Lowering high uric acid did not protect the kidneys in two randomised trials

A high blood level of uric acid — the substance that causes gout — reliably tracks with kidney disease getting worse, which made lowering it look like an obvious way to protect the kidneys. Two randomised trials tested that idea directly, and both found no benefit: lowering urate with the drug allopurinol did not slow the decline in kidney function compared with placebo [s1] [s2]. It is a clean example of an association that did not survive being tested as a treatment.

Why the idea was so plausible

Elevated serum urate is associated with the progression of chronic kidney disease — the observational link is consistent and biologically reasonable, since urate can drive inflammation and vascular changes in the kidney [s1]. Allopurinol, a long-established medicine, lowers urate effectively. So the hypothesis wrote itself: reduce the urate, spare the kidney. It is precisely the kind of well-motivated idea that needs a randomised trial, because an association between a marker and a bad outcome does not establish that pushing the marker down changes the outcome.

The first trial: chronic kidney disease

CKD-FIX enrolled adults with stage 3 or 4 chronic kidney disease who were at high risk of progression — defined by significant protein in the urine or an eGFR that had already dropped by at least 3.0 mL/min/1.73m² in the previous year — and, notably, no history of gout [s1]. Participants were randomised to allopurinol, at 100 to 300 mg daily, or placebo [s1]. The trial was stopped early for slow recruitment, after 369 of an intended 620 patients had been randomised, with 363 included in the main analysis; their mean eGFR was 31.7 mL/min/1.73m² and mean serum urate 8.2 mg/dL — a group with substantial disease and elevated urate, the population the treatment should most help [s1].

It did not. Over the two-year primary outcome, eGFR fell by 3.33 mL/min/1.73m² per year in the allopurinol group and 3.23 in the placebo group — a mean difference of −0.10 (95% CI, −1.18 to 0.97; P = 0.85), which is to say no difference at all [s1]. Serious adverse events were common and near-identical between groups: 46% with allopurinol, 44% with placebo [s1]. The conclusion was that urate-lowering with allopurinol did not slow the decline in kidney function [s1].

The second trial: type 1 diabetes

PERL asked the same question in a different, carefully studied population: people with type 1 diabetes and early-to-moderate diabetic kidney disease, in whom higher urate is likewise linked to faster decline [s2]. It randomised 530 participants — 267 to allopurinol, 263 to placebo — and measured kidney function with a precise gold-standard method (iohexol clearance) after three years plus a washout period [s2]. The drug did its pharmacological job: serum urate fell from 6.1 to 3.9 mg/dL with allopurinol and stayed at 6.1 with placebo [s2].

Again the kidneys were unmoved. After washout, the between-group difference in measured GFR was 0.001 mL/min/1.73m² (95% CI, −1.9 to 1.9; P = 0.99) — as close to exactly zero as a trial result comes [s2]. The yearly decline was −3.0 with allopurinol and −2.5 with placebo, and if anything the urinary albumin excretion rate ran 40% higher in the allopurinol group [s2]. The authors found no evidence of clinically meaningful benefit from urate-lowering on kidney outcomes in this group [s2].

What the two trials establish, and what they don't

Two independent randomised trials, in two different at-risk populations, lowering urate effectively and finding no protection for the kidney, is a strong signal against the treatment idea — much stronger than the observational association that motivated it [s1] [s2]. There is an important boundary, though: neither trial studied people who had gout, and both deliberately excluded or did not target that group [s1]. So this evidence speaks to using allopurinol to protect the kidneys on the basis of a high urate number alone. It says nothing against treating gout itself, which has its own separate indications, and it does not touch the many other, evidence-backed measures for slowing kidney disease. The finding is specific: a raised urate level, in the absence of gout, is not a target you can treat your way out of for the kidney's sake.

What this leaves a reader with

High uric acid predicts worse kidney disease, but lowering it with allopurinol did not slow kidney decline in either of the two trials built to test it [s1] [s2]. Whether a given person should take allopurinol is a decision about their specific situation — gout above all — and one for a clinician, not a conclusion to draw from a urate number on a lab report.

This article is informational and is not medical advice, and does not recommend for or against any medication.

Sources

• Effects of Allopurinol on the Progression of Chronic Kidney Disease (CKD-FIX) — New England Journal of Medicine, 2020-06-25
• Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes (PERL) — New England Journal of Medicine, 2020-06-25