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Dropping race-based eGFR adjustment gains traction in U.S.
a measure of renal function.
The move aims to correct a race-based health access inequity that’s been in place for more than 2 decades, say advocates, while others voice concern that the change threatens over-diagnosis of both chronic and end-stage kidney disease in some patients.
In late June, the Boston-based Massachusetts General Brigham health system stopped noting the race-based modifier when its laboratories reported eGFR, and the leadership sent its staff a message discouraging them from applying the modifier. A similar change in eGFR reporting started on June 1 at the University of Washington health system, UW Medicine, Seattle.
These steps followed what is widely regarded as the first institutional change away from race-based adjustment of eGFR, which began in March 2017 at Beth Israel Deaconess Medical Center in Boston, and they have come amid a growing movement by some individual U.S. physicians to drop the modifier from their practice.
“Momentum is clearly building,” said Nwamaka D. Eneanya, MD, a nephrologist at the University of Pennsylvania in Philadelphia and lead author of a commentary published a little more than a year ago that laid out the case for reconsidering how to calculate eGFR in African Americans.
“Many discussions are happening at other [US] academic medical centers,” Dr. Eneanya added, including the system where she works.
Why was the decision taken to modify eGFR in African Americans?
The concept is that the formula used to calculate eGFR systematically underestimates the value in African Americans. Hence, it requires a small but meaningful up-adjustment, which can be traced back to the introduction of the Modification of Diet in Renal Disease (MDRD) study equation in 1999.
The idea was perpetuated in an improved calculation formula, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), that came out a decade later.
These are the most widely used U.S. approaches to eGFR calculation, with the newer CKD-EPI formula predominating.
The rationale for including a modifier for Blacks in the 2009 formula was for improved accuracy relative to the standard reference measure based on iothalamate clearance.
The data used to develop the CKD-EPI formula showed that Black individuals in the dataset had, on average, GFR levels that were 16% higher than people of other races with the same age, sex, and serum creatinine level, according to a recent commentary. The first author, Andrew S. Levey, MD, was also lead author of the reports that introduced both the MDRD and CKD-EPI equations.
But the argument withers in the light of both its flimsy underpinning – race assessment – and the medical and social consequences of its application, say those who have sought change.
Reporting eGFR by race might do more harm than good
“Race is a social, not a biological, construct and the kidney-function race multiplier ignores the substantial genetic diversity within self-identified Black patients,” said Thomas D. Sequist, MD, professor of medicine at Harvard Medical School in Boston and chief patient experience and equity officer for Mass General Brigham, who spearheaded the policy change for that system.
“Do we really believe that the population breaks down into just ‘Black’ and ‘not Black,’ as the CKD-EPI equation asks us to believe?” he said in an interview. “The equation was developed from a few thousand patients, and we now apply it to millions of people using a very imprecise measure – race.”
“Reporting eGFR by race perpetuates a notion that race is a biologic construct when it’s not,” agreed Rajnish Mehrotra, MD, a professor and chief of nephrology at the University of Washington in Seattle and leader of the eGFR change within his medical system.
Equally compelling, said Dr. Mehrotra, Dr. Sequist, and others, are the health inequities that have resulted from routinely raising the eGFR in African Americans.
This has led to “withholding treatment from people longer than needed. We arrived at the conclusion that reporting eGFR by race does more harm than good,” Dr. Mehrotra said in an interview.
Dr. Sequist added: “Researchers across Mass General Brigham have demonstrated that use of these race multipliers can lead to important delays in care for Black patients, such as timely evaluation for kidney transplantation.”
“Our main concern is that race correction is creating harm.”
Dr. Eneanya concurs: “It was never designed to oppress patients, but that’s where we are. No one ever thought about the repercussions of using race.”
And while the movement to eliminate the race modifier is clearly gaining steam, it’s also receiving pushback from those who see benefit from the modification and have concern that its abolition could lead to overestimates of kidney disease severity.
Some clinicians “have a hard time letting the race modifier go,” Dr. Eneanya noted.
“In the nephrology community, it’s pretty controversial”
In their 2020 commentary, Levey and coauthors wrote: “We propose a more cautious approach that maintains and improves accuracy of GFR estimates and avoids disadvantaging any racial group.”
Their suggested remedies included full disclosure of use of race, accommodation of people who decline to self-identify themselves that way, shared decision-making, and “mindful” use of cystatin C, an alternative to serum creatinine for calculating eGFR.
The latter is regarded as more precise and accurate than serum creatinine across populations but is often not as readily available to many clinicians. Their article also supported looking for even better and more accessible ways to calculate eGFR.
“In the nephrology community, it’s pretty controversial,” said Mallika L. Mendu, MD, a nephrologist at Brigham and Women’s Hospital in Boston, Massachusetts, who has studied the effects of using the modifier on patient assessment.
Her recent review of Mass General Brigham patients found that close to a third of African Americans would have been reclassified with a more severe form of kidney disease if their eGFR had remained unmodified.
“That raised concerns that, by using race adjustment we’re potentially leading to less equitable outcomes for African American patients,” she said. “I’d rather over diagnose than not diagnose in a timely way.”
The research that led to development of the MDRD and CKD-EPI equations “are gold-standard studies” that “saw a real difference,” Dr. Mendu acknowledged in an interview. “But the way those studies were run and the way they defined the patients was problematic.” Despite that, “many nephrologists” agree with the position taken by Dr. Levey and coauthors in their recent commentary, she said.
She added that she stopped using the modifier about a year ago in her own practice, well before the system where she works adopted the same approach.
Consensus takes time
In one sign of the controversy, a quartet of clinicians affiliated with San Francisco General Hospital (SFGH) recently posted an online petition in which they noted that the race modifier had been eliminated in eGFR reports from the hospital’s laboratory in October 2019, but more recently had been slated for reinstitution. “We were deeply distressed to recently discover the intended plan to revert back to race-based eGFR reporting at SFGH,” they noted.
The same four clinicians also wrote an opinion piece calling for elimination of the modifier in November 2019 in the San Francisco Examiner.
Controversy will likely linger as the movement to withdraw the race modifier spreads without clear agreement on what to do instead.
Dr. Mehrotra said he’s received inquiries about his system’s experience from clinicians at several U.S. medical centers and systems, and he remains comfortable applying the unadjusted CKD-EPI formula to all adults, an approach he called “sufficient.”
Other physicians, like nephrologist Vanessa Grubbs, MD, call for a rapid shift to a cystatin C–based, fully race-neutral method for calculating eGFR, a position she detailed in a recent editorial.
And at the University of Pennsylvania, where the health system continues to issue eGFR reports with the race modifier, Dr. Eneanya says that she stopped using the modifier “some time” ago.
“People have a hard time letting it go because it is so important in clinical care. Getting everyone to come to a consensus takes time,” she said.
Dr. Eneanya, Dr. Sequist, and Dr. Mendu have reported no relevant financial relationships. Dr. Mehrotra has been a consultant for Baxter Healthcare.
A version of this article originally appeared on Medscape.com.
a measure of renal function.
The move aims to correct a race-based health access inequity that’s been in place for more than 2 decades, say advocates, while others voice concern that the change threatens over-diagnosis of both chronic and end-stage kidney disease in some patients.
In late June, the Boston-based Massachusetts General Brigham health system stopped noting the race-based modifier when its laboratories reported eGFR, and the leadership sent its staff a message discouraging them from applying the modifier. A similar change in eGFR reporting started on June 1 at the University of Washington health system, UW Medicine, Seattle.
These steps followed what is widely regarded as the first institutional change away from race-based adjustment of eGFR, which began in March 2017 at Beth Israel Deaconess Medical Center in Boston, and they have come amid a growing movement by some individual U.S. physicians to drop the modifier from their practice.
“Momentum is clearly building,” said Nwamaka D. Eneanya, MD, a nephrologist at the University of Pennsylvania in Philadelphia and lead author of a commentary published a little more than a year ago that laid out the case for reconsidering how to calculate eGFR in African Americans.
“Many discussions are happening at other [US] academic medical centers,” Dr. Eneanya added, including the system where she works.
Why was the decision taken to modify eGFR in African Americans?
The concept is that the formula used to calculate eGFR systematically underestimates the value in African Americans. Hence, it requires a small but meaningful up-adjustment, which can be traced back to the introduction of the Modification of Diet in Renal Disease (MDRD) study equation in 1999.
The idea was perpetuated in an improved calculation formula, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), that came out a decade later.
These are the most widely used U.S. approaches to eGFR calculation, with the newer CKD-EPI formula predominating.
The rationale for including a modifier for Blacks in the 2009 formula was for improved accuracy relative to the standard reference measure based on iothalamate clearance.
The data used to develop the CKD-EPI formula showed that Black individuals in the dataset had, on average, GFR levels that were 16% higher than people of other races with the same age, sex, and serum creatinine level, according to a recent commentary. The first author, Andrew S. Levey, MD, was also lead author of the reports that introduced both the MDRD and CKD-EPI equations.
But the argument withers in the light of both its flimsy underpinning – race assessment – and the medical and social consequences of its application, say those who have sought change.
Reporting eGFR by race might do more harm than good
“Race is a social, not a biological, construct and the kidney-function race multiplier ignores the substantial genetic diversity within self-identified Black patients,” said Thomas D. Sequist, MD, professor of medicine at Harvard Medical School in Boston and chief patient experience and equity officer for Mass General Brigham, who spearheaded the policy change for that system.
“Do we really believe that the population breaks down into just ‘Black’ and ‘not Black,’ as the CKD-EPI equation asks us to believe?” he said in an interview. “The equation was developed from a few thousand patients, and we now apply it to millions of people using a very imprecise measure – race.”
“Reporting eGFR by race perpetuates a notion that race is a biologic construct when it’s not,” agreed Rajnish Mehrotra, MD, a professor and chief of nephrology at the University of Washington in Seattle and leader of the eGFR change within his medical system.
Equally compelling, said Dr. Mehrotra, Dr. Sequist, and others, are the health inequities that have resulted from routinely raising the eGFR in African Americans.
This has led to “withholding treatment from people longer than needed. We arrived at the conclusion that reporting eGFR by race does more harm than good,” Dr. Mehrotra said in an interview.
Dr. Sequist added: “Researchers across Mass General Brigham have demonstrated that use of these race multipliers can lead to important delays in care for Black patients, such as timely evaluation for kidney transplantation.”
“Our main concern is that race correction is creating harm.”
Dr. Eneanya concurs: “It was never designed to oppress patients, but that’s where we are. No one ever thought about the repercussions of using race.”
And while the movement to eliminate the race modifier is clearly gaining steam, it’s also receiving pushback from those who see benefit from the modification and have concern that its abolition could lead to overestimates of kidney disease severity.
Some clinicians “have a hard time letting the race modifier go,” Dr. Eneanya noted.
“In the nephrology community, it’s pretty controversial”
In their 2020 commentary, Levey and coauthors wrote: “We propose a more cautious approach that maintains and improves accuracy of GFR estimates and avoids disadvantaging any racial group.”
Their suggested remedies included full disclosure of use of race, accommodation of people who decline to self-identify themselves that way, shared decision-making, and “mindful” use of cystatin C, an alternative to serum creatinine for calculating eGFR.
The latter is regarded as more precise and accurate than serum creatinine across populations but is often not as readily available to many clinicians. Their article also supported looking for even better and more accessible ways to calculate eGFR.
“In the nephrology community, it’s pretty controversial,” said Mallika L. Mendu, MD, a nephrologist at Brigham and Women’s Hospital in Boston, Massachusetts, who has studied the effects of using the modifier on patient assessment.
Her recent review of Mass General Brigham patients found that close to a third of African Americans would have been reclassified with a more severe form of kidney disease if their eGFR had remained unmodified.
“That raised concerns that, by using race adjustment we’re potentially leading to less equitable outcomes for African American patients,” she said. “I’d rather over diagnose than not diagnose in a timely way.”
The research that led to development of the MDRD and CKD-EPI equations “are gold-standard studies” that “saw a real difference,” Dr. Mendu acknowledged in an interview. “But the way those studies were run and the way they defined the patients was problematic.” Despite that, “many nephrologists” agree with the position taken by Dr. Levey and coauthors in their recent commentary, she said.
She added that she stopped using the modifier about a year ago in her own practice, well before the system where she works adopted the same approach.
Consensus takes time
In one sign of the controversy, a quartet of clinicians affiliated with San Francisco General Hospital (SFGH) recently posted an online petition in which they noted that the race modifier had been eliminated in eGFR reports from the hospital’s laboratory in October 2019, but more recently had been slated for reinstitution. “We were deeply distressed to recently discover the intended plan to revert back to race-based eGFR reporting at SFGH,” they noted.
The same four clinicians also wrote an opinion piece calling for elimination of the modifier in November 2019 in the San Francisco Examiner.
Controversy will likely linger as the movement to withdraw the race modifier spreads without clear agreement on what to do instead.
Dr. Mehrotra said he’s received inquiries about his system’s experience from clinicians at several U.S. medical centers and systems, and he remains comfortable applying the unadjusted CKD-EPI formula to all adults, an approach he called “sufficient.”
Other physicians, like nephrologist Vanessa Grubbs, MD, call for a rapid shift to a cystatin C–based, fully race-neutral method for calculating eGFR, a position she detailed in a recent editorial.
And at the University of Pennsylvania, where the health system continues to issue eGFR reports with the race modifier, Dr. Eneanya says that she stopped using the modifier “some time” ago.
“People have a hard time letting it go because it is so important in clinical care. Getting everyone to come to a consensus takes time,” she said.
Dr. Eneanya, Dr. Sequist, and Dr. Mendu have reported no relevant financial relationships. Dr. Mehrotra has been a consultant for Baxter Healthcare.
A version of this article originally appeared on Medscape.com.
a measure of renal function.
The move aims to correct a race-based health access inequity that’s been in place for more than 2 decades, say advocates, while others voice concern that the change threatens over-diagnosis of both chronic and end-stage kidney disease in some patients.
In late June, the Boston-based Massachusetts General Brigham health system stopped noting the race-based modifier when its laboratories reported eGFR, and the leadership sent its staff a message discouraging them from applying the modifier. A similar change in eGFR reporting started on June 1 at the University of Washington health system, UW Medicine, Seattle.
These steps followed what is widely regarded as the first institutional change away from race-based adjustment of eGFR, which began in March 2017 at Beth Israel Deaconess Medical Center in Boston, and they have come amid a growing movement by some individual U.S. physicians to drop the modifier from their practice.
“Momentum is clearly building,” said Nwamaka D. Eneanya, MD, a nephrologist at the University of Pennsylvania in Philadelphia and lead author of a commentary published a little more than a year ago that laid out the case for reconsidering how to calculate eGFR in African Americans.
“Many discussions are happening at other [US] academic medical centers,” Dr. Eneanya added, including the system where she works.
Why was the decision taken to modify eGFR in African Americans?
The concept is that the formula used to calculate eGFR systematically underestimates the value in African Americans. Hence, it requires a small but meaningful up-adjustment, which can be traced back to the introduction of the Modification of Diet in Renal Disease (MDRD) study equation in 1999.
The idea was perpetuated in an improved calculation formula, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), that came out a decade later.
These are the most widely used U.S. approaches to eGFR calculation, with the newer CKD-EPI formula predominating.
The rationale for including a modifier for Blacks in the 2009 formula was for improved accuracy relative to the standard reference measure based on iothalamate clearance.
The data used to develop the CKD-EPI formula showed that Black individuals in the dataset had, on average, GFR levels that were 16% higher than people of other races with the same age, sex, and serum creatinine level, according to a recent commentary. The first author, Andrew S. Levey, MD, was also lead author of the reports that introduced both the MDRD and CKD-EPI equations.
But the argument withers in the light of both its flimsy underpinning – race assessment – and the medical and social consequences of its application, say those who have sought change.
Reporting eGFR by race might do more harm than good
“Race is a social, not a biological, construct and the kidney-function race multiplier ignores the substantial genetic diversity within self-identified Black patients,” said Thomas D. Sequist, MD, professor of medicine at Harvard Medical School in Boston and chief patient experience and equity officer for Mass General Brigham, who spearheaded the policy change for that system.
“Do we really believe that the population breaks down into just ‘Black’ and ‘not Black,’ as the CKD-EPI equation asks us to believe?” he said in an interview. “The equation was developed from a few thousand patients, and we now apply it to millions of people using a very imprecise measure – race.”
“Reporting eGFR by race perpetuates a notion that race is a biologic construct when it’s not,” agreed Rajnish Mehrotra, MD, a professor and chief of nephrology at the University of Washington in Seattle and leader of the eGFR change within his medical system.
Equally compelling, said Dr. Mehrotra, Dr. Sequist, and others, are the health inequities that have resulted from routinely raising the eGFR in African Americans.
This has led to “withholding treatment from people longer than needed. We arrived at the conclusion that reporting eGFR by race does more harm than good,” Dr. Mehrotra said in an interview.
Dr. Sequist added: “Researchers across Mass General Brigham have demonstrated that use of these race multipliers can lead to important delays in care for Black patients, such as timely evaluation for kidney transplantation.”
“Our main concern is that race correction is creating harm.”
Dr. Eneanya concurs: “It was never designed to oppress patients, but that’s where we are. No one ever thought about the repercussions of using race.”
And while the movement to eliminate the race modifier is clearly gaining steam, it’s also receiving pushback from those who see benefit from the modification and have concern that its abolition could lead to overestimates of kidney disease severity.
Some clinicians “have a hard time letting the race modifier go,” Dr. Eneanya noted.
“In the nephrology community, it’s pretty controversial”
In their 2020 commentary, Levey and coauthors wrote: “We propose a more cautious approach that maintains and improves accuracy of GFR estimates and avoids disadvantaging any racial group.”
