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Balanced crystalloid fluids surpass saline for kidney transplant
ORLANDO – Using a low-chloride, balanced crystalloid solution for all intravenous fluids received by patients who received a deceased donor kidney transplant resulted in significantly fewer episodes of delayed graft function, compared with patients who received saline as their IV fluids, in a new multicenter trial with 807 randomized and evaluable patients called BEST-Fluids.
“The findings suggest that balanced crystalloids should be the standard-of-care IV fluid in deceased donor kidney transplantations,” Michael G. Collins, MBChB, PhD, said at the annual meeting of the American Society of Nephrology.
“Balanced crystalloids are cheap, readily available worldwide, and this simple change in kidney transplant practice can easily be implemented in global practice ... almost immediately,” said Dr. Collins, a nephrologist at Royal Adelaide Hospital, Australia.
A 1-L bag of balanced crystalloid fluid is more expensive; however, it has a U.S. retail cost of about $2-$5 per bag, compared with about $1 per bag of saline fluid, Dr. Collins added.
Various other commentators had mixed views. Some agreed with Dr. Collins and said the switch could be made immediately, although one researcher wanted to see more trials. Another wondered why balanced crystalloid fluid hadn’t seemed to provide benefit in studies in acute kidney injury.
Treating 10 patients prevents one delayed graft function
The incidence of delayed graft function, defined as the need for dialysis during the 7 days following transplantation, occurred in 30.0% of 404 patients who received balanced crystalloid fluids (Plasma-Lyte 148) and in 39.7% of 403 patients who received saline starting at the time of randomization (prior to surgery) until 48 hours post-surgery, Dr. Collins reported.
This translated into a significant, adjusted relative risk reduction of 26% and a number needed to treat of 10 to result in one avoided episode of delayed graft function.
Preventing delayed graft function is important because it is a “major complication” of deceased donor kidney transplantation that usually occurs in about 30%-50% of people who receive these organs, Dr. Collins explained. Incident delayed graft function leads to higher hospitalization costs because of a prolonged need for dialysis and extended hospital days, as well as increased risk for long-term graft failure and death.
A secondary outcome – the number of dialysis sessions required during the 28 days following transplantation – was 406 sessions among those who received balanced crystalloid fluids and 596 sessions among the controls who received saline, a significant adjusted relative decrease of 30%.
Freedom from need for dialysis by 12 weeks after surgery increased by a significant 10% among those treated with balanced crystalloid fluids, compared with controls. The balanced crystalloid fluids were also significantly linked with an average 1-L increase in urine output during the first 2 days after transplantation, compared with controls.
Chloride is the culprit
“I think this is driven by the harmful effects of saline,” which is currently the standard fluid that kidney transplant patients receive worldwide, said Dr. Collins. Specifically, he cited the chloride content of saline – which contains 0.9% sodium chloride – as the culprit by causing reduced kidney perfusion.
“Some data suggest that saline may be harmful because of chloride acidosis producing vasoconstriction and increasing ischemia,” commented Karen A. Griffin, MD, chief of the renal section at the Edward Hines, Jr. VA Medical Center, Hines, Illinois. But Dr. Griffin said she’d like to see further study of balanced crystalloid fluids in this setting before she’d be comfortable using it routinely as a replacement for saline.
However, Pascale H. Lane, MD, a pediatric nephrologist with Oklahoma University Health, Oklahoma City, predicted that based on these results, “I think it will be rapidly embraced” by U.S. clinicians. Dr. Lane expressed concern about the availability of an adequate supply of balanced crystalloid fluid, but Dr. Collins said he did not believe supply would be an issue based on current availability.
This was “a beautiful study, very well done, with nice results, and a very easy switch to balanced crystalloid fluids without harm,” commented Richard Lafayette, MD, a nephrologist and professor of medicine at Stanford (Calif.) University.
Success attributed to early treatment
But Dr. Lafayette also wondered, “Why should this work for transplant patients when it did not work for patients who develop acute kidney injury in the ICU?” And he found it hard to understand how the impact of the balanced crystalloid fluid could manifest so quickly, with a change in urine output during the first day following surgery.
Dr. Collins attributed the rapid effects and overall success to the early initiation of balanced crystalloid fluids before the transplant occurred.
The BEST-Fluids trial ran at 16 centers in Australia and New Zealand and enrolled patients from January 2018 to August 2020. It enrolled adults and children scheduled to receive a deceased donor kidney, excluding those who weighed less than 20 kg and those who received multiple organs.
Enrolled patients averaged about 55 years old, about 63% were men, and their average duration on dialysis prior to surgery was about 30 months. The study randomized 808 patients who received their transplanted kidney, with 807 included in the efficacy analysis. Patients in each of the two groups showed very close balance for all reported parameters of patient and donor characteristics. During the period of randomized fluid treatment, patients in the balanced crystalloid group received an average of just over 8 L of fluid, while those in the control group received an average of just over 7 L.
During follow-up, serious adverse events were rare and balanced, with three in the balanced crystalloid group and four among controls.
The only significant difference in adverse events was the rate of ICU admissions that required ventilation, which occurred in one patient in the balanced crystalloid group and 12 controls.
BEST-Fluids received balanced crystalloid and saline solutions at no charge from Baxter Healthcare, which markets Plasma-Lyte 148. The study received no other commercial funding. Dr. Collins, Dr. Griffin, and Dr. Lane have reported no relevant financial relationships. Dr. Lafayette has received personal fees and grants from Alexion, Aurinia, Calliditas, Omeros, Pfizer, Roche, Travere, and Vera and has been an advisor to Akahest and Equillium.
A version of this article first appeared on Medscape.com.
ORLANDO – Using a low-chloride, balanced crystalloid solution for all intravenous fluids received by patients who received a deceased donor kidney transplant resulted in significantly fewer episodes of delayed graft function, compared with patients who received saline as their IV fluids, in a new multicenter trial with 807 randomized and evaluable patients called BEST-Fluids.
“The findings suggest that balanced crystalloids should be the standard-of-care IV fluid in deceased donor kidney transplantations,” Michael G. Collins, MBChB, PhD, said at the annual meeting of the American Society of Nephrology.
“Balanced crystalloids are cheap, readily available worldwide, and this simple change in kidney transplant practice can easily be implemented in global practice ... almost immediately,” said Dr. Collins, a nephrologist at Royal Adelaide Hospital, Australia.
A 1-L bag of balanced crystalloid fluid is more expensive; however, it has a U.S. retail cost of about $2-$5 per bag, compared with about $1 per bag of saline fluid, Dr. Collins added.
Various other commentators had mixed views. Some agreed with Dr. Collins and said the switch could be made immediately, although one researcher wanted to see more trials. Another wondered why balanced crystalloid fluid hadn’t seemed to provide benefit in studies in acute kidney injury.
Treating 10 patients prevents one delayed graft function
The incidence of delayed graft function, defined as the need for dialysis during the 7 days following transplantation, occurred in 30.0% of 404 patients who received balanced crystalloid fluids (Plasma-Lyte 148) and in 39.7% of 403 patients who received saline starting at the time of randomization (prior to surgery) until 48 hours post-surgery, Dr. Collins reported.
This translated into a significant, adjusted relative risk reduction of 26% and a number needed to treat of 10 to result in one avoided episode of delayed graft function.
Preventing delayed graft function is important because it is a “major complication” of deceased donor kidney transplantation that usually occurs in about 30%-50% of people who receive these organs, Dr. Collins explained. Incident delayed graft function leads to higher hospitalization costs because of a prolonged need for dialysis and extended hospital days, as well as increased risk for long-term graft failure and death.
A secondary outcome – the number of dialysis sessions required during the 28 days following transplantation – was 406 sessions among those who received balanced crystalloid fluids and 596 sessions among the controls who received saline, a significant adjusted relative decrease of 30%.
Freedom from need for dialysis by 12 weeks after surgery increased by a significant 10% among those treated with balanced crystalloid fluids, compared with controls. The balanced crystalloid fluids were also significantly linked with an average 1-L increase in urine output during the first 2 days after transplantation, compared with controls.
Chloride is the culprit
“I think this is driven by the harmful effects of saline,” which is currently the standard fluid that kidney transplant patients receive worldwide, said Dr. Collins. Specifically, he cited the chloride content of saline – which contains 0.9% sodium chloride – as the culprit by causing reduced kidney perfusion.
