Lower Urinary Connective Tissue Growth Factor Levels and Incident CKD Stage 3 in the General Population

Abstract

Connective tissue growth factor (CTGF) is involved in the development and progression of kidney diseases, including diabetic nephropathy and kidney fibrosis, but also may have a role in mesangial repair after injury. It is unknown whether, in the general population, urinary CTGF levels are associated with a decrease in estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m(2) (ie, development of chronic kidney disease [CKD] stage 3). Nested case-control. 100 cases of incident CKD stage 3 and 100 age-and sex-matched controls in the Framingham Heart Study; 141 cases and 135 age-, sex-, and race-matched controls in the Atherosclerosis Risk in Communities (ARIC) Study. Controls had eGFR ≥60 mL/min/1.73 m(2) at follow-up in both studies. Urinary CTGF concentrations. Incident CKD stage 3, defined as eGFR <60 mL/min/1.73 m(2). Stored urine samples from Framingham Heart Study and ARIC were measured for CTGF. Covariates were obtained from Framingham Heart Study and ARIC participant examinations. In the Framingham Heart Study, the median baseline urinary CTGF concentration was lower in cases (1.35 ng/mL) than controls (2.35 ng/mL; paired t test, P < 0.0001). The multivariable-adjusted OR for incident CKD stage 3 was 0.33 (95% CI, 0.17-0.64; P < 0.001) per 1-standard deviation in log urinary CTGF level after adjustment for CKD risk factors, baseline eGFR, and baseline log urinary albumin-creatinine ratio, with similar results in participants without diabetes (n = 184). Results were not materially different when urinary CTGF level was indexed to urinary creatinine level (multivariable-adjusted OR, 0.34; 95% CI, 0.21-0.56; P < 0.001). A similar, but nonsignificant, trend of risk of incident CKD stage 3 with lower baseline urinary CTGF concentration was observed in an independent case-control study conducted in the ARIC Study, with the strongest results observed in participants free of diabetes. This inverse relationship was robust in meta-analysis of both the overall and diabetes-free groups. Observational study; causality cannot be inferred. Lower urinary CTGF concentrations precede the onset of CKD stage 3 in the general population. Further work is required to fully characterize how CTGF level influences risk of CKD.