Their suggested remedies included full disclosure of use of race, accommodation of people who decline to self-identify themselves that way, shared decision-making, and “mindful” use of cystatin C, an alternative to serum creatinine for calculating eGFR.
The latter is regarded as more precise and accurate than serum creatinine across populations but is often not as readily available to many clinicians. Their article also supported looking for even better and more accessible ways to calculate eGFR.
“In the nephrology community, it’s pretty controversial,” said Mallika L. Mendu, MD, a nephrologist at Brigham and Women’s Hospital in Boston, Massachusetts, who has studied the effects of using the modifier on patient assessment.
Her recent review of Mass General Brigham patients found that close to a third of African Americans would have been reclassified with a more severe form of kidney disease if their eGFR had remained unmodified.
“That raised concerns that, by using race adjustment we’re potentially leading to less equitable outcomes for African American patients,” she said. “I’d rather over diagnose than not diagnose in a timely way.”
The research that led to development of the MDRD and CKD-EPI equations “are gold-standard studies” that “saw a real difference,” Dr. Mendu acknowledged in an interview. “But the way those studies were run and the way they defined the patients was problematic.” Despite that, “many nephrologists” agree with the position taken by Dr. Levey and coauthors in their recent commentary, she said.
She added that she stopped using the modifier about a year ago in her own practice, well before the system where she works adopted the same approach.
Consensus takes time
In one sign of the controversy, a quartet of clinicians affiliated with San Francisco General Hospital (SFGH) recently posted an online petition in which they noted that the race modifier had been eliminated in eGFR reports from the hospital’s laboratory in October 2019, but more recently had been slated for reinstitution. “We were deeply distressed to recently discover the intended plan to revert back to race-based eGFR reporting at SFGH,” they noted.
The same four clinicians also wrote an opinion piece calling for elimination of the modifier in November 2019 in the San Francisco Examiner.
Controversy will likely linger as the movement to withdraw the race modifier spreads without clear agreement on what to do instead.
Dr. Mehrotra said he’s received inquiries about his system’s experience from clinicians at several U.S. medical centers and systems, and he remains comfortable applying the unadjusted CKD-EPI formula to all adults, an approach he called “sufficient.”
Other physicians, like nephrologist Vanessa Grubbs, MD, call for a rapid shift to a cystatin C–based, fully race-neutral method for calculating eGFR, a position she detailed in a recent editorial.
And at the University of Pennsylvania, where the health system continues to issue eGFR reports with the race modifier, Dr. Eneanya says that she stopped using the modifier “some time” ago.
“People have a hard time letting it go because it is so important in clinical care. Getting everyone to come to a consensus takes time,” she said.
Dr. Eneanya, Dr. Sequist, and Dr. Mendu have reported no relevant financial relationships. Dr. Mehrotra has been a consultant for Baxter Healthcare.
A version of this article originally appeared on Medscape.com.
One-year mortality after dialysis initiation nearly double prior estimates
Background: The United States Renal Data System registry estimates that approximately 30% of patients die within 1 year of initiating hemodialysis.
Study design: Retrospective, observational analysis.
Setting: The Health and Retirement Study is a nationally representative survey of Medicare beneficiaries during 1998-2014. Medicare claims were linked to mortality data from the National Death Index.
Synopsis: Among 391 patients who initiated dialysis, 22.5%, 44.2%, and 54.5% died within 30 days, 6 months, and 1 year, respectively. After multivariate adjustment, 1-year mortality was higher among those who initiated dialysis while inpatients (hazard ratio, 2.17; 62.2%), had any activity of daily living dependence prior to dialysis (HR, 1.88; 73.0%), or had more than four comorbidities (HR, 1.5; 59.9%).
Bottom line: Medicare beneficiaries may have significantly higher mortality after initiating dialysis than prior data suggest.
Citation: Wachterman MW et al. One-year mortality after dialysis initiation among older adults. JAMA Intern Med. 2019 Apr 22. doi: 10.1001/jamainternmed.2019.0125.
Dr. Lublin is a hospitalist at the University of Colorado at Denver, Aurora.
Background: The United States Renal Data System registry estimates that approximately 30% of patients die within 1 year of initiating hemodialysis.
Study design: Retrospective, observational analysis.
Setting: The Health and Retirement Study is a nationally representative survey of Medicare beneficiaries during 1998-2014. Medicare claims were linked to mortality data from the National Death Index.
Synopsis: Among 391 patients who initiated dialysis, 22.5%, 44.2%, and 54.5% died within 30 days, 6 months, and 1 year, respectively. After multivariate adjustment, 1-year mortality was higher among those who initiated dialysis while inpatients (hazard ratio, 2.17; 62.2%), had any activity of daily living dependence prior to dialysis (HR, 1.88; 73.0%), or had more than four comorbidities (HR, 1.5; 59.9%).
Bottom line: Medicare beneficiaries may have significantly higher mortality after initiating dialysis than prior data suggest.
Citation: Wachterman MW et al. One-year mortality after dialysis initiation among older adults. JAMA Intern Med. 2019 Apr 22. doi: 10.1001/jamainternmed.2019.0125.
Dr. Lublin is a hospitalist at the University of Colorado at Denver, Aurora.
Background: The United States Renal Data System registry estimates that approximately 30% of patients die within 1 year of initiating hemodialysis.
Study design: Retrospective, observational analysis.
Setting: The Health and Retirement Study is a nationally representative survey of Medicare beneficiaries during 1998-2014. Medicare claims were linked to mortality data from the National Death Index.
Synopsis: Among 391 patients who initiated dialysis, 22.5%, 44.2%, and 54.5% died within 30 days, 6 months, and 1 year, respectively. After multivariate adjustment, 1-year mortality was higher among those who initiated dialysis while inpatients (hazard ratio, 2.17; 62.2%), had any activity of daily living dependence prior to dialysis (HR, 1.88; 73.0%), or had more than four comorbidities (HR, 1.5; 59.9%).
Bottom line: Medicare beneficiaries may have significantly higher mortality after initiating dialysis than prior data suggest.
Citation: Wachterman MW et al. One-year mortality after dialysis initiation among older adults. JAMA Intern Med. 2019 Apr 22. doi: 10.1001/jamainternmed.2019.0125.
Dr. Lublin is a hospitalist at the University of Colorado at Denver, Aurora.
Canagliflozin protects diabetic kidneys
Background: Type 2 diabetes is the leading cause of kidney failure worldwide. Few treatment options exist to help improve on this outcome in patients with chronic kidney disease.
Study design: CREDENCE (industry-sponsored) double-blind, randomized placebo-controlled trial.
Setting: 695 sites in 34 countries, 4,401 patients.
Synopsis: The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. Canagliflozin reduced serious adverse renal events or death from renal or cardiovascular causes at 2.62 years (11.1% vs. 15.5% with placebo; number needed to treat, 23).Bottom line: Canagliflozin lowered serious adverse renal events people with type 2 diabetics who also had chronic kidney disease.
Citation: Perkovic V et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019 Apr 14. doi: 10-1056/NEJMoa1811744.
Dr. Hoegh is a hospitalist at the University of Colorado at Denver, Aurora.
Background: Type 2 diabetes is the leading cause of kidney failure worldwide. Few treatment options exist to help improve on this outcome in patients with chronic kidney disease.
Study design: CREDENCE (industry-sponsored) double-blind, randomized placebo-controlled trial.
Setting: 695 sites in 34 countries, 4,401 patients.
Synopsis: The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. Canagliflozin reduced serious adverse renal events or death from renal or cardiovascular causes at 2.62 years (11.1% vs. 15.5% with placebo; number needed to treat, 23).Bottom line: Canagliflozin lowered serious adverse renal events people with type 2 diabetics who also had chronic kidney disease.
Citation: Perkovic V et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019 Apr 14. doi: 10-1056/NEJMoa1811744.
Dr. Hoegh is a hospitalist at the University of Colorado at Denver, Aurora.
Background: Type 2 diabetes is the leading cause of kidney failure worldwide. Few treatment options exist to help improve on this outcome in patients with chronic kidney disease.
Study design: CREDENCE (industry-sponsored) double-blind, randomized placebo-controlled trial.
Setting: 695 sites in 34 countries, 4,401 patients.
Synopsis: The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. Canagliflozin reduced serious adverse renal events or death from renal or cardiovascular causes at 2.62 years (11.1% vs. 15.5% with placebo; number needed to treat, 23).Bottom line: Canagliflozin lowered serious adverse renal events people with type 2 diabetics who also had chronic kidney disease.
Citation: Perkovic V et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019 Apr 14. doi: 10-1056/NEJMoa1811744.
Dr. Hoegh is a hospitalist at the University of Colorado at Denver, Aurora.
Where does dexamethasone fit in with diabetic ketoacidosis in COVID-19?
A new article in the Journal of Clinical Endocrinology & Metabolism (JCEM) addresses unique concerns and considerations regarding diabetic ketoacidosis (DKA) in the setting of COVID-19.
Corresponding author Marie E. McDonnell, MD, director of the diabetes program at Brigham and Women’s Hospital, Boston, Massachusetts, discussed the recommendations with Medscape Medical News and also spoke about the news this week that the corticosteroid dexamethasone reduced death rates in severely ill patients with COVID-19.
The full JCEM article, by lead author Nadine E. Palermo, DO, Division of Endocrinology, Diabetes, and Hypertension, also at Brigham and Women’s Hospital, covers DKA diagnosis and triage, and emphasizes that usual hospital protocols for DKA management may need to be adjusted during COVID-19 to help preserve personal protective equipment and ICU beds.
“Hospitals and clinicians need to be able to quickly identify and manage DKA in COVID patients to save lives. This involves determining the options for management, including when less intensive subcutaneous insulin is indicated, and understanding how to guide patients on avoiding this serious complication,” McDonnell said in an Endocrine Society statement.
What about dexamethasone for severe COVID-19 in diabetes?
The new article briefly touches on the fact that upward adjustments to intensive intravenous insulin therapy for DKA may be necessary in patients with COVID-19 who are receiving concomitant corticosteroids or vasopressors.
But it was written prior to the June 16 announcement of the “RECOVERY” trial results with dexamethasone. The UK National Health Service immediately approved the drug’s use in the COVID-19 setting, despite the fact that there has been no published article on the findings yet.
McDonnell told Medscape Medical News that she would need to see formal results to better understand exactly which patients were studied and which ones benefited.
“The peer review will be critical. It looks as if it only benefits people who need respiratory support, but I want to understand that in much more detail,” she said. “If they all had acute respiratory distress syndrome [ARDS],” that’s different.
“There are already some data supporting steroid use in ARDS,” she noted, but added that not all of it suggests benefit.
She pointed to one of several studies now showing that diabetes, and hyperglycemia among people without a prior diabetes diagnosis, are both strong predictors of mortality in hospitalized patients with COVID-19.
“There was a very clear relationship between hyperglycemia and outcomes. We really shouldn’t put people at risk until we have clear data,” she said.
If, once the data are reviewed and appropriate dexamethasone becomes an established treatment for severe COVID-19, hyperglycemia would be a concern among all patients, not just those with previously diagnosed diabetes, she noted.
“We know a good number of people with prediabetes develop hyperglycemia when put on steroids. They can push people over the edge. We’re not going to miss anybody, but treating steroid-induced hyperglycemia is really hard,” McDonnell explained.
She also recommended 2014 guidance from Diabetes UK and the Association of British Clinical Diabetologists, which addresses management of inpatient steroid-induced DKA in patients with and without pre-existing diabetes.
Another major concern, she said, is “patients trying to get dexamethasone when they start to get sick” because this is not the right population to use this agent.
“We worry about people who do not need this drug. If they have diabetes, they put themselves at risk of hyperglycemia, which then increases the risk of severe COVID-19. And then they’re also putting themselves at risk of DKA. It would just be bad medicine,” she said.
Managing DKA in the face of COVID-19: Flexibility is key
In the JCEM article, Palermo and colleagues emphasize that the usual hospital protocols for DKA management may need to be adjusted during COVID-19 in the interest of reducing transmission risk and preserving scare resources.
They provide evidence for alternative treatment strategies, such as the use of subcutaneous rather than intravenous insulin when appropriate.
“We wanted to outline when exactly you should consider nonintensive management strategies for DKA,” McDonnell further explained to Medscape Medical News.
“That would include those with mild or some with moderate DKA. ... The idea is to remind our colleagues about that because hospitals tend to operate on a protocol-driven algorithmic methodology, they can forget to step off the usual care pathway even if evidence supports that,” she said.
But on the other hand, she also said that, in some very complex or severely ill patients with COVID-19, classical intravenous insulin therapy makes the most sense even if their DKA is mild.
The outpatient setting: Prevention and preparation
The new article also addresses several concerns regarding DKA prevention in the outpatient setting.
As with other guidelines, it includes a reminder that patients with diabetes should be advised to discontinue sodium-glucose cotransporter 2 (SGLT2) inhibitors if they become ill with COVID-19, especially if they’re not eating or drinking normally, because they raise the risk for DKA.
Also, for patients with type 1 diabetes, particularly those with a history of repeated DKA, “this is the time to make sure we reach out to patients to refill their insulin prescriptions and address issues related to cost and other access difficulties,” McDonnell said.
The authors also emphasize that insulin starts and education should not be postponed during the pandemic. “Patients identified as meeting criteria to start insulin should be referred for urgent education, either in person or, whenever possible and practical, via video teleconferencing,” they urge.
McDonnell has reported receiving research funding from Novo Nordisk. The other two authors have reported no relevant financial relationships.
This article first appeared on Medscape.com.
A new article in the Journal of Clinical Endocrinology & Metabolism (JCEM) addresses unique concerns and considerations regarding diabetic ketoacidosis (DKA) in the setting of COVID-19.
Corresponding author Marie E. McDonnell, MD, director of the diabetes program at Brigham and Women’s Hospital, Boston, Massachusetts, discussed the recommendations with Medscape Medical News and also spoke about the news this week that the corticosteroid dexamethasone reduced death rates in severely ill patients with COVID-19.
The full JCEM article, by lead author Nadine E. Palermo, DO, Division of Endocrinology, Diabetes, and Hypertension, also at Brigham and Women’s Hospital, covers DKA diagnosis and triage, and emphasizes that usual hospital protocols for DKA management may need to be adjusted during COVID-19 to help preserve personal protective equipment and ICU beds.
“Hospitals and clinicians need to be able to quickly identify and manage DKA in COVID patients to save lives. This involves determining the options for management, including when less intensive subcutaneous insulin is indicated, and understanding how to guide patients on avoiding this serious complication,” McDonnell said in an Endocrine Society statement.
What about dexamethasone for severe COVID-19 in diabetes?
The new article briefly touches on the fact that upward adjustments to intensive intravenous insulin therapy for DKA may be necessary in patients with COVID-19 who are receiving concomitant corticosteroids or vasopressors.
But it was written prior to the June 16 announcement of the “RECOVERY” trial results with dexamethasone. The UK National Health Service immediately approved the drug’s use in the COVID-19 setting, despite the fact that there has been no published article on the findings yet.
McDonnell told Medscape Medical News that she would need to see formal results to better understand exactly which patients were studied and which ones benefited.
“The peer review will be critical. It looks as if it only benefits people who need respiratory support, but I want to understand that in much more detail,” she said. “If they all had acute respiratory distress syndrome [ARDS],” that’s different.
“There are already some data supporting steroid use in ARDS,” she noted, but added that not all of it suggests benefit.
She pointed to one of several studies now showing that diabetes, and hyperglycemia among people without a prior diabetes diagnosis, are both strong predictors of mortality in hospitalized patients with COVID-19.
“There was a very clear relationship between hyperglycemia and outcomes. We really shouldn’t put people at risk until we have clear data,” she said.
If, once the data are reviewed and appropriate dexamethasone becomes an established treatment for severe COVID-19, hyperglycemia would be a concern among all patients, not just those with previously diagnosed diabetes, she noted.
“We know a good number of people with prediabetes develop hyperglycemia when put on steroids. They can push people over the edge. We’re not going to miss anybody, but treating steroid-induced hyperglycemia is really hard,” McDonnell explained.
She also recommended 2014 guidance from Diabetes UK and the Association of British Clinical Diabetologists, which addresses management of inpatient steroid-induced DKA in patients with and without pre-existing diabetes.
Another major concern, she said, is “patients trying to get dexamethasone when they start to get sick” because this is not the right population to use this agent.
“We worry about people who do not need this drug. If they have diabetes, they put themselves at risk of hyperglycemia, which then increases the risk of severe COVID-19. And then they’re also putting themselves at risk of DKA. It would just be bad medicine,” she said.
Managing DKA in the face of COVID-19: Flexibility is key
In the JCEM article, Palermo and colleagues emphasize that the usual hospital protocols for DKA management may need to be adjusted during COVID-19 in the interest of reducing transmission risk and preserving scare resources.
They provide evidence for alternative treatment strategies, such as the use of subcutaneous rather than intravenous insulin when appropriate.
“We wanted to outline when exactly you should consider nonintensive management strategies for DKA,” McDonnell further explained to Medscape Medical News.
“That would include those with mild or some with moderate DKA. ... The idea is to remind our colleagues about that because hospitals tend to operate on a protocol-driven algorithmic methodology, they can forget to step off the usual care pathway even if evidence supports that,” she said.
But on the other hand, she also said that, in some very complex or severely ill patients with COVID-19, classical intravenous insulin therapy makes the most sense even if their DKA is mild.
The outpatient setting: Prevention and preparation
The new article also addresses several concerns regarding DKA prevention in the outpatient setting.
As with other guidelines, it includes a reminder that patients with diabetes should be advised to discontinue sodium-glucose cotransporter 2 (SGLT2) inhibitors if they become ill with COVID-19, especially if they’re not eating or drinking normally, because they raise the risk for DKA.
Also, for patients with type 1 diabetes, particularly those with a history of repeated DKA, “this is the time to make sure we reach out to patients to refill their insulin prescriptions and address issues related to cost and other access difficulties,” McDonnell said.
