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.

[1]  D. Kuypers,et al.  Diagnosis and prevention of chronic kidney allograft loss , 2011, The Lancet.

[2]  J. Wetzels,et al.  Renal proximal tubular dysfunction is a major determinant of urinary connective tissue growth factor excretion. , 2010, American journal of physiology. Renal physiology.

[3]  R. Goldschmeding,et al.  Connective tissue growth factor (CTGF/CCN2) is increased in peritoneal dialysis patients with high peritoneal solute transport rate. , 2010, American journal of physiology. Renal physiology.

[4]  Huaiqiang Sun,et al.  Urinary connective tissue growth factor increases far earlier than histopathological damage and functional deterioration in early chronic renal allograft injury , 2009, Scandinavian journal of urology and nephrology.

[5]  Y. Lu,et al.  Inhibition of connective tissue growth factor by small interfering RNA prevents renal fibrosis in rats undergoing chronic allograft nephropathy. , 2008, Transplantation proceedings.

[6]  F. Jakob,et al.  Connective Tissue Growth Factor Does Not Affect Transforming Growth Factor-Beta 1-Induced Smad3 Phosphorylation and T Lymphocyte Proliferation Inhibition , 2008, International Archives of Allergy and Immunology.

[7]  D. Abraham,et al.  Connective tissue growth factor: Structure–function relationships of a mosaic, multifunctional protein , 2008, Growth factors.

[8]  E. Lerut,et al.  CYP3A5 and CYP3A4 but not MDR1 Single‐nucleotide Polymorphisms Determine Long‐term Tacrolimus Disposition and Drug‐related Nephrotoxicity in Renal Recipients , 2007, Clinical pharmacology and therapeutics.

[9]  A. Gressner,et al.  Differential effects of TGF-beta on connective tissue growth factor (CTGF/CCN2) expression in hepatic stellate cells and hepatocytes. , 2007, Journal of hepatology.

[10]  G. Russ,et al.  Kidney Transplant Rejection in Australia and New Zealand: Relationships Between Rejection and Graft Outcome , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[11]  M. Rico,et al.  Connective tissue growth factor (CTGF/CCN2) is a downstream mediator for TGF‐β1‐induced extracellular matrix production in osteoblasts , 2007, Journal of cellular physiology.

[12]  F Verrecchia,et al.  [Cellular and molecular mechanisms of fibrosis]. , 2006, Annales de pathologie.

[13]  R. Mannon,et al.  Connective Tissue Growth Factor is a Biomarker and Mediator of Kidney Allograft Fibrosis , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[14]  R. Johnson,et al.  Hypoxic induction of Ctgf is directly mediated by Hif-1. , 2004, American journal of physiology. Renal physiology.

[15]  Philip F Halloran,et al.  Banff 2003 Meeting Report: New Diagnostic Insights and Standards , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[16]  J. Schold,et al.  Long‐Term Renal Allograft Survival: Have we Made Significant Progress or is it Time to Rethink our Analytic and Therapeutic Strategies? , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[17]  Gary R. Grotendorst,et al.  Combinatorial signaling pathways determine fibroblast proliferation and myofibroblast differentiation , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  W. Daniel,et al.  Activated human platelets release connective tissue growth factor , 2004, Thrombosis and Haemostasis.

[19]  D. Ganten,et al.  Angiotensin II induces connective tissue growth factor gene expression via calcineurin-dependent pathways. , 2003, The American journal of pathology.

[20]  M. Fishbein,et al.  Antibody‐Mediated Rejection Criteria – an Addition to the Banff ′97 Classification of Renal Allograft Rejection , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[21]  K. Nakao,et al.  Role of connective tissue growth factor in fibronectin expression and tubulointerstitial fibrosis. , 2002, American journal of physiology. Renal physiology.

[22]  T. Nakaki,et al.  Static Pressure Regulates Connective Tissue Growth Factor Expression in Human Mesangial Cells* 210 , 2001, The Journal of Biological Chemistry.

[23]  M. Spiteri,et al.  Enhanced insulin-like growth factor binding protein-related protein 2 (Connective tissue growth factor) expression in patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis. , 1999, American journal of respiratory cell and molecular biology.

[24]  V. Paradis,et al.  Expression of connective tissue growth factor in experimental rat and human liver fibrosis , 1999, Hepatology.

[25]  A. Levey,et al.  A More Accurate Method To Estimate Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation , 1999, Annals of Internal Medicine.

[26]  H. E. Hansen,et al.  The Banff 97 working classification of renal allograft pathology. , 1999, Kidney international.

[27]  R. Bende,et al.  Expression of connective tissue growth factor in human renal fibrosis. , 1998, Kidney international.

[28]  Gary R. Grotendorst,et al.  Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders. , 1996, The Journal of investigative dermatology.

[29]  Gary R. Grotendorst,et al.  Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10 , 1991, The Journal of cell biology.

[30]  H. Parving,et al.  Urinary connective tissue growth factor excretion correlates with clinical markers of renal disease in a large population of type 1 diabetic patients with diabetic nephropathy. , 2006, Diabetes care.