High-Impact Trials Offer Potential Solutions to Clinical Conundrums

Steroid balancing act

IgA nephropathy is a common cause of kidney disease in younger adults and is a consequence of autoimmune attacks on the kidneys (1). Most studies’ use of corticosteroids in these patients have not been adequately powered to assess kidney outcomes, said Vlado Perkovic, MBB, PhD, the TESTING trial's co-senior author and dean of medicine, University of New South Wales in Australia. To help fill this gap, the trial initially planned to randomize 503 patients with IgA to a full dose of methylprednisolone starting at 0.6−0.8 mg/kg/day to a maximum dose of 48 mg/day for 2 months, followed by gradual weaning from the drug over 4 to 7 months or placebo.

However, the identification (2) of an increased incidence of serious infections, including four that were fatal, in patients taking methylprednisolone led to the change in the trial protocol in which 241 patients were randomized to a reduced dose of methylprednisolone of 0.4 mg/kg/day to a maximum of 32 mg/day, followed by weaning. When the results from both steroid groups were analyzed after an average of 4 years of follow-up, there was a 47% reduction in a composite endpoint of 40% decline in estimated glomerular filtration rate (eGFR) or kidney failure compared with the placebo group and a 41% reduction in kidney failure, according to the data presented by Perkovic. A subgroup analysis of the lower dose group compared with placebo found a 73% reduction in the composite endpoint over an average of 2.5 years’ follow-up. Perkovic noted that one patient in the lower dose group also died of a serious infection.

In the full dose group, for every 100 patients treated, methylprednisolone would precipitate about 12 fewer primary outcome kidney events but about 12 serious adverse events, Perkovic said. In the reduced dose group, for every 100 treated, there would be almost 17 fewer primary outcome kidney events with 2.4 serious events, he said. Perkovic said the results support existing guidelines that recommend nephrologists discuss the benefits and risks of corticosteroids with patients with IgA nephropathy who are at a high risk of kidney events.

“We provide additional data that will help inform those conversations by providing more precision about the risks and benefits of different approaches,” Perkovic said. “[The results] suggest this should be offered to high-risk people.”

The evidence shows that a lower dose of methylprednisolone is effective at reducing kidney-related events and resulted in fewer serious adverse events than higher doses, St. Peter said. “This is good news for patients with IgA nephropathy and their nephrologists who want them to get the benefits from an effective treatment but with less risk of a severe infection or other serious side effects that are common with higher steroid doses,” she added.

New options for old challenges

Other high-impact studies presented during the session offered promising new options to solve longstanding challenges in nephrology, including a treatment for RNA inhibitor-reduced oxalate levels in patients with primary hyperoxaluria type 1 (PH1); a potential oral alternative to injectable therapies for anemia in patients with chronic kidney disease (CKD); and an inexpensive, older drug that may help control hypertension in patients with stage 4 CKD.

An injectable RNA inhibitor called lumasiran reduced urinary oxalate levels by one-third in patients with PH1 who were not on dialysis and by 42% among those on dialysis, according to results from the Evaluate Lumasiran in Patients with Advanced Primary Hyperoxaluria Type 1 (ILLUMINATE-C) study presented at Kidney Week by its lead author Mini Michael, MD, MMed, associate professor at Baylor College of Medicine in Houston, TX. PH1 is a rare condition associated with oxalate overproduction, kidney disease, and multi-organ damage. The trial enrolled 21 patients and followed them for 6 months.

“[Oxalate] changes of this magnitude may change long-term patient outcomes,” Michael said. She and her colleagues are continuing to follow patients to assess longer term outcomes.

“It is exciting to see a new therapy which has the potential to change the dynamic of a rare and serious disease [like PH1] that mainly affects the kidneys but can result in multi-organ damage,” St. Peter said. She noted the condition often results in the need for dialysis, kidney transplant, or liver and kidney transplant. She said one remaining question is whether lumasiran will reduce kidney disease progression, the need for dialysis, or the need for kidney and liver transplantation.

