplemental subcutaneous doses of short- or rapid-acting insulin preparations can be given for blood glucose elevation greater than 180 mg/dL.

AVOID ORAL AGENTS AND NONINSULIN INJECTABLES

Oral antidiabetic agents and noninsulin injectables (Table 4) should generally be avoided in hospitalized patients, especially for those with decompensated heart failure, renal insufficiency, hypoperfusion, or chronic pulmonary disease, or for those given intravenous contrast. Most oral medications used to treat diabetes are affected by reduced kidney function, resulting in prolonged drug exposure and increased risk of hypoglycemia in patients with moderate to severe CKD (stages 3–5).

Metformin, a biguanide, is contraindicated in patients with high serum creatinine levels (> 1.5 mg/dL in men, > 1.4 mg/dL in women) because of the theoretical risk of lactic acidosis.40

Sulfonylurea clearance depends on kidney function.41 Severe prolonged episodes of hypoglycemia have been reported in dialysis patients taking these drugs, except with glipizide, which carries a lower risk.41,42

Repaglinide, a nonsulfonylurea insulin secretagogue, can be used in CKD stages 3 to 4 without any dosage adjustment.43

Thiazolidinediones have been reported to slow the progression of diabetic kidney disease independent of glycemic control.44 Adverse effects include fluid retention, edema, and congestive heart failure. Thiazolidinediones should not be used in patients with New York Heart Association class 3 or 4 heart failure,45 and so should not be prescribed in the hospital except for patients who are clinically stable or ready for discharge.

Quick-release bromocriptine, a dopamine receptor agonist, has been shown to be effective in lowering fasting plasma glucose levels and hemoglobin A1c, and improving glucose tolerance in obese patients with type 2 diabetes, although its usefulness in hospitalized patients with diabetes is not known.46,47

Dipeptidyl peptidase inhibitors. Sitagliptin and saxagliptin have been shown to be safe and effective in hospitalized patients with type 2 diabetes.48 However, except for linagliptin, dose reduction is recommended in patients with CKD stage 3 and higher.49–52

GLP-1 receptor agonists. Drugs of this class are potent agents for the reduction of glucose in the outpatient setting but are relatively contraindicated if the GFR is less than 30 mL/min, and they are currently not used in the hospital.

BLOOD GLUCOSE MONITORING IN HOSPITALIZED PATIENTS

Bedside blood glucose monitoring is recommended for all hospitalized patients with known diabetes with or without CKD, those with newly recognized hyperglycemia, and those who receive therapy associated with high risk for hyperglycemia, such as glucocorticoid therapy and enteral and parenteral nutrition. For patients on scheduled diets, fingerstick blood glucose monitoring is recommended before meals and at bedtime. In patients with no oral intake or on continuous enteral or parenteral nutrition, blood glucose monitoring every 4 to 6 hours is recommended. More frequent monitoring (eg, adding a 3:00 am check) may be prudent in patients with CKD.

Continuous glucose monitoring systems use a sensor inserted under the skin and transmit information via radio to a wireless monitor. Such systems are more expensive than conventional glucose monitoring but may enable better glucose control by providing real-time glucose measurements, with levels displayed at 5-minute or 1-minute intervals. Marshall et al53 confirmed this technology’s accuracy and precision in uremic patients on dialysis.

Considerations for peritoneal dialysis

For patients on peritoneal dialysis, glucose in the dialysate exacerbates hyperglycemia. Dialysis solutions with the glucose polymer icodextrin as the osmotic agent instead of glucose have been suggested to reduce glucose exposure.

Glucose monitoring systems measure interstitial fluid glucose by the glucose oxidase reaction and therefore are not affected by icodextrin. However, icodextrin is converted to maltose, a disaccharide composed of two glucose molecules, which can cause spuriously high readings in devices that use test strips containing the enzymes glucose dehydrogenase pyrroloquinoline quinone or glucose dye oxidoreductase. Spurious hyperglycemia may lead to giving too much insulin, in turn leading to symptomatic hypoglycemia.

Clinicians caring for patients receiving icodextrin should ensure that the glucose monitoring system uses only test strips that contain glucose oxidase, glucose dehydrogenase-nicotinamide adenine dinucleotide, or glucose dehydrogenase-flavin adenine dinucleotide, which are not affected by icodextrin.54

IMPROVING QUALITY

Hospitalized patients face many barriers to optimal glycemic control. Less experienced practitioners tend to have insufficient knowledge of insulin preparations and appropriate insulin dosing. Also, diabetes is often listed as a secondary diagnosis and so may be overlooked by the inpatient care team.

Educational programs should be instituted to overcome these barriers and improve knowledge related to inpatient diabetes care. When necessary, the appropriate use of consultants is important in hospitalized settings to improve quality and make hospital care more efficient and cost-effective.

No national benchmarks currently exist for inpatient diabetes care, and they need to be developed to ensure best practices. Physicians should take the initiative to remedy this by collaborating with other healthcare providers, such as dedicated diabetes educators, nursing staff, pharmacists, registered dietitians, and physicians with expertise in diabetes management, with the aim of achieving optimum glycemic control and minimizing hypoglycemia. 

References
  1. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351:1296–1305.
  2. Newman DJ, Mattock MB, Dawnay AB, et al. Systematic review on urine albumin testing for early detection of diabetic complications. Health Technol Assess 2005; 9:iii–vi, xiii–163.
  3. Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002; 87:978–982.
  4. Golden SH, Peart-Vigilance C, Kao WH, Brancati FL. Perioperative glycemic control and the risk of infectious complications in a cohort of adults with diabetes. Diabetes Care 1999; 22:1408–1414.
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  16. Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545–2559.
  17. Kovesdy CP, Park JC, Kalantar-Zadeh K. Glycemic control and burnt-out diabetes in ESRD. Semin Dial 2010; 23:148–156.
  18. De Marchi S, Cecchin E, Camurri C, et al. Origin of glycosylated hemoglobin A1 in chronic renal failure. Int J Artif Organs 1983; 6:77–82.
  19. Brown JN, Kemp DW, Brice KR. Class effect of erythropoietin therapy on hemoglobin A(1c) in a patient with diabetes mellitus and chronic kidney disease not undergoing hemodialysis. Pharmacotherapy 2009; 29:468–472.
  20. Morgan L, Marenah CB, Jeffcoate WJ, Morgan AG. Glycated proteins as indices of glycemic control in diabetic patients with chronic renal failure. Diabet Med 1996; 13:514–519.
  21. Peacock TP, Shihabi ZK, Bleyer AJ, et al. Comparison of glycated albumin and hemoglobin A(1c) levels in diabetic subjects on hemodialysis. Kidney Int 2008; 73:1062–1068.
  22. Joy MS, Cefalu WT, Hogan SL, Nachman PH. Long-term glycemic control measurements in diabetic patients receiving hemodialysis. Am J Kidney Dis 2002; 39:297–307.
  23. Inaba M, Okuno S, Kumeda Y, et al; Osaka CKD Expert Research Group. Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietin injection. J Am Soc Nephrol 2007; 18:896–903.
  24. Mittman N, Desiraju B, Fazil I, et al. Serum fructosamine versus glycosylated hemoglobin as an index of glycemic control, hospitalization, and infection in diabetic hemodialysis patients. Kidney Int 2010; 78(suppl 117):S41–S45.
  25. Alskar O, Korelli J, Duffull SB. A pharmacokinetic model for the glycation of albumin. J Pharmacokinet Pharmacodyn 2012; 39:273–282.
  26. Qaseem A, Humphrey LL, Chou R, Snow V, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2011; 154:260–267.
  27. Murad MH, Coburn JA, Coto-Yglesias F, et al. Glycemic control in non-critically ill hospitalized patients: a systematic review and meta-analysis. J Clin Endocrinol Metab 2012; 97:49–58.
  28. Bogun M, Inzucchi SE. Inpatient management of diabetes and hyperglycemia. Clin Ther 2013; 35:724–733.
  29. Miller DB. Glycemic targets in hospital and barriers to attaining them. Can J Diabetes 2014; 38:74–78.
  30. Eidemak I, Feldt-Rasmussen B, Kanstrup IL, Nielsen SL, Schmitz O, Strandgaard S. Insulin resistance and hyperinsulinaemia in mild to moderate progressive chronic renal failure and its association with aerobic work capacity. Diabetologia 1995; 38:565–572.
  31. Svensson M, Yu Z, Eriksson J. A small reduction in glomerular filtration is accompanied by insulin resistance in type I diabetes patients with diabetic nephropathy. Eur J Clin Invest 2002; 32:100–109.
  32. Rave K, Heise T, Pfutzner A, Heinemann L, Sawicki P. Impact of diabetic nephropathy on pharmacodynamics and pharmacokinetic properties of insulin in type I diabetic patients. Diabetes Care 2001; 24:886–890.
  33. Biesenbach G, Raml A, Schmekal B, Eichbauer-Sturm G. Decreased insulin requirement in relation to GFR in nephropathic type 1 and insulin-treated type 2 diabetic patients. Diabet Med 2003; 20:642–645.
  34. Holmes G, Galitz L, Hu P, Lyness W. Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment. Br J Clin Pharmacol 2005; 60:469–476.
  35. Lindholm A, Jacobsen LV. Clinical pharmacokinetics and pharmacodynamics of insulin aspart. Clin Pharmacokinet 2001; 40:641–659.
  36. Bolli GB, Hahn AD, Schmidt R, et al. Plasma exposure to insulin glargine and its metabolites M1 and M2 after subcutaneous injection of therapeutic and supratherapeutic doses of glargine in subjects with type 1 diabetes. Diabetes Care 2012; 35:2626–2630.
  37. Nielsen S. Time course and kinetics of proximal tubular processing of insulin. Am J Physiol 1992; 262:F813–F822.
  38. Sobngwi E, Enoru S, Ashuntantang G, et al. Day-to-day variation of insulin requirements of patients with type 2 diabetes and end-stage renal disease undergoing maintenance hemodialysis. Diabetes Care 2010; 33:1409–1412.
  39. Quellhorst E. Insulin therapy during peritoneal dialysis: pros and cons of various forms of administration. J Am Soc Nephrol 2002; 13(suppl 1):S92–S96.
  40. Davidson MB, Peters AL. An overview of metformin in the treatment of type 2 diabetes mellitus. Am J Med 1997; 102:99–110.
  41. Ahmed Z, Simon B, Choudhury D. Management of diabetes in patients with chronic kidney disease. Postgrad Med 2009; 121:52–60.
  42. Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood glucose in diabetic patients with renal failure. Diabetes Metab 2000; 26(suppl 4):73–85.
  43. Hasslacher C; Multinational Repaglinide Renal Study Group. Safety and efficacy of repaglinide in type 2 diabetic patients with and without impaired renal function. Diabetes Care 2003; 26:886–891.
  44. Iglesias P, Dies JJ. Peroxisome proliferator-activated receptor gamma agonists in renal disease. Eur J Endocrinol 2006; 154:613–621.
  45. Hollenberg NK. Considerations for management of fluid dynamic issues associated with thiazolidinediones. Am J Med 2003; 115(suppl. 8A) 111S–115S.
  46. Kamath V, Jones CN, Yip JC, et al. Effects of a quick-release form of bromocriptine (Ergoset) on fasting and postprandial plasma glucose, insulin, lipid, and lipoprotein concentrations in obese nondiabetic hyperinsulinemic women. Diabetes Care 1997; 20:1697–1701.
  47. Pijl H, Ohashi S, Matsuda M, et al. Bromocriptine: a novel approach to the treatment of type 2 diabetes. Diabetes Care 2000; 23:1154–1161.
  48. Umpierrez GE, Gianchandani R, Smiley D, et al. Safety and efficacy of sitagliptin therapy for the inpatient management of general medicine and surgery patients with type 2 diabetes: a pilot, randomized, controlled study. Diabetes Care 2013; 36:3430–3435.
  49. Chan JC, Scott R, Arjona Ferreira JC, et al. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes Metab 2008; 10:545–555.
  50. Bergman AJ, Cote J, Yi B, et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care 2007; 30:1862–1864.
  51. Onglyza package insert. www.azpicentral.com/onglyza/pi_onglyza.pdf. Accessed March 8, 2016.
  52. Gallwitz B. Safety and efficacy of linagliptin in type 2 diabetes patients with common renal and cardiovascular risk factors. Ther Adv Endocrinol Metab 2013; 4:95–105.
  53. Marshall J, Jennings P, Scott A, Fluck RJ, McIntyre CW. Glycemic control in diabetic CAPD patients assessed by continuous glucose monitoring system (CGMS). Kidney Int 2003; 64:1480–1486.
  54. Schleis TG. Interference of maltose, icodextrin, galactose, or xylose with some blood glucose monitoring systems. Pharmacotherapy 2007; 27:1313–1321.
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Robert J. Tanenberg, MD, FACP
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Address: Robert J. Tanenberg, MD, FACP, Division of Endocrinology, Department of Medicine, Brody School of Medicine at East Carolina University, Room 3E-129 Brody Medical Science Building, 600 Moye Boulevard, Greenville, NC 27834; [email protected]

Dr. Tanenberg has disclosed performing research funded by Novo Nordisk.

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Address: Robert J. Tanenberg, MD, FACP, Division of Endocrinology, Department of Medicine, Brody School of Medicine at East Carolina University, Room 3E-129 Brody Medical Science Building, 600 Moye Boulevard, Greenville, NC 27834; [email protected]

Dr. Tanenberg has disclosed performing research funded by Novo Nordisk.

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Shridhar N. Iyer, MD, PhD, FACP
Department of Medicine, Albany Medical Center, Albany, NY

Robert J. Tanenberg, MD, FACP
Division of Endocrinology, Department of Medicine, Brody School of Medicine at East Carolina University and Medical Director for Diabetes at Vidant Medical Center, Greenville, NC

Address: Robert J. Tanenberg, MD, FACP, Division of Endocrinology, Department of Medicine, Brody School of Medicine at East Carolina University, Room 3E-129 Brody Medical Science Building, 600 Moye Boulevard, Greenville, NC 27834; [email protected]

Dr. Tanenberg has disclosed performing research funded by Novo Nordisk.

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Related Articles

Managing glycemic control in hospitalized patients with chronic kidney disease (CKD) and diabetes mellitus is a challenge, with no published guidelines. In this setting, avoiding hypoglycemia takes precedence over meeting strict blood glucose targets. Optimal management is essential to reduce hypoglycemia and the risk of death from cardiovascular disease.1

This article reviews the evidence to guide diabetes management in hospitalized patients with CKD, focusing on blood glucose monitoring, insulin dosing, and concerns about other diabetic agents.

FOCUS ON AVOIDING HYPOGLYCEMIA

CKD is common, estimated to affect more than 50 million people worldwide.2 Diabetes mellitus is the primary cause of kidney failure in 45% of dialysis patients with CKD.

Tight control comes with a cost

Hyperglycemia in hospitalized patients is associated with a higher risk of death, a higher risk of infections, and a longer hospital stay.3,4 In 2001, Van den Berghe et al5 found that intensive insulin therapy reduced the mortality rate in critically ill patients in the surgical intensive care unit. But subsequent studies6,7 found that intensive insulin therapy to achieve tight glycemic control increased rates of morbidity and mortality without adding clinical benefit.

Randomized clinical trials in outpatients have shown that tight control of blood glucose levels reduces microvascular and macrovascular complications in patients with type 1 diabetes.8–10 In the Diabetes Control and Complications Trial,9 compared with conventional therapy, intensive insulin therapy reduced the incidence of retinopathy progression (4.7 vs 1.2 cases per 100 patient-years, number needed to treat [NNT] = 3 for 10 years) and clinical neuropathy (9.8 vs 3.1 per 100 patient-years, NNT = 1.5 for 10 years). The long-term likelihood of a cardiovascular event was also significantly lower in the intensive treatment group (0.38 vs 0.80 events per 100 patient-years).9

Similarly, in the Epidemiology of Diabetes Interventions and Complications follow-up study, the intensive therapy group had fewer cardiovascular deaths.11 On the other hand, the risk of severe hypoglycemia and subsequent coma or seizure was significantly higher in the intensive therapy group than in the conventional therapy group (16.3 vs 5.4 per 100 patient-years).8

CKD increases hypoglycemia risk

Chronic kidney disease is a risk factor for hypoglycemia in hospitalized patients
Figure 1. Incidence of hypoglycemic episodes in hospitalized patients with or without chronic kidney disease (CKD) and diabetes in a Veterans Administration study.12 All differences compared with the reference group (no CKD, no diabetes) were statistically significant (P < .0001).

Moen et al12 found that the incidence of hypoglycemia was significantly higher in patients with CKD (estimated glomerular filtration rate [GFR] < 60 mL/min) with or without diabetes, and that patients with both conditions were at greatest risk (Figure 1). Multiple factors contribute to the increased risk of hypoglycemia: patients with advanced CKD tend to have poor nutrition, resulting in reduced glycogen stores, and a smaller renal mass reduces renal gluconeogenesis and decreases the elimination of insulin and oral antidiabetic agents.

After the onset of diabetic nephropathy, progression of renal complications and overall life expectancy are influenced by earlier glycemic control.8 Development of diabetic nephropathy is commonly accompanied by changes in metabolic control, particularly an increased risk of hypoglycemia.13 In addition, episodes of severe hypoglycemia constitute an independent cardiovascular risk factor.14

Aggressive glycemic control in hospitalized patients, particularly those with advanced CKD, is associated with a risk of hypoglycemia without overall improvement in outcomes.15 Elderly patients with type 2 diabetes are similar to patients with CKD in that they have a reduced GFR and are thus more sensitive to insulin. In both groups, intensifying glycemic control, especially in the hospital, is associated with more frequent episodes of severe hypoglycemia.16 The focus should be not only on maintaining optimal blood glucose concentration, but also on preventing hypoglycemia.

‘Burnt-out’ diabetes

Paradoxically, patients with end-stage renal disease and type 2 diabetes often experience altered glucose homeostasis with markedly improved glycemic control. They may attain normoglycemia and normalization of hemoglobin A1c, a condition known as “burnt-out” diabetes. Its precise mechanism is not understood and its significance remains unclear (Table 1).17

HEMOGLOBIN A1c CAN BE FALSELY HIGH OR FALSELY LOW

Hemoglobin A1c measurement is used to diagnose diabetes and to assess long-term glycemic control. It is a measure of the fraction of hemoglobin that has been glycated by exposure to glucose. Because the average lifespan of a red cell is 120 days, the hemoglobin A1c value reflects the mean blood glucose concentration over the preceding 3 months.

But hemoglobin A1c measurement has limitations: any condition that alters the lifespan of erythrocytes leads to higher or lower hemoglobin A1c levels. Hemoglobin A1c levels are also affected by kidney dysfunction, hemolysis, and acidosis.18

Falsely high hemoglobin A1c levels are associated with conditions that prolong the lifespan of erythrocytes, such as asplenia. Iron deficiency also increases the average age of circulating red cells because of reduced red cell production. For patients in whom blood glucose measurements do not correlate with hemoglobin A1c measurements, iron deficiency anemia should be considered before altering a treatment regimen.

Falsely low hemoglobin A1c levels are associated with conditions of more rapid erythrocyte turnover, such as autoimmune hemolytic anemia, hereditary spherocytosis, and acute blood loss anemia. In patients with CKD, recombinant erythropoietin treatment lowers hemoglobin A1c levels by increasing the number of immature red cells, which are less likely to glycosylate.19

Morgan et al20 compared the association between hemoglobin A1c and blood glucose levels in diabetic patients with moderate to severe CKD not requiring dialysis and in diabetic patients with normal renal function and found no difference between these two groups, suggesting that hemoglobin A1c is reliable in this setting. But study results conflict for patients on dialysis, making the usefulness of hemoglobin A1c testing for those patients less clear. In one study, hemoglobin A1c testing underestimated glycemic control,20 but other studies found that glycemic control was overestimated.21,22

Alternatives to hemoglobin A1c

Other measures of long-term glycemic control such as fructosamine and glycated albumin levels are sometimes used in conditions in which hemoglobin A1c may not be reliable.

Albumin also undergoes glycation when exposed to glucose. Glycated albumin appears to be a better measure of glycemic control in patients with CKD and diabetes than serum fructosamine,23 which has failed to show a significant correlation with blood glucose levels in patients with CKD.24 However, because serum albumin has a short half-life, glycated albumin reflects glycemic control in only the approximately 1 to 2 weeks before sampling,25 so monthly monitoring is required.

Glycated albumin levels may be reduced due to increased albumin turnover in patients with nephrotic-range proteinuria and in diabetic patients on peritoneal dialysis. Several issues remain unclear, such as the appropriate target level of glycated albumin and at what stage of CKD it should replace hemoglobin A1c testing. If an improved assay that is unaffected by changes in serum albumin becomes available, it may be appropriate to use glycated albumin measurements to assess long-term glycemic control for patients with CKD.

In general, therapeutic decisions to achieve optimum glycemic control in patients with diabetes and CKD should be based on hemoglobin A1c testing, multiple glucose measurements, and patient symptoms of hypoglycemia or hyperglycemia. The best measure for assessing glycemic control in hospitalized patients with CKD remains multiple blood glucose testing daily.

INSULIN THERAPY PREFERRED

Although several studies have evaluated inpatient glycemic control,26–29 no guidelines have been published for hospitalized patients with diabetes and CKD. Insulin therapy is preferred for achieving glycemic control in acutely ill or hospitalized patients with diabetes. Oral hypoglycemic agents should be discontinued.

Regardless of the form of insulin chosen to treat diabetes, caution is needed for patients with kidney disease. During hospitalization, clinical changes are expected owing to illness and differences in caloric intake and physical activity, resulting in altered insulin sensitivity. Insulin-treated hospitalized patients require individualized care, including multiple daily blood glucose tests and insulin therapy modifications for ideal glycemic control.

For surgical or medical intensive care patients on insulin therapy, the target blood glucose level before meals should be 140 mg/dL, and the target random level should be less than 180 mg/dL.15,26–29

Basal-bolus insulin

Sliding-scale therapy should be avoided as the only method for glycemic control. Instead, scheduled subcutaneous basal insulin once or twice daily combined with rapid- or short-acting insulin with meals is recommended.

Basal-bolus insulin therapy, one of the most advanced and flexible insulin replacement therapies, mimics endogenous insulin release and offers great advantages in diabetes care. Using mealtime bolus insulin permits variation in the amount of food eaten; more insulin can be taken with a larger meal and less with smaller meals. A bolus approach offers the flexibility of administering rapid-acting insulin immediately after meals when oral intake is variable.

Individualize insulin therapy

Optimizing glycemic control requires an understanding of the altered pharmacokinetics and pharmacodynamics of insulin in patients with diabetic nephropathy. Table 2 shows the pharmacokinetic profiles of insulin preparations in healthy people. Analogue insulins, which are manufactured by recombinant DNA technology, have conformational changes in the insulin molecule that alter their pharmacokinetics and pharmacodynamics. The rapid-acting analogue insulins are absorbed quickly, making them suitable for postprandial glucose control.

Changes in GFR are associated with altered pharmacokinetics and pharmacodynamics of insulin,30,31 but unlike for oral antidiabetic agents, these properties are not well characterized for insulin preparations in patients with renal insufficiency.13,32–36

CKD may reduce insulin clearance. Rave et al32 reported that the clearance of regular human insulin was reduced by 30% to 40% in patients with type 1 diabetes and a mean estimated GFR of 54 mL/min. They found that the metabolic activity of insulin lispro was more robust than that of short-acting regular human insulin in patients with diabetic nephropathy. In another study, patients with diabetes treated with insulin aspart did not show any significant change in the required insulin dosage in relation to the renal filtration rate.34 Biesenbach et al33 found a 38% reduction in insulin requirements in patients with type 1 diabetes as estimated GFR decreased from 80 mL/min to 10 mL/min. Further studies are required to better understand the safety of insulin in treating hospitalized patients with diabetes and renal insufficiency.

Few studies have compared the pharmacodynamics of long-acting insulins in relation to declining renal function. The long-acting analogue insulins have less of a peak than human insulin and thus better mimic endogenous insulin secretion. For insulin detemir, Lindholm and Jacobsen found no significant differences in the pharmacokinetics related to the stages of CKD.35 When using the long-acting insulins glargine or detemir, one should consider giving much lower doses (half the initial starting dosage) and titrating the dosage until target fasting glucose concentrations are reached to prevent hypoglycemia.