The authors also emphasize that insulin starts and education should not be postponed during the pandemic. “Patients identified as meeting criteria to start insulin should be referred for urgent education, either in person or, whenever possible and practical, via video teleconferencing,” they urge.
McDonnell has reported receiving research funding from Novo Nordisk. The other two authors have reported no relevant financial relationships.
This article first appeared on Medscape.com.
A new article in the Journal of Clinical Endocrinology & Metabolism (JCEM) addresses unique concerns and considerations regarding diabetic ketoacidosis (DKA) in the setting of COVID-19.
Corresponding author Marie E. McDonnell, MD, director of the diabetes program at Brigham and Women’s Hospital, Boston, Massachusetts, discussed the recommendations with Medscape Medical News and also spoke about the news this week that the corticosteroid dexamethasone reduced death rates in severely ill patients with COVID-19.
The full JCEM article, by lead author Nadine E. Palermo, DO, Division of Endocrinology, Diabetes, and Hypertension, also at Brigham and Women’s Hospital, covers DKA diagnosis and triage, and emphasizes that usual hospital protocols for DKA management may need to be adjusted during COVID-19 to help preserve personal protective equipment and ICU beds.
“Hospitals and clinicians need to be able to quickly identify and manage DKA in COVID patients to save lives. This involves determining the options for management, including when less intensive subcutaneous insulin is indicated, and understanding how to guide patients on avoiding this serious complication,” McDonnell said in an Endocrine Society statement.
What about dexamethasone for severe COVID-19 in diabetes?
The new article briefly touches on the fact that upward adjustments to intensive intravenous insulin therapy for DKA may be necessary in patients with COVID-19 who are receiving concomitant corticosteroids or vasopressors.
But it was written prior to the June 16 announcement of the “RECOVERY” trial results with dexamethasone. The UK National Health Service immediately approved the drug’s use in the COVID-19 setting, despite the fact that there has been no published article on the findings yet.
McDonnell told Medscape Medical News that she would need to see formal results to better understand exactly which patients were studied and which ones benefited.
“The peer review will be critical. It looks as if it only benefits people who need respiratory support, but I want to understand that in much more detail,” she said. “If they all had acute respiratory distress syndrome [ARDS],” that’s different.
“There are already some data supporting steroid use in ARDS,” she noted, but added that not all of it suggests benefit.
She pointed to one of several studies now showing that diabetes, and hyperglycemia among people without a prior diabetes diagnosis, are both strong predictors of mortality in hospitalized patients with COVID-19.
“There was a very clear relationship between hyperglycemia and outcomes. We really shouldn’t put people at risk until we have clear data,” she said.
If, once the data are reviewed and appropriate dexamethasone becomes an established treatment for severe COVID-19, hyperglycemia would be a concern among all patients, not just those with previously diagnosed diabetes, she noted.
“We know a good number of people with prediabetes develop hyperglycemia when put on steroids. They can push people over the edge. We’re not going to miss anybody, but treating steroid-induced hyperglycemia is really hard,” McDonnell explained.
She also recommended 2014 guidance from Diabetes UK and the Association of British Clinical Diabetologists, which addresses management of inpatient steroid-induced DKA in patients with and without pre-existing diabetes.
Another major concern, she said, is “patients trying to get dexamethasone when they start to get sick” because this is not the right population to use this agent.
“We worry about people who do not need this drug. If they have diabetes, they put themselves at risk of hyperglycemia, which then increases the risk of severe COVID-19. And then they’re also putting themselves at risk of DKA. It would just be bad medicine,” she said.
Managing DKA in the face of COVID-19: Flexibility is key
In the JCEM article, Palermo and colleagues emphasize that the usual hospital protocols for DKA management may need to be adjusted during COVID-19 in the interest of reducing transmission risk and preserving scare resources.
They provide evidence for alternative treatment strategies, such as the use of subcutaneous rather than intravenous insulin when appropriate.
“We wanted to outline when exactly you should consider nonintensive management strategies for DKA,” McDonnell further explained to Medscape Medical News.
“That would include those with mild or some with moderate DKA. ... The idea is to remind our colleagues about that because hospitals tend to operate on a protocol-driven algorithmic methodology, they can forget to step off the usual care pathway even if evidence supports that,” she said.
But on the other hand, she also said that, in some very complex or severely ill patients with COVID-19, classical intravenous insulin therapy makes the most sense even if their DKA is mild.
The outpatient setting: Prevention and preparation
The new article also addresses several concerns regarding DKA prevention in the outpatient setting.
As with other guidelines, it includes a reminder that patients with diabetes should be advised to discontinue sodium-glucose cotransporter 2 (SGLT2) inhibitors if they become ill with COVID-19, especially if they’re not eating or drinking normally, because they raise the risk for DKA.
Also, for patients with type 1 diabetes, particularly those with a history of repeated DKA, “this is the time to make sure we reach out to patients to refill their insulin prescriptions and address issues related to cost and other access difficulties,” McDonnell said.
The authors also emphasize that insulin starts and education should not be postponed during the pandemic. “Patients identified as meeting criteria to start insulin should be referred for urgent education, either in person or, whenever possible and practical, via video teleconferencing,” they urge.
McDonnell has reported receiving research funding from Novo Nordisk. The other two authors have reported no relevant financial relationships.
This article first appeared on Medscape.com.
Belimumab safely improved renal function in lupus nephritis patients
compared with control patients who only received standard therapy, in a randomized, multicenter trial with 446 evaluable patients, a finding that may help extend this treatment to a new group of lupus patients.
“The largest” treatment study of lupus nephritis reported to date showed that belimumab, approved by the Food and Drug Administration in 2011 for treating patients with systemic lupus erythematosus (SLE), administered at a standard dosage of 10 mg intravenously every 4 weeks, “significantly improved multiple lupus nephritis renal responses versus standard therapy alone while maintaining an acceptable safety profile,” Richard A. Furie, MD, said at the annual European Congress of Rheumatology, held online this year due to COVID-19.
The study’s primary endpoint was a composite measure that Dr. Furie and associates called the Primary Endpoint Renal Response, which required patients to have achieved a urinary protein-to-creatinine ratio of 0.7 or less (compared with an enrollment level of 1.0 or greater), an estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 kg/m2 and no more than 20% below its preflare level, and continuation on the assigned treatment regimen. After 104 weeks on this treatment, which followed a 60-day induction phase that included treatment with a high-dose glucocorticoid, the percentages of patients who met the Primary Endpoint Renal Response criteria were 32% in the control arm who received standard treatment at the discretion of their treating clinicians plus placebo infusions and 43% in patients who received belimumab infusions in addition to their standard care. This calculated out to a 55% relative increase in this response with belimumab, a statistically significant result, reported Dr. Furie, professor of medicine at Hofstra University, Hempstead, N.Y., and chief of rheumatology at Northwell Health in Manhasset, N.Y.
Patients who received belimumab also had similar and statistically significant levels of improvement for several secondary endpoints, including one called Complete Renal Response, which required a protein-to-creatinine ratio of no greater than 0.5, an eGFR of at least 90 mL/min per 1.73 kg/m2 and no more than 10% below its preflare level, and maintaining the assigned treatment. The Complete Renal Response after 104 weeks was 20% among control patients and 30% among those maintained on belimumab, a 74% relative improvement that was statistically significant. The total percentage of patients with any renal-related event after 104 weeks was 28% among the control patients and 16% among those who received belimumab, a statistically significant difference.
“The fact that the primary and all key secondary endpoints were successfully attained is a major accomplishment in lupus nephritis as well as in any SLE study,” Dr. Furie said in an interview. The study’s 2-year design “provided insight into the durability of the response,” and the steady divergence of the endpoint events in the two study arms beginning after about 24 weeks into the randomized phase “provided data regarding the rapidity of onset of action.” Collectively, the endpoints “mimic our real-life treatment goals: reduce disease activity, prevent flares, preserve renal function, lower steroid treatment, and do it all safely,” he concluded.
Results confirm benefit to subset of patients
“Belimumab is a safe and effective treatment for a significant subset of patients with lupus. We already knew that. Now we have even more confirmation,” commented Joan T. Merrill, MD, a professor of medicine at the University of Oklahoma Health Sciences Center and a rheumatologist who specializes in SLE at the Oklahoma Medical Research Foundation, both in Oklahoma City. “There have already been at least four international trials demonstrating belimumab’s efficacy in general lupus. Some patients in these earlier trials had nephritis, so it should not be surprising to see similar results in a trial restricted to patients with active nephritis, given the drug’s mechanism of action. Belimumab has repeatedly shown early and sustained benefits above what background treatments achieve, and belimumab has also proven to be safe to add to standard-of-care treatments,” she said in an interview.
The BLISS-LN (Efficacy and Safety of Belimumab in Patients With Active Lupus Nephritis) study enrolled patients at any of 118 centers in 20 countries, including the United States. All patients enrolled in the trial were adults with biopsy-confirmed, clinically active lupus nephritis and a urinary protein-to-creatinine ratio of at least 1.0, and need for induction therapy. The 60-day induction run-in phase began with high-dose glucocorticoids plus either cyclophosphamide or mycophenolate mofetil (CellCept), followed by maintenance on low-dose glucocorticoids and either azathioprine or mycophenolate mofetil. Nearly three-quarters of patients received mycophenolate mofetil–based induction. Once treatment with either belimumab or placebo began in the study’s main phase, the glucocorticoid dosage had to drop with tapering to no more than 10 mg/day within 24 weeks or the patient was considered a treatment failure.
Thoughts on current and future use of belimumab
The current labeled indication for belimumab is for “treatment of patients aged 5 years and older with active, autoantibody-positive systemic lupus erythematosus who are receiving standard therapy,” an inclusive SLE population, but the label also adds this caveat: “Limitations of use: The efficacy of Benlysta has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus.” According to Dr. Furie’s report, GlaxoSmithKline, the company that markets belimumab, plans to seek a labeled indication for lupus nephritis for the drug during 2020.
“I doubt the drug is widely used as yet in clinical practice for lupus nephritis,” although it is being prescribed to selected SLE patients in current, routine practice, said Dr. Merrill, a coinvestigator on some belimumab studies. What also remains unknown is the efficacy of belimumab monotherapy. “We don’t know which subset of patients might benefit from belimumab alone,” she noted. Nor is it known whether belimumab treatment of patients with SLE but without lupus nephritis will forestall later development of lupus nephritis.
“With the introduction of the subcutaneous formulation a few years ago, there has been greater belimumab use” overall in patients with SLE, said Dr. Furie, and with a safety and efficacy record now established in five separate, reported studies in addition to the new BLISS-LN study: BLISS-52, BLISS-76, BLISS-SC, BLISS-NE ASIA, and PLUTO. “The pivotal studies [BLISS-52 and BLISS-76] were done in patients with SLE but without nephritis in need of aggressive induction therapy. About 15% of the trial cohorts had low-level renal involvement,” and post hoc analyses suggested that the benefit in those patients was similar to patients without renal involvement, which led to the BLISS-LN study. “In theory, no SLE patients with high-level nephritis should be on belimumab at this time,” based on its labeling, although some SLE patients with low-level renal disease may now receive the drug because they also have other affected organs, such as skin and joints, Dr. Furie said.
“These are encouraging results,” commented George K. Bertsias, MD, a rheumatologist and SLE specialist at the University of Crete in Heraklion, Greece. He particularly cited the “significant effect from add-on belimumab” on top of treatment with mycophenolate mofetil, an “established and effective treatment for lupus nephritis. The data provide additional evidence for the efficacy of belimumab in SLE, and also in lupus nephritis,” he said in an interview, and “having an official labeled indication for active nephritis will enhance use of the drug” in such patients. “Considering the favorable effects of the drug on SLE, especially preventing major flares, and on lupus nephritis it is possible that the drug will be particularly suitable for SLE patients who are at high risk for developing lupus nephritis, although such an effect remains to be determined.” Until now, belimumab has generally been prescribed to SLE patients who have disease manifestations in organs outside of the kidneys, he noted.
BLISS-LN was sponsored by GlaxoSmithKline. Dr. Furie is a consultant to and has received research funding from GlaxoSmithKline, and several of the study’s coauthors are employees of the company. Dr. Merrill has been a consultant to GlaxoSmithKline as well as to several other companies and has been a coinvestigator on belimumab studies. Dr. Bertsias has been a consultant to Novartis and has received research funding from GlaxoSmithKline.
SOURCE: Furie RA et al. Ann Rheum Dis. 2020 Jun;79[suppl 1]:103, Abstract OP0164.
compared with control patients who only received standard therapy, in a randomized, multicenter trial with 446 evaluable patients, a finding that may help extend this treatment to a new group of lupus patients.
“The largest” treatment study of lupus nephritis reported to date showed that belimumab, approved by the Food and Drug Administration in 2011 for treating patients with systemic lupus erythematosus (SLE), administered at a standard dosage of 10 mg intravenously every 4 weeks, “significantly improved multiple lupus nephritis renal responses versus standard therapy alone while maintaining an acceptable safety profile,” Richard A. Furie, MD, said at the annual European Congress of Rheumatology, held online this year due to COVID-19.
The study’s primary endpoint was a composite measure that Dr. Furie and associates called the Primary Endpoint Renal Response, which required patients to have achieved a urinary protein-to-creatinine ratio of 0.7 or less (compared with an enrollment level of 1.0 or greater), an estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 kg/m2 and no more than 20% below its preflare level, and continuation on the assigned treatment regimen. After 104 weeks on this treatment, which followed a 60-day induction phase that included treatment with a high-dose glucocorticoid, the percentages of patients who met the Primary Endpoint Renal Response criteria were 32% in the control arm who received standard treatment at the discretion of their treating clinicians plus placebo infusions and 43% in patients who received belimumab infusions in addition to their standard care. This calculated out to a 55% relative increase in this response with belimumab, a statistically significant result, reported Dr. Furie, professor of medicine at Hofstra University, Hempstead, N.Y., and chief of rheumatology at Northwell Health in Manhasset, N.Y.
Patients who received belimumab also had similar and statistically significant levels of improvement for several secondary endpoints, including one called Complete Renal Response, which required a protein-to-creatinine ratio of no greater than 0.5, an eGFR of at least 90 mL/min per 1.73 kg/m2 and no more than 10% below its preflare level, and maintaining the assigned treatment. The Complete Renal Response after 104 weeks was 20% among control patients and 30% among those maintained on belimumab, a 74% relative improvement that was statistically significant. The total percentage of patients with any renal-related event after 104 weeks was 28% among the control patients and 16% among those who received belimumab, a statistically significant difference.
“The fact that the primary and all key secondary endpoints were successfully attained is a major accomplishment in lupus nephritis as well as in any SLE study,” Dr. Furie said in an interview. The study’s 2-year design “provided insight into the durability of the response,” and the steady divergence of the endpoint events in the two study arms beginning after about 24 weeks into the randomized phase “provided data regarding the rapidity of onset of action.” Collectively, the endpoints “mimic our real-life treatment goals: reduce disease activity, prevent flares, preserve renal function, lower steroid treatment, and do it all safely,” he concluded.
Results confirm benefit to subset of patients
“Belimumab is a safe and effective treatment for a significant subset of patients with lupus. We already knew that. Now we have even more confirmation,” commented Joan T. Merrill, MD, a professor of medicine at the University of Oklahoma Health Sciences Center and a rheumatologist who specializes in SLE at the Oklahoma Medical Research Foundation, both in Oklahoma City. “There have already been at least four international trials demonstrating belimumab’s efficacy in general lupus. Some patients in these earlier trials had nephritis, so it should not be surprising to see similar results in a trial restricted to patients with active nephritis, given the drug’s mechanism of action. Belimumab has repeatedly shown early and sustained benefits above what background treatments achieve, and belimumab has also proven to be safe to add to standard-of-care treatments,” she said in an interview.
The BLISS-LN (Efficacy and Safety of Belimumab in Patients With Active Lupus Nephritis) study enrolled patients at any of 118 centers in 20 countries, including the United States. All patients enrolled in the trial were adults with biopsy-confirmed, clinically active lupus nephritis and a urinary protein-to-creatinine ratio of at least 1.0, and need for induction therapy. The 60-day induction run-in phase began with high-dose glucocorticoids plus either cyclophosphamide or mycophenolate mofetil (CellCept), followed by maintenance on low-dose glucocorticoids and either azathioprine or mycophenolate mofetil. Nearly three-quarters of patients received mycophenolate mofetil–based induction. Once treatment with either belimumab or placebo began in the study’s main phase, the glucocorticoid dosage had to drop with tapering to no more than 10 mg/day within 24 weeks or the patient was considered a treatment failure.
Thoughts on current and future use of belimumab
The current labeled indication for belimumab is for “treatment of patients aged 5 years and older with active, autoantibody-positive systemic lupus erythematosus who are receiving standard therapy,” an inclusive SLE population, but the label also adds this caveat: “Limitations of use: The efficacy of Benlysta has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus.” According to Dr. Furie’s report, GlaxoSmithKline, the company that markets belimumab, plans to seek a labeled indication for lupus nephritis for the drug during 2020.
“I doubt the drug is widely used as yet in clinical practice for lupus nephritis,” although it is being prescribed to selected SLE patients in current, routine practice, said Dr. Merrill, a coinvestigator on some belimumab studies. What also remains unknown is the efficacy of belimumab monotherapy. “We don’t know which subset of patients might benefit from belimumab alone,” she noted. Nor is it known whether belimumab treatment of patients with SLE but without lupus nephritis will forestall later development of lupus nephritis.
