Clinical Pearls & Morning Reports
Doria et al. conducted a placebo-controlled trial that evaluated whether reduction of the serum urate level with allopurinol therapy could slow the decline in glomerular filtration rate (GFR) in persons with type 1 diabetes, early-to-moderate diabetic kidney disease, and a serum urate level of at least 4.5 mg per deciliter. Read the NEJM Original Article here.
Q: What is the effectiveness of existing therapies to preserve GFR in early diabetic kidney disease?
A: Although blood-pressure control and, more specifically, renin–angiotensin system inhibition slow the progression of relatively advanced diabetic kidney disease, evidence of preservation of the GFR by these interventions at earlier stages is limited. Thus, new treatments, especially for early diabetic kidney disease, are needed.
Q: Why might serum urate be the target of an intervention to preserve GFR in early diabetic kidney disease?
A: Serum urate is a potential target on the basis of evidence from animal models and observational studies involving humans. Higher levels of serum urate, even within the normal range, predicted albuminuria and early decline in the GFR as well as a higher rate of cardiovascular events and higher mortality in cohorts of patients with type 1 diabetes. Moreover, reduction in the serum urate level slowed the decline in the GFR in two small clinical trials involving participants with moderate chronic kidney disease, approximately 25% of whom had diabetes.
A: This randomized clinical trial showed no evidence of a clinically meaningful benefit of serum urate lowering with allopurinol on kidney outcomes in patients with type 1 diabetes and early-to-moderate diabetic kidney disease who were treated, as indicated, with renin–angiotensin system inhibitors. Despite 3 years of sustained serum urate reduction, there was no evidence of a difference between the allopurinol group and the placebo group in the primary outcome, the baseline-adjusted iohexol-based GFR after a 2-month washout period. In addition, the authors found no evidence of a clinically meaningful benefit with regard to secondary outcomes, including the iohexol-based GFR at the end of the intervention period, the iohexol-based and estimated GFR slopes, and serum creatinine doubling or progression to end-stage kidney disease in a time-to-event analysis. Prespecified subgroup analyses did not show heterogeneity in the effect of allopurinol on the primary outcome. Therefore, 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.
A: Given the preponderance of white patients in the trial, the results may not be fully applicable to other races or ethnic groups. Similarly, the results should not be generalized to patients with other stages of diabetic kidney disease; to patients with type 2 diabetes, in whom increased serum urate may relate to other processes, such as the metabolic syndrome; or to patients with other causes of chronic kidney disease.