Nephrology

Background: ACE-I and ARB therapy is widely used for hypertension, albuminuric chronic kidney disease, heart failure with reduced ejection fraction, and coronary artery disease. They are known to potentially cause hemodynamic reductions in eGFR, hyperkalemia, and acute kidney injury. We know to temporarily discontinue ACE-I or ARB in patients with eGFR less than 60 mL/min per 1.73 m² who have serious intercurrent illness that increases the risk of acute kidney injury, but existing literature evaluating the risks and benefits of using ACE-I and ARBs in individuals with advanced chronic kidney disease is conflicting.

Although this study is observational it has a large sample size and confounding factors have been accounted for by propensity score matching. The results are clinically relevant in daily practice.

Bottom line: Continuing ACE-I or ARB after an eGFR decrease to below 30 mL/min per m² is associated with lower risk of mortality and MACE without significant increased risk of end-stage kidney disease.

Citation: Qiao Y et al. Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate. JAMA Intern Med. 2020 Mar 9;180(5):718-26.

Dr. Kumar is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

Background: ACE-I and ARB therapy is widely used for hypertension, albuminuric chronic kidney disease, heart failure with reduced ejection fraction, and coronary artery disease. They are known to potentially cause hemodynamic reductions in eGFR, hyperkalemia, and acute kidney injury. We know to temporarily discontinue ACE-I or ARB in patients with eGFR less than 60 mL/min per 1.73 m² who have serious intercurrent illness that increases the risk of acute kidney injury, but existing literature evaluating the risks and benefits of using ACE-I and ARBs in individuals with advanced chronic kidney disease is conflicting.

Although this study is observational it has a large sample size and confounding factors have been accounted for by propensity score matching. The results are clinically relevant in daily practice.

Bottom line: Continuing ACE-I or ARB after an eGFR decrease to below 30 mL/min per m² is associated with lower risk of mortality and MACE without significant increased risk of end-stage kidney disease.

Citation: Qiao Y et al. Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate. JAMA Intern Med. 2020 Mar 9;180(5):718-26.

Dr. Kumar is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

Background: ACE-I and ARB therapy is widely used for hypertension, albuminuric chronic kidney disease, heart failure with reduced ejection fraction, and coronary artery disease. They are known to potentially cause hemodynamic reductions in eGFR, hyperkalemia, and acute kidney injury. We know to temporarily discontinue ACE-I or ARB in patients with eGFR less than 60 mL/min per 1.73 m² who have serious intercurrent illness that increases the risk of acute kidney injury, but existing literature evaluating the risks and benefits of using ACE-I and ARBs in individuals with advanced chronic kidney disease is conflicting.

Although this study is observational it has a large sample size and confounding factors have been accounted for by propensity score matching. The results are clinically relevant in daily practice.

Bottom line: Continuing ACE-I or ARB after an eGFR decrease to below 30 mL/min per m² is associated with lower risk of mortality and MACE without significant increased risk of end-stage kidney disease.

Citation: Qiao Y et al. Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate. JAMA Intern Med. 2020 Mar 9;180(5):718-26.

Dr. Kumar is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

The Food and Drug Administration has approved difelikefalin for treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis, the first agent approved from a novel class of kappa opioid receptor agonists.

Olivier Le Moal/Getty Images

Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.

“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.

Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
 

Two pivotal trials with fewer than 900 total randomized patients

The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.

Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.

In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.

The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.

In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.

Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
 

What will it cost, and will it be covered?

The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.

Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.

Other nephrologists have a more positive take on the existing treatment options.

“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.

“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
 

Adverse-event profiles

In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.

An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”

Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.

“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”

Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.

The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.

The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.

[email protected]

The Food and Drug Administration has approved difelikefalin for treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis, the first agent approved from a novel class of kappa opioid receptor agonists.

Olivier Le Moal/Getty Images

Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.

“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.

Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
 

Two pivotal trials with fewer than 900 total randomized patients

The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.

Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.

In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.

The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.

In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.

Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
 

What will it cost, and will it be covered?

The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.

Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.

Other nephrologists have a more positive take on the existing treatment options.

“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.

“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
 

Adverse-event profiles

In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.

An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”

Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.

“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”

Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.

The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.

The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.

[email protected]

The Food and Drug Administration has approved difelikefalin for treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis, the first agent approved from a novel class of kappa opioid receptor agonists.

Olivier Le Moal/Getty Images

Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.

“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.

Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
 

Two pivotal trials with fewer than 900 total randomized patients

The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.

Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.

In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.

The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.

In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.

Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
 

What will it cost, and will it be covered?

The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.

Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.

Other nephrologists have a more positive take on the existing treatment options.

“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.

“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
 

Adverse-event profiles

In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.

An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”

Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.

“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”

Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.

The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.

The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.

[email protected]

Kidney transplantation has recently been happening at a record pace and with unprecedented success despite patients having more risk factors than ever before.

HYWARDS/Thinkstock

During 2016-2019, U.S. centers performed kidney transplants in nearly 77,000 patients, a jump of almost 25% compared with 4-year averages of about 62,000 patients throughout 2004-2015. That works out to about 15,000 more patients receiving donor kidneys, Sundaram Hariharan, MD, and associates reported in the New England Journal of Medicine in a review of all U.S. renal transplantations performed during 1996-2019.

Coupled with the volume uptick during this 24-year period were new lows in graft losses and patient deaths. By 2018, mortality during the first year following transplantation occurred at about a 1% rate among patients who had received a kidney from a living donor, and at about a 3% rate when the organ came from a deceased donor, nearly half the rate of 2 decades earlier, in 1996. Rates of first-year graft loss during 2017 were also about half of what they had been in 1996, occurring in about 2% of patients who received a living donor organ and in about 6% of those who got a kidney from a deceased donor during 2017.

“Twenty years ago, kidney transplantation was the preferred option compared with dialysis, and even more so now,” summed up Dr. Hariharan, a senior transplant nephrologist and professor of medicine and surgery at the University of Pittsburgh Medical Center and first author of the report. Kidney transplantation survival at U.S. centers “improved steadily over the past 24 years, despite patient variables becoming worse,” he said in an interview.
 

Kidney recipients are older, more obese, and have more prevalent diabetes

During the period studied, kidney transplant recipients became on average older and more obese, and had a higher prevalence of diabetes; the age of organ donors grew as well. The prevalence of diabetes among patients who received a kidney from a deceased donor increased from 24% during 1996-1999 to 36% during 2016-2019, while diabetes prevalence among recipients of an organ from a living donor rose from 25% in 1996-1999 to 29% during 2016-2019.

The improved graft and patient survival numbers “are very encouraging trends,” said Michelle A. Josephson, MD, professor and medical director of kidney transplantation at the University of Chicago, who was not involved with the report. “We have been hearing for a number of years that short-term graft survival had improved, but I’m thrilled to learn that long-term survival has also improved.”

The report documented 10-year survival of graft recipients during 2008-2011 of 67%, up from 61% during 1996-1999, and a 10-year overall graft survival rate of 54% in the 2008-2011 cohort, an improvement from the 42% rate in patients who received their organs in 1996-1999, changes Dr. Hariharan characterized as “modest.”

These improvements in long-term graft and patient survival are “meaningful, and particularly notable that outcomes improved despite increased complexity of the transplant population,” said Krista L. Lentine, MD, PhD, professor and medical director of living donation at Saint Louis University. But “despite these improvements, long-term graft survival remains limited,” she cautioned, especially because of risks for substantial complications from chronic immunosuppressive treatment including infection, cancer, glucose intolerance, and dyslipidemia.

The analysis reported by Dr. Hariharan and his associates used data collected by the Scientific Registry of Transplant Patients, run under contract with the U.S. Department of Health and Human Services, which has tracked all patients who have had kidney transplants at U.S. centers since the late 1980s, said Dr. Hariharan. The database included just over 362,000 total transplants during the 24-year period studied, with 36% of all transplants involving organs from living donors with the remaining patients receiving kidneys from deceased donors.

Living donations still stagnant; deceased-donor kidneys rise

The data showed that the rate of transplants from living donors was stagnant for 2 decades, with 22,525 patients transplanted during 2000-2003, and 23,746 transplanted during 2016-2019, with very similar rates during the intervening years. The recent spurt in transplants during 2016-2019 compared with the preceding decade depended almost entirely on kidneys from deceased donors. This rate jumped from the steady, slow rise it showed during 1996-2015, when deceased-donor transplants rose from about 30,000 during 1996-1999 to about 41,000 during 2012-2015, to a more dramatic increase of about 12,000 additional transplants during the most recent period, adding up to a total of more than 53,000 transplants from deceased donors during 2016-2019.

“I strongly recommend organs from living donors” when feasible, said Dr. Hariharan. “At some centers, a high proportion of transplants use living donors, but not at other centers,” he said.

It’s unknown why transplants using organs from deceased donors has shown this growth, but Dr. Hariharan suggested a multifactorial explanation. Those factors include growth in the number of patients with end-stage renal disease who require dialysis, increased numbers of patients listed for kidney transplant, new approaches that allow organs from older donors and those infected with pathogens such as hepatitis C virus or HIV, greater numbers of people and families agreeing to donate organs, and possibly the opioid crisis that may have led to increased organ donation. The number of U.S. centers performing kidney transplants rose from fewer than 200 about a quarter of a century ago to about 250 today, he added.

‘Immuno Bill’ guarantees Medicare coverage for immunosuppression

Dr. Hariharan voiced optimism that graft and patient survival rates will continue to improve going forward. One factor will likely be the passage in late 2020 of the “Immuno Bill” by the U.S. Congress, which among other things mandated ongoing coverage starting in 2023 for immunosuppressive drugs for all Medicare beneficiaries with a kidney transplant. Until then, Medicare provides coverage for only 36 months, a time limit that has resulted in nearly 400 kidney recipients annually losing coverage of their immunosuppression medications.

Dr. Hariharan and coauthors called the existing potential for discontinuation of immunosuppressive drug an “unnecessary impediment to long-term survival for which patients and society paid a heavy price.”

“Kidney transplantation, especially from living donors, offers patients with kidney failure the best chance for long-term survival and improved quality of life, with lower cost to the health care system,” Dr. Lentine said in an interview. Despite the many positive trends detailed in the report from Dr. Hariharan and coauthors, “the vast majority of the more than 700,000 people in the United States with kidney failure will not have an opportunity to receive a transplant due to limitations in organ supply.” And many patients who receive a kidney transplant eventually must resume dialysis because of “limited long-term graft survival resulting from allograft nephropathy, recurrent native disease, medication nonadherence, or other causes.” Plus many potentially transplantable organs go unused.

Dr. Lentine cited a position statement issued in July 2021 by the National Kidney Foundation that made several recommendations on how to improve access to kidney transplants and improve outcomes. “Expanding opportunities for safe living donation, eliminating racial disparities in living-donor access, improving wait-list access and transport readiness, maximizing use of deceased-donor organs, and extending graft longevity are critical priorities,” said Dr. Lentine, lead author on the statement.

“For many or even most patients with kidney failure transplantation is the optimal form of renal replacement. The better recent outcomes and evolving management strategies make transplantation an even more attractive option,” said Dr. Josephson. Improved outcomes among U.S. transplant patients also highlights the “importance of increasing access to kidney transplantation” for all people with kidney failure who could benefit from this treatment, she added.

Dr. Hariharan and Dr. Lentine had no relevant disclosures. Dr. Josephson has been a consultant to UCB and has an ownership interest in Seagen.

[email protected]

Kidney transplantation has recently been happening at a record pace and with unprecedented success despite patients having more risk factors than ever before.

HYWARDS/Thinkstock

During 2016-2019, U.S. centers performed kidney transplants in nearly 77,000 patients, a jump of almost 25% compared with 4-year averages of about 62,000 patients throughout 2004-2015. That works out to about 15,000 more patients receiving donor kidneys, Sundaram Hariharan, MD, and associates reported in the New England Journal of Medicine in a review of all U.S. renal transplantations performed during 1996-2019.

Coupled with the volume uptick during this 24-year period were new lows in graft losses and patient deaths. By 2018, mortality during the first year following transplantation occurred at about a 1% rate among patients who had received a kidney from a living donor, and at about a 3% rate when the organ came from a deceased donor, nearly half the rate of 2 decades earlier, in 1996. Rates of first-year graft loss during 2017 were also about half of what they had been in 1996, occurring in about 2% of patients who received a living donor organ and in about 6% of those who got a kidney from a deceased donor during 2017.

“Twenty years ago, kidney transplantation was the preferred option compared with dialysis, and even more so now,” summed up Dr. Hariharan, a senior transplant nephrologist and professor of medicine and surgery at the University of Pittsburgh Medical Center and first author of the report. Kidney transplantation survival at U.S. centers “improved steadily over the past 24 years, despite patient variables becoming worse,” he said in an interview.
 

Kidney recipients are older, more obese, and have more prevalent diabetes

During the period studied, kidney transplant recipients became on average older and more obese, and had a higher prevalence of diabetes; the age of organ donors grew as well. The prevalence of diabetes among patients who received a kidney from a deceased donor increased from 24% during 1996-1999 to 36% during 2016-2019, while diabetes prevalence among recipients of an organ from a living donor rose from 25% in 1996-1999 to 29% during 2016-2019.

The improved graft and patient survival numbers “are very encouraging trends,” said Michelle A. Josephson, MD, professor and medical director of kidney transplantation at the University of Chicago, who was not involved with the report. “We have been hearing for a number of years that short-term graft survival had improved, but I’m thrilled to learn that long-term survival has also improved.”

The report documented 10-year survival of graft recipients during 2008-2011 of 67%, up from 61% during 1996-1999, and a 10-year overall graft survival rate of 54% in the 2008-2011 cohort, an improvement from the 42% rate in patients who received their organs in 1996-1999, changes Dr. Hariharan characterized as “modest.”

These improvements in long-term graft and patient survival are “meaningful, and particularly notable that outcomes improved despite increased complexity of the transplant population,” said Krista L. Lentine, MD, PhD, professor and medical director of living donation at Saint Louis University. But “despite these improvements, long-term graft survival remains limited,” she cautioned, especially because of risks for substantial complications from chronic immunosuppressive treatment including infection, cancer, glucose intolerance, and dyslipidemia.

The analysis reported by Dr. Hariharan and his associates used data collected by the Scientific Registry of Transplant Patients, run under contract with the U.S. Department of Health and Human Services, which has tracked all patients who have had kidney transplants at U.S. centers since the late 1980s, said Dr. Hariharan. The database included just over 362,000 total transplants during the 24-year period studied, with 36% of all transplants involving organs from living donors with the remaining patients receiving kidneys from deceased donors.

Living donations still stagnant; deceased-donor kidneys rise

The data showed that the rate of transplants from living donors was stagnant for 2 decades, with 22,525 patients transplanted during 2000-2003, and 23,746 transplanted during 2016-2019, with very similar rates during the intervening years. The recent spurt in transplants during 2016-2019 compared with the preceding decade depended almost entirely on kidneys from deceased donors. This rate jumped from the steady, slow rise it showed during 1996-2015, when deceased-donor transplants rose from about 30,000 during 1996-1999 to about 41,000 during 2012-2015, to a more dramatic increase of about 12,000 additional transplants during the most recent period, adding up to a total of more than 53,000 transplants from deceased donors during 2016-2019.

“I strongly recommend organs from living donors” when feasible, said Dr. Hariharan. “At some centers, a high proportion of transplants use living donors, but not at other centers,” he said.

It’s unknown why transplants using organs from deceased donors has shown this growth, but Dr. Hariharan suggested a multifactorial explanation. Those factors include growth in the number of patients with end-stage renal disease who require dialysis, increased numbers of patients listed for kidney transplant, new approaches that allow organs from older donors and those infected with pathogens such as hepatitis C virus or HIV, greater numbers of people and families agreeing to donate organs, and possibly the opioid crisis that may have led to increased organ donation. The number of U.S. centers performing kidney transplants rose from fewer than 200 about a quarter of a century ago to about 250 today, he added.

‘Immuno Bill’ guarantees Medicare coverage for immunosuppression

Dr. Hariharan voiced optimism that graft and patient survival rates will continue to improve going forward. One factor will likely be the passage in late 2020 of the “Immuno Bill” by the U.S. Congress, which among other things mandated ongoing coverage starting in 2023 for immunosuppressive drugs for all Medicare beneficiaries with a kidney transplant. Until then, Medicare provides coverage for only 36 months, a time limit that has resulted in nearly 400 kidney recipients annually losing coverage of their immunosuppression medications.

Dr. Hariharan and coauthors called the existing potential for discontinuation of immunosuppressive drug an “unnecessary impediment to long-term survival for which patients and society paid a heavy price.”

“Kidney transplantation, especially from living donors, offers patients with kidney failure the best chance for long-term survival and improved quality of life, with lower cost to the health care system,” Dr. Lentine said in an interview. Despite the many positive trends detailed in the report from Dr. Hariharan and coauthors, “the vast majority of the more than 700,000 people in the United States with kidney failure will not have an opportunity to receive a transplant due to limitations in organ supply.” And many patients who receive a kidney transplant eventually must resume dialysis because of “limited long-term graft survival resulting from allograft nephropathy, recurrent native disease, medication nonadherence, or other causes.” Plus many potentially transplantable organs go unused.

Dr. Lentine cited a position statement issued in July 2021 by the National Kidney Foundation that made several recommendations on how to improve access to kidney transplants and improve outcomes. “Expanding opportunities for safe living donation, eliminating racial disparities in living-donor access, improving wait-list access and transport readiness, maximizing use of deceased-donor organs, and extending graft longevity are critical priorities,” said Dr. Lentine, lead author on the statement.

“For many or even most patients with kidney failure transplantation is the optimal form of renal replacement. The better recent outcomes and evolving management strategies make transplantation an even more attractive option,” said Dr. Josephson. Improved outcomes among U.S. transplant patients also highlights the “importance of increasing access to kidney transplantation” for all people with kidney failure who could benefit from this treatment, she added.

Dr. Hariharan and Dr. Lentine had no relevant disclosures. Dr. Josephson has been a consultant to UCB and has an ownership interest in Seagen.

[email protected]

Kidney transplantation has recently been happening at a record pace and with unprecedented success despite patients having more risk factors than ever before.

HYWARDS/Thinkstock

During 2016-2019, U.S. centers performed kidney transplants in nearly 77,000 patients, a jump of almost 25% compared with 4-year averages of about 62,000 patients throughout 2004-2015. That works out to about 15,000 more patients receiving donor kidneys, Sundaram Hariharan, MD, and associates reported in the New England Journal of Medicine in a review of all U.S. renal transplantations performed during 1996-2019.

Coupled with the volume uptick during this 24-year period were new lows in graft losses and patient deaths. By 2018, mortality during the first year following transplantation occurred at about a 1% rate among patients who had received a kidney from a living donor, and at about a 3% rate when the organ came from a deceased donor, nearly half the rate of 2 decades earlier, in 1996. Rates of first-year graft loss during 2017 were also about half of what they had been in 1996, occurring in about 2% of patients who received a living donor organ and in about 6% of those who got a kidney from a deceased donor during 2017.