“Some data suggest that saline may be harmful because of chloride acidosis producing vasoconstriction and increasing ischemia,” commented Karen A. Griffin, MD, chief of the renal section at the Edward Hines, Jr. VA Medical Center, Hines, Illinois. But Dr. Griffin said she’d like to see further study of balanced crystalloid fluids in this setting before she’d be comfortable using it routinely as a replacement for saline.
However, Pascale H. Lane, MD, a pediatric nephrologist with Oklahoma University Health, Oklahoma City, predicted that based on these results, “I think it will be rapidly embraced” by U.S. clinicians. Dr. Lane expressed concern about the availability of an adequate supply of balanced crystalloid fluid, but Dr. Collins said he did not believe supply would be an issue based on current availability.
This was “a beautiful study, very well done, with nice results, and a very easy switch to balanced crystalloid fluids without harm,” commented Richard Lafayette, MD, a nephrologist and professor of medicine at Stanford (Calif.) University.
Success attributed to early treatment
But Dr. Lafayette also wondered, “Why should this work for transplant patients when it did not work for patients who develop acute kidney injury in the ICU?” And he found it hard to understand how the impact of the balanced crystalloid fluid could manifest so quickly, with a change in urine output during the first day following surgery.
Dr. Collins attributed the rapid effects and overall success to the early initiation of balanced crystalloid fluids before the transplant occurred.
The BEST-Fluids trial ran at 16 centers in Australia and New Zealand and enrolled patients from January 2018 to August 2020. It enrolled adults and children scheduled to receive a deceased donor kidney, excluding those who weighed less than 20 kg and those who received multiple organs.
Enrolled patients averaged about 55 years old, about 63% were men, and their average duration on dialysis prior to surgery was about 30 months. The study randomized 808 patients who received their transplanted kidney, with 807 included in the efficacy analysis. Patients in each of the two groups showed very close balance for all reported parameters of patient and donor characteristics. During the period of randomized fluid treatment, patients in the balanced crystalloid group received an average of just over 8 L of fluid, while those in the control group received an average of just over 7 L.
During follow-up, serious adverse events were rare and balanced, with three in the balanced crystalloid group and four among controls.
The only significant difference in adverse events was the rate of ICU admissions that required ventilation, which occurred in one patient in the balanced crystalloid group and 12 controls.
BEST-Fluids received balanced crystalloid and saline solutions at no charge from Baxter Healthcare, which markets Plasma-Lyte 148. The study received no other commercial funding. Dr. Collins, Dr. Griffin, and Dr. Lane have reported no relevant financial relationships. Dr. Lafayette has received personal fees and grants from Alexion, Aurinia, Calliditas, Omeros, Pfizer, Roche, Travere, and Vera and has been an advisor to Akahest and Equillium.
A version of this article first appeared on Medscape.com.
ORLANDO – Using a low-chloride, balanced crystalloid solution for all intravenous fluids received by patients who received a deceased donor kidney transplant resulted in significantly fewer episodes of delayed graft function, compared with patients who received saline as their IV fluids, in a new multicenter trial with 807 randomized and evaluable patients called BEST-Fluids.
“The findings suggest that balanced crystalloids should be the standard-of-care IV fluid in deceased donor kidney transplantations,” Michael G. Collins, MBChB, PhD, said at the annual meeting of the American Society of Nephrology.
“Balanced crystalloids are cheap, readily available worldwide, and this simple change in kidney transplant practice can easily be implemented in global practice ... almost immediately,” said Dr. Collins, a nephrologist at Royal Adelaide Hospital, Australia.
A 1-L bag of balanced crystalloid fluid is more expensive; however, it has a U.S. retail cost of about $2-$5 per bag, compared with about $1 per bag of saline fluid, Dr. Collins added.
Various other commentators had mixed views. Some agreed with Dr. Collins and said the switch could be made immediately, although one researcher wanted to see more trials. Another wondered why balanced crystalloid fluid hadn’t seemed to provide benefit in studies in acute kidney injury.
Treating 10 patients prevents one delayed graft function
The incidence of delayed graft function, defined as the need for dialysis during the 7 days following transplantation, occurred in 30.0% of 404 patients who received balanced crystalloid fluids (Plasma-Lyte 148) and in 39.7% of 403 patients who received saline starting at the time of randomization (prior to surgery) until 48 hours post-surgery, Dr. Collins reported.
This translated into a significant, adjusted relative risk reduction of 26% and a number needed to treat of 10 to result in one avoided episode of delayed graft function.
Preventing delayed graft function is important because it is a “major complication” of deceased donor kidney transplantation that usually occurs in about 30%-50% of people who receive these organs, Dr. Collins explained. Incident delayed graft function leads to higher hospitalization costs because of a prolonged need for dialysis and extended hospital days, as well as increased risk for long-term graft failure and death.
A secondary outcome – the number of dialysis sessions required during the 28 days following transplantation – was 406 sessions among those who received balanced crystalloid fluids and 596 sessions among the controls who received saline, a significant adjusted relative decrease of 30%.
Freedom from need for dialysis by 12 weeks after surgery increased by a significant 10% among those treated with balanced crystalloid fluids, compared with controls. The balanced crystalloid fluids were also significantly linked with an average 1-L increase in urine output during the first 2 days after transplantation, compared with controls.
Chloride is the culprit
“I think this is driven by the harmful effects of saline,” which is currently the standard fluid that kidney transplant patients receive worldwide, said Dr. Collins. Specifically, he cited the chloride content of saline – which contains 0.9% sodium chloride – as the culprit by causing reduced kidney perfusion.
“Some data suggest that saline may be harmful because of chloride acidosis producing vasoconstriction and increasing ischemia,” commented Karen A. Griffin, MD, chief of the renal section at the Edward Hines, Jr. VA Medical Center, Hines, Illinois. But Dr. Griffin said she’d like to see further study of balanced crystalloid fluids in this setting before she’d be comfortable using it routinely as a replacement for saline.
However, Pascale H. Lane, MD, a pediatric nephrologist with Oklahoma University Health, Oklahoma City, predicted that based on these results, “I think it will be rapidly embraced” by U.S. clinicians. Dr. Lane expressed concern about the availability of an adequate supply of balanced crystalloid fluid, but Dr. Collins said he did not believe supply would be an issue based on current availability.
This was “a beautiful study, very well done, with nice results, and a very easy switch to balanced crystalloid fluids without harm,” commented Richard Lafayette, MD, a nephrologist and professor of medicine at Stanford (Calif.) University.
Success attributed to early treatment
But Dr. Lafayette also wondered, “Why should this work for transplant patients when it did not work for patients who develop acute kidney injury in the ICU?” And he found it hard to understand how the impact of the balanced crystalloid fluid could manifest so quickly, with a change in urine output during the first day following surgery.
Dr. Collins attributed the rapid effects and overall success to the early initiation of balanced crystalloid fluids before the transplant occurred.
The BEST-Fluids trial ran at 16 centers in Australia and New Zealand and enrolled patients from January 2018 to August 2020. It enrolled adults and children scheduled to receive a deceased donor kidney, excluding those who weighed less than 20 kg and those who received multiple organs.
Enrolled patients averaged about 55 years old, about 63% were men, and their average duration on dialysis prior to surgery was about 30 months. The study randomized 808 patients who received their transplanted kidney, with 807 included in the efficacy analysis. Patients in each of the two groups showed very close balance for all reported parameters of patient and donor characteristics. During the period of randomized fluid treatment, patients in the balanced crystalloid group received an average of just over 8 L of fluid, while those in the control group received an average of just over 7 L.
During follow-up, serious adverse events were rare and balanced, with three in the balanced crystalloid group and four among controls.
The only significant difference in adverse events was the rate of ICU admissions that required ventilation, which occurred in one patient in the balanced crystalloid group and 12 controls.
BEST-Fluids received balanced crystalloid and saline solutions at no charge from Baxter Healthcare, which markets Plasma-Lyte 148. The study received no other commercial funding. Dr. Collins, Dr. Griffin, and Dr. Lane have reported no relevant financial relationships. Dr. Lafayette has received personal fees and grants from Alexion, Aurinia, Calliditas, Omeros, Pfizer, Roche, Travere, and Vera and has been an advisor to Akahest and Equillium.
A version of this article first appeared on Medscape.com.
