Plasma CTGF is independently related to an increased risk of cardiovascular events and mortality in patients with atherosclerotic disease: the SMART study.

AIMS: Connective tissue growth factor (CTGF) plays a key role in tissue fibrogenesis and growing evidence indicates a pathogenic role in cardiovascular disease. Aim of this study is to investigate the association of connective tissue growth factor (CTGF/CCN2) with cardiovascular risk and mortality in patients with manifest vascular disease. METHODS AND RESULTS: Plasma CTGF was measured by ELISA in a prospective cohort study of 1227 patients with manifest vascular disease (mean age 59.0 ± 9.9 years). Linear regression analysis was performed to quantify the association between CTGF and cardiovascular risk factors. Results are expressed as beta (ß) regression coefficients with 95% confidence intervals (CI). The relation between CTGF and the occurrence of new cardiovascular events and mortality was assessed with Cox proportional hazard analysis. Adjustments were made for potential confounding factors. Plasma CTGF was positively related to total cholesterol (ß 0.040;95%CI 0.013-0.067) and LDL cholesterol (ß 0.031;95%CI 0.000-0.062) and inversely to glomerular filtration rate (ß -0.004;95%CI -0.005 to -0.002). CTGF was significantly lower in patients with cerebrovascular disease. During a median follow-up of 6.5 years (IQR 5.3-7.4) 131 subjects died, 92 experienced an ischemic cardiac complication and 45 an ischemic stroke. CTGF was associated with an increased risk of new vascular events (HR 1.21;95%CI 1.04-1.42), ischemic cardiac events (HR 1.41;95%CI 1.18-1.67) and all-cause mortality (HR 1.18;95%CI 1.00-1.38) for every 1 nmol/L increase in CTGF. No relation was observed between CTGF and the occurrence of ischemic stroke. CONCLUSIONS: In patients with manifest vascular disease, elevated plasma CTGF confers an increased risk of new cardiovascular events and all-cause mortality.

Local therapeutic efficacy with reduced systemic side effects by rapamycin-loaded subcapsular microspheres.

Kidney injury triggers fibrosis, the final common pathway of chronic kidney disease (CKD). The increase of CKD prevalence worldwide urgently calls for new therapies. Available systemic treatment such as rapamycin are associated with serious side effects. To study the potential of local antifibrotic therapy, we administered rapamycin-loaded microspheres under the kidney capsule of ureter-obstructed rats and assessed the local antifibrotic effects and systemic side effects of rapamycin. After 7 days, microsphere depots were easily identifiable under the kidney capsule. Both systemic and local rapamycin treatment reduced intrarenal mTOR activity, myofibroblast accumulation, expression of fibrotic genes, and T-lymphocyte infiltration. Upon local treatment, inhibition of mTOR activity and reduction of myofibroblast accumulation were limited to the immediate vicinity of the subcapsular pocket, while reduction of T-cell infiltration was widespread. In contrast to systemically administered rapamycin, local treatment did not induce off target effects such as weight loss. Thus subcapsular delivery of rapamycin-loaded microspheres successfully inhibited local fibrotic response in UUO with less systemic effects. Therapeutic effect of released rapamycin was most prominent in close vicinity to the implanted microspheres.

Urinary connective tissue growth factor is associated with human renal allograft fibrogenesis.

BACKGROUND: Connective tissue growth factor (CTGF) is a key mediator of tissue fibrogenesis in kidney disease. Its involvement in renal allograft fibrosis was recently demonstrated in a mouse model. METHODS: We prospectively studied the association between urinary CTGF (CTGFu) levels and renal allograft fibrosis during the first 2 years after transplantation. Histologic and biochemical data were collected from 315 kidney transplant recipients enrolled in a protocol biopsy-based clinical program. RESULTS: At 3, 12, and 24 months after transplantation, CTGFu levels were independently associated with the degree of interstitial fibrosis in protocol biopsies, scored according to the revised 1997 Banff criteria. In a subgroup of 164 patients with pristine biopsies at 3 months, higher CTGFu levels at 3 months were associated with moderate and severe interstitial fibrosis developed at 24 months after transplantation. CONCLUSIONS: As it is readily quantifiable in urine, a role for CTGFu as a noninvasive candidate biomarker and predictor of human renal allograft fibrogenesis deserves further study.

Compensatory growth of congenital solitary kidneys in pigs reflects increased nephron numbers rather than hypertrophy.

BACKGROUND: Patients with unilateral MultiCystic Kidney Dysplasia (MCKD) or unilateral renal agenesis (URA) have a congenital solitary functioning kidney (CSFK) that is compensatory enlarged. The question whether this enlargement is due to increased nephron numbers and/or to nephron hypertrophy is unresolved. This question is of utmost clinical importance, since hypertrophy is associated with a risk of developing hypertension and proteinuria later in life with consequent development of CKD and cardiovascular disease. METHODOLOGY/PRINCIPAL FINDINGS: In a cohort of 32,000 slaughter pigs, 7 congenital solitary functioning kidneys and 7 control kidneys were identified and harvested. Cortex volume was measured and with a 3-dimensional stereologic technique the number and volume of glomeruli was determined and compared. The mean total cortex volume was increased by more than 80% and the mean number of glomeruli per kidney was 50% higher in CSFKs than in a single control kidney, equaling 75% of the total nephron number in both kidneys of control subjects. The mean total glomerular volume in the CSFKs was not increased relative to the controls. CONCLUSIONS/SIGNIFICANCE: Thus, in pigs, compensatory enlargement of a CSFK is based on increased nephron numbers. Extrapolation of these findings to the human situation suggests that patients with a CSFK might not be at increased risk for developing hyperfiltration-associated renal and cardiovascular disease in later life due to a lower nephron number.