“With the introduction of the subcutaneous formulation a few years ago, there has been greater belimumab use” overall in patients with SLE, said Dr. Furie, and with a safety and efficacy record now established in five separate, reported studies in addition to the new BLISS-LN study: BLISS-52, BLISS-76, BLISS-SC, BLISS-NE ASIA, and PLUTO. “The pivotal studies [BLISS-52 and BLISS-76] were done in patients with SLE but without nephritis in need of aggressive induction therapy. About 15% of the trial cohorts had low-level renal involvement,” and post hoc analyses suggested that the benefit in those patients was similar to patients without renal involvement, which led to the BLISS-LN study. “In theory, no SLE patients with high-level nephritis should be on belimumab at this time,” based on its labeling, although some SLE patients with low-level renal disease may now receive the drug because they also have other affected organs, such as skin and joints, Dr. Furie said.
“These are encouraging results,” commented George K. Bertsias, MD, a rheumatologist and SLE specialist at the University of Crete in Heraklion, Greece. He particularly cited the “significant effect from add-on belimumab” on top of treatment with mycophenolate mofetil, an “established and effective treatment for lupus nephritis. The data provide additional evidence for the efficacy of belimumab in SLE, and also in lupus nephritis,” he said in an interview, and “having an official labeled indication for active nephritis will enhance use of the drug” in such patients. “Considering the favorable effects of the drug on SLE, especially preventing major flares, and on lupus nephritis it is possible that the drug will be particularly suitable for SLE patients who are at high risk for developing lupus nephritis, although such an effect remains to be determined.” Until now, belimumab has generally been prescribed to SLE patients who have disease manifestations in organs outside of the kidneys, he noted.
BLISS-LN was sponsored by GlaxoSmithKline. Dr. Furie is a consultant to and has received research funding from GlaxoSmithKline, and several of the study’s coauthors are employees of the company. Dr. Merrill has been a consultant to GlaxoSmithKline as well as to several other companies and has been a coinvestigator on belimumab studies. Dr. Bertsias has been a consultant to Novartis and has received research funding from GlaxoSmithKline.
SOURCE: Furie RA et al. Ann Rheum Dis. 2020 Jun;79[suppl 1]:103, Abstract OP0164.
compared with control patients who only received standard therapy, in a randomized, multicenter trial with 446 evaluable patients, a finding that may help extend this treatment to a new group of lupus patients.
“The largest” treatment study of lupus nephritis reported to date showed that belimumab, approved by the Food and Drug Administration in 2011 for treating patients with systemic lupus erythematosus (SLE), administered at a standard dosage of 10 mg intravenously every 4 weeks, “significantly improved multiple lupus nephritis renal responses versus standard therapy alone while maintaining an acceptable safety profile,” Richard A. Furie, MD, said at the annual European Congress of Rheumatology, held online this year due to COVID-19.
The study’s primary endpoint was a composite measure that Dr. Furie and associates called the Primary Endpoint Renal Response, which required patients to have achieved a urinary protein-to-creatinine ratio of 0.7 or less (compared with an enrollment level of 1.0 or greater), an estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 kg/m2 and no more than 20% below its preflare level, and continuation on the assigned treatment regimen. After 104 weeks on this treatment, which followed a 60-day induction phase that included treatment with a high-dose glucocorticoid, the percentages of patients who met the Primary Endpoint Renal Response criteria were 32% in the control arm who received standard treatment at the discretion of their treating clinicians plus placebo infusions and 43% in patients who received belimumab infusions in addition to their standard care. This calculated out to a 55% relative increase in this response with belimumab, a statistically significant result, reported Dr. Furie, professor of medicine at Hofstra University, Hempstead, N.Y., and chief of rheumatology at Northwell Health in Manhasset, N.Y.
Patients who received belimumab also had similar and statistically significant levels of improvement for several secondary endpoints, including one called Complete Renal Response, which required a protein-to-creatinine ratio of no greater than 0.5, an eGFR of at least 90 mL/min per 1.73 kg/m2 and no more than 10% below its preflare level, and maintaining the assigned treatment. The Complete Renal Response after 104 weeks was 20% among control patients and 30% among those maintained on belimumab, a 74% relative improvement that was statistically significant. The total percentage of patients with any renal-related event after 104 weeks was 28% among the control patients and 16% among those who received belimumab, a statistically significant difference.
“The fact that the primary and all key secondary endpoints were successfully attained is a major accomplishment in lupus nephritis as well as in any SLE study,” Dr. Furie said in an interview. The study’s 2-year design “provided insight into the durability of the response,” and the steady divergence of the endpoint events in the two study arms beginning after about 24 weeks into the randomized phase “provided data regarding the rapidity of onset of action.” Collectively, the endpoints “mimic our real-life treatment goals: reduce disease activity, prevent flares, preserve renal function, lower steroid treatment, and do it all safely,” he concluded.
Results confirm benefit to subset of patients
“Belimumab is a safe and effective treatment for a significant subset of patients with lupus. We already knew that. Now we have even more confirmation,” commented Joan T. Merrill, MD, a professor of medicine at the University of Oklahoma Health Sciences Center and a rheumatologist who specializes in SLE at the Oklahoma Medical Research Foundation, both in Oklahoma City. “There have already been at least four international trials demonstrating belimumab’s efficacy in general lupus. Some patients in these earlier trials had nephritis, so it should not be surprising to see similar results in a trial restricted to patients with active nephritis, given the drug’s mechanism of action. Belimumab has repeatedly shown early and sustained benefits above what background treatments achieve, and belimumab has also proven to be safe to add to standard-of-care treatments,” she said in an interview.
The BLISS-LN (Efficacy and Safety of Belimumab in Patients With Active Lupus Nephritis) study enrolled patients at any of 118 centers in 20 countries, including the United States. All patients enrolled in the trial were adults with biopsy-confirmed, clinically active lupus nephritis and a urinary protein-to-creatinine ratio of at least 1.0, and need for induction therapy. The 60-day induction run-in phase began with high-dose glucocorticoids plus either cyclophosphamide or mycophenolate mofetil (CellCept), followed by maintenance on low-dose glucocorticoids and either azathioprine or mycophenolate mofetil. Nearly three-quarters of patients received mycophenolate mofetil–based induction. Once treatment with either belimumab or placebo began in the study’s main phase, the glucocorticoid dosage had to drop with tapering to no more than 10 mg/day within 24 weeks or the patient was considered a treatment failure.
Thoughts on current and future use of belimumab
The current labeled indication for belimumab is for “treatment of patients aged 5 years and older with active, autoantibody-positive systemic lupus erythematosus who are receiving standard therapy,” an inclusive SLE population, but the label also adds this caveat: “Limitations of use: The efficacy of Benlysta has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus.” According to Dr. Furie’s report, GlaxoSmithKline, the company that markets belimumab, plans to seek a labeled indication for lupus nephritis for the drug during 2020.
“I doubt the drug is widely used as yet in clinical practice for lupus nephritis,” although it is being prescribed to selected SLE patients in current, routine practice, said Dr. Merrill, a coinvestigator on some belimumab studies. What also remains unknown is the efficacy of belimumab monotherapy. “We don’t know which subset of patients might benefit from belimumab alone,” she noted. Nor is it known whether belimumab treatment of patients with SLE but without lupus nephritis will forestall later development of lupus nephritis.
“With the introduction of the subcutaneous formulation a few years ago, there has been greater belimumab use” overall in patients with SLE, said Dr. Furie, and with a safety and efficacy record now established in five separate, reported studies in addition to the new BLISS-LN study: BLISS-52, BLISS-76, BLISS-SC, BLISS-NE ASIA, and PLUTO. “The pivotal studies [BLISS-52 and BLISS-76] were done in patients with SLE but without nephritis in need of aggressive induction therapy. About 15% of the trial cohorts had low-level renal involvement,” and post hoc analyses suggested that the benefit in those patients was similar to patients without renal involvement, which led to the BLISS-LN study. “In theory, no SLE patients with high-level nephritis should be on belimumab at this time,” based on its labeling, although some SLE patients with low-level renal disease may now receive the drug because they also have other affected organs, such as skin and joints, Dr. Furie said.
“These are encouraging results,” commented George K. Bertsias, MD, a rheumatologist and SLE specialist at the University of Crete in Heraklion, Greece. He particularly cited the “significant effect from add-on belimumab” on top of treatment with mycophenolate mofetil, an “established and effective treatment for lupus nephritis. The data provide additional evidence for the efficacy of belimumab in SLE, and also in lupus nephritis,” he said in an interview, and “having an official labeled indication for active nephritis will enhance use of the drug” in such patients. “Considering the favorable effects of the drug on SLE, especially preventing major flares, and on lupus nephritis it is possible that the drug will be particularly suitable for SLE patients who are at high risk for developing lupus nephritis, although such an effect remains to be determined.” Until now, belimumab has generally been prescribed to SLE patients who have disease manifestations in organs outside of the kidneys, he noted.
BLISS-LN was sponsored by GlaxoSmithKline. Dr. Furie is a consultant to and has received research funding from GlaxoSmithKline, and several of the study’s coauthors are employees of the company. Dr. Merrill has been a consultant to GlaxoSmithKline as well as to several other companies and has been a coinvestigator on belimumab studies. Dr. Bertsias has been a consultant to Novartis and has received research funding from GlaxoSmithKline.
SOURCE: Furie RA et al. Ann Rheum Dis. 2020 Jun;79[suppl 1]:103, Abstract OP0164.
FROM THE EULAR 2020 E-CONGRESS
Dapagliflozin’s T2D renal protection extends to ‘fast decline’ of eGFR
Treatment of patients with type 2 diabetes with the SGLT2 inhibitor dapagliflozin led to a significant drop in the occurrence of ‘fast decline’ of renal function in more than 15,000 patients enrolled in the drug’s main cardiovascular outcome trial, another example of the potent renal protective effects of agents from this drug class.
Among patients with type 2 diabetes enrolled in the DECLARE-TIMI 58 trial, the incidence of a fast decline in renal function, defined as a drop in estimated glomerular filtration rate (eGFR) of at least 3 mL/min per 1.73 m2, was 27% among patients treated with dapagliflozin and 37% in control patients who received placebo, a statistically significant difference for this post-hoc analysis, Itamar Raz, MD, said at the virtual annual scientific sessions of the American Diabetes Association.
This finding, which adds to a long list of other renal function parameters reported to have been improved by treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors, “emphasizes the value of SGLT2 inhibitors as an important component of both prevention and treatment of chronic kidney disease among patients with type 2 diabetes,” said Dr. Raz, a diabetes researcher and professor of medicine at Hadassah University Hospital in Jerusalem.
The primary, prespecified renal outcomes in DECLARE-TIMI 58 were a cardiorenal composite outcome of sustained decline of at least 40% in eGFR to less than 60 mL/min per 1.73 m2, end-stage renal disease (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR of less than 15 mL/min per 1.73 m2), or death from renal or cardiovascular causes; and a second prespecified renal-specific composite outcome that was the same except for excluding death from cardiovascular causes. The results showed that the cardiorenal outcome dropped by a statistically significant 24% with dapagliflozin treatment relative to control patients, and the renal-specific outcome fell by a statistically significant 47% with dapagliflozin relative to control patients (Lancet Diab Endocrinol. 2019 Aug 1;7[8];606-17).
The new findings on the incidence of fast decline in renal function help to further flesh out the scope of renal benefit exerted by SGLT2 inhibitors like dapagliflozin in patients with type 2 diabetes, said experts. Fast decline is a relatively recently devised measure of a high-risk, precipitous loss of renal function that has been defined as a drop of either 3 or 5 mL/min per 1.73 m2 per year (Kidney Int. 2017 Jun;91[6]:1300-11); for this analysis Dr. Raz and his associates used the less stringent definition.
Finding and treating ‘fast decliners’
The new report from Dr. Raz “confirms the original [renal] findings and looks to expand them to a particularly high risk group: the fast decliners,” commented Robert A. Gabbay, MD, chief science & medical officer of the ADA. “In some ways, the group of patients that we need to find a better treatment for most are those whose GFR declines quickly. We don’t always know who they are until after the fact, and studies have been looking for markers that might prospectively identify them,” he said in an interview.
The new analysis showed that dapagliflozin “was effective in this subgroup of patients. Furthermore, it didn’t matter if they had significant baseline disease or not. Even people with normal kidney function [at baseline] who were still fast decliners fared better with the drug than without it. This suggests that, if it can be confirmed in a prospective study, dapagliflozin might be effective very early in the course of treatment if we can identify who will be the fast decliners.”
Dr. Raz and his associates had the data necessary to calculate the rates of eGFR decline during the full follow-up period for 15,012 of the 17,160 patients enrolled in DECLARE-TIMI 58, and they found that 4,788 (32%) were fast decliners and 10,224 had a slower rate of renal deterioration. The average annual decline in eGFR during the period from 6 months after study entry through 4 years was 6.3 mL/min per 1.73 m2 per year (median of 5.1 mL/min per 1.73 m2 per year) among the fast decliners, and zero (median of 0.6 mL/min per 1.73 m2 per year) among the other patients.
Overcoming dapagliflozin’s initial eGFR reduction
The researchers focused on the 6-month to 4-year period of treatment as more representative of the impact of dapagliflozin because the SGLT2 inhibitors have an established pattern of triggering an initial, moderate decline in eGFR over roughly the first 6 months on the drug, which is similar to what happens to patients who start treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.
“Some patients get as much as a 10% decline in eGFR” when SGLT2 inhibitor treatment starts, but “patients do better over time even with this initial hit,” the same way they do on drugs that act on the renin-angiotensin system, explained Silvio E. Inzucchi, MD, an endocrinologist and professor of medicine at Yale University in New Haven who has extensively studied the SGLT2 inhibitors.
The analyses reported by Dr. Raz showed that the protection against fast decline during the 6-month to 4-year period with dapagliflozin treatment was consistent across a range of patient subgroups regardless of age, duration of their type 2 diabetes, their baseline level of hyperglycemia, and their baseline eGFR. Nearly half the patients enrolled in DECLARE-TIMI 58 had an eGFR at baseline of at least 91 mL/min per 1.73 m2 and in this subgroup the incidence of fast decliners was 23% with dapagliflozin and 31% on placebo. Among the 45% of patients who began with an eGFR of 60-90 mL/min per 1.73 m2 the fast-decliner incidence was 32% and 43% when on or off dapagliflozin. Among the 7% of patients who entered with an eGFR below 60 mL/min per 1.73 m2, the fast-decliner incidence was 25% on dapagliflozin and 36% among controls. All the between-group differences were statistically significant.
The incidence of fast decliners was also lower with dapagliflozin treatment when the analysis included the entire first 4 years on treatment, including the first 6 months when SGLT2s usually spikes a loss of renal function. For the entire 4-year period, fast decline occurred among 34% of patients on dapagliflozin and in 37% of control patients, a statistically significant difference.
The mechanisms behind the consistent renal-protective effects of the SGLT2 inhibitors remain unclear right now, but likely seem related to the “perfect” diuretic action the drugs produce, said Dr. Inzucchi. “They’re not as hugely effective as diuretics, but they’re gentler.” While the SGLT2 inhibitors cause a modest amount of fluid loss ”for some reason they don’t activate the compensatory mechanisms that prevent further reductions in plasma volume,” a property that manifests as little or no change in catecholamines or renin-angiotensin activity, which sets this diuretic action apart from what happens with conventional diuretic drugs, he said in an interview.
In DECLARE-TIMI 58 treatment with dapagliflozin met its primary safety outcome of noninferiority to placebo with respect to major adverse cardiovascular events. The results failed to show statistically significant superiority for one of the primary efficacy endpoints, the rate of major adverse coronary events, but they did show significantly better performance for the second primary efficacy outcome of the rate of cardiovascular death or hospitalization for heart failure, which occurred in 4.9% of patients treated with dapagliflozin and in 5.8% of the control patients during a median follow-up of 4.2 years (N Engl J Med. 2019 Jan 24;380[4]:347-57).
DECLARE-TIMI 58 was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Raz has been an advisor to and speaker on behalf of AstraZeneca as well as several other companies. Dr. Gabbay had no relevant disclosures. Dr. Inzucchi has been a consultant to AstraZeneca, and also to Abbott, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics.
SOURCE: Raz I et al. ADA 2020, Abstract 303-OR.
Treatment of patients with type 2 diabetes with the SGLT2 inhibitor dapagliflozin led to a significant drop in the occurrence of ‘fast decline’ of renal function in more than 15,000 patients enrolled in the drug’s main cardiovascular outcome trial, another example of the potent renal protective effects of agents from this drug class.
Among patients with type 2 diabetes enrolled in the DECLARE-TIMI 58 trial, the incidence of a fast decline in renal function, defined as a drop in estimated glomerular filtration rate (eGFR) of at least 3 mL/min per 1.73 m2, was 27% among patients treated with dapagliflozin and 37% in control patients who received placebo, a statistically significant difference for this post-hoc analysis, Itamar Raz, MD, said at the virtual annual scientific sessions of the American Diabetes Association.
This finding, which adds to a long list of other renal function parameters reported to have been improved by treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors, “emphasizes the value of SGLT2 inhibitors as an important component of both prevention and treatment of chronic kidney disease among patients with type 2 diabetes,” said Dr. Raz, a diabetes researcher and professor of medicine at Hadassah University Hospital in Jerusalem.
The primary, prespecified renal outcomes in DECLARE-TIMI 58 were a cardiorenal composite outcome of sustained decline of at least 40% in eGFR to less than 60 mL/min per 1.73 m2, end-stage renal disease (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR of less than 15 mL/min per 1.73 m2), or death from renal or cardiovascular causes; and a second prespecified renal-specific composite outcome that was the same except for excluding death from cardiovascular causes. The results showed that the cardiorenal outcome dropped by a statistically significant 24% with dapagliflozin treatment relative to control patients, and the renal-specific outcome fell by a statistically significant 47% with dapagliflozin relative to control patients (Lancet Diab Endocrinol. 2019 Aug 1;7[8];606-17).
