Effects of antiproteinuric intervention on elevated connective tissue growth factor (CTGF/CCN-2) plasma and urine levels in nondiabetic nephropathy

Abstract

Background and objectives: Connective tissue growth factor (CTGF/CCN-2) is a key player in fibrosis. Plasma CTGF levels predict end-stage renal disease and mortality in diabetic chronic kidney disease (CKD), supporting roles in intra- and extrarenal fibrosis. Few data are available on CTGF in nondiabetic CKD. We investigated CTGF levels and effects of antiproteinuric interventions in nondiabetic proteinuric CKD.

Design, setting, participants, & measurements: In a crossover randomized controlled trial, 33 nondiabetic CKD patients (3.2 [2.5 to 4.0] g/24 h proteinuria) were treated during 6-week periods with placebo, ARB (100 mg/d losartan), and ARB plus diuretics (100 mg/d losartan plus 25 mg/d hydrochlorothiazide) combined with consecutively regular and low sodium diets (193 ± 62 versus 93 ± 52 mmol Na(+)/d).

Results: CTGF was elevated in plasma (464 [387 to 556] pmol/L) and urine (205 [135 to 311] pmol/24 h) of patients compared with healthy controls (n = 21; 96 [86 to 108] pmol/L and 73 [55 to 98] pmol/24 h). Urinary CTGF was lowered by antiproteinuric intervention, in proportion to the reduction of proteinuria, with normalization during triple therapy (CTGF 99 [67 to 146] in CKD versus 73 [55 to 98] pmol/24 h in controls). In contrast, plasma CTGF was not affected.

Conclusions: Urinary and plasma CTGF are elevated in nondiabetic CKD. Only urinary CTGF is normalized by antiproteinuric intervention, consistent with amelioration of tubular dysfunction. The lack of effect on plasma CTGF suggests that its driving force might be independent of proteinuria and that short-term antiproteinuric interventions are not sufficient to correct the systemic profibrotic state in CKD.

Figure 1.

Response of proteinuria and CTGF to ARB, LS, and diuretics. Proteinuria (panel A) and CTGF levels (panel B and C) are shown as geometric means with 95% confidence intervals. Figure 1A was adapted and modified from the original study (20). ARB, angiotensin receptor blockade; LS, low sodium diet. @P < 0.05 versus all, *P < 0.05 versus healthy controls, #P < 0.05 versus placebo+RS in CKD patients, †P < 0.05 versus placebo+LS in CKD patients, ∞P < 0.05 versus ARB+RS in CKD patients, ‡P < 0.05 versus ARB+LS in CKD patients, □P < 0.05 versus ARB+diuretics+RS in CKD patients.

Figure 2.

The reduction of urinary CTGF parallels the reduction in proteinuria. Proteinuria and CTGF levels are shown as geometric means with 95% confidence intervals. (Panel A) Stepwise concomitant reduction of proteinuria and urinary CTGF during the six different treatment periods. ^aPlacebo plus regular sodium diet (RS). ^bPlacebo plus low sodium diet (LS). ^cAngiotensin receptor blockade (ARB) plus RS. ^dARB+LS. ^eARB+RS+diuretics. ^fARB+LS+diuretics. (Panel B) Percentage change in proteinuria and urinary CTGF by LS combined with placebo (change from placebo+RS), ARB combined with RS (change from placebo+RS), diuretics combined with ARB+RS (change from ARB+RS), and ARB+diuretics+LS (change from placebo+RS), respectively.