AT KIDNEY WEEK 2022
EHR alerts flag acute kidney injury and avert progression
ORLANDO – Automated alerts sent to clinicians via patients’ electronic health records identified patients with diagnosable acute kidney injury (AKI) who were taking one or more medications that could potentially further worsen their renal function. This led to a significant increase in discontinuations of the problematic drugs and better clinical outcomes in a subgroup of patients in a new multicenter, randomized study with more than 5,000 participants.
“Automated alerts for AKI can increase the rate of cessation of potentially nephrotoxic medications without endangering patients,” said F. Perry Wilson, MD, at Kidney Week 2022, organized by the American Society of Nephrology.
In addition, the study provides “limited evidence that these alerts change clinical practice,” said Dr. Wilson, a nephrologist and director of the clinical and translational research accelerator at Yale School of Medicine in New Haven, Conn.
“It was encouraging to get providers to change their behavior” by quickly stopping treatment with potentially nephrotoxic medications in patients with incident AKI. But the results also confirmed that “patient decision-support systems tend to not be panaceas,” Dr. Wilson explained in an interview. Instead, “they tend to marginally improve” patients’ clinical status.
“Our hope is that widespread use may make some difference on a population scale, but rarely are these game changers,” he admitted.
“This was a very nice study showing how we can leverage the EHR to look not only at drugs but also contrast agents to direct educational efforts aimed at clinicians about when to discontinue” these treatments, commented Karen A. Griffin, MD, who was not involved with the study.
A danger for alert fatigue
But the results also showed that more research is needed to better refine this approach, added Dr. Griffin, a professor at Loyola University Chicago, Maywood, Ill., and chief of the renal section at the Edward Hines Jr. VA Medical Center in Hines, Ill. And she expressed caution about expanding the alerts that clinicians receive “because of the potential for alert fatigue.”
Dr. Wilson also acknowledged the danger for alert fatigue. “We’re doing these studies to try to reduce the number of alerts,” he said. “Most clinicians say that if we could show an alert improves patient outcomes, they would embrace it.”
Dr. Wilson and associates designed their current study to evaluate an enhanced type of alert that not only warned clinicians that a patient had developed AKI but also gave them an option to potentially intervene by stopping treatment with a medication that could possibly exacerbate worsening renal function. This enhancement followed their experience in a 2021 study that tested a purely informational alert that gave physicians no guidance about what actions to take to more quickly resolve the AKI.
These findings plus results from other studies suggested that “purely informational alerts may not be enough. They need to be linked” to suggested changes in patient management, Dr. Wilson explained.
Targeting NSAIDS, RAAS inhibitors, and PPIs
The new study used automated EHR analysis to not only identify patients with incident AKI, but also to flag medications these patients were receiving from any of three classes suspected of worsening renal function: nonsteroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system (RAAS) inhibitors (which include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), and proton-pump inhibitors (PPIs).
“Our hypothesis was that giving clinicians actionable advice could significantly improve patient outcomes,” Dr. Wilson said. “NSAIDs are frequently discontinued” in patients who develop AKI. “RAAS inhibitors are sometimes discontinued,” although the benefit from doing this remains unproven and controversial. “PPIs are rarely discontinued,” and may be an underappreciated contributor to AKI by causing interstitial nephritis in some patients.
The prospective study included 5,060 adults admitted with a diagnosis of stage 1 AKI at any of four Yale-affiliated teaching hospitals who were also taking agents from at least one of the three targeted drug classes at the time of admission. Clinicians caring for 2,532 of these patients received an alert about the AKI diagnosis and use of the questionable medications, while those caring for the 2,528 control patients received no alert and delivered usual care.
The study excluded patients with higher-risk profiles, including those with extremely elevated serum creatinine levels at admission (4.0 mg/dL or higher), those recently treated with dialysis, and patients with end-stage kidney disease.
The study had two primary outcomes. One measured the impact of the intervention on stopping the targeted drugs. The second assessed the clinical effect of the intervention on progression of AKI to a higher stage, need for dialysis, or death during either the duration of hospitalization or during the first 14 days following randomization.
Overall, a 9% relative increase in discontinuations
In general, the intervention had a modest but significant effect on cessation of the targeted drug classes within 24 hours of sending the alert.
Overall, there was about a 58% discontinuation rate among controls and about a 62% discontinuation rate among patients managed using the alerts, a significant 9% relative increase in any drug discontinuation, Dr. Wilson reported.
Discontinuations of NSAIDs occurred at the highest rate, in about 80% of patients in both groups, and the intervention showed no significant effect on stopping agents from this class. Discontinuations of RAAS inhibitors showed the largest absolute difference in between-group effect, about a 10–percentage point increase that represented a significant 14% relative increase in stopping agents from this class. Discontinuations of PPIs occurred at the lowest rate, in roughly 20% of patients, but the alert intervention had the greatest impact by raising the relative rate of stopping by a significant 26% compared with controls.
Analysis of the effect of the intervention on the combined clinical outcome showed a less robust impact. The alerts produced no significant change in the clinical outcome overall, or in the use of NSAIDs or RAAS inhibitors. However, the change in use of PPIs following the alerts significantly linked with a 12% relative drop in the incidence of the combined clinical endpoint of progression of AKI to a higher stage, need for dialysis, or death.
The results were consistent across several prespecified subgroups based on parameters such as age, sex, and race, but these analyses showed a signal that the alerts were most helpful for patients who had serum creatinine levels at admission of less than 0.5 mg/dL.
Dr. Wilson speculated that the alerts might have been especially effective for these patients because their low creatinine levels might otherwise mask AKI onset.
A safety analysis showed no evidence that the alert interventions and drug cessations increased the incidence of any complications.
PPIs may distinguish ‘sicker’ patients
Dr. Wilson cited two potential explanations for why the tested alerts appeared most effective for patients taking a PPI at the time of admission. One is that PPIs are underappreciated as a contributor to AKI, a possibility supported by the low rates of discontinuation in both the control and intervention groups.
In addition, treatment with a PPI may be a marker of “sicker” patients who may have more to gain from quicker identification of their AKI. For example, 28% of the patients who were taking a PPI at admission were in the ICU when they entered the study compared with a 14% rate of ICU care among everyone else.
PPIs were also the most-used targeted drug class among enrolled patients, used by 65% at baseline, compared with 53% who were taking a RAAS inhibitor and about 31% who were taking an NSAID. About 6% of enrolled patients were taking agents from all three classes at baseline, and 36% were on treatment with agents from two of the classes.
The next step is to assess adding more refinement to the alert process, Dr. Wilson said. He and his associates are now running a study in which an AKI alert goes to a “kidney action team” that includes a trained clinician and a pharmacist. The team would review the patient who triggered the alert and quickly make an individualized assessment of the best intervention for resolving the AKI.
The study received no commercial funding. Dr. Wilson has received research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop. Dr. Griffin has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ORLANDO – Automated alerts sent to clinicians via patients’ electronic health records identified patients with diagnosable acute kidney injury (AKI) who were taking one or more medications that could potentially further worsen their renal function. This led to a significant increase in discontinuations of the problematic drugs and better clinical outcomes in a subgroup of patients in a new multicenter, randomized study with more than 5,000 participants.
“Automated alerts for AKI can increase the rate of cessation of potentially nephrotoxic medications without endangering patients,” said F. Perry Wilson, MD, at Kidney Week 2022, organized by the American Society of Nephrology.
In addition, the study provides “limited evidence that these alerts change clinical practice,” said Dr. Wilson, a nephrologist and director of the clinical and translational research accelerator at Yale School of Medicine in New Haven, Conn.
“It was encouraging to get providers to change their behavior” by quickly stopping treatment with potentially nephrotoxic medications in patients with incident AKI. But the results also confirmed that “patient decision-support systems tend to not be panaceas,” Dr. Wilson explained in an interview. Instead, “they tend to marginally improve” patients’ clinical status.
“Our hope is that widespread use may make some difference on a population scale, but rarely are these game changers,” he admitted.
“This was a very nice study showing how we can leverage the EHR to look not only at drugs but also contrast agents to direct educational efforts aimed at clinicians about when to discontinue” these treatments, commented Karen A. Griffin, MD, who was not involved with the study.