The new findings on the incidence of fast decline in renal function help to further flesh out the scope of renal benefit exerted by SGLT2 inhibitors like dapagliflozin in patients with type 2 diabetes, said experts. Fast decline is a relatively recently devised measure of a high-risk, precipitous loss of renal function that has been defined as a drop of either 3 or 5 mL/min per 1.73 m2 per year (Kidney Int. 2017 Jun;91[6]:1300-11); for this analysis Dr. Raz and his associates used the less stringent definition.
Finding and treating ‘fast decliners’
The new report from Dr. Raz “confirms the original [renal] findings and looks to expand them to a particularly high risk group: the fast decliners,” commented Robert A. Gabbay, MD, chief science & medical officer of the ADA. “In some ways, the group of patients that we need to find a better treatment for most are those whose GFR declines quickly. We don’t always know who they are until after the fact, and studies have been looking for markers that might prospectively identify them,” he said in an interview.
The new analysis showed that dapagliflozin “was effective in this subgroup of patients. Furthermore, it didn’t matter if they had significant baseline disease or not. Even people with normal kidney function [at baseline] who were still fast decliners fared better with the drug than without it. This suggests that, if it can be confirmed in a prospective study, dapagliflozin might be effective very early in the course of treatment if we can identify who will be the fast decliners.”
Dr. Raz and his associates had the data necessary to calculate the rates of eGFR decline during the full follow-up period for 15,012 of the 17,160 patients enrolled in DECLARE-TIMI 58, and they found that 4,788 (32%) were fast decliners and 10,224 had a slower rate of renal deterioration. The average annual decline in eGFR during the period from 6 months after study entry through 4 years was 6.3 mL/min per 1.73 m2 per year (median of 5.1 mL/min per 1.73 m2 per year) among the fast decliners, and zero (median of 0.6 mL/min per 1.73 m2 per year) among the other patients.
Overcoming dapagliflozin’s initial eGFR reduction
The researchers focused on the 6-month to 4-year period of treatment as more representative of the impact of dapagliflozin because the SGLT2 inhibitors have an established pattern of triggering an initial, moderate decline in eGFR over roughly the first 6 months on the drug, which is similar to what happens to patients who start treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.
“Some patients get as much as a 10% decline in eGFR” when SGLT2 inhibitor treatment starts, but “patients do better over time even with this initial hit,” the same way they do on drugs that act on the renin-angiotensin system, explained Silvio E. Inzucchi, MD, an endocrinologist and professor of medicine at Yale University in New Haven who has extensively studied the SGLT2 inhibitors.
The analyses reported by Dr. Raz showed that the protection against fast decline during the 6-month to 4-year period with dapagliflozin treatment was consistent across a range of patient subgroups regardless of age, duration of their type 2 diabetes, their baseline level of hyperglycemia, and their baseline eGFR. Nearly half the patients enrolled in DECLARE-TIMI 58 had an eGFR at baseline of at least 91 mL/min per 1.73 m2 and in this subgroup the incidence of fast decliners was 23% with dapagliflozin and 31% on placebo. Among the 45% of patients who began with an eGFR of 60-90 mL/min per 1.73 m2 the fast-decliner incidence was 32% and 43% when on or off dapagliflozin. Among the 7% of patients who entered with an eGFR below 60 mL/min per 1.73 m2, the fast-decliner incidence was 25% on dapagliflozin and 36% among controls. All the between-group differences were statistically significant.
The incidence of fast decliners was also lower with dapagliflozin treatment when the analysis included the entire first 4 years on treatment, including the first 6 months when SGLT2s usually spikes a loss of renal function. For the entire 4-year period, fast decline occurred among 34% of patients on dapagliflozin and in 37% of control patients, a statistically significant difference.
The mechanisms behind the consistent renal-protective effects of the SGLT2 inhibitors remain unclear right now, but likely seem related to the “perfect” diuretic action the drugs produce, said Dr. Inzucchi. “They’re not as hugely effective as diuretics, but they’re gentler.” While the SGLT2 inhibitors cause a modest amount of fluid loss ”for some reason they don’t activate the compensatory mechanisms that prevent further reductions in plasma volume,” a property that manifests as little or no change in catecholamines or renin-angiotensin activity, which sets this diuretic action apart from what happens with conventional diuretic drugs, he said in an interview.
In DECLARE-TIMI 58 treatment with dapagliflozin met its primary safety outcome of noninferiority to placebo with respect to major adverse cardiovascular events. The results failed to show statistically significant superiority for one of the primary efficacy endpoints, the rate of major adverse coronary events, but they did show significantly better performance for the second primary efficacy outcome of the rate of cardiovascular death or hospitalization for heart failure, which occurred in 4.9% of patients treated with dapagliflozin and in 5.8% of the control patients during a median follow-up of 4.2 years (N Engl J Med. 2019 Jan 24;380[4]:347-57).
DECLARE-TIMI 58 was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Raz has been an advisor to and speaker on behalf of AstraZeneca as well as several other companies. Dr. Gabbay had no relevant disclosures. Dr. Inzucchi has been a consultant to AstraZeneca, and also to Abbott, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics.
SOURCE: Raz I et al. ADA 2020, Abstract 303-OR.
Treatment of patients with type 2 diabetes with the SGLT2 inhibitor dapagliflozin led to a significant drop in the occurrence of ‘fast decline’ of renal function in more than 15,000 patients enrolled in the drug’s main cardiovascular outcome trial, another example of the potent renal protective effects of agents from this drug class.
Among patients with type 2 diabetes enrolled in the DECLARE-TIMI 58 trial, the incidence of a fast decline in renal function, defined as a drop in estimated glomerular filtration rate (eGFR) of at least 3 mL/min per 1.73 m2, was 27% among patients treated with dapagliflozin and 37% in control patients who received placebo, a statistically significant difference for this post-hoc analysis, Itamar Raz, MD, said at the virtual annual scientific sessions of the American Diabetes Association.
This finding, which adds to a long list of other renal function parameters reported to have been improved by treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors, “emphasizes the value of SGLT2 inhibitors as an important component of both prevention and treatment of chronic kidney disease among patients with type 2 diabetes,” said Dr. Raz, a diabetes researcher and professor of medicine at Hadassah University Hospital in Jerusalem.
The primary, prespecified renal outcomes in DECLARE-TIMI 58 were a cardiorenal composite outcome of sustained decline of at least 40% in eGFR to less than 60 mL/min per 1.73 m2, end-stage renal disease (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR of less than 15 mL/min per 1.73 m2), or death from renal or cardiovascular causes; and a second prespecified renal-specific composite outcome that was the same except for excluding death from cardiovascular causes. The results showed that the cardiorenal outcome dropped by a statistically significant 24% with dapagliflozin treatment relative to control patients, and the renal-specific outcome fell by a statistically significant 47% with dapagliflozin relative to control patients (Lancet Diab Endocrinol. 2019 Aug 1;7[8];606-17).
The new findings on the incidence of fast decline in renal function help to further flesh out the scope of renal benefit exerted by SGLT2 inhibitors like dapagliflozin in patients with type 2 diabetes, said experts. Fast decline is a relatively recently devised measure of a high-risk, precipitous loss of renal function that has been defined as a drop of either 3 or 5 mL/min per 1.73 m2 per year (Kidney Int. 2017 Jun;91[6]:1300-11); for this analysis Dr. Raz and his associates used the less stringent definition.
Finding and treating ‘fast decliners’
The new report from Dr. Raz “confirms the original [renal] findings and looks to expand them to a particularly high risk group: the fast decliners,” commented Robert A. Gabbay, MD, chief science & medical officer of the ADA. “In some ways, the group of patients that we need to find a better treatment for most are those whose GFR declines quickly. We don’t always know who they are until after the fact, and studies have been looking for markers that might prospectively identify them,” he said in an interview.
The new analysis showed that dapagliflozin “was effective in this subgroup of patients. Furthermore, it didn’t matter if they had significant baseline disease or not. Even people with normal kidney function [at baseline] who were still fast decliners fared better with the drug than without it. This suggests that, if it can be confirmed in a prospective study, dapagliflozin might be effective very early in the course of treatment if we can identify who will be the fast decliners.”
Dr. Raz and his associates had the data necessary to calculate the rates of eGFR decline during the full follow-up period for 15,012 of the 17,160 patients enrolled in DECLARE-TIMI 58, and they found that 4,788 (32%) were fast decliners and 10,224 had a slower rate of renal deterioration. The average annual decline in eGFR during the period from 6 months after study entry through 4 years was 6.3 mL/min per 1.73 m2 per year (median of 5.1 mL/min per 1.73 m2 per year) among the fast decliners, and zero (median of 0.6 mL/min per 1.73 m2 per year) among the other patients.
Overcoming dapagliflozin’s initial eGFR reduction
The researchers focused on the 6-month to 4-year period of treatment as more representative of the impact of dapagliflozin because the SGLT2 inhibitors have an established pattern of triggering an initial, moderate decline in eGFR over roughly the first 6 months on the drug, which is similar to what happens to patients who start treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.
“Some patients get as much as a 10% decline in eGFR” when SGLT2 inhibitor treatment starts, but “patients do better over time even with this initial hit,” the same way they do on drugs that act on the renin-angiotensin system, explained Silvio E. Inzucchi, MD, an endocrinologist and professor of medicine at Yale University in New Haven who has extensively studied the SGLT2 inhibitors.
The analyses reported by Dr. Raz showed that the protection against fast decline during the 6-month to 4-year period with dapagliflozin treatment was consistent across a range of patient subgroups regardless of age, duration of their type 2 diabetes, their baseline level of hyperglycemia, and their baseline eGFR. Nearly half the patients enrolled in DECLARE-TIMI 58 had an eGFR at baseline of at least 91 mL/min per 1.73 m2 and in this subgroup the incidence of fast decliners was 23% with dapagliflozin and 31% on placebo. Among the 45% of patients who began with an eGFR of 60-90 mL/min per 1.73 m2 the fast-decliner incidence was 32% and 43% when on or off dapagliflozin. Among the 7% of patients who entered with an eGFR below 60 mL/min per 1.73 m2, the fast-decliner incidence was 25% on dapagliflozin and 36% among controls. All the between-group differences were statistically significant.
The incidence of fast decliners was also lower with dapagliflozin treatment when the analysis included the entire first 4 years on treatment, including the first 6 months when SGLT2s usually spikes a loss of renal function. For the entire 4-year period, fast decline occurred among 34% of patients on dapagliflozin and in 37% of control patients, a statistically significant difference.
The mechanisms behind the consistent renal-protective effects of the SGLT2 inhibitors remain unclear right now, but likely seem related to the “perfect” diuretic action the drugs produce, said Dr. Inzucchi. “They’re not as hugely effective as diuretics, but they’re gentler.” While the SGLT2 inhibitors cause a modest amount of fluid loss ”for some reason they don’t activate the compensatory mechanisms that prevent further reductions in plasma volume,” a property that manifests as little or no change in catecholamines or renin-angiotensin activity, which sets this diuretic action apart from what happens with conventional diuretic drugs, he said in an interview.
In DECLARE-TIMI 58 treatment with dapagliflozin met its primary safety outcome of noninferiority to placebo with respect to major adverse cardiovascular events. The results failed to show statistically significant superiority for one of the primary efficacy endpoints, the rate of major adverse coronary events, but they did show significantly better performance for the second primary efficacy outcome of the rate of cardiovascular death or hospitalization for heart failure, which occurred in 4.9% of patients treated with dapagliflozin and in 5.8% of the control patients during a median follow-up of 4.2 years (N Engl J Med. 2019 Jan 24;380[4]:347-57).
DECLARE-TIMI 58 was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Raz has been an advisor to and speaker on behalf of AstraZeneca as well as several other companies. Dr. Gabbay had no relevant disclosures. Dr. Inzucchi has been a consultant to AstraZeneca, and also to Abbott, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics.
SOURCE: Raz I et al. ADA 2020, Abstract 303-OR.
FROM ADA 2020
Be vigilant for scleroderma renal crisis
Scleroderma renal crisis is often the most challenging type of scleroderma emergency to identify promptly, according to Francesco Boin, MD, professor of medicine and director of the scleroderma center at the University of California, San Francisco.
“Fortunately, it’s not a frequent event. But it’s severe enough that all rheumatologists should be aware of it,” he said at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.
Atypical presentations occur in 30%
Scleroderma renal crisis (SRC) occurs in 5%-10% of scleroderma patients. A vexing feature of this emergency is that not uncommonly it actually precedes the diagnosis of scleroderma. Indeed, 20% of patients with SRC present with sine scleroderma – that is, they have no skin disease and their renal crisis is their first symptom of scleroderma. In contrast, critical digital ischemia – the most common scleroderma emergency – is invariably preceded by worsening episodes of Raynaud’s, and impending intestinal pseudo-obstruction – also among the most common scleroderma emergencies – is heralded by an established history of dysmotility, loss of appetite, abdominal bloating, small intestinal bacterial overgrowth, and bowel distension.
While sine SRC often poses a formidable diagnostic challenge, SRC occurs most often in patients with early, rapidly progressing diffuse scleroderma skin disease. Indeed, the median duration of scleroderma when SRC strikes is just 8 months. The use of glucocorticoids at 15 mg or more per day, or at lower doses for a lengthy period, is an independent risk factor for SRC. Detection of anti–RNA polymerase III antibodies warrants increased vigilance, since 60% of patients with SRC are anti–RNA polymerase III antibody positive. Other autoantibodies are not a risk factor. Neither is preexisting hypertension nor a high baseline serum creatinine.
The classic textbook presentation of SRC is abrupt onset of blood pressures greater than 20 mm Hg above normal for that individual, along with sudden renal failure; a climbing creatinine; proteinuria; and expressions of malignant hypertension such as pulmonary edema, new-onset heart failure, encephalopathy, and/or development of a thrombotic microangiopathy.
Notably, however, 30% of individuals with SRC don’t fit this picture at all. They may present with abrupt-onset severe hypertension but no evidence of renal failure, at least early on. Or they may have sudden renal failure without a hypertensive crisis. Alternatively, they may have no signs of malignant hypertension, just an asymptomatic pericardial effusion or mild arrhythmias.
“Also, the thrombotic microangiopathy can be present without the other features of scleroderma renal crisis, so no renal failure or hypertensive emergency. Be aware of the possibility of atypical presentations, and always suspect this unfolding problem in the right individuals,” the rheumatologist urged.
Anyone with scleroderma who presents with new-onset hypertension needs to begin keeping a careful home blood pressure diary. If the blood pressure shoots up, or symptoms of malignant hypertension develop, or laboratory monitoring reveals evidence of thrombotic microangiopathy, the patient should immediately go to the ED because these events are often followed by accelerated progression to renal crisis.
Inpatient management of SRC is critical. “In the hospital we can monitor renal function in a more refined way, we can manage the malignant hypertension, and early on, hospitalization provides the opportunity to do a renal biopsy. I always consider doing this early. The pathologist often pushes back, but I think it’s relevant. It confirms the diagnosis. We’ve had patients where we were surprised: We thought it was scleroderma renal crisis, but instead they had interstitial nephritis or glomerulonephritis. Most important, biopsy has major prognostic implications: You can measure the extent of damage and therefore have a sense of whether the patient will be able to recover renal function,” Dr. Boin explained.
Prognosis and predictors
Outcome of SRC is often poor: the 1-year mortality is 20%-30%, with a 5-year mortality of 30%-50%. Normotensive SRC with renal crisis, which accounts for about 10% of all cases of SRC, is particularly serious in its implication, with a 1-year mortality of 60%. Half of patients with SRC require hemodialysis, and only one-quarter of them recover spontaneous renal function.
Predictors of worse outcome include older age at onset of SRC, male gender, a serum creatinine level above 3 mg/dL at presentation, incomplete blood pressure control within the first 3 days of the crisis, and normotensive SRC. Use of an ACE inhibitor prior to SRC is also an independent predictor of poor outcome, possibly because by keeping the blood pressure under control the medication blunts recognition of the unfolding renal crisis.
“This is why experts don’t recommend prophylactic ACE inhibitors in patients who are at risk for SRC,” according to Dr. Boin.
He reported having no financial conflicts regarding his presentation.
Scleroderma renal crisis is often the most challenging type of scleroderma emergency to identify promptly, according to Francesco Boin, MD, professor of medicine and director of the scleroderma center at the University of California, San Francisco.
“Fortunately, it’s not a frequent event. But it’s severe enough that all rheumatologists should be aware of it,” he said at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.
Atypical presentations occur in 30%
Scleroderma renal crisis (SRC) occurs in 5%-10% of scleroderma patients. A vexing feature of this emergency is that not uncommonly it actually precedes the diagnosis of scleroderma. Indeed, 20% of patients with SRC present with sine scleroderma – that is, they have no skin disease and their renal crisis is their first symptom of scleroderma. In contrast, critical digital ischemia – the most common scleroderma emergency – is invariably preceded by worsening episodes of Raynaud’s, and impending intestinal pseudo-obstruction – also among the most common scleroderma emergencies – is heralded by an established history of dysmotility, loss of appetite, abdominal bloating, small intestinal bacterial overgrowth, and bowel distension.
While sine SRC often poses a formidable diagnostic challenge, SRC occurs most often in patients with early, rapidly progressing diffuse scleroderma skin disease. Indeed, the median duration of scleroderma when SRC strikes is just 8 months. The use of glucocorticoids at 15 mg or more per day, or at lower doses for a lengthy period, is an independent risk factor for SRC. Detection of anti–RNA polymerase III antibodies warrants increased vigilance, since 60% of patients with SRC are anti–RNA polymerase III antibody positive. Other autoantibodies are not a risk factor. Neither is preexisting hypertension nor a high baseline serum creatinine.
The classic textbook presentation of SRC is abrupt onset of blood pressures greater than 20 mm Hg above normal for that individual, along with sudden renal failure; a climbing creatinine; proteinuria; and expressions of malignant hypertension such as pulmonary edema, new-onset heart failure, encephalopathy, and/or development of a thrombotic microangiopathy.
