Urate-lowering therapy with allopurinol, a xanthine oxidase inhibitor, does not appear to slow progression of chronic kidney disease (CKD) in important subgroups, according to findings from 2 new randomized controlled trials published online ahead of print in the New England Journal of Medicine.

In the Preventing Early Renal Loss in Diabetes trial (PERL; NCT02017171), allopurinol did not slow kidney function decline in patients (mean age 51 years) with type 1 diabetes (mean vintage 35 years; mean hemoglobin A1c of 8.2%), a baseline estimated glomerular filtration rate (GFR) of 40.0 to 99.9 mL/min/1.73 m2, and a normal to high serum urate level of at least 4.5 mg/dL.

Over 3 years, mean serum urate decreased from 6.1 to 3.9 mg/dL among the 267 patients randomly assigned to allopurinol (whereas it remained at 6.1 mg/dL among the 263 patients assigned to placebo). Yet the iohexol-measured GFR, the primary end point, was identical in both groups (61.2 mL/min/1.73 m2), Alessandro Doria, MD, PhD, MPH, of Joslin Diabetes Center in Boston, and colleagues reported.

By the end of the intervention period, the mean decrease in iohexol-measured GFR was -3.0 mL/min/1.73 m2 with allopurinol vs -2.5 mL/min/1.73 m2 with placebo. There were no clinically meaningful differences in estimated GFR slopes, serum creatinine doubling, or progression to end-stage kidney disease (ESKD). The allopurinol group exhibited a 40% higher urinary albumin excretion rate that warrants further investigation, according to the researchers. Notably, most patients were receiving renin-angiotensin system (RAS) inhibitors at baseline: 87.5% vs 92.5%, respectively.  


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Dr Doria’s team wrote that “a reduction in the serum urate level by allopurinol did not appear to effectively alter the progression of diabetic kidney disease at early-to-moderate stages in persons with type 1 diabetes.”

In the Controlled Trial of Slowing of Kidney Disease Progression from the Inhibition of Xanthine Oxidase (CKD-FIX; ACTRN12611000791932), Sunil V. Badve, PhD, of the George Institute for Global Health in Newtown, New South Wales, Australia, and collaborators investigated urate-lowering therapy in patients with stage 3 to 4 CKD (mean age 62 years) with no gout history who had a rapid decline in estimated GFR (at least -3.0 mL/min/1.73 m2 in the past 12 months) or a urinary albumin to creatinine ratio of 265 mg/g or higher. Mean serum urate at baseline was 8.2 mg/dL.

Serum urate in the allopurinol group declined to 5.1 mg/dL at 12 weeks and held at 5.3 mg/dL for up to 104 weeks (whereas it remained at 8.2 mg/dL in the placebo group). Yet annual eGFR decline did not differ significantly between the allopurinol and the placebo group: -3.33 vs -3.23 mL/min/1.73 m2, respectively, Dr Badve’s team reported. They also observed no greater decreases in proteinuria, blood pressure, or the risk of the composite kidney outcome of a decline in eGFR (either 40% or 30%), ESKD, or death with allopurinol. In this study, 76% of patients were receiving RAS inhibitors at baseline.

“The lack of benefit of allopurinol in slowing the progression of chronic kidney disease in our trial is noteworthy because we specifically enrolled patients who had an elevated risk of progression in order to maximize the potential to show an effect of allopurinol on the decline in eGFR” Dr Badve’s team explained.

In an accompanying editorial, Daniel I. Feig, MD, PhD, MPH, of the University of Alabama School of Medicine in Birmingham, called attention to patients’ older age and disease severity. “The finding that middle-aged persons with diabetic nephropathy (as in the PERL trial) or with advanced, rapidly progressing proteinuric kidney disease (as in CKD-FIX) do not have a reduction in CKD progression beyond standard of care with renin-angiotensin system inhibition when treated with allopurinol indicates that for such patients, allopurinol is not indicated for CKD control. However, these trials did not address urate-lowering therapy, either pharmacologic or dietary, in younger patients or in those with earlier stages of CKD.”

According to Dr Feig, preliminary in vitro and in vivo studies indicated that increased serum uric acid leads to elevated blood pressure that may initially be helped by uric acid reduction – that is before irreversible loss of vascular compliance and renal injury. He urged more high-quality randomized, controlled trials in these areas.

In both studies, serious adverse events occurred in similar proportions of the allopurinol and placebo groups.

Disclosure: Several authors declared affiliations with the pharmaceutical industry. Please see the original references for a full list of authors’ disclosures.

References

Doria A, Galecki AT, Spino C, et al. Serum urate lowering with allopurinol and kidney function in type 1 diabetes [published online June 24, 2020]. N Engl J Med. doi: 10.1056/NEJMoa1916624

Badve SV, Pascoe EM, Tiku A, et al. Effects of allopurinol on the progression of chronic kidney disease [published online June 24, 2020]. N Engl J Med. doi: 10.1056/NEJMoa1915833

Feig DI, et al. Urate-lowering therapy and chronic kidney disease progression [published online June 24, 2020]. N Engl J Med. doi: 10.1056/NEJMe2015886