A danger for alert fatigue
But the results also showed that more research is needed to better refine this approach, added Dr. Griffin, a professor at Loyola University Chicago, Maywood, Ill., and chief of the renal section at the Edward Hines Jr. VA Medical Center in Hines, Ill. And she expressed caution about expanding the alerts that clinicians receive “because of the potential for alert fatigue.”
Dr. Wilson also acknowledged the danger for alert fatigue. “We’re doing these studies to try to reduce the number of alerts,” he said. “Most clinicians say that if we could show an alert improves patient outcomes, they would embrace it.”
Dr. Wilson and associates designed their current study to evaluate an enhanced type of alert that not only warned clinicians that a patient had developed AKI but also gave them an option to potentially intervene by stopping treatment with a medication that could possibly exacerbate worsening renal function. This enhancement followed their experience in a 2021 study that tested a purely informational alert that gave physicians no guidance about what actions to take to more quickly resolve the AKI.
These findings plus results from other studies suggested that “purely informational alerts may not be enough. They need to be linked” to suggested changes in patient management, Dr. Wilson explained.
Targeting NSAIDS, RAAS inhibitors, and PPIs
The new study used automated EHR analysis to not only identify patients with incident AKI, but also to flag medications these patients were receiving from any of three classes suspected of worsening renal function: nonsteroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system (RAAS) inhibitors (which include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), and proton-pump inhibitors (PPIs).
“Our hypothesis was that giving clinicians actionable advice could significantly improve patient outcomes,” Dr. Wilson said. “NSAIDs are frequently discontinued” in patients who develop AKI. “RAAS inhibitors are sometimes discontinued,” although the benefit from doing this remains unproven and controversial. “PPIs are rarely discontinued,” and may be an underappreciated contributor to AKI by causing interstitial nephritis in some patients.
The prospective study included 5,060 adults admitted with a diagnosis of stage 1 AKI at any of four Yale-affiliated teaching hospitals who were also taking agents from at least one of the three targeted drug classes at the time of admission. Clinicians caring for 2,532 of these patients received an alert about the AKI diagnosis and use of the questionable medications, while those caring for the 2,528 control patients received no alert and delivered usual care.
The study excluded patients with higher-risk profiles, including those with extremely elevated serum creatinine levels at admission (4.0 mg/dL or higher), those recently treated with dialysis, and patients with end-stage kidney disease.
The study had two primary outcomes. One measured the impact of the intervention on stopping the targeted drugs. The second assessed the clinical effect of the intervention on progression of AKI to a higher stage, need for dialysis, or death during either the duration of hospitalization or during the first 14 days following randomization.
Overall, a 9% relative increase in discontinuations
In general, the intervention had a modest but significant effect on cessation of the targeted drug classes within 24 hours of sending the alert.
Overall, there was about a 58% discontinuation rate among controls and about a 62% discontinuation rate among patients managed using the alerts, a significant 9% relative increase in any drug discontinuation, Dr. Wilson reported.
Discontinuations of NSAIDs occurred at the highest rate, in about 80% of patients in both groups, and the intervention showed no significant effect on stopping agents from this class. Discontinuations of RAAS inhibitors showed the largest absolute difference in between-group effect, about a 10–percentage point increase that represented a significant 14% relative increase in stopping agents from this class. Discontinuations of PPIs occurred at the lowest rate, in roughly 20% of patients, but the alert intervention had the greatest impact by raising the relative rate of stopping by a significant 26% compared with controls.
Analysis of the effect of the intervention on the combined clinical outcome showed a less robust impact. The alerts produced no significant change in the clinical outcome overall, or in the use of NSAIDs or RAAS inhibitors. However, the change in use of PPIs following the alerts significantly linked with a 12% relative drop in the incidence of the combined clinical endpoint of progression of AKI to a higher stage, need for dialysis, or death.
The results were consistent across several prespecified subgroups based on parameters such as age, sex, and race, but these analyses showed a signal that the alerts were most helpful for patients who had serum creatinine levels at admission of less than 0.5 mg/dL.
Dr. Wilson speculated that the alerts might have been especially effective for these patients because their low creatinine levels might otherwise mask AKI onset.
A safety analysis showed no evidence that the alert interventions and drug cessations increased the incidence of any complications.
PPIs may distinguish ‘sicker’ patients
Dr. Wilson cited two potential explanations for why the tested alerts appeared most effective for patients taking a PPI at the time of admission. One is that PPIs are underappreciated as a contributor to AKI, a possibility supported by the low rates of discontinuation in both the control and intervention groups.
In addition, treatment with a PPI may be a marker of “sicker” patients who may have more to gain from quicker identification of their AKI. For example, 28% of the patients who were taking a PPI at admission were in the ICU when they entered the study compared with a 14% rate of ICU care among everyone else.
PPIs were also the most-used targeted drug class among enrolled patients, used by 65% at baseline, compared with 53% who were taking a RAAS inhibitor and about 31% who were taking an NSAID. About 6% of enrolled patients were taking agents from all three classes at baseline, and 36% were on treatment with agents from two of the classes.
The next step is to assess adding more refinement to the alert process, Dr. Wilson said. He and his associates are now running a study in which an AKI alert goes to a “kidney action team” that includes a trained clinician and a pharmacist. The team would review the patient who triggered the alert and quickly make an individualized assessment of the best intervention for resolving the AKI.
The study received no commercial funding. Dr. Wilson has received research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop. Dr. Griffin has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ORLANDO – Automated alerts sent to clinicians via patients’ electronic health records identified patients with diagnosable acute kidney injury (AKI) who were taking one or more medications that could potentially further worsen their renal function. This led to a significant increase in discontinuations of the problematic drugs and better clinical outcomes in a subgroup of patients in a new multicenter, randomized study with more than 5,000 participants.
“Automated alerts for AKI can increase the rate of cessation of potentially nephrotoxic medications without endangering patients,” said F. Perry Wilson, MD, at Kidney Week 2022, organized by the American Society of Nephrology.
In addition, the study provides “limited evidence that these alerts change clinical practice,” said Dr. Wilson, a nephrologist and director of the clinical and translational research accelerator at Yale School of Medicine in New Haven, Conn.
“It was encouraging to get providers to change their behavior” by quickly stopping treatment with potentially nephrotoxic medications in patients with incident AKI. But the results also confirmed that “patient decision-support systems tend to not be panaceas,” Dr. Wilson explained in an interview. Instead, “they tend to marginally improve” patients’ clinical status.
“Our hope is that widespread use may make some difference on a population scale, but rarely are these game changers,” he admitted.
“This was a very nice study showing how we can leverage the EHR to look not only at drugs but also contrast agents to direct educational efforts aimed at clinicians about when to discontinue” these treatments, commented Karen A. Griffin, MD, who was not involved with the study.
A danger for alert fatigue
But the results also showed that more research is needed to better refine this approach, added Dr. Griffin, a professor at Loyola University Chicago, Maywood, Ill., and chief of the renal section at the Edward Hines Jr. VA Medical Center in Hines, Ill. And she expressed caution about expanding the alerts that clinicians receive “because of the potential for alert fatigue.”
Dr. Wilson also acknowledged the danger for alert fatigue. “We’re doing these studies to try to reduce the number of alerts,” he said. “Most clinicians say that if we could show an alert improves patient outcomes, they would embrace it.”
Dr. Wilson and associates designed their current study to evaluate an enhanced type of alert that not only warned clinicians that a patient had developed AKI but also gave them an option to potentially intervene by stopping treatment with a medication that could possibly exacerbate worsening renal function. This enhancement followed their experience in a 2021 study that tested a purely informational alert that gave physicians no guidance about what actions to take to more quickly resolve the AKI.
These findings plus results from other studies suggested that “purely informational alerts may not be enough. They need to be linked” to suggested changes in patient management, Dr. Wilson explained.
Targeting NSAIDS, RAAS inhibitors, and PPIs
The new study used automated EHR analysis to not only identify patients with incident AKI, but also to flag medications these patients were receiving from any of three classes suspected of worsening renal function: nonsteroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system (RAAS) inhibitors (which include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), and proton-pump inhibitors (PPIs).
“Our hypothesis was that giving clinicians actionable advice could significantly improve patient outcomes,” Dr. Wilson said. “NSAIDs are frequently discontinued” in patients who develop AKI. “RAAS inhibitors are sometimes discontinued,” although the benefit from doing this remains unproven and controversial. “PPIs are rarely discontinued,” and may be an underappreciated contributor to AKI by causing interstitial nephritis in some patients.