“Twenty years ago, kidney transplantation was the preferred option compared with dialysis, and even more so now,” summed up Dr. Hariharan, a senior transplant nephrologist and professor of medicine and surgery at the University of Pittsburgh Medical Center and first author of the report. Kidney transplantation survival at U.S. centers “improved steadily over the past 24 years, despite patient variables becoming worse,” he said in an interview.
 

Kidney recipients are older, more obese, and have more prevalent diabetes

During the period studied, kidney transplant recipients became on average older and more obese, and had a higher prevalence of diabetes; the age of organ donors grew as well. The prevalence of diabetes among patients who received a kidney from a deceased donor increased from 24% during 1996-1999 to 36% during 2016-2019, while diabetes prevalence among recipients of an organ from a living donor rose from 25% in 1996-1999 to 29% during 2016-2019.

The improved graft and patient survival numbers “are very encouraging trends,” said Michelle A. Josephson, MD, professor and medical director of kidney transplantation at the University of Chicago, who was not involved with the report. “We have been hearing for a number of years that short-term graft survival had improved, but I’m thrilled to learn that long-term survival has also improved.”

The report documented 10-year survival of graft recipients during 2008-2011 of 67%, up from 61% during 1996-1999, and a 10-year overall graft survival rate of 54% in the 2008-2011 cohort, an improvement from the 42% rate in patients who received their organs in 1996-1999, changes Dr. Hariharan characterized as “modest.”

These improvements in long-term graft and patient survival are “meaningful, and particularly notable that outcomes improved despite increased complexity of the transplant population,” said Krista L. Lentine, MD, PhD, professor and medical director of living donation at Saint Louis University. But “despite these improvements, long-term graft survival remains limited,” she cautioned, especially because of risks for substantial complications from chronic immunosuppressive treatment including infection, cancer, glucose intolerance, and dyslipidemia.

The analysis reported by Dr. Hariharan and his associates used data collected by the Scientific Registry of Transplant Patients, run under contract with the U.S. Department of Health and Human Services, which has tracked all patients who have had kidney transplants at U.S. centers since the late 1980s, said Dr. Hariharan. The database included just over 362,000 total transplants during the 24-year period studied, with 36% of all transplants involving organs from living donors with the remaining patients receiving kidneys from deceased donors.

Living donations still stagnant; deceased-donor kidneys rise

The data showed that the rate of transplants from living donors was stagnant for 2 decades, with 22,525 patients transplanted during 2000-2003, and 23,746 transplanted during 2016-2019, with very similar rates during the intervening years. The recent spurt in transplants during 2016-2019 compared with the preceding decade depended almost entirely on kidneys from deceased donors. This rate jumped from the steady, slow rise it showed during 1996-2015, when deceased-donor transplants rose from about 30,000 during 1996-1999 to about 41,000 during 2012-2015, to a more dramatic increase of about 12,000 additional transplants during the most recent period, adding up to a total of more than 53,000 transplants from deceased donors during 2016-2019.

“I strongly recommend organs from living donors” when feasible, said Dr. Hariharan. “At some centers, a high proportion of transplants use living donors, but not at other centers,” he said.

It’s unknown why transplants using organs from deceased donors has shown this growth, but Dr. Hariharan suggested a multifactorial explanation. Those factors include growth in the number of patients with end-stage renal disease who require dialysis, increased numbers of patients listed for kidney transplant, new approaches that allow organs from older donors and those infected with pathogens such as hepatitis C virus or HIV, greater numbers of people and families agreeing to donate organs, and possibly the opioid crisis that may have led to increased organ donation. The number of U.S. centers performing kidney transplants rose from fewer than 200 about a quarter of a century ago to about 250 today, he added.

‘Immuno Bill’ guarantees Medicare coverage for immunosuppression

Dr. Hariharan voiced optimism that graft and patient survival rates will continue to improve going forward. One factor will likely be the passage in late 2020 of the “Immuno Bill” by the U.S. Congress, which among other things mandated ongoing coverage starting in 2023 for immunosuppressive drugs for all Medicare beneficiaries with a kidney transplant. Until then, Medicare provides coverage for only 36 months, a time limit that has resulted in nearly 400 kidney recipients annually losing coverage of their immunosuppression medications.

Dr. Hariharan and coauthors called the existing potential for discontinuation of immunosuppressive drug an “unnecessary impediment to long-term survival for which patients and society paid a heavy price.”

“Kidney transplantation, especially from living donors, offers patients with kidney failure the best chance for long-term survival and improved quality of life, with lower cost to the health care system,” Dr. Lentine said in an interview. Despite the many positive trends detailed in the report from Dr. Hariharan and coauthors, “the vast majority of the more than 700,000 people in the United States with kidney failure will not have an opportunity to receive a transplant due to limitations in organ supply.” And many patients who receive a kidney transplant eventually must resume dialysis because of “limited long-term graft survival resulting from allograft nephropathy, recurrent native disease, medication nonadherence, or other causes.” Plus many potentially transplantable organs go unused.

Dr. Lentine cited a position statement issued in July 2021 by the National Kidney Foundation that made several recommendations on how to improve access to kidney transplants and improve outcomes. “Expanding opportunities for safe living donation, eliminating racial disparities in living-donor access, improving wait-list access and transport readiness, maximizing use of deceased-donor organs, and extending graft longevity are critical priorities,” said Dr. Lentine, lead author on the statement.

“For many or even most patients with kidney failure transplantation is the optimal form of renal replacement. The better recent outcomes and evolving management strategies make transplantation an even more attractive option,” said Dr. Josephson. Improved outcomes among U.S. transplant patients also highlights the “importance of increasing access to kidney transplantation” for all people with kidney failure who could benefit from this treatment, she added.

Dr. Hariharan and Dr. Lentine had no relevant disclosures. Dr. Josephson has been a consultant to UCB and has an ownership interest in Seagen.

[email protected]

U.S. prescribing data from 160,000 adults with type 2 diabetes and diabetic kidney disease showed a notable uptick in new prescriptions for sodium-glucose cotransporter 2 inhibitors and less dramatic gains for glucagonlike peptide–1 receptor agonists during 2019 and continuing into early 2020, compared with prior years, with usage levels of both classes during the first quarter of 2020 rivaling those of more traditional agents including metformin and insulin.

During the first 3 months of 2020, initiation of a SGLT2 inhibitor constituted 13% of all new starts of an antidiabetes drug among adults with type 2 diabetes and diabetic kidney disease (DKD). This compared with initiation rates during the same early 2020 period of 17% for GLP-1 receptor agonists, 19% for metformin, 16% for sulfonylureas, 15% for insulins, 14% for thiazolidinediones, and 6% for dipeptidyl peptidase–4 inhibitors, the seven drug classes examined in a study published in Diabetes Care.

Early 2020 was the first time that starts of a GLP-1 receptor agonist ranked second (behind only metformin) among these seven drug classes in the studied U.S. population, and early 2020 also marked an unprecedentedly high start rate for SGLT2 inhibitors that nearly tripled the roughly 5% rate in place as recently as 2018.
 

Rises are ‘what we expected’

The recent rise of SGLT2 inhibitors and GLP-1 receptor agonists in these patients “was what we expected,” given the evidence for both classes in slowing progression of DKD, said Julie M. Paik, MD, senior author on the study and a nephrologist and pharmacoepidemiologist at Brigham and Women’s Hospital in Boston.

“We’ve seen other beneficial drugs slow on the uptake, so it’s not surprising to see it here, and I’m optimistic” about further increases going forward, she said in an interview.

Both drug classes “were originally marketed as diabetes drugs,” and it is only since 2019, with the publication of trials showing dramatic renal benefits from canagliflozin (Invokana) in CREDENCE, and from dapagliflozin (Farxiga) in DAPA-CKD in 2020 that the evidence became truly compelling for SGLT2 inhibitors. This evidence also led to new renal-protection indications approved by the Food and Drug Administration for canagliflozin and for dapagliflozin, noted Dr. Paik.

Evidence for renal protection also emerged in 2017 for the GLP-1 receptor agonist liraglutide (Victoza) in the LEADER trial, and for dulaglutide (Trulicity) in the AWARD-7 trial, although neither drug has received a renal indication in its labeling.

By 2020, guidelines for managing patients with type 2 diabetes and chronic kidney disease from the influential Kidney Disease: Improving Global Outcomes organization had identified agents from the SGLT2 inhibitor class as top-tier options, along with metformin, for treating these patients, with agents from the GLP-1 receptor agonist class as the top third class to add in patients who require additional glycemic control.

Additional analyses Dr. Paik and associates ran showed how this played out in terms of which specialists prescribed these drugs during the full period studied beginning in 2013. Throughout this roughly 7-year span, about 70% of the prescriptions written for either SGLT2 inhibitors or for GLP-1 receptor agonists were from internal medicine physicians, followed by about 20% written by endocrinologists. Prescriptions from nephrologists, as well as from cardiologists, have hovered at about 5% each, but seem poised to start rising based on the recently added indications and newer treatment recommendations.

“It’s good to see the recent uptick in use since 2019,” Katherine R. Tuttle, MD, commented in an interview. It’s a positive development for U.S. public health, “but we need to do more to disseminate and implement these life-, kidney-, and heart-saving therapies.”

Future use could approach 80% of DKD patients

Dr. Tuttle estimated that “target” levels of use for SGLT2 inhibitors and for GLP-1 receptor agonists “could reasonably approach 80%” for patients with type 2 diabetes and diabetic kidney disease.

“We will likely move to combination therapy” with simultaneous use of agents from both classes in a targeted way using “precision phenotyping based on clinical characteristics, and eventually perhaps by biomarkers, kidney biopsies, or both.” Combined treatment with both an SGLT2 inhibitor and a GLP-1 receptor agonist may be especially suited to patients with type 2 diabetes, atherosclerotic cardiovascular disease, low estimated glomerular filtration rate, and need for better glycemic control and weight loss, a profile that is “pretty typical” in real-world practice, said Dr. Tuttle, a nephrologist and endocrinologist and executive director for research at Providence Healthcare in Spokane, Wash.
 

Study included patients with commercial or Medicare Advantage coverage

The study used information in an Optum database that included patients enrolled in either commercial or in Medicare Advantage health insurance plans from 2013 to the first quarter of 2020. This included 160,489 adults with type 2 diabetes and DKD who started during that period at least one agent from any of the seven included drug classes.

This focus may have biased the findings because, overall, U.S. coverage of the relatively expensive agents from the SGLT2 inhibitor and GLP-1 receptor agonist classes has often been problematic.

“There are issues of cost, coverage, and access” using these medications, as well as limited data on cost-effectiveness, Dr. Paik acknowledged. Additional issues that have helped generate prescribing lags include concerns about possible adverse effects, low familiarity by providers with these drugs early on, and limited trial experience using them in older patients. The process of clinicians growing more comfortable prescribing these new agents has depended on their “working through the evidence,” she explained.

The FDA’s approval in July 2021 of finerenone (Kerendia) for treating patients with type 2 diabetes and chronic kidney disease threw yet another new variable into the prescribing mix for these patients.

“SGLT2 inhibitors are here to stay as a new standard of care for patients with diabetic kidney disease, but combination with finerenone might be especially useful for patients with diabetic kidney disease and heart failure,” Dr. Tuttle suggested. A new generation of clinical trials will likely soon launch to test these combinations, she predicted.

Dr. Paik had no disclosures. Dr. Tuttle has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

[email protected]

U.S. prescribing data from 160,000 adults with type 2 diabetes and diabetic kidney disease showed a notable uptick in new prescriptions for sodium-glucose cotransporter 2 inhibitors and less dramatic gains for glucagonlike peptide–1 receptor agonists during 2019 and continuing into early 2020, compared with prior years, with usage levels of both classes during the first quarter of 2020 rivaling those of more traditional agents including metformin and insulin.

During the first 3 months of 2020, initiation of a SGLT2 inhibitor constituted 13% of all new starts of an antidiabetes drug among adults with type 2 diabetes and diabetic kidney disease (DKD). This compared with initiation rates during the same early 2020 period of 17% for GLP-1 receptor agonists, 19% for metformin, 16% for sulfonylureas, 15% for insulins, 14% for thiazolidinediones, and 6% for dipeptidyl peptidase–4 inhibitors, the seven drug classes examined in a study published in Diabetes Care.

Early 2020 was the first time that starts of a GLP-1 receptor agonist ranked second (behind only metformin) among these seven drug classes in the studied U.S. population, and early 2020 also marked an unprecedentedly high start rate for SGLT2 inhibitors that nearly tripled the roughly 5% rate in place as recently as 2018.
 

Rises are ‘what we expected’

The recent rise of SGLT2 inhibitors and GLP-1 receptor agonists in these patients “was what we expected,” given the evidence for both classes in slowing progression of DKD, said Julie M. Paik, MD, senior author on the study and a nephrologist and pharmacoepidemiologist at Brigham and Women’s Hospital in Boston.

“We’ve seen other beneficial drugs slow on the uptake, so it’s not surprising to see it here, and I’m optimistic” about further increases going forward, she said in an interview.

Both drug classes “were originally marketed as diabetes drugs,” and it is only since 2019, with the publication of trials showing dramatic renal benefits from canagliflozin (Invokana) in CREDENCE, and from dapagliflozin (Farxiga) in DAPA-CKD in 2020 that the evidence became truly compelling for SGLT2 inhibitors. This evidence also led to new renal-protection indications approved by the Food and Drug Administration for canagliflozin and for dapagliflozin, noted Dr. Paik.

Evidence for renal protection also emerged in 2017 for the GLP-1 receptor agonist liraglutide (Victoza) in the LEADER trial, and for dulaglutide (Trulicity) in the AWARD-7 trial, although neither drug has received a renal indication in its labeling.

By 2020, guidelines for managing patients with type 2 diabetes and chronic kidney disease from the influential Kidney Disease: Improving Global Outcomes organization had identified agents from the SGLT2 inhibitor class as top-tier options, along with metformin, for treating these patients, with agents from the GLP-1 receptor agonist class as the top third class to add in patients who require additional glycemic control.

Additional analyses Dr. Paik and associates ran showed how this played out in terms of which specialists prescribed these drugs during the full period studied beginning in 2013. Throughout this roughly 7-year span, about 70% of the prescriptions written for either SGLT2 inhibitors or for GLP-1 receptor agonists were from internal medicine physicians, followed by about 20% written by endocrinologists. Prescriptions from nephrologists, as well as from cardiologists, have hovered at about 5% each, but seem poised to start rising based on the recently added indications and newer treatment recommendations.

“It’s good to see the recent uptick in use since 2019,” Katherine R. Tuttle, MD, commented in an interview. It’s a positive development for U.S. public health, “but we need to do more to disseminate and implement these life-, kidney-, and heart-saving therapies.”

Future use could approach 80% of DKD patients

Dr. Tuttle estimated that “target” levels of use for SGLT2 inhibitors and for GLP-1 receptor agonists “could reasonably approach 80%” for patients with type 2 diabetes and diabetic kidney disease.

“We will likely move to combination therapy” with simultaneous use of agents from both classes in a targeted way using “precision phenotyping based on clinical characteristics, and eventually perhaps by biomarkers, kidney biopsies, or both.” Combined treatment with both an SGLT2 inhibitor and a GLP-1 receptor agonist may be especially suited to patients with type 2 diabetes, atherosclerotic cardiovascular disease, low estimated glomerular filtration rate, and need for better glycemic control and weight loss, a profile that is “pretty typical” in real-world practice, said Dr. Tuttle, a nephrologist and endocrinologist and executive director for research at Providence Healthcare in Spokane, Wash.
 

Study included patients with commercial or Medicare Advantage coverage

The study used information in an Optum database that included patients enrolled in either commercial or in Medicare Advantage health insurance plans from 2013 to the first quarter of 2020. This included 160,489 adults with type 2 diabetes and DKD who started during that period at least one agent from any of the seven included drug classes.

This focus may have biased the findings because, overall, U.S. coverage of the relatively expensive agents from the SGLT2 inhibitor and GLP-1 receptor agonist classes has often been problematic.

“There are issues of cost, coverage, and access” using these medications, as well as limited data on cost-effectiveness, Dr. Paik acknowledged. Additional issues that have helped generate prescribing lags include concerns about possible adverse effects, low familiarity by providers with these drugs early on, and limited trial experience using them in older patients. The process of clinicians growing more comfortable prescribing these new agents has depended on their “working through the evidence,” she explained.

The FDA’s approval in July 2021 of finerenone (Kerendia) for treating patients with type 2 diabetes and chronic kidney disease threw yet another new variable into the prescribing mix for these patients.

“SGLT2 inhibitors are here to stay as a new standard of care for patients with diabetic kidney disease, but combination with finerenone might be especially useful for patients with diabetic kidney disease and heart failure,” Dr. Tuttle suggested. A new generation of clinical trials will likely soon launch to test these combinations, she predicted.

Dr. Paik had no disclosures. Dr. Tuttle has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

[email protected]

U.S. prescribing data from 160,000 adults with type 2 diabetes and diabetic kidney disease showed a notable uptick in new prescriptions for sodium-glucose cotransporter 2 inhibitors and less dramatic gains for glucagonlike peptide–1 receptor agonists during 2019 and continuing into early 2020, compared with prior years, with usage levels of both classes during the first quarter of 2020 rivaling those of more traditional agents including metformin and insulin.

During the first 3 months of 2020, initiation of a SGLT2 inhibitor constituted 13% of all new starts of an antidiabetes drug among adults with type 2 diabetes and diabetic kidney disease (DKD). This compared with initiation rates during the same early 2020 period of 17% for GLP-1 receptor agonists, 19% for metformin, 16% for sulfonylureas, 15% for insulins, 14% for thiazolidinediones, and 6% for dipeptidyl peptidase–4 inhibitors, the seven drug classes examined in a study published in Diabetes Care.

Early 2020 was the first time that starts of a GLP-1 receptor agonist ranked second (behind only metformin) among these seven drug classes in the studied U.S. population, and early 2020 also marked an unprecedentedly high start rate for SGLT2 inhibitors that nearly tripled the roughly 5% rate in place as recently as 2018.
 

Rises are ‘what we expected’

The recent rise of SGLT2 inhibitors and GLP-1 receptor agonists in these patients “was what we expected,” given the evidence for both classes in slowing progression of DKD, said Julie M. Paik, MD, senior author on the study and a nephrologist and pharmacoepidemiologist at Brigham and Women’s Hospital in Boston.

“We’ve seen other beneficial drugs slow on the uptake, so it’s not surprising to see it here, and I’m optimistic” about further increases going forward, she said in an interview.

Both drug classes “were originally marketed as diabetes drugs,” and it is only since 2019, with the publication of trials showing dramatic renal benefits from canagliflozin (Invokana) in CREDENCE, and from dapagliflozin (Farxiga) in DAPA-CKD in 2020 that the evidence became truly compelling for SGLT2 inhibitors. This evidence also led to new renal-protection indications approved by the Food and Drug Administration for canagliflozin and for dapagliflozin, noted Dr. Paik.

Evidence for renal protection also emerged in 2017 for the GLP-1 receptor agonist liraglutide (Victoza) in the LEADER trial, and for dulaglutide (Trulicity) in the AWARD-7 trial, although neither drug has received a renal indication in its labeling.