Table 3 summarizes recommended insulin dosage adjustments in CKD based on the literature and our clinical experience.

 

 

Considerations for dialysis patients

Subcutaneously administered insulin is eliminated renally, unlike endogenous insulin, which undergoes first-pass metabolism in the liver.13,37 As renal function declines, insulin clearance decreases and the insulin dosage must be reduced to prevent hypoglycemia.

Patients on hemodialysis or peritoneal dialysis pose a challenge for insulin dosing. Hemodialysis improves insulin sensitivity but also increases insulin clearance, making it difficult to determine insulin requirements. Sobngwi et al38 conducted a study in diabetic patients with end-stage renal disease on hemodialysis, using a 24-hour euglycemic clamp. They found that exogenous basal insulin requirements were 25% lower on the day after hemodialysis compared with the day before, but premeal insulin requirements stayed the same.

Peritoneal dialysis exposes patients to a high glucose load via the peritoneum, which can worsen insulin resistance. Intraperitoneal administration of insulin during peritoneal dialysis provides a more physiologic effect than subcutaneous administration: it prevents fluctuations of blood glucose and the formation of insulin antibodies. But insulin requirements are higher owing to a dilutional effect and to insulin binding to the plastic surface of the dialysis fluid reservoir.39

GLYCEMIC CONTROL FOR PROCEDURES

No guidelines have been established regarding the optimal blood glucose range for diabetic patients with CKD undergoing diagnostic or surgical procedures. Given the risk of hypoglycemia in such settings, less-stringent targets are reasonable, ie, premeal blood glucose levels of 140 mg/dL and random blood glucose levels of less than 180 mg/dL.

Before surgery, consideration should be given to the type of diabetes, surgical procedure, and metabolic control. Patients on insulin detemir or glargine as part of a basal-bolus regimen with rapid-acting insulin may safely be given the full dose of their basal insulin the night before or the morning of their procedure. However, patients on neutral protamine Hagedorn (NPH) insulin as a part of their basal-bolus regimen should receive half of their usual dose due to a difference in pharmacokinetic profile compared with insulin glargine or detemir.

In insulin-treated patients undergoing prolonged procedures (eg, coronary artery bypass grafting, transplant):

  • Discontinue subcutaneous insulin and start an intravenous insulin infusion, titrated to maintain a blood glucose range of 140 to 180 mg/dL
  • Subcutaneous insulin management may be acceptable for patients undergoing shorter outpatient procedures
  • Supplemental subcutaneous doses of short- or rapid-acting insulin preparations can be given for blood glucose elevation greater than 180 mg/dL.

AVOID ORAL AGENTS AND NONINSULIN INJECTABLES

Oral antidiabetic agents and noninsulin injectables (Table 4) should generally be avoided in hospitalized patients, especially for those with decompensated heart failure, renal insufficiency, hypoperfusion, or chronic pulmonary disease, or for those given intravenous contrast. Most oral medications used to treat diabetes are affected by reduced kidney function, resulting in prolonged drug exposure and increased risk of hypoglycemia in patients with moderate to severe CKD (stages 3–5).

Metformin, a biguanide, is contraindicated in patients with high serum creatinine levels (> 1.5 mg/dL in men, > 1.4 mg/dL in women) because of the theoretical risk of lactic acidosis.40

Sulfonylurea clearance depends on kidney function.41 Severe prolonged episodes of hypoglycemia have been reported in dialysis patients taking these drugs, except with glipizide, which carries a lower risk.41,42

Repaglinide, a nonsulfonylurea insulin secretagogue, can be used in CKD stages 3 to 4 without any dosage adjustment.43

Thiazolidinediones have been reported to slow the progression of diabetic kidney disease independent of glycemic control.44 Adverse effects include fluid retention, edema, and congestive heart failure. Thiazolidinediones should not be used in patients with New York Heart Association class 3 or 4 heart failure,45 and so should not be prescribed in the hospital except for patients who are clinically stable or ready for discharge.

Quick-release bromocriptine, a dopamine receptor agonist, has been shown to be effective in lowering fasting plasma glucose levels and hemoglobin A1c, and improving glucose tolerance in obese patients with type 2 diabetes, although its usefulness in hospitalized patients with diabetes is not known.46,47

Dipeptidyl peptidase inhibitors. Sitagliptin and saxagliptin have been shown to be safe and effective in hospitalized patients with type 2 diabetes.48 However, except for linagliptin, dose reduction is recommended in patients with CKD stage 3 and higher.49–52

GLP-1 receptor agonists. Drugs of this class are potent agents for the reduction of glucose in the outpatient setting but are relatively contraindicated if the GFR is less than 30 mL/min, and they are currently not used in the hospital.

BLOOD GLUCOSE MONITORING IN HOSPITALIZED PATIENTS

Bedside blood glucose monitoring is recommended for all hospitalized patients with known diabetes with or without CKD, those with newly recognized hyperglycemia, and those who receive therapy associated with high risk for hyperglycemia, such as glucocorticoid therapy and enteral and parenteral nutrition. For patients on scheduled diets, fingerstick blood glucose monitoring is recommended before meals and at bedtime. In patients with no oral intake or on continuous enteral or parenteral nutrition, blood glucose monitoring every 4 to 6 hours is recommended. More frequent monitoring (eg, adding a 3:00 am check) may be prudent in patients with CKD.

Continuous glucose monitoring systems use a sensor inserted under the skin and transmit information via radio to a wireless monitor. Such systems are more expensive than conventional glucose monitoring but may enable better glucose control by providing real-time glucose measurements, with levels displayed at 5-minute or 1-minute intervals. Marshall et al53 confirmed this technology’s accuracy and precision in uremic patients on dialysis.

Considerations for peritoneal dialysis

For patients on peritoneal dialysis, glucose in the dialysate exacerbates hyperglycemia. Dialysis solutions with the glucose polymer icodextrin as the osmotic agent instead of glucose have been suggested to reduce glucose exposure.

Glucose monitoring systems measure interstitial fluid glucose by the glucose oxidase reaction and therefore are not affected by icodextrin. However, icodextrin is converted to maltose, a disaccharide composed of two glucose molecules, which can cause spuriously high readings in devices that use test strips containing the enzymes glucose dehydrogenase pyrroloquinoline quinone or glucose dye oxidoreductase. Spurious hyperglycemia may lead to giving too much insulin, in turn leading to symptomatic hypoglycemia.

Clinicians caring for patients receiving icodextrin should ensure that the glucose monitoring system uses only test strips that contain glucose oxidase, glucose dehydrogenase-nicotinamide adenine dinucleotide, or glucose dehydrogenase-flavin adenine dinucleotide, which are not affected by icodextrin.54

IMPROVING QUALITY

Hospitalized patients face many barriers to optimal glycemic control. Less experienced practitioners tend to have insufficient knowledge of insulin preparations and appropriate insulin dosing. Also, diabetes is often listed as a secondary diagnosis and so may be overlooked by the inpatient care team.

Educational programs should be instituted to overcome these barriers and improve knowledge related to inpatient diabetes care. When necessary, the appropriate use of consultants is important in hospitalized settings to improve quality and make hospital care more efficient and cost-effective.

No national benchmarks currently exist for inpatient diabetes care, and they need to be developed to ensure best practices. Physicians should take the initiative to remedy this by collaborating with other healthcare providers, such as dedicated diabetes educators, nursing staff, pharmacists, registered dietitians, and physicians with expertise in diabetes management, with the aim of achieving optimum glycemic control and minimizing hypoglycemia. 

Managing glycemic control in hospitalized patients with chronic kidney disease (CKD) and diabetes mellitus is a challenge, with no published guidelines. In this setting, avoiding hypoglycemia takes precedence over meeting strict blood glucose targets. Optimal management is essential to reduce hypoglycemia and the risk of death from cardiovascular disease.1

This article reviews the evidence to guide diabetes management in hospitalized patients with CKD, focusing on blood glucose monitoring, insulin dosing, and concerns about other diabetic agents.

FOCUS ON AVOIDING HYPOGLYCEMIA

CKD is common, estimated to affect more than 50 million people worldwide.2 Diabetes mellitus is the primary cause of kidney failure in 45% of dialysis patients with CKD.

Tight control comes with a cost

Hyperglycemia in hospitalized patients is associated with a higher risk of death, a higher risk of infections, and a longer hospital stay.3,4 In 2001, Van den Berghe et al5 found that intensive insulin therapy reduced the mortality rate in critically ill patients in the surgical intensive care unit. But subsequent studies6,7 found that intensive insulin therapy to achieve tight glycemic control increased rates of morbidity and mortality without adding clinical benefit.

Randomized clinical trials in outpatients have shown that tight control of blood glucose levels reduces microvascular and macrovascular complications in patients with type 1 diabetes.8–10 In the Diabetes Control and Complications Trial,9 compared with conventional therapy, intensive insulin therapy reduced the incidence of retinopathy progression (4.7 vs 1.2 cases per 100 patient-years, number needed to treat [NNT] = 3 for 10 years) and clinical neuropathy (9.8 vs 3.1 per 100 patient-years, NNT = 1.5 for 10 years). The long-term likelihood of a cardiovascular event was also significantly lower in the intensive treatment group (0.38 vs 0.80 events per 100 patient-years).9

Similarly, in the Epidemiology of Diabetes Interventions and Complications follow-up study, the intensive therapy group had fewer cardiovascular deaths.11 On the other hand, the risk of severe hypoglycemia and subsequent coma or seizure was significantly higher in the intensive therapy group than in the conventional therapy group (16.3 vs 5.4 per 100 patient-years).8

CKD increases hypoglycemia risk

Chronic kidney disease is a risk factor for hypoglycemia in hospitalized patients
Figure 1. Incidence of hypoglycemic episodes in hospitalized patients with or without chronic kidney disease (CKD) and diabetes in a Veterans Administration study.12 All differences compared with the reference group (no CKD, no diabetes) were statistically significant (P < .0001).

Moen et al12 found that the incidence of hypoglycemia was significantly higher in patients with CKD (estimated glomerular filtration rate [GFR] < 60 mL/min) with or without diabetes, and that patients with both conditions were at greatest risk (Figure 1). Multiple factors contribute to the increased risk of hypoglycemia: patients with advanced CKD tend to have poor nutrition, resulting in reduced glycogen stores, and a smaller renal mass reduces renal gluconeogenesis and decreases the elimination of insulin and oral antidiabetic agents.

After the onset of diabetic nephropathy, progression of renal complications and overall life expectancy are influenced by earlier glycemic control.8 Development of diabetic nephropathy is commonly accompanied by changes in metabolic control, particularly an increased risk of hypoglycemia.13 In addition, episodes of severe hypoglycemia constitute an independent cardiovascular risk factor.14

Aggressive glycemic control in hospitalized patients, particularly those with advanced CKD, is associated with a risk of hypoglycemia without overall improvement in outcomes.15 Elderly patients with type 2 diabetes are similar to patients with CKD in that they have a reduced GFR and are thus more sensitive to insulin. In both groups, intensifying glycemic control, especially in the hospital, is associated with more frequent episodes of severe hypoglycemia.16 The focus should be not only on maintaining optimal blood glucose concentration, but also on preventing hypoglycemia.

‘Burnt-out’ diabetes

Paradoxically, patients with end-stage renal disease and type 2 diabetes often experience altered glucose homeostasis with markedly improved glycemic control. They may attain normoglycemia and normalization of hemoglobin A1c, a condition known as “burnt-out” diabetes. Its precise mechanism is not understood and its significance remains unclear (Table 1).17

HEMOGLOBIN A1c CAN BE FALSELY HIGH OR FALSELY LOW

Hemoglobin A1c measurement is used to diagnose diabetes and to assess long-term glycemic control. It is a measure of the fraction of hemoglobin that has been glycated by exposure to glucose. Because the average lifespan of a red cell is 120 days, the hemoglobin A1c value reflects the mean blood glucose concentration over the preceding 3 months.

But hemoglobin A1c measurement has limitations: any condition that alters the lifespan of erythrocytes leads to higher or lower hemoglobin A1c levels. Hemoglobin A1c levels are also affected by kidney dysfunction, hemolysis, and acidosis.18

Falsely high hemoglobin A1c levels are associated with conditions that prolong the lifespan of erythrocytes, such as asplenia. Iron deficiency also increases the average age of circulating red cells because of reduced red cell production. For patients in whom blood glucose measurements do not correlate with hemoglobin A1c measurements, iron deficiency anemia should be considered before altering a treatment regimen.

Falsely low hemoglobin A1c levels are associated with conditions of more rapid erythrocyte turnover, such as autoimmune hemolytic anemia, hereditary spherocytosis, and acute blood loss anemia. In patients with CKD, recombinant erythropoietin treatment lowers hemoglobin A1c levels by increasing the number of immature red cells, which are less likely to glycosylate.19

Morgan et al20 compared the association between hemoglobin A1c and blood glucose levels in diabetic patients with moderate to severe CKD not requiring dialysis and in diabetic patients with normal renal function and found no difference between these two groups, suggesting that hemoglobin A1c is reliable in this setting. But study results conflict for patients on dialysis, making the usefulness of hemoglobin A1c testing for those patients less clear. In one study, hemoglobin A1c testing underestimated glycemic control,20 but other studies found that glycemic control was overestimated.21,22

Alternatives to hemoglobin A1c

Other measures of long-term glycemic control such as fructosamine and glycated albumin levels are sometimes used in conditions in which hemoglobin A1c may not be reliable.

Albumin also undergoes glycation when exposed to glucose. Glycated albumin appears to be a better measure of glycemic control in patients with CKD and diabetes than serum fructosamine,23 which has failed to show a significant correlation with blood glucose levels in patients with CKD.24 However, because serum albumin has a short half-life, glycated albumin reflects glycemic control in only the approximately 1 to 2 weeks before sampling,25 so monthly monitoring is required.

Glycated albumin levels may be reduced due to increased albumin turnover in patients with nephrotic-range proteinuria and in diabetic patients on peritoneal dialysis. Several issues remain unclear, such as the appropriate target level of glycated albumin and at what stage of CKD it should replace hemoglobin A1c testing. If an improved assay that is unaffected by changes in serum albumin becomes available, it may be appropriate to use glycated albumin measurements to assess long-term glycemic control for patients with CKD.

In general, therapeutic decisions to achieve optimum glycemic control in patients with diabetes and CKD should be based on hemoglobin A1c testing, multiple glucose measurements, and patient symptoms of hypoglycemia or hyperglycemia. The best measure for assessing glycemic control in hospitalized patients with CKD remains multiple blood glucose testing daily.

INSULIN THERAPY PREFERRED

Although several studies have evaluated inpatient glycemic control,26–29 no guidelines have been published for hospitalized patients with diabetes and CKD. Insulin therapy is preferred for achieving glycemic control in acutely ill or hospitalized patients with diabetes. Oral hypoglycemic agents should be discontinued.

Regardless of the form of insulin chosen to treat diabetes, caution is needed for patients with kidney disease. During hospitalization, clinical changes are expected owing to illness and differences in caloric intake and physical activity, resulting in altered insulin sensitivity. Insulin-treated hospitalized patients require individualized care, including multiple daily blood glucose tests and insulin therapy modifications for ideal glycemic control.

For surgical or medical intensive care patients on insulin therapy, the target blood glucose level before meals should be 140 mg/dL, and the target random level should be less than 180 mg/dL.15,26–29

Basal-bolus insulin

Sliding-scale therapy should be avoided as the only method for glycemic control. Instead, scheduled subcutaneous basal insulin once or twice daily combined with rapid- or short-acting insulin with meals is recommended.

Basal-bolus insulin therapy, one of the most advanced and flexible insulin replacement therapies, mimics endogenous insulin release and offers great advantages in diabetes care. Using mealtime bolus insulin permits variation in the amount of food eaten; more insulin can be taken with a larger meal and less with smaller meals. A bolus approach offers the flexibility of administering rapid-acting insulin immediately after meals when oral intake is variable.

Individualize insulin therapy

Optimizing glycemic control requires an understanding of the altered pharmacokinetics and pharmacodynamics of insulin in patients with diabetic nephropathy. Table 2 shows the pharmacokinetic profiles of insulin preparations in healthy people. Analogue insulins, which are manufactured by recombinant DNA technology, have conformational changes in the insulin molecule that alter their pharmacokinetics and pharmacodynamics. The rapid-acting analogue insulins are absorbed quickly, making them suitable for postprandial glucose control.

Changes in GFR are associated with altered pharmacokinetics and pharmacodynamics of insulin,30,31 but unlike for oral antidiabetic agents, these properties are not well characterized for insulin preparations in patients with renal insufficiency.13,32–36

CKD may reduce insulin clearance. Rave et al32 reported that the clearance of regular human insulin was reduced by 30% to 40% in patients with type 1 diabetes and a mean estimated GFR of 54 mL/min. They found that the metabolic activity of insulin lispro was more robust than that of short-acting regular human insulin in patients with diabetic nephropathy. In another study, patients with diabetes treated with insulin aspart did not show any significant change in the required insulin dosage in relation to the renal filtration rate.34 Biesenbach et al33 found a 38% reduction in insulin requirements in patients with type 1 diabetes as estimated GFR decreased from 80 mL/min to 10 mL/min. Further studies are required to better understand the safety of insulin in treating hospitalized patients with diabetes and renal insufficiency.

Few studies have compared the pharmacodynamics of long-acting insulins in relation to declining renal function. The long-acting analogue insulins have less of a peak than human insulin and thus better mimic endogenous insulin secretion. For insulin detemir, Lindholm and Jacobsen found no significant differences in the pharmacokinetics related to the stages of CKD.35 When using the long-acting insulins glargine or detemir, one should consider giving much lower doses (half the initial starting dosage) and titrating the dosage until target fasting glucose concentrations are reached to prevent hypoglycemia.

Table 3 summarizes recommended insulin dosage adjustments in CKD based on the literature and our clinical experience.

 

 

Considerations for dialysis patients

Subcutaneously administered insulin is eliminated renally, unlike endogenous insulin, which undergoes first-pass metabolism in the liver.13,37 As renal function declines, insulin clearance decreases and the insulin dosage must be reduced to prevent hypoglycemia.

Patients on hemodialysis or peritoneal dialysis pose a challenge for insulin dosing. Hemodialysis improves insulin sensitivity but also increases insulin clearance, making it difficult to determine insulin requirements. Sobngwi et al38 conducted a study in diabetic patients with end-stage renal disease on hemodialysis, using a 24-hour euglycemic clamp. They found that exogenous basal insulin requirements were 25% lower on the day after hemodialysis compared with the day before, but premeal insulin requirements stayed the same.

Peritoneal dialysis exposes patients to a high glucose load via the peritoneum, which can worsen insulin resistance. Intraperitoneal administration of insulin during peritoneal dialysis provides a more physiologic effect than subcutaneous administration: it prevents fluctuations of blood glucose and the formation of insulin antibodies. But insulin requirements are higher owing to a dilutional effect and to insulin binding to the plastic surface of the dialysis fluid reservoir.39

GLYCEMIC CONTROL FOR PROCEDURES

No guidelines have been established regarding the optimal blood glucose range for diabetic patients with CKD undergoing diagnostic or surgical procedures. Given the risk of hypoglycemia in such settings, less-stringent targets are reasonable, ie, premeal blood glucose levels of 140 mg/dL and random blood glucose levels of less than 180 mg/dL.

Before surgery, consideration should be given to the type of diabetes, surgical procedure, and metabolic control. Patients on insulin detemir or glargine as part of a basal-bolus regimen with rapid-acting insulin may safely be given the full dose of their basal insulin the night before or the morning of their procedure. However, patients on neutral protamine Hagedorn (NPH) insulin as a part of their basal-bolus regimen should receive half of their usual dose due to a difference in pharmacokinetic profile compared with insulin glargine or detemir.

In insulin-treated patients undergoing prolonged procedures (eg, coronary artery bypass grafting, transplant):

  • Discontinue subcutaneous insulin and start an intravenous insulin infusion, titrated to maintain a blood glucose range of 140 to 180 mg/dL
  • Subcutaneous insulin management may be acceptable for patients undergoing shorter outpatient procedures
  • Supplemental subcutaneous doses of short- or rapid-acting insulin preparations can be given for blood glucose elevation greater than 180 mg/dL.

AVOID ORAL AGENTS AND NONINSULIN INJECTABLES

Oral antidiabetic agents and noninsulin injectables (Table 4) should generally be avoided in hospitalized patients, especially for those with decompensated heart failure, renal insufficiency, hypoperfusion, or chronic pulmonary disease, or for those given intravenous contrast. Most oral medications used to treat diabetes are affected by reduced kidney function, resulting in prolonged drug exposure and increased risk of hypoglycemia in patients with moderate to severe CKD (stages 3–5).

Metformin, a biguanide, is contraindicated in patients with high serum creatinine levels (> 1.5 mg/dL in men, > 1.4 mg/dL in women) because of the theoretical risk of lactic acidosis.40

Sulfonylurea clearance depends on kidney function.41 Severe prolonged episodes of hypoglycemia have been reported in dialysis patients taking these drugs, except with glipizide, which carries a lower risk.41,42

Repaglinide, a nonsulfonylurea insulin secretagogue, can be used in CKD stages 3 to 4 without any dosage adjustment.43

Thiazolidinediones have been reported to slow the progression of diabetic kidney disease independent of glycemic control.44 Adverse effects include fluid retention, edema, and congestive heart failure. Thiazolidinediones should not be used in patients with New York Heart Association class 3 or 4 heart failure,45 and so should not be prescribed in the hospital except for patients who are clinically stable or ready for discharge.

Quick-release bromocriptine, a dopamine receptor agonist, has been shown to be effective in lowering fasting plasma glucose levels and hemoglobin A1c, and improving glucose tolerance in obese patients with type 2 diabetes, although its usefulness in hospitalized patients with diabetes is not known.46,47

Dipeptidyl peptidase inhibitors. Sitagliptin and saxagliptin have been shown to be safe and effective in hospitalized patients with type 2 diabetes.48 However, except for linagliptin, dose reduction is recommended in patients with CKD stage 3 and higher.49–52

GLP-1 receptor agonists. Drugs of this class are potent agents for the reduction of glucose in the outpatient setting but are relatively contraindicated if the GFR is less than 30 mL/min, and they are currently not used in the hospital.

BLOOD GLUCOSE MONITORING IN HOSPITALIZED PATIENTS

Bedside blood glucose monitoring is recommended for all hospitalized patients with known diabetes with or without CKD, those with newly recognized hyperglycemia, and those who receive therapy associated with high risk for hyperglycemia, such as glucocorticoid therapy and enteral and parenteral nutrition. For patients on scheduled diets, fingerstick blood glucose monitoring is recommended before meals and at bedtime. In patients with no oral intake or on continuous enteral or parenteral nutrition, blood glucose monitoring every 4 to 6 hours is recommended. More frequent monitoring (eg, adding a 3:00 am check) may be prudent in patients with CKD.

Continuous glucose monitoring systems use a sensor inserted under the skin and transmit information via radio to a wireless monitor. Such systems are more expensive than conventional glucose monitoring but may enable better glucose control by providing real-time glucose measurements, with levels displayed at 5-minute or 1-minute intervals. Marshall et al53 confirmed this technology’s accuracy and precision in uremic patients on dialysis.

Considerations for peritoneal dialysis

For patients on peritoneal dialysis, glucose in the dialysate exacerbates hyperglycemia. Dialysis solutions with the glucose polymer icodextrin as the osmotic agent instead of glucose have been suggested to reduce glucose exposure.

Glucose monitoring systems measure interstitial fluid glucose by the glucose oxidase reaction and therefore are not affected by icodextrin. However, icodextrin is converted to maltose, a disaccharide composed of two glucose molecules, which can cause spuriously high readings in devices that use test strips containing the enzymes glucose dehydrogenase pyrroloquinoline quinone or glucose dye oxidoreductase. Spurious hyperglycemia may lead to giving too much insulin, in turn leading to symptomatic hypoglycemia.

Clinicians caring for patients receiving icodextrin should ensure that the glucose monitoring system uses only test strips that contain glucose oxidase, glucose dehydrogenase-nicotinamide adenine dinucleotide, or glucose dehydrogenase-flavin adenine dinucleotide, which are not affected by icodextrin.54

IMPROVING QUALITY

Hospitalized patients face many barriers to optimal glycemic control. Less experienced practitioners tend to have insufficient knowledge of insulin preparations and appropriate insulin dosing. Also, diabetes is often listed as a secondary diagnosis and so may be overlooked by the inpatient care team.