The prospective study included 5,060 adults admitted with a diagnosis of stage 1 AKI at any of four Yale-affiliated teaching hospitals who were also taking agents from at least one of the three targeted drug classes at the time of admission. Clinicians caring for 2,532 of these patients received an alert about the AKI diagnosis and use of the questionable medications, while those caring for the 2,528 control patients received no alert and delivered usual care.
The study excluded patients with higher-risk profiles, including those with extremely elevated serum creatinine levels at admission (4.0 mg/dL or higher), those recently treated with dialysis, and patients with end-stage kidney disease.
The study had two primary outcomes. One measured the impact of the intervention on stopping the targeted drugs. The second assessed the clinical effect of the intervention on progression of AKI to a higher stage, need for dialysis, or death during either the duration of hospitalization or during the first 14 days following randomization.
Overall, a 9% relative increase in discontinuations
In general, the intervention had a modest but significant effect on cessation of the targeted drug classes within 24 hours of sending the alert.
Overall, there was about a 58% discontinuation rate among controls and about a 62% discontinuation rate among patients managed using the alerts, a significant 9% relative increase in any drug discontinuation, Dr. Wilson reported.
Discontinuations of NSAIDs occurred at the highest rate, in about 80% of patients in both groups, and the intervention showed no significant effect on stopping agents from this class. Discontinuations of RAAS inhibitors showed the largest absolute difference in between-group effect, about a 10–percentage point increase that represented a significant 14% relative increase in stopping agents from this class. Discontinuations of PPIs occurred at the lowest rate, in roughly 20% of patients, but the alert intervention had the greatest impact by raising the relative rate of stopping by a significant 26% compared with controls.
Analysis of the effect of the intervention on the combined clinical outcome showed a less robust impact. The alerts produced no significant change in the clinical outcome overall, or in the use of NSAIDs or RAAS inhibitors. However, the change in use of PPIs following the alerts significantly linked with a 12% relative drop in the incidence of the combined clinical endpoint of progression of AKI to a higher stage, need for dialysis, or death.
The results were consistent across several prespecified subgroups based on parameters such as age, sex, and race, but these analyses showed a signal that the alerts were most helpful for patients who had serum creatinine levels at admission of less than 0.5 mg/dL.
Dr. Wilson speculated that the alerts might have been especially effective for these patients because their low creatinine levels might otherwise mask AKI onset.
A safety analysis showed no evidence that the alert interventions and drug cessations increased the incidence of any complications.
PPIs may distinguish ‘sicker’ patients
Dr. Wilson cited two potential explanations for why the tested alerts appeared most effective for patients taking a PPI at the time of admission. One is that PPIs are underappreciated as a contributor to AKI, a possibility supported by the low rates of discontinuation in both the control and intervention groups.
In addition, treatment with a PPI may be a marker of “sicker” patients who may have more to gain from quicker identification of their AKI. For example, 28% of the patients who were taking a PPI at admission were in the ICU when they entered the study compared with a 14% rate of ICU care among everyone else.
PPIs were also the most-used targeted drug class among enrolled patients, used by 65% at baseline, compared with 53% who were taking a RAAS inhibitor and about 31% who were taking an NSAID. About 6% of enrolled patients were taking agents from all three classes at baseline, and 36% were on treatment with agents from two of the classes.
The next step is to assess adding more refinement to the alert process, Dr. Wilson said. He and his associates are now running a study in which an AKI alert goes to a “kidney action team” that includes a trained clinician and a pharmacist. The team would review the patient who triggered the alert and quickly make an individualized assessment of the best intervention for resolving the AKI.
The study received no commercial funding. Dr. Wilson has received research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop. Dr. Griffin has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT KIDNEY WEEK 2022
Dialysis not always best option in advanced kidney disease
ORLANDO – , new research shows.
“Patients mostly start dialysis because of unpleasant symptoms that cause suffering, including high potassium levels and high levels of uremic toxins in the blood,” senior author Kamyar Kalantar-Zadeh, MD, PhD, MPH, told this news organization.
“Conservative management serves to address and manage these symptoms and levels of toxicities without dialysis, so conservative management is an alternative approach, and patients should always be given a choice between [the two],” stressed Dr. Kalantar-Zadeh, professor of medicine at the University of California, Irvine.
The results were presented during the annual meeting of the American Society of Nephrology.
“There has been growing recognition of the importance of conservative nondialytic management as an alternative patient-centered treatment strategy for advanced kidney disease. However, conservative management remains under-utilized in the United States, which may in part be due to uncertainties regarding which patients will most benefit from dialysis versus nondialytic treatment,” said first author Connie Rhee, MD, also of the University of California, Irvine.
“We hope that these findings and further research can help inform treatment options for patients, care partners, and providers in the shared decision-making process of conservative management versus dialysis,” added Dr. Rhee, in a press release from the American Society of Nephrology.
Asked for comment, Sarah Davison, MD, noted that part of the Society’s strategy is, in fact, to promote conservative kidney management (CKM) as a key component of integrated care for patients with kidney failure. Dr. Davison is professor of medicine and chair of the International Society Working Group for Kidney Supportive Care and Conservative Kidney Management.
“We’ve recognized for a long time that there are many patients for whom dialysis provides neither a survival advantage nor a quality of life advantage,” she told this news organization.
“These patients tend to be those who have multiple morbidities, who are more frail, and who tend to be older, and in fact, the patients can live as long, if not longer, with better symptom management and better quality of life by not being on dialysis,” she stressed.
Study details
In the study, using data from the Optum Labs Data Warehouse, patients with advanced CKD were categorized according to whether or not they received conservative management, defined as those who did not receive dialysis within 2 years of the index eGFR (first eGFR < 25 mL/min/1.73m2) versus receipt of dialysis parsed as late versus early dialysis transition (eGFR < 15 vs. ≥ 15 mL/min/1.73m2 at dialysis initiation).
Hospitalization rates were compared between those treated with conservative management, compared with late or early dialysis.
“Among 309,188 advanced CKD patients who met eligibility [criteria], 55% of patients had greater than or equal to 1 hospitalization(s) within 2 years of the index eGFR,” the authors report. The most common causes of hospitalization among all patients were congestive heart failure, respiratory symptoms, or hypertension.
In most racial groups (non-Hispanic White, non-Hispanic Black, and Hispanic patients), patients on dialysis had higher hospitalization rates than those who received conservative management, and patients who started dialysis early (transitioned to dialysis at higher levels of kidney function) demonstrated the highest rates across all age groups, compared with those who started dialysis late (transitioned to dialysis at lower levels of kidney function) or were treated with conservative management.
Among Asian patients, those on dialysis also had higher hospitalization rates than those receiving conservative management, but patients who started dialysis late had higher rates than those on early dialysis, especially in older age groups, possibly because they were sicker, Dr. Kalantar-Zadeh suggested.
Conservative care has pros and cons, but Canada has embraced it
As Dr. Kalantar-Zadeh explained, conservative management has its pros and cons, compared with dialysis. “Conservative management requires that patients work with the multidisciplinary team including nephrologists, nutritionists, and others to try to manage CKD without dialysis, so it requires patient participation.”
On the other hand, dialysis is both easier and more lucrative than conservative management, at least for nephrologists, as they are well-trained in dialysis care, and it can be systematically applied. As to which patients with CKD might be optimal candidates for conservative management, Dr. Kalantar-Zadeh agreed this requires further study.
But he acknowledged that most nephrologists are not hugely supportive of conservative management because they are less well-trained in it, and it is more time-consuming. The one promising change is a new model introduced in 2022, a value-based kidney care model, that, if implemented, will be more incentivizing for nephrologists to offer conservative care more widely.
Dr. Davison meanwhile believes the “vast majority” of nephrologists based in Canada – as she is – are “highly supportive” of CKM as an important modality.
“The challenge, however, is that many nephrologists remain unsure as to how to best deliver or optimize all aspects of CKM, whether that is symptom management, advanced care planning, or how they must manage symptoms to align with a patient’s goals,” Dr. Davison explained.
“But it’s not that they do not believe in the value of CKM.”
Indeed, in her province, Alberta, nephrologists have been offering CKM for decades, and while they are currently standardizing care to make it easier to deliver, there is no financial incentive to offer dialysis over CKM.