By 2020, guidelines for managing patients with type 2 diabetes and chronic kidney disease from the influential Kidney Disease: Improving Global Outcomes organization had identified agents from the SGLT2 inhibitor class as top-tier options, along with metformin, for treating these patients, with agents from the GLP-1 receptor agonist class as the top third class to add in patients who require additional glycemic control.

Additional analyses Dr. Paik and associates ran showed how this played out in terms of which specialists prescribed these drugs during the full period studied beginning in 2013. Throughout this roughly 7-year span, about 70% of the prescriptions written for either SGLT2 inhibitors or for GLP-1 receptor agonists were from internal medicine physicians, followed by about 20% written by endocrinologists. Prescriptions from nephrologists, as well as from cardiologists, have hovered at about 5% each, but seem poised to start rising based on the recently added indications and newer treatment recommendations.

“It’s good to see the recent uptick in use since 2019,” Katherine R. Tuttle, MD, commented in an interview. It’s a positive development for U.S. public health, “but we need to do more to disseminate and implement these life-, kidney-, and heart-saving therapies.”

Future use could approach 80% of DKD patients

Dr. Tuttle estimated that “target” levels of use for SGLT2 inhibitors and for GLP-1 receptor agonists “could reasonably approach 80%” for patients with type 2 diabetes and diabetic kidney disease.

“We will likely move to combination therapy” with simultaneous use of agents from both classes in a targeted way using “precision phenotyping based on clinical characteristics, and eventually perhaps by biomarkers, kidney biopsies, or both.” Combined treatment with both an SGLT2 inhibitor and a GLP-1 receptor agonist may be especially suited to patients with type 2 diabetes, atherosclerotic cardiovascular disease, low estimated glomerular filtration rate, and need for better glycemic control and weight loss, a profile that is “pretty typical” in real-world practice, said Dr. Tuttle, a nephrologist and endocrinologist and executive director for research at Providence Healthcare in Spokane, Wash.
 

Study included patients with commercial or Medicare Advantage coverage

The study used information in an Optum database that included patients enrolled in either commercial or in Medicare Advantage health insurance plans from 2013 to the first quarter of 2020. This included 160,489 adults with type 2 diabetes and DKD who started during that period at least one agent from any of the seven included drug classes.

This focus may have biased the findings because, overall, U.S. coverage of the relatively expensive agents from the SGLT2 inhibitor and GLP-1 receptor agonist classes has often been problematic.

“There are issues of cost, coverage, and access” using these medications, as well as limited data on cost-effectiveness, Dr. Paik acknowledged. Additional issues that have helped generate prescribing lags include concerns about possible adverse effects, low familiarity by providers with these drugs early on, and limited trial experience using them in older patients. The process of clinicians growing more comfortable prescribing these new agents has depended on their “working through the evidence,” she explained.

The FDA’s approval in July 2021 of finerenone (Kerendia) for treating patients with type 2 diabetes and chronic kidney disease threw yet another new variable into the prescribing mix for these patients.

“SGLT2 inhibitors are here to stay as a new standard of care for patients with diabetic kidney disease, but combination with finerenone might be especially useful for patients with diabetic kidney disease and heart failure,” Dr. Tuttle suggested. A new generation of clinical trials will likely soon launch to test these combinations, she predicted.

Dr. Paik had no disclosures. Dr. Tuttle has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

[email protected]

The presence of chronic kidney disease (CKD) or end-stage renal disease (ESRD) is associated with worse in-hospital and short-term outcomes after left atrial appendage (LAA) closure, a nationwide study shows.

Patients with ESRD were particularly vulnerable, having about 6.5-fold higher odds of in-hospital mortality than those without CKD and about 11.5-fold higher odds than those with CKD, even after adjustment for potential confounders.

Patients with CKD had higher rates of stroke or transient ischemic attack (TIA) and more short-term readmissions for bleeding, Keerat Rai Ahuja, MD, Reading Hospital-Tower Health, West Reading, Pennsylvania, and colleagues reported August 16 in JACC: Cardiovascular Interventions.

CKD and ESRD are known to be associated with an increased risk for stroke and bleeding in patients with atrial fibrillation (AFib), yet data are limited on the safety and efficacy of LAA closure for stroke prevention in AFib patients with CKD or ESRD, they note.  

“It’s important to know about CKD and understand that there may be an association with worse levels of CKD and worse outcomes, but the data that strikes me is really that for end-stage renal disease,” Matthew Sherwood, MD, MHS, who was not involved with the study, said in an interview.

He noted that data have not been published for patients with CKD and ESRD enrolled in the pivotal PROTECT-AF and PREVAIL trials of Boston Scientific’s Watchman device or from large clinical registries such as EWOLUTION and the company’s continued access protocol registries.

Further, it’s not well understood what the best strategy is to prevent stroke in AFib patients with ESRD and whether they benefit from anticoagulation with warfarin or any of the newer agents. “Thus, it’s hard to then say: ‘Well they have worse outcomes with Watchman,’ which is true as shown in this study, but they may not have any other options based upon the lack of data for oral anticoagulants in end-stage kidney disease patients,” said Dr. Sherwood, from the Inova Heart and Vascular Institute, Falls Church, Virginia.

The lack of clarity is concerning, given rising atrial fibrillation cases and the prevalence of abnormal renal function in everyday practice. In the present study – involving 21,274 patients undergoing LAA closure between 2016 and 2017 in the Nationwide Readmissions Database – 18.6% of patients had CKD stages I to V and 2.7% had ESRD based on ICD-10 codes.

In-hospital mortality was increased only in patients with ESRD. In all, 3.3% of patients with ESRD and 0.4% of those with no CKD died in hospital (adjusted odds ratio [aOR], 6.48), as did 0.5% of patients with CKD (aOR, 11.43; both P <.001).

“These patients represent a sicker population at baseline and have an inherent greater risk for mortality in cardiac interventions, as noted in other studies of structural heart interventions,” Dr. Ahuja and colleagues write.

Patients with CKD had a higher risk for in-hospital stroke or TIA than patients with no CKD (1.8% vs. 1.3%; aOR, 1.35; P = .038) and this risk continued up to 90 days after discharge (1.7% vs. 1.0%; aOR, 1.67; P = .007).

The in-hospital stroke rate was numerically higher in patients with ESRD compared with no CKD (aOR, 1.18; P = .62).

The authors point out that previous LAA closure and CKD studies have reported no differences in in-hospital or subsequent stroke/TIA rates in patients with and without CKD. Possible explanations are that patients with CKD in the present study had higher CHA2DS2-VASc scores than those without CKD (4.18 vs. 3.62) and, second, patients with CKD and AFib are known to have higher risk for thromboembolic events than those with AFib without CKD.

CKD patients were also more likely than those without CKD to experience in-hospital acute kidney injury or hemodialysis (aOR, 5.02; P <.001).

CKD has been shown to be independently associated with acute kidney injury (AKI) after LAA closure. AKI may have long-term thromboembolic consequences, the authors suggest, with one study reporting higher stroke risk at midterm follow-up in patients with AKI.

“As with other cardiac interventions in patients with CKD, efforts should be made to optimize preoperative renal function, minimize contrast volume, and avoid abrupt hemodynamic changes such as hypotension during the procedure to prevent AKI,” Dr. Ahuja and colleagues write.

Patients with CKD and ESRD had longer index length of stay than those without CKD but had similar rates of other in-hospital complications, such as systemic embolization, bleeding/transfusion, vascular complications, and pericardial tamponade requiring intervention.

Among the short-term outcomes, 30- and 90-day all-cause readmissions were increased in patients with CKD and ESRD compared with those without CKD, and 30-day bleeding readmissions were increased within the CKD cohort.

“With Watchman and left atrial appendage closure, what we see is that they have higher rates of readmission and other problems,” Dr. Sherwood said. “I think we understand that that’s probably related not to the procedure itself, not because the Watchman doesn’t work for end-stage kidney disease, but because the patients themselves are likely higher risk.”

Commonly used risk scores for atrial fibrillation, however, don’t take into account advanced kidney disease, he added.

Besides the inherent limitations of observational studies, Dr. Sherwood and the authors point to the lack of laboratory variables and procedural variables in the database, the fact that CKD was defined using ICD-10 codes, that outcomes were not clinically adjudicated, that unmeasured confounders likely still exist, and that long-term follow-up is lacking.

Dr. Sherwood, who wrote an editorial accompanying the study, said that the release of outcomes data from CKD and ESRD patients in the major clinical trials would be helpful going forward, as would possible involvement with the Kidney Disease Improving Global Outcomes organization.

“One of the main points of this study is that we just need a lot more research diving into this patient population,” he said.

The authors report no relevant financial relationships. Dr. Sherwood reports honoraria from Janssen and Medtronic. Editorial coauthor Sean Pokorney reports research grant support from Gilead, Boston Scientific, Pfizer, Bristol Myers Squibb, Janssen, and the Food and Drug Administration; and advisory board, consulting, and honoraria supports from Medtronic, Boston Scientific, Pfizer, Bristol Myers Squibb, Philips, and Zoll.

A version of this article first appeared on Medscape.com.

The presence of chronic kidney disease (CKD) or end-stage renal disease (ESRD) is associated with worse in-hospital and short-term outcomes after left atrial appendage (LAA) closure, a nationwide study shows.

Patients with ESRD were particularly vulnerable, having about 6.5-fold higher odds of in-hospital mortality than those without CKD and about 11.5-fold higher odds than those with CKD, even after adjustment for potential confounders.

Patients with CKD had higher rates of stroke or transient ischemic attack (TIA) and more short-term readmissions for bleeding, Keerat Rai Ahuja, MD, Reading Hospital-Tower Health, West Reading, Pennsylvania, and colleagues reported August 16 in JACC: Cardiovascular Interventions.

CKD and ESRD are known to be associated with an increased risk for stroke and bleeding in patients with atrial fibrillation (AFib), yet data are limited on the safety and efficacy of LAA closure for stroke prevention in AFib patients with CKD or ESRD, they note.  

“It’s important to know about CKD and understand that there may be an association with worse levels of CKD and worse outcomes, but the data that strikes me is really that for end-stage renal disease,” Matthew Sherwood, MD, MHS, who was not involved with the study, said in an interview.

He noted that data have not been published for patients with CKD and ESRD enrolled in the pivotal PROTECT-AF and PREVAIL trials of Boston Scientific’s Watchman device or from large clinical registries such as EWOLUTION and the company’s continued access protocol registries.

Further, it’s not well understood what the best strategy is to prevent stroke in AFib patients with ESRD and whether they benefit from anticoagulation with warfarin or any of the newer agents. “Thus, it’s hard to then say: ‘Well they have worse outcomes with Watchman,’ which is true as shown in this study, but they may not have any other options based upon the lack of data for oral anticoagulants in end-stage kidney disease patients,” said Dr. Sherwood, from the Inova Heart and Vascular Institute, Falls Church, Virginia.

The lack of clarity is concerning, given rising atrial fibrillation cases and the prevalence of abnormal renal function in everyday practice. In the present study – involving 21,274 patients undergoing LAA closure between 2016 and 2017 in the Nationwide Readmissions Database – 18.6% of patients had CKD stages I to V and 2.7% had ESRD based on ICD-10 codes.

In-hospital mortality was increased only in patients with ESRD. In all, 3.3% of patients with ESRD and 0.4% of those with no CKD died in hospital (adjusted odds ratio [aOR], 6.48), as did 0.5% of patients with CKD (aOR, 11.43; both P <.001).

“These patients represent a sicker population at baseline and have an inherent greater risk for mortality in cardiac interventions, as noted in other studies of structural heart interventions,” Dr. Ahuja and colleagues write.

Patients with CKD had a higher risk for in-hospital stroke or TIA than patients with no CKD (1.8% vs. 1.3%; aOR, 1.35; P = .038) and this risk continued up to 90 days after discharge (1.7% vs. 1.0%; aOR, 1.67; P = .007).

The in-hospital stroke rate was numerically higher in patients with ESRD compared with no CKD (aOR, 1.18; P = .62).

The authors point out that previous LAA closure and CKD studies have reported no differences in in-hospital or subsequent stroke/TIA rates in patients with and without CKD. Possible explanations are that patients with CKD in the present study had higher CHA2DS2-VASc scores than those without CKD (4.18 vs. 3.62) and, second, patients with CKD and AFib are known to have higher risk for thromboembolic events than those with AFib without CKD.

CKD patients were also more likely than those without CKD to experience in-hospital acute kidney injury or hemodialysis (aOR, 5.02; P <.001).

CKD has been shown to be independently associated with acute kidney injury (AKI) after LAA closure. AKI may have long-term thromboembolic consequences, the authors suggest, with one study reporting higher stroke risk at midterm follow-up in patients with AKI.

“As with other cardiac interventions in patients with CKD, efforts should be made to optimize preoperative renal function, minimize contrast volume, and avoid abrupt hemodynamic changes such as hypotension during the procedure to prevent AKI,” Dr. Ahuja and colleagues write.

Patients with CKD and ESRD had longer index length of stay than those without CKD but had similar rates of other in-hospital complications, such as systemic embolization, bleeding/transfusion, vascular complications, and pericardial tamponade requiring intervention.

Among the short-term outcomes, 30- and 90-day all-cause readmissions were increased in patients with CKD and ESRD compared with those without CKD, and 30-day bleeding readmissions were increased within the CKD cohort.

“With Watchman and left atrial appendage closure, what we see is that they have higher rates of readmission and other problems,” Dr. Sherwood said. “I think we understand that that’s probably related not to the procedure itself, not because the Watchman doesn’t work for end-stage kidney disease, but because the patients themselves are likely higher risk.”

Commonly used risk scores for atrial fibrillation, however, don’t take into account advanced kidney disease, he added.

Besides the inherent limitations of observational studies, Dr. Sherwood and the authors point to the lack of laboratory variables and procedural variables in the database, the fact that CKD was defined using ICD-10 codes, that outcomes were not clinically adjudicated, that unmeasured confounders likely still exist, and that long-term follow-up is lacking.

Dr. Sherwood, who wrote an editorial accompanying the study, said that the release of outcomes data from CKD and ESRD patients in the major clinical trials would be helpful going forward, as would possible involvement with the Kidney Disease Improving Global Outcomes organization.

“One of the main points of this study is that we just need a lot more research diving into this patient population,” he said.

The authors report no relevant financial relationships. Dr. Sherwood reports honoraria from Janssen and Medtronic. Editorial coauthor Sean Pokorney reports research grant support from Gilead, Boston Scientific, Pfizer, Bristol Myers Squibb, Janssen, and the Food and Drug Administration; and advisory board, consulting, and honoraria supports from Medtronic, Boston Scientific, Pfizer, Bristol Myers Squibb, Philips, and Zoll.

A version of this article first appeared on Medscape.com.

The presence of chronic kidney disease (CKD) or end-stage renal disease (ESRD) is associated with worse in-hospital and short-term outcomes after left atrial appendage (LAA) closure, a nationwide study shows.

Patients with ESRD were particularly vulnerable, having about 6.5-fold higher odds of in-hospital mortality than those without CKD and about 11.5-fold higher odds than those with CKD, even after adjustment for potential confounders.

Patients with CKD had higher rates of stroke or transient ischemic attack (TIA) and more short-term readmissions for bleeding, Keerat Rai Ahuja, MD, Reading Hospital-Tower Health, West Reading, Pennsylvania, and colleagues reported August 16 in JACC: Cardiovascular Interventions.

CKD and ESRD are known to be associated with an increased risk for stroke and bleeding in patients with atrial fibrillation (AFib), yet data are limited on the safety and efficacy of LAA closure for stroke prevention in AFib patients with CKD or ESRD, they note.  

“It’s important to know about CKD and understand that there may be an association with worse levels of CKD and worse outcomes, but the data that strikes me is really that for end-stage renal disease,” Matthew Sherwood, MD, MHS, who was not involved with the study, said in an interview.

He noted that data have not been published for patients with CKD and ESRD enrolled in the pivotal PROTECT-AF and PREVAIL trials of Boston Scientific’s Watchman device or from large clinical registries such as EWOLUTION and the company’s continued access protocol registries.

Further, it’s not well understood what the best strategy is to prevent stroke in AFib patients with ESRD and whether they benefit from anticoagulation with warfarin or any of the newer agents. “Thus, it’s hard to then say: ‘Well they have worse outcomes with Watchman,’ which is true as shown in this study, but they may not have any other options based upon the lack of data for oral anticoagulants in end-stage kidney disease patients,” said Dr. Sherwood, from the Inova Heart and Vascular Institute, Falls Church, Virginia.

The lack of clarity is concerning, given rising atrial fibrillation cases and the prevalence of abnormal renal function in everyday practice. In the present study – involving 21,274 patients undergoing LAA closure between 2016 and 2017 in the Nationwide Readmissions Database – 18.6% of patients had CKD stages I to V and 2.7% had ESRD based on ICD-10 codes.

In-hospital mortality was increased only in patients with ESRD. In all, 3.3% of patients with ESRD and 0.4% of those with no CKD died in hospital (adjusted odds ratio [aOR], 6.48), as did 0.5% of patients with CKD (aOR, 11.43; both P <.001).

“These patients represent a sicker population at baseline and have an inherent greater risk for mortality in cardiac interventions, as noted in other studies of structural heart interventions,” Dr. Ahuja and colleagues write.

Patients with CKD had a higher risk for in-hospital stroke or TIA than patients with no CKD (1.8% vs. 1.3%; aOR, 1.35; P = .038) and this risk continued up to 90 days after discharge (1.7% vs. 1.0%; aOR, 1.67; P = .007).

The in-hospital stroke rate was numerically higher in patients with ESRD compared with no CKD (aOR, 1.18; P = .62).

The authors point out that previous LAA closure and CKD studies have reported no differences in in-hospital or subsequent stroke/TIA rates in patients with and without CKD. Possible explanations are that patients with CKD in the present study had higher CHA2DS2-VASc scores than those without CKD (4.18 vs. 3.62) and, second, patients with CKD and AFib are known to have higher risk for thromboembolic events than those with AFib without CKD.

CKD patients were also more likely than those without CKD to experience in-hospital acute kidney injury or hemodialysis (aOR, 5.02; P <.001).

CKD has been shown to be independently associated with acute kidney injury (AKI) after LAA closure. AKI may have long-term thromboembolic consequences, the authors suggest, with one study reporting higher stroke risk at midterm follow-up in patients with AKI.

“As with other cardiac interventions in patients with CKD, efforts should be made to optimize preoperative renal function, minimize contrast volume, and avoid abrupt hemodynamic changes such as hypotension during the procedure to prevent AKI,” Dr. Ahuja and colleagues write.

Patients with CKD and ESRD had longer index length of stay than those without CKD but had similar rates of other in-hospital complications, such as systemic embolization, bleeding/transfusion, vascular complications, and pericardial tamponade requiring intervention.

Among the short-term outcomes, 30- and 90-day all-cause readmissions were increased in patients with CKD and ESRD compared with those without CKD, and 30-day bleeding readmissions were increased within the CKD cohort.

“With Watchman and left atrial appendage closure, what we see is that they have higher rates of readmission and other problems,” Dr. Sherwood said. “I think we understand that that’s probably related not to the procedure itself, not because the Watchman doesn’t work for end-stage kidney disease, but because the patients themselves are likely higher risk.”