Educational programs should be instituted to overcome these barriers and improve knowledge related to inpatient diabetes care. When necessary, the appropriate use of consultants is important in hospitalized settings to improve quality and make hospital care more efficient and cost-effective.

No national benchmarks currently exist for inpatient diabetes care, and they need to be developed to ensure best practices. Physicians should take the initiative to remedy this by collaborating with other healthcare providers, such as dedicated diabetes educators, nursing staff, pharmacists, registered dietitians, and physicians with expertise in diabetes management, with the aim of achieving optimum glycemic control and minimizing hypoglycemia. 

References
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  4. Golden SH, Peart-Vigilance C, Kao WH, Brancati FL. Perioperative glycemic control and the risk of infectious complications in a cohort of adults with diabetes. Diabetes Care 1999; 22:1408–1414.
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  6. NICE-SUGAR Study Investigators; Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360:1283–1297.
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References
  1. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351:1296–1305.
  2. Newman DJ, Mattock MB, Dawnay AB, et al. Systematic review on urine albumin testing for early detection of diabetic complications. Health Technol Assess 2005; 9:iii–vi, xiii–163.
  3. Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002; 87:978–982.
  4. Golden SH, Peart-Vigilance C, Kao WH, Brancati FL. Perioperative glycemic control and the risk of infectious complications in a cohort of adults with diabetes. Diabetes Care 1999; 22:1408–1414.
  5. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345:1359–1367.
  6. NICE-SUGAR Study Investigators; Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360:1283–1297.
  7. Brunkhorst FM, Engel C, Bloos F, et al; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358:125–139.
  8. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993; 329:977–986.
  9. Effect of intensive diabetes management on macrovascular events and risk factors in the Diabetes Control and Complications Trial. Am J Cardiol 1995; 75:894–903.
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  11. Writing Group for the DCCT/EDIC Research Group; Orchard TJ, Nathan DM, Zinman B, et al. Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA 2015; 313:45–53.
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  16. Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545–2559.
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  19. Brown JN, Kemp DW, Brice KR. Class effect of erythropoietin therapy on hemoglobin A(1c) in a patient with diabetes mellitus and chronic kidney disease not undergoing hemodialysis. Pharmacotherapy 2009; 29:468–472.
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  21. Peacock TP, Shihabi ZK, Bleyer AJ, et al. Comparison of glycated albumin and hemoglobin A(1c) levels in diabetic subjects on hemodialysis. Kidney Int 2008; 73:1062–1068.
  22. Joy MS, Cefalu WT, Hogan SL, Nachman PH. Long-term glycemic control measurements in diabetic patients receiving hemodialysis. Am J Kidney Dis 2002; 39:297–307.
  23. Inaba M, Okuno S, Kumeda Y, et al; Osaka CKD Expert Research Group. Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietin injection. J Am Soc Nephrol 2007; 18:896–903.
  24. Mittman N, Desiraju B, Fazil I, et al. Serum fructosamine versus glycosylated hemoglobin as an index of glycemic control, hospitalization, and infection in diabetic hemodialysis patients. Kidney Int 2010; 78(suppl 117):S41–S45.
  25. Alskar O, Korelli J, Duffull SB. A pharmacokinetic model for the glycation of albumin. J Pharmacokinet Pharmacodyn 2012; 39:273–282.
  26. Qaseem A, Humphrey LL, Chou R, Snow V, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2011; 154:260–267.
  27. Murad MH, Coburn JA, Coto-Yglesias F, et al. Glycemic control in non-critically ill hospitalized patients: a systematic review and meta-analysis. J Clin Endocrinol Metab 2012; 97:49–58.
  28. Bogun M, Inzucchi SE. Inpatient management of diabetes and hyperglycemia. Clin Ther 2013; 35:724–733.
  29. Miller DB. Glycemic targets in hospital and barriers to attaining them. Can J Diabetes 2014; 38:74–78.
  30. Eidemak I, Feldt-Rasmussen B, Kanstrup IL, Nielsen SL, Schmitz O, Strandgaard S. Insulin resistance and hyperinsulinaemia in mild to moderate progressive chronic renal failure and its association with aerobic work capacity. Diabetologia 1995; 38:565–572.
  31. Svensson M, Yu Z, Eriksson J. A small reduction in glomerular filtration is accompanied by insulin resistance in type I diabetes patients with diabetic nephropathy. Eur J Clin Invest 2002; 32:100–109.
  32. Rave K, Heise T, Pfutzner A, Heinemann L, Sawicki P. Impact of diabetic nephropathy on pharmacodynamics and pharmacokinetic properties of insulin in type I diabetic patients. Diabetes Care 2001; 24:886–890.
  33. Biesenbach G, Raml A, Schmekal B, Eichbauer-Sturm G. Decreased insulin requirement in relation to GFR in nephropathic type 1 and insulin-treated type 2 diabetic patients. Diabet Med 2003; 20:642–645.
  34. Holmes G, Galitz L, Hu P, Lyness W. Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment. Br J Clin Pharmacol 2005; 60:469–476.
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  39. Quellhorst E. Insulin therapy during peritoneal dialysis: pros and cons of various forms of administration. J Am Soc Nephrol 2002; 13(suppl 1):S92–S96.
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  43. Hasslacher C; Multinational Repaglinide Renal Study Group. Safety and efficacy of repaglinide in type 2 diabetic patients with and without impaired renal function. Diabetes Care 2003; 26:886–891.
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  53. Marshall J, Jennings P, Scott A, Fluck RJ, McIntyre CW. Glycemic control in diabetic CAPD patients assessed by continuous glucose monitoring system (CGMS). Kidney Int 2003; 64:1480–1486.
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Cleveland Clinic Journal of Medicine - 83(4)
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Cleveland Clinic Journal of Medicine - 83(4)
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Managing diabetes in hospitalized patients with chronic kidney disease
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Managing diabetes in hospitalized patients with chronic kidney disease
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Diabetes mellitus, chronic kidney disease, CKD, insulin, hemoglobin A1c, blood glucose, blood sugar, hypoglycemia, hospital, glycemic control, Shridhar Iyer, Robert Tanenberg
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Diabetes mellitus, chronic kidney disease, CKD, insulin, hemoglobin A1c, blood glucose, blood sugar, hypoglycemia, hospital, glycemic control, Shridhar Iyer, Robert Tanenberg
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KEY POINTS

  • Hemoglobin A1c values are often unreliable in patients with end-stage renal disease; close monitoring by fingerstick testing or a continuous monitoring system is recommended during hospitalization.
  • Insulin is the preferred treatment for hospitalized patients with diabetes; oral antidiabetic agents should be avoided.
  • Blood glucose targets for hospitalized patients with diabetes or stress hyperglycemia should be less than 140 mg/dL before meals, and random values should be less than 180 mg/dL.
  • A basal-bolus insulin approach is flexible and mimics endogenous insulin release.
  • Many insulin-treated patients with type 2 diabetes and CKD stop needing insulin as kidney disease progresses.
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IMWG issues renal impairment recommendations for myeloma patients

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IMWG issues renal impairment recommendations for myeloma patients

The International Myeloma Working Group has issued new recommendations for the diagnosis and management of multiple myeloma–related renal impairment. Depending on whether the condition is defined as elevated serum creatinine or decreased estimated glomerular filtration rate (eGFR), an estimated 20%-50% of patients with multiple myeloma have renal impairment at the time of diagnosis.

The guidelines recommend that all patients with multiple myeloma (MM) at diagnosis and at disease assessment should be tested for serum creatinine, eGFR, electrolytes, and serum free light chain, if available. Additionally, they recommend that all patients have urine electrophoresis of a sample from a 24-hour urine collection. All of the above are grade A recommendations (J Clin Oncol. 2016 Mar 14. doi: 10.1200/JCO.2015.65.0044).

©London_England/Thinkstock

Patients with nonselective proteinuria or significant albuminuria should undergo renal biopsy to determine the cause of the underlying impairment, the IMWG says (grade B recommendation).

For evaluation of eGFR in patients with stabilized serum creatinine, the IMWG favors the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, but also acknowledges that eGFR can be assessed with the Modification of Diet in Renal Disease (MDRD) formula (grade A).

“CKD-EPI seems to more accurately reflect GFR than does MDRD, mostly in higher levels of GFR,” the IMWG wrote.

Because the reversibility of renal dysfunction can affect treatment choice, the recommendations noted that for patients on dialysis, achieving independence from dialysis is “strong indication of improvement. For all other patients, IMWG criteria for renal response to therapy are recommended (grade B).

Management

“Acute renal impairment is a myeloma emergency. Diagnosis should be established as fast as possible, and antimyeloma therapy should be started immediately after confirmation of diagnosis to rapidly restore renal function,” working group members wrote.

Supportive care with increased hydration – at least 3 liters per day – is “mandatory” for all with suspected MM-related renal impairment, they add.

The recommendations also noted that antimyeloma therapy should be initiated immediately to reduce the load of toxic serum free light chains, which can help to improve renal function.

“Bortezomib [Velcade]-based regimens remain the cornerstone of the management of myeloma-related renal impairment (grade A). High-dose dexamethasone should be administered at least for the first month of therapy (grade B),” the working group members wrote.

Lenalidomide (Revlimid) can be given, but because it is excreted through the kidneys, the dose must be adjusted according to the degree of renal impairment. In contrast, thalidomide is not excreted and does not require dose modification in this population.

Patients who are eligible for autologous stem cell transplant could receive bortezomib in a three-drug regimen with thalidomide and dexamethasone, or in combination with a conventional chemotherapeutic agent, either doxorubicin or cyclophosphamide. Patients who are not eligible for transplant can be treated with bortezomib, melphalan, and prednisone, the recommendations said, but add that there are no data on the use of this regimen in patients who are on dialysis.

Regarding newer proteasome inhibitors, the guidelines note that carfilzomib (Kyprolis) can be given safely to patients with creatinine clearance above 15 mL/min, and that the recently approved oral agent, ixazomib (Ninlaro), with lenalidomide and dexamethasone can be administered to patients with clearance rates above 30 mL/min (grade A).

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The International Myeloma Working Group has issued new recommendations for the diagnosis and management of multiple myeloma–related renal impairment. Depending on whether the condition is defined as elevated serum creatinine or decreased estimated glomerular filtration rate (eGFR), an estimated 20%-50% of patients with multiple myeloma have renal impairment at the time of diagnosis.

The guidelines recommend that all patients with multiple myeloma (MM) at diagnosis and at disease assessment should be tested for serum creatinine, eGFR, electrolytes, and serum free light chain, if available. Additionally, they recommend that all patients have urine electrophoresis of a sample from a 24-hour urine collection. All of the above are grade A recommendations (J Clin Oncol. 2016 Mar 14. doi: 10.1200/JCO.2015.65.0044).

©London_England/Thinkstock

Patients with nonselective proteinuria or significant albuminuria should undergo renal biopsy to determine the cause of the underlying impairment, the IMWG says (grade B recommendation).

For evaluation of eGFR in patients with stabilized serum creatinine, the IMWG favors the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, but also acknowledges that eGFR can be assessed with the Modification of Diet in Renal Disease (MDRD) formula (grade A).

“CKD-EPI seems to more accurately reflect GFR than does MDRD, mostly in higher levels of GFR,” the IMWG wrote.

Because the reversibility of renal dysfunction can affect treatment choice, the recommendations noted that for patients on dialysis, achieving independence from dialysis is “strong indication of improvement. For all other patients, IMWG criteria for renal response to therapy are recommended (grade B).

Management

“Acute renal impairment is a myeloma emergency. Diagnosis should be established as fast as possible, and antimyeloma therapy should be started immediately after confirmation of diagnosis to rapidly restore renal function,” working group members wrote.

Supportive care with increased hydration – at least 3 liters per day – is “mandatory” for all with suspected MM-related renal impairment, they add.

The recommendations also noted that antimyeloma therapy should be initiated immediately to reduce the load of toxic serum free light chains, which can help to improve renal function.

“Bortezomib [Velcade]-based regimens remain the cornerstone of the management of myeloma-related renal impairment (grade A). High-dose dexamethasone should be administered at least for the first month of therapy (grade B),” the working group members wrote.

Lenalidomide (Revlimid) can be given, but because it is excreted through the kidneys, the dose must be adjusted according to the degree of renal impairment. In contrast, thalidomide is not excreted and does not require dose modification in this population.

Patients who are eligible for autologous stem cell transplant could receive bortezomib in a three-drug regimen with thalidomide and dexamethasone, or in combination with a conventional chemotherapeutic agent, either doxorubicin or cyclophosphamide. Patients who are not eligible for transplant can be treated with bortezomib, melphalan, and prednisone, the recommendations said, but add that there are no data on the use of this regimen in patients who are on dialysis.

Regarding newer proteasome inhibitors, the guidelines note that carfilzomib (Kyprolis) can be given safely to patients with creatinine clearance above 15 mL/min, and that the recently approved oral agent, ixazomib (Ninlaro), with lenalidomide and dexamethasone can be administered to patients with clearance rates above 30 mL/min (grade A).

The International Myeloma Working Group has issued new recommendations for the diagnosis and management of multiple myeloma–related renal impairment. Depending on whether the condition is defined as elevated serum creatinine or decreased estimated glomerular filtration rate (eGFR), an estimated 20%-50% of patients with multiple myeloma have renal impairment at the time of diagnosis.

The guidelines recommend that all patients with multiple myeloma (MM) at diagnosis and at disease assessment should be tested for serum creatinine, eGFR, electrolytes, and serum free light chain, if available. Additionally, they recommend that all patients have urine electrophoresis of a sample from a 24-hour urine collection. All of the above are grade A recommendations (J Clin Oncol. 2016 Mar 14. doi: 10.1200/JCO.2015.65.0044).

©London_England/Thinkstock

Patients with nonselective proteinuria or significant albuminuria should undergo renal biopsy to determine the cause of the underlying impairment, the IMWG says (grade B recommendation).

For evaluation of eGFR in patients with stabilized serum creatinine, the IMWG favors the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, but also acknowledges that eGFR can be assessed with the Modification of Diet in Renal Disease (MDRD) formula (grade A).

“CKD-EPI seems to more accurately reflect GFR than does MDRD, mostly in higher levels of GFR,” the IMWG wrote.

Because the reversibility of renal dysfunction can affect treatment choice, the recommendations noted that for patients on dialysis, achieving independence from dialysis is “strong indication of improvement. For all other patients, IMWG criteria for renal response to therapy are recommended (grade B).

Management

“Acute renal impairment is a myeloma emergency. Diagnosis should be established as fast as possible, and antimyeloma therapy should be started immediately after confirmation of diagnosis to rapidly restore renal function,” working group members wrote.

Supportive care with increased hydration – at least 3 liters per day – is “mandatory” for all with suspected MM-related renal impairment, they add.

The recommendations also noted that antimyeloma therapy should be initiated immediately to reduce the load of toxic serum free light chains, which can help to improve renal function.

“Bortezomib [Velcade]-based regimens remain the cornerstone of the management of myeloma-related renal impairment (grade A). High-dose dexamethasone should be administered at least for the first month of therapy (grade B),” the working group members wrote.

Lenalidomide (Revlimid) can be given, but because it is excreted through the kidneys, the dose must be adjusted according to the degree of renal impairment. In contrast, thalidomide is not excreted and does not require dose modification in this population.

Patients who are eligible for autologous stem cell transplant could receive bortezomib in a three-drug regimen with thalidomide and dexamethasone, or in combination with a conventional chemotherapeutic agent, either doxorubicin or cyclophosphamide. Patients who are not eligible for transplant can be treated with bortezomib, melphalan, and prednisone, the recommendations said, but add that there are no data on the use of this regimen in patients who are on dialysis.

Regarding newer proteasome inhibitors, the guidelines note that carfilzomib (Kyprolis) can be given safely to patients with creatinine clearance above 15 mL/min, and that the recently approved oral agent, ixazomib (Ninlaro), with lenalidomide and dexamethasone can be administered to patients with clearance rates above 30 mL/min (grade A).

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Key clinical point: All patients diagnosed with multiple myeloma should be evaluated for renal impairment.

Major finding: Bortezomib-based regimens are the standard of care for patients with multiple myeloma.

Data source: Evidence-based clinical recommendations.

Disclosures: Many coauthors disclosed multiple relationships with companies that make antimyeloma therapies and other medications.

Test All Kidney Transplant Patients for Hepatitis E

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Test All Kidney Transplant Patients for Hepatitis E

All kidney transplant recipients with abnormal liver function test results should be tested for hepatitis E virus RNA, according to a recent finding by French investigators.

Hepatitis E virus (HEV) is most often transmitted through the fecal-oral route in contaminated drinking water or food, but it also can be transmitted by blood and blood products. A research letter from Dr. Vincent Mallett of the Université Paris Descartes Sorbonne Paris Cité and colleagues published in Annals of Internal Medicine reported a case of HEV transmission to a kidney transplant recipient through plasma exchange.

CDC/Wikimedia Commons/Public Domain

Nineteen months after a 48-year-old patient received a kidney transplant, Dr. Mallett and his colleagues detected HEV RNA genotype 3f in the patient’s blood based on sequencing, and the patient tested positive for anti-HEV IgG and negative for anti-HEV IgM. The physicians confirmed that the patient had been infected for more than 1 year by finding HEV RNA in a frozen plasma sample drawn 5 months after transplantation. The kidney donor had tested negative for HEV RNA, and the patient’s stored blood samples tested negative for HEV markers before transplantation.

The investigators said that the method of HEV transmission remained undetermined until the investigators tested for HEV RNA in stored samples of all 18 blood products used during the peritransplantation period. From a single sample of fresh frozen plasma from a donor who had tested negative on multiple occasions for hepatitis C virus, HIV-1 and -2, and hepatitis B virus before the plasma was used, the researchers recovered a strain of HEV identical to the one infecting the patient. This plasma had been used during a plasma exchange for treating acute humoral rejection.

Plasma exchange typically involves the removal of 2-5 L of plasma several times a week, Dr. Mallett and associates said, which often is replaced with donor plasma. If replacement involves 2.5 L (10 bags) of donor plasma, which is a typical amount, then the risk for HEV is 10 times greater than the risk involving a single bag.

“In some circumstances, replacement procedures use plasma that has been pooled from many donors and then treated with solvents and detergents to inactivate infectious agents,” they wrote. “However, HEV is not affected by this treatment, so pooling multiplies the risk for infection.”

On the basis of these findings, the coauthors said that “all kidney transplant recipients with abnormal liver function test results, especially those treated with plasma exchange, should be tested for HEV RNA.”

Read the letter in Annals of Internal Medicine (2016 Mar 1. doi: 10.7326/L15-0502).

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All kidney transplant recipients with abnormal liver function test results should be tested for hepatitis E virus RNA, according to a recent finding by French investigators.

Hepatitis E virus (HEV) is most often transmitted through the fecal-oral route in contaminated drinking water or food, but it also can be transmitted by blood and blood products. A research letter from Dr. Vincent Mallett of the Université Paris Descartes Sorbonne Paris Cité and colleagues published in Annals of Internal Medicine reported a case of HEV transmission to a kidney transplant recipient through plasma exchange.

CDC/Wikimedia Commons/Public Domain

Nineteen months after a 48-year-old patient received a kidney transplant, Dr. Mallett and his colleagues detected HEV RNA genotype 3f in the patient’s blood based on sequencing, and the patient tested positive for anti-HEV IgG and negative for anti-HEV IgM. The physicians confirmed that the patient had been infected for more than 1 year by finding HEV RNA in a frozen plasma sample drawn 5 months after transplantation. The kidney donor had tested negative for HEV RNA, and the patient’s stored blood samples tested negative for HEV markers before transplantation.

The investigators said that the method of HEV transmission remained undetermined until the investigators tested for HEV RNA in stored samples of all 18 blood products used during the peritransplantation period. From a single sample of fresh frozen plasma from a donor who had tested negative on multiple occasions for hepatitis C virus, HIV-1 and -2, and hepatitis B virus before the plasma was used, the researchers recovered a strain of HEV identical to the one infecting the patient. This plasma had been used during a plasma exchange for treating acute humoral rejection.

Plasma exchange typically involves the removal of 2-5 L of plasma several times a week, Dr. Mallett and associates said, which often is replaced with donor plasma. If replacement involves 2.5 L (10 bags) of donor plasma, which is a typical amount, then the risk for HEV is 10 times greater than the risk involving a single bag.

“In some circumstances, replacement procedures use plasma that has been pooled from many donors and then treated with solvents and detergents to inactivate infectious agents,” they wrote. “However, HEV is not affected by this treatment, so pooling multiplies the risk for infection.”

On the basis of these findings, the coauthors said that “all kidney transplant recipients with abnormal liver function test results, especially those treated with plasma exchange, should be tested for HEV RNA.”

Read the letter in Annals of Internal Medicine (2016 Mar 1. doi: 10.7326/L15-0502).

All kidney transplant recipients with abnormal liver function test results should be tested for hepatitis E virus RNA, according to a recent finding by French investigators.

Hepatitis E virus (HEV) is most often transmitted through the fecal-oral route in contaminated drinking water or food, but it also can be transmitted by blood and blood products. A research letter from Dr. Vincent Mallett of the Université Paris Descartes Sorbonne Paris Cité and colleagues published in Annals of Internal Medicine reported a case of HEV transmission to a kidney transplant recipient through plasma exchange.

CDC/Wikimedia Commons/Public Domain

Nineteen months after a 48-year-old patient received a kidney transplant, Dr. Mallett and his colleagues detected HEV RNA genotype 3f in the patient’s blood based on sequencing, and the patient tested positive for anti-HEV IgG and negative for anti-HEV IgM. The physicians confirmed that the patient had been infected for more than 1 year by finding HEV RNA in a frozen plasma sample drawn 5 months after transplantation. The kidney donor had tested negative for HEV RNA, and the patient’s stored blood samples tested negative for HEV markers before transplantation.

The investigators said that the method of HEV transmission remained undetermined until the investigators tested for HEV RNA in stored samples of all 18 blood products used during the peritransplantation period. From a single sample of fresh frozen plasma from a donor who had tested negative on multiple occasions for hepatitis C virus, HIV-1 and -2, and hepatitis B virus before the plasma was used, the researchers recovered a strain of HEV identical to the one infecting the patient. This plasma had been used during a plasma exchange for treating acute humoral rejection.

Plasma exchange typically involves the removal of 2-5 L of plasma several times a week, Dr. Mallett and associates said, which often is replaced with donor plasma. If replacement involves 2.5 L (10 bags) of donor plasma, which is a typical amount, then the risk for HEV is 10 times greater than the risk involving a single bag.

“In some circumstances, replacement procedures use plasma that has been pooled from many donors and then treated with solvents and detergents to inactivate infectious agents,” they wrote. “However, HEV is not affected by this treatment, so pooling multiplies the risk for infection.”

On the basis of these findings, the coauthors said that “all kidney transplant recipients with abnormal liver function test results, especially those treated with plasma exchange, should be tested for HEV RNA.”

Read the letter in Annals of Internal Medicine (2016 Mar 1. doi: 10.7326/L15-0502).

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Test All Kidney Transplant Patients for Hepatitis E
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Test all kidney transplant patients for hepatitis E

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Test all kidney transplant patients for hepatitis E

All kidney transplant recipients with abnormal liver function test results should be tested for hepatitis E virus RNA, according to a recent finding by French investigators.

Hepatitis E virus (HEV) is most often transmitted through the fecal-oral route in contaminated drinking water or food, but it also can be transmitted by blood and blood products. A research letter from Dr. Vincent Mallett of the Université Paris Descartes Sorbonne Paris Cité and colleagues published in Annals of Internal Medicine reported a case of HEV transmission to a kidney transplant recipient through plasma exchange.

CDC/Wikimedia Commons/Public Domain

Nineteen months after a 48-year-old patient received a kidney transplant, Dr. Mallett and his colleagues detected HEV RNA genotype 3f in the patient’s blood based on sequencing, and the patient tested positive for anti-HEV IgG and negative for anti-HEV IgM. The physicians confirmed that the patient had been infected for more than 1 year by finding HEV RNA in a frozen plasma sample drawn 5 months after transplantation. The kidney donor had tested negative for HEV RNA, and the patient’s stored blood samples tested negative for HEV markers before transplantation.

