The dirty little secret of urate-lowering therapy: useless to stop chronic kidney disease progression and may increase mortality

Abstract

Hyperuricaemia is frequent in chronic kidney disease (CKD). Observational studies have shown an association with adverse outcomes and acquired hyperuricaemia (meaning serum urate levels as low as 1.0 mg/dL) in animal models induces kidney injury. This evidence does not justify the widespread use of urate-lowering drugs for asymptomatic hyperuricaemia in CKD. However, promising results from small, open-label studies led some physicians to prescribe urate-lowering drugs to slow CKD progression. Two recent, large, placebo-controlled trials (CKD-FIX and PERL) showed no benefit from urate lowering with allopurinol on the primary endpoint of CKD progression, confirming prior negative results. Despite these negative findings, it was still argued that the study population could be optimized by enrolling younger non-proteinuric CKD patients with better preserved glomerular filtration rate (GFR). However, in these low-risk patients, GFR may be stable under placebo conditions. Additionally, the increased mortality trends already identified in gout trials of urate-lowering therapy were also observed in CKD-FIX and PERL, sending a strong safety signal: 21/449 (4.7%) and 10/444 (2.2%) patients died in the combined allopurinol and placebo groups, respectively [chi-squared P-value 0.048; relative risk 2.07 (95% CI 0.98-4.34); P = 0.06]. Given the absent evidence of benefit in multiple clinical trials and the potentially serious safety issues, the clear message should be that urate-lowering therapy should not be prescribed for the indication of slowing CKD progression. Additionally, regulatory agencies should urgently reassess the safety of chronic prescription of urate-lowering drugs for any indication.