Genetic risk score for plasma uric acid levels is associated with early rapid kidney function decline in type 2 diabetes

Abstract
Context: Observational studies have shown that elevated uric acid (UA) is associated with chronic kidney disease (CKD). However, whether the relationship is causal remains unclear.

Objectives : To determine the association of plasma UA and incident CKD and the causal relationship between plasma UA and rapid decline in kidney function (RDKF) in patients with type 2 diabetes (T2D).

Design and participants: : Multivariable cox regression was conducted to evaluate the hazard ratio (HR) between plasma UA and incident CKD among 1,300 normoalbuminuric patients in two T2D cohorts (DN=402, SMART2D=898). A weighted genetic risk score (wGRS) was calculated based on ten single nucleotide polymorphism (SNPs) identified in genome-wide association studies of UA in East Asians. Mendelian randomisation (MR) analysis was performed among 1,146 Chinese T2D patients without CKD(estimated glomerular filtration rate (eGFR) >60ml/min/1.73m2) at baseline (DN=478, SMART2D=668). The wGRS and individual SNPs were used as genetic instruments and RDKF was defined as eGFR decline of 5ml/min/1.73m2/yr or greater.

Results : During the mean follow-up of 5.2 and 5.4 years, 81 (9%) and 46 (11%) participants in the SMART2D and DN cohorts developed CKD, respectively. 1-SD increment in plasma UA conferred higher risk of incident CKD (DN, adjusted-HR=1.40, 95%CI 1.02-1.91, P=0.036; SMART2D, adjusted-HR=1.31, 95%CI 1.04-1.64, P=0.018). Higher wGRS was associated with increased odds for RDKF (meta-adjusted odds ratio=1.12, 95%CI 1.01-1.24,P=0.030, Phet= 0.606).

Conclusions : Elevated plasma UA is an independent risk factor of incident CKD. Furthermore, plasma UA potentially has a causal role in early eGFR loss in T2D patients.