OBJECTIVE -Excretion of growth factors in the urine has been implicated in the pathogenesis of tubulointerstitial disease that characterizes proteinuric renal disease. In this crosssectional 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 ϭ 0.76, P Ͻ 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 ϫ/Ϭ 1.3 ng/mg, microalbuminuria 2.1 ϫ/Ϭ 1.7 ng/mg, untreated macroalbuminuria 203 ϫ/Ϭ 3.8 ng/mg, and geometric mean ϫ/Ϭ tolerance factor; P Ͻ 0.05 for normoalbuminuria versus microalbuminuria, P Ͻ 0.001 for microalbuminuria versus macroalbuminuria). Urinary CTGF-N was lower (Ͻ30-fold) in macroalbuminuric subjects treated with ACE inhibitors (6.5 ϫ/Ϭ 1.7 ng/mg; P Ͻ 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.

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OBJECTIVE -Transforming growth factor-␤ (TGF-␤) is a prosclerotic growth factor implicated in the pathogenesis of diabetic nephropathy. In addition to high glucose, other factors implicated in renal fibrosis and increased TGF-␤ synthesis include angiotensin II and high dietary sodium intake. The aim of this study was to examine the effect of angiotensin receptor blockade (ARB) and dietary sodium restriction on the plasma concentration and urinary excretion of TGF-␤ in hypertensive patients with type 2 diabetes and elevated albumin excretion rate (AER). RESEARCH DESIGN AND METHODS-Twenty-one subjects with hypertension and AER between 10 and 200 g/min were randomized to receive either 50 mg losartan daily (n ϭ 11) or placebo (n ϭ 10). Drug therapy was given in two 4-week phases, separated by a 4-week washout period. In the last 2 weeks of each phase, patients were assigned to regular-or lowsodium diets in random order. Parameters measured at week 0 and 4 of each phase included plasma TGF-␤ concentration, TGF-␤ urinary excretion, AER, clinic mean arterial blood pressure, and urinary sodium excretion.RESULTS -Plasma TGF-␤ was unaffected by losartan treatment or sodium intake. In the losartan group, urinary TGF-␤ excretion decreased by 23.2% (Ϫ39.2 and 13.6) [median (interquartile range)] and 38.5% (Ϫ46.8 and Ϫ6.1) in the regular-and low-sodium phases, respectively (P Ͻ 0.05 for drug effect). In the placebo group, median changes of 0.0% (Ϫ12.1 and 44.4) and 0.0% (Ϫ29.2 and 110.7) occurred in the regular-and low-sodium phases, respectively. Sodium restriction did not affect urinary TGF-␤ excretion in either losartan-or placebo-treated patients (P ϭ 0.54 for overall dietary effect), and there was no evidence of interaction between drug and diet (P ϭ 0.29).CONCLUSIONS -In hypertensive type 2 diabetic patients with elevated AER, the ARB losartan, but not sodium restriction, reduced urinary TGF-␤ excretion. These data suggest that the renoprotective effects of losartan in patients with type 2 diabetes and nephropathy may include a reduction in renal TGF-␤ production.