Patient-Care Innovations, ICU Alerts Show Promise in Trials

Kidney health inequities

Many Black Americans may face substantial barriers to heart- and kidney-healthy diets owing to socioeconomic constraints, a void in nutrition information, or living in food deserts. However, a study presented by Deidra Crews, MD, ScM, professor and deputy director of the Johns Hopkins Center for Health Equity in Baltimore, MD, showed that coaching paired with subsidies for healthy food might help Black individuals with kidney diseases overcome these barriers. Crews presented the study results during the High-Impact Clinical Trials session at Kidney Week 2022.

Crews and her colleagues randomly assigned 142 Black adults with hypertension and chronic kidney disease (CKD) to receive a $30 grocery gift card weekly for 4 months, with or without coaching about high-potassium foods and how to follow the Dietary Approaches to Stop Hypertension (DASH) diet. The group without coaching received a brief overview of DASH and a brochure at the start of the study. A dietician coached the other group about using their gift card to purchase high-potassium foods online for home delivery.

Crews and the 5PLUS Nuts + Beans for Kidneys investigators (1) followed the participants for 8 months after the gift cards stopped being provided, and participants in the coaching group continued to receive telephone-based coaching during that period. The coached participants increased dietary potassium intake and fruit and vegetable consumption. Individuals with a very high urine albumin-to-creatinine ratio (UACR) at baseline had a 73% decrease with coaching compared with a 21% increase among those without coaching. Patients with diabetes also saw greater benefits from coaching.

“Future dietary interventions that incorporate coaching or health education along with healthy food provision may better address kidney health inequities,” Crews said.

Asked by attendee Don Wesson, MD, MBA, professor of medicine at Texas A&M College of Medicine in Dallas, how sustainable the intervention was, Crews responded that health systems or the supplemental food assistance program might implement the approach to help patients with hypertension and CKD who are food insecure.

Kidney-safe care

Results from the Better Evidence for Selecting Transplant Fluids (BEST-Fluids) trial (2) suggest that a balanced low-chloride crystalloid solution, called Plasma-Lyte 148, may be a better alternative to saline during a kidney transplant.

The trial randomized approximately 800 patients undergoing transplant to either saline or Plasma-Lyte 148 intravenous (IV) fluids during and after transplant surgery. Approximately 39% of patients in the saline group needed dialysis after surgery compared with only 30% in the Plasma-Lyte 148 group. The trial’s co-principal investigator Michael Collins, MBChB, PhD, a senior consultant nephrologist at the Royal Adelaide Hospital, Australia, presented the results and said the number needed to treat with Plasma-Lyte 148 to prevent one case of delayed graft function was 10. There were similar rates of hyperkalemia in the two groups and no significant differences in rejection, graft failure, or death for up to 52 weeks post-surgery.

“These findings suggest that balanced crystalloids should be the standard IV fluid in deceased donor transplantation,” Collins said. “This simple change in kidney transplant practice can be easily implemented globally, now.”

During the question-and-answer session following the presentation, attendee Richard Lafayette, MD, professor in the Division of Nephrology at Stanford University, CA, agreed that this would be an easy switch. However, he raised concerns about why the study saw an immediate benefit in the Plasma-Lyte 148 group and why studies using balanced IV solutions have not shown a similar benefit in patients with acute kidney injury (AKI) in the ICU. Collins responded that his study’s results are consistent with the SALT-ED (3) and SMART (4) studies and that patients in many trials in the ICU may have received saline before being randomized to an alternate IV fluid.

Nephrotoxic drug alerts

In other work (5) presented during the High-Impact Clinical Trials session, investigators found that automatic alerts to discontinue some nephrotoxic drugs given to patients in the ICU may improve patient outcomes.

F. Perry Wilson, MD, MSCE, and colleagues conducted an open-label, parallel-group trial to test the alerts at four US hospitals between August 2020 and November 2021. Wilson is associate professor and director of the Clinical and Translational Research Accelerator at Yale School of Medicine, New Haven, CT.

Approximately 5000 patients in the ICU with clinical signs of AKI, whose physicians were ordering non-steroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system inhibitors, and proton pump inhibitors (PPIs), participated in the trial. Clinicians discontinued potentially nephrotoxic medications in 61.1% of patients after receiving an electronic pop-up at order entry alerting them to the patient’s AKI. Clinicians who did not receive the pop-up discontinued potentially nephrotoxic medications for 55.9% of the patients in the control group. The difference between the groups was not statistically significant overall. However, there was a statistically significant increase in PPI discontinuation. The researchers did not see any safety signals associated with the alerts.

“Automated alerts for AKI can increase the rate of cessation of potentially nephrotoxic medications without endangering patients,” Wilson said.

“That was a very nice study showing how we can leverage the power of the electronic medical record,” said panel moderator Karen Griffin, MD, professor of medicine at Loyola University Medical Center in Chicago, IL, and Renal Section chief at the Edward Hines Jr. Veterans Affairs Hospital in Maywood, IL. “But as a practicing physician, I fear the potential of more alerts because of alert fatigue.”