Oral daprodustat may be an alternative to injectable erythropoiesis-stimulating agents (ESAs) for treating anemia in patients with CKD, according to a presentation by Ajay Singh, MBBS, MBA, a nephrologist at Brigham and Women's Hospital and Harvard University in Boston, MA. The results of the Anemia Studies in Chronic Kidney Disease: Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor Daprodustat (ASCEND) trials in patients on dialysis (3) and not on dialysis (4) were published in The New England Journal of Medicine simultaneously. The trials enrolled 6800 patients and showed that daprodustat was non-inferior to ESAs for treating anemia patients with CKD who were receiving dialysis and those who did not require dialysis. It was also non-inferior to ESAs when the researchers looked at major adverse cardiovascular adverse events.

In a press briefing about the results, Singh noted that many patients currently don't have access to ESA treatment. Additionally, patients may be more likely to comply with and tolerate an oral medication, he said.

“The nephrology community has been hoping that the new hypoxia-inducible factor prolyl hydroxylase inhibitor would represent a new era in the treatment of anemia in CKD, with better efficacy and/or safety than ESAs,” St. Peter said. “It's a little disappointing that daprodustat was only shown to be non-inferior and not superior in efficacy or safety endpoints as ESAs. Regardless, it would be nice to have an oral option for anemia management, particularly in non-dialysis-dependent patients with CKD.”

The Chlorthalidone in Chronic Kidney Disease (CLICK) study (5) randomized 160 patients with stage 4 CKD and hypertension to chlorthalidone or placebo and found the low-cost medication reduced systolic blood pressure by 11 mm Hg within 4 weeks, according to a presentation by Rajiv Agarwal, MD, of the Indiana University School of Medicine in Indianapolis. It also lowered albuminuria by one-half over 12 weeks.

“The results of the CLICK study dispelled the myth that thiazide diuretics are not effective for blood pressure management when eGFR is less than 30 mL/min/1.73 m²,” St. Peter said. “This study sets the stage for chlorthalidone to become a main component of blood pressure management in patients with stage 4 CKD.”

St. Peter cautioned, however, that clinicians need to do more frequent monitoring in patients already receiving a loop diuretic because the combination increased the risk of hypokalemia and increased serum creatinine due to a combination diuretic effect.

Other studies presented during the High-Impact Clinical Trials session included the following:

• The EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction) trial, presented by Faiez Zannad, showed that empagliflozin reduced cardiovascular death and heart failure hospitalization and slowed kidney decline in patients with heart failure with preserved ejection fraction with and without CKD (6).

• The ADVOCATE (A Phase 3 Clinical Trial of CCX168 [Avacopan] in Patients with ANCA [Anti-Neutrophil Cytoplasmic Autoantibody]-Associated Vasculitis) trial showed that patients with ANCA-associated vasculitis taking avacopan had better recovery of kidney function than patients taking prednisone, as explained by David Jayne (7). The US Food and Drug Administration approved use of avacopan for ANCA-associated vasculitis (8).

• Five-year follow-up results from the Ellipsys Vascular Access System pivotal trial of an ultrasound-guided, percutaneous outpatient technique for creating an arteriovenous fistula show that patients’ use of the fistula remained above 90% at 5 years, and only one-half to one-quarter of patients needed a second procedure, said Jeffrey Hull, MD, director of the Richmond Vascular Center in Virginia, during a press briefing about the results.

• Another study presented by Aditi Sinha, MD, MBBS, PhD, professor of pediatrics at the All India Institute of Medical Sciences in New Delhi, showed no benefit to extending prednisone treatment for longer than 12 weeks for very young children with nephrotic syndrome. The open-label, multi-center study that randomized 172 children younger than 4 years with nephrotic syndrome to 12 or 24 weeks of prednisone found the proportions of patients who achieved sustained remission, relapse rates, or time-to-first relapse were not significantly different between the groups. Adverse effects were similar in the two groups, she said.