Commonly used risk scores for atrial fibrillation, however, don’t take into account advanced kidney disease, he added.

Besides the inherent limitations of observational studies, Dr. Sherwood and the authors point to the lack of laboratory variables and procedural variables in the database, the fact that CKD was defined using ICD-10 codes, that outcomes were not clinically adjudicated, that unmeasured confounders likely still exist, and that long-term follow-up is lacking.

Dr. Sherwood, who wrote an editorial accompanying the study, said that the release of outcomes data from CKD and ESRD patients in the major clinical trials would be helpful going forward, as would possible involvement with the Kidney Disease Improving Global Outcomes organization.

“One of the main points of this study is that we just need a lot more research diving into this patient population,” he said.

The authors report no relevant financial relationships. Dr. Sherwood reports honoraria from Janssen and Medtronic. Editorial coauthor Sean Pokorney reports research grant support from Gilead, Boston Scientific, Pfizer, Bristol Myers Squibb, Janssen, and the Food and Drug Administration; and advisory board, consulting, and honoraria supports from Medtronic, Boston Scientific, Pfizer, Bristol Myers Squibb, Philips, and Zoll.

A version of this article first appeared on Medscape.com.

With the approval by the Food and Drug Administration of the calcineurin inhibitor voclosporin (Lupkynis) in January and belimumab (Benlysta) a month before that, clinicians now have new options for treating lupus nephritis in combination with a background immunosuppressive agent, such as mycophenolate mofetil.

But which combination should clinicians choose?

Brad Rovin, MD, a nephrologist with the Ohio State University Wexner Medical Center, Columbus, who worked on the phase 3 voclosprin trial, pointed to that drug’s fast reduction in proteinuria in a session of the Pan American League of Associations for Rheumatology (PANLAR) 2021 Annual Meeting. That effect on proteinuria is likely due to its effect on podocytes, special epithelial cells that cover the outside of capillaries in the kidney, he said.

These crucial cells have an elaborate cytoskeleton that is stabilized by the protein synaptopodin, which can be subject to harm from calcineurin. But because voclosporin blocks calcineurin, synaptopodin is protected, which consequently protects podocytes and the kidney, Dr. Rovin said.

“There’s a lot of data in the nephrology literature that suggests as you lose podocytes, you actually can develop glomerular sclerosis and loss of renal function,” he said. “In fact, if you lose a critical number of podocytes, then no matter what you do, the kidney is likely to progress to end-stage kidney disease.

“The way I think about it now is, what else do these drugs add? And this idea of preserving the histology of the kidney is really important, and this can be done with voclosporin,” Dr. Rovin said.

Belimumab is also hailed as an effective tool, particularly for the prevention of flares. In the trial leading to its approval), just under 16% of patients experienced a renal-related event or death over 2 years, compared with 28% of the group that received placebo. Those receiving belimumab had a 50% greater chance of reaching the primary efficacy renal response, which was defined as a ratio of urinary protein to creatinine of 0.7 or less, an estimated glomerular filtration rate that was no worse than 20% below the pre-flare value or at least 60 mL/min per 1.73 m², and no use of rescue therapy for treatment failure.

The endpoints in the belimumab lupus nephritis trial were “quite rigorous,” Richard A. Furie, MD, said in the same session at the meeting. Patients with class V lupus nephritis were included in the trial, although disease of this severity is known to be particularly difficult to treat, he noted.

“There’s little question that our patients with lupus nephritis will benefit from such a therapeutic approach” with belimumab and mycophenolate, said Dr. Furie, professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, in Hempstead, N.Y. “But regardless of which combination clinicians use, we are making advances, and that means better outcomes for our patients with lupus and lupus nephritis.”

Graciela Alarcon, MD, MPH, professor emeritus of medicine at the University of Alabama at Birmingham, who moderated the discussion, said there is no sure answer regarding the best choice for clinicians.

“As long as there’s no head-to-head comparison between the two new compounds, I don’t think that the question can be answered,” she said.

Indeed, the answer for many clinicians might be that for certain patients, dual therapy isn’t necessary, Dr. Furie said.

“The fundamental question, before we choose the second drug, is whether a second drug should be chosen,” he said. “There’s a lot of people in the community who are just sticking to the old-fashioned algorithm and that is just choosing one drug, like mycophenolate. ... Others might pick a second drug, but not until they see that mycophenolate is not doing an effective job.”

All agreed that the response rates are still not optimal for patients with lupus nephritis, even with these new combinations – they are still only in the 30%-40% range.

“We haven’t really boosted the response rate to where we want it to be, at least as measured by our current measurements and composite renal response,” Dr. Rovin said.

With voclosporin’s protective effects and belimumab’s flare prevention, the two could potentially be used together at some point, he suggested.

“I think these two drugs show us the possibility that we might use them together and get rid of the older drugs, and really minimize the older drugs and then use them on a longer-term basis to preserve kidney function, as well as keep the lupus in check,” he said.

A version of this article first appeared on Medscape.com.

With the approval by the Food and Drug Administration of the calcineurin inhibitor voclosporin (Lupkynis) in January and belimumab (Benlysta) a month before that, clinicians now have new options for treating lupus nephritis in combination with a background immunosuppressive agent, such as mycophenolate mofetil.

But which combination should clinicians choose?

Brad Rovin, MD, a nephrologist with the Ohio State University Wexner Medical Center, Columbus, who worked on the phase 3 voclosprin trial, pointed to that drug’s fast reduction in proteinuria in a session of the Pan American League of Associations for Rheumatology (PANLAR) 2021 Annual Meeting. That effect on proteinuria is likely due to its effect on podocytes, special epithelial cells that cover the outside of capillaries in the kidney, he said.

These crucial cells have an elaborate cytoskeleton that is stabilized by the protein synaptopodin, which can be subject to harm from calcineurin. But because voclosporin blocks calcineurin, synaptopodin is protected, which consequently protects podocytes and the kidney, Dr. Rovin said.

“There’s a lot of data in the nephrology literature that suggests as you lose podocytes, you actually can develop glomerular sclerosis and loss of renal function,” he said. “In fact, if you lose a critical number of podocytes, then no matter what you do, the kidney is likely to progress to end-stage kidney disease.

“The way I think about it now is, what else do these drugs add? And this idea of preserving the histology of the kidney is really important, and this can be done with voclosporin,” Dr. Rovin said.

Belimumab is also hailed as an effective tool, particularly for the prevention of flares. In the trial leading to its approval), just under 16% of patients experienced a renal-related event or death over 2 years, compared with 28% of the group that received placebo. Those receiving belimumab had a 50% greater chance of reaching the primary efficacy renal response, which was defined as a ratio of urinary protein to creatinine of 0.7 or less, an estimated glomerular filtration rate that was no worse than 20% below the pre-flare value or at least 60 mL/min per 1.73 m², and no use of rescue therapy for treatment failure.

The endpoints in the belimumab lupus nephritis trial were “quite rigorous,” Richard A. Furie, MD, said in the same session at the meeting. Patients with class V lupus nephritis were included in the trial, although disease of this severity is known to be particularly difficult to treat, he noted.

“There’s little question that our patients with lupus nephritis will benefit from such a therapeutic approach” with belimumab and mycophenolate, said Dr. Furie, professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, in Hempstead, N.Y. “But regardless of which combination clinicians use, we are making advances, and that means better outcomes for our patients with lupus and lupus nephritis.”

Graciela Alarcon, MD, MPH, professor emeritus of medicine at the University of Alabama at Birmingham, who moderated the discussion, said there is no sure answer regarding the best choice for clinicians.

“As long as there’s no head-to-head comparison between the two new compounds, I don’t think that the question can be answered,” she said.

Indeed, the answer for many clinicians might be that for certain patients, dual therapy isn’t necessary, Dr. Furie said.

“The fundamental question, before we choose the second drug, is whether a second drug should be chosen,” he said. “There’s a lot of people in the community who are just sticking to the old-fashioned algorithm and that is just choosing one drug, like mycophenolate. ... Others might pick a second drug, but not until they see that mycophenolate is not doing an effective job.”

All agreed that the response rates are still not optimal for patients with lupus nephritis, even with these new combinations – they are still only in the 30%-40% range.

“We haven’t really boosted the response rate to where we want it to be, at least as measured by our current measurements and composite renal response,” Dr. Rovin said.

With voclosporin’s protective effects and belimumab’s flare prevention, the two could potentially be used together at some point, he suggested.

“I think these two drugs show us the possibility that we might use them together and get rid of the older drugs, and really minimize the older drugs and then use them on a longer-term basis to preserve kidney function, as well as keep the lupus in check,” he said.

A version of this article first appeared on Medscape.com.

With the approval by the Food and Drug Administration of the calcineurin inhibitor voclosporin (Lupkynis) in January and belimumab (Benlysta) a month before that, clinicians now have new options for treating lupus nephritis in combination with a background immunosuppressive agent, such as mycophenolate mofetil.

But which combination should clinicians choose?

Brad Rovin, MD, a nephrologist with the Ohio State University Wexner Medical Center, Columbus, who worked on the phase 3 voclosprin trial, pointed to that drug’s fast reduction in proteinuria in a session of the Pan American League of Associations for Rheumatology (PANLAR) 2021 Annual Meeting. That effect on proteinuria is likely due to its effect on podocytes, special epithelial cells that cover the outside of capillaries in the kidney, he said.

These crucial cells have an elaborate cytoskeleton that is stabilized by the protein synaptopodin, which can be subject to harm from calcineurin. But because voclosporin blocks calcineurin, synaptopodin is protected, which consequently protects podocytes and the kidney, Dr. Rovin said.

“There’s a lot of data in the nephrology literature that suggests as you lose podocytes, you actually can develop glomerular sclerosis and loss of renal function,” he said. “In fact, if you lose a critical number of podocytes, then no matter what you do, the kidney is likely to progress to end-stage kidney disease.

“The way I think about it now is, what else do these drugs add? And this idea of preserving the histology of the kidney is really important, and this can be done with voclosporin,” Dr. Rovin said.

Belimumab is also hailed as an effective tool, particularly for the prevention of flares. In the trial leading to its approval), just under 16% of patients experienced a renal-related event or death over 2 years, compared with 28% of the group that received placebo. Those receiving belimumab had a 50% greater chance of reaching the primary efficacy renal response, which was defined as a ratio of urinary protein to creatinine of 0.7 or less, an estimated glomerular filtration rate that was no worse than 20% below the pre-flare value or at least 60 mL/min per 1.73 m², and no use of rescue therapy for treatment failure.

The endpoints in the belimumab lupus nephritis trial were “quite rigorous,” Richard A. Furie, MD, said in the same session at the meeting. Patients with class V lupus nephritis were included in the trial, although disease of this severity is known to be particularly difficult to treat, he noted.

“There’s little question that our patients with lupus nephritis will benefit from such a therapeutic approach” with belimumab and mycophenolate, said Dr. Furie, professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, in Hempstead, N.Y. “But regardless of which combination clinicians use, we are making advances, and that means better outcomes for our patients with lupus and lupus nephritis.”

Graciela Alarcon, MD, MPH, professor emeritus of medicine at the University of Alabama at Birmingham, who moderated the discussion, said there is no sure answer regarding the best choice for clinicians.

“As long as there’s no head-to-head comparison between the two new compounds, I don’t think that the question can be answered,” she said.

Indeed, the answer for many clinicians might be that for certain patients, dual therapy isn’t necessary, Dr. Furie said.

“The fundamental question, before we choose the second drug, is whether a second drug should be chosen,” he said. “There’s a lot of people in the community who are just sticking to the old-fashioned algorithm and that is just choosing one drug, like mycophenolate. ... Others might pick a second drug, but not until they see that mycophenolate is not doing an effective job.”

All agreed that the response rates are still not optimal for patients with lupus nephritis, even with these new combinations – they are still only in the 30%-40% range.

“We haven’t really boosted the response rate to where we want it to be, at least as measured by our current measurements and composite renal response,” Dr. Rovin said.

With voclosporin’s protective effects and belimumab’s flare prevention, the two could potentially be used together at some point, he suggested.

“I think these two drugs show us the possibility that we might use them together and get rid of the older drugs, and really minimize the older drugs and then use them on a longer-term basis to preserve kidney function, as well as keep the lupus in check,” he said.

A version of this article first appeared on Medscape.com.

Among adults at high risk of type 2 diabetes – the leading cause of kidney disease – those who received vitamin D supplements as opposed to placebo for close to 3 years did not have significant differences in kidney function, in a secondary analysis of the Vitamin D and Type 2 Diabetes (D2d) study.

However, most of these adults with prediabetes plus obesity or overweight also had sufficient serum levels of 25-hydroxyvitamin D (25[OH]D) and a low risk for adverse kidney outcomes at study entry.

“The benefits of vitamin D might be greater in people with low blood vitamin D levels and/or reduced kidney function,” lead author Sun H. Kim, MD, Stanford (Calif.) University, speculated in a statement from the American Society of Nephrology.

The study was published online August 6 in the Clinical Journal of the American Society of Nephrology.

“The D2d study is unique because we recruited individuals with high-risk prediabetes, having two out of three abnormal glucose values, and we recruited more than 2,000 participants, representing the largest vitamin D diabetes prevention trial to date,” Dr. Kim pointed out.

Although the study did not show a benefit of vitamin D supplements on kidney function outcomes, 43% of participants were already taking up to 1,000 IU of vitamin D daily when they entered the study, she noted.

A subgroup analysis of individuals who were not taking vitamin D at study entry found that vitamin D supplements were associated with lowered proteinuria, “which means that it could have a beneficial effect on kidney health,” said Dr. Kim, cautioning that “additional studies are needed to look into this further.”
 

Effect of vitamin D on three kidney function outcomes

Although low levels of serum 25(OH)D are associated with kidney disease, few trials have evaluated how vitamin D supplements might affect kidney function, Dr. Kim and colleagues write.

The D2d trial, they note, found that vitamin D supplements did not lower the risk of incident diabetes in people with prediabetes recruited from medical centers across the United States, as previously reported in 2019.

However, since then, meta-analyses that included the D2d trial have reported a significant 11%-12% reduction in diabetes risk in people with prediabetes who took vitamin D supplements.

The current secondary analysis of D2d aimed to investigate whether vitamin D supplements affect kidney function in people with prediabetes.

A total of 2,166 participants in D2d with complete kidney function data were included in the analysis.

The three study outcomes were change in estimated glomerular filtration rate (eGFR) from baseline, change in urine albumin-to-creatinine ratio (UACR) from baseline, and worsening Kidney Disease: Improving Global Outcomes (KDIGO) risk score (which takes eGFR and UACR into account).

At baseline, patients were a mean age of 60, had a mean body mass index (BMI) of 32 kg/m², and 44% were women.

Most (79%) had hypertension, 52% were receiving antihypertensives, and 33% were receiving an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB).

Participants had a mean serum 25(OH) level of 28 ng/mL.

They had a mean eGFR of 87 mL/min/1.73 m² and a mean UACR of 11 mg/g. Only 10% had a moderate, high, or very high KDIGO risk score.

Participants were randomized to receive a daily gel pill containing 4,000 IU vitamin D3 (cholecalciferol) or placebo.

Medication adherence was high (83%) in both groups during a median follow-up of 2.9 years.

There was no significant between-group difference in the following kidney function outcomes:

• 28 patients in the vitamin D group and 30 patients in the placebo group had a worsening KDIGO risk score.
• The mean difference in eGFR from baseline was -1.0 mL/min/1.73 m² in the vitamin D group and -0.1 mL/min/1.73 m² in the placebo group.
• The mean difference in UACR from baseline was 2.7 mg/g in the vitamin D group and 2.0 mg/g in the placebo group.  

The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Among adults at high risk of type 2 diabetes – the leading cause of kidney disease – those who received vitamin D supplements as opposed to placebo for close to 3 years did not have significant differences in kidney function, in a secondary analysis of the Vitamin D and Type 2 Diabetes (D2d) study.

However, most of these adults with prediabetes plus obesity or overweight also had sufficient serum levels of 25-hydroxyvitamin D (25[OH]D) and a low risk for adverse kidney outcomes at study entry.

“The benefits of vitamin D might be greater in people with low blood vitamin D levels and/or reduced kidney function,” lead author Sun H. Kim, MD, Stanford (Calif.) University, speculated in a statement from the American Society of Nephrology.

The study was published online August 6 in the Clinical Journal of the American Society of Nephrology.

“The D2d study is unique because we recruited individuals with high-risk prediabetes, having two out of three abnormal glucose values, and we recruited more than 2,000 participants, representing the largest vitamin D diabetes prevention trial to date,” Dr. Kim pointed out.

Although the study did not show a benefit of vitamin D supplements on kidney function outcomes, 43% of participants were already taking up to 1,000 IU of vitamin D daily when they entered the study, she noted.

A subgroup analysis of individuals who were not taking vitamin D at study entry found that vitamin D supplements were associated with lowered proteinuria, “which means that it could have a beneficial effect on kidney health,” said Dr. Kim, cautioning that “additional studies are needed to look into this further.”
 

Effect of vitamin D on three kidney function outcomes

Although low levels of serum 25(OH)D are associated with kidney disease, few trials have evaluated how vitamin D supplements might affect kidney function, Dr. Kim and colleagues write.

The D2d trial, they note, found that vitamin D supplements did not lower the risk of incident diabetes in people with prediabetes recruited from medical centers across the United States, as previously reported in 2019.

However, since then, meta-analyses that included the D2d trial have reported a significant 11%-12% reduction in diabetes risk in people with prediabetes who took vitamin D supplements.

The current secondary analysis of D2d aimed to investigate whether vitamin D supplements affect kidney function in people with prediabetes.

A total of 2,166 participants in D2d with complete kidney function data were included in the analysis.

The three study outcomes were change in estimated glomerular filtration rate (eGFR) from baseline, change in urine albumin-to-creatinine ratio (UACR) from baseline, and worsening Kidney Disease: Improving Global Outcomes (KDIGO) risk score (which takes eGFR and UACR into account).

At baseline, patients were a mean age of 60, had a mean body mass index (BMI) of 32 kg/m², and 44% were women.

Most (79%) had hypertension, 52% were receiving antihypertensives, and 33% were receiving an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB).

Participants had a mean serum 25(OH) level of 28 ng/mL.

They had a mean eGFR of 87 mL/min/1.73 m² and a mean UACR of 11 mg/g. Only 10% had a moderate, high, or very high KDIGO risk score.

Participants were randomized to receive a daily gel pill containing 4,000 IU vitamin D3 (cholecalciferol) or placebo.

Medication adherence was high (83%) in both groups during a median follow-up of 2.9 years.

There was no significant between-group difference in the following kidney function outcomes:

• 28 patients in the vitamin D group and 30 patients in the placebo group had a worsening KDIGO risk score.
• The mean difference in eGFR from baseline was -1.0 mL/min/1.73 m² in the vitamin D group and -0.1 mL/min/1.73 m² in the placebo group.
• The mean difference in UACR from baseline was 2.7 mg/g in the vitamin D group and 2.0 mg/g in the placebo group.  

The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Among adults at high risk of type 2 diabetes – the leading cause of kidney disease – those who received vitamin D supplements as opposed to placebo for close to 3 years did not have significant differences in kidney function, in a secondary analysis of the Vitamin D and Type 2 Diabetes (D2d) study.

