Effects of Antiproteinuric Intervention on Elevated Connective Tissue Growth Factor (CTGF/CCN-2) Plasma and Urine Levels in Nondiabetic Nephropathy

Abstract

SummaryBackground 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, & measurementsIn 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 Ϯ 62 versus 93 Ϯ 52 mmol Na ϩ /d). 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. Results

Sodium restriction on top of renin–angiotensin–aldosterone system blockade increases circulating levels of N-acetyl-seryl-aspartyl-lysyl-proline in chronic kidney disease patients

“…Rise in AcSDKP as an anti-inflammatory and antifibrotic factor is well in line with data demonstrating anti-inflammatory and antifibrotic effects of sodium restriction [7,12]. The beneficial effect of sodium restriction upon inflammation and fibrosis in CKD is supported by the reduction in urinary excretion of fibrotic CTGF [12].…”

“…The mechanisms underlying this increased efficacy of RAAS-blockade during sodium restriction are incompletely understood, but may relate to a shift in the balance between vasoconstrictor and vasodilator angiotensins [8] and effects of sodium status on vascular and renal tissue ACE activity [9][10][11]. This is supported by a reduction in urinary excretion of the fibrotic connective tissue growth factor (CTGF) in response to sodium restriction in addition to ARB in patients with nondiabetic chronic kidney disease (CKD) [12]. This is supported by a reduction in urinary excretion of the fibrotic connective tissue growth factor (CTGF) in response to sodium restriction in addition to ARB in patients with nondiabetic chronic kidney disease (CKD) [12].…”

Plasma Vitamin D Level and Change in Albuminuria and eGFR According to Sodium Intake

“…Increased renal ACE activity caused by high sodium intake combined with increased renin production caused by low vitamin D (24,37) may concertedly promote progression of albuminuria. Proinflammatory and profibrotic pathways could also underlie the interaction, because both vitamin D deficiency (25,(37)(38)(39) and high sodium intake (11,40,41) have been linked to increased renal inflammation and fibrosis.…”

The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response

“…Several independent studies have evaluated CCN2 levels in the urine and/or serum in several chronic kidney diseases. Some groups have found elevated levels of the full-length CCN2, 5,6 or the N-terminal, 6,7 or the C-terminal [8][9][10] CCN2 fragments determined by ELISA, using antibodies that recognized each part of the molecule. Based on these data, CCN2 has been proposed as a risk biomarker of human diabetic nephropathy and other forms of chronic kidney disease, 2,5-10 and for cardiac dysfunction in patients exhibiting myocardial fibrosis and chronic heart failure.…”