Time to target uric acid to retard CKD progression

Abstract

Uric acid (UA) remains a possible risk factor of chronic kidney disease (CKD) but its potential role should be elucidated given a fact that multidisciplinary treatments assure a sole strategy to inhibit the progression to end-stage renal disease (ESRD). In clinical setting, most observational studies showed that elevation of serum uric acid (SUA) independently predicts the incidence and the development of CKD. The meta-analysis showed that SUA-lowering therapy with allopurinol may retard the progression of CKD but did not reach conclusive results due to small-sized studies. Larger scale, randomized placebo-controlled trials to assess SUA-lowering therapy are needed. Our recent analysis by propensity score methods has shown that the threshold of SUA should be less than 6.5 mg/dL to abrogate ESRD. In animal models an increase in SUA by the administration of oxonic acid, uricase inhibitor, or nephrectomy can induce glomerular hypertension, arteriolosclerosis including afferent arteriolopathy and tubulointerstitial fibrosis. The ever-growing discoveries of urate transporters prompt us to learn UA metabolism in the kidney and intestine. One example is that the intestinal ABCG2 may play a compensatory role at face of decreased renal clearance of UA in nephrectomized rats, the trigger of which is not a uremic toxin but SUA itself. This review will summarize the recent knowledge on the relationship between SUA and the kidney and try to draw a conclusion when and how to treat asymptomatic hyperuricemia accompanied by CKD. Finally we will address a future perspective on UA study including a Mendelian randomization approach.

Serum Uric Acid and Progression of Kidney Disease: A Longitudinal Analysis and Mini-Review

“…Evidence for the role of hyperuricemia in the CKD progression is controversial[30]. Although some studies showed no association between hyperuricemia and the progression of CKD [10–14], other studies found hyperuricemia may hasten the failing of renal function measured by eGFR or increase the risk of developing ESRD(Table 4) [31–42].…”

Uric Acid in the Follow-Up Determines 30% Decline in Estimated GFR Over 2 Years: a Propensity Score Analysis

“…Since the impact of proteinuria is so enormous as to mask other risk factors, the classical risk analysis failed to draw consistent results. Hyperuricemia has been among such risk factors because preceding investigations showed the positive results whereas not in other observational studies as reviewed in the recent literature [2]. The independent significance of serum uric acid (SUA) was indeed abolished when adjusted for the existence of kidney dysfunction [3][4][5][6].…”

Uric acid in the pathogenesis of metabolic, renal, and cardiovascular diseases: A review

“…ABCG2 is also expressed in the liver and intestine [75]. As UA excretion falls in cases of CKD, compensatory increase in intestinal secretion of UA ensues [76], [77]. Whether UA is a cause or an association to renal diseases is a question that still waits for a definitive answer.…”

“…XO inhibitors possibly delay the progression of CKD in adult hyperuricemic and hypertensive patients [119]. The target SUA should be <6.5 mg/dL to delay progression [77], [118].…”