“We are now seeing those elements of kidney supportive care as part of core competencies to manage any person with chronic illness, including CKD,” Dr. Davison said.
“So it’s absolutely doable, and contrary to one of the myths about CKM, it is not more time-consuming than dialysis – not when you know how to do it. You are just shifting your focus,” she emphasized.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Kalantar-Zadeh has reported receiving honoraria and medical directorship fees from Fresenius and DaVita. Dr. Davison has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ORLANDO – , new research shows.
“Patients mostly start dialysis because of unpleasant symptoms that cause suffering, including high potassium levels and high levels of uremic toxins in the blood,” senior author Kamyar Kalantar-Zadeh, MD, PhD, MPH, told this news organization.
“Conservative management serves to address and manage these symptoms and levels of toxicities without dialysis, so conservative management is an alternative approach, and patients should always be given a choice between [the two],” stressed Dr. Kalantar-Zadeh, professor of medicine at the University of California, Irvine.
The results were presented during the annual meeting of the American Society of Nephrology.
“There has been growing recognition of the importance of conservative nondialytic management as an alternative patient-centered treatment strategy for advanced kidney disease. However, conservative management remains under-utilized in the United States, which may in part be due to uncertainties regarding which patients will most benefit from dialysis versus nondialytic treatment,” said first author Connie Rhee, MD, also of the University of California, Irvine.
“We hope that these findings and further research can help inform treatment options for patients, care partners, and providers in the shared decision-making process of conservative management versus dialysis,” added Dr. Rhee, in a press release from the American Society of Nephrology.
Asked for comment, Sarah Davison, MD, noted that part of the Society’s strategy is, in fact, to promote conservative kidney management (CKM) as a key component of integrated care for patients with kidney failure. Dr. Davison is professor of medicine and chair of the International Society Working Group for Kidney Supportive Care and Conservative Kidney Management.
“We’ve recognized for a long time that there are many patients for whom dialysis provides neither a survival advantage nor a quality of life advantage,” she told this news organization.
“These patients tend to be those who have multiple morbidities, who are more frail, and who tend to be older, and in fact, the patients can live as long, if not longer, with better symptom management and better quality of life by not being on dialysis,” she stressed.
Study details
In the study, using data from the Optum Labs Data Warehouse, patients with advanced CKD were categorized according to whether or not they received conservative management, defined as those who did not receive dialysis within 2 years of the index eGFR (first eGFR < 25 mL/min/1.73m2) versus receipt of dialysis parsed as late versus early dialysis transition (eGFR < 15 vs. ≥ 15 mL/min/1.73m2 at dialysis initiation).
Hospitalization rates were compared between those treated with conservative management, compared with late or early dialysis.
“Among 309,188 advanced CKD patients who met eligibility [criteria], 55% of patients had greater than or equal to 1 hospitalization(s) within 2 years of the index eGFR,” the authors report. The most common causes of hospitalization among all patients were congestive heart failure, respiratory symptoms, or hypertension.
In most racial groups (non-Hispanic White, non-Hispanic Black, and Hispanic patients), patients on dialysis had higher hospitalization rates than those who received conservative management, and patients who started dialysis early (transitioned to dialysis at higher levels of kidney function) demonstrated the highest rates across all age groups, compared with those who started dialysis late (transitioned to dialysis at lower levels of kidney function) or were treated with conservative management.
Among Asian patients, those on dialysis also had higher hospitalization rates than those receiving conservative management, but patients who started dialysis late had higher rates than those on early dialysis, especially in older age groups, possibly because they were sicker, Dr. Kalantar-Zadeh suggested.
Conservative care has pros and cons, but Canada has embraced it
As Dr. Kalantar-Zadeh explained, conservative management has its pros and cons, compared with dialysis. “Conservative management requires that patients work with the multidisciplinary team including nephrologists, nutritionists, and others to try to manage CKD without dialysis, so it requires patient participation.”
On the other hand, dialysis is both easier and more lucrative than conservative management, at least for nephrologists, as they are well-trained in dialysis care, and it can be systematically applied. As to which patients with CKD might be optimal candidates for conservative management, Dr. Kalantar-Zadeh agreed this requires further study.
But he acknowledged that most nephrologists are not hugely supportive of conservative management because they are less well-trained in it, and it is more time-consuming. The one promising change is a new model introduced in 2022, a value-based kidney care model, that, if implemented, will be more incentivizing for nephrologists to offer conservative care more widely.
Dr. Davison meanwhile believes the “vast majority” of nephrologists based in Canada – as she is – are “highly supportive” of CKM as an important modality.
“The challenge, however, is that many nephrologists remain unsure as to how to best deliver or optimize all aspects of CKM, whether that is symptom management, advanced care planning, or how they must manage symptoms to align with a patient’s goals,” Dr. Davison explained.
“But it’s not that they do not believe in the value of CKM.”
Indeed, in her province, Alberta, nephrologists have been offering CKM for decades, and while they are currently standardizing care to make it easier to deliver, there is no financial incentive to offer dialysis over CKM.
“We are now seeing those elements of kidney supportive care as part of core competencies to manage any person with chronic illness, including CKD,” Dr. Davison said.
“So it’s absolutely doable, and contrary to one of the myths about CKM, it is not more time-consuming than dialysis – not when you know how to do it. You are just shifting your focus,” she emphasized.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Kalantar-Zadeh has reported receiving honoraria and medical directorship fees from Fresenius and DaVita. Dr. Davison has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ORLANDO – , new research shows.
“Patients mostly start dialysis because of unpleasant symptoms that cause suffering, including high potassium levels and high levels of uremic toxins in the blood,” senior author Kamyar Kalantar-Zadeh, MD, PhD, MPH, told this news organization.
“Conservative management serves to address and manage these symptoms and levels of toxicities without dialysis, so conservative management is an alternative approach, and patients should always be given a choice between [the two],” stressed Dr. Kalantar-Zadeh, professor of medicine at the University of California, Irvine.
The results were presented during the annual meeting of the American Society of Nephrology.
“There has been growing recognition of the importance of conservative nondialytic management as an alternative patient-centered treatment strategy for advanced kidney disease. However, conservative management remains under-utilized in the United States, which may in part be due to uncertainties regarding which patients will most benefit from dialysis versus nondialytic treatment,” said first author Connie Rhee, MD, also of the University of California, Irvine.
“We hope that these findings and further research can help inform treatment options for patients, care partners, and providers in the shared decision-making process of conservative management versus dialysis,” added Dr. Rhee, in a press release from the American Society of Nephrology.
Asked for comment, Sarah Davison, MD, noted that part of the Society’s strategy is, in fact, to promote conservative kidney management (CKM) as a key component of integrated care for patients with kidney failure. Dr. Davison is professor of medicine and chair of the International Society Working Group for Kidney Supportive Care and Conservative Kidney Management.
“We’ve recognized for a long time that there are many patients for whom dialysis provides neither a survival advantage nor a quality of life advantage,” she told this news organization.
“These patients tend to be those who have multiple morbidities, who are more frail, and who tend to be older, and in fact, the patients can live as long, if not longer, with better symptom management and better quality of life by not being on dialysis,” she stressed.
Study details
In the study, using data from the Optum Labs Data Warehouse, patients with advanced CKD were categorized according to whether or not they received conservative management, defined as those who did not receive dialysis within 2 years of the index eGFR (first eGFR < 25 mL/min/1.73m2) versus receipt of dialysis parsed as late versus early dialysis transition (eGFR < 15 vs. ≥ 15 mL/min/1.73m2 at dialysis initiation).
Hospitalization rates were compared between those treated with conservative management, compared with late or early dialysis.
“Among 309,188 advanced CKD patients who met eligibility [criteria], 55% of patients had greater than or equal to 1 hospitalization(s) within 2 years of the index eGFR,” the authors report. The most common causes of hospitalization among all patients were congestive heart failure, respiratory symptoms, or hypertension.
In most racial groups (non-Hispanic White, non-Hispanic Black, and Hispanic patients), patients on dialysis had higher hospitalization rates than those who received conservative management, and patients who started dialysis early (transitioned to dialysis at higher levels of kidney function) demonstrated the highest rates across all age groups, compared with those who started dialysis late (transitioned to dialysis at lower levels of kidney function) or were treated with conservative management.