Griffin questioned whether targeted clinician education about the kidney risks of PPIs would be better. Wilson said that trials could help reduce the number of alerts by weeding out ineffective warnings. He and his team are currently testing whether sending the alerts to a dedicated team of clinicians who could provide more nuanced recommendations to the ordering clinician would be beneficial.

Cold dialysate debate

Cold dialysate did not reduce cardiovascular deaths or hospital admission compared with standard temperature dialysate, according to results of a massive dialysis center-based randomized trial (6) in Ontario, Canada. It also made patients uncomfortably cold.

The open-label MyTEMP trial randomized 84 Ontario hemodialysis centers to use dialysate cooled to 0.5°C below the patient’s body temperature or standard temperature dialysate at 36.5°C. Over 4 years, more than 15,000 patients received hemodialysis at the participating centers. The cardiovascular-related deaths or hospitalizations for myocardial infarction, ischemic stroke, or congestive heart failure occurred in 21.4% of the 8000 patients who received cold dialysate and 22.4% of the 7413 patients in the standard temperature dialysate group, a statistically insignificant difference. More patients in the cold dialysate group reported feeling uncomfortably cold, with approximately one-quarter rating it as the worst possible feeling.

“A lack of cardiovascular benefit compounded by the likelihood of patient discomfort provides no justification to adopt cooler dialysate as a center-wide policy,” said Amit Garg, MD, PhD, professor in the Division of Nephrology at Western University and scientist at the Lawson Health Research Institute, both in Ontario, during his presentation. “If I do prescribe cooler dialysate for certain patients, such as those with refractory interdialytic hypotension, I plan to do so more carefully and monitor how well it’s tolerated.”

During the question-and-answer session, Maarten Taal, MBChB, MMed, MD, professor of medicine at the University of Nottingham in the United Kingdom, noted the study might be the largest to date in patients undergoing dialysis. However, Taal questioned why the team chose 36.5°C when many dialysis units and most previous clinical trials of cold dialysate used 37°C as the standard temperature. Garg said that 36.5°C is standard in Ontario.

“The separation between our two groups is perhaps smaller than other trials,” Garg said, and although he did not refute the results of previous trials that suggested a benefit of cold dialysate, he cautioned that 26 previous trials included 460 patients.

“We have to be quite cautious about our confidence in the previous results,” Garg added.

Targeting IgA nephropathy

There is a desperate need for new therapies to reduce glomerular inflammation and kidney fibrosis in patients with IgA nephropathy, said Jonathan Barratt, PhD, the Mayer Professor of Renal Medicine at the University of Leicester in the United Kingdom. Currently, the standard of care is goal-directed, supportive therapy, but he said that many patients still experience glomerular inflammation and progressive kidney function decline.

Barratt presented the results of a phase 2 study (7) of an investigational therapy called cemdisiran. The drug is an RNA interference therapy that suppresses the production of complement component 5 in the liver. Barratt explained that complement activation is linked with glomerular inflammation and loss of kidney function.

He and colleagues randomized 31 patients with IgA nephropathy at high risk of kidney disease progression despite supportive care in a 2:1 ratio to receive 600 mg of cemdisiran subcutaneously or a placebo once every 4 weeks in addition to standard care. Patients in the cemdisiran group had a 37.4% adjusted geometric mean reduction in a 24-hour urine protein-to-creatinine ratio compared with the placebo group, suggesting reduced kidney damage. The cemdisiran group also had an average reduction of 98.7% in serum levels of complement component 5 between the start of the trial and week 32. The researchers will continue to follow the patients for a 156-week open-label extension.

“This novel RNA interfering therapy cemdisiran is capable of reducing the production of C5 in the liver,” Barratt said. So far, he noted, that is translating into reductions of hematuria and proteinuria, but he cautioned that larger and longer studies are necessary.

Additional trials

Other high-impact trials presented at Kidney Week 2022 found the following:

• The hydrochloric acid binder veverimer did not slow CKD progression or improve physical function in patients with metabolic acidosis in the phase 3 VALOR-CKD trial (8), which enrolled 1480 patients at 191 sites in 34 countries (abstract FR-OR65, 2022).

• In the 6609-patient EMPA-KIDNEY trial, 10 mg of the sodium glucose co-transporter 2 (SGLT2) inhibitor empagliflozin daily reduced kidney disease progression or cardiovascular death in patients with kidney diseases, with or without diabetes, by 28% compared with placebo (abstract FR-OR68, 2022) (9).

• A meta-analysis of data from 13 SGLT2 inhibitor clinical trials found a 40% reduction in kidney disease progression and approximately one-quarter reduction in AKI with similar benefits for patients with CKD, with and without diabetes. Patients with diabetes did have approximately one event of ketoacidosis or lower-limb amputation per 1000 patient-years compared with none in the non-diabetic group, but presenter Natalie Staplin, associate professor and senior statistician in the Renal Studies Group at the University of Oxford, United Kingdom, concluded that the absolute benefits outweighed the risks (abstract FR-OR69, 2022) (10).

• A phase 2 study that randomized 140 patients with type 2 diabetes and CKD to isuzinaxib or placebo for 12 weeks found an average 21% reduction in the UACR in the intervention group versus a 2.5% UACR reduction in the placebo group. A larger benefit was seen in patients with very low kidney function (abstract FR-OR62, 2022) (11).