The investigators said that the method of HEV transmission remained undetermined until the investigators tested for HEV RNA in stored samples of all 18 blood products used during the peritransplantation period. From a single sample of fresh frozen plasma from a donor who had tested negative on multiple occasions for hepatitis C virus, HIV-1 and -2, and hepatitis B virus before the plasma was used, the researchers recovered a strain of HEV identical to the one infecting the patient. This plasma had been used during a plasma exchange for treating acute humoral rejection.

Plasma exchange typically involves the removal of 2-5 L of plasma several times a week, Dr. Mallett and associates said, which often is replaced with donor plasma. If replacement involves 2.5 L (10 bags) of donor plasma, which is a typical amount, then the risk for HEV is 10 times greater than the risk involving a single bag.

“In some circumstances, replacement procedures use plasma that has been pooled from many donors and then treated with solvents and detergents to inactivate infectious agents,” they wrote. “However, HEV is not affected by this treatment, so pooling multiplies the risk for infection.”

On the basis of these findings, the coauthors said that “all kidney transplant recipients with abnormal liver function test results, especially those treated with plasma exchange, should be tested for HEV RNA.”

Read the letter in Annals of Internal Medicine (2016 Mar 1. doi: 10.7326/L15-0502).

[email protected]

On Twitter @richpizzi

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All kidney transplant recipients with abnormal liver function test results should be tested for hepatitis E virus RNA, according to a recent finding by French investigators.

Hepatitis E virus (HEV) is most often transmitted through the fecal-oral route in contaminated drinking water or food, but it also can be transmitted by blood and blood products. A research letter from Dr. Vincent Mallett of the Université Paris Descartes Sorbonne Paris Cité and colleagues published in Annals of Internal Medicine reported a case of HEV transmission to a kidney transplant recipient through plasma exchange.

CDC/Wikimedia Commons/Public Domain

Nineteen months after a 48-year-old patient received a kidney transplant, Dr. Mallett and his colleagues detected HEV RNA genotype 3f in the patient’s blood based on sequencing, and the patient tested positive for anti-HEV IgG and negative for anti-HEV IgM. The physicians confirmed that the patient had been infected for more than 1 year by finding HEV RNA in a frozen plasma sample drawn 5 months after transplantation. The kidney donor had tested negative for HEV RNA, and the patient’s stored blood samples tested negative for HEV markers before transplantation.

The investigators said that the method of HEV transmission remained undetermined until the investigators tested for HEV RNA in stored samples of all 18 blood products used during the peritransplantation period. From a single sample of fresh frozen plasma from a donor who had tested negative on multiple occasions for hepatitis C virus, HIV-1 and -2, and hepatitis B virus before the plasma was used, the researchers recovered a strain of HEV identical to the one infecting the patient. This plasma had been used during a plasma exchange for treating acute humoral rejection.

Plasma exchange typically involves the removal of 2-5 L of plasma several times a week, Dr. Mallett and associates said, which often is replaced with donor plasma. If replacement involves 2.5 L (10 bags) of donor plasma, which is a typical amount, then the risk for HEV is 10 times greater than the risk involving a single bag.

“In some circumstances, replacement procedures use plasma that has been pooled from many donors and then treated with solvents and detergents to inactivate infectious agents,” they wrote. “However, HEV is not affected by this treatment, so pooling multiplies the risk for infection.”

On the basis of these findings, the coauthors said that “all kidney transplant recipients with abnormal liver function test results, especially those treated with plasma exchange, should be tested for HEV RNA.”

Read the letter in Annals of Internal Medicine (2016 Mar 1. doi: 10.7326/L15-0502).

[email protected]

On Twitter @richpizzi

All kidney transplant recipients with abnormal liver function test results should be tested for hepatitis E virus RNA, according to a recent finding by French investigators.

Hepatitis E virus (HEV) is most often transmitted through the fecal-oral route in contaminated drinking water or food, but it also can be transmitted by blood and blood products. A research letter from Dr. Vincent Mallett of the Université Paris Descartes Sorbonne Paris Cité and colleagues published in Annals of Internal Medicine reported a case of HEV transmission to a kidney transplant recipient through plasma exchange.

CDC/Wikimedia Commons/Public Domain

Nineteen months after a 48-year-old patient received a kidney transplant, Dr. Mallett and his colleagues detected HEV RNA genotype 3f in the patient’s blood based on sequencing, and the patient tested positive for anti-HEV IgG and negative for anti-HEV IgM. The physicians confirmed that the patient had been infected for more than 1 year by finding HEV RNA in a frozen plasma sample drawn 5 months after transplantation. The kidney donor had tested negative for HEV RNA, and the patient’s stored blood samples tested negative for HEV markers before transplantation.

The investigators said that the method of HEV transmission remained undetermined until the investigators tested for HEV RNA in stored samples of all 18 blood products used during the peritransplantation period. From a single sample of fresh frozen plasma from a donor who had tested negative on multiple occasions for hepatitis C virus, HIV-1 and -2, and hepatitis B virus before the plasma was used, the researchers recovered a strain of HEV identical to the one infecting the patient. This plasma had been used during a plasma exchange for treating acute humoral rejection.

Plasma exchange typically involves the removal of 2-5 L of plasma several times a week, Dr. Mallett and associates said, which often is replaced with donor plasma. If replacement involves 2.5 L (10 bags) of donor plasma, which is a typical amount, then the risk for HEV is 10 times greater than the risk involving a single bag.

“In some circumstances, replacement procedures use plasma that has been pooled from many donors and then treated with solvents and detergents to inactivate infectious agents,” they wrote. “However, HEV is not affected by this treatment, so pooling multiplies the risk for infection.”

On the basis of these findings, the coauthors said that “all kidney transplant recipients with abnormal liver function test results, especially those treated with plasma exchange, should be tested for HEV RNA.”

Read the letter in Annals of Internal Medicine (2016 Mar 1. doi: 10.7326/L15-0502).

[email protected]

On Twitter @richpizzi

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Cardiorenal Syndrome Type 1: Renal Dysfunction in Acute Decompensated Heart Failure

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Cardiorenal Syndrome Type 1: Renal Dysfunction in Acute Decompensated Heart Failure

From the Cardiovascular Division, Department of Internal Medicine, University of Minnesota, Minneapolis, MN.

 

Abstract

  • Objective: To present a review of cardiorenal syndrome type 1 (CRS1).
  • Methods: Review of the literature.
  • Results: Acute kidney injury occurs in approximately one-third of patients with acute decompensated heart failure (ADHF) and the resultant condition was named CRS1. A growing body of literature shows CRS1 patients are at high risk for poor outcomes, and thus there is an urgent need to understand the pathophysiology and subsequently develop effective treatments. In this review we discuss prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, and ongoing clinical trials and highlight questions and problems physicians will face moving forward with this common and challenging condition.
  • Conclusion: Further research is needed to understand the pathophysiology of this complex clinical entity and to develop effective treatments.

 

Acute decompensated heart failure (ADHF) is an epidemic facing physicians throughout the world. In the United States alone, ADHF accounts for over 1 million hospitalizations annually, with costs in 2012 reaching $30.7 billion [1]. Despite the advances in chronic heart failure management, ADHF continues to be associated with poor outcomes as exemplified by 30-day readmission rates of over 20% and in-hospital mortality rates of 5% to 6%, both of which have not significantly improved over the past 20 years [2,3]. One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction. An analysis from the Acute Decompensated Heart Failure National Registry (ADHERE) revealed the combination of renal dysfunction (creatinine > 2.75 mg/dL and blood urea nitrogen (BUN) > 43 mg/dL) and hypotension (systolic blood pressure (SBP) < 115 mm Hg) upon admission was associated with an in-hospital mortality of > 20% [4]. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry documented a 16.3% in-hospital mortality when patients had a SBP < 100 mm Hg and creatinine > 2.0 mg/dL at admission [5].

The presence of acute kidney injury in the setting of ADHF is a very common occurrence and was termed cardiorenal syndrome type 1 (CRS1) [6]. The prevalence of CRS1 in single-centered studies ranged from 32% to 40% of all ADHF admissions [7,8]. If this estimate holds true throughout the United States, there would be 320,000 to 400,000 hospitalizations for CRS1 annually, highlighting the magnitude of this problem. Moreover, with the number of patients with heart failure expected to continue to rise, CRS1 will only become more prevalent in the future. In this review we discuss the prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, ongoing clinical trials, and highlight questions and problems physicians will face moving forward in this common and challenging condition.

Pathogenesis of CRS1

Hemodynamic Effects

The early hypothesis for renal dysfunction in ADHF centered on hemodynamics, as reduced cardiac output was believed to decrease renal perfusion. However, analysis of invasive hemodynamics from patients with ADHF suggested that central venous pressure (CVP) was actually a better predictor of the development of CRS1 than cardiac output. In a single-center study conducted at the Cleveland Clinic, hemodynamics from 145 patients with ADHF were evaluated and surprisingly baseline cardiac index was greater in the patients with CRS1 than patients without renal dysfunction (2.0 ± 0.8 L/min/m2 vs 1.8 ± 0.4 L/min/m2= 0.008). However, baseline CVP was higher in the CRS1 group (18 ± 7 mm Hg vs 12 ± 6 mm Hg; = 0.001), and there was a heightened risk of developing CRS1 as CVP increased. In fact, 75% of the patients with a CVP of > 24 mm Hg developed renal impairment [9]. In a retrospective study of the Evaluation Study of Congestive Heart Failure and Pulmonary Arterial Catheter Effectiveness (ESCAPE) trial, the only hemodynamic parameter that correlated with baseline creatinine was CVP. However, no invasive measures predicted worsening renal function during hospitalization [10]. Finally, an experiment that used isolated canine kidneys showed increased venous pressure acutely reduced urine production. Interestingly, this relationship was dependent on arterial pressure; as arterial flow decreased smaller increases in CVP were needed to reduce urine output [11]. Together, these data suggest increased CVP plays an important role in CRS1, but imply hemodynamics alone may not fully explain the pathophysiology of CRS1.

Inflammation

As information about how hemodynamics incompletely predict renal dysfunction in ADHF became available, alternative hypotheses were investigated to gain a deeper understanding of the pathophysiology underlying CRS1. A pathological role of inflammation in CRS1 has gained attention due to recent publications. First of all, serum levels of the pro-inflammatory cytokines TNF-a and IL-6 were elevated in patients with CRS1 when compared to health controls [12]. Interestingly, Virzi et al showed that the median value of IL-6 was 5 times higher in CRS1 patients when compared to ADHF patients without renal dysfunction [13]. The negative consequences of elevated serum cytokines were demonstrated when incubation of a human cell line of monocytes with serum from CRS1 patients induced apoptosis in 81% of cells compared to just 11% of cells with control serum [12]. It is possible that cytokine-induced apoptosis could occur in other cell types in different organs in patients with CRS1, which may contribute to both cardiac and renal dysfunction. Finally, analysis from a rat model of CRS1 revealed macrophage infiltration into the kidneys and increased numbers of activated monocytes in the peripheral blood. Interestingly, monocyte/macrophage depletion using liposome clodronate prevented chronic renal dysfunction in the rat model [14]. In summary, these data suggest inflammation contributes to CRS1 pathophysiology, but more experimental data is needed to determine if there is a causal relationship.

Oxidative Stress

Very recently, oxidative stress was proposed to play a role in CRS1. Virzi et al analyzed serum levels of markers of oxidative stress and compared ADHF patients without renal impairment to CRS1 patients. The markers of oxidative stress, which included myeloperoxidase, nitric oxide, copper/zinc superoxide dismutase, and endogenous peroxidase, were all significantly higher in CRS1 patients [13]. While provocative, the tissues responsible for the generation of these molecules and the subsequent effects have not yet been fully elucidated.

The proposed pathophysiology is seen in the Figure.

Prognostication

Severity of Acute Kidney Injury

Initial publications did not document a strong link between kidney injury and poor outcomes in ADHF. Firstly, Ather et al performed a single-centered study that investigated how change in renal function defined by change in creatinine, estimated GFR, and BUN affected outcomes one year post admission for ADHF. Kidney injury defined by a change in creatinine or in estimated GFR was not associated with increased risk of mortality, but a change in BUN was associated with increased mortality in a univariate analysis [15]. Testani et al retrospectively analyzed patients from the ESCAPE trial and found worsening renal function defined by a ≥ 20% reduction in estimated GFR was not significantly associated with 180-day mortality, but there was a trend towards higher mortality (hazard ration 1.4; = 0.11) [16]. Importantly, neither of 2 these studies assessed how severity of AKI impacted outcomes, which may have contributed to the weak relationships observed.

However, when AKI severity in CRS1 was quantified, poor outcomes were more likely as AKI severity increased. Firstly, Roy et al determined how AKI impacted adverse events (mortality, rehospitalization, or need for dialysis) rates in 637 patients with ADHF. Severity of AKI was quantified using RIFLE, AKIN, and KDIGO guidelines (Table 1), and the authors found that as the severity of renal injury increased, the likelihood of an adverse event was higher. In fact, the most severe AKI grade using all 3 AKI grading systems resulted in an odds ratio ranging from 45.3 to 101.6 for an adverse event at 30 days when compared to no kidney injury [7]. Hata et al documented that AKI (defined using RIFLE criteria) in ADHF resulted in a longer ICU stay, total hospital length of stay, and higher in-hospital mortality rates, and patients with a failure-grade AKI had in-hospital mortality rate of 49.1% [17]. Finally, Li et al evaluated AKI in 1005 patients with ADHF and showed that AKI defined by RIFLE, AKIN, or KDIGO methods increased risk of in-hospital mortality, and that a KDIGO grade 3 AKI was associated with a 35.5% in-hospital mortality rate [8]. These data indicate CRS1 is associated with poor outcomes, and there is a heightened risk of adverse events as AKI severity increases.

Diuretic Responsiveness

Using change in serum creatinine as a marker of renal impairment may not be the best choice for predicting outcomes in CRS1 because the lab values are not a real-time measure of kidney function and serum creatinine can be affected by both body mass and pharmaceutical agents. Therefore, the prognosticating ability of urine production relative to diuretic dose as a surrogate measure of renal function in ADHF was investigated by several groups (Table 2). Testani et al examined urine output per 40 mg of furosemide and tracked outcomes in 2 cohorts: patients admitted with ADHF at the University of Pennsylvania (657 patients) and patients from the ESCAPE trial (390 patients). Patients were split into high responders or low responders based on the median value. In both of the patient cohorts, low diuretic efficiency was associated with increased mortality using a multivariate model (hazard ratio of 1.36 in the Penn patients and 2.86 in the ESCAPE patients). The combination of low diuretic efficiency and high diuretic dose (> 280 mg in the Penn cohort and > 240 mg in the ESCAPE cohort) resulted in the worst prognosis, with mortality rates of approximately 70% at 6 years in the Penn cohort and approximately 35% at 180 days in the ESCAPE cohort [18].

Voors et al performed a retrospective analysis of diuretic responsiveness in 1161 patients from the Relaxin in Acute Heart Failure (RELAX-AHF) trial. Diuretic responsiveness was defined as weight change (kg) per diuretic dose (IV furosemide and PO furosemide) over 5 days and then patients were separated into tertiles. The lowest tertile group had an approximate 20% incidence of 60-day combined end-point of death, heart failure or renal failure readmission compared to less than 10% incidence in the middle and upper tertiles. Interestingly, when the effects of worsening renal function (WRF), defined as creatinine change of ≥ 0.3 mg/dL, were examined in patients stratified by diuretic response, WRF did not offer additional prognostic information [19].

Finally, Valenete et al analyzed diuretic response in 1745 patients from the PROTECT trial (Placebo-Controlled Randomized Study of the Selective A1-Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Diuretic response was calculated using the weight change per 40 mg of furosemide, and as diuretic response declined there was increasing risk of 60-day rehospitalization and 180-day mortality rates. In fact, the lowest quintile responders had a 25% mortality rate at 180 days [20].

Emerging Biomarkers

Urine Neutrophil Gelatinase-Associated Lipocalin

Because previous studies showed urinary levels of NGAL was an earlier and more reliable marker of renal dysfunction than creatinine in AKI [21], it was studied as a possible biomarker for the development of CRS1 in ADHF. A single-centered study quantified levels of urine NGAL in 100 patients admitted with heart failure and then tracked the rates of acute kidney injury. Urine NGAL was elevated in patients that developed AKI and a cut-off value 12 ng/mL had a sensitivity of 79% and specificity of 67% for predicting CRS1 [22]. While promising, further studies are needed to better define the role of NGAL in CRS1.

Cystatin C

Cystatin C is a ubiquitously expressed cysteine protease that has a constant production rate and is freely filtered by the glomerulus without being secreted into the tubules, and has effectively prognosticated outcomes in ADHF [23]. Lassus et al showed an adjusted hazard ratio of 3.2 (2.0–5.3) for 12-month mortality when cystatin C levels were elevated. Moreover, patients with the highest tertitle of NT-proBNP and cystatin C had a 48.7% 1-year mortality. Interestingly, patients with an elevated cystatin C but normal creatinine had a 40.6% 1-year mortality compared to 12.6% for those with normal cystatin C and creatinine [24]. Furthermore, Arimoto et al showed elevated cystatin C predicted death or rehospitalization in a small cohort of ADHF patients in Japan [25]. Also, Naruse et al showed cystatin C was a better predictor of cardiac death than estimated GFR by the Modification of Diet in Renal Disease Study (MDRD) equation [26]. Finally, Manzano-Fernandez et al showed the highest tertile of cystatin C was a significant independent risk factor for 2-year death or rehospitalization while creatinine and MDRD estimates of GFR were not [27]. In agreement with Lassus et al, elevations in either 2 or 3 of cystatin C, troponin, and NT-proBNP predicted death or rehospitalization when compared to those with normal levels of these 3 markers [27]. In conclusion, cystatin C either alone or in combination with other biomarkers identifies high-risk patients.

Kidney Injury Molecule 1

Kidney injury molecule 1 (KIM-1) is a type-1 cell membrane glycoprotein expressed in regenerating proximal tubular cells but not under normal conditions [28]. Although associated with increased risk of hospitalization and mortality in chronic heart failure [29,30], elevated levels of urinary KIM-1 did not predict mortality in ADHF [31]. Further studies are needed to elucidate the utility of KIM-1 in CRS1.

Treatment Approaches

Diuretics

Loop diuretics are the main treatment for decongestion of patients with CRS1. To date, no clinical trial has compared the different loop diuretics (furosemide, bumetanide, torsemide, or ethacrynic acid) to each other, so there is no clear choice of which loop diuretic is the best. However, dosing scheme was investigated in the Dose Optimization Strategies Evaluation (DOSE) trial. In this trial, 308 patients were randomized in a 1:1:1:1 design in which patients were placed in groups with low-dose (equivalent to oral dose) or high-dose (2.5 times oral dose) intermittent parental therapy or alternatively low-dose or high-dose continuous drip therapy. There were no differences in dyspnea, fluid changes, change in creatinine, hospital length stay, or rehospitalization and death rates when the intermittent and drip approaches were compared. However, the high-dose arm had decreased dyspnea, increased volume removal, but there were more occurrences of AKIs when compared to the low-dose arm [32].

In clinical practice, if loop diuretic treatment does not result in the desired urine output, a second-site diuretic may be added to potentiate diuresis. Unfortunately, there is little data on this common clinical practice and thus the optimal choice of second site agent (chlorthiazide or metolazone) is unknown. Frequently, the deciding factor is based upon cost or concern that oral absorption of metolazone will be ineffective. However, Moranville et al recently performed a retrospective assessment comparing chlorthiazide (22 patients) to metolazone (33 patients) in ADHF patients with renal dysfunction defined by a creatinine clearance of 15–50 mL/min. There was a nonsignificant trend towards increased urine output in the metolazone group, no differences in the rates of adverse events, and the chlorthiazide group actually had a longer hospital stay [33]. While potentially promising results, the retrospective nature of the study made it difficult to determine if the differences were due to treatment approach or dissimilarities of patient illness. Nonetheless, physicians must remain vigilant when implementing the second-site diuretic approach because it can lead to marked diuretic response leading to metabolic derangements including hypokalemia, hyponatremia, hypomagnesaemia, and metabolic alkalosis.

Inotropes

The use of inotropic agents such as dobutamine or milrinone can be used to augment cardiac function when there is a known low-output state for better renal perfusion in CRS1. Unfortunately, there is little objective data available about the utility of this widely implemented approach. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of a Chronic Heart Failure (OPTIME-HF) trial did not show improved renal function with milrinone treatment [34]. The use of levosimendan, a cardiac calcium sensitizer that increases contractility not currently approved in the United States, was compared to dobutamine in the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial, and there were no differences in rates of renal failure when the 2 groups were compared [35]. Nonetheless, if cardiac output is severely compromised, inotropes can be used for CRS1 treatment, but they should be used cautiously due the increased risks of lethal arrhythmias.

Dopamine

Use of low-dose dopamine to stimulate D1 and D2 receptors as a way to increase renal blood flow and promote increased glomerular filtration and urine production was extensively studied in ADHF. A small trial showed use of low dose dopamine had renal protective effects in a total of 20 patients [36]. However, when larger trials were conducted, such beneficial results were not consistently observed. The Dopamine in Acute Decompensated Heart Failure (DAD-HF I) trial compared low-dose furosemide plus low-dose dopamine (5 µg/kg/min) to high-dose furosemide alone in 60 patients. There were no differences in total diuresis, hospital stay, and 60-day mortality or rehospitalization rates, but there was a reduction in the renal dysfunction at the 24-hour time point in the dopamine-treated arm (6.7% versus 30%) [37]. The Dopamine in Acute Decompensated Heart Failure II trial randomized 161 ADHF patients to high-dose furosemide, low-dose furosemide and lose dose dopamine (5 µg/kg/min), or low-dose furosemide and assessed dyspnea, worsening renal function, length of stay, 60-day and one-year all-cause mortality and hospitalization for heart failure. Dopamine treatment did not improve any of the outcomes measured [38]. Finally, the most recent trial to examine the effects of dopamine was the Renal Optimization Strategies Evaluation (ROSE) trial. In this trial, there were 360 patients with ADHF randomized to nesiritide or dopamine versus placebo in a 2:1 design. When comparing dopamine (111 patients) treatment to placebo (115 patients), there were no differences in urine output, renal function as determined by cystatin C levels, or symptomatic improvements. However, there was more tachycardia in the dopamine group [39]. Currently, there is not strong evidence supporting routine use of dopamine in CRS1.

Nesiritide

Use of nesiritide, recombinant brain natriuretic peptide, was also investigated as a way to enhance urine production through the natriuretic effects of the peptide. The first attempt to explore this hypothesis was the B-Type Natriuretic Peptide in Cardiorenal Decompensation Syndrome (BNP-CARDS) trial. BNP-CARDS showed a 48-hour infusion of nesiritide (39 patients) or placebo (36 patients) in patients with ADHF and renal dysfunction (estimated GFR between 15–60 mL/min) did not reduce the incidence of worsening renal function as defined by a rise in serum creatinine by 20% [40]. A similar approach was implemented in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial which examined over 7000 patients with ADHF. 3496 patients were treated with nesiritide and 3511 patients were treated with placebo for 24 hours and up to 7 days. Nesiritide treatment did not alter dyspnea at 6 and 24 hours, improve renal function as determined by creatinine change, or alter the combined end-point of rehospitalization or death 30 at days [41]. The ROSE trial examined the effects of nesiritide (117 patients) versus placebo (115 patients) for urine production, change in renal function as defined by change in cystatin C, and decongestion (urinary sodium excretion, weight change, and change in NT-proBNP) at 72 hours. Nesiritide did not alter any of the outcomes investigated [39]. Finally, a single-centered study conducted at the Mayo Clinic examined the effects of nesiritide (37 patients) or placebo (35 patients) with ADHF and pre-existing renal dysfunction (estimated GFR between 20 and 60 mL/min). These investigators found nesiritide treatment resulted in less renal dysfunction as measured by creatinine and BUN, but no changes in diuretic responsiveness, duration of hospitalization, or rehospitalization rates. Nesiritide did reduce serum endothelin levels, but had no effect on ANP, NT-pro BNP, renin, angiotensin II, or aldosterone [42]. In summary, nesiritide does not appear to have significant renal protective effects in ADHF.