Among Asian patients, those on dialysis also had higher hospitalization rates than those receiving conservative management, but patients who started dialysis late had higher rates than those on early dialysis, especially in older age groups, possibly because they were sicker, Dr. Kalantar-Zadeh suggested.
Conservative care has pros and cons, but Canada has embraced it
As Dr. Kalantar-Zadeh explained, conservative management has its pros and cons, compared with dialysis. “Conservative management requires that patients work with the multidisciplinary team including nephrologists, nutritionists, and others to try to manage CKD without dialysis, so it requires patient participation.”
On the other hand, dialysis is both easier and more lucrative than conservative management, at least for nephrologists, as they are well-trained in dialysis care, and it can be systematically applied. As to which patients with CKD might be optimal candidates for conservative management, Dr. Kalantar-Zadeh agreed this requires further study.
But he acknowledged that most nephrologists are not hugely supportive of conservative management because they are less well-trained in it, and it is more time-consuming. The one promising change is a new model introduced in 2022, a value-based kidney care model, that, if implemented, will be more incentivizing for nephrologists to offer conservative care more widely.
Dr. Davison meanwhile believes the “vast majority” of nephrologists based in Canada – as she is – are “highly supportive” of CKM as an important modality.
“The challenge, however, is that many nephrologists remain unsure as to how to best deliver or optimize all aspects of CKM, whether that is symptom management, advanced care planning, or how they must manage symptoms to align with a patient’s goals,” Dr. Davison explained.
“But it’s not that they do not believe in the value of CKM.”
Indeed, in her province, Alberta, nephrologists have been offering CKM for decades, and while they are currently standardizing care to make it easier to deliver, there is no financial incentive to offer dialysis over CKM.
“We are now seeing those elements of kidney supportive care as part of core competencies to manage any person with chronic illness, including CKD,” Dr. Davison said.
“So it’s absolutely doable, and contrary to one of the myths about CKM, it is not more time-consuming than dialysis – not when you know how to do it. You are just shifting your focus,” she emphasized.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Kalantar-Zadeh has reported receiving honoraria and medical directorship fees from Fresenius and DaVita. Dr. Davison has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT KIDNEY WEEK 2022
Study sheds new light on RAS inhibitors’ role for advanced CKD
ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m2.
Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, , for 3 years.
People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.
“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.
The results were simultaneously published in the New England Journal of Medicine.
Similar eGFR levels after 3 years
While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.
Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.
“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.
And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.
Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m2 in the discontinuation group and 13.3 mL/min per 1.73 m2 in the 205 patients in the continuation group, a difference that was not significant.
In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).
The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
Participants had an eGFR less than 30 mL/min per 1.73 m2
The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m2 who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m2 during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.
The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.
Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.
People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.
The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m2, and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m2. Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.
Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
Continue RAS inhibitors in advanced CKD for best outcomes
Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.
But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”
“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”
“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.
STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m2.
Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, , for 3 years.
People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.
“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.
The results were simultaneously published in the New England Journal of Medicine.
Similar eGFR levels after 3 years
While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.
Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.
“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.
And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.
Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m2 in the discontinuation group and 13.3 mL/min per 1.73 m2 in the 205 patients in the continuation group, a difference that was not significant.
In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).
The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
Participants had an eGFR less than 30 mL/min per 1.73 m2
The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m2 who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m2 during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.
The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.
Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.
People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.
The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m2, and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m2. Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.
Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
Continue RAS inhibitors in advanced CKD for best outcomes
Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.
But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”
“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”
“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.
STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m2.
Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, , for 3 years.
People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.
“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.
The results were simultaneously published in the New England Journal of Medicine.
Similar eGFR levels after 3 years
While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.
Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.
“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.
And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.
Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m2 in the discontinuation group and 13.3 mL/min per 1.73 m2 in the 205 patients in the continuation group, a difference that was not significant.
In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).
The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
Participants had an eGFR less than 30 mL/min per 1.73 m2
The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m2 who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m2 during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.
The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.
Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.
People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.
The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m2, and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m2. Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.
Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
Continue RAS inhibitors in advanced CKD for best outcomes
Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.
But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”
“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”
“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.
STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT KIDNEY WEEK 2022
Moving the needle: SGLT2 inhibitor role for isolated kidney disease
ORLANDO – in a pivotal trial with more than 6,600 patients.
This confirms the efficacy for this population that was previously seen with dapagliflozin, another agent from the same class, in the DAPA-CKD trial.
In the new trial, EMPA-Kidney, treatment with empagliflozin 10 mg daily for a median of 2.0 years led to a significant 28% relative risk reduction in the primary combined endpoint in comparison with placebo, William G. Herrington, MD, reported at the annual meeting of the American Society of Nephrology.
The results were simultaneously published in the New England Journal of Medicine.
In 2020, a different team of researchers running DAPA-CKD reported that during a median of 2.4 years, treatment of 4,304 patients with dapagliflozin 10 mg daily resulted in a significant 39% relative risk reduction, compared with placebo for an identical combined primary endpoint. Enrollment criteria for the DAPA-CKD trial were mostly similar to that of the current trial.
‘Remarkably similar’ findings
Results from EMPA-Kidney and DAPA-CKD are “remarkably similar,” said Dr. Herrington during a press briefing at the meeting.
He also noted that when the EMPA-Kidney study began – before results from DAPA-CKD were known – “we never imagined such a large effect” on important endpoints in people with CKD.
In addition to cardiovascular death, the combined primary endpoint included the incidence of renal death, incident end-stage kidney disease, a sustained decrease in estimated glomerular filtration rate to less than 10 mL/min per 1.73m2, or a sustained decrease in eGFR of at least 40% from baseline.
Having similar evidence from both trials “will hopefully provide people with the confidence to start to use SGLT2 inhibitors as standard care in people with CKD” who match enrollment criteria of the two trials, added Dr. Herrington, a nephrologist at the University of Oxford (England).
The analyses he reported also showed that empagliflozin had similar efficacy for the primary endpoint regardless of whether patients had type 2 diabetes at the time of enrollment and regardless of their eGFR at entry.
To enter EMPA-Kidney, people needed to have either an eGFR of 20-44 mL/min per 1.73m2 with no minimum level of albuminuria or an eGFR of 45-89 mL/min per 1.73m2 with a urine albumin-to-creatinine ratio (UACR) of at least 200 mg/g.
In contrast, to enroll in DAPA-CKD, patients had to have a UACR of at least 200 mg/g. This means that for the first time, EMPA-Kidney produced data on the relationship between albuminuria severity and the impact of treatment with an SGLT2 inhibitor in the enrolled population.
A signal of greater efficacy with higher UACR
A total of 6,609 patients underwent randomization in EMPA-Kidney. During a median of 2.0 years of follow-up, the primary endpoint – progression of kidney disease or death from cardiovascular causes – occurred in 432 of 3,304 patients (13.1%) in the empagliflozin group and in 558 of 3,305 patients (16.9%) in the placebo group (hazard ratio, 0.72; P < .001).
The results “suggested that the effects [of empagliflozin] are greater in patients with higher levels of albuminuria, with statistically significant heterogeneity between this subgroup and those with a UACR of less than 200 mg/g (P = .02),” Dr. Herrington said.
Of the study population, 54% had no evidence of diabetes at enrollment.
Having data from a second large trial of an SGLT2 inhibitor that included people with isolated CKD who did not have diabetes or heart failure “will start to move the needle” on using this class of drugs in these types of patients, commented F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn.
On the basis of the DAPA-CKD results, in April 2021 the Food and Drug Administration expanded dapagliflozin’s indications to include CKD, yet, “a lot of nephrologists consider SGLT2 inhibitors to be agents for people with diabetes or heart failure, and they defer prescribing them to endocrinologists and cardiologists,” Dr. Wilson said in an interview.
‘Flozinators’ rising
But Pascale H. Lane, MD, a pediatric nephrologist at the University of Oklahoma Health Sciences Center, Oklahoma City, commented that many nephrologists she knows have been prescribing dapagliflozin “widely” to their patients with CKD.
“I know many adult nephrologists who use it almost universally now,” Dr. Lane said. “They call themselves ‘flozinators.’ ”
EMPA-Kidney was sponsored by Boehringer Ingelheim, the company that along with Lilly markets empagliflozin (Jardiance). Dr. Herrington, Dr. Wilson, and Dr. Lane disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ORLANDO – in a pivotal trial with more than 6,600 patients.