However, most of these adults with prediabetes plus obesity or overweight also had sufficient serum levels of 25-hydroxyvitamin D (25[OH]D) and a low risk for adverse kidney outcomes at study entry.

“The benefits of vitamin D might be greater in people with low blood vitamin D levels and/or reduced kidney function,” lead author Sun H. Kim, MD, Stanford (Calif.) University, speculated in a statement from the American Society of Nephrology.

The study was published online August 6 in the Clinical Journal of the American Society of Nephrology.

“The D2d study is unique because we recruited individuals with high-risk prediabetes, having two out of three abnormal glucose values, and we recruited more than 2,000 participants, representing the largest vitamin D diabetes prevention trial to date,” Dr. Kim pointed out.

Although the study did not show a benefit of vitamin D supplements on kidney function outcomes, 43% of participants were already taking up to 1,000 IU of vitamin D daily when they entered the study, she noted.

A subgroup analysis of individuals who were not taking vitamin D at study entry found that vitamin D supplements were associated with lowered proteinuria, “which means that it could have a beneficial effect on kidney health,” said Dr. Kim, cautioning that “additional studies are needed to look into this further.”
 

Effect of vitamin D on three kidney function outcomes

Although low levels of serum 25(OH)D are associated with kidney disease, few trials have evaluated how vitamin D supplements might affect kidney function, Dr. Kim and colleagues write.

The D2d trial, they note, found that vitamin D supplements did not lower the risk of incident diabetes in people with prediabetes recruited from medical centers across the United States, as previously reported in 2019.

However, since then, meta-analyses that included the D2d trial have reported a significant 11%-12% reduction in diabetes risk in people with prediabetes who took vitamin D supplements.

The current secondary analysis of D2d aimed to investigate whether vitamin D supplements affect kidney function in people with prediabetes.

A total of 2,166 participants in D2d with complete kidney function data were included in the analysis.

The three study outcomes were change in estimated glomerular filtration rate (eGFR) from baseline, change in urine albumin-to-creatinine ratio (UACR) from baseline, and worsening Kidney Disease: Improving Global Outcomes (KDIGO) risk score (which takes eGFR and UACR into account).

At baseline, patients were a mean age of 60, had a mean body mass index (BMI) of 32 kg/m², and 44% were women.

Most (79%) had hypertension, 52% were receiving antihypertensives, and 33% were receiving an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB).

Participants had a mean serum 25(OH) level of 28 ng/mL.

They had a mean eGFR of 87 mL/min/1.73 m² and a mean UACR of 11 mg/g. Only 10% had a moderate, high, or very high KDIGO risk score.

Participants were randomized to receive a daily gel pill containing 4,000 IU vitamin D3 (cholecalciferol) or placebo.

Medication adherence was high (83%) in both groups during a median follow-up of 2.9 years.

There was no significant between-group difference in the following kidney function outcomes:

• 28 patients in the vitamin D group and 30 patients in the placebo group had a worsening KDIGO risk score.
• The mean difference in eGFR from baseline was -1.0 mL/min/1.73 m² in the vitamin D group and -0.1 mL/min/1.73 m² in the placebo group.
• The mean difference in UACR from baseline was 2.7 mg/g in the vitamin D group and 2.0 mg/g in the placebo group.  

The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The American Medical Association publicly acknowledged in November 2020 that race is a social construct without biological basis, with many other leading medical organizations following suit.¹ Historically, biased science based on observed human physical differences has incorrectly asserted a racial biological hierarchy.^2,3 Today, leading health care organizations recognize that the effects of racist policies in housing, education, employment, and the criminal justice system contribute to health disparities and have a disproportionately negative impact on Black, Indigenous, and People of Color.^3,4 

Racial classification systems are fraught with bias. Trying to classify a complex and nuanced identity such as race into discrete categories does not capture the extensive heterogeneity at the individual level or within the increasingly diverse, multiracial population.⁵ Racial and ethnic categories used in collecting census data and research, as defined by the US Office of Management and Budget, have evolved over time.⁶ These changes in classification are a reflection of changes in the political environment, not changes in scientific knowledge of race and ethnicity.⁶

The Use of Race in Research and Practice

In the United States, racial minorities bear a disproportionate burden of morbidity and mortality across all major disease categories.³ These disparities cannot be explained by genetics.⁴ The Human Genome Project in 2003 confirmed that racial categories have no biologic or genetic basis and that there is more intraracial than interracial genetic variation.³ Nevertheless, significant misapplication of race in medical research and clinical practice remains. Instead of attributing observed differences in health outcomes between racial groups to innate physiological differences between the groups, clinicians and researchers must carefully consider the impact of racism.⁷ This includes considering the complex interactions between socioeconomic, political, and environmental factors, and how they affect health.³

While race is not biologic, the effects of racism can have biologic effects, and advocates appropriately cite the need to collect race as an important category in epidemiological analysis. When race and ethnicity are used as a study variable, bioethicists Kaplan and Bennett recommend that researchers: (1) account for limitations due to imprecision of racial categories; (2) avoid attributing causality when there is an association between race/ethnicity and a health outcome; and (3) refrain from exacerbating racial disparities.⁶

At the bedside, race has become embedded in clinical, seemingly objective, decision-making tools used across medical specialties.⁸ These algorithms often use observational outcomes data and draw conclusions by explicitly or implicitly assuming biological differences among races. By crudely adjusting for race without identifying the root cause for observed racial differences, these tools can further magnify health inequities.⁸ With the increased recognition that race cannot be used as a proxy for genetic ancestry, and that racial and ethnic categories are complex sociopolitical constructs that have changed over time, the practice of race-based medicine is increasingly being criticized.⁸

This article presents a case for the removal of the race coefficient from estimated glomerular filtration rate (eGFR) calculations that exacerbate disparities in kidney health by overestimating kidney function in Black patients.⁸ The main justification for using the race coefficient stems from the disproven assumption that Black people have more muscle mass compared with non-Black people.⁹  The questioning of this racist assertion has led to a national movement to reevaluate the use of race in eGFR calculations.

Racial Disparities in Kidney Disease

According to epidemiological data published by the National Kidney Foundation (NKF) and American Society of Nephrology (ASN), 37 million people in the United States have chronic kidney disease (CKD).¹⁰ Black Americans make up 13% of the US population yet they account for more than 30% of patients with end-stage kidney disease (ESKD) and 35% of those on dialysis.^10,11 There is a 3 times greater risk for progression from early-stage CKD to ESKD in Black Americans when compared to the risk for White Americans.¹¹ Black patients are younger at the time of CKD diagnosis and, once diagnosed, experience a faster progression to ESKD.¹² These disparities are partially attributable to delays in diagnosis, preventative measures, and referrals to nephrology care.¹²  

In a VA medical center study, although Black patients were referred to nephrology care at higher rates than White patients, Black patients had faster progression to CKD stage 5.¹³ An earlier study showed that, at any given eGFR, Black patients have higher levels of albuminuria compared to White patients.¹⁴ While the reasons behind this observation are likely complex and multifactorial, one hypothesis is that Black patients were already at a more advanced stage of kidney disease at the time of referral as a result of the overestimation of eGFR calculations related to the use of a race coefficient.

Additionally, numerous analyses have revealed that Black patients are less likely to be identified as transplant candidates, less likely to be referred for transplant evaluation and, once on the waiting list, wait longer than do White patients.^11,15

Estimated Glomerular Filtration Rate

It is imperative that clinicians have the most accurate measure of GFR to ensure timely diagnosis and appropriate management in patients with CKD. The gold standard for determining renal function requires measuring GFR using an ideal, exogenous, filtration marker such as iothalamate. However, this process is complex and time-consuming, rendering it infeasible in routine care. As a result, we usually estimate GFR using endogenous serum markers such as creatinine and cystatin C. Due to availability and cost, serum creatinine (SCr) is the most widely used marker for estimating kidney function. However, many pitfalls are inherent in its use, including the effects of tubular secretion, extrarenal clearance, and day-to-day variability in creatinine generation related to muscle mass, diet, and activity.¹⁶ The 2 most widely used estimation equations are the Modification of Diet in Renal Disease (MDRD) study equation and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation; both equations incorporate correction factors for age, sex, and race. 

The VA uses MDRD, which was derived and validated in a cohort of 1628 patients that included only 197 Black patients (12%), resulting in an eGFR for Black patients that is 21% higher than is the eGFR for non-Black patients with the same SCr value.⁹ In the VA electronic health record, the race coefficient is incorporated directly into eGFR laboratory calculations based on the race that the veteran self-identified during intake. Because the laboratory reports only a race-adjusted eGFR, there is a lack of transparency as many health care providers and patients are unaware that a race coefficient is used in eGFR calculations at the VA.  

Case for Removing Race Coefficient

When applied to cohorts outside the original study, both the MDRD and CKD-EPI equations have proved to be highly biased, imprecise, and inaccurate when compared to measured GFR (mGFR).^15,17 For any given eGFR, the possible mGFR may span 3 stages of CKD, underscoring the limitations of using such a crude estimate in clinical decision making.¹⁷ 

Current Kidney Estimation Pitfalls

A recent cohort study by Zelnick and colleagues that included 1658 self-identified Black adults showed less bias between mGFR and eGFR without the use of a race coefficient, and a shorter median time to transplant eligibility by 1.9 years.¹⁵ This study provides further evidence that these equations were derived from a biased observational data set that overestimates eGFR in Black patients living with CKD. This overestimation is particularly egregious for frail or malnourished patients with CKD and multiple comorbidities, with many potential harmful clinical consequences.

In addition, multiple international studies in African countries have demonstrated worse performance of eGFR calculations when using the race coefficient than without it. In the Democratic Republic of the Congo, eGFR was calculated for adults using MDRD with and without the race coefficient, as well as CKD-EPI with and without the race coefficient, and then compared to mGFR. Both the MDRD and the CKD-EPI equations overestimated GFR when using the race coefficient, and notably the equations without the race coefficient had better correlation to mGFR.¹⁸ Similar data were also found in studies from South Africa, the Ivory Coast, Brazil, and Europe.^19-22

Clinical Consequences of Race Coefficient Use

The use of a race coefficient in these estimation equations causes adverse clinical outcomes. In early stages of CKD, overestimation of eGFR using the race coefficient can cause an under-recognition of CKD, and can lead to delays in diagnosis and failure to implement measures to slow its progression, such as minimizing drug-related nephrotoxic injury and iatrogenic acute kidney injury. Consequently, a patient with an overestimated eGFR may suffer an accelerated progression to ESKD and premature mortality from cardiovascular disease.²³ 

In advanced CKD stages, eGFR overestimation may result in delayed referral to a nephrologist (recommended at eGFR < 30mL/min/1.73 m²), nutrition counseling, renal replacement therapy education, timely referral for renal replacement therapy access placement, and transplant evaluation (can be listed when eGFR < 20 mL/min/1.73 m²).^16,24,25 

In the Clinical Vignette, it is clear from the information presented that Mr. C’s concerns are well-founded. Table 1 presents the impact on eGFR caused by the race coefficient using the MDRD and CKD-EPI equations. In many VA systems, this overestimation would prevent him from being referred for a kidney transplant at this visit, thereby perpetuating racial health disparities in kidney transplantation. 

Concerns About Removal of Race From eGFR Calculations

Opponents of removing the race coefficient assert that a lower eGFR will preclude some patients from qualifying for medications such as metformin and certain anticoagulants, or that it may result in subtherapeutic dosing of drugs such as antibiotics and chemotherapeutic agents.²⁶ These recommendations are in place for patient safety, so conversely maintaining the race coefficient and overestimating eGFR will expose some patients to medication toxicity. Another fear is that lower eGFRs will have the unintended consequence of limiting the kidney donor pool. However, this can be prevented by following current guidelines to use mGFR in settings where accurate GFR is imperative.¹⁶ Additionally, some nephrologists have expressed concern that diagnosing more patients with advanced stages of CKD will result in inappropriately early initiation of dialysis. Again, this risk can be mitigated by ensuring that nephrologists consider multiple clinical factors and data points, not simply eGFR when deciding to initiate dialysis. Also, an increase in referrals to nephrology may occur when the race coefficient is removed and increased wait times at some VA medical centers could be a concern. An increase in appropriate referrals would show that removing the race coefficient was having its intended effect—more veterans with advanced CKD being seen by nephrologists.

When considering the lack of biological plausibility, inaccuracy, and the clinical harms associated with the use of the race coefficient in eGFR calculations, the benefits of removing the race coefficient from eGFR calculations within the VA far outweigh any potential risks.  

A Call for Equity

The National Conversation on Race and eGFR

To advance health equity, members of the medical community have advocated for the removal of the race coefficient from eGFR calculations for years. Beth Israel Deaconess Medical Center was the first establishment to institute this change in 2017. Since then, many health systems across the country that are affiliated with Veterans Health Administration (VHA) medical centers have removed the race coefficient from eGFR equations (Table 2). Many other hospital systems are contemplating this change. 

In July 2020, the NKF and the ASN established a joint task force dedicated to reassessing the inclusion of race in eGFR calculations. This task force acknowledges that race is a social, not biological, construct.¹² The NKF/ASN task force is now in the second of its 3-phase process. In March 2021, prior to publication of their phase 1 findings, they announced “(1) race modifiers should not be included in equations to estimate kidney function; and (2) current race-based equations should be replaced by a suitable approach that is accurate, inclusive, and standardized in every laboratory in the United States. Any such approach must not differentially introduce bias, inaccuracy, or inequalities.”²⁷

Health Equity in the VHA

In January 2021, President Biden issued an executive order to advance racial equity and support underserved communities through the federal government and its agencies. The VHA is the largest integrated health care system in the United States serving 9 million veterans and is one of the largest federal agencies. As VA clinicians, it is our responsibility to examine the evidence, consider national guidance, and ensure health equity for veterans by practicing unbiased medicine. The evidence and the interim guidance from the NKF-ASN task force clearly indicate that the race coefficient should no longer be used.²⁷ It is imperative that we make these changes immediately knowing that the use of race in kidney function calculators is harming Black veterans. Similar to finding evidence of harm in a treatment group in a clinical trial, it is unethical to wait. Removal of the race coefficient in eGFR calculations will allow VHA clinicians to provide timely and high-quality care to our patients as well as establish the VHA as a national leader in health equity.

VISN 12 Leads the Way

On May 11, 2021, the VA Great Lakes Health Care System, Veterans Integrated Service Network (VISN) 12, leaders responded to this author group’s call to advance health equity and voted to remove the race coefficient from eGFR calculations. Other VISNs should follow, and the VHA should continue to work with national leaders and experts to establish and implement superior tools to ensure the highest quality of kidney health care for all veterans.  

Acknowledgments
The authors would like to thank the medical students across the nation who have been leading the charge on this important issue. The authors are also thankful for the collaboration and support of all members of the Jesse Brown for Black Lives (JB4BL) Task Force. 

The American Medical Association publicly acknowledged in November 2020 that race is a social construct without biological basis, with many other leading medical organizations following suit.¹ Historically, biased science based on observed human physical differences has incorrectly asserted a racial biological hierarchy.^2,3 Today, leading health care organizations recognize that the effects of racist policies in housing, education, employment, and the criminal justice system contribute to health disparities and have a disproportionately negative impact on Black, Indigenous, and People of Color.^3,4 

Racial classification systems are fraught with bias. Trying to classify a complex and nuanced identity such as race into discrete categories does not capture the extensive heterogeneity at the individual level or within the increasingly diverse, multiracial population.⁵ Racial and ethnic categories used in collecting census data and research, as defined by the US Office of Management and Budget, have evolved over time.⁶ These changes in classification are a reflection of changes in the political environment, not changes in scientific knowledge of race and ethnicity.⁶

The Use of Race in Research and Practice

In the United States, racial minorities bear a disproportionate burden of morbidity and mortality across all major disease categories.³ These disparities cannot be explained by genetics.⁴ The Human Genome Project in 2003 confirmed that racial categories have no biologic or genetic basis and that there is more intraracial than interracial genetic variation.³ Nevertheless, significant misapplication of race in medical research and clinical practice remains. Instead of attributing observed differences in health outcomes between racial groups to innate physiological differences between the groups, clinicians and researchers must carefully consider the impact of racism.⁷ This includes considering the complex interactions between socioeconomic, political, and environmental factors, and how they affect health.³

While race is not biologic, the effects of racism can have biologic effects, and advocates appropriately cite the need to collect race as an important category in epidemiological analysis. When race and ethnicity are used as a study variable, bioethicists Kaplan and Bennett recommend that researchers: (1) account for limitations due to imprecision of racial categories; (2) avoid attributing causality when there is an association between race/ethnicity and a health outcome; and (3) refrain from exacerbating racial disparities.⁶

At the bedside, race has become embedded in clinical, seemingly objective, decision-making tools used across medical specialties.⁸ These algorithms often use observational outcomes data and draw conclusions by explicitly or implicitly assuming biological differences among races. By crudely adjusting for race without identifying the root cause for observed racial differences, these tools can further magnify health inequities.⁸ With the increased recognition that race cannot be used as a proxy for genetic ancestry, and that racial and ethnic categories are complex sociopolitical constructs that have changed over time, the practice of race-based medicine is increasingly being criticized.⁸

This article presents a case for the removal of the race coefficient from estimated glomerular filtration rate (eGFR) calculations that exacerbate disparities in kidney health by overestimating kidney function in Black patients.⁸ The main justification for using the race coefficient stems from the disproven assumption that Black people have more muscle mass compared with non-Black people.⁹  The questioning of this racist assertion has led to a national movement to reevaluate the use of race in eGFR calculations.

Racial Disparities in Kidney Disease

According to epidemiological data published by the National Kidney Foundation (NKF) and American Society of Nephrology (ASN), 37 million people in the United States have chronic kidney disease (CKD).¹⁰ Black Americans make up 13% of the US population yet they account for more than 30% of patients with end-stage kidney disease (ESKD) and 35% of those on dialysis.^10,11 There is a 3 times greater risk for progression from early-stage CKD to ESKD in Black Americans when compared to the risk for White Americans.¹¹ Black patients are younger at the time of CKD diagnosis and, once diagnosed, experience a faster progression to ESKD.¹² These disparities are partially attributable to delays in diagnosis, preventative measures, and referrals to nephrology care.¹²  

In a VA medical center study, although Black patients were referred to nephrology care at higher rates than White patients, Black patients had faster progression to CKD stage 5.¹³ An earlier study showed that, at any given eGFR, Black patients have higher levels of albuminuria compared to White patients.¹⁴ While the reasons behind this observation are likely complex and multifactorial, one hypothesis is that Black patients were already at a more advanced stage of kidney disease at the time of referral as a result of the overestimation of eGFR calculations related to the use of a race coefficient.