Adenosine A1 Receptor Antagonists

The use of adenosine receptor antagonists to prevent adenosine-mediated vasoconstriction of renal vasculature in ADHF has also been examined. The first study conducted was a small double-blind randomized-controlled trial that investigated the effects of rolofylline, an adenosine A-1 antagonist, in patients with ADHF and an estimated creatinine clearance of 20-80 mL/min. The study had 27 patients in the placebo arm, 29 patients that received 2.5 mg of rolofylline, 31 patients received 15 mg of rolofylline, 30 patients received 30 mg of rolofylline, and 29 patients received 60 mg of rolofylline, all of which was daily for up to 3 days. Rolofylline treatment increased urine output on day 1 and improved renal function on day 2 [43]. These positive results led to the Placebo-Controlled Randomized Study of Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Trial. PROTECT assessed the effects of rolofylline (1356) or placebo (677) in patients with ADHF and an estimated creatinine clearance between 20 and 80 mL/min. There were no significant differences in renal function out to 14 days, but rolofylline led to more weight loss than placebo [44,45]. In a subgroup analysis of patients with severe baseline renal dysfunction (creatinine clearance of less than 30 mL/min), rolofylline reduced the combined 60-day end-point of hospitalization due to cardiovascular or renal cause and death [45]. Finally, the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (REACH-UP) trial probed the effects of rolofylline (36 patients) or placebo (40 patients) in patients with ADHF and renal impairment (creatinine clearance of 20-60 mL/min). Rolofylline treatment did not alter renal function, but there was a nonsignificant trend towards reduction in 60-day combined end-point of hospitalization due to renal or cardiovascular causes or death [46]. In summary, the use of rolofylline has not been conclusively associated with improved outcomes in CRS1.

Vasopressin Antagonists

The use of vasopressin antagonists to induce aquaphoresis and combat hyponatremia was studied in ADHF. Vasopressin antagonists were first investigated in the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist (ACTIV) trial. ACTIV involved 3 doses of tolvaptan (78 patients received 30 mg, 84 patients received 60 mg, and 77 patients received 90 mg) versus placebo (80 patients), and tolvaptan increased urine production and decreased body weight compared to placebo without compromising renal function. A post-hoc analysis of patients with renal dysfunction (BUN > 29 mg/dL) and severe volume overload revealed a survival benefit at 60 days [47]. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVERST) trial compared placebo (2061 patients) versus 30 mg/day of tolvaptan (2072 patients) within 48 hours after admission in an identical 2-trial design. Tolvaptan increased weight loss and reduced dyspnea acutely but did not alter all-cause mortality or cardiovascular or heart failure hospitalization rates out to 24 months post index hospitalization [48,49]. These data suggest vasopressin antagonists may potentiate diuresis acutely but likely do not improve long-term outcomes.

Corticosteroids

The use of corticosteroids in ADHF has been controversial as there were initial concerns that corticosteroids would increase fluid retention. However, corticosteroids augmented diuretic response and improved renal function in 13 ADHF patients who had inadequate response to sequential nephron blockage [50]. Furthermore, Zhang et al showed that prednisone treatment in 35 patients admitted with ADHF increased urinary volume, reduced dyspnea, reduced uric acid, and improved renal function [51]. These promising results led to the Cardiac Outcome Prevention Effectiveness of Glucocorticoids in Acute Decompensated Heart Failure (COPE-ADHF) trial. In this single-centered study, 102 patients with ADHF were randomized to either placebo [51] or corticosteroids [51] and the outcomes recorded included urinary volume, change in creatinine, and cardiovascular death at 30 days. Use of corticosteroids improved renal function, increased urine output, and reduced mortality (3/51 in corticosteroid group versus 10/51 in the placebo group) [52]. The mechanisms underlying the improvements with corticosteroids were not determined, but were hypothesized to be facilitation of natriuretic peptides or dilation of renal vasculature through activation of nitric oxide pathway or dopaminergic system.

Serelaxin

Serelaxin is a recombinantly expressed human relaxin-2, a peptide hormone present during pregnancy which facilitates physiological cardiovascular and renal adaptations [53–55], which showed potential benefits in CRS1. Analysis of the RELAX-AHF trial revealed serelaxin reduced incidence of worsening renal function at day 2 of treatment as defined by changes in serum creatinine, cystatin C, and BUN. Importantly, worsening renal function defined by cystatin C changes was associated with increased 180-day mortality in this analysis [56]. The mechanisms by which serelaxin prevented renal dysfunction are currently unknown as serelaxin treatment did not improve diuretic efficiency [19].

Ultrafiltration

Another treatment choice in CRS1 is mechanical removal of salt and water via ultrafiltration. Ultrafiltration showed early promise in Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure trial (UNLOAD) trial. In this study, 200 patients with ADHF were randomized to either ultrafiltration or medical management with loop diuretics. Use of ultrafiltration increased volume removal without any differences in renal function and reduced rehospitalization rates at 90 days [57].

However, when ultrafiltration was employed specifically in CRS1 patients in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure trial (CARESS-HF), UF was not superior to medical treatment. There were 188 patients studied in CARESS-HF, and in the ultrafiltration arm there was increased risk of renal dysfunction, no differences in volume removal, and no change in rehospitalization rates at 90 days [58]. When trying to reconcile UNLOAD and CARESS-HF, the medical treatment arm in CARESS-HF was much more standardized and aggressive and UNLOAD was earlier implementation of ultrafiltration, which may have explained the differences. Interestingly, ultrafiltration was hypothesized to be advantageous over diuretic therapy through reduced activation of the renin-angiotensin-aldosterone system, but analysis of the patients from CARESS-HF showed higher levels of plasma renin activity and no difference in aldosterone levels in ultrafiltration patients [59].

Two meta-analyses have examined the use of ultrafiltration versus medical management in ADHF and both showed ultrafiltration was more effective in volume removal than medical therapy but did not improve rehospitalization or mortality rates [60,61]. This fact combined with the risks of vascular access placement and bleeding from anticoagulation limits to routine use of ultrafiltration in CRS1.

Continuous Renal Replacement Therapy

Once renal function deteriorates to the point that renal replacement therapy is needed for both volume removal and solute clearance in CRS1, continuous renal replacement therapy (CRRT) may be implemented. Unfortunately, there are few available data for this group of advanced CRS1 patients to guide physicians. There was a single-centered study conducted in Egypt that randomized 40 ADHF patients to either IV furosemide or CRRT. The patients treated with CRRT had greater weight loss and decreased length of stay in the ICU, but there were no differences in dialysis dependence rates or 30-day mortality [62]. Two single-centered studies reported outcomes associated with advanced CRS1 requiring CRRT. In a study conducted at the Cleveland Clinic, 63 patients with CRS1 were treated with ultrafiltration, of which 37 were converted to CRRT due to worsening renal function. Of the 37 patients treated with CRRT, 16 died in the hospital and 4 were discharged with hospice care [63]. In another retrospective study performed at the University of Alabama-Birmingham, use of rescue CRRT in advanced CRS1 was examined in 37 patients. 23 patients died during hospitalization and 2 were discharged to hospice care [64]. Combination of the Cleveland Clinic and University of Alabama-Birmingham studies revealed patients requiring CRRT in the setting of advanced CRS1 had an in-hospital mortality or palliative discharge rate of 60.8% (45/74). Clearly, this population needs further investigation to prevent such poor outcomes.

A summary of treatment approaches for CRS1 is presented in Table 3.

Future Treatment Options

Ongoing and Unreported Clinical Trials

Unfortunately, none of the current treatments for CRS1 have definitive improvements in outcomes, but there are several ongoing clinical trials which will hopefully identify novel treatment strategies. First of all, the Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure (Diuresis-CHF) trial is being conducted in Belgium. This study will examine the effects of acetazolamide with low dose diuretic versus high dose diuretics in one aim and the effects of upfront spironolactone in another. The outcomes analyzed will include total natriuresis, potassium homeostasis, NT-proBNP changes, change in renal function, peak serum levels of renin and aldosterone, weight change, urine volume, and change in edema (NCT01973335). The Protocolized Diuretic Strategy in Cardiorenal Failure (ProDius) trial is being performed at the University of Pittsburgh, and will determine the effects of a protocolized diuretic approach to target 3-5 liters of urine production a day versus standard therapy and will track the change in body weight, length of hospitalization, reshospitalization rates, mortality rates, venous compliance of internal jugular vein, clinical decongestion, change in renal function, and urine output (NCT01921829). The Levosimendan versus Dobutamine for Renal Function in Heart Failure (ELDOR) study is ongoing in Sweden and will probe the acute effects of levosimendan and dobutamine on renal perfusion. The endpoints will include changes in renal blood flow, GFR, renal vascular resistance, central hemodynamics, renal oxygen extraction and consumptions, and filtration fraction (NCT02133105). Finally, the Safety and Efficacy of Low Dose Hypertonic Saline and High Dose Furosemide for Congestive Heart Failure (REaCH) trial probed the effects of combination of hypertonic saline and furosemide versus furosemide in patients with ADHF and renal impairment defined by a GFR<60 mL/min. The outcomes were change in renal function, diuretic response, length of hospital stay, readmission rates, weight loss, BNP levels, and included a cost analysis. The study was completed but results are not currently available (NCT01028170)

Should Inflammation Be Targeted in CRS1?

Although proposed to play a role in the pathophysiology of CRS1, inflammation has not been explicitly targeted as a treatment for CRS1. One possible way to combat inflammation could be inhibition of the IL-6 pathway, which is support by preclinical work as previous studies showed IL-6 knockout mice were resistant to HgCl2-induced renal injury and death [65] and IL-6 has negative inotropic effects in both isolated cardiomyocytes [66] and intact animals [67]. Thus, IL-6 antagonism may improve both cardiac and renal function, an ideal scenario for CRS1 patients. The availability of tocilizumab, an FDA-approved humanized antibody to the IL-6 receptor, may allow for investigation of this hypothesis in the future. Although not examined in the COPE-ADHF trial, an alternative explanation for the improvements associated with corticosteroids treatment were the anti-inflammatory effects. If this were true, corticosteroids would represent a relatively cheap treatment option for CRS1 patients, but more studies need to be conducted before this approach is widely implemented. Finally, use of cytokine profiling may be used to enrich a population of CRS1 patients that could be investigated in future clinical trials using anti-inflammatory medications.

Unanswered Questions Moving Forward

Severity of AKI and Treatment Effects

An important unknown that warrants further investigation is if the severity of AKI should dictate treatment choice in CRS1. As discussed above, increasing severity of AKI resulted in elevated risk of adverse events, but it remains unknown whether different treatments offer benefits for more or less severe renal impairment. Perhaps, future studies aimed at defining outcomes from different treatment strategies stratified by severity of renal dysfunction may reveal which patients benefit from the various treatment options for CRS1.

How Do We Best Define Renal Dysfunction in CRS1?

Currently, there is no accepted definition of renal dysfunction in CRS1. As discussed above, using the AKIN, KDIGO, or RIFLE scoring systems or diuretic responsiveness effectively differentiated outcomes in patients with CRS1. However, an agreed-upon definition would likely benefit the field going forward so this population could be systematically investigated in future studies.

Conclusion

In summary, CRS1 is a common clinical entity associated with poor patient outcomes. A complex pathophysiology marked by reduced cardiac output, increased central venous pressure, inflammation, and oxidative stress underlies the disease process. Unfortunately, no current treatment approach shows consistent improvements in outcomes, highlighting the urgent need for further research to reduce the burden that CRS1 imposes.

 

Corresponding author: Kurt W. Prins, MD, PhD, MMC 580 Mayo, 420 Delaware St SE, Minneapolis, MN 55455, [email protected].

Funding/support: Dr. Prins is funded by NIH F32 grant HL129554 and Dr. Thenappen is funded by AHA Scientist Development Grant 15SDG25560048.

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Journal of Clinical Outcomes Management - OCTOBER 2015, VOL. 22, NO. 10
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From the Cardiovascular Division, Department of Internal Medicine, University of Minnesota, Minneapolis, MN.

 

Abstract

  • Objective: To present a review of cardiorenal syndrome type 1 (CRS1).
  • Methods: Review of the literature.
  • Results: Acute kidney injury occurs in approximately one-third of patients with acute decompensated heart failure (ADHF) and the resultant condition was named CRS1. A growing body of literature shows CRS1 patients are at high risk for poor outcomes, and thus there is an urgent need to understand the pathophysiology and subsequently develop effective treatments. In this review we discuss prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, and ongoing clinical trials and highlight questions and problems physicians will face moving forward with this common and challenging condition.
  • Conclusion: Further research is needed to understand the pathophysiology of this complex clinical entity and to develop effective treatments.

 

Acute decompensated heart failure (ADHF) is an epidemic facing physicians throughout the world. In the United States alone, ADHF accounts for over 1 million hospitalizations annually, with costs in 2012 reaching $30.7 billion [1]. Despite the advances in chronic heart failure management, ADHF continues to be associated with poor outcomes as exemplified by 30-day readmission rates of over 20% and in-hospital mortality rates of 5% to 6%, both of which have not significantly improved over the past 20 years [2,3]. One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction. An analysis from the Acute Decompensated Heart Failure National Registry (ADHERE) revealed the combination of renal dysfunction (creatinine > 2.75 mg/dL and blood urea nitrogen (BUN) > 43 mg/dL) and hypotension (systolic blood pressure (SBP) < 115 mm Hg) upon admission was associated with an in-hospital mortality of > 20% [4]. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry documented a 16.3% in-hospital mortality when patients had a SBP < 100 mm Hg and creatinine > 2.0 mg/dL at admission [5].

The presence of acute kidney injury in the setting of ADHF is a very common occurrence and was termed cardiorenal syndrome type 1 (CRS1) [6]. The prevalence of CRS1 in single-centered studies ranged from 32% to 40% of all ADHF admissions [7,8]. If this estimate holds true throughout the United States, there would be 320,000 to 400,000 hospitalizations for CRS1 annually, highlighting the magnitude of this problem. Moreover, with the number of patients with heart failure expected to continue to rise, CRS1 will only become more prevalent in the future. In this review we discuss the prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, ongoing clinical trials, and highlight questions and problems physicians will face moving forward in this common and challenging condition.

Pathogenesis of CRS1

Hemodynamic Effects

The early hypothesis for renal dysfunction in ADHF centered on hemodynamics, as reduced cardiac output was believed to decrease renal perfusion. However, analysis of invasive hemodynamics from patients with ADHF suggested that central venous pressure (CVP) was actually a better predictor of the development of CRS1 than cardiac output. In a single-center study conducted at the Cleveland Clinic, hemodynamics from 145 patients with ADHF were evaluated and surprisingly baseline cardiac index was greater in the patients with CRS1 than patients without renal dysfunction (2.0 ± 0.8 L/min/m2 vs 1.8 ± 0.4 L/min/m2= 0.008). However, baseline CVP was higher in the CRS1 group (18 ± 7 mm Hg vs 12 ± 6 mm Hg; = 0.001), and there was a heightened risk of developing CRS1 as CVP increased. In fact, 75% of the patients with a CVP of > 24 mm Hg developed renal impairment [9]. In a retrospective study of the Evaluation Study of Congestive Heart Failure and Pulmonary Arterial Catheter Effectiveness (ESCAPE) trial, the only hemodynamic parameter that correlated with baseline creatinine was CVP. However, no invasive measures predicted worsening renal function during hospitalization [10]. Finally, an experiment that used isolated canine kidneys showed increased venous pressure acutely reduced urine production. Interestingly, this relationship was dependent on arterial pressure; as arterial flow decreased smaller increases in CVP were needed to reduce urine output [11]. Together, these data suggest increased CVP plays an important role in CRS1, but imply hemodynamics alone may not fully explain the pathophysiology of CRS1.

Inflammation

As information about how hemodynamics incompletely predict renal dysfunction in ADHF became available, alternative hypotheses were investigated to gain a deeper understanding of the pathophysiology underlying CRS1. A pathological role of inflammation in CRS1 has gained attention due to recent publications. First of all, serum levels of the pro-inflammatory cytokines TNF-a and IL-6 were elevated in patients with CRS1 when compared to health controls [12]. Interestingly, Virzi et al showed that the median value of IL-6 was 5 times higher in CRS1 patients when compared to ADHF patients without renal dysfunction [13]. The negative consequences of elevated serum cytokines were demonstrated when incubation of a human cell line of monocytes with serum from CRS1 patients induced apoptosis in 81% of cells compared to just 11% of cells with control serum [12]. It is possible that cytokine-induced apoptosis could occur in other cell types in different organs in patients with CRS1, which may contribute to both cardiac and renal dysfunction. Finally, analysis from a rat model of CRS1 revealed macrophage infiltration into the kidneys and increased numbers of activated monocytes in the peripheral blood. Interestingly, monocyte/macrophage depletion using liposome clodronate prevented chronic renal dysfunction in the rat model [14]. In summary, these data suggest inflammation contributes to CRS1 pathophysiology, but more experimental data is needed to determine if there is a causal relationship.

Oxidative Stress

Very recently, oxidative stress was proposed to play a role in CRS1. Virzi et al analyzed serum levels of markers of oxidative stress and compared ADHF patients without renal impairment to CRS1 patients. The markers of oxidative stress, which included myeloperoxidase, nitric oxide, copper/zinc superoxide dismutase, and endogenous peroxidase, were all significantly higher in CRS1 patients [13]. While provocative, the tissues responsible for the generation of these molecules and the subsequent effects have not yet been fully elucidated.

The proposed pathophysiology is seen in the Figure.

Prognostication

Severity of Acute Kidney Injury

Initial publications did not document a strong link between kidney injury and poor outcomes in ADHF. Firstly, Ather et al performed a single-centered study that investigated how change in renal function defined by change in creatinine, estimated GFR, and BUN affected outcomes one year post admission for ADHF. Kidney injury defined by a change in creatinine or in estimated GFR was not associated with increased risk of mortality, but a change in BUN was associated with increased mortality in a univariate analysis [15]. Testani et al retrospectively analyzed patients from the ESCAPE trial and found worsening renal function defined by a ≥ 20% reduction in estimated GFR was not significantly associated with 180-day mortality, but there was a trend towards higher mortality (hazard ration 1.4; = 0.11) [16]. Importantly, neither of 2 these studies assessed how severity of AKI impacted outcomes, which may have contributed to the weak relationships observed.

However, when AKI severity in CRS1 was quantified, poor outcomes were more likely as AKI severity increased. Firstly, Roy et al determined how AKI impacted adverse events (mortality, rehospitalization, or need for dialysis) rates in 637 patients with ADHF. Severity of AKI was quantified using RIFLE, AKIN, and KDIGO guidelines (Table 1), and the authors found that as the severity of renal injury increased, the likelihood of an adverse event was higher. In fact, the most severe AKI grade using all 3 AKI grading systems resulted in an odds ratio ranging from 45.3 to 101.6 for an adverse event at 30 days when compared to no kidney injury [7]. Hata et al documented that AKI (defined using RIFLE criteria) in ADHF resulted in a longer ICU stay, total hospital length of stay, and higher in-hospital mortality rates, and patients with a failure-grade AKI had in-hospital mortality rate of 49.1% [17]. Finally, Li et al evaluated AKI in 1005 patients with ADHF and showed that AKI defined by RIFLE, AKIN, or KDIGO methods increased risk of in-hospital mortality, and that a KDIGO grade 3 AKI was associated with a 35.5% in-hospital mortality rate [8]. These data indicate CRS1 is associated with poor outcomes, and there is a heightened risk of adverse events as AKI severity increases.

Diuretic Responsiveness

Using change in serum creatinine as a marker of renal impairment may not be the best choice for predicting outcomes in CRS1 because the lab values are not a real-time measure of kidney function and serum creatinine can be affected by both body mass and pharmaceutical agents. Therefore, the prognosticating ability of urine production relative to diuretic dose as a surrogate measure of renal function in ADHF was investigated by several groups (Table 2). Testani et al examined urine output per 40 mg of furosemide and tracked outcomes in 2 cohorts: patients admitted with ADHF at the University of Pennsylvania (657 patients) and patients from the ESCAPE trial (390 patients). Patients were split into high responders or low responders based on the median value. In both of the patient cohorts, low diuretic efficiency was associated with increased mortality using a multivariate model (hazard ratio of 1.36 in the Penn patients and 2.86 in the ESCAPE patients). The combination of low diuretic efficiency and high diuretic dose (> 280 mg in the Penn cohort and > 240 mg in the ESCAPE cohort) resulted in the worst prognosis, with mortality rates of approximately 70% at 6 years in the Penn cohort and approximately 35% at 180 days in the ESCAPE cohort [18].

Voors et al performed a retrospective analysis of diuretic responsiveness in 1161 patients from the Relaxin in Acute Heart Failure (RELAX-AHF) trial. Diuretic responsiveness was defined as weight change (kg) per diuretic dose (IV furosemide and PO furosemide) over 5 days and then patients were separated into tertiles. The lowest tertile group had an approximate 20% incidence of 60-day combined end-point of death, heart failure or renal failure readmission compared to less than 10% incidence in the middle and upper tertiles. Interestingly, when the effects of worsening renal function (WRF), defined as creatinine change of ≥ 0.3 mg/dL, were examined in patients stratified by diuretic response, WRF did not offer additional prognostic information [19].

Finally, Valenete et al analyzed diuretic response in 1745 patients from the PROTECT trial (Placebo-Controlled Randomized Study of the Selective A1-Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Diuretic response was calculated using the weight change per 40 mg of furosemide, and as diuretic response declined there was increasing risk of 60-day rehospitalization and 180-day mortality rates. In fact, the lowest quintile responders had a 25% mortality rate at 180 days [20].

Emerging Biomarkers

Urine Neutrophil Gelatinase-Associated Lipocalin

Because previous studies showed urinary levels of NGAL was an earlier and more reliable marker of renal dysfunction than creatinine in AKI [21], it was studied as a possible biomarker for the development of CRS1 in ADHF. A single-centered study quantified levels of urine NGAL in 100 patients admitted with heart failure and then tracked the rates of acute kidney injury. Urine NGAL was elevated in patients that developed AKI and a cut-off value 12 ng/mL had a sensitivity of 79% and specificity of 67% for predicting CRS1 [22]. While promising, further studies are needed to better define the role of NGAL in CRS1.

Cystatin C

Cystatin C is a ubiquitously expressed cysteine protease that has a constant production rate and is freely filtered by the glomerulus without being secreted into the tubules, and has effectively prognosticated outcomes in ADHF [23]. Lassus et al showed an adjusted hazard ratio of 3.2 (2.0–5.3) for 12-month mortality when cystatin C levels were elevated. Moreover, patients with the highest tertitle of NT-proBNP and cystatin C had a 48.7% 1-year mortality. Interestingly, patients with an elevated cystatin C but normal creatinine had a 40.6% 1-year mortality compared to 12.6% for those with normal cystatin C and creatinine [24]. Furthermore, Arimoto et al showed elevated cystatin C predicted death or rehospitalization in a small cohort of ADHF patients in Japan [25]. Also, Naruse et al showed cystatin C was a better predictor of cardiac death than estimated GFR by the Modification of Diet in Renal Disease Study (MDRD) equation [26]. Finally, Manzano-Fernandez et al showed the highest tertile of cystatin C was a significant independent risk factor for 2-year death or rehospitalization while creatinine and MDRD estimates of GFR were not [27]. In agreement with Lassus et al, elevations in either 2 or 3 of cystatin C, troponin, and NT-proBNP predicted death or rehospitalization when compared to those with normal levels of these 3 markers [27]. In conclusion, cystatin C either alone or in combination with other biomarkers identifies high-risk patients.

Kidney Injury Molecule 1

Kidney injury molecule 1 (KIM-1) is a type-1 cell membrane glycoprotein expressed in regenerating proximal tubular cells but not under normal conditions [28]. Although associated with increased risk of hospitalization and mortality in chronic heart failure [29,30], elevated levels of urinary KIM-1 did not predict mortality in ADHF [31]. Further studies are needed to elucidate the utility of KIM-1 in CRS1.

