PHILADELPHIA — Some of the latest research in the field of nephrology presented at the American Society of Nephrology’s Kidney Week included sparsentan in focal segmental glomerulosclerosis, combination treatment with an SGLT2 inhibitor and an endothelin A receptor antagonist, and a novel aldosterone synthase inhibitor in chronic kidney disease. Below are a few more highlights.
Cell Therapy Eases Need for Immunosuppressive Drugs After Transplant
In updated results to a phase III trial, the investigational cellular product MDR-101 helped eliminate the need for immunosuppressive drugs in HLA-matched living donor kidney transplants.
All 19 patients who received the MDR-101 infusion were able to successfully discontinue immunosuppressive drugs within the year after treatment. Two years after treatment, 17 of 19 remained off immunosuppressive drugs for an entire year.
Treatment success — at least 2 years without immunosuppressive drugs — was achieved by 12 of the 19 patients (63%). “The goal was 48%,” said Daniel Brennan, MD, of Medeor Therapeutics in San Francisco.
However, some patients who had to resume treatment experienced acute rejection.
A total of 10% (n=2) of infusion recipients experienced recurrence of baseline disease, both of which were IgA nephropathy.
MDR-101 is an allogeneic cellular product intended to induce mixed chimerism and immune tolerance to allow for elimination of all immunosuppressant drugs, while preserving transplant kidney function and averting transplant kidney rejection, Brennan explained.
“This innovative trial provides direction toward reducing the need for life-long anti-rejection medications in transplant recipients,” added co-investigator Dixon Kaufman, MD, PhD, of the UW Health Transplant Center at the University of Wisconsin-Madison, in a statement. “With the achievement of mixed chimerism in this trial, we are on course to provide a safer and more effective treatment approach for many patients in need of a kidney transplant.”
Bardoxolone Methyl for Diabetic Kidney Disease
Bardoxolone methyl — an investigative activator of the KEAP1-NRF2 pathway — helped to significantly slow kidney decline in people with diabetic kidney disease, the phase III AYAME study showed.
Patients on this treatment had a 44% reduced risk for the composite primary outcome of a 30% or greater decrease in eGFR or progression to end-stage kidney disease (ESKD) compared with placebo (HR 0.56, 95% CI 0.45-0.69, P<0.001). Over the course of the 3-year trial, 45.3% of placebo patients progressed to this endpoint whereas only 30.2% of bardoxolone methyl-treated patients did.
Also achieving the trial’s key secondary endpoint, bardoxolone methyl patients had a 31% lower risk for experiencing a 40% or more drop in eGFR or progression to ESKD. But two other secondary endpoints missed significance: The progression to ESKD isolated out, and progression to a 53% or more eGFR decline combined with ESKD. ESKD was defined as the need for dialysis, an eGFR of 6 mL/min/1.73 m2 or less for more than 4 weeks, or kidney transplant.
“It may be possible that [bardoxolone methyl] doesn’t show improvement in eGFR in some populations with a rapid decline in kidney function like those who reached ESKD in this study. However, we have no supplementary data on this hypothesis,” said Tadao Akizawa, MD, of Showa University School of Medicine in Tokyo, during a presentation of the findings.
The treatment was generally well-tolerated with a similar array of events occurring in both groups. There were five deaths in the placebo group and seven in the bardoxolone methyl group.
The 1,013-participant trial recruited patients with an eGFR of 15 ml/min/1.73 m2 to below 60 ml/min/1.73 m2, and urinary albumin creatinine ratio of 3,500 mg/g or less without the risk factors of heart failure (HF). The earlier phase III BEACON trial for this drug was terminated early due to an imbalance of early-onset HF between the two groups. This didn’t occur in the current trial (24 vs 26 cardiac events with placebo).
Spironolactone in High-Risk Hemodialysis Patients
Daily treatment with spironolactone failed to lower the risk of major adverse cardiovascular events (MACE) in high-risk hemodialysis patients, primary results of the international randomized ALCHEMIST trial showed.
During the year-long trial, MACE incidence was no different between patients assigned up to a 25-mg daily dose of the aldosterone antagonist or placebo, at 78 versus 79 events (HR 0.996, 95% CI 0.729-1.362), Patrick Rossignol, MD, PhD, of Université Lorraine in France, reported here.
The composite primary outcome of MACE included first-time events of non-fatal myocardial infarction, acute coronary syndrome, or stroke; hospitalization for HF; or cardiovascular death.
When separated out individually, spironolactone only was able to significantly reduce the risk of hospitalization for HF by 59%.
“Secondary analyses will help us understand this finding,” said Rossignol, noting that no prespecified subgroups appeared to benefit from the daily treatment.
All of the 644 randomized chronic hemodialysis patients included in the trial had at least one cardiovascular comorbidity, abnormality, or risk factor. Around 90% had hypertension, 69% had dyslipidemia, 69% had diabetes, about three-fourths had a history of cardiovascular disease, and 12% had a history of HF hospitalization.
Overall, spironolactone was well tolerated. A few more patients on spironolactone experienced hyperkalemia and gynecomastia.
AYAME was funded by Kyowa Kirin.
The MDR-101 study was funded by the California Institute of Regenerative Medicine.
ALCHEMIST was funded by the French Ministry of Health.
Akizawa, Brennan, and Rossignol disclosed multiple relationships with industry.
Kidney Week 2023
Source Reference: Kaufman D, et al “MDR-101-MLK update: operational immune tolerance achieved in living related HLA-matched kidney transplant recipient” Kidney Week 2023; FR-OR115.
Kidney Week 2023
Source Reference: Akizawa T, et al “AYAME study: randomized, double-blind, placebo-controlled phase 3 study of bardoxolone methyl in diabetic kidney disease (DKD) patients” Kidney Week 2023; FR-OR110.
Kidney Week 2023
Source Reference: Rossignol P, et al “Aldosterone Antagonist Chronic Hemodialysis Interventional Survival Trial (ALCHEMIST): primary results” Kidney Week 2023; FR-OR113.