Additionally, numerous analyses have revealed that Black patients are less likely to be identified as transplant candidates, less likely to be referred for transplant evaluation and, once on the waiting list, wait longer than do White patients.^11,15

Estimated Glomerular Filtration Rate

It is imperative that clinicians have the most accurate measure of GFR to ensure timely diagnosis and appropriate management in patients with CKD. The gold standard for determining renal function requires measuring GFR using an ideal, exogenous, filtration marker such as iothalamate. However, this process is complex and time-consuming, rendering it infeasible in routine care. As a result, we usually estimate GFR using endogenous serum markers such as creatinine and cystatin C. Due to availability and cost, serum creatinine (SCr) is the most widely used marker for estimating kidney function. However, many pitfalls are inherent in its use, including the effects of tubular secretion, extrarenal clearance, and day-to-day variability in creatinine generation related to muscle mass, diet, and activity.¹⁶ The 2 most widely used estimation equations are the Modification of Diet in Renal Disease (MDRD) study equation and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation; both equations incorporate correction factors for age, sex, and race. 

The VA uses MDRD, which was derived and validated in a cohort of 1628 patients that included only 197 Black patients (12%), resulting in an eGFR for Black patients that is 21% higher than is the eGFR for non-Black patients with the same SCr value.⁹ In the VA electronic health record, the race coefficient is incorporated directly into eGFR laboratory calculations based on the race that the veteran self-identified during intake. Because the laboratory reports only a race-adjusted eGFR, there is a lack of transparency as many health care providers and patients are unaware that a race coefficient is used in eGFR calculations at the VA.  

Case for Removing Race Coefficient

When applied to cohorts outside the original study, both the MDRD and CKD-EPI equations have proved to be highly biased, imprecise, and inaccurate when compared to measured GFR (mGFR).^15,17 For any given eGFR, the possible mGFR may span 3 stages of CKD, underscoring the limitations of using such a crude estimate in clinical decision making.¹⁷ 

Current Kidney Estimation Pitfalls

A recent cohort study by Zelnick and colleagues that included 1658 self-identified Black adults showed less bias between mGFR and eGFR without the use of a race coefficient, and a shorter median time to transplant eligibility by 1.9 years.¹⁵ This study provides further evidence that these equations were derived from a biased observational data set that overestimates eGFR in Black patients living with CKD. This overestimation is particularly egregious for frail or malnourished patients with CKD and multiple comorbidities, with many potential harmful clinical consequences.

In addition, multiple international studies in African countries have demonstrated worse performance of eGFR calculations when using the race coefficient than without it. In the Democratic Republic of the Congo, eGFR was calculated for adults using MDRD with and without the race coefficient, as well as CKD-EPI with and without the race coefficient, and then compared to mGFR. Both the MDRD and the CKD-EPI equations overestimated GFR when using the race coefficient, and notably the equations without the race coefficient had better correlation to mGFR.¹⁸ Similar data were also found in studies from South Africa, the Ivory Coast, Brazil, and Europe.^19-22

Clinical Consequences of Race Coefficient Use

The use of a race coefficient in these estimation equations causes adverse clinical outcomes. In early stages of CKD, overestimation of eGFR using the race coefficient can cause an under-recognition of CKD, and can lead to delays in diagnosis and failure to implement measures to slow its progression, such as minimizing drug-related nephrotoxic injury and iatrogenic acute kidney injury. Consequently, a patient with an overestimated eGFR may suffer an accelerated progression to ESKD and premature mortality from cardiovascular disease.²³ 

In advanced CKD stages, eGFR overestimation may result in delayed referral to a nephrologist (recommended at eGFR < 30mL/min/1.73 m²), nutrition counseling, renal replacement therapy education, timely referral for renal replacement therapy access placement, and transplant evaluation (can be listed when eGFR < 20 mL/min/1.73 m²).^16,24,25 

In the Clinical Vignette, it is clear from the information presented that Mr. C’s concerns are well-founded. Table 1 presents the impact on eGFR caused by the race coefficient using the MDRD and CKD-EPI equations. In many VA systems, this overestimation would prevent him from being referred for a kidney transplant at this visit, thereby perpetuating racial health disparities in kidney transplantation. 

Concerns About Removal of Race From eGFR Calculations

Opponents of removing the race coefficient assert that a lower eGFR will preclude some patients from qualifying for medications such as metformin and certain anticoagulants, or that it may result in subtherapeutic dosing of drugs such as antibiotics and chemotherapeutic agents.²⁶ These recommendations are in place for patient safety, so conversely maintaining the race coefficient and overestimating eGFR will expose some patients to medication toxicity. Another fear is that lower eGFRs will have the unintended consequence of limiting the kidney donor pool. However, this can be prevented by following current guidelines to use mGFR in settings where accurate GFR is imperative.¹⁶ Additionally, some nephrologists have expressed concern that diagnosing more patients with advanced stages of CKD will result in inappropriately early initiation of dialysis. Again, this risk can be mitigated by ensuring that nephrologists consider multiple clinical factors and data points, not simply eGFR when deciding to initiate dialysis. Also, an increase in referrals to nephrology may occur when the race coefficient is removed and increased wait times at some VA medical centers could be a concern. An increase in appropriate referrals would show that removing the race coefficient was having its intended effect—more veterans with advanced CKD being seen by nephrologists.

When considering the lack of biological plausibility, inaccuracy, and the clinical harms associated with the use of the race coefficient in eGFR calculations, the benefits of removing the race coefficient from eGFR calculations within the VA far outweigh any potential risks.  

A Call for Equity

The National Conversation on Race and eGFR

To advance health equity, members of the medical community have advocated for the removal of the race coefficient from eGFR calculations for years. Beth Israel Deaconess Medical Center was the first establishment to institute this change in 2017. Since then, many health systems across the country that are affiliated with Veterans Health Administration (VHA) medical centers have removed the race coefficient from eGFR equations (Table 2). Many other hospital systems are contemplating this change. 

In July 2020, the NKF and the ASN established a joint task force dedicated to reassessing the inclusion of race in eGFR calculations. This task force acknowledges that race is a social, not biological, construct.¹² The NKF/ASN task force is now in the second of its 3-phase process. In March 2021, prior to publication of their phase 1 findings, they announced “(1) race modifiers should not be included in equations to estimate kidney function; and (2) current race-based equations should be replaced by a suitable approach that is accurate, inclusive, and standardized in every laboratory in the United States. Any such approach must not differentially introduce bias, inaccuracy, or inequalities.”²⁷

Health Equity in the VHA

In January 2021, President Biden issued an executive order to advance racial equity and support underserved communities through the federal government and its agencies. The VHA is the largest integrated health care system in the United States serving 9 million veterans and is one of the largest federal agencies. As VA clinicians, it is our responsibility to examine the evidence, consider national guidance, and ensure health equity for veterans by practicing unbiased medicine. The evidence and the interim guidance from the NKF-ASN task force clearly indicate that the race coefficient should no longer be used.²⁷ It is imperative that we make these changes immediately knowing that the use of race in kidney function calculators is harming Black veterans. Similar to finding evidence of harm in a treatment group in a clinical trial, it is unethical to wait. Removal of the race coefficient in eGFR calculations will allow VHA clinicians to provide timely and high-quality care to our patients as well as establish the VHA as a national leader in health equity.

VISN 12 Leads the Way

On May 11, 2021, the VA Great Lakes Health Care System, Veterans Integrated Service Network (VISN) 12, leaders responded to this author group’s call to advance health equity and voted to remove the race coefficient from eGFR calculations. Other VISNs should follow, and the VHA should continue to work with national leaders and experts to establish and implement superior tools to ensure the highest quality of kidney health care for all veterans.  

Acknowledgments
The authors would like to thank the medical students across the nation who have been leading the charge on this important issue. The authors are also thankful for the collaboration and support of all members of the Jesse Brown for Black Lives (JB4BL) Task Force. 

The American Medical Association publicly acknowledged in November 2020 that race is a social construct without biological basis, with many other leading medical organizations following suit.¹ Historically, biased science based on observed human physical differences has incorrectly asserted a racial biological hierarchy.^2,3 Today, leading health care organizations recognize that the effects of racist policies in housing, education, employment, and the criminal justice system contribute to health disparities and have a disproportionately negative impact on Black, Indigenous, and People of Color.^3,4 

Racial classification systems are fraught with bias. Trying to classify a complex and nuanced identity such as race into discrete categories does not capture the extensive heterogeneity at the individual level or within the increasingly diverse, multiracial population.⁵ Racial and ethnic categories used in collecting census data and research, as defined by the US Office of Management and Budget, have evolved over time.⁶ These changes in classification are a reflection of changes in the political environment, not changes in scientific knowledge of race and ethnicity.⁶

The Use of Race in Research and Practice

In the United States, racial minorities bear a disproportionate burden of morbidity and mortality across all major disease categories.³ These disparities cannot be explained by genetics.⁴ The Human Genome Project in 2003 confirmed that racial categories have no biologic or genetic basis and that there is more intraracial than interracial genetic variation.³ Nevertheless, significant misapplication of race in medical research and clinical practice remains. Instead of attributing observed differences in health outcomes between racial groups to innate physiological differences between the groups, clinicians and researchers must carefully consider the impact of racism.⁷ This includes considering the complex interactions between socioeconomic, political, and environmental factors, and how they affect health.³

While race is not biologic, the effects of racism can have biologic effects, and advocates appropriately cite the need to collect race as an important category in epidemiological analysis. When race and ethnicity are used as a study variable, bioethicists Kaplan and Bennett recommend that researchers: (1) account for limitations due to imprecision of racial categories; (2) avoid attributing causality when there is an association between race/ethnicity and a health outcome; and (3) refrain from exacerbating racial disparities.⁶

At the bedside, race has become embedded in clinical, seemingly objective, decision-making tools used across medical specialties.⁸ These algorithms often use observational outcomes data and draw conclusions by explicitly or implicitly assuming biological differences among races. By crudely adjusting for race without identifying the root cause for observed racial differences, these tools can further magnify health inequities.⁸ With the increased recognition that race cannot be used as a proxy for genetic ancestry, and that racial and ethnic categories are complex sociopolitical constructs that have changed over time, the practice of race-based medicine is increasingly being criticized.⁸

This article presents a case for the removal of the race coefficient from estimated glomerular filtration rate (eGFR) calculations that exacerbate disparities in kidney health by overestimating kidney function in Black patients.⁸ The main justification for using the race coefficient stems from the disproven assumption that Black people have more muscle mass compared with non-Black people.⁹  The questioning of this racist assertion has led to a national movement to reevaluate the use of race in eGFR calculations.

Racial Disparities in Kidney Disease

According to epidemiological data published by the National Kidney Foundation (NKF) and American Society of Nephrology (ASN), 37 million people in the United States have chronic kidney disease (CKD).¹⁰ Black Americans make up 13% of the US population yet they account for more than 30% of patients with end-stage kidney disease (ESKD) and 35% of those on dialysis.^10,11 There is a 3 times greater risk for progression from early-stage CKD to ESKD in Black Americans when compared to the risk for White Americans.¹¹ Black patients are younger at the time of CKD diagnosis and, once diagnosed, experience a faster progression to ESKD.¹² These disparities are partially attributable to delays in diagnosis, preventative measures, and referrals to nephrology care.¹²  

In a VA medical center study, although Black patients were referred to nephrology care at higher rates than White patients, Black patients had faster progression to CKD stage 5.¹³ An earlier study showed that, at any given eGFR, Black patients have higher levels of albuminuria compared to White patients.¹⁴ While the reasons behind this observation are likely complex and multifactorial, one hypothesis is that Black patients were already at a more advanced stage of kidney disease at the time of referral as a result of the overestimation of eGFR calculations related to the use of a race coefficient.

Additionally, numerous analyses have revealed that Black patients are less likely to be identified as transplant candidates, less likely to be referred for transplant evaluation and, once on the waiting list, wait longer than do White patients.^11,15

Estimated Glomerular Filtration Rate

It is imperative that clinicians have the most accurate measure of GFR to ensure timely diagnosis and appropriate management in patients with CKD. The gold standard for determining renal function requires measuring GFR using an ideal, exogenous, filtration marker such as iothalamate. However, this process is complex and time-consuming, rendering it infeasible in routine care. As a result, we usually estimate GFR using endogenous serum markers such as creatinine and cystatin C. Due to availability and cost, serum creatinine (SCr) is the most widely used marker for estimating kidney function. However, many pitfalls are inherent in its use, including the effects of tubular secretion, extrarenal clearance, and day-to-day variability in creatinine generation related to muscle mass, diet, and activity.¹⁶ The 2 most widely used estimation equations are the Modification of Diet in Renal Disease (MDRD) study equation and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation; both equations incorporate correction factors for age, sex, and race. 

The VA uses MDRD, which was derived and validated in a cohort of 1628 patients that included only 197 Black patients (12%), resulting in an eGFR for Black patients that is 21% higher than is the eGFR for non-Black patients with the same SCr value.⁹ In the VA electronic health record, the race coefficient is incorporated directly into eGFR laboratory calculations based on the race that the veteran self-identified during intake. Because the laboratory reports only a race-adjusted eGFR, there is a lack of transparency as many health care providers and patients are unaware that a race coefficient is used in eGFR calculations at the VA.  

Case for Removing Race Coefficient

When applied to cohorts outside the original study, both the MDRD and CKD-EPI equations have proved to be highly biased, imprecise, and inaccurate when compared to measured GFR (mGFR).^15,17 For any given eGFR, the possible mGFR may span 3 stages of CKD, underscoring the limitations of using such a crude estimate in clinical decision making.¹⁷ 

Current Kidney Estimation Pitfalls

A recent cohort study by Zelnick and colleagues that included 1658 self-identified Black adults showed less bias between mGFR and eGFR without the use of a race coefficient, and a shorter median time to transplant eligibility by 1.9 years.¹⁵ This study provides further evidence that these equations were derived from a biased observational data set that overestimates eGFR in Black patients living with CKD. This overestimation is particularly egregious for frail or malnourished patients with CKD and multiple comorbidities, with many potential harmful clinical consequences.

In addition, multiple international studies in African countries have demonstrated worse performance of eGFR calculations when using the race coefficient than without it. In the Democratic Republic of the Congo, eGFR was calculated for adults using MDRD with and without the race coefficient, as well as CKD-EPI with and without the race coefficient, and then compared to mGFR. Both the MDRD and the CKD-EPI equations overestimated GFR when using the race coefficient, and notably the equations without the race coefficient had better correlation to mGFR.¹⁸ Similar data were also found in studies from South Africa, the Ivory Coast, Brazil, and Europe.^19-22

Clinical Consequences of Race Coefficient Use

The use of a race coefficient in these estimation equations causes adverse clinical outcomes. In early stages of CKD, overestimation of eGFR using the race coefficient can cause an under-recognition of CKD, and can lead to delays in diagnosis and failure to implement measures to slow its progression, such as minimizing drug-related nephrotoxic injury and iatrogenic acute kidney injury. Consequently, a patient with an overestimated eGFR may suffer an accelerated progression to ESKD and premature mortality from cardiovascular disease.²³ 

In advanced CKD stages, eGFR overestimation may result in delayed referral to a nephrologist (recommended at eGFR < 30mL/min/1.73 m²), nutrition counseling, renal replacement therapy education, timely referral for renal replacement therapy access placement, and transplant evaluation (can be listed when eGFR < 20 mL/min/1.73 m²).^16,24,25 

In the Clinical Vignette, it is clear from the information presented that Mr. C’s concerns are well-founded. Table 1 presents the impact on eGFR caused by the race coefficient using the MDRD and CKD-EPI equations. In many VA systems, this overestimation would prevent him from being referred for a kidney transplant at this visit, thereby perpetuating racial health disparities in kidney transplantation. 

Concerns About Removal of Race From eGFR Calculations

Opponents of removing the race coefficient assert that a lower eGFR will preclude some patients from qualifying for medications such as metformin and certain anticoagulants, or that it may result in subtherapeutic dosing of drugs such as antibiotics and chemotherapeutic agents.²⁶ These recommendations are in place for patient safety, so conversely maintaining the race coefficient and overestimating eGFR will expose some patients to medication toxicity. Another fear is that lower eGFRs will have the unintended consequence of limiting the kidney donor pool. However, this can be prevented by following current guidelines to use mGFR in settings where accurate GFR is imperative.¹⁶ Additionally, some nephrologists have expressed concern that diagnosing more patients with advanced stages of CKD will result in inappropriately early initiation of dialysis. Again, this risk can be mitigated by ensuring that nephrologists consider multiple clinical factors and data points, not simply eGFR when deciding to initiate dialysis. Also, an increase in referrals to nephrology may occur when the race coefficient is removed and increased wait times at some VA medical centers could be a concern. An increase in appropriate referrals would show that removing the race coefficient was having its intended effect—more veterans with advanced CKD being seen by nephrologists.

When considering the lack of biological plausibility, inaccuracy, and the clinical harms associated with the use of the race coefficient in eGFR calculations, the benefits of removing the race coefficient from eGFR calculations within the VA far outweigh any potential risks.  

A Call for Equity

The National Conversation on Race and eGFR

To advance health equity, members of the medical community have advocated for the removal of the race coefficient from eGFR calculations for years. Beth Israel Deaconess Medical Center was the first establishment to institute this change in 2017. Since then, many health systems across the country that are affiliated with Veterans Health Administration (VHA) medical centers have removed the race coefficient from eGFR equations (Table 2). Many other hospital systems are contemplating this change. 

In July 2020, the NKF and the ASN established a joint task force dedicated to reassessing the inclusion of race in eGFR calculations. This task force acknowledges that race is a social, not biological, construct.¹² The NKF/ASN task force is now in the second of its 3-phase process. In March 2021, prior to publication of their phase 1 findings, they announced “(1) race modifiers should not be included in equations to estimate kidney function; and (2) current race-based equations should be replaced by a suitable approach that is accurate, inclusive, and standardized in every laboratory in the United States. Any such approach must not differentially introduce bias, inaccuracy, or inequalities.”²⁷

Health Equity in the VHA

In January 2021, President Biden issued an executive order to advance racial equity and support underserved communities through the federal government and its agencies. The VHA is the largest integrated health care system in the United States serving 9 million veterans and is one of the largest federal agencies. As VA clinicians, it is our responsibility to examine the evidence, consider national guidance, and ensure health equity for veterans by practicing unbiased medicine. The evidence and the interim guidance from the NKF-ASN task force clearly indicate that the race coefficient should no longer be used.²⁷ It is imperative that we make these changes immediately knowing that the use of race in kidney function calculators is harming Black veterans. Similar to finding evidence of harm in a treatment group in a clinical trial, it is unethical to wait. Removal of the race coefficient in eGFR calculations will allow VHA clinicians to provide timely and high-quality care to our patients as well as establish the VHA as a national leader in health equity.

VISN 12 Leads the Way

On May 11, 2021, the VA Great Lakes Health Care System, Veterans Integrated Service Network (VISN) 12, leaders responded to this author group’s call to advance health equity and voted to remove the race coefficient from eGFR calculations. Other VISNs should follow, and the VHA should continue to work with national leaders and experts to establish and implement superior tools to ensure the highest quality of kidney health care for all veterans.  

Acknowledgments
The authors would like to thank the medical students across the nation who have been leading the charge on this important issue. The authors are also thankful for the collaboration and support of all members of the Jesse Brown for Black Lives (JB4BL) Task Force. 

Study Overview

Objective. To evaluate the efficacy and safety of the combination of nivolumab plus cabozantinib as compared with sunitinib monotherapy in the treatment of previously untreated advanced renal cell carcinoma (RCC).

Design. Multicenter, international, open-label, randomized, phase 3 trial.

