Circulating thrombospondin-2 level for identifying individuals with rapidly declining kidney function trajectory in type 2 diabetes: a prospective study of the Hong Kong West Diabetes Registry

Abstract

ABSTRACT Background Thrombospondin-2 (TSP2) is a matricellular protein with tissue expression induced by hyperglycaemia. TSP2 has been implicated in non-diabetic renal injury in preclinical studies and high circulating levels were associated with worse kidney function in cross-sectional clinical studies. Therefore, we investigated the prospective associations of circulating TSP2 level with kidney function decline and the trajectories of estimated glomerular filtration rate (eGFR) in type 2 diabetes. Methods Baseline serum TSP2 level was measured in 5471 patients with type 2 diabetes to evaluate its association with incident eGFR decline, defined as ≥40% sustained eGFR decline, using multivariable Cox regression analysis. Among participants with relatively preserved kidney function (baseline eGFR ≥60 mL/min/1.73 m2), joint latent class modelling was employed to identify three different eGFR trajectories. Their associations with baseline serum TSP2 were evaluated using multinomial logistic regression analysis. The predictive performance of serum TSP2 level was examined using time-dependent c-statistics and calibration statistics. Results Over a median follow-up of 8.8 years, 1083 patients (19.8%) developed eGFR decline. Baseline serum TSP2 level was independently associated with incident eGFR decline [hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.07–1.37, P = .002]. With internal validation, incorporating serum TSP2 to a model of clinical risk factors including albuminuria led to significant improvement in c-statistics from 83.9 to 84.4 (P < .001). Among patients with eGFR ≥60 mL/min/1.73 m2, baseline serum TSP2 level was independently associated with a rapidly declining eGFR trajectory (HR 1.63, 95% CI 1.26–2.10, P < .001). Conclusion Serum TSP2 level was independently associated with incident eGFR decline, particularly a rapidly declining trajectory, in type 2 diabetes.