Notably, however, 30% of individuals with SRC don’t fit this picture at all. They may present with abrupt-onset severe hypertension but no evidence of renal failure, at least early on. Or they may have sudden renal failure without a hypertensive crisis. Alternatively, they may have no signs of malignant hypertension, just an asymptomatic pericardial effusion or mild arrhythmias.
“Also, the thrombotic microangiopathy can be present without the other features of scleroderma renal crisis, so no renal failure or hypertensive emergency. Be aware of the possibility of atypical presentations, and always suspect this unfolding problem in the right individuals,” the rheumatologist urged.
Anyone with scleroderma who presents with new-onset hypertension needs to begin keeping a careful home blood pressure diary. If the blood pressure shoots up, or symptoms of malignant hypertension develop, or laboratory monitoring reveals evidence of thrombotic microangiopathy, the patient should immediately go to the ED because these events are often followed by accelerated progression to renal crisis.
Inpatient management of SRC is critical. “In the hospital we can monitor renal function in a more refined way, we can manage the malignant hypertension, and early on, hospitalization provides the opportunity to do a renal biopsy. I always consider doing this early. The pathologist often pushes back, but I think it’s relevant. It confirms the diagnosis. We’ve had patients where we were surprised: We thought it was scleroderma renal crisis, but instead they had interstitial nephritis or glomerulonephritis. Most important, biopsy has major prognostic implications: You can measure the extent of damage and therefore have a sense of whether the patient will be able to recover renal function,” Dr. Boin explained.
Prognosis and predictors
Outcome of SRC is often poor: the 1-year mortality is 20%-30%, with a 5-year mortality of 30%-50%. Normotensive SRC with renal crisis, which accounts for about 10% of all cases of SRC, is particularly serious in its implication, with a 1-year mortality of 60%. Half of patients with SRC require hemodialysis, and only one-quarter of them recover spontaneous renal function.
Predictors of worse outcome include older age at onset of SRC, male gender, a serum creatinine level above 3 mg/dL at presentation, incomplete blood pressure control within the first 3 days of the crisis, and normotensive SRC. Use of an ACE inhibitor prior to SRC is also an independent predictor of poor outcome, possibly because by keeping the blood pressure under control the medication blunts recognition of the unfolding renal crisis.
“This is why experts don’t recommend prophylactic ACE inhibitors in patients who are at risk for SRC,” according to Dr. Boin.
He reported having no financial conflicts regarding his presentation.
Scleroderma renal crisis is often the most challenging type of scleroderma emergency to identify promptly, according to Francesco Boin, MD, professor of medicine and director of the scleroderma center at the University of California, San Francisco.
“Fortunately, it’s not a frequent event. But it’s severe enough that all rheumatologists should be aware of it,” he said at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.
Atypical presentations occur in 30%
Scleroderma renal crisis (SRC) occurs in 5%-10% of scleroderma patients. A vexing feature of this emergency is that not uncommonly it actually precedes the diagnosis of scleroderma. Indeed, 20% of patients with SRC present with sine scleroderma – that is, they have no skin disease and their renal crisis is their first symptom of scleroderma. In contrast, critical digital ischemia – the most common scleroderma emergency – is invariably preceded by worsening episodes of Raynaud’s, and impending intestinal pseudo-obstruction – also among the most common scleroderma emergencies – is heralded by an established history of dysmotility, loss of appetite, abdominal bloating, small intestinal bacterial overgrowth, and bowel distension.
While sine SRC often poses a formidable diagnostic challenge, SRC occurs most often in patients with early, rapidly progressing diffuse scleroderma skin disease. Indeed, the median duration of scleroderma when SRC strikes is just 8 months. The use of glucocorticoids at 15 mg or more per day, or at lower doses for a lengthy period, is an independent risk factor for SRC. Detection of anti–RNA polymerase III antibodies warrants increased vigilance, since 60% of patients with SRC are anti–RNA polymerase III antibody positive. Other autoantibodies are not a risk factor. Neither is preexisting hypertension nor a high baseline serum creatinine.
The classic textbook presentation of SRC is abrupt onset of blood pressures greater than 20 mm Hg above normal for that individual, along with sudden renal failure; a climbing creatinine; proteinuria; and expressions of malignant hypertension such as pulmonary edema, new-onset heart failure, encephalopathy, and/or development of a thrombotic microangiopathy.
Notably, however, 30% of individuals with SRC don’t fit this picture at all. They may present with abrupt-onset severe hypertension but no evidence of renal failure, at least early on. Or they may have sudden renal failure without a hypertensive crisis. Alternatively, they may have no signs of malignant hypertension, just an asymptomatic pericardial effusion or mild arrhythmias.
“Also, the thrombotic microangiopathy can be present without the other features of scleroderma renal crisis, so no renal failure or hypertensive emergency. Be aware of the possibility of atypical presentations, and always suspect this unfolding problem in the right individuals,” the rheumatologist urged.
Anyone with scleroderma who presents with new-onset hypertension needs to begin keeping a careful home blood pressure diary. If the blood pressure shoots up, or symptoms of malignant hypertension develop, or laboratory monitoring reveals evidence of thrombotic microangiopathy, the patient should immediately go to the ED because these events are often followed by accelerated progression to renal crisis.
Inpatient management of SRC is critical. “In the hospital we can monitor renal function in a more refined way, we can manage the malignant hypertension, and early on, hospitalization provides the opportunity to do a renal biopsy. I always consider doing this early. The pathologist often pushes back, but I think it’s relevant. It confirms the diagnosis. We’ve had patients where we were surprised: We thought it was scleroderma renal crisis, but instead they had interstitial nephritis or glomerulonephritis. Most important, biopsy has major prognostic implications: You can measure the extent of damage and therefore have a sense of whether the patient will be able to recover renal function,” Dr. Boin explained.
Prognosis and predictors
Outcome of SRC is often poor: the 1-year mortality is 20%-30%, with a 5-year mortality of 30%-50%. Normotensive SRC with renal crisis, which accounts for about 10% of all cases of SRC, is particularly serious in its implication, with a 1-year mortality of 60%. Half of patients with SRC require hemodialysis, and only one-quarter of them recover spontaneous renal function.
Predictors of worse outcome include older age at onset of SRC, male gender, a serum creatinine level above 3 mg/dL at presentation, incomplete blood pressure control within the first 3 days of the crisis, and normotensive SRC. Use of an ACE inhibitor prior to SRC is also an independent predictor of poor outcome, possibly because by keeping the blood pressure under control the medication blunts recognition of the unfolding renal crisis.
“This is why experts don’t recommend prophylactic ACE inhibitors in patients who are at risk for SRC,” according to Dr. Boin.
He reported having no financial conflicts regarding his presentation.
FROM SOTA 2020
24-year-old man • prednisone therapy for nephrotic syndrome • diffuse maculopapular rash • pruritis
THE CASE
A 24-year-old man with no past medical history was referred to a nephrologist for a 5-month history of leg swelling and weight gain. His only medication was furosemide 40 mg/d, prescribed by his primary care physician. His physical examination was unremarkable except for lower extremity and scrotal edema.
Laboratory values included a creatinine of 0.8 mg/dL (reference range, 0.6 to 1.2 mg/dL); hemoglobin concentration, 14.4 g/dL (reference range, 14 to 18 g/dL); albumin, 1.9 g/dL (reference range, 3.5 to 5.5 g/dL); and glucose, 80 mg/dL (reference range, 74 to 106 mg/dL). Electrolyte levels were normal. Urinalysis revealed 3+ blood and 4+ protein on dipstick, as well as the presence of granular and lipid casts on microscopic exam. A 24-hour urine collection contained 10.5 g of protein. Antinuclear antibody titers, complement levels, hepatitis serologies, and antineutrophil cytoplasmic antibody titers were all normal.
A renal biopsy revealed idiopathic focal segmental glomerulosclerosis. The patient was started on oral prednisone 40 mg twice daily.
Two days later, he developed a diffuse pruritic maculopapular rash. He stopped taking the prednisone, and the rash resolved over the next 3 to 5 days. He was then instructed to restart the prednisone for his nephrotic syndrome. When he developed a new but similar rash, the prednisone was discontinued. The rash again resolved.
THE DIAGNOSIS
Since the patient had already been taking furosemide for 6 weeks without an adverse reaction, it was presumed that the prednisone tablet was causing his rash. It would be unusual for prednisone itself to cause a drug eruption, so an additive or coloring agent in the tablet was thought to be responsible for the reaction.
We noted that the patient had been taking a 20-mg orange tablet of prednisone. So we opted to “tweak” the prescription and prescribe the same daily dose but in the form of 10-mg white tablets. The patient tolerated this new regimen without any adverse effects and completed a full 9 months of prednisone therapy without any recurrence of skin lesions. His glomerular disease went into remission.
DISCUSSION
Excipients are inert substances that are added to a food or drug to provide the desired consistency, appearance, or form. They are also used as a preservative for substance stabilization.
Continue to: There are many reports in the literature...
There are many reports in the literature of adverse reactions to excipients.1-3 These include skin rashes induced by the coloring agent in the capsule shell of rifampicin2 and a rash that developed from a coloring agent in oral iron.3 Other reports have noted dyes in foods and even toothpaste as triggers.4,5
Hypersensitivity. Although a specific reaction to prednisone was considered unlikely in this case, type IV delayed hypersensitivity reactions to corticosteroids have been reported. The most common type of corticosteroid-related allergy is contact dermatitis associated with topical corticosteroid use.6 Many cases of delayed maculopapular reactions are thought to be T-cell–mediated type IV reactions.6
Type I immediate hypersensitivity reactions to corticosteroids are also well documented. In a literature review of 120 immediate hypersensitivity reactions to corticosteroids, anaphylactic symptoms were more commonly reported than urticaria or angioedema.7 Intravenous exposure was most frequently associated with reactions, followed by the intra-articular and oral routes of administration.7
Causative agents. The same literature review identified methylprednisolone as the most common steroid to cause a reaction; dexamethasone and prednisone were the least frequently associated with reactions.7 Pharmacologically inactive ingredients were implicated in 28% of the corticosteroid hypersensitivity reactions.7
Additives suspected to be triggers include succinate and phosphate esters, carboxymethylcellulose, polyethylene glycol, and lactose. Interestingly, there have been reports of acute allergic reactions to methylprednisolone sodium succinate 40 mg/mL intravenous preparation in children with milk allergy, due to lactose contaminated with milk protein.8,9
Continue to: Yellow dye was to blame
Yellow dye was to blame. In our case, the 20-mg tablet that the patient had been taking contained the coloring agent FD&C yellow #6, an azo dye also known as sunset yellow or E-110 in Europe. Several reports have described adverse reactions to this coloring agent.1,3 There were other additives in the 20-mg tablet, but a comparison revealed that the 10-mg tablet contained identical substances—but no dye. Thus, it was most likely that the coloring agent was the cause of the patient’s probable type IV exanthematous drug reaction.
Our patient
The patient was instructed to avoid all medications and food containing FD&C yellow #6. No formal allergy testing or re-challenge was performed, since the patient did well under the care of his nephrologist.
THE TAKEAWAY
It’s important to recognize that adverse drug reactions can occur from any medication—not only from the drug itself, but also from excipients contained within. This case reminds us that when a patient complains of an adverse effect to a medication, dyes and inactive ingredients need to be considered as possible inciting agents.
CORRESPONDENCE
Neil E. Soifer, MD, Lakeside Nephrology, 2277 West Howard, Chicago, IL 60645; [email protected]
1. Swerlick RA, Campbell CF. Medication dyes as a source of drug allergy. J Drugs Dermatol. 2013;12:99-102.
2. Calişkaner Z, Oztürk S, Karaayvaz M. Not all adverse drug reactions originate from active component: coloring agent-induced skin eruption in a patient treated with rifampicin. Allergy. 2003;58:1077-1079.
3. Rogkakou A, Guerra L, Scordamaglia A, et al. Severe skin reaction to excipients of an oral iron treatment. Allergy. 2007;62:334-335.
4. Zaknun D, Schroecksnadel S, Kurz K, et al. Potential role of antioxidant food supplements, preservatives and colorants in the pathogenesis of allergy and asthma. Int Arch Allergy Immunol. 2012;157:113-124.
5. Barbaud A. Place of excipients in systemic drug allergy. Immunol Allergy Clin N Am. 2014;34:671-679.
6. Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105:259-273.
7. Patel A, Bahna S. Immediate hypersensitivity reactions to corticosteroids. Ann Allergy Asthma Immunol. 2015;115:178-182.
8. Eda A, Sugai K, Shioya H, et al. Acute allergic reaction due to milk proteins contaminating lactose added to corticosteroid for injection. Allergol Int. 2009;58:137-139.
9. Levy Y, Segal N, Nahum A, et al. Hypersensitivity to methylprednisolone sodium succinate in children with milk allergy. J Allergy Clin Immunol Pract. 2014;2:471-474.
THE CASE
A 24-year-old man with no past medical history was referred to a nephrologist for a 5-month history of leg swelling and weight gain. His only medication was furosemide 40 mg/d, prescribed by his primary care physician. His physical examination was unremarkable except for lower extremity and scrotal edema.
Laboratory values included a creatinine of 0.8 mg/dL (reference range, 0.6 to 1.2 mg/dL); hemoglobin concentration, 14.4 g/dL (reference range, 14 to 18 g/dL); albumin, 1.9 g/dL (reference range, 3.5 to 5.5 g/dL); and glucose, 80 mg/dL (reference range, 74 to 106 mg/dL). Electrolyte levels were normal. Urinalysis revealed 3+ blood and 4+ protein on dipstick, as well as the presence of granular and lipid casts on microscopic exam. A 24-hour urine collection contained 10.5 g of protein. Antinuclear antibody titers, complement levels, hepatitis serologies, and antineutrophil cytoplasmic antibody titers were all normal.
A renal biopsy revealed idiopathic focal segmental glomerulosclerosis. The patient was started on oral prednisone 40 mg twice daily.
Two days later, he developed a diffuse pruritic maculopapular rash. He stopped taking the prednisone, and the rash resolved over the next 3 to 5 days. He was then instructed to restart the prednisone for his nephrotic syndrome. When he developed a new but similar rash, the prednisone was discontinued. The rash again resolved.
THE DIAGNOSIS
Since the patient had already been taking furosemide for 6 weeks without an adverse reaction, it was presumed that the prednisone tablet was causing his rash. It would be unusual for prednisone itself to cause a drug eruption, so an additive or coloring agent in the tablet was thought to be responsible for the reaction.
We noted that the patient had been taking a 20-mg orange tablet of prednisone. So we opted to “tweak” the prescription and prescribe the same daily dose but in the form of 10-mg white tablets. The patient tolerated this new regimen without any adverse effects and completed a full 9 months of prednisone therapy without any recurrence of skin lesions. His glomerular disease went into remission.
DISCUSSION
Excipients are inert substances that are added to a food or drug to provide the desired consistency, appearance, or form. They are also used as a preservative for substance stabilization.
Continue to: There are many reports in the literature...
There are many reports in the literature of adverse reactions to excipients.1-3 These include skin rashes induced by the coloring agent in the capsule shell of rifampicin2 and a rash that developed from a coloring agent in oral iron.3 Other reports have noted dyes in foods and even toothpaste as triggers.4,5
Hypersensitivity. Although a specific reaction to prednisone was considered unlikely in this case, type IV delayed hypersensitivity reactions to corticosteroids have been reported. The most common type of corticosteroid-related allergy is contact dermatitis associated with topical corticosteroid use.6 Many cases of delayed maculopapular reactions are thought to be T-cell–mediated type IV reactions.6
Type I immediate hypersensitivity reactions to corticosteroids are also well documented. In a literature review of 120 immediate hypersensitivity reactions to corticosteroids, anaphylactic symptoms were more commonly reported than urticaria or angioedema.7 Intravenous exposure was most frequently associated with reactions, followed by the intra-articular and oral routes of administration.7
Causative agents. The same literature review identified methylprednisolone as the most common steroid to cause a reaction; dexamethasone and prednisone were the least frequently associated with reactions.7 Pharmacologically inactive ingredients were implicated in 28% of the corticosteroid hypersensitivity reactions.7
Additives suspected to be triggers include succinate and phosphate esters, carboxymethylcellulose, polyethylene glycol, and lactose. Interestingly, there have been reports of acute allergic reactions to methylprednisolone sodium succinate 40 mg/mL intravenous preparation in children with milk allergy, due to lactose contaminated with milk protein.8,9
Continue to: Yellow dye was to blame
Yellow dye was to blame. In our case, the 20-mg tablet that the patient had been taking contained the coloring agent FD&C yellow #6, an azo dye also known as sunset yellow or E-110 in Europe. Several reports have described adverse reactions to this coloring agent.1,3 There were other additives in the 20-mg tablet, but a comparison revealed that the 10-mg tablet contained identical substances—but no dye. Thus, it was most likely that the coloring agent was the cause of the patient’s probable type IV exanthematous drug reaction.
Our patient
The patient was instructed to avoid all medications and food containing FD&C yellow #6. No formal allergy testing or re-challenge was performed, since the patient did well under the care of his nephrologist.
THE TAKEAWAY
It’s important to recognize that adverse drug reactions can occur from any medication—not only from the drug itself, but also from excipients contained within. This case reminds us that when a patient complains of an adverse effect to a medication, dyes and inactive ingredients need to be considered as possible inciting agents.
CORRESPONDENCE
Neil E. Soifer, MD, Lakeside Nephrology, 2277 West Howard, Chicago, IL 60645; [email protected]
THE CASE
A 24-year-old man with no past medical history was referred to a nephrologist for a 5-month history of leg swelling and weight gain. His only medication was furosemide 40 mg/d, prescribed by his primary care physician. His physical examination was unremarkable except for lower extremity and scrotal edema.