Treatment Approaches

Diuretics

Loop diuretics are the main treatment for decongestion of patients with CRS1. To date, no clinical trial has compared the different loop diuretics (furosemide, bumetanide, torsemide, or ethacrynic acid) to each other, so there is no clear choice of which loop diuretic is the best. However, dosing scheme was investigated in the Dose Optimization Strategies Evaluation (DOSE) trial. In this trial, 308 patients were randomized in a 1:1:1:1 design in which patients were placed in groups with low-dose (equivalent to oral dose) or high-dose (2.5 times oral dose) intermittent parental therapy or alternatively low-dose or high-dose continuous drip therapy. There were no differences in dyspnea, fluid changes, change in creatinine, hospital length stay, or rehospitalization and death rates when the intermittent and drip approaches were compared. However, the high-dose arm had decreased dyspnea, increased volume removal, but there were more occurrences of AKIs when compared to the low-dose arm [32].

In clinical practice, if loop diuretic treatment does not result in the desired urine output, a second-site diuretic may be added to potentiate diuresis. Unfortunately, there is little data on this common clinical practice and thus the optimal choice of second site agent (chlorthiazide or metolazone) is unknown. Frequently, the deciding factor is based upon cost or concern that oral absorption of metolazone will be ineffective. However, Moranville et al recently performed a retrospective assessment comparing chlorthiazide (22 patients) to metolazone (33 patients) in ADHF patients with renal dysfunction defined by a creatinine clearance of 15–50 mL/min. There was a nonsignificant trend towards increased urine output in the metolazone group, no differences in the rates of adverse events, and the chlorthiazide group actually had a longer hospital stay [33]. While potentially promising results, the retrospective nature of the study made it difficult to determine if the differences were due to treatment approach or dissimilarities of patient illness. Nonetheless, physicians must remain vigilant when implementing the second-site diuretic approach because it can lead to marked diuretic response leading to metabolic derangements including hypokalemia, hyponatremia, hypomagnesaemia, and metabolic alkalosis.

Inotropes

The use of inotropic agents such as dobutamine or milrinone can be used to augment cardiac function when there is a known low-output state for better renal perfusion in CRS1. Unfortunately, there is little objective data available about the utility of this widely implemented approach. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of a Chronic Heart Failure (OPTIME-HF) trial did not show improved renal function with milrinone treatment [34]. The use of levosimendan, a cardiac calcium sensitizer that increases contractility not currently approved in the United States, was compared to dobutamine in the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial, and there were no differences in rates of renal failure when the 2 groups were compared [35]. Nonetheless, if cardiac output is severely compromised, inotropes can be used for CRS1 treatment, but they should be used cautiously due the increased risks of lethal arrhythmias.

Dopamine

Use of low-dose dopamine to stimulate D1 and D2 receptors as a way to increase renal blood flow and promote increased glomerular filtration and urine production was extensively studied in ADHF. A small trial showed use of low dose dopamine had renal protective effects in a total of 20 patients [36]. However, when larger trials were conducted, such beneficial results were not consistently observed. The Dopamine in Acute Decompensated Heart Failure (DAD-HF I) trial compared low-dose furosemide plus low-dose dopamine (5 µg/kg/min) to high-dose furosemide alone in 60 patients. There were no differences in total diuresis, hospital stay, and 60-day mortality or rehospitalization rates, but there was a reduction in the renal dysfunction at the 24-hour time point in the dopamine-treated arm (6.7% versus 30%) [37]. The Dopamine in Acute Decompensated Heart Failure II trial randomized 161 ADHF patients to high-dose furosemide, low-dose furosemide and lose dose dopamine (5 µg/kg/min), or low-dose furosemide and assessed dyspnea, worsening renal function, length of stay, 60-day and one-year all-cause mortality and hospitalization for heart failure. Dopamine treatment did not improve any of the outcomes measured [38]. Finally, the most recent trial to examine the effects of dopamine was the Renal Optimization Strategies Evaluation (ROSE) trial. In this trial, there were 360 patients with ADHF randomized to nesiritide or dopamine versus placebo in a 2:1 design. When comparing dopamine (111 patients) treatment to placebo (115 patients), there were no differences in urine output, renal function as determined by cystatin C levels, or symptomatic improvements. However, there was more tachycardia in the dopamine group [39]. Currently, there is not strong evidence supporting routine use of dopamine in CRS1.

Nesiritide

Use of nesiritide, recombinant brain natriuretic peptide, was also investigated as a way to enhance urine production through the natriuretic effects of the peptide. The first attempt to explore this hypothesis was the B-Type Natriuretic Peptide in Cardiorenal Decompensation Syndrome (BNP-CARDS) trial. BNP-CARDS showed a 48-hour infusion of nesiritide (39 patients) or placebo (36 patients) in patients with ADHF and renal dysfunction (estimated GFR between 15–60 mL/min) did not reduce the incidence of worsening renal function as defined by a rise in serum creatinine by 20% [40]. A similar approach was implemented in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial which examined over 7000 patients with ADHF. 3496 patients were treated with nesiritide and 3511 patients were treated with placebo for 24 hours and up to 7 days. Nesiritide treatment did not alter dyspnea at 6 and 24 hours, improve renal function as determined by creatinine change, or alter the combined end-point of rehospitalization or death 30 at days [41]. The ROSE trial examined the effects of nesiritide (117 patients) versus placebo (115 patients) for urine production, change in renal function as defined by change in cystatin C, and decongestion (urinary sodium excretion, weight change, and change in NT-proBNP) at 72 hours. Nesiritide did not alter any of the outcomes investigated [39]. Finally, a single-centered study conducted at the Mayo Clinic examined the effects of nesiritide (37 patients) or placebo (35 patients) with ADHF and pre-existing renal dysfunction (estimated GFR between 20 and 60 mL/min). These investigators found nesiritide treatment resulted in less renal dysfunction as measured by creatinine and BUN, but no changes in diuretic responsiveness, duration of hospitalization, or rehospitalization rates. Nesiritide did reduce serum endothelin levels, but had no effect on ANP, NT-pro BNP, renin, angiotensin II, or aldosterone [42]. In summary, nesiritide does not appear to have significant renal protective effects in ADHF.

Adenosine A1 Receptor Antagonists

The use of adenosine receptor antagonists to prevent adenosine-mediated vasoconstriction of renal vasculature in ADHF has also been examined. The first study conducted was a small double-blind randomized-controlled trial that investigated the effects of rolofylline, an adenosine A-1 antagonist, in patients with ADHF and an estimated creatinine clearance of 20-80 mL/min. The study had 27 patients in the placebo arm, 29 patients that received 2.5 mg of rolofylline, 31 patients received 15 mg of rolofylline, 30 patients received 30 mg of rolofylline, and 29 patients received 60 mg of rolofylline, all of which was daily for up to 3 days. Rolofylline treatment increased urine output on day 1 and improved renal function on day 2 [43]. These positive results led to the Placebo-Controlled Randomized Study of Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Trial. PROTECT assessed the effects of rolofylline (1356) or placebo (677) in patients with ADHF and an estimated creatinine clearance between 20 and 80 mL/min. There were no significant differences in renal function out to 14 days, but rolofylline led to more weight loss than placebo [44,45]. In a subgroup analysis of patients with severe baseline renal dysfunction (creatinine clearance of less than 30 mL/min), rolofylline reduced the combined 60-day end-point of hospitalization due to cardiovascular or renal cause and death [45]. Finally, the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (REACH-UP) trial probed the effects of rolofylline (36 patients) or placebo (40 patients) in patients with ADHF and renal impairment (creatinine clearance of 20-60 mL/min). Rolofylline treatment did not alter renal function, but there was a nonsignificant trend towards reduction in 60-day combined end-point of hospitalization due to renal or cardiovascular causes or death [46]. In summary, the use of rolofylline has not been conclusively associated with improved outcomes in CRS1.

Vasopressin Antagonists

The use of vasopressin antagonists to induce aquaphoresis and combat hyponatremia was studied in ADHF. Vasopressin antagonists were first investigated in the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist (ACTIV) trial. ACTIV involved 3 doses of tolvaptan (78 patients received 30 mg, 84 patients received 60 mg, and 77 patients received 90 mg) versus placebo (80 patients), and tolvaptan increased urine production and decreased body weight compared to placebo without compromising renal function. A post-hoc analysis of patients with renal dysfunction (BUN > 29 mg/dL) and severe volume overload revealed a survival benefit at 60 days [47]. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVERST) trial compared placebo (2061 patients) versus 30 mg/day of tolvaptan (2072 patients) within 48 hours after admission in an identical 2-trial design. Tolvaptan increased weight loss and reduced dyspnea acutely but did not alter all-cause mortality or cardiovascular or heart failure hospitalization rates out to 24 months post index hospitalization [48,49]. These data suggest vasopressin antagonists may potentiate diuresis acutely but likely do not improve long-term outcomes.

Corticosteroids

The use of corticosteroids in ADHF has been controversial as there were initial concerns that corticosteroids would increase fluid retention. However, corticosteroids augmented diuretic response and improved renal function in 13 ADHF patients who had inadequate response to sequential nephron blockage [50]. Furthermore, Zhang et al showed that prednisone treatment in 35 patients admitted with ADHF increased urinary volume, reduced dyspnea, reduced uric acid, and improved renal function [51]. These promising results led to the Cardiac Outcome Prevention Effectiveness of Glucocorticoids in Acute Decompensated Heart Failure (COPE-ADHF) trial. In this single-centered study, 102 patients with ADHF were randomized to either placebo [51] or corticosteroids [51] and the outcomes recorded included urinary volume, change in creatinine, and cardiovascular death at 30 days. Use of corticosteroids improved renal function, increased urine output, and reduced mortality (3/51 in corticosteroid group versus 10/51 in the placebo group) [52]. The mechanisms underlying the improvements with corticosteroids were not determined, but were hypothesized to be facilitation of natriuretic peptides or dilation of renal vasculature through activation of nitric oxide pathway or dopaminergic system.

Serelaxin

Serelaxin is a recombinantly expressed human relaxin-2, a peptide hormone present during pregnancy which facilitates physiological cardiovascular and renal adaptations [53–55], which showed potential benefits in CRS1. Analysis of the RELAX-AHF trial revealed serelaxin reduced incidence of worsening renal function at day 2 of treatment as defined by changes in serum creatinine, cystatin C, and BUN. Importantly, worsening renal function defined by cystatin C changes was associated with increased 180-day mortality in this analysis [56]. The mechanisms by which serelaxin prevented renal dysfunction are currently unknown as serelaxin treatment did not improve diuretic efficiency [19].

Ultrafiltration

Another treatment choice in CRS1 is mechanical removal of salt and water via ultrafiltration. Ultrafiltration showed early promise in Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure trial (UNLOAD) trial. In this study, 200 patients with ADHF were randomized to either ultrafiltration or medical management with loop diuretics. Use of ultrafiltration increased volume removal without any differences in renal function and reduced rehospitalization rates at 90 days [57].

However, when ultrafiltration was employed specifically in CRS1 patients in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure trial (CARESS-HF), UF was not superior to medical treatment. There were 188 patients studied in CARESS-HF, and in the ultrafiltration arm there was increased risk of renal dysfunction, no differences in volume removal, and no change in rehospitalization rates at 90 days [58]. When trying to reconcile UNLOAD and CARESS-HF, the medical treatment arm in CARESS-HF was much more standardized and aggressive and UNLOAD was earlier implementation of ultrafiltration, which may have explained the differences. Interestingly, ultrafiltration was hypothesized to be advantageous over diuretic therapy through reduced activation of the renin-angiotensin-aldosterone system, but analysis of the patients from CARESS-HF showed higher levels of plasma renin activity and no difference in aldosterone levels in ultrafiltration patients [59].

Two meta-analyses have examined the use of ultrafiltration versus medical management in ADHF and both showed ultrafiltration was more effective in volume removal than medical therapy but did not improve rehospitalization or mortality rates [60,61]. This fact combined with the risks of vascular access placement and bleeding from anticoagulation limits to routine use of ultrafiltration in CRS1.

Continuous Renal Replacement Therapy

Once renal function deteriorates to the point that renal replacement therapy is needed for both volume removal and solute clearance in CRS1, continuous renal replacement therapy (CRRT) may be implemented. Unfortunately, there are few available data for this group of advanced CRS1 patients to guide physicians. There was a single-centered study conducted in Egypt that randomized 40 ADHF patients to either IV furosemide or CRRT. The patients treated with CRRT had greater weight loss and decreased length of stay in the ICU, but there were no differences in dialysis dependence rates or 30-day mortality [62]. Two single-centered studies reported outcomes associated with advanced CRS1 requiring CRRT. In a study conducted at the Cleveland Clinic, 63 patients with CRS1 were treated with ultrafiltration, of which 37 were converted to CRRT due to worsening renal function. Of the 37 patients treated with CRRT, 16 died in the hospital and 4 were discharged with hospice care [63]. In another retrospective study performed at the University of Alabama-Birmingham, use of rescue CRRT in advanced CRS1 was examined in 37 patients. 23 patients died during hospitalization and 2 were discharged to hospice care [64]. Combination of the Cleveland Clinic and University of Alabama-Birmingham studies revealed patients requiring CRRT in the setting of advanced CRS1 had an in-hospital mortality or palliative discharge rate of 60.8% (45/74). Clearly, this population needs further investigation to prevent such poor outcomes.

A summary of treatment approaches for CRS1 is presented in Table 3.

Future Treatment Options

Ongoing and Unreported Clinical Trials

Unfortunately, none of the current treatments for CRS1 have definitive improvements in outcomes, but there are several ongoing clinical trials which will hopefully identify novel treatment strategies. First of all, the Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure (Diuresis-CHF) trial is being conducted in Belgium. This study will examine the effects of acetazolamide with low dose diuretic versus high dose diuretics in one aim and the effects of upfront spironolactone in another. The outcomes analyzed will include total natriuresis, potassium homeostasis, NT-proBNP changes, change in renal function, peak serum levels of renin and aldosterone, weight change, urine volume, and change in edema (NCT01973335). The Protocolized Diuretic Strategy in Cardiorenal Failure (ProDius) trial is being performed at the University of Pittsburgh, and will determine the effects of a protocolized diuretic approach to target 3-5 liters of urine production a day versus standard therapy and will track the change in body weight, length of hospitalization, reshospitalization rates, mortality rates, venous compliance of internal jugular vein, clinical decongestion, change in renal function, and urine output (NCT01921829). The Levosimendan versus Dobutamine for Renal Function in Heart Failure (ELDOR) study is ongoing in Sweden and will probe the acute effects of levosimendan and dobutamine on renal perfusion. The endpoints will include changes in renal blood flow, GFR, renal vascular resistance, central hemodynamics, renal oxygen extraction and consumptions, and filtration fraction (NCT02133105). Finally, the Safety and Efficacy of Low Dose Hypertonic Saline and High Dose Furosemide for Congestive Heart Failure (REaCH) trial probed the effects of combination of hypertonic saline and furosemide versus furosemide in patients with ADHF and renal impairment defined by a GFR<60 mL/min. The outcomes were change in renal function, diuretic response, length of hospital stay, readmission rates, weight loss, BNP levels, and included a cost analysis. The study was completed but results are not currently available (NCT01028170)

Should Inflammation Be Targeted in CRS1?

Although proposed to play a role in the pathophysiology of CRS1, inflammation has not been explicitly targeted as a treatment for CRS1. One possible way to combat inflammation could be inhibition of the IL-6 pathway, which is support by preclinical work as previous studies showed IL-6 knockout mice were resistant to HgCl2-induced renal injury and death [65] and IL-6 has negative inotropic effects in both isolated cardiomyocytes [66] and intact animals [67]. Thus, IL-6 antagonism may improve both cardiac and renal function, an ideal scenario for CRS1 patients. The availability of tocilizumab, an FDA-approved humanized antibody to the IL-6 receptor, may allow for investigation of this hypothesis in the future. Although not examined in the COPE-ADHF trial, an alternative explanation for the improvements associated with corticosteroids treatment were the anti-inflammatory effects. If this were true, corticosteroids would represent a relatively cheap treatment option for CRS1 patients, but more studies need to be conducted before this approach is widely implemented. Finally, use of cytokine profiling may be used to enrich a population of CRS1 patients that could be investigated in future clinical trials using anti-inflammatory medications.

Unanswered Questions Moving Forward

Severity of AKI and Treatment Effects

An important unknown that warrants further investigation is if the severity of AKI should dictate treatment choice in CRS1. As discussed above, increasing severity of AKI resulted in elevated risk of adverse events, but it remains unknown whether different treatments offer benefits for more or less severe renal impairment. Perhaps, future studies aimed at defining outcomes from different treatment strategies stratified by severity of renal dysfunction may reveal which patients benefit from the various treatment options for CRS1.

How Do We Best Define Renal Dysfunction in CRS1?

Currently, there is no accepted definition of renal dysfunction in CRS1. As discussed above, using the AKIN, KDIGO, or RIFLE scoring systems or diuretic responsiveness effectively differentiated outcomes in patients with CRS1. However, an agreed-upon definition would likely benefit the field going forward so this population could be systematically investigated in future studies.

Conclusion

In summary, CRS1 is a common clinical entity associated with poor patient outcomes. A complex pathophysiology marked by reduced cardiac output, increased central venous pressure, inflammation, and oxidative stress underlies the disease process. Unfortunately, no current treatment approach shows consistent improvements in outcomes, highlighting the urgent need for further research to reduce the burden that CRS1 imposes.

 

Corresponding author: Kurt W. Prins, MD, PhD, MMC 580 Mayo, 420 Delaware St SE, Minneapolis, MN 55455, [email protected].

Funding/support: Dr. Prins is funded by NIH F32 grant HL129554 and Dr. Thenappen is funded by AHA Scientist Development Grant 15SDG25560048.

From the Cardiovascular Division, Department of Internal Medicine, University of Minnesota, Minneapolis, MN.

 

Abstract

  • Objective: To present a review of cardiorenal syndrome type 1 (CRS1).
  • Methods: Review of the literature.
  • Results: Acute kidney injury occurs in approximately one-third of patients with acute decompensated heart failure (ADHF) and the resultant condition was named CRS1. A growing body of literature shows CRS1 patients are at high risk for poor outcomes, and thus there is an urgent need to understand the pathophysiology and subsequently develop effective treatments. In this review we discuss prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, and ongoing clinical trials and highlight questions and problems physicians will face moving forward with this common and challenging condition.
  • Conclusion: Further research is needed to understand the pathophysiology of this complex clinical entity and to develop effective treatments.

 

Acute decompensated heart failure (ADHF) is an epidemic facing physicians throughout the world. In the United States alone, ADHF accounts for over 1 million hospitalizations annually, with costs in 2012 reaching $30.7 billion [1]. Despite the advances in chronic heart failure management, ADHF continues to be associated with poor outcomes as exemplified by 30-day readmission rates of over 20% and in-hospital mortality rates of 5% to 6%, both of which have not significantly improved over the past 20 years [2,3]. One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction. An analysis from the Acute Decompensated Heart Failure National Registry (ADHERE) revealed the combination of renal dysfunction (creatinine > 2.75 mg/dL and blood urea nitrogen (BUN) > 43 mg/dL) and hypotension (systolic blood pressure (SBP) < 115 mm Hg) upon admission was associated with an in-hospital mortality of > 20% [4]. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry documented a 16.3% in-hospital mortality when patients had a SBP < 100 mm Hg and creatinine > 2.0 mg/dL at admission [5].

The presence of acute kidney injury in the setting of ADHF is a very common occurrence and was termed cardiorenal syndrome type 1 (CRS1) [6]. The prevalence of CRS1 in single-centered studies ranged from 32% to 40% of all ADHF admissions [7,8]. If this estimate holds true throughout the United States, there would be 320,000 to 400,000 hospitalizations for CRS1 annually, highlighting the magnitude of this problem. Moreover, with the number of patients with heart failure expected to continue to rise, CRS1 will only become more prevalent in the future. In this review we discuss the prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, ongoing clinical trials, and highlight questions and problems physicians will face moving forward in this common and challenging condition.

Pathogenesis of CRS1

Hemodynamic Effects

The early hypothesis for renal dysfunction in ADHF centered on hemodynamics, as reduced cardiac output was believed to decrease renal perfusion. However, analysis of invasive hemodynamics from patients with ADHF suggested that central venous pressure (CVP) was actually a better predictor of the development of CRS1 than cardiac output. In a single-center study conducted at the Cleveland Clinic, hemodynamics from 145 patients with ADHF were evaluated and surprisingly baseline cardiac index was greater in the patients with CRS1 than patients without renal dysfunction (2.0 ± 0.8 L/min/m2 vs 1.8 ± 0.4 L/min/m2= 0.008). However, baseline CVP was higher in the CRS1 group (18 ± 7 mm Hg vs 12 ± 6 mm Hg; = 0.001), and there was a heightened risk of developing CRS1 as CVP increased. In fact, 75% of the patients with a CVP of > 24 mm Hg developed renal impairment [9]. In a retrospective study of the Evaluation Study of Congestive Heart Failure and Pulmonary Arterial Catheter Effectiveness (ESCAPE) trial, the only hemodynamic parameter that correlated with baseline creatinine was CVP. However, no invasive measures predicted worsening renal function during hospitalization [10]. Finally, an experiment that used isolated canine kidneys showed increased venous pressure acutely reduced urine production. Interestingly, this relationship was dependent on arterial pressure; as arterial flow decreased smaller increases in CVP were needed to reduce urine output [11]. Together, these data suggest increased CVP plays an important role in CRS1, but imply hemodynamics alone may not fully explain the pathophysiology of CRS1.

Inflammation

As information about how hemodynamics incompletely predict renal dysfunction in ADHF became available, alternative hypotheses were investigated to gain a deeper understanding of the pathophysiology underlying CRS1. A pathological role of inflammation in CRS1 has gained attention due to recent publications. First of all, serum levels of the pro-inflammatory cytokines TNF-a and IL-6 were elevated in patients with CRS1 when compared to health controls [12]. Interestingly, Virzi et al showed that the median value of IL-6 was 5 times higher in CRS1 patients when compared to ADHF patients without renal dysfunction [13]. The negative consequences of elevated serum cytokines were demonstrated when incubation of a human cell line of monocytes with serum from CRS1 patients induced apoptosis in 81% of cells compared to just 11% of cells with control serum [12]. It is possible that cytokine-induced apoptosis could occur in other cell types in different organs in patients with CRS1, which may contribute to both cardiac and renal dysfunction. Finally, analysis from a rat model of CRS1 revealed macrophage infiltration into the kidneys and increased numbers of activated monocytes in the peripheral blood. Interestingly, monocyte/macrophage depletion using liposome clodronate prevented chronic renal dysfunction in the rat model [14]. In summary, these data suggest inflammation contributes to CRS1 pathophysiology, but more experimental data is needed to determine if there is a causal relationship.

Oxidative Stress

Very recently, oxidative stress was proposed to play a role in CRS1. Virzi et al analyzed serum levels of markers of oxidative stress and compared ADHF patients without renal impairment to CRS1 patients. The markers of oxidative stress, which included myeloperoxidase, nitric oxide, copper/zinc superoxide dismutase, and endogenous peroxidase, were all significantly higher in CRS1 patients [13]. While provocative, the tissues responsible for the generation of these molecules and the subsequent effects have not yet been fully elucidated.

The proposed pathophysiology is seen in the Figure.

Prognostication

Severity of Acute Kidney Injury

Initial publications did not document a strong link between kidney injury and poor outcomes in ADHF. Firstly, Ather et al performed a single-centered study that investigated how change in renal function defined by change in creatinine, estimated GFR, and BUN affected outcomes one year post admission for ADHF. Kidney injury defined by a change in creatinine or in estimated GFR was not associated with increased risk of mortality, but a change in BUN was associated with increased mortality in a univariate analysis [15]. Testani et al retrospectively analyzed patients from the ESCAPE trial and found worsening renal function defined by a ≥ 20% reduction in estimated GFR was not significantly associated with 180-day mortality, but there was a trend towards higher mortality (hazard ration 1.4; = 0.11) [16]. Importantly, neither of 2 these studies assessed how severity of AKI impacted outcomes, which may have contributed to the weak relationships observed.