Intervention. Patients were randomized in a 1:1 fashion to 1 of 2 treatment arms:

• Arm A: Nivolumab intravenously 240 mg every 2 weeks plus cabozantinib orally 40 mg once daily.
• Arm B: Sunitinib orally 50 mg daily for 4 weeks, followed by 2 weeks off therapy (6-week cycle).

Randomization was stratified by the International Metastatic RCC Database Consortium prognostic risk score (low-, intermediate-, and high-risk). Treatment was continued until disease progression or development of unacceptable toxic side effects with a maximum of 2-year duration of Nivolumab therapy.

Settings and participants. Adults with previously untreated advanced RCC with a clear cell component were eligible for enrollment. Subjects were excluded if they had active central nervous system metastases or active autoimmune disease.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS) as assessed by an independent review committee. Secondary endpoints included overall survival, objective response rate, safety, and PFS as assessed by investigators. All subgroup analyses were prespecified. Efficacy was assessed in the intention-to-treat population, including all patients who underwent randomization.

Main results. A total of 651 patients underwent randomization: 323 to the nivolumab plus cabozantinib group, and 328 to the sunitinib group. Baseline demographics were balanced. The median follow-up period for overall survival (OS) was 18.1 months. The primary reason for treatment discontinuation in any group was disease progression. PFS as indicated by an independent review committee was significantly longer in the nivolumab plus cabozantinib group compared to the sunitinib group (median 16.6 months vs 8.2 months; hazard ratio [HR] 0.51, P < .001). The median OS was not reached for any group. Overall survival was longer in the nivolumab plus cabozantinib group compared to the sunitinib group (HR 0.60, 95% CI: 0.40-0.89; P = .001). The objective response rate was 55.7% with the nivolumab plus cabozantinib group versus 27.1% with sunitinib (P < .001). The complete response rate was 8% in the nivolumab plus cabozantinib group compared to 4.6% in the sunitinib group. The median time to response was 2.8 months with nivolumab plus cabozantinib and 4.2 months in the sunitinib group, while the median duration of response was 20.2 months and 11.5 months, respectively.

Nearly all patients (about 99% in each group) had an adverse event (AE). Hypertension was the most common side effect, with grade 3 or higher seen in 12.5% in the nivolumab plus cabzantinib group and 13.1% in the sunitinib group. Other grade 3 or higher side effects occurring in at least 10% of patients in any group were hyponatremia, diarrhea, palmar-plantar erythrodysesthesia, hypothyroidism, and fatigue. AEs of any cause leading to discontinuation of the therapy occurred in 19.7% in the nivolumab plus cabzantinib group vs 16.9% of the sunitinib group. One death was considered to be treatment-related (small intestinal perforation) in the nivolumab plus cabozantinib group vs 2 treatment-related deaths with sunitinib (pneumonia and respiratory distress). In the nivolumab plus cabozantinib group, 57% of the patients had a dose reduction of cabozantinib and 52% had a reduction in sunitinib dosage.

Using the Functional Assessment of Cancer Therapy-Kidney Symptoms Index, patients in the nivolumab plus cabozantinib group reported better health-related quality of life and less disease-related symptoms compared to the sunitinib group.

Commentary

The treatment landscape for frontline therapy for patients with advanced RCC has rapidly expanded over the last several years and has revolutionized cancer care. Ushered in by the results from the CheckMate 214 study highlighting the efficacy of dual checkpoint inhibition with nivolumab and ipilimumab in intermediate and poor risk patients, several subsequent trials have demonstrated improved outcomes with combination therapy with immune checkpoint inhibitors and tyrosine-kinase inhibitors (TKI). To date, data from Keynote-426 (pembrolizumab plus axitinib vs sunitinib), Javelin Renal 101 (avelumab plus axitinib vs sunitinib) and the CLEAR trial (lenvatinib plus pembrolizumab vs levatinib plus everolimus vs sunitinib) have demonstrated superiority of immune checkpoint inhibitor/TKI combinations over sunitinb in the first-line setting.^1-5

The current phase 3, CheckMate 9ER trial adds yet another dynamic option for patients with advanced clear cell RCC. While cross-trial comparisons are fraught with important caveats, the median PFS of almost 16.6 months and complete response rate of 8% the nivolumab plus cabozantinib group compares favorably with other combinations. Data from the CLEAR study with the combination of lenvatinib and pembrolizumab showed a complete response rate approaching 16%. Importantly, the current study highlights improved quality of life with the combination of cabozantinib and nivolumab compared to sunitinib alone adding to the efficacy and benefits of this combination treatment.

The selection of first line therapy for patients with advanced RCC should be always guided by individual patient characteristics, and any single immune checkpoint inhibitor/TKI combination is not “superior” to any other. Perhaps more importantly is developing an understanding of the overlapping toxicity profiles of checkpoint inhibitors and TKIs. Again, this trial results are consistent with prior studies in terms of the adverse event profile which were not trivial, and almost all patients (99%) experienced AEs. It is important for oncologists to understand the management of the toxicities with these combinations and dose reductions as appropriate. It is worth noting that 19% of patients with nivolumab plus cabozantinib received glucocorticoids for management of immune-related AEs.

While long-term follow-up data will be needed to further understand the durability of response to this combination, nivolumab-cabozantinib represents an exciting new option for patients with advanced clear cell RCC. As we continue to see improvement in outcomes in clear cell histology, further work must focus on optimization of therapy in non-clear cell RCC as this is a population that is not represented in these data sets. Furthermore, future efforts should begin to explore triplet combinations and biomarker driven patient selection for upfront therapy in ordercontinue to improve outcomes in patients with advanced RCC.

Applications for Clinical Practice

The combination of nivolumab plus cabozantinib adds to the growing list of highly active checkpoint inhibitor/TKI combinations for first-line treatment of advanced RCC. With significant higher response rates, improved outcomes, and improvement in the quality of life, this combination will add another standard treatment option for patients with previously untreated advanced RCC.

Study Overview

Objective. To evaluate the efficacy and safety of the combination of nivolumab plus cabozantinib as compared with sunitinib monotherapy in the treatment of previously untreated advanced renal cell carcinoma (RCC).

Design. Multicenter, international, open-label, randomized, phase 3 trial.

Intervention. Patients were randomized in a 1:1 fashion to 1 of 2 treatment arms:

• Arm A: Nivolumab intravenously 240 mg every 2 weeks plus cabozantinib orally 40 mg once daily.
• Arm B: Sunitinib orally 50 mg daily for 4 weeks, followed by 2 weeks off therapy (6-week cycle).

Randomization was stratified by the International Metastatic RCC Database Consortium prognostic risk score (low-, intermediate-, and high-risk). Treatment was continued until disease progression or development of unacceptable toxic side effects with a maximum of 2-year duration of Nivolumab therapy.

Settings and participants. Adults with previously untreated advanced RCC with a clear cell component were eligible for enrollment. Subjects were excluded if they had active central nervous system metastases or active autoimmune disease.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS) as assessed by an independent review committee. Secondary endpoints included overall survival, objective response rate, safety, and PFS as assessed by investigators. All subgroup analyses were prespecified. Efficacy was assessed in the intention-to-treat population, including all patients who underwent randomization.

Main results. A total of 651 patients underwent randomization: 323 to the nivolumab plus cabozantinib group, and 328 to the sunitinib group. Baseline demographics were balanced. The median follow-up period for overall survival (OS) was 18.1 months. The primary reason for treatment discontinuation in any group was disease progression. PFS as indicated by an independent review committee was significantly longer in the nivolumab plus cabozantinib group compared to the sunitinib group (median 16.6 months vs 8.2 months; hazard ratio [HR] 0.51, P < .001). The median OS was not reached for any group. Overall survival was longer in the nivolumab plus cabozantinib group compared to the sunitinib group (HR 0.60, 95% CI: 0.40-0.89; P = .001). The objective response rate was 55.7% with the nivolumab plus cabozantinib group versus 27.1% with sunitinib (P < .001). The complete response rate was 8% in the nivolumab plus cabozantinib group compared to 4.6% in the sunitinib group. The median time to response was 2.8 months with nivolumab plus cabozantinib and 4.2 months in the sunitinib group, while the median duration of response was 20.2 months and 11.5 months, respectively.

Nearly all patients (about 99% in each group) had an adverse event (AE). Hypertension was the most common side effect, with grade 3 or higher seen in 12.5% in the nivolumab plus cabzantinib group and 13.1% in the sunitinib group. Other grade 3 or higher side effects occurring in at least 10% of patients in any group were hyponatremia, diarrhea, palmar-plantar erythrodysesthesia, hypothyroidism, and fatigue. AEs of any cause leading to discontinuation of the therapy occurred in 19.7% in the nivolumab plus cabzantinib group vs 16.9% of the sunitinib group. One death was considered to be treatment-related (small intestinal perforation) in the nivolumab plus cabozantinib group vs 2 treatment-related deaths with sunitinib (pneumonia and respiratory distress). In the nivolumab plus cabozantinib group, 57% of the patients had a dose reduction of cabozantinib and 52% had a reduction in sunitinib dosage.

Using the Functional Assessment of Cancer Therapy-Kidney Symptoms Index, patients in the nivolumab plus cabozantinib group reported better health-related quality of life and less disease-related symptoms compared to the sunitinib group.

Commentary

The treatment landscape for frontline therapy for patients with advanced RCC has rapidly expanded over the last several years and has revolutionized cancer care. Ushered in by the results from the CheckMate 214 study highlighting the efficacy of dual checkpoint inhibition with nivolumab and ipilimumab in intermediate and poor risk patients, several subsequent trials have demonstrated improved outcomes with combination therapy with immune checkpoint inhibitors and tyrosine-kinase inhibitors (TKI). To date, data from Keynote-426 (pembrolizumab plus axitinib vs sunitinib), Javelin Renal 101 (avelumab plus axitinib vs sunitinib) and the CLEAR trial (lenvatinib plus pembrolizumab vs levatinib plus everolimus vs sunitinib) have demonstrated superiority of immune checkpoint inhibitor/TKI combinations over sunitinb in the first-line setting.^1-5

The current phase 3, CheckMate 9ER trial adds yet another dynamic option for patients with advanced clear cell RCC. While cross-trial comparisons are fraught with important caveats, the median PFS of almost 16.6 months and complete response rate of 8% the nivolumab plus cabozantinib group compares favorably with other combinations. Data from the CLEAR study with the combination of lenvatinib and pembrolizumab showed a complete response rate approaching 16%. Importantly, the current study highlights improved quality of life with the combination of cabozantinib and nivolumab compared to sunitinib alone adding to the efficacy and benefits of this combination treatment.

The selection of first line therapy for patients with advanced RCC should be always guided by individual patient characteristics, and any single immune checkpoint inhibitor/TKI combination is not “superior” to any other. Perhaps more importantly is developing an understanding of the overlapping toxicity profiles of checkpoint inhibitors and TKIs. Again, this trial results are consistent with prior studies in terms of the adverse event profile which were not trivial, and almost all patients (99%) experienced AEs. It is important for oncologists to understand the management of the toxicities with these combinations and dose reductions as appropriate. It is worth noting that 19% of patients with nivolumab plus cabozantinib received glucocorticoids for management of immune-related AEs.

While long-term follow-up data will be needed to further understand the durability of response to this combination, nivolumab-cabozantinib represents an exciting new option for patients with advanced clear cell RCC. As we continue to see improvement in outcomes in clear cell histology, further work must focus on optimization of therapy in non-clear cell RCC as this is a population that is not represented in these data sets. Furthermore, future efforts should begin to explore triplet combinations and biomarker driven patient selection for upfront therapy in ordercontinue to improve outcomes in patients with advanced RCC.

Applications for Clinical Practice

The combination of nivolumab plus cabozantinib adds to the growing list of highly active checkpoint inhibitor/TKI combinations for first-line treatment of advanced RCC. With significant higher response rates, improved outcomes, and improvement in the quality of life, this combination will add another standard treatment option for patients with previously untreated advanced RCC.

Study Overview

Objective. To evaluate the efficacy and safety of the combination of nivolumab plus cabozantinib as compared with sunitinib monotherapy in the treatment of previously untreated advanced renal cell carcinoma (RCC).

Design. Multicenter, international, open-label, randomized, phase 3 trial.

Intervention. Patients were randomized in a 1:1 fashion to 1 of 2 treatment arms:

• Arm A: Nivolumab intravenously 240 mg every 2 weeks plus cabozantinib orally 40 mg once daily.
• Arm B: Sunitinib orally 50 mg daily for 4 weeks, followed by 2 weeks off therapy (6-week cycle).

Randomization was stratified by the International Metastatic RCC Database Consortium prognostic risk score (low-, intermediate-, and high-risk). Treatment was continued until disease progression or development of unacceptable toxic side effects with a maximum of 2-year duration of Nivolumab therapy.

Settings and participants. Adults with previously untreated advanced RCC with a clear cell component were eligible for enrollment. Subjects were excluded if they had active central nervous system metastases or active autoimmune disease.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS) as assessed by an independent review committee. Secondary endpoints included overall survival, objective response rate, safety, and PFS as assessed by investigators. All subgroup analyses were prespecified. Efficacy was assessed in the intention-to-treat population, including all patients who underwent randomization.

Main results. A total of 651 patients underwent randomization: 323 to the nivolumab plus cabozantinib group, and 328 to the sunitinib group. Baseline demographics were balanced. The median follow-up period for overall survival (OS) was 18.1 months. The primary reason for treatment discontinuation in any group was disease progression. PFS as indicated by an independent review committee was significantly longer in the nivolumab plus cabozantinib group compared to the sunitinib group (median 16.6 months vs 8.2 months; hazard ratio [HR] 0.51, P < .001). The median OS was not reached for any group. Overall survival was longer in the nivolumab plus cabozantinib group compared to the sunitinib group (HR 0.60, 95% CI: 0.40-0.89; P = .001). The objective response rate was 55.7% with the nivolumab plus cabozantinib group versus 27.1% with sunitinib (P < .001). The complete response rate was 8% in the nivolumab plus cabozantinib group compared to 4.6% in the sunitinib group. The median time to response was 2.8 months with nivolumab plus cabozantinib and 4.2 months in the sunitinib group, while the median duration of response was 20.2 months and 11.5 months, respectively.

Nearly all patients (about 99% in each group) had an adverse event (AE). Hypertension was the most common side effect, with grade 3 or higher seen in 12.5% in the nivolumab plus cabzantinib group and 13.1% in the sunitinib group. Other grade 3 or higher side effects occurring in at least 10% of patients in any group were hyponatremia, diarrhea, palmar-plantar erythrodysesthesia, hypothyroidism, and fatigue. AEs of any cause leading to discontinuation of the therapy occurred in 19.7% in the nivolumab plus cabzantinib group vs 16.9% of the sunitinib group. One death was considered to be treatment-related (small intestinal perforation) in the nivolumab plus cabozantinib group vs 2 treatment-related deaths with sunitinib (pneumonia and respiratory distress). In the nivolumab plus cabozantinib group, 57% of the patients had a dose reduction of cabozantinib and 52% had a reduction in sunitinib dosage.

Using the Functional Assessment of Cancer Therapy-Kidney Symptoms Index, patients in the nivolumab plus cabozantinib group reported better health-related quality of life and less disease-related symptoms compared to the sunitinib group.

Commentary

The treatment landscape for frontline therapy for patients with advanced RCC has rapidly expanded over the last several years and has revolutionized cancer care. Ushered in by the results from the CheckMate 214 study highlighting the efficacy of dual checkpoint inhibition with nivolumab and ipilimumab in intermediate and poor risk patients, several subsequent trials have demonstrated improved outcomes with combination therapy with immune checkpoint inhibitors and tyrosine-kinase inhibitors (TKI). To date, data from Keynote-426 (pembrolizumab plus axitinib vs sunitinib), Javelin Renal 101 (avelumab plus axitinib vs sunitinib) and the CLEAR trial (lenvatinib plus pembrolizumab vs levatinib plus everolimus vs sunitinib) have demonstrated superiority of immune checkpoint inhibitor/TKI combinations over sunitinb in the first-line setting.^1-5

The current phase 3, CheckMate 9ER trial adds yet another dynamic option for patients with advanced clear cell RCC. While cross-trial comparisons are fraught with important caveats, the median PFS of almost 16.6 months and complete response rate of 8% the nivolumab plus cabozantinib group compares favorably with other combinations. Data from the CLEAR study with the combination of lenvatinib and pembrolizumab showed a complete response rate approaching 16%. Importantly, the current study highlights improved quality of life with the combination of cabozantinib and nivolumab compared to sunitinib alone adding to the efficacy and benefits of this combination treatment.

The selection of first line therapy for patients with advanced RCC should be always guided by individual patient characteristics, and any single immune checkpoint inhibitor/TKI combination is not “superior” to any other. Perhaps more importantly is developing an understanding of the overlapping toxicity profiles of checkpoint inhibitors and TKIs. Again, this trial results are consistent with prior studies in terms of the adverse event profile which were not trivial, and almost all patients (99%) experienced AEs. It is important for oncologists to understand the management of the toxicities with these combinations and dose reductions as appropriate. It is worth noting that 19% of patients with nivolumab plus cabozantinib received glucocorticoids for management of immune-related AEs.

While long-term follow-up data will be needed to further understand the durability of response to this combination, nivolumab-cabozantinib represents an exciting new option for patients with advanced clear cell RCC. As we continue to see improvement in outcomes in clear cell histology, further work must focus on optimization of therapy in non-clear cell RCC as this is a population that is not represented in these data sets. Furthermore, future efforts should begin to explore triplet combinations and biomarker driven patient selection for upfront therapy in ordercontinue to improve outcomes in patients with advanced RCC.

Applications for Clinical Practice

The combination of nivolumab plus cabozantinib adds to the growing list of highly active checkpoint inhibitor/TKI combinations for first-line treatment of advanced RCC. With significant higher response rates, improved outcomes, and improvement in the quality of life, this combination will add another standard treatment option for patients with previously untreated advanced RCC.

U.S. primary care physicians are not properly checking patients with type 2 diabetes for chronic kidney disease (CKD) nearly as often as they should, meaning many of these patients miss getting a timely diagnosis.

Inadequate measurement of urinary albumin-to-creatinine ratio (uACR) is the issue.

Review of data from more than half a million U.S. primary care patients with type 2 diabetes seen at any of 1,164 practice sites run by any of 24 health care organizations during 2016-2019 showed that barely more than half, 52%, had both their uACR and estimated glomerular filtration rate (eGFR) checked annually as recommended by several U.S. medical societies, and just 73% had both values checked during a 3-year period, Nikita Stempniewicz, MSc, and associates reported in Diabetes Care.

More detailed data showed that measurement of eGFR was reasonably robust, measured at a 90% rate annually and in 97% of patients at least once every 3 years. But recording uACR values lagged, with a 53% annual rate and a 74% rate of measurement at least once every 3 years, reported Mr. Stempniewicz, director of research and analytics for the American Medical Group Association, a trade association based in Alexandria, Va. The 24 health care organizations that supplied the study’s data are all members of this association.

Prevailing recommendations from various medical societies call for annual monitoring of urinary albumin in patients with type 2 diabetes and specify the uACR, such as in the Standards of Medical Care in Diabetes from the American Diabetes Association, as well as in recommendations promoted by the National Kidney Foundation.
 

