November 12-17, 2003
American Society of Nephrology (ASN) Renal Week 2003, San Diego, CA.

Connective Tissue Growth Factor (CTGF): A Biomarker of Chronic Allograft Nephropathy (CAN). Roslyn B. Mannon, Orlena Cheng, Xiaojie Zhang, Steven Hoffmann, William Usinger, Allan Kirk. TAB, NIDDK/NIH/DHHS, Bethesda, MD; FibroGen, South San Francisco, CA.

CAN continues to be one of the leading causes of late graft failure despite improvements in immunosuppressive strategies. Recently, we demonstrated that CTGF, a pleiotropic cytokine and downstream effector of TGF, is upregulated in mouse kidney allografts with CAN but not in nonrejecting isografts. We hypothesize that CTGF is upregulated in human transplant recipients and may be a valuable marker of disease. To this end, we prospectively measured CTGF protein by ELISA in the serum and urine of kidney transplant recipients (N=26) and obtained protocol kidney biopsy tissue at reperfusion and at serial intervals post-transplant for gene expression analysis.

In transplant recipients, serum (49.13.5 ng/ml) and urine (32.26.0 ng/mg creatinine) CTGF levels were significantly elevated compared to nontransplanted, healthy individuals (n=10; 3.91.3 ng/ml and 0.80.2 ng/mg creatinine respectively; p<0.001). While neither serum nor urinary levels correlated with recipient demographics, graft factors, or immunosuppression, mean urinary CTGF levels were highest in recipients with biopsy proven CAN (54.716.0 ng/mg creat), and lowest in recipients with normal histology (22.24.0 ng/mg creat; p=0.02). We also measured CTGF mRNA expression in protocol kidney biopsies by real-time PCR. In 5 patients with grade 2 or 3 CAN by Banff criteria, CTGF mRNA was 3-8-fold higher compared to normal kidney tissue, detected as early as day 19 post-transplant. While there were no significant increases in CTGF mRNA expression in recipients with acute cellular rejection, subclinical cellular rejection or normal histology, there was a 5-fold increase in CTGF expression in biopsies following reperfusion (p=0.01). Thus, CTGF is highly expressed in human transplant recipients with CAN. Furthermore, marked elevation in expression of this fibrogenic cytokine is seen following graft ischemia and reperfusion. These studies suggest that the induction of CTGF following transplantation may regulate the fibrogenic process of CAN. Understanding the regulation of this molecule may allow for earlier diagnosis and treatment of this disorder.