However, when AKI severity in CRS1 was quantified, poor outcomes were more likely as AKI severity increased. Firstly, Roy et al determined how AKI impacted adverse events (mortality, rehospitalization, or need for dialysis) rates in 637 patients with ADHF. Severity of AKI was quantified using RIFLE, AKIN, and KDIGO guidelines (Table 1), and the authors found that as the severity of renal injury increased, the likelihood of an adverse event was higher. In fact, the most severe AKI grade using all 3 AKI grading systems resulted in an odds ratio ranging from 45.3 to 101.6 for an adverse event at 30 days when compared to no kidney injury [7]. Hata et al documented that AKI (defined using RIFLE criteria) in ADHF resulted in a longer ICU stay, total hospital length of stay, and higher in-hospital mortality rates, and patients with a failure-grade AKI had in-hospital mortality rate of 49.1% [17]. Finally, Li et al evaluated AKI in 1005 patients with ADHF and showed that AKI defined by RIFLE, AKIN, or KDIGO methods increased risk of in-hospital mortality, and that a KDIGO grade 3 AKI was associated with a 35.5% in-hospital mortality rate [8]. These data indicate CRS1 is associated with poor outcomes, and there is a heightened risk of adverse events as AKI severity increases.

Diuretic Responsiveness

Using change in serum creatinine as a marker of renal impairment may not be the best choice for predicting outcomes in CRS1 because the lab values are not a real-time measure of kidney function and serum creatinine can be affected by both body mass and pharmaceutical agents. Therefore, the prognosticating ability of urine production relative to diuretic dose as a surrogate measure of renal function in ADHF was investigated by several groups (Table 2). Testani et al examined urine output per 40 mg of furosemide and tracked outcomes in 2 cohorts: patients admitted with ADHF at the University of Pennsylvania (657 patients) and patients from the ESCAPE trial (390 patients). Patients were split into high responders or low responders based on the median value. In both of the patient cohorts, low diuretic efficiency was associated with increased mortality using a multivariate model (hazard ratio of 1.36 in the Penn patients and 2.86 in the ESCAPE patients). The combination of low diuretic efficiency and high diuretic dose (> 280 mg in the Penn cohort and > 240 mg in the ESCAPE cohort) resulted in the worst prognosis, with mortality rates of approximately 70% at 6 years in the Penn cohort and approximately 35% at 180 days in the ESCAPE cohort [18].

Voors et al performed a retrospective analysis of diuretic responsiveness in 1161 patients from the Relaxin in Acute Heart Failure (RELAX-AHF) trial. Diuretic responsiveness was defined as weight change (kg) per diuretic dose (IV furosemide and PO furosemide) over 5 days and then patients were separated into tertiles. The lowest tertile group had an approximate 20% incidence of 60-day combined end-point of death, heart failure or renal failure readmission compared to less than 10% incidence in the middle and upper tertiles. Interestingly, when the effects of worsening renal function (WRF), defined as creatinine change of ≥ 0.3 mg/dL, were examined in patients stratified by diuretic response, WRF did not offer additional prognostic information [19].

Finally, Valenete et al analyzed diuretic response in 1745 patients from the PROTECT trial (Placebo-Controlled Randomized Study of the Selective A1-Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Diuretic response was calculated using the weight change per 40 mg of furosemide, and as diuretic response declined there was increasing risk of 60-day rehospitalization and 180-day mortality rates. In fact, the lowest quintile responders had a 25% mortality rate at 180 days [20].

Emerging Biomarkers

Urine Neutrophil Gelatinase-Associated Lipocalin

Because previous studies showed urinary levels of NGAL was an earlier and more reliable marker of renal dysfunction than creatinine in AKI [21], it was studied as a possible biomarker for the development of CRS1 in ADHF. A single-centered study quantified levels of urine NGAL in 100 patients admitted with heart failure and then tracked the rates of acute kidney injury. Urine NGAL was elevated in patients that developed AKI and a cut-off value 12 ng/mL had a sensitivity of 79% and specificity of 67% for predicting CRS1 [22]. While promising, further studies are needed to better define the role of NGAL in CRS1.

Cystatin C

Cystatin C is a ubiquitously expressed cysteine protease that has a constant production rate and is freely filtered by the glomerulus without being secreted into the tubules, and has effectively prognosticated outcomes in ADHF [23]. Lassus et al showed an adjusted hazard ratio of 3.2 (2.0–5.3) for 12-month mortality when cystatin C levels were elevated. Moreover, patients with the highest tertitle of NT-proBNP and cystatin C had a 48.7% 1-year mortality. Interestingly, patients with an elevated cystatin C but normal creatinine had a 40.6% 1-year mortality compared to 12.6% for those with normal cystatin C and creatinine [24]. Furthermore, Arimoto et al showed elevated cystatin C predicted death or rehospitalization in a small cohort of ADHF patients in Japan [25]. Also, Naruse et al showed cystatin C was a better predictor of cardiac death than estimated GFR by the Modification of Diet in Renal Disease Study (MDRD) equation [26]. Finally, Manzano-Fernandez et al showed the highest tertile of cystatin C was a significant independent risk factor for 2-year death or rehospitalization while creatinine and MDRD estimates of GFR were not [27]. In agreement with Lassus et al, elevations in either 2 or 3 of cystatin C, troponin, and NT-proBNP predicted death or rehospitalization when compared to those with normal levels of these 3 markers [27]. In conclusion, cystatin C either alone or in combination with other biomarkers identifies high-risk patients.

Kidney Injury Molecule 1

Kidney injury molecule 1 (KIM-1) is a type-1 cell membrane glycoprotein expressed in regenerating proximal tubular cells but not under normal conditions [28]. Although associated with increased risk of hospitalization and mortality in chronic heart failure [29,30], elevated levels of urinary KIM-1 did not predict mortality in ADHF [31]. Further studies are needed to elucidate the utility of KIM-1 in CRS1.

Treatment Approaches

Diuretics

Loop diuretics are the main treatment for decongestion of patients with CRS1. To date, no clinical trial has compared the different loop diuretics (furosemide, bumetanide, torsemide, or ethacrynic acid) to each other, so there is no clear choice of which loop diuretic is the best. However, dosing scheme was investigated in the Dose Optimization Strategies Evaluation (DOSE) trial. In this trial, 308 patients were randomized in a 1:1:1:1 design in which patients were placed in groups with low-dose (equivalent to oral dose) or high-dose (2.5 times oral dose) intermittent parental therapy or alternatively low-dose or high-dose continuous drip therapy. There were no differences in dyspnea, fluid changes, change in creatinine, hospital length stay, or rehospitalization and death rates when the intermittent and drip approaches were compared. However, the high-dose arm had decreased dyspnea, increased volume removal, but there were more occurrences of AKIs when compared to the low-dose arm [32].

In clinical practice, if loop diuretic treatment does not result in the desired urine output, a second-site diuretic may be added to potentiate diuresis. Unfortunately, there is little data on this common clinical practice and thus the optimal choice of second site agent (chlorthiazide or metolazone) is unknown. Frequently, the deciding factor is based upon cost or concern that oral absorption of metolazone will be ineffective. However, Moranville et al recently performed a retrospective assessment comparing chlorthiazide (22 patients) to metolazone (33 patients) in ADHF patients with renal dysfunction defined by a creatinine clearance of 15–50 mL/min. There was a nonsignificant trend towards increased urine output in the metolazone group, no differences in the rates of adverse events, and the chlorthiazide group actually had a longer hospital stay [33]. While potentially promising results, the retrospective nature of the study made it difficult to determine if the differences were due to treatment approach or dissimilarities of patient illness. Nonetheless, physicians must remain vigilant when implementing the second-site diuretic approach because it can lead to marked diuretic response leading to metabolic derangements including hypokalemia, hyponatremia, hypomagnesaemia, and metabolic alkalosis.

Inotropes

The use of inotropic agents such as dobutamine or milrinone can be used to augment cardiac function when there is a known low-output state for better renal perfusion in CRS1. Unfortunately, there is little objective data available about the utility of this widely implemented approach. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of a Chronic Heart Failure (OPTIME-HF) trial did not show improved renal function with milrinone treatment [34]. The use of levosimendan, a cardiac calcium sensitizer that increases contractility not currently approved in the United States, was compared to dobutamine in the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial, and there were no differences in rates of renal failure when the 2 groups were compared [35]. Nonetheless, if cardiac output is severely compromised, inotropes can be used for CRS1 treatment, but they should be used cautiously due the increased risks of lethal arrhythmias.

Dopamine

Use of low-dose dopamine to stimulate D1 and D2 receptors as a way to increase renal blood flow and promote increased glomerular filtration and urine production was extensively studied in ADHF. A small trial showed use of low dose dopamine had renal protective effects in a total of 20 patients [36]. However, when larger trials were conducted, such beneficial results were not consistently observed. The Dopamine in Acute Decompensated Heart Failure (DAD-HF I) trial compared low-dose furosemide plus low-dose dopamine (5 µg/kg/min) to high-dose furosemide alone in 60 patients. There were no differences in total diuresis, hospital stay, and 60-day mortality or rehospitalization rates, but there was a reduction in the renal dysfunction at the 24-hour time point in the dopamine-treated arm (6.7% versus 30%) [37]. The Dopamine in Acute Decompensated Heart Failure II trial randomized 161 ADHF patients to high-dose furosemide, low-dose furosemide and lose dose dopamine (5 µg/kg/min), or low-dose furosemide and assessed dyspnea, worsening renal function, length of stay, 60-day and one-year all-cause mortality and hospitalization for heart failure. Dopamine treatment did not improve any of the outcomes measured [38]. Finally, the most recent trial to examine the effects of dopamine was the Renal Optimization Strategies Evaluation (ROSE) trial. In this trial, there were 360 patients with ADHF randomized to nesiritide or dopamine versus placebo in a 2:1 design. When comparing dopamine (111 patients) treatment to placebo (115 patients), there were no differences in urine output, renal function as determined by cystatin C levels, or symptomatic improvements. However, there was more tachycardia in the dopamine group [39]. Currently, there is not strong evidence supporting routine use of dopamine in CRS1.

Nesiritide

Use of nesiritide, recombinant brain natriuretic peptide, was also investigated as a way to enhance urine production through the natriuretic effects of the peptide. The first attempt to explore this hypothesis was the B-Type Natriuretic Peptide in Cardiorenal Decompensation Syndrome (BNP-CARDS) trial. BNP-CARDS showed a 48-hour infusion of nesiritide (39 patients) or placebo (36 patients) in patients with ADHF and renal dysfunction (estimated GFR between 15–60 mL/min) did not reduce the incidence of worsening renal function as defined by a rise in serum creatinine by 20% [40]. A similar approach was implemented in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial which examined over 7000 patients with ADHF. 3496 patients were treated with nesiritide and 3511 patients were treated with placebo for 24 hours and up to 7 days. Nesiritide treatment did not alter dyspnea at 6 and 24 hours, improve renal function as determined by creatinine change, or alter the combined end-point of rehospitalization or death 30 at days [41]. The ROSE trial examined the effects of nesiritide (117 patients) versus placebo (115 patients) for urine production, change in renal function as defined by change in cystatin C, and decongestion (urinary sodium excretion, weight change, and change in NT-proBNP) at 72 hours. Nesiritide did not alter any of the outcomes investigated [39]. Finally, a single-centered study conducted at the Mayo Clinic examined the effects of nesiritide (37 patients) or placebo (35 patients) with ADHF and pre-existing renal dysfunction (estimated GFR between 20 and 60 mL/min). These investigators found nesiritide treatment resulted in less renal dysfunction as measured by creatinine and BUN, but no changes in diuretic responsiveness, duration of hospitalization, or rehospitalization rates. Nesiritide did reduce serum endothelin levels, but had no effect on ANP, NT-pro BNP, renin, angiotensin II, or aldosterone [42]. In summary, nesiritide does not appear to have significant renal protective effects in ADHF.

Adenosine A1 Receptor Antagonists

The use of adenosine receptor antagonists to prevent adenosine-mediated vasoconstriction of renal vasculature in ADHF has also been examined. The first study conducted was a small double-blind randomized-controlled trial that investigated the effects of rolofylline, an adenosine A-1 antagonist, in patients with ADHF and an estimated creatinine clearance of 20-80 mL/min. The study had 27 patients in the placebo arm, 29 patients that received 2.5 mg of rolofylline, 31 patients received 15 mg of rolofylline, 30 patients received 30 mg of rolofylline, and 29 patients received 60 mg of rolofylline, all of which was daily for up to 3 days. Rolofylline treatment increased urine output on day 1 and improved renal function on day 2 [43]. These positive results led to the Placebo-Controlled Randomized Study of Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Trial. PROTECT assessed the effects of rolofylline (1356) or placebo (677) in patients with ADHF and an estimated creatinine clearance between 20 and 80 mL/min. There were no significant differences in renal function out to 14 days, but rolofylline led to more weight loss than placebo [44,45]. In a subgroup analysis of patients with severe baseline renal dysfunction (creatinine clearance of less than 30 mL/min), rolofylline reduced the combined 60-day end-point of hospitalization due to cardiovascular or renal cause and death [45]. Finally, the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (REACH-UP) trial probed the effects of rolofylline (36 patients) or placebo (40 patients) in patients with ADHF and renal impairment (creatinine clearance of 20-60 mL/min). Rolofylline treatment did not alter renal function, but there was a nonsignificant trend towards reduction in 60-day combined end-point of hospitalization due to renal or cardiovascular causes or death [46]. In summary, the use of rolofylline has not been conclusively associated with improved outcomes in CRS1.

Vasopressin Antagonists

The use of vasopressin antagonists to induce aquaphoresis and combat hyponatremia was studied in ADHF. Vasopressin antagonists were first investigated in the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist (ACTIV) trial. ACTIV involved 3 doses of tolvaptan (78 patients received 30 mg, 84 patients received 60 mg, and 77 patients received 90 mg) versus placebo (80 patients), and tolvaptan increased urine production and decreased body weight compared to placebo without compromising renal function. A post-hoc analysis of patients with renal dysfunction (BUN > 29 mg/dL) and severe volume overload revealed a survival benefit at 60 days [47]. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVERST) trial compared placebo (2061 patients) versus 30 mg/day of tolvaptan (2072 patients) within 48 hours after admission in an identical 2-trial design. Tolvaptan increased weight loss and reduced dyspnea acutely but did not alter all-cause mortality or cardiovascular or heart failure hospitalization rates out to 24 months post index hospitalization [48,49]. These data suggest vasopressin antagonists may potentiate diuresis acutely but likely do not improve long-term outcomes.

Corticosteroids

The use of corticosteroids in ADHF has been controversial as there were initial concerns that corticosteroids would increase fluid retention. However, corticosteroids augmented diuretic response and improved renal function in 13 ADHF patients who had inadequate response to sequential nephron blockage [50]. Furthermore, Zhang et al showed that prednisone treatment in 35 patients admitted with ADHF increased urinary volume, reduced dyspnea, reduced uric acid, and improved renal function [51]. These promising results led to the Cardiac Outcome Prevention Effectiveness of Glucocorticoids in Acute Decompensated Heart Failure (COPE-ADHF) trial. In this single-centered study, 102 patients with ADHF were randomized to either placebo [51] or corticosteroids [51] and the outcomes recorded included urinary volume, change in creatinine, and cardiovascular death at 30 days. Use of corticosteroids improved renal function, increased urine output, and reduced mortality (3/51 in corticosteroid group versus 10/51 in the placebo group) [52]. The mechanisms underlying the improvements with corticosteroids were not determined, but were hypothesized to be facilitation of natriuretic peptides or dilation of renal vasculature through activation of nitric oxide pathway or dopaminergic system.

Serelaxin

Serelaxin is a recombinantly expressed human relaxin-2, a peptide hormone present during pregnancy which facilitates physiological cardiovascular and renal adaptations [53–55], which showed potential benefits in CRS1. Analysis of the RELAX-AHF trial revealed serelaxin reduced incidence of worsening renal function at day 2 of treatment as defined by changes in serum creatinine, cystatin C, and BUN. Importantly, worsening renal function defined by cystatin C changes was associated with increased 180-day mortality in this analysis [56]. The mechanisms by which serelaxin prevented renal dysfunction are currently unknown as serelaxin treatment did not improve diuretic efficiency [19].

Ultrafiltration

Another treatment choice in CRS1 is mechanical removal of salt and water via ultrafiltration. Ultrafiltration showed early promise in Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure trial (UNLOAD) trial. In this study, 200 patients with ADHF were randomized to either ultrafiltration or medical management with loop diuretics. Use of ultrafiltration increased volume removal without any differences in renal function and reduced rehospitalization rates at 90 days [57].

However, when ultrafiltration was employed specifically in CRS1 patients in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure trial (CARESS-HF), UF was not superior to medical treatment. There were 188 patients studied in CARESS-HF, and in the ultrafiltration arm there was increased risk of renal dysfunction, no differences in volume removal, and no change in rehospitalization rates at 90 days [58]. When trying to reconcile UNLOAD and CARESS-HF, the medical treatment arm in CARESS-HF was much more standardized and aggressive and UNLOAD was earlier implementation of ultrafiltration, which may have explained the differences. Interestingly, ultrafiltration was hypothesized to be advantageous over diuretic therapy through reduced activation of the renin-angiotensin-aldosterone system, but analysis of the patients from CARESS-HF showed higher levels of plasma renin activity and no difference in aldosterone levels in ultrafiltration patients [59].

Two meta-analyses have examined the use of ultrafiltration versus medical management in ADHF and both showed ultrafiltration was more effective in volume removal than medical therapy but did not improve rehospitalization or mortality rates [60,61]. This fact combined with the risks of vascular access placement and bleeding from anticoagulation limits to routine use of ultrafiltration in CRS1.

Continuous Renal Replacement Therapy

Once renal function deteriorates to the point that renal replacement therapy is needed for both volume removal and solute clearance in CRS1, continuous renal replacement therapy (CRRT) may be implemented. Unfortunately, there are few available data for this group of advanced CRS1 patients to guide physicians. There was a single-centered study conducted in Egypt that randomized 40 ADHF patients to either IV furosemide or CRRT. The patients treated with CRRT had greater weight loss and decreased length of stay in the ICU, but there were no differences in dialysis dependence rates or 30-day mortality [62]. Two single-centered studies reported outcomes associated with advanced CRS1 requiring CRRT. In a study conducted at the Cleveland Clinic, 63 patients with CRS1 were treated with ultrafiltration, of which 37 were converted to CRRT due to worsening renal function. Of the 37 patients treated with CRRT, 16 died in the hospital and 4 were discharged with hospice care [63]. In another retrospective study performed at the University of Alabama-Birmingham, use of rescue CRRT in advanced CRS1 was examined in 37 patients. 23 patients died during hospitalization and 2 were discharged to hospice care [64]. Combination of the Cleveland Clinic and University of Alabama-Birmingham studies revealed patients requiring CRRT in the setting of advanced CRS1 had an in-hospital mortality or palliative discharge rate of 60.8% (45/74). Clearly, this population needs further investigation to prevent such poor outcomes.

A summary of treatment approaches for CRS1 is presented in Table 3.

Future Treatment Options

Ongoing and Unreported Clinical Trials

Unfortunately, none of the current treatments for CRS1 have definitive improvements in outcomes, but there are several ongoing clinical trials which will hopefully identify novel treatment strategies. First of all, the Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure (Diuresis-CHF) trial is being conducted in Belgium. This study will examine the effects of acetazolamide with low dose diuretic versus high dose diuretics in one aim and the effects of upfront spironolactone in another. The outcomes analyzed will include total natriuresis, potassium homeostasis, NT-proBNP changes, change in renal function, peak serum levels of renin and aldosterone, weight change, urine volume, and change in edema (NCT01973335). The Protocolized Diuretic Strategy in Cardiorenal Failure (ProDius) trial is being performed at the University of Pittsburgh, and will determine the effects of a protocolized diuretic approach to target 3-5 liters of urine production a day versus standard therapy and will track the change in body weight, length of hospitalization, reshospitalization rates, mortality rates, venous compliance of internal jugular vein, clinical decongestion, change in renal function, and urine output (NCT01921829). The Levosimendan versus Dobutamine for Renal Function in Heart Failure (ELDOR) study is ongoing in Sweden and will probe the acute effects of levosimendan and dobutamine on renal perfusion. The endpoints will include changes in renal blood flow, GFR, renal vascular resistance, central hemodynamics, renal oxygen extraction and consumptions, and filtration fraction (NCT02133105). Finally, the Safety and Efficacy of Low Dose Hypertonic Saline and High Dose Furosemide for Congestive Heart Failure (REaCH) trial probed the effects of combination of hypertonic saline and furosemide versus furosemide in patients with ADHF and renal impairment defined by a GFR<60 mL/min. The outcomes were change in renal function, diuretic response, length of hospital stay, readmission rates, weight loss, BNP levels, and included a cost analysis. The study was completed but results are not currently available (NCT01028170)

Should Inflammation Be Targeted in CRS1?

Although proposed to play a role in the pathophysiology of CRS1, inflammation has not been explicitly targeted as a treatment for CRS1. One possible way to combat inflammation could be inhibition of the IL-6 pathway, which is support by preclinical work as previous studies showed IL-6 knockout mice were resistant to HgCl2-induced renal injury and death [65] and IL-6 has negative inotropic effects in both isolated cardiomyocytes [66] and intact animals [67]. Thus, IL-6 antagonism may improve both cardiac and renal function, an ideal scenario for CRS1 patients. The availability of tocilizumab, an FDA-approved humanized antibody to the IL-6 receptor, may allow for investigation of this hypothesis in the future. Although not examined in the COPE-ADHF trial, an alternative explanation for the improvements associated with corticosteroids treatment were the anti-inflammatory effects. If this were true, corticosteroids would represent a relatively cheap treatment option for CRS1 patients, but more studies need to be conducted before this approach is widely implemented. Finally, use of cytokine profiling may be used to enrich a population of CRS1 patients that could be investigated in future clinical trials using anti-inflammatory medications.

Unanswered Questions Moving Forward

Severity of AKI and Treatment Effects

An important unknown that warrants further investigation is if the severity of AKI should dictate treatment choice in CRS1. As discussed above, increasing severity of AKI resulted in elevated risk of adverse events, but it remains unknown whether different treatments offer benefits for more or less severe renal impairment. Perhaps, future studies aimed at defining outcomes from different treatment strategies stratified by severity of renal dysfunction may reveal which patients benefit from the various treatment options for CRS1.

How Do We Best Define Renal Dysfunction in CRS1?

Currently, there is no accepted definition of renal dysfunction in CRS1. As discussed above, using the AKIN, KDIGO, or RIFLE scoring systems or diuretic responsiveness effectively differentiated outcomes in patients with CRS1. However, an agreed-upon definition would likely benefit the field going forward so this population could be systematically investigated in future studies.

Conclusion

In summary, CRS1 is a common clinical entity associated with poor patient outcomes. A complex pathophysiology marked by reduced cardiac output, increased central venous pressure, inflammation, and oxidative stress underlies the disease process. Unfortunately, no current treatment approach shows consistent improvements in outcomes, highlighting the urgent need for further research to reduce the burden that CRS1 imposes.

 

Corresponding author: Kurt W. Prins, MD, PhD, MMC 580 Mayo, 420 Delaware St SE, Minneapolis, MN 55455, [email protected].

Funding/support: Dr. Prins is funded by NIH F32 grant HL129554 and Dr. Thenappen is funded by AHA Scientist Development Grant 15SDG25560048.

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49. Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST outcome trial. JAMA 2007;297:1319–31.

50. Liu C, Liu G, Zhou C, et al. Potent diuretic effects of prednisone in heart failure patients with refractory diuretic resistance. Can J Cardiol 2007;23:865–8.

51. Zhang H, Liu C, Ji Z, et al. Prednisone adding to usual care treatment for refractory decompensated congestive heart failure. Int Heart J 2008;49:587–95.

52. Liu C, Liu K and COPE-ADHF Study Group. Cardiac outcome prevention effectiveness of glucocorticoids in acute decompensated heart failure: COPE-ADHF study. J Cardiovasc Pharmacol 2014;63:333–8.

53. Teichman SL, Unemori E, Teerlink JR, et al. Relaxin: Review of biology and potential role in treating heart failure. Curr Heart Fail Rep 2010;7:75–82.

54. Conrad KP, Shroff SG. Effects of relaxin on arterial dilation, remodeling, and mechanical properties. Curr Hypertens Rep 2011;13:409–20.

55. Du XJ, Bathgate RA, Samuel CS, et al. Cardiovascular effects of relaxin: From basic science to clinical therapy. Nat Rev Cardiol 2010;7:48–58.