Missing half the CKD patients with eGFR only

“Half the patients with type 2 diabetes and chronic kidney disease have elevated albuminuria without decreased eGFR and would not be detected with eGFR testing alone,” Mr. Stempniewicz noted in an interview.

“Many patients who present for nephrology care are incompletely assessed with only low eGFR but no urine testing. Missing albuminuria testing and uACR values means patients with high levels of albuminuria but normal kidney function go undetected and thus are not able to benefit from evidenced-based interventions, including nephrology services,” said Joseph A. Vassalotti, MD, a nephrologist, chief medical officer for the National Kidney Foundation, and a coauthor of the report.

Not testing patients with type 2 diabetes regularly for their uACR “is a missed opportunity to identify the highest-risk patients and treat them,” added Josef Coresh, MD, PhD, a professor of clinical epidemiology at Johns Hopkins University, Baltimore, and senior author on the study. Measurement of albuminuria is especially important for these patients because medications from the sodium-glucose cotransporter 2 inhibitor class have been proven to slow progression of CKD in patients with type 2 diabetes, but these drugs are expensive, and in some cases have labeling that specifies the presence of albuminuria.

“I have no doubt that improving albuminuria testing is a critical step to identify patients with diabetes at highest risk who should get the best treatment possible, including SGLT2 inhibitors,” Dr. Coresh said in an interview.

The new report is not the first to document inadequate assessment of albuminuria and uACR among primary care physicians (PCPs), but it came from the largest reported U.S. study to date. “eGFR is commonly collected in a routine laboratory blood panel, but collecting urine requires additional work flow,” noted Cara B. Litvin, MD, a general internal medicine researcher at the Medical University of South Carolina, Charleston, who has tested interventions aimed at boosting CKD assessment by PCPs and was not involved in the new study.

“There have also been conflicting guidelines,” such as a “now-inactive guideline from the American College of Physicians that recommended against routine urine albumin screening in patients with diabetes and already on treatment with an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker,” she said.
 

New renal drugs change the stakes

The availability of newer drugs for slowing CKD progression such as the SGLT2 inhibitors will help trigger greater support for routine albuminuria testing, Dr. Litvin predicted in an interview. “Now that we have more medications that can reduce albuminuria and improve outcomes, I see screening for albuminuria increasing.” Finerenone (Kerendia) is another new agent from a new class that recently received Food and Drug Administration approval for treating CKD in patients with type 2 diabetes.

Other drivers of increased uACR testing she expects include revised clinical practice guidelines, and new quality measures of clinical care.

“Undertesting of albuminuria means that [nephrologists] have incomplete data to detect and completely risk stratify the CKD population. That in turn results in a reduced ability to match population health interventions to the severity of the condition or the risk stratification based on eGFR and uACR,” Dr. Vassalotti said in an interview.

“We are missing opportunities to prevent or delay kidney failure and reduce the risk of cardiovascular events and cardiovascular death in these patients, particularly now that we have a number of medications that offer kidney and cardiovascular protection such as SGLT2 inhibitors,” he added. “Leaders in nephrology are beginning to understand the consequences of undertesting, and are working to innovate to improve risk stratification, CKD detection, and apply interventions to give Americans living with CKD better outcomes.”

Strategies proven to boost albuminuria testing

Mr. Stempniewicz and coauthors cited in their report potential strategies for improving albuminuria testing, including benchmarking to identify best-performing sites for albumin testing within a health system and encouraging replication of identified best practices at lower-performing sites, and implementation of clinical-decision support tools in the EHR such as pop-up test reminders.

These were among the tools tested in two studies led by Dr. Litvin. One study, with results reported in 2016, involved 12 small U.S. primary care practices with a total of more than 30,000 patients and compared performance in a series of clinical quality measures at baseline with performance after 2 years of receiving various interventions designed to boost awareness for albuminuria testing.

The second study, with findings reported in 2019, involved 21 U.S. primary care practices that collectively cared for more than 100,000 patients and randomized the practices to either undergo interventions aimed at boosting testing awareness or to serve as controls.

Results from both studies showed significant and substantial increases in serial testing for albuminuria in patients with diabetes or hypertension when practices received the interventions.

“We showed that [using a] clinical-decision support tool, along with standing orders to automatically collect urine specimens, dramatically increased screening for urinary albumin in primary care practices,” Dr. Litvin said. “However, perhaps because of conflicting guidelines and clinical inertia there hasn’t been a major impetus for primary care practices in general to improve screening.” She hopes that will quickly change.

“As we have shown, adoption of EHR-based reminders along with standing orders can very quickly improve screening for albuminuria in primary care.”

Variation in testing rates among sites ‘tremendous’

One finding of the new study gives Mr. Stempniewicz hope for greater future testing: The large variance that the researchers saw in albuminuria testing rates within individual health systems.

“The paper shows that higher rates of testing are completely achievable within each system. Some clinics do very well, and the other units can learn from these local successes,” he said. At least half the organizations in the study had individual sites that fell into the top 10% for testing rates across all the greater than 1,000 sites included, and those same organizations also had at least one site that fell into the bottom 10% for testing.

“The variation is tremendous, and highlights an opportunity for improvement,” declared Mr. Stempniewicz.

“For routine testing, you need systems that help people. Clinicians shouldn’t have to think about doing routine testing. It should just happen,” said Dr. Coresh.

The study was funded in part by Janssen. Mr. Stempniewicz and Dr. Litvin had no disclosures. Dr. Coresh is an adviser to Healthy.io, a company that markets a home albuminuria testing kit to patients. Dr. Vassalotti has received personal fees from Renalytix.

[email protected]

U.S. primary care physicians are not properly checking patients with type 2 diabetes for chronic kidney disease (CKD) nearly as often as they should, meaning many of these patients miss getting a timely diagnosis.

Inadequate measurement of urinary albumin-to-creatinine ratio (uACR) is the issue.

Review of data from more than half a million U.S. primary care patients with type 2 diabetes seen at any of 1,164 practice sites run by any of 24 health care organizations during 2016-2019 showed that barely more than half, 52%, had both their uACR and estimated glomerular filtration rate (eGFR) checked annually as recommended by several U.S. medical societies, and just 73% had both values checked during a 3-year period, Nikita Stempniewicz, MSc, and associates reported in Diabetes Care.

More detailed data showed that measurement of eGFR was reasonably robust, measured at a 90% rate annually and in 97% of patients at least once every 3 years. But recording uACR values lagged, with a 53% annual rate and a 74% rate of measurement at least once every 3 years, reported Mr. Stempniewicz, director of research and analytics for the American Medical Group Association, a trade association based in Alexandria, Va. The 24 health care organizations that supplied the study’s data are all members of this association.

Prevailing recommendations from various medical societies call for annual monitoring of urinary albumin in patients with type 2 diabetes and specify the uACR, such as in the Standards of Medical Care in Diabetes from the American Diabetes Association, as well as in recommendations promoted by the National Kidney Foundation.
 

Missing half the CKD patients with eGFR only

“Half the patients with type 2 diabetes and chronic kidney disease have elevated albuminuria without decreased eGFR and would not be detected with eGFR testing alone,” Mr. Stempniewicz noted in an interview.

“Many patients who present for nephrology care are incompletely assessed with only low eGFR but no urine testing. Missing albuminuria testing and uACR values means patients with high levels of albuminuria but normal kidney function go undetected and thus are not able to benefit from evidenced-based interventions, including nephrology services,” said Joseph A. Vassalotti, MD, a nephrologist, chief medical officer for the National Kidney Foundation, and a coauthor of the report.

Not testing patients with type 2 diabetes regularly for their uACR “is a missed opportunity to identify the highest-risk patients and treat them,” added Josef Coresh, MD, PhD, a professor of clinical epidemiology at Johns Hopkins University, Baltimore, and senior author on the study. Measurement of albuminuria is especially important for these patients because medications from the sodium-glucose cotransporter 2 inhibitor class have been proven to slow progression of CKD in patients with type 2 diabetes, but these drugs are expensive, and in some cases have labeling that specifies the presence of albuminuria.

“I have no doubt that improving albuminuria testing is a critical step to identify patients with diabetes at highest risk who should get the best treatment possible, including SGLT2 inhibitors,” Dr. Coresh said in an interview.

The new report is not the first to document inadequate assessment of albuminuria and uACR among primary care physicians (PCPs), but it came from the largest reported U.S. study to date. “eGFR is commonly collected in a routine laboratory blood panel, but collecting urine requires additional work flow,” noted Cara B. Litvin, MD, a general internal medicine researcher at the Medical University of South Carolina, Charleston, who has tested interventions aimed at boosting CKD assessment by PCPs and was not involved in the new study.

“There have also been conflicting guidelines,” such as a “now-inactive guideline from the American College of Physicians that recommended against routine urine albumin screening in patients with diabetes and already on treatment with an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker,” she said.
 

New renal drugs change the stakes

The availability of newer drugs for slowing CKD progression such as the SGLT2 inhibitors will help trigger greater support for routine albuminuria testing, Dr. Litvin predicted in an interview. “Now that we have more medications that can reduce albuminuria and improve outcomes, I see screening for albuminuria increasing.” Finerenone (Kerendia) is another new agent from a new class that recently received Food and Drug Administration approval for treating CKD in patients with type 2 diabetes.

Other drivers of increased uACR testing she expects include revised clinical practice guidelines, and new quality measures of clinical care.

“Undertesting of albuminuria means that [nephrologists] have incomplete data to detect and completely risk stratify the CKD population. That in turn results in a reduced ability to match population health interventions to the severity of the condition or the risk stratification based on eGFR and uACR,” Dr. Vassalotti said in an interview.

“We are missing opportunities to prevent or delay kidney failure and reduce the risk of cardiovascular events and cardiovascular death in these patients, particularly now that we have a number of medications that offer kidney and cardiovascular protection such as SGLT2 inhibitors,” he added. “Leaders in nephrology are beginning to understand the consequences of undertesting, and are working to innovate to improve risk stratification, CKD detection, and apply interventions to give Americans living with CKD better outcomes.”

Strategies proven to boost albuminuria testing

Mr. Stempniewicz and coauthors cited in their report potential strategies for improving albuminuria testing, including benchmarking to identify best-performing sites for albumin testing within a health system and encouraging replication of identified best practices at lower-performing sites, and implementation of clinical-decision support tools in the EHR such as pop-up test reminders.

These were among the tools tested in two studies led by Dr. Litvin. One study, with results reported in 2016, involved 12 small U.S. primary care practices with a total of more than 30,000 patients and compared performance in a series of clinical quality measures at baseline with performance after 2 years of receiving various interventions designed to boost awareness for albuminuria testing.

The second study, with findings reported in 2019, involved 21 U.S. primary care practices that collectively cared for more than 100,000 patients and randomized the practices to either undergo interventions aimed at boosting testing awareness or to serve as controls.

Results from both studies showed significant and substantial increases in serial testing for albuminuria in patients with diabetes or hypertension when practices received the interventions.

“We showed that [using a] clinical-decision support tool, along with standing orders to automatically collect urine specimens, dramatically increased screening for urinary albumin in primary care practices,” Dr. Litvin said. “However, perhaps because of conflicting guidelines and clinical inertia there hasn’t been a major impetus for primary care practices in general to improve screening.” She hopes that will quickly change.

“As we have shown, adoption of EHR-based reminders along with standing orders can very quickly improve screening for albuminuria in primary care.”

Variation in testing rates among sites ‘tremendous’

One finding of the new study gives Mr. Stempniewicz hope for greater future testing: The large variance that the researchers saw in albuminuria testing rates within individual health systems.

“The paper shows that higher rates of testing are completely achievable within each system. Some clinics do very well, and the other units can learn from these local successes,” he said. At least half the organizations in the study had individual sites that fell into the top 10% for testing rates across all the greater than 1,000 sites included, and those same organizations also had at least one site that fell into the bottom 10% for testing.

“The variation is tremendous, and highlights an opportunity for improvement,” declared Mr. Stempniewicz.

“For routine testing, you need systems that help people. Clinicians shouldn’t have to think about doing routine testing. It should just happen,” said Dr. Coresh.

The study was funded in part by Janssen. Mr. Stempniewicz and Dr. Litvin had no disclosures. Dr. Coresh is an adviser to Healthy.io, a company that markets a home albuminuria testing kit to patients. Dr. Vassalotti has received personal fees from Renalytix.

[email protected]

U.S. primary care physicians are not properly checking patients with type 2 diabetes for chronic kidney disease (CKD) nearly as often as they should, meaning many of these patients miss getting a timely diagnosis.

Inadequate measurement of urinary albumin-to-creatinine ratio (uACR) is the issue.

Review of data from more than half a million U.S. primary care patients with type 2 diabetes seen at any of 1,164 practice sites run by any of 24 health care organizations during 2016-2019 showed that barely more than half, 52%, had both their uACR and estimated glomerular filtration rate (eGFR) checked annually as recommended by several U.S. medical societies, and just 73% had both values checked during a 3-year period, Nikita Stempniewicz, MSc, and associates reported in Diabetes Care.

More detailed data showed that measurement of eGFR was reasonably robust, measured at a 90% rate annually and in 97% of patients at least once every 3 years. But recording uACR values lagged, with a 53% annual rate and a 74% rate of measurement at least once every 3 years, reported Mr. Stempniewicz, director of research and analytics for the American Medical Group Association, a trade association based in Alexandria, Va. The 24 health care organizations that supplied the study’s data are all members of this association.

Prevailing recommendations from various medical societies call for annual monitoring of urinary albumin in patients with type 2 diabetes and specify the uACR, such as in the Standards of Medical Care in Diabetes from the American Diabetes Association, as well as in recommendations promoted by the National Kidney Foundation.
 

Missing half the CKD patients with eGFR only

“Half the patients with type 2 diabetes and chronic kidney disease have elevated albuminuria without decreased eGFR and would not be detected with eGFR testing alone,” Mr. Stempniewicz noted in an interview.

“Many patients who present for nephrology care are incompletely assessed with only low eGFR but no urine testing. Missing albuminuria testing and uACR values means patients with high levels of albuminuria but normal kidney function go undetected and thus are not able to benefit from evidenced-based interventions, including nephrology services,” said Joseph A. Vassalotti, MD, a nephrologist, chief medical officer for the National Kidney Foundation, and a coauthor of the report.

Not testing patients with type 2 diabetes regularly for their uACR “is a missed opportunity to identify the highest-risk patients and treat them,” added Josef Coresh, MD, PhD, a professor of clinical epidemiology at Johns Hopkins University, Baltimore, and senior author on the study. Measurement of albuminuria is especially important for these patients because medications from the sodium-glucose cotransporter 2 inhibitor class have been proven to slow progression of CKD in patients with type 2 diabetes, but these drugs are expensive, and in some cases have labeling that specifies the presence of albuminuria.

“I have no doubt that improving albuminuria testing is a critical step to identify patients with diabetes at highest risk who should get the best treatment possible, including SGLT2 inhibitors,” Dr. Coresh said in an interview.

The new report is not the first to document inadequate assessment of albuminuria and uACR among primary care physicians (PCPs), but it came from the largest reported U.S. study to date. “eGFR is commonly collected in a routine laboratory blood panel, but collecting urine requires additional work flow,” noted Cara B. Litvin, MD, a general internal medicine researcher at the Medical University of South Carolina, Charleston, who has tested interventions aimed at boosting CKD assessment by PCPs and was not involved in the new study.

“There have also been conflicting guidelines,” such as a “now-inactive guideline from the American College of Physicians that recommended against routine urine albumin screening in patients with diabetes and already on treatment with an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker,” she said.
 

New renal drugs change the stakes

The availability of newer drugs for slowing CKD progression such as the SGLT2 inhibitors will help trigger greater support for routine albuminuria testing, Dr. Litvin predicted in an interview. “Now that we have more medications that can reduce albuminuria and improve outcomes, I see screening for albuminuria increasing.” Finerenone (Kerendia) is another new agent from a new class that recently received Food and Drug Administration approval for treating CKD in patients with type 2 diabetes.

Other drivers of increased uACR testing she expects include revised clinical practice guidelines, and new quality measures of clinical care.

“Undertesting of albuminuria means that [nephrologists] have incomplete data to detect and completely risk stratify the CKD population. That in turn results in a reduced ability to match population health interventions to the severity of the condition or the risk stratification based on eGFR and uACR,” Dr. Vassalotti said in an interview.

“We are missing opportunities to prevent or delay kidney failure and reduce the risk of cardiovascular events and cardiovascular death in these patients, particularly now that we have a number of medications that offer kidney and cardiovascular protection such as SGLT2 inhibitors,” he added. “Leaders in nephrology are beginning to understand the consequences of undertesting, and are working to innovate to improve risk stratification, CKD detection, and apply interventions to give Americans living with CKD better outcomes.”

Strategies proven to boost albuminuria testing

Mr. Stempniewicz and coauthors cited in their report potential strategies for improving albuminuria testing, including benchmarking to identify best-performing sites for albumin testing within a health system and encouraging replication of identified best practices at lower-performing sites, and implementation of clinical-decision support tools in the EHR such as pop-up test reminders.

These were among the tools tested in two studies led by Dr. Litvin. One study, with results reported in 2016, involved 12 small U.S. primary care practices with a total of more than 30,000 patients and compared performance in a series of clinical quality measures at baseline with performance after 2 years of receiving various interventions designed to boost awareness for albuminuria testing.

The second study, with findings reported in 2019, involved 21 U.S. primary care practices that collectively cared for more than 100,000 patients and randomized the practices to either undergo interventions aimed at boosting testing awareness or to serve as controls.

Results from both studies showed significant and substantial increases in serial testing for albuminuria in patients with diabetes or hypertension when practices received the interventions.

“We showed that [using a] clinical-decision support tool, along with standing orders to automatically collect urine specimens, dramatically increased screening for urinary albumin in primary care practices,” Dr. Litvin said. “However, perhaps because of conflicting guidelines and clinical inertia there hasn’t been a major impetus for primary care practices in general to improve screening.” She hopes that will quickly change.

“As we have shown, adoption of EHR-based reminders along with standing orders can very quickly improve screening for albuminuria in primary care.”

Variation in testing rates among sites ‘tremendous’

One finding of the new study gives Mr. Stempniewicz hope for greater future testing: The large variance that the researchers saw in albuminuria testing rates within individual health systems.

“The paper shows that higher rates of testing are completely achievable within each system. Some clinics do very well, and the other units can learn from these local successes,” he said. At least half the organizations in the study had individual sites that fell into the top 10% for testing rates across all the greater than 1,000 sites included, and those same organizations also had at least one site that fell into the bottom 10% for testing.

“The variation is tremendous, and highlights an opportunity for improvement,” declared Mr. Stempniewicz.

“For routine testing, you need systems that help people. Clinicians shouldn’t have to think about doing routine testing. It should just happen,” said Dr. Coresh.

The study was funded in part by Janssen. Mr. Stempniewicz and Dr. Litvin had no disclosures. Dr. Coresh is an adviser to Healthy.io, a company that markets a home albuminuria testing kit to patients. Dr. Vassalotti has received personal fees from Renalytix.

[email protected]