This confirms the efficacy for this population that was previously seen with dapagliflozin, another agent from the same class, in the DAPA-CKD trial.
In the new trial, EMPA-Kidney, treatment with empagliflozin 10 mg daily for a median of 2.0 years led to a significant 28% relative risk reduction in the primary combined endpoint in comparison with placebo, William G. Herrington, MD, reported at the annual meeting of the American Society of Nephrology.
The results were simultaneously published in the New England Journal of Medicine.
In 2020, a different team of researchers running DAPA-CKD reported that during a median of 2.4 years, treatment of 4,304 patients with dapagliflozin 10 mg daily resulted in a significant 39% relative risk reduction, compared with placebo for an identical combined primary endpoint. Enrollment criteria for the DAPA-CKD trial were mostly similar to that of the current trial.
‘Remarkably similar’ findings
Results from EMPA-Kidney and DAPA-CKD are “remarkably similar,” said Dr. Herrington during a press briefing at the meeting.
He also noted that when the EMPA-Kidney study began – before results from DAPA-CKD were known – “we never imagined such a large effect” on important endpoints in people with CKD.
In addition to cardiovascular death, the combined primary endpoint included the incidence of renal death, incident end-stage kidney disease, a sustained decrease in estimated glomerular filtration rate to less than 10 mL/min per 1.73m2, or a sustained decrease in eGFR of at least 40% from baseline.
Having similar evidence from both trials “will hopefully provide people with the confidence to start to use SGLT2 inhibitors as standard care in people with CKD” who match enrollment criteria of the two trials, added Dr. Herrington, a nephrologist at the University of Oxford (England).
The analyses he reported also showed that empagliflozin had similar efficacy for the primary endpoint regardless of whether patients had type 2 diabetes at the time of enrollment and regardless of their eGFR at entry.
To enter EMPA-Kidney, people needed to have either an eGFR of 20-44 mL/min per 1.73m2 with no minimum level of albuminuria or an eGFR of 45-89 mL/min per 1.73m2 with a urine albumin-to-creatinine ratio (UACR) of at least 200 mg/g.
In contrast, to enroll in DAPA-CKD, patients had to have a UACR of at least 200 mg/g. This means that for the first time, EMPA-Kidney produced data on the relationship between albuminuria severity and the impact of treatment with an SGLT2 inhibitor in the enrolled population.
A signal of greater efficacy with higher UACR
A total of 6,609 patients underwent randomization in EMPA-Kidney. During a median of 2.0 years of follow-up, the primary endpoint – progression of kidney disease or death from cardiovascular causes – occurred in 432 of 3,304 patients (13.1%) in the empagliflozin group and in 558 of 3,305 patients (16.9%) in the placebo group (hazard ratio, 0.72; P < .001).
The results “suggested that the effects [of empagliflozin] are greater in patients with higher levels of albuminuria, with statistically significant heterogeneity between this subgroup and those with a UACR of less than 200 mg/g (P = .02),” Dr. Herrington said.
Of the study population, 54% had no evidence of diabetes at enrollment.
Having data from a second large trial of an SGLT2 inhibitor that included people with isolated CKD who did not have diabetes or heart failure “will start to move the needle” on using this class of drugs in these types of patients, commented F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn.
On the basis of the DAPA-CKD results, in April 2021 the Food and Drug Administration expanded dapagliflozin’s indications to include CKD, yet, “a lot of nephrologists consider SGLT2 inhibitors to be agents for people with diabetes or heart failure, and they defer prescribing them to endocrinologists and cardiologists,” Dr. Wilson said in an interview.
‘Flozinators’ rising
But Pascale H. Lane, MD, a pediatric nephrologist at the University of Oklahoma Health Sciences Center, Oklahoma City, commented that many nephrologists she knows have been prescribing dapagliflozin “widely” to their patients with CKD.
“I know many adult nephrologists who use it almost universally now,” Dr. Lane said. “They call themselves ‘flozinators.’ ”
EMPA-Kidney was sponsored by Boehringer Ingelheim, the company that along with Lilly markets empagliflozin (Jardiance). Dr. Herrington, Dr. Wilson, and Dr. Lane disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ORLANDO – in a pivotal trial with more than 6,600 patients.
This confirms the efficacy for this population that was previously seen with dapagliflozin, another agent from the same class, in the DAPA-CKD trial.
In the new trial, EMPA-Kidney, treatment with empagliflozin 10 mg daily for a median of 2.0 years led to a significant 28% relative risk reduction in the primary combined endpoint in comparison with placebo, William G. Herrington, MD, reported at the annual meeting of the American Society of Nephrology.
The results were simultaneously published in the New England Journal of Medicine.
In 2020, a different team of researchers running DAPA-CKD reported that during a median of 2.4 years, treatment of 4,304 patients with dapagliflozin 10 mg daily resulted in a significant 39% relative risk reduction, compared with placebo for an identical combined primary endpoint. Enrollment criteria for the DAPA-CKD trial were mostly similar to that of the current trial.
‘Remarkably similar’ findings
Results from EMPA-Kidney and DAPA-CKD are “remarkably similar,” said Dr. Herrington during a press briefing at the meeting.
He also noted that when the EMPA-Kidney study began – before results from DAPA-CKD were known – “we never imagined such a large effect” on important endpoints in people with CKD.
In addition to cardiovascular death, the combined primary endpoint included the incidence of renal death, incident end-stage kidney disease, a sustained decrease in estimated glomerular filtration rate to less than 10 mL/min per 1.73m2, or a sustained decrease in eGFR of at least 40% from baseline.
Having similar evidence from both trials “will hopefully provide people with the confidence to start to use SGLT2 inhibitors as standard care in people with CKD” who match enrollment criteria of the two trials, added Dr. Herrington, a nephrologist at the University of Oxford (England).
The analyses he reported also showed that empagliflozin had similar efficacy for the primary endpoint regardless of whether patients had type 2 diabetes at the time of enrollment and regardless of their eGFR at entry.
To enter EMPA-Kidney, people needed to have either an eGFR of 20-44 mL/min per 1.73m2 with no minimum level of albuminuria or an eGFR of 45-89 mL/min per 1.73m2 with a urine albumin-to-creatinine ratio (UACR) of at least 200 mg/g.
In contrast, to enroll in DAPA-CKD, patients had to have a UACR of at least 200 mg/g. This means that for the first time, EMPA-Kidney produced data on the relationship between albuminuria severity and the impact of treatment with an SGLT2 inhibitor in the enrolled population.
A signal of greater efficacy with higher UACR
A total of 6,609 patients underwent randomization in EMPA-Kidney. During a median of 2.0 years of follow-up, the primary endpoint – progression of kidney disease or death from cardiovascular causes – occurred in 432 of 3,304 patients (13.1%) in the empagliflozin group and in 558 of 3,305 patients (16.9%) in the placebo group (hazard ratio, 0.72; P < .001).
The results “suggested that the effects [of empagliflozin] are greater in patients with higher levels of albuminuria, with statistically significant heterogeneity between this subgroup and those with a UACR of less than 200 mg/g (P = .02),” Dr. Herrington said.
Of the study population, 54% had no evidence of diabetes at enrollment.
Having data from a second large trial of an SGLT2 inhibitor that included people with isolated CKD who did not have diabetes or heart failure “will start to move the needle” on using this class of drugs in these types of patients, commented F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn.
On the basis of the DAPA-CKD results, in April 2021 the Food and Drug Administration expanded dapagliflozin’s indications to include CKD, yet, “a lot of nephrologists consider SGLT2 inhibitors to be agents for people with diabetes or heart failure, and they defer prescribing them to endocrinologists and cardiologists,” Dr. Wilson said in an interview.
‘Flozinators’ rising
But Pascale H. Lane, MD, a pediatric nephrologist at the University of Oklahoma Health Sciences Center, Oklahoma City, commented that many nephrologists she knows have been prescribing dapagliflozin “widely” to their patients with CKD.
“I know many adult nephrologists who use it almost universally now,” Dr. Lane said. “They call themselves ‘flozinators.’ ”
EMPA-Kidney was sponsored by Boehringer Ingelheim, the company that along with Lilly markets empagliflozin (Jardiance). Dr. Herrington, Dr. Wilson, and Dr. Lane disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT KIDNEY WEEK 2022