Non-albuminuric renal impairment is a strong predictor of mortality in individuals with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicentre study

Non-albuminuric renal impairment has become the prevailing diabetic kidney disease (DKD) phenotype in individuals with type 2 diabetes and an estimated GFR (eGFR) < 60 ml min(-1) 1.73 m(-2). In the present study, we compared the rate and determinants of all-cause death in individuals with this phenotype with those in individuals with albuminuric phenotypes. This observational prospective cohort study enrolled 15,773 individuals with type 2 diabetes in 2006-2008. Based on baseline albuminuria and eGFR, individuals were classified as having: no DKD (Alb(-)/eGFR(-)), albuminuria alone (Alb(+)/eGFR(-)), reduced eGFR alone (Alb(-)/eGFR(+)), or both albuminuria and reduced eGFR (Alb(+)/eGFR(+)). Vital status on 31 October 2015 was retrieved for 15,656 individuals (99.26%). Mortality risk adjusted for confounders was lowest for Alb(-)/eGFR(-) (reference category) and highest for Alb(+)/eGFR(+) (HR 2.08 [95% CI 1.88, 2.30]), with similar values for Alb(+)/eGFR(-) (1.45 [1.33, 1.58]) and Alb(-)/eGFR(+) (1.58 [1.43, 1.75]). Similar results were obtained when individuals were stratified by sex, age (except in the lowest age category) and prior cardiovascular disease. In normoalbuminuric individuals with eGFR < 45 ml min(-1) 1.73 m(-2), especially with low albuminuria (10-29 mg/day), risk was higher than in microalbuminuric and similar to macroalbuminuric individuals with preserved eGFR. Using recursive partitioning and amalgamation analysis, prevalent cardiovascular disease and lower HDL-cholesterol were the most relevant correlates of mortality in all phenotypes. Higher albuminuria within the normoalbuminuric range was associated with death in non-albuminuric DKD, whereas the classic 'microvascular signatures', such as glycaemic exposure and retinopathy, were correlates of mortality only in individuals with albuminuric phenotypes. Non-albuminuric renal impairment is a strong predictor of mortality, thus supporting a major prognostic impact of renal dysfunction irrespective of albuminuria. Correlates of death partly differ from the albuminuric forms, indicating that non-albuminuric DKD is a distinct phenotype.