Laboratory values included a creatinine of 0.8 mg/dL (reference range, 0.6 to 1.2 mg/dL); hemoglobin concentration, 14.4 g/dL (reference range, 14 to 18 g/dL); albumin, 1.9 g/dL (reference range, 3.5 to 5.5 g/dL); and glucose, 80 mg/dL (reference range, 74 to 106 mg/dL). Electrolyte levels were normal. Urinalysis revealed 3+ blood and 4+ protein on dipstick, as well as the presence of granular and lipid casts on microscopic exam. A 24-hour urine collection contained 10.5 g of protein. Antinuclear antibody titers, complement levels, hepatitis serologies, and antineutrophil cytoplasmic antibody titers were all normal.
A renal biopsy revealed idiopathic focal segmental glomerulosclerosis. The patient was started on oral prednisone 40 mg twice daily.
Two days later, he developed a diffuse pruritic maculopapular rash. He stopped taking the prednisone, and the rash resolved over the next 3 to 5 days. He was then instructed to restart the prednisone for his nephrotic syndrome. When he developed a new but similar rash, the prednisone was discontinued. The rash again resolved.
THE DIAGNOSIS
Since the patient had already been taking furosemide for 6 weeks without an adverse reaction, it was presumed that the prednisone tablet was causing his rash. It would be unusual for prednisone itself to cause a drug eruption, so an additive or coloring agent in the tablet was thought to be responsible for the reaction.
We noted that the patient had been taking a 20-mg orange tablet of prednisone. So we opted to “tweak” the prescription and prescribe the same daily dose but in the form of 10-mg white tablets. The patient tolerated this new regimen without any adverse effects and completed a full 9 months of prednisone therapy without any recurrence of skin lesions. His glomerular disease went into remission.
DISCUSSION
Excipients are inert substances that are added to a food or drug to provide the desired consistency, appearance, or form. They are also used as a preservative for substance stabilization.
Continue to: There are many reports in the literature...
There are many reports in the literature of adverse reactions to excipients.1-3 These include skin rashes induced by the coloring agent in the capsule shell of rifampicin2 and a rash that developed from a coloring agent in oral iron.3 Other reports have noted dyes in foods and even toothpaste as triggers.4,5
Hypersensitivity. Although a specific reaction to prednisone was considered unlikely in this case, type IV delayed hypersensitivity reactions to corticosteroids have been reported. The most common type of corticosteroid-related allergy is contact dermatitis associated with topical corticosteroid use.6 Many cases of delayed maculopapular reactions are thought to be T-cell–mediated type IV reactions.6
Type I immediate hypersensitivity reactions to corticosteroids are also well documented. In a literature review of 120 immediate hypersensitivity reactions to corticosteroids, anaphylactic symptoms were more commonly reported than urticaria or angioedema.7 Intravenous exposure was most frequently associated with reactions, followed by the intra-articular and oral routes of administration.7
Causative agents. The same literature review identified methylprednisolone as the most common steroid to cause a reaction; dexamethasone and prednisone were the least frequently associated with reactions.7 Pharmacologically inactive ingredients were implicated in 28% of the corticosteroid hypersensitivity reactions.7
Additives suspected to be triggers include succinate and phosphate esters, carboxymethylcellulose, polyethylene glycol, and lactose. Interestingly, there have been reports of acute allergic reactions to methylprednisolone sodium succinate 40 mg/mL intravenous preparation in children with milk allergy, due to lactose contaminated with milk protein.8,9
Continue to: Yellow dye was to blame
Yellow dye was to blame. In our case, the 20-mg tablet that the patient had been taking contained the coloring agent FD&C yellow #6, an azo dye also known as sunset yellow or E-110 in Europe. Several reports have described adverse reactions to this coloring agent.1,3 There were other additives in the 20-mg tablet, but a comparison revealed that the 10-mg tablet contained identical substances—but no dye. Thus, it was most likely that the coloring agent was the cause of the patient’s probable type IV exanthematous drug reaction.
Our patient
The patient was instructed to avoid all medications and food containing FD&C yellow #6. No formal allergy testing or re-challenge was performed, since the patient did well under the care of his nephrologist.
THE TAKEAWAY
It’s important to recognize that adverse drug reactions can occur from any medication—not only from the drug itself, but also from excipients contained within. This case reminds us that when a patient complains of an adverse effect to a medication, dyes and inactive ingredients need to be considered as possible inciting agents.
CORRESPONDENCE
Neil E. Soifer, MD, Lakeside Nephrology, 2277 West Howard, Chicago, IL 60645; [email protected]
1. Swerlick RA, Campbell CF. Medication dyes as a source of drug allergy. J Drugs Dermatol. 2013;12:99-102.
2. Calişkaner Z, Oztürk S, Karaayvaz M. Not all adverse drug reactions originate from active component: coloring agent-induced skin eruption in a patient treated with rifampicin. Allergy. 2003;58:1077-1079.
3. Rogkakou A, Guerra L, Scordamaglia A, et al. Severe skin reaction to excipients of an oral iron treatment. Allergy. 2007;62:334-335.
4. Zaknun D, Schroecksnadel S, Kurz K, et al. Potential role of antioxidant food supplements, preservatives and colorants in the pathogenesis of allergy and asthma. Int Arch Allergy Immunol. 2012;157:113-124.
5. Barbaud A. Place of excipients in systemic drug allergy. Immunol Allergy Clin N Am. 2014;34:671-679.
6. Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105:259-273.
7. Patel A, Bahna S. Immediate hypersensitivity reactions to corticosteroids. Ann Allergy Asthma Immunol. 2015;115:178-182.
8. Eda A, Sugai K, Shioya H, et al. Acute allergic reaction due to milk proteins contaminating lactose added to corticosteroid for injection. Allergol Int. 2009;58:137-139.
9. Levy Y, Segal N, Nahum A, et al. Hypersensitivity to methylprednisolone sodium succinate in children with milk allergy. J Allergy Clin Immunol Pract. 2014;2:471-474.
1. Swerlick RA, Campbell CF. Medication dyes as a source of drug allergy. J Drugs Dermatol. 2013;12:99-102.
2. Calişkaner Z, Oztürk S, Karaayvaz M. Not all adverse drug reactions originate from active component: coloring agent-induced skin eruption in a patient treated with rifampicin. Allergy. 2003;58:1077-1079.
3. Rogkakou A, Guerra L, Scordamaglia A, et al. Severe skin reaction to excipients of an oral iron treatment. Allergy. 2007;62:334-335.
4. Zaknun D, Schroecksnadel S, Kurz K, et al. Potential role of antioxidant food supplements, preservatives and colorants in the pathogenesis of allergy and asthma. Int Arch Allergy Immunol. 2012;157:113-124.
5. Barbaud A. Place of excipients in systemic drug allergy. Immunol Allergy Clin N Am. 2014;34:671-679.
6. Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105:259-273.
7. Patel A, Bahna S. Immediate hypersensitivity reactions to corticosteroids. Ann Allergy Asthma Immunol. 2015;115:178-182.
8. Eda A, Sugai K, Shioya H, et al. Acute allergic reaction due to milk proteins contaminating lactose added to corticosteroid for injection. Allergol Int. 2009;58:137-139.
9. Levy Y, Segal N, Nahum A, et al. Hypersensitivity to methylprednisolone sodium succinate in children with milk allergy. J Allergy Clin Immunol Pract. 2014;2:471-474.
Large COVID-19 dataset: Kidney injury in >35% of those in hospital
As a new report shows that over a third of U.S. patients hospitalized with COVID-19 developed acute kidney injury (AKI), and nearly 15% of these patients needed dialysis, experts in the field are calling for more robust research into multiple aspects of this increasingly important issue.
Among 5,449 patients admitted to 13 Northwell Health New York–based hospitals between March and April 2020, 36.6% (1,993) developed AKI.
– the rate of kidney injury was 89.7% among ventilated patients, compared with 21.7% among other patients.
AKI in COVID-19 was also linked to a poor prognosis: 35% of those who developed AKI had died at the time of publication.
The study includes the largest defined cohort of hospitalized COVID-19 patients to date with a focus on AKI, says Jamie S. Hirsch, MD, of Northwell Health in Great Neck, N.Y., and colleagues in their article published online in Kidney International.
The findings track with those of a study of New York hospitals published online in The Lancet. In that dataset, just under a third (31%) of critically ill patients developed severe kidney damage and needed dialysis.
Both of these studies help solidify the experiences of clinicians on the ground, with many U.S. hospitals in the early phases of the pandemic underestimating the problem of AKI and having to scramble to find enough dialysis machines and dialysate solution to treat the most severely affected patients.
“We hope to learn more about the COVID-19–related AKI in the coming weeks, and that by sharing what we have learned from our patients, other doctors and their patients can benefit,” said senior author of the new study, Kenar D. Jhaveri, MD, associated chief of nephrology at Hofstra/Northwell.
The new report also comes as scientists from the National Institute of Diabetes and Digestive and Kidney Diseases highlighted the importance of AKI as a sequela of COVID-19 in an editorial published in Diabetes Care.
They, too, said that it is vitally important to better understand what is happening, as more and more hospitals will face COVID-19 patients with this complication.
“The natural history and heterogeneity of the kidney disease caused by COVID-19 need to be unraveled,” one of the authors, Robert A. Star, MD, director of the division of kidney, urologic, and hematologic diseases at NIDDK, said in an interview.
Such research is key because “low kidney function is an exclusion criterion in current studies” examining antiviral medications in COVID-19, he said. “Clinical trials are needed to test therapeutic interventions to prevent or treat COVID-19–induced AKI.”
Extremely ill patients develop AKI as their condition deteriorates
Identifying risk factors for the development of AKI in COVID-19 will be critical in helping shed more light on diagnostic and predictive biomarkers, Dr. Star said.
Dr. Hirsch and colleagues said that extremely ill patients often develop kidney failure as their condition deteriorates, and this happens quickly. Indeed, the clearest risk factors for the development of AKI were “the need for ventilator support or vasopressor drug treatment.”
Other independent predictors of AKI were older age, black race, diabetes, hypertension, and cardiovascular disease.
Of those on mechanical ventilation overall in the more than 5,000-patient study, almost a quarter (23.2%) developed AKI and needed renal replacement therapy, which consisted of either intermittent or continuous hemodialysis.
Dr. Star and associates wrote that these numbers are important because of the knock-on effects.
“Hemodialysis in critically ill infected patients is associated with significant clotting complications and mortality as well as increased infection risk to staff,” they pointed out.
Dr. Star said that “the incidence rate of AKI reported in this study is higher than what had been previously reported by others in the United States and China and may reflect differences in population demographics, severity of illness, prevalence of comorbidities, socioeconomic factors, patient volume overwhelming hospital capacity, or other factors not yet determined.
“It may be caused by dehydration (volume depletion), heart failure, the inflammatory response to the virus (cytokine storm), respiratory failure, clotting of blood vessels (hypercoagulation), muscle tissue breakdown (rhabdomyolysis), and/or a direct viral infection of the kidney,” he said.
Renal biopsies from patients with AKI may help shed some light
The editorialists went on to say that findings from kidney biopsies of COVID-19 patients with AKI may help shed some light on this condition.
“While difficult to perform, kidney biopsies from patients with early AKI could help us understand the underlying pathophysiologies at the cellular and molecular level and begin to target specific treatments to specific subgroups of patients,” they wrote.
The authors noted that, as part of funding opportunities provided by the National Institutes of Health for COVID-19 research, the NIDDK has published a Notice of Special Interest outlining the most urgent areas in need of research, with one of the focuses being on the kidney.
“As the research community emerges from the crisis situation, there should be renewed efforts for multidisciplinary research to conduct integrated basic, translational, and clinical studies aimed at greatly increasing the knowledge base to understand how both the current COVID-19 threat and future health threats affect both healthy people and people with chronic diseases and conditions,” the editorials noted.
The authors of the Diabetes Care editorial have reported no relevant financial relationships. Dr. Jhaveri has reported being a consultant for Astex Pharmaceuticals.
A version of this article originally appeared on Medscape.com.
As a new report shows that over a third of U.S. patients hospitalized with COVID-19 developed acute kidney injury (AKI), and nearly 15% of these patients needed dialysis, experts in the field are calling for more robust research into multiple aspects of this increasingly important issue.
Among 5,449 patients admitted to 13 Northwell Health New York–based hospitals between March and April 2020, 36.6% (1,993) developed AKI.
– the rate of kidney injury was 89.7% among ventilated patients, compared with 21.7% among other patients.
AKI in COVID-19 was also linked to a poor prognosis: 35% of those who developed AKI had died at the time of publication.
The study includes the largest defined cohort of hospitalized COVID-19 patients to date with a focus on AKI, says Jamie S. Hirsch, MD, of Northwell Health in Great Neck, N.Y., and colleagues in their article published online in Kidney International.
The findings track with those of a study of New York hospitals published online in The Lancet. In that dataset, just under a third (31%) of critically ill patients developed severe kidney damage and needed dialysis.
Both of these studies help solidify the experiences of clinicians on the ground, with many U.S. hospitals in the early phases of the pandemic underestimating the problem of AKI and having to scramble to find enough dialysis machines and dialysate solution to treat the most severely affected patients.
“We hope to learn more about the COVID-19–related AKI in the coming weeks, and that by sharing what we have learned from our patients, other doctors and their patients can benefit,” said senior author of the new study, Kenar D. Jhaveri, MD, associated chief of nephrology at Hofstra/Northwell.
The new report also comes as scientists from the National Institute of Diabetes and Digestive and Kidney Diseases highlighted the importance of AKI as a sequela of COVID-19 in an editorial published in Diabetes Care.
They, too, said that it is vitally important to better understand what is happening, as more and more hospitals will face COVID-19 patients with this complication.
“The natural history and heterogeneity of the kidney disease caused by COVID-19 need to be unraveled,” one of the authors, Robert A. Star, MD, director of the division of kidney, urologic, and hematologic diseases at NIDDK, said in an interview.
Such research is key because “low kidney function is an exclusion criterion in current studies” examining antiviral medications in COVID-19, he said. “Clinical trials are needed to test therapeutic interventions to prevent or treat COVID-19–induced AKI.”
Extremely ill patients develop AKI as their condition deteriorates
Identifying risk factors for the development of AKI in COVID-19 will be critical in helping shed more light on diagnostic and predictive biomarkers, Dr. Star said.
Dr. Hirsch and colleagues said that extremely ill patients often develop kidney failure as their condition deteriorates, and this happens quickly. Indeed, the clearest risk factors for the development of AKI were “the need for ventilator support or vasopressor drug treatment.”
Other independent predictors of AKI were older age, black race, diabetes, hypertension, and cardiovascular disease.
Of those on mechanical ventilation overall in the more than 5,000-patient study, almost a quarter (23.2%) developed AKI and needed renal replacement therapy, which consisted of either intermittent or continuous hemodialysis.
Dr. Star and associates wrote that these numbers are important because of the knock-on effects.
“Hemodialysis in critically ill infected patients is associated with significant clotting complications and mortality as well as increased infection risk to staff,” they pointed out.
Dr. Star said that “the incidence rate of AKI reported in this study is higher than what had been previously reported by others in the United States and China and may reflect differences in population demographics, severity of illness, prevalence of comorbidities, socioeconomic factors, patient volume overwhelming hospital capacity, or other factors not yet determined.
“It may be caused by dehydration (volume depletion), heart failure, the inflammatory response to the virus (cytokine storm), respiratory failure, clotting of blood vessels (hypercoagulation), muscle tissue breakdown (rhabdomyolysis), and/or a direct viral infection of the kidney,” he said.
Renal biopsies from patients with AKI may help shed some light
The editorialists went on to say that findings from kidney biopsies of COVID-19 patients with AKI may help shed some light on this condition.
“While difficult to perform, kidney biopsies from patients with early AKI could help us understand the underlying pathophysiologies at the cellular and molecular level and begin to target specific treatments to specific subgroups of patients,” they wrote.
The authors noted that, as part of funding opportunities provided by the National Institutes of Health for COVID-19 research, the NIDDK has published a Notice of Special Interest outlining the most urgent areas in need of research, with one of the focuses being on the kidney.
“As the research community emerges from the crisis situation, there should be renewed efforts for multidisciplinary research to conduct integrated basic, translational, and clinical studies aimed at greatly increasing the knowledge base to understand how both the current COVID-19 threat and future health threats affect both healthy people and people with chronic diseases and conditions,” the editorials noted.
The authors of the Diabetes Care editorial have reported no relevant financial relationships. Dr. Jhaveri has reported being a consultant for Astex Pharmaceuticals.
A version of this article originally appeared on Medscape.com.
As a new report shows that over a third of U.S. patients hospitalized with COVID-19 developed acute kidney injury (AKI), and nearly 15% of these patients needed dialysis, experts in the field are calling for more robust research into multiple aspects of this increasingly important issue.
Among 5,449 patients admitted to 13 Northwell Health New York–based hospitals between March and April 2020, 36.6% (1,993) developed AKI.
– the rate of kidney injury was 89.7% among ventilated patients, compared with 21.7% among other patients.
AKI in COVID-19 was also linked to a poor prognosis: 35% of those who developed AKI had died at the time of publication.
The study includes the largest defined cohort of hospitalized COVID-19 patients to date with a focus on AKI, says Jamie S. Hirsch, MD, of Northwell Health in Great Neck, N.Y., and colleagues in their article published online in Kidney International.
The findings track with those of a study of New York hospitals published online in The Lancet. In that dataset, just under a third (31%) of critically ill patients developed severe kidney damage and needed dialysis.
Both of these studies help solidify the experiences of clinicians on the ground, with many U.S. hospitals in the early phases of the pandemic underestimating the problem of AKI and having to scramble to find enough dialysis machines and dialysate solution to treat the most severely affected patients.
