Connective tissue growth factor and susceptibility to renal and vascular disease risk in type 1 diabetes.

OBJECTIVE: We explored the relevance and significance of connective tissue growth factor (CTGF) as a determinant of renal and vascular complications among type 1 diabetic patients. METHODS AND RESULTS: We measured the circulating and urinary levels of CTGF and CTGF N fragment in 1050 subjects with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study cohort. We found that hypertensive diabetic subjects have significantly higher levels of plasma log CTGF N fragment relative to normotensive subjects (P = 0.0005). Multiple regression analysis showed a positive and independent association between CTGF N fragment levels and log albumin excretion rate (P < 0.0001). In categorical analysis, patients with macroalbuminuria had higher levels of CTGF N fragment than diabetic subjects with or without microalbuminuria (P < 0.0001). Univariate and multiple regression analyses demonstrated an independent and significant association of log CTGF N fragment with the common and internal carotid intima-media thickness. The relative risk for increased carotid intima-media thickness was higher in patients with concomitantly elevated plasma CTGF N fragment and macroalbuminuria relative to patients with normal plasma CTGF N fragment and normal albuminuria (relative risk = 4.76; 95% confidence interval, 2.21-10.25; P < 0.0001). CONCLUSION: These findings demonstrate that plasma CTGF is a risk marker of diabetic renal and vascular disease.

Urinary connective tissue growth factor excretion in patients with type 1 diabetes and nephropathy.

OBJECTIVE: Excretion of growth factors in the urine has been implicated in the pathogenesis of tubulointerstitial disease that characterizes proteinuric renal disease. In this cross-sectional study, we sought to examine the urinary excretion of the profibrotic cytokine connective tissue growth factor (CTGF) in type 1 diabetic patients with incipient and overt diabetic nephropathy. RESEARCH DESIGN AND METHODS: We recruited 31 subjects with type 1 diabetes from a hospital diabetes outpatient clinic. Of these, 10 subjects were normoalbuminuric, 8 were microalbuminuric and not receiving ACE inhibitor treatment, and 13 were macroalbuminuric, 8 of whom were receiving ACE inhibitor treatment. Urinary CTGF NH(2)-terminal fragment (CTGF-N) was determined by enzyme-linked immunosorbent assay and expressed relative to urinary creatinine. RESULTS: Urinary CTGF-N was closely correlated with the degree of albuminuria (r = 0.76, P < 0.001). In comparison with normoalbuminuric subjects, urinary CTGF-N was increased 10- and 100-fold in micro- and untreated macroalbuminuric subjects, respectively (CTGF-N-to-creatinine ratio: normoalbuminuria 0.23 x// 1.3 ng/mg, microalbuminuria 2.1 x// 1.7 ng/mg, untreated macroalbuminuria 203 x// 3.8 ng/mg, and geometric mean x// tolerance factor; P < 0.05 for normoalbuminuria versus microalbuminuria, P < 0.001 for microalbuminuria versus macroalbuminuria). Urinary CTGF-N was lower (<30-fold) in macroalbuminuric subjects treated with ACE inhibitors (6.5 x// 1.7 ng/mg; P < 0.01 vs. untreated macroalbuminuria) compared with their untreated counterparts. CONCLUSIONS: In this cross-sectional study, the magnitude of urinary CTGF-N excretion was related to the severity of diabetic nephropathy. In the context of its known profibrotic actions, these findings suggest that CTGF may contribute to the chronic tubulointerstitial fibrosis that accompanies proteinuric renal disease. Prospective and interventional studies will be needed to determine whether urinary CTGF-N may provide a reliable surrogate marker of renal injury and a meaningful indicator of response to therapy.