The results of several high-impact clinical trials with the potential to impact kidney-related medical care in the future were presented at this year’s American Society of Nephrology (ASN) Kidney Week (2–7 November 2021, virtual). Highlights from this session included promising five-year data from the Ellipsys pivotal trial, and fresh evidence on the treatment of IgA nephropathy, anaemia and several other conditions commonly affecting kidney disease patients.
As outlined by an ASN press release, the Ellipsys pivotal trial demonstrated the early safety and efficacy of a minimally invasive procedure to create an arteriovenous fistula (AVF) in the arms of patients requiring haemodialysis. In a recent analysis of long-term data, investigators found that this procedure provided durable access for haemodialysis through five years—with a high rate of fistula use, and low rates of secondary procedures and complications.
“The data demonstrate safety, effectiveness, and durability of the Ellipsys fistula as an alternative to surgery for patients needing dialysis,” said lead author Jeffrey Hull (Richmond Vascular Center, Richmond, USA), who presented these results to ASN Kidney Week attendees. “In ongoing studies, the costs and clinical benefits of the Ellipsys fistula are being further evaluated.”
Elsewhere, lead author Mini Michael (Baylor College of Medicine/Texas Children’s Hospital, Houston, USA) presented data from the single-arm ILLUMINATE-C phase 3 study, in which patients with the rare genetic disorder primary hyperoxaluria type 1 (PH1) and chronic kidney disease (CKD)—including patients on haemodialysis—were treated with lumasiran (an RNAi therapeutic indicated for the treatment of PH1 to lower urinary oxalate levels in paediatric and adult patients). She reported that patients experienced substantial reductions in plasma oxalate in the study.
“We know that high plasma oxalate levels are associated with severe and potentially life-threatening complications, including deposition of oxalate in the heart, bones, skin and eyes of these patients—a condition known as systemic oxalosis—resulting in multiorgan dysfunction,” said Michael. “Thus, a drop in oxalate levels of the magnitude seen in this study is promising and we hope will translate into improved long-term clinical outcomes, including oxalosis, which is something that we plan to further evaluate in the ILLUMINATE-C extension period.”
A further highlight from this session saw the results of the TESTING study, which assessed the effects of oral methylprednisolone compared with placebo on major kidney outcomes and safety in IgA nephropathy patients, presented by co-senior author Vlado Perkovic (University of New South Wales, Sydney, Australia). Across the 503 randomised participants, and over an average follow-up of 4.2 years, methylprednisolone reduced the risk of the primary outcome (composite of 40% eGFR decline or kidney failure) by 47% and kidney failure by 41% compared to the trial’s placebo group. “The TESTING trial showed that two different doses of a cheap type of oral steroid, taken for six to nine months, reduced the risk of major kidney events and kidney failure,” added Perkovic. “The risk of adverse events, especially infections, was increased mainly with high-dose treatment, suggesting that reduced-dose therapy best balances risks and benefits.”
In a new analysis of data from the EMPEROR-Preserved study, which previously showed that empagliflozin reduced cardiovascular deaths and heart failure hospitalisations, and slowed kidney function decline, in patients with heart failure and a preserved ejection fraction (HFpEF), these benefits were found to have been experienced in patients regardless of the presence or absence of CKD, and across a broad spectrum of baseline kidney function. The analysis included 5,988 patients who were randomised, of whom 3,198 (53%) had prevalent CKD.
“As part of the active and, so far, disappointing quest for a therapy to help patients with HFpEF, the EMPEROR-Preserved trial is the first trial showing unequivocal cardiac and renal benefits in such patients,” said lead author Faiez Zannad (Université de Lorraine, Nancy, France). “This trial reproduces the same benefits also observed in patients with heart failure and reduced ejection fraction. Therefore, empagliflozin is the first drug ever showing a consistent improvement of cardiovascular outcomes and a slowing of kidney function decline across the full spectrum of kidney function, including patients with CKD, across the full spectrum of cardiac ejection fraction and in patients with and without diabetes.”
The findings of a multicentre randomised controlled trial (RCT) comparing three- and six-month initial prednisone therapy in young (<four-year-old) children with nephrotic syndrome followed this—with lead author Aditi Sinha (All India Institute of Medical Sciences, New Delhi, India) reporting that proportions of patients with sustained remission and frequent relapses at one and two years, time to relapse or frequent relapses, and relapse rates, were all similar between the three- and six-month groups. “Our findings suggest that prolonging initial therapy beyond 12 weeks does not significantly impact the subsequent frequency of relapses,” said Sinha. “Young children with the first episode of nephrotic syndrome should receive similar treatment as older children.”
The ASCEND programme, which consists of more than 8,000 CKD patients, includes two pivotal phase 3 studies investigating the efficacy and cardiovascular safety of daprodustat—an oral hypoxia-inducible factor prolyl hydroxylase inhibitor—as a novel alternative to injectable erythropoiesis-stimulating agents (ESAs), the current standard of care for anaemia in this patient population. According to data presented at ASN Kidney Week, these studies independently met their primary safety and efficacy endpoints, showing daprodustat improved or maintained haemoglobin with no increased cardiovascular risk compared with ESAs across both dialysis and non-dialysis patients.
“Evidence found that daprodustat is an oral option as effective and safe as an ESA, and is well-tolerated, which underscores that using an oral agent, such as daprodustat, could help improve accessibility and compliance for patients with anaemia of CKD who ordinarily cannot access treatment because, in many patients, ESA needs to be administered by a healthcare provider,” said lead author and chair of the steering committee for the ASCEND programme Ajay Singh (Brigham and Women’s Hospital/Harvard Medical School, Boston, USA). “In addition to stimulating natural production of erythropoietin, daprodustat causes changes in markers of iron metabolism in the body, which may heed a benefit, and it works well in patients who have poor response to ESA.”
Rajiv Agarwal (Indiana University School of Medicine and Roudebush VA, Indianapolis, USA) also presented results from the CLICK study, in which 160 patients with hypertension and stage 4 CKD were randomised to receive placebo or US Food and Drug Administration (FDA)-approved hypertension treatment chlorthalidone. This low-cost medication lowered blood pressure in patients within four weeks, and this lowering was sustained over a 12-week treatment period, he stated, while the adjusted change from baseline in 24-hour systolic blood pressure was -0.5mmHg in the placebo group and -11.0mmHg in the chlorthalidone group. The drug also lowered albuminuria—a marker of kidney dysfunction—by 50% over 12 weeks, suggesting that it may have kidney-protective effects.
Finally, in the phase 3 ADVOCATE trial, patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis were randomised to receive avacopan, an oral inhibitor of the C5a complement receptor, or prednisone taper on a background of either cyclophosphamide (followed by azathioprine) or rituximab. Patients in the avacopan group experienced greater recovery of kidney function compared with patients in the prednisone group, especially patients with advanced kidney dysfunction. These data were presented by David Jayne (University of Cambridge, Cambridge, UK).