“We hope to learn more about the COVID-19–related AKI in the coming weeks, and that by sharing what we have learned from our patients, other doctors and their patients can benefit,” said senior author of the new study, Kenar D. Jhaveri, MD, associated chief of nephrology at Hofstra/Northwell.
The new report also comes as scientists from the National Institute of Diabetes and Digestive and Kidney Diseases highlighted the importance of AKI as a sequela of COVID-19 in an editorial published in Diabetes Care.
They, too, said that it is vitally important to better understand what is happening, as more and more hospitals will face COVID-19 patients with this complication.
“The natural history and heterogeneity of the kidney disease caused by COVID-19 need to be unraveled,” one of the authors, Robert A. Star, MD, director of the division of kidney, urologic, and hematologic diseases at NIDDK, said in an interview.
Such research is key because “low kidney function is an exclusion criterion in current studies” examining antiviral medications in COVID-19, he said. “Clinical trials are needed to test therapeutic interventions to prevent or treat COVID-19–induced AKI.”
Extremely ill patients develop AKI as their condition deteriorates
Identifying risk factors for the development of AKI in COVID-19 will be critical in helping shed more light on diagnostic and predictive biomarkers, Dr. Star said.
Dr. Hirsch and colleagues said that extremely ill patients often develop kidney failure as their condition deteriorates, and this happens quickly. Indeed, the clearest risk factors for the development of AKI were “the need for ventilator support or vasopressor drug treatment.”
Other independent predictors of AKI were older age, black race, diabetes, hypertension, and cardiovascular disease.
Of those on mechanical ventilation overall in the more than 5,000-patient study, almost a quarter (23.2%) developed AKI and needed renal replacement therapy, which consisted of either intermittent or continuous hemodialysis.
Dr. Star and associates wrote that these numbers are important because of the knock-on effects.
“Hemodialysis in critically ill infected patients is associated with significant clotting complications and mortality as well as increased infection risk to staff,” they pointed out.
Dr. Star said that “the incidence rate of AKI reported in this study is higher than what had been previously reported by others in the United States and China and may reflect differences in population demographics, severity of illness, prevalence of comorbidities, socioeconomic factors, patient volume overwhelming hospital capacity, or other factors not yet determined.
“It may be caused by dehydration (volume depletion), heart failure, the inflammatory response to the virus (cytokine storm), respiratory failure, clotting of blood vessels (hypercoagulation), muscle tissue breakdown (rhabdomyolysis), and/or a direct viral infection of the kidney,” he said.
Renal biopsies from patients with AKI may help shed some light
The editorialists went on to say that findings from kidney biopsies of COVID-19 patients with AKI may help shed some light on this condition.
“While difficult to perform, kidney biopsies from patients with early AKI could help us understand the underlying pathophysiologies at the cellular and molecular level and begin to target specific treatments to specific subgroups of patients,” they wrote.
The authors noted that, as part of funding opportunities provided by the National Institutes of Health for COVID-19 research, the NIDDK has published a Notice of Special Interest outlining the most urgent areas in need of research, with one of the focuses being on the kidney.
“As the research community emerges from the crisis situation, there should be renewed efforts for multidisciplinary research to conduct integrated basic, translational, and clinical studies aimed at greatly increasing the knowledge base to understand how both the current COVID-19 threat and future health threats affect both healthy people and people with chronic diseases and conditions,” the editorials noted.
The authors of the Diabetes Care editorial have reported no relevant financial relationships. Dr. Jhaveri has reported being a consultant for Astex Pharmaceuticals.
A version of this article originally appeared on Medscape.com.
Proteins in urine may predict active lupus nephritis
according to a cross-sectional study published in Nature Communications. The proteins that best differentiate active lupus nephritis from inactive systemic lupus erythematosus (SLE) vary across ethnicities, the researchers wrote.
“A longitudinal study is warranted to investigate how these molecules relate to disease pathology and progression over time,” said senior study author Chandra Mohan, MD, PhD, of the department of biomedical engineering at the University of Houston, and colleagues. In addition, researchers should investigate the roles of protein biomarkers ALCAM, PF-4, properdin, VCAM-1, and sE-selectin in mediating lupus nephritis.
Limitations of renal biopsy
About 60% of patients with SLE will develop lupus nephritis, and 10%-15% of patients who develop lupus nephritis progress to end-stage renal disease. Although renal biopsy is the gold standard for the diagnosis of renal involvement in SLE, biopsies are invasive, not serially repeatable, and may not represent the entire kidney, Dr. Mohan and colleagues wrote.
To identify potential urinary biomarkers of lupus nephritis using an unbiased, proteomic approach, the investigators screened urine samples from 23 participants – 7 with active lupus nephritis, 8 with inactive SLE, and 8 healthy controls. They used an aptamer-based screen to investigate more than 1,100 proteins. The researchers then validated biomarker candidates using enzyme-linked immunosorbent assays. Independent cross-sectional cohorts included 127 patients with inactive SLE, 107 patients with active lupus nephritis, 67 patients with active nonrenal lupus, and 74 healthy controls. The cohorts included patients who were African American, Caucasian, and Asian. The researchers excluded patients with renal failure and pediatric patients.
Of the 12 urine proteins studied, 10 outperformed traditional laboratory measures, such as C3/C4 and anti–double stranded DNA, in discriminating active lupus nephritis from inactive SLE, wrote Dr. Mohan and colleagues. A Lasso regression analysis found that the best predictive model included 8 of the 12 urine proteins as well as race. The model discriminated active lupus nephritis from inactive SLE with an area under the receiver operating characteristic curve (AUC) of 0.98.
Among African Americans, urine proteins that best distinguished active lupus nephritis from inactive disease included PF-4 (AUC, 0.88), VCAM-1 (AUC, 0.87), properdin (AUC, 0.85), and ALCAM (AUC, 0.84). Among Caucasians, they included sE-selectin (AUC, 0.87), VCAM-1 (AUC, 0.84), BFL-1 (AUC, 0.81), and hemopexin (AUC, 0.80). Among Asians, they included ALCAM (AUC, 0.93), VCAM-1 (AUC, 0.92), TFPI (AUC, 0.88), and PF-4 (AUC, 0.83).
The study is “unique in highlighting the importance of tailoring the biomarkers to patient ethnicity,” the researchers wrote.
Basing subgroups on race rather than phenotypic profiles
“This is an important study because it confirms the ability to predict active lupus nephritis from urine samples and utilized advanced technologies to find key markers for that,” said Joan T. Merrill, MD, of the Oklahoma Medical Research Foundation in Oklahoma City. “It is unfortunate that investigators with access to such advanced technology are still using an outdated and extremely questionable method for distinguishing subgroups of patients, that of race.”
Grouping patients by phenotypic profiles that reflect current disease states “would be a more accurate method for finding optimal urinary markers for active nephritis,” and is “likely to prove more accurate for individuals in all races,” Dr. Merrill said. Certain racial subgroups may be more likely to have particular disease phenotypes, “which are usually identified based on gene pathway coexpression patterns.” Still, “people who self-identify as a given race are not genetically identical,” Dr. Merrill added. “In fact, this is a very blunt instrument, compared to phenotypic profiling now available for lupus patients.”
SLE and lupus nephritis are “heavily influenced by genetics,” and African Americans are three times more likely than Caucasians to develop SLE and are more like to develop end-stage renal disease, Dr. Mohan and colleagues wrote. Nevertheless, “influence from environmental triggers or socioeconomic factors cannot be ruled out,” they added. “Although patient demographics are widely known to affect SLE disease manifestations and outcomes, there are virtually no studies investigating this phenomenon in the context of disease biomarkers; most SLE biomarkers studies focus on one demographic group or all ethnic groups combined, which yield results that may not be equally predictive in all demographic groups of SLE patients.”
Dr. Mohan is collaborating with a biotechnology company to study drugs that may block ALCAM, according to a University of Houston news release. ALCAM is involved in immune and inflammatory responses, the researchers noted. “When all SLE patients were combined, urine ALCAM levels had the strongest bearing on disease activity status, in an unsupervised Bayesian network analysis,” they wrote. “Urine ALCAM also emerged as one of the few proteins that distinguished active [lupus nephritis] from active nonrenal lupus.”
National Institutes of Health grants supported the research. The investigators had no competing interests.
SOURCE: Stanley S et al. Nat Commun. 2020 May 4. doi: 10.1038/s41467-020-15986-3.
according to a cross-sectional study published in Nature Communications. The proteins that best differentiate active lupus nephritis from inactive systemic lupus erythematosus (SLE) vary across ethnicities, the researchers wrote.
“A longitudinal study is warranted to investigate how these molecules relate to disease pathology and progression over time,” said senior study author Chandra Mohan, MD, PhD, of the department of biomedical engineering at the University of Houston, and colleagues. In addition, researchers should investigate the roles of protein biomarkers ALCAM, PF-4, properdin, VCAM-1, and sE-selectin in mediating lupus nephritis.
Limitations of renal biopsy
About 60% of patients with SLE will develop lupus nephritis, and 10%-15% of patients who develop lupus nephritis progress to end-stage renal disease. Although renal biopsy is the gold standard for the diagnosis of renal involvement in SLE, biopsies are invasive, not serially repeatable, and may not represent the entire kidney, Dr. Mohan and colleagues wrote.
To identify potential urinary biomarkers of lupus nephritis using an unbiased, proteomic approach, the investigators screened urine samples from 23 participants – 7 with active lupus nephritis, 8 with inactive SLE, and 8 healthy controls. They used an aptamer-based screen to investigate more than 1,100 proteins. The researchers then validated biomarker candidates using enzyme-linked immunosorbent assays. Independent cross-sectional cohorts included 127 patients with inactive SLE, 107 patients with active lupus nephritis, 67 patients with active nonrenal lupus, and 74 healthy controls. The cohorts included patients who were African American, Caucasian, and Asian. The researchers excluded patients with renal failure and pediatric patients.
Of the 12 urine proteins studied, 10 outperformed traditional laboratory measures, such as C3/C4 and anti–double stranded DNA, in discriminating active lupus nephritis from inactive SLE, wrote Dr. Mohan and colleagues. A Lasso regression analysis found that the best predictive model included 8 of the 12 urine proteins as well as race. The model discriminated active lupus nephritis from inactive SLE with an area under the receiver operating characteristic curve (AUC) of 0.98.
Among African Americans, urine proteins that best distinguished active lupus nephritis from inactive disease included PF-4 (AUC, 0.88), VCAM-1 (AUC, 0.87), properdin (AUC, 0.85), and ALCAM (AUC, 0.84). Among Caucasians, they included sE-selectin (AUC, 0.87), VCAM-1 (AUC, 0.84), BFL-1 (AUC, 0.81), and hemopexin (AUC, 0.80). Among Asians, they included ALCAM (AUC, 0.93), VCAM-1 (AUC, 0.92), TFPI (AUC, 0.88), and PF-4 (AUC, 0.83).
The study is “unique in highlighting the importance of tailoring the biomarkers to patient ethnicity,” the researchers wrote.
Basing subgroups on race rather than phenotypic profiles
“This is an important study because it confirms the ability to predict active lupus nephritis from urine samples and utilized advanced technologies to find key markers for that,” said Joan T. Merrill, MD, of the Oklahoma Medical Research Foundation in Oklahoma City. “It is unfortunate that investigators with access to such advanced technology are still using an outdated and extremely questionable method for distinguishing subgroups of patients, that of race.”
Grouping patients by phenotypic profiles that reflect current disease states “would be a more accurate method for finding optimal urinary markers for active nephritis,” and is “likely to prove more accurate for individuals in all races,” Dr. Merrill said. Certain racial subgroups may be more likely to have particular disease phenotypes, “which are usually identified based on gene pathway coexpression patterns.” Still, “people who self-identify as a given race are not genetically identical,” Dr. Merrill added. “In fact, this is a very blunt instrument, compared to phenotypic profiling now available for lupus patients.”
SLE and lupus nephritis are “heavily influenced by genetics,” and African Americans are three times more likely than Caucasians to develop SLE and are more like to develop end-stage renal disease, Dr. Mohan and colleagues wrote. Nevertheless, “influence from environmental triggers or socioeconomic factors cannot be ruled out,” they added. “Although patient demographics are widely known to affect SLE disease manifestations and outcomes, there are virtually no studies investigating this phenomenon in the context of disease biomarkers; most SLE biomarkers studies focus on one demographic group or all ethnic groups combined, which yield results that may not be equally predictive in all demographic groups of SLE patients.”
Dr. Mohan is collaborating with a biotechnology company to study drugs that may block ALCAM, according to a University of Houston news release. ALCAM is involved in immune and inflammatory responses, the researchers noted. “When all SLE patients were combined, urine ALCAM levels had the strongest bearing on disease activity status, in an unsupervised Bayesian network analysis,” they wrote. “Urine ALCAM also emerged as one of the few proteins that distinguished active [lupus nephritis] from active nonrenal lupus.”
National Institutes of Health grants supported the research. The investigators had no competing interests.
SOURCE: Stanley S et al. Nat Commun. 2020 May 4. doi: 10.1038/s41467-020-15986-3.
according to a cross-sectional study published in Nature Communications. The proteins that best differentiate active lupus nephritis from inactive systemic lupus erythematosus (SLE) vary across ethnicities, the researchers wrote.
“A longitudinal study is warranted to investigate how these molecules relate to disease pathology and progression over time,” said senior study author Chandra Mohan, MD, PhD, of the department of biomedical engineering at the University of Houston, and colleagues. In addition, researchers should investigate the roles of protein biomarkers ALCAM, PF-4, properdin, VCAM-1, and sE-selectin in mediating lupus nephritis.
Limitations of renal biopsy
About 60% of patients with SLE will develop lupus nephritis, and 10%-15% of patients who develop lupus nephritis progress to end-stage renal disease. Although renal biopsy is the gold standard for the diagnosis of renal involvement in SLE, biopsies are invasive, not serially repeatable, and may not represent the entire kidney, Dr. Mohan and colleagues wrote.
To identify potential urinary biomarkers of lupus nephritis using an unbiased, proteomic approach, the investigators screened urine samples from 23 participants – 7 with active lupus nephritis, 8 with inactive SLE, and 8 healthy controls. They used an aptamer-based screen to investigate more than 1,100 proteins. The researchers then validated biomarker candidates using enzyme-linked immunosorbent assays. Independent cross-sectional cohorts included 127 patients with inactive SLE, 107 patients with active lupus nephritis, 67 patients with active nonrenal lupus, and 74 healthy controls. The cohorts included patients who were African American, Caucasian, and Asian. The researchers excluded patients with renal failure and pediatric patients.
Of the 12 urine proteins studied, 10 outperformed traditional laboratory measures, such as C3/C4 and anti–double stranded DNA, in discriminating active lupus nephritis from inactive SLE, wrote Dr. Mohan and colleagues. A Lasso regression analysis found that the best predictive model included 8 of the 12 urine proteins as well as race. The model discriminated active lupus nephritis from inactive SLE with an area under the receiver operating characteristic curve (AUC) of 0.98.
Among African Americans, urine proteins that best distinguished active lupus nephritis from inactive disease included PF-4 (AUC, 0.88), VCAM-1 (AUC, 0.87), properdin (AUC, 0.85), and ALCAM (AUC, 0.84). Among Caucasians, they included sE-selectin (AUC, 0.87), VCAM-1 (AUC, 0.84), BFL-1 (AUC, 0.81), and hemopexin (AUC, 0.80). Among Asians, they included ALCAM (AUC, 0.93), VCAM-1 (AUC, 0.92), TFPI (AUC, 0.88), and PF-4 (AUC, 0.83).
The study is “unique in highlighting the importance of tailoring the biomarkers to patient ethnicity,” the researchers wrote.
Basing subgroups on race rather than phenotypic profiles
“This is an important study because it confirms the ability to predict active lupus nephritis from urine samples and utilized advanced technologies to find key markers for that,” said Joan T. Merrill, MD, of the Oklahoma Medical Research Foundation in Oklahoma City. “It is unfortunate that investigators with access to such advanced technology are still using an outdated and extremely questionable method for distinguishing subgroups of patients, that of race.”
Grouping patients by phenotypic profiles that reflect current disease states “would be a more accurate method for finding optimal urinary markers for active nephritis,” and is “likely to prove more accurate for individuals in all races,” Dr. Merrill said. Certain racial subgroups may be more likely to have particular disease phenotypes, “which are usually identified based on gene pathway coexpression patterns.” Still, “people who self-identify as a given race are not genetically identical,” Dr. Merrill added. “In fact, this is a very blunt instrument, compared to phenotypic profiling now available for lupus patients.”
SLE and lupus nephritis are “heavily influenced by genetics,” and African Americans are three times more likely than Caucasians to develop SLE and are more like to develop end-stage renal disease, Dr. Mohan and colleagues wrote. Nevertheless, “influence from environmental triggers or socioeconomic factors cannot be ruled out,” they added. “Although patient demographics are widely known to affect SLE disease manifestations and outcomes, there are virtually no studies investigating this phenomenon in the context of disease biomarkers; most SLE biomarkers studies focus on one demographic group or all ethnic groups combined, which yield results that may not be equally predictive in all demographic groups of SLE patients.”
Dr. Mohan is collaborating with a biotechnology company to study drugs that may block ALCAM, according to a University of Houston news release. ALCAM is involved in immune and inflammatory responses, the researchers noted. “When all SLE patients were combined, urine ALCAM levels had the strongest bearing on disease activity status, in an unsupervised Bayesian network analysis,” they wrote. “Urine ALCAM also emerged as one of the few proteins that distinguished active [lupus nephritis] from active nonrenal lupus.”
National Institutes of Health grants supported the research. The investigators had no competing interests.
SOURCE: Stanley S et al. Nat Commun. 2020 May 4. doi: 10.1038/s41467-020-15986-3.
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