56. Metra M, Cotter G, Davison BA, et al. Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the relaxin in acute heart failure (RELAX-AHF) development program: Correlation with outcomes. J Am Coll Cardiol 2013;61:196-206.

57. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007;49:675–83.

58. Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012;367:2296–304.

59. Mentz RJ, Stevens SR, DeVore AD, et al. Decongestion strategies and renin-angiotensin-aldosterone system activation in acute heart failure. JACC Heart Fail 2015;3:97–107.

60. Ebrahim B, Sindhura K, Okoroh J, et al. Meta-analysis of ultrafiltration versus diuretics treatment option for overload volume reduction in patients with acute decompensated heart failure. Arq Bras Cardiol 2015;104:417–25.

61. Kwong JS, Yu CM. Ultrafiltration for acute decompensated heart failure: A systematic review and meta-analysis of randomized controlled trials. Int J Cardiol 2014;172:395–402.

62. Badawy SS, Fahmy A. Efficacy and cardiovascular tolerability of continuous veno-venous hemodiafiltration in acute decompensated heart failure: A randomized comparative study. J Crit Care 2012;27:106.e7-106.13.

63. Patarroyo M, Wehbe E, Hanna M, et al. Cardiorenal outcomes after slow continuous ultrafiltration therapy in refractory patients with advanced decompensated heart failure. J Am Coll Cardiol 2012;60:1906–12.

64. Prins KW, Wille KM, Tallaj JA, Tolwani AJ. Assessing continuous renal replacement therapy as a rescue strategy in cardiorenal syndrome 1. Clin Kidney J 2015;8:87–92.

65. Nechemia-Arbely Y, Barkan D, Pizov G, et al. IL-6/IL-6R axis plays a critical role in acute kidney injury. J Am Soc Nephrol 2008;19:1106–15.

66. Pathan N, Franklin JL, Eleftherohorinou H, et al. Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase. Crit Care Med 2011;39:1692–711.

67. Janssen SP, Gayan-Ramirez G, Van den Bergh A, et al. Interleukin-6 causes myocardial failure and skeletal muscle atrophy in rats. Circulation 2005;111:996–1005.

68. Bellomo R, Ronco C, Kellum JA and Acute Dialysis Quality Initiative workgroup. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: The second international consensus conference of the acute dialysis quality initiative (ADQI) group. Crit Care 2004;8:R204-12.

69. Mehta RL, Kellum JA, Shah SV, et al and Acute Kidney Injury Network. Acute kidney injury network: Report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31.

70. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guidelines for acute kidney injury. Kidney Inter Suppl 2012;2:19–36.

References

1. Mozaffarian D, Benjamin EJ, Go AS,et al. Heart disease and stroke statistics--2015 update: A report from the american heart association. Circulation 2015;131:e29–322.

2. Gheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO. Rehospitalization for heart failure: problems and perspectives. J Am Coll Cardiol 2013;61:391–403.

3. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the medicare fee-for-service program. N Engl J Med 2009;360:1418–28.

4. Fonarow GC, Adams KF Jr, Abraham WT, et al and ADHERE Scientific Advisory Committee, Study Group, and Investigators. Risk stratification for in-hospital mortality in acutely decompensated heart failure: Classification and regression tree analysis. JAMA 2005;293:572–80.

5. Abraham WT, Fonarow GC, Albert NM, et al. Predictors of in-hospital mortality in patients hospitalized for heart failure: Insights from the organized program to initiate lifesaving treatment in hospitalized patients with heart failure (OPTIMIZE-HF). J Am Coll Cardiol 2008;52:347–56.

6. Ronco C, Haapio M, House AA, et al. Cardiorenal syndrome. J Am Coll Cardiol 2008:52:1527–39.

7. Roy AK, Mc Gorrian C, Treacy C, et al. A comparison of traditional and novel definitions (RIFLE, AKIN, and KDIGO) of acute kidney injury for the prediction of outcomes in acute decompensated heart failure. Cardiorenal Med 2013;3:26–37.

8. Li Z, Cai L, Liang X, et al. Identification and predicting short-term prognosis of early cardiorenal syndrome type 1: KDIGO is superior to RIFLE or AKIN. PLoS One 2014;9:e114369.

9. Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009:53:589–96.

10. Nohria A, Hasselblad V, Stebbins A, et al. Cardiorenal interactions: Insights from the ESCAPE trial. J Am Coll Cardiol 2008:51:1268–74.

11. Winton FR. The influence of venous pressure on the isolated mammalian kidney. J Physiol 1931;72:49–61.

12. Virzi GM, Torregrossa R, Cruz DN, et al. Cardiorenal syndrome type 1 may be immunologically mediated: A pilot evaluation of monocyte apoptosis. Cardiorenal Med 2012;2:33–42.

13. Virzi GM, Clementi A, de Cal M, et al. Oxidative stress: Dual pathway induction in cardiorenal syndrome type 1 pathogenesis. Oxid Med Cell Longev 2015;391790.

14. Cho E, Kim M, Ko YS, et al. Role of inflammation in the pathogenesis of cardiorenal syndrome in a rat myocardial infarction model. Nephrol Dial Transplant 2013;28:2766–78.

15. Ather S, Bavishi C, McCauley MD, et al. Worsening renal function is not associated with response to treatment in acute heart failure. Int J Cardiol 2013;167:1912–7.

16. Testani JM, McCauley BD, Kimmel SE, Shannon RP. Characteristics of patients with improvement or worsening in renal function during treatment of acute decompensated heart failure. Am J Cardiol 2010;106:1763–69.

17. Hata N, Yokoyama S, Shinada T, et al. Acute kidney injury and outcomes in acute decompensated heart failure: Evaluation of the RIFLE criteria in an acutely ill heart failure population. Eur J Heart Fail 2010;12:32–7.

18. Testani JM, Brisco MA, Turner JM, et al. Loop diuretic efficiency: A metric of diuretic responsiveness with prognostic importance in acute decompensated heart failure. Circ Heart Fail 2014;7:261–70.

19. Voors AA, Davison BA, Teerlink JR, et al. Diuretic response in patients with acute decompensated heart failure: Characteristics and clinical outcome--an analysis from RELAX-AHF. Eur J Heart Fail 2014;16:1230–40.

20. Valente MA, Voors AA, Damman K, et al. Diuretic response in acute heart failure: Clinical characteristics and prognostic significance. Eur Heart J 2014;35:1284–93.

21. Devarajan P. Neutrophil gelatinase-associated lipocalin: A troponin-like biomarker for human acute kidney injury. Nephrology (Carlton) 2010;15:419–28.

22. Soyler C, Tanriover MD, Ascioglu S, et al. Urine neutrophil gelatinase-associated lipocalin levels predict acute kidney injury in acute decompensated heart failure patients. Ren Fail 2015;5.

23. Brisco MA,Testani JM. Novel renal biomarkers to assess cardiorenal syndrome. Curr Heart Fail Rep 2014;11;485–99.

24. Lassus J, Harjola VP, Sund R, et al. and FINN-AKVA Study group. Prognostic value of cystatin C in acute heart failure in relation to other markers of renal function and NT-proBNP. Eur Heart J 2007;28:1841–7.

25. Arimoto T, Takeishi Y, Niizeki T, et al. Cystatin C, a novel measure of renal function, is an independent predictor of cardiac events in patients with heart failure. J Card Fail 2005;11:595–601.

26. Naruse H, Ishii J, Kawai T, et al. Cystatin C in acute heart failure without advanced renal impairment. Am J Med 2009;122:566–73.

27. Manzano-Fernandez S, Boronat-Garcia M, Albaladejo-Oton MD, et al. Complementary prognostic value of cystatin C, N-terminal pro-B-type natriuretic peptide and cardiac troponin T in patients with acute heart failure. Am J Cardiol 2009;103:1753–9.

28. Bonventre JV, Yang L. Kidney injury molecule-1. Curr Opin Crit Care 2010;16:556–61.

29. Damman K, Van Veldhuisen DJ, Navis G, et al. Tubular damage in chronic systolic heart failure is associated with reduced survival independent of glomerular filtration rate. Heart 2010;96:1297–302.

30. Jungbauer CG, Birner C, Jung B, et al. Kidney injury molecule-1 and N-acetyl-beta-D-glucosaminidase in chronic heart failure: Possible biomarkers of cardiorenal syndrome. Eur J Heart Fail 2011;13:1104–10.

31. Verbrugge FH, Dupont M, Shao Z, et al. Novel urinary biomarkers in detecting acute kidney injury, persistent renal impairment, and all-cause mortality following decongestive therapy in acute decompensated heart failure. J Card Fail 2013;19:621–8.

32. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011;364:797–805.

33. Moranville MP, Choi S, Hogg J, et al. Comparison of metolazone versus chlorothiazide in acute decompensated heart failure with diuretic resistance. Cardiovasc Ther 2015;33;42–9.

34. Cuffe MS, Califf RM, Adams KF Jr, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: A randomized controlled trial. JAMA 2002;287:1541–7.

35. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: The SURVIVE randomized trial. JAMA 2007;297:1883–91.

36. Varriale P, Mossavi A. The benefit of low-dose dopamine during vigorous diuresis for congestive heart failure associated with renal insufficiency: Does it protect renal function? Clin Cardiol 1997;20:627–30.

37. Giamouzis G, Butler J, Starling RC, et al. Impact of dopamine infusion on renal function in hospitalized heart failure patients: Results of the dopamine in acute decompensated heart failure (DAD-HF) trial. J Card Fail 2010;16:922–30.

38. Triposkiadis FK, Butler J, Karayannis G, et al. Efficacy and safety of high dose versus low dose furosemide with or without dopamine infusion: The dopamine in acute decompensated heart failure II (DAD-HF II) trial. Int J Cardiol 2014;172:115–21.

39. Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: The ROSE acute heart failure randomized trial. JAMA 2013;310:2533–43.

40. Witteles RM, Kao D, Christopherson D, et al. Impact of nesiritide on renal function in patients with acute decompensated heart failure and pre-existing renal dysfunction a randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol 2007;50:1835–40.

41 O'Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32–43.

42. Owan TE, Chen HH, Frantz RP, et al. The effects of nesiritide on renal function and diuretic responsiveness in acutely decompensated heart failure patients with renal dysfunction. J Card Fail 2008;14:267–75.

43. Givertz MM, Massie BM, Fields TK, et al and CKI-201 and CKI-202 Investigators. The effects of KW-3902, an adenosine A1-receptor antagonist,on diuresis and renal function in patients with acute decompensated heart failure and renal impairment or diuretic resistance. J Am Coll Cardiol 2007;50:1551–60.

44. Massie BM, O'Connor CM, Metra M, et al. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010;363:1419–28.

45. Voors AA, Dittrich HC, Massie BM, et al. Effects of the adenosine A1 receptor antagonist rolofylline on renal function in patients with acute heart failure and renal dysfunction: Results from PROTECT (placebo-controlled randomized study of the selective adenosine A1 receptor antagonist rolofylline for patients hospitalized with acute decompensated heart failure and volume overload to assess treatment effect on congestion and renal function). J Am Coll Cardiol 2011;57:1899–907.

46. Gottlieb SS, Givertz MM, Metra M, et al. The effects of adenosine A(1) receptor antagonism in patients with acute decompensated heart failure and worsening renal function: The REACH UP study. J Card Fail 2010;16:714–9.

47. Gheorghiade M, Gattis WA, O'Connor CM, et al. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: A randomized controlled trial. JAMA 2004;291:1963–71.

48. Gheorghiade M, Konstam MA, Burnett JC Jr, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: The EVEREST clinical status trials. JAMA 2007;297:1332–43.

49. Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST outcome trial. JAMA 2007;297:1319–31.

50. Liu C, Liu G, Zhou C, et al. Potent diuretic effects of prednisone in heart failure patients with refractory diuretic resistance. Can J Cardiol 2007;23:865–8.

51. Zhang H, Liu C, Ji Z, et al. Prednisone adding to usual care treatment for refractory decompensated congestive heart failure. Int Heart J 2008;49:587–95.

52. Liu C, Liu K and COPE-ADHF Study Group. Cardiac outcome prevention effectiveness of glucocorticoids in acute decompensated heart failure: COPE-ADHF study. J Cardiovasc Pharmacol 2014;63:333–8.

53. Teichman SL, Unemori E, Teerlink JR, et al. Relaxin: Review of biology and potential role in treating heart failure. Curr Heart Fail Rep 2010;7:75–82.

54. Conrad KP, Shroff SG. Effects of relaxin on arterial dilation, remodeling, and mechanical properties. Curr Hypertens Rep 2011;13:409–20.

55. Du XJ, Bathgate RA, Samuel CS, et al. Cardiovascular effects of relaxin: From basic science to clinical therapy. Nat Rev Cardiol 2010;7:48–58.

56. Metra M, Cotter G, Davison BA, et al. Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the relaxin in acute heart failure (RELAX-AHF) development program: Correlation with outcomes. J Am Coll Cardiol 2013;61:196-206.

57. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007;49:675–83.

58. Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012;367:2296–304.

59. Mentz RJ, Stevens SR, DeVore AD, et al. Decongestion strategies and renin-angiotensin-aldosterone system activation in acute heart failure. JACC Heart Fail 2015;3:97–107.

60. Ebrahim B, Sindhura K, Okoroh J, et al. Meta-analysis of ultrafiltration versus diuretics treatment option for overload volume reduction in patients with acute decompensated heart failure. Arq Bras Cardiol 2015;104:417–25.

61. Kwong JS, Yu CM. Ultrafiltration for acute decompensated heart failure: A systematic review and meta-analysis of randomized controlled trials. Int J Cardiol 2014;172:395–402.

62. Badawy SS, Fahmy A. Efficacy and cardiovascular tolerability of continuous veno-venous hemodiafiltration in acute decompensated heart failure: A randomized comparative study. J Crit Care 2012;27:106.e7-106.13.

63. Patarroyo M, Wehbe E, Hanna M, et al. Cardiorenal outcomes after slow continuous ultrafiltration therapy in refractory patients with advanced decompensated heart failure. J Am Coll Cardiol 2012;60:1906–12.

64. Prins KW, Wille KM, Tallaj JA, Tolwani AJ. Assessing continuous renal replacement therapy as a rescue strategy in cardiorenal syndrome 1. Clin Kidney J 2015;8:87–92.

65. Nechemia-Arbely Y, Barkan D, Pizov G, et al. IL-6/IL-6R axis plays a critical role in acute kidney injury. J Am Soc Nephrol 2008;19:1106–15.

66. Pathan N, Franklin JL, Eleftherohorinou H, et al. Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase. Crit Care Med 2011;39:1692–711.

67. Janssen SP, Gayan-Ramirez G, Van den Bergh A, et al. Interleukin-6 causes myocardial failure and skeletal muscle atrophy in rats. Circulation 2005;111:996–1005.

68. Bellomo R, Ronco C, Kellum JA and Acute Dialysis Quality Initiative workgroup. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: The second international consensus conference of the acute dialysis quality initiative (ADQI) group. Crit Care 2004;8:R204-12.

69. Mehta RL, Kellum JA, Shah SV, et al and Acute Kidney Injury Network. Acute kidney injury network: Report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31.

70. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guidelines for acute kidney injury. Kidney Inter Suppl 2012;2:19–36.

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Q) Recently, I have seen four or five Asian-American patients with really bad kidney function. All of them were thin but had diabetes, hypertension, and a serum creatinine > 2 mg/dL. The kidney disease was a shock to them (and me). Am I missing something here?

Diabetes and hypertension are the most common causes of chronic kidney disease (CKD), with diabetes slightly edging out hypertension for the number 1 slot.1 Although Asian Americans have a tendency toward a lower body mass index (BMI) than the general population, this does not exclude them from developing diabetes or hypertension.

About 20% (1 in 5) of Asian-American adults have both diabetes and hypertension. In fact, Asian Americans with a BMI ≤ 25 often develop type 2 diabetes (T2DM), which is a direct contrast to other racial and ethnic groups in whom T2DM is more prevalent at higher BMIs. The current thinking is that Asian Americans have a higher percentage of body fat at lower BMIs.2 Among racial and ethnic subgroups, Asian Americans have the highest prevalence of undiagnosed diabetes (close to 50%).2

In 2004, after adjusting for lower BMI, McNeely and Boyko found that the incidence of diabetes in Asian Americans was 60% higher than in the Hispanic population.3 In 2015, this influenced the American Diabetes Association (ADA) to change its recommendation for diabetes screening in Asian Americans, lowering the threshold to a BMI of 23.4

Since abdominal or visceral fat is a risk factor for heart disease, hypertension, and diabetes, and it appears that the Asian-American population carries excess fat centrally, this population is also at risk for cardiac disease.5 For that reason, in this population, the American Heart Association recommends measuring waist circumference to screen for hidden abdominal adiposity.6

Thus, the trend you are seeing in your patient population is really only the tip of the iceberg. The Asian-American population is the fastest-growing ethnic group in the United States.3 It’s time to update your diabetes screening protocols. —SWM

Shushanne Wynter-Minott, DNP, FNP-BC
Memorial Healthcare System, Hollywood, Florida

References
1. CDC. National Chronic Kidney Disease Fact Sheet, 2014. www.cdc.gov/diabetes/pubs/pdf/kidney_Factsheet.pdf. Accessed February 3, 2016.
2. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988-2012. JAMA. 2015;314(10):1021-1029.
3. McNeely MJ, Boyko EJ. Type 2 diabetes prevalence in Asian Americans: results of a national health survey. Diabetes Care. 2004;27(1):66-69.
4. American Diabetes Association. Standards of medical care in diabetes­­—2015: summary of revisions. Diabetes Care. 2015;38(suppl):S4.
5. Park YW, Allison DB, Heymsfield SB, Gallagher D. Larger amounts of visceral adipose tissue in Asian Americans. Obes Res. 2001;9(7):381-387.
6. Rao G, Powell-Wiley TM, Ancheta I, et al; American Heart Association Obesity Committee of the Council on Lifestyle and Cardiometabolic Health. Identification of obesity and cardiovascular risk in ethnically and racially diverse populations: a scientific statement from the American Heart Association. Circulation. 2015;132(5):457-472.

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Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National Kidney Foundation’s Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a retired PA who works with the American Academy of Nephrology PAs and is also past chair of the NKF-CAP. This month’s responses were authored by Shushanne Wynter-Minott, DNP, FNP-BC, who practices with Memorial Healthcare System in Hollywood, Florida, and Cindy Smith, DNP, APRN, CNN-NP, FNP-BC, who practice with Renal Consultants, PLLC, in South Charleston, West Virgina.

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Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National Kidney Foundation’s Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a retired PA who works with the American Academy of Nephrology PAs and is also past chair of the NKF-CAP. This month’s responses were authored by Shushanne Wynter-Minott, DNP, FNP-BC, who practices with Memorial Healthcare System in Hollywood, Florida, and Cindy Smith, DNP, APRN, CNN-NP, FNP-BC, who practice with Renal Consultants, PLLC, in South Charleston, West Virgina.

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Q) Recently, I have seen four or five Asian-American patients with really bad kidney function. All of them were thin but had diabetes, hypertension, and a serum creatinine > 2 mg/dL. The kidney disease was a shock to them (and me). Am I missing something here?

Diabetes and hypertension are the most common causes of chronic kidney disease (CKD), with diabetes slightly edging out hypertension for the number 1 slot.1 Although Asian Americans have a tendency toward a lower body mass index (BMI) than the general population, this does not exclude them from developing diabetes or hypertension.

About 20% (1 in 5) of Asian-American adults have both diabetes and hypertension. In fact, Asian Americans with a BMI ≤ 25 often develop type 2 diabetes (T2DM), which is a direct contrast to other racial and ethnic groups in whom T2DM is more prevalent at higher BMIs. The current thinking is that Asian Americans have a higher percentage of body fat at lower BMIs.2 Among racial and ethnic subgroups, Asian Americans have the highest prevalence of undiagnosed diabetes (close to 50%).2

In 2004, after adjusting for lower BMI, McNeely and Boyko found that the incidence of diabetes in Asian Americans was 60% higher than in the Hispanic population.3 In 2015, this influenced the American Diabetes Association (ADA) to change its recommendation for diabetes screening in Asian Americans, lowering the threshold to a BMI of 23.4

Since abdominal or visceral fat is a risk factor for heart disease, hypertension, and diabetes, and it appears that the Asian-American population carries excess fat centrally, this population is also at risk for cardiac disease.5 For that reason, in this population, the American Heart Association recommends measuring waist circumference to screen for hidden abdominal adiposity.6

Thus, the trend you are seeing in your patient population is really only the tip of the iceberg. The Asian-American population is the fastest-growing ethnic group in the United States.3 It’s time to update your diabetes screening protocols. —SWM

Shushanne Wynter-Minott, DNP, FNP-BC
Memorial Healthcare System, Hollywood, Florida

References
1. CDC. National Chronic Kidney Disease Fact Sheet, 2014. www.cdc.gov/diabetes/pubs/pdf/kidney_Factsheet.pdf. Accessed February 3, 2016.
2. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988-2012. JAMA. 2015;314(10):1021-1029.
3. McNeely MJ, Boyko EJ. Type 2 diabetes prevalence in Asian Americans: results of a national health survey. Diabetes Care. 2004;27(1):66-69.
4. American Diabetes Association. Standards of medical care in diabetes­­—2015: summary of revisions. Diabetes Care. 2015;38(suppl):S4.
5. Park YW, Allison DB, Heymsfield SB, Gallagher D. Larger amounts of visceral adipose tissue in Asian Americans. Obes Res. 2001;9(7):381-387.
6. Rao G, Powell-Wiley TM, Ancheta I, et al; American Heart Association Obesity Committee of the Council on Lifestyle and Cardiometabolic Health. Identification of obesity and cardiovascular risk in ethnically and racially diverse populations: a scientific statement from the American Heart Association. Circulation. 2015;132(5):457-472.

Q) Recently, I have seen four or five Asian-American patients with really bad kidney function. All of them were thin but had diabetes, hypertension, and a serum creatinine > 2 mg/dL. The kidney disease was a shock to them (and me). Am I missing something here?

Diabetes and hypertension are the most common causes of chronic kidney disease (CKD), with diabetes slightly edging out hypertension for the number 1 slot.1 Although Asian Americans have a tendency toward a lower body mass index (BMI) than the general population, this does not exclude them from developing diabetes or hypertension.

About 20% (1 in 5) of Asian-American adults have both diabetes and hypertension. In fact, Asian Americans with a BMI ≤ 25 often develop type 2 diabetes (T2DM), which is a direct contrast to other racial and ethnic groups in whom T2DM is more prevalent at higher BMIs. The current thinking is that Asian Americans have a higher percentage of body fat at lower BMIs.2 Among racial and ethnic subgroups, Asian Americans have the highest prevalence of undiagnosed diabetes (close to 50%).2

In 2004, after adjusting for lower BMI, McNeely and Boyko found that the incidence of diabetes in Asian Americans was 60% higher than in the Hispanic population.3 In 2015, this influenced the American Diabetes Association (ADA) to change its recommendation for diabetes screening in Asian Americans, lowering the threshold to a BMI of 23.4

Since abdominal or visceral fat is a risk factor for heart disease, hypertension, and diabetes, and it appears that the Asian-American population carries excess fat centrally, this population is also at risk for cardiac disease.5 For that reason, in this population, the American Heart Association recommends measuring waist circumference to screen for hidden abdominal adiposity.6

Thus, the trend you are seeing in your patient population is really only the tip of the iceberg. The Asian-American population is the fastest-growing ethnic group in the United States.3 It’s time to update your diabetes screening protocols. —SWM

Shushanne Wynter-Minott, DNP, FNP-BC
Memorial Healthcare System, Hollywood, Florida

References
1. CDC. National Chronic Kidney Disease Fact Sheet, 2014. www.cdc.gov/diabetes/pubs/pdf/kidney_Factsheet.pdf. Accessed February 3, 2016.
2. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988-2012. JAMA. 2015;314(10):1021-1029.
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Issue
Clinician Reviews - 26(3)
Issue
Clinician Reviews - 26(3)
Page Number
24
Page Number
24
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Kidney Disease: Surprising Patients
Display Headline
Kidney Disease: Surprising Patients
Legacy Keywords
nephrology, kidney, kidney disease, Asian American, fracture, diabetes, hypertension
Legacy Keywords
nephrology, kidney, kidney disease, Asian American, fracture, diabetes, hypertension
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