Plasma connective tissue growth factor is an independent predictor of end-stage renal disease and mortality in type 1 diabetic nephropathy

doi:10.2337/dc07-2469

Plasma connective tissue growth factor is an independent predictor of end-stage renal disease and mortality in type 1 diabetic nephropathy

Tri Q. Nguyen, MD¹,
Lise Tarnow, MD, DMSC²,
Anders Jorsal²,
Noelynn Oliver, PHD³,
Peggy Roestenberg, PHD¹,
Yasuhiko Ito, MD⁴,
Hans-Henrik Parving, MD, DMSC^5,,⁶,
Peter Rossing, MD, DMSC²,
Frans A. van Nieuwenhoven, PHD¹ and
Roel Goldschmeding, MD, PHD (R.Goldschmeding{at}umcutrecht.nl)¹

¹Pathology, University Medical Center Utrecht, Utrecht, Netherlands
²Steno Diabetes Center, Gentofte, Denmark
³FibroGen, Inc, South San Francisco, CA, USA
⁴Nephrology, Nagoya University School of Medicine, Nagoya, Japan
⁵Endocrinology, Rigshospitalet, Copenhagen, Denmark, and
⁶Faculty of Health Science, Aarhus University, Aarhus, Denmark

Abstract

Objective: We evaluated the predictive value of baseline plasma connective tissue growth factor (CTGF; CCN-2) in a prospective study of patients with type 1 diabetes.

Research Design and Methods: Subjects were 198 type 1 diabetic patients with established diabetic nephropathy and 188 type 1 diabetic patients with persistent normoalbuminuria. Follow-up time was 12.8 years. Prediction of end-stage renal disease (ESRD) and mortality by plasma CTGF was analyzed in conjunction with conventional risk factors.

Results: Plasma CTGF was higher in patients with nephropathy than in patients with normoalbuminuria (median 381 pmol/l [interquartile range 270-630] vs. 235 [168-353]). In patients with nephropathy, elevated plasma CTGF was an independent predictor of ESRD (covariate-adjusted hazard ratio 1.6 [95% CI 1.1-2.5]), and correlated with the rate of decline in GFR (cumulative R=0.46). Area under the ROC curve for prediction of ESRD was 0.72. Plasma CTGF above a cutoff level of 413 pmol/l predicted ESRD with a sensitivity of 73% and a specificity of 63%, and was associated with a higher rate of decline in GFR (5.4±4.9 ml/min/1.73 m²/year vs. 3.3±3.5). Moreover, in patients with nephrotic range albuminuria (>3 g/day), plasma CTGF was the only predictor of ESRD (covariate-adjusted hazard ratio 4.5 [2.0-10.4]). Plasma CTGF was an independent predictor also of overall mortality (covariate-adjusted hazard ratio 1.4 [1.1-1.7]). In contrast, in normoalbuminuric patients, plasma CTGF did not correlate with clinical parameters and did not predict outcome.

Conclusions: Plasma CTGF contributes significantly to prediction of ESRD and mortality in patients with type 1 diabetic nephropathy.