NDT Advance Access originally published online on October 12, 2005
Nephrology Dialysis Transplantation 2005 20(12):2812-2819; doi:10.1093/ndt/gfi172
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Chronic allograft nephropathy: expression and localization of PAI-1 and PPAR-
1 Department of Pathology, 2 Department of Biostatistics and Medicine and 3 Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA
Correspondence and offprint requests to: Agnes B. Fogo, MD, Department of Pathology, C3310 Medical Center North, Vanderbilt University Medical Center, Nashville, TN 37232-2561. Email: agnes.fogo{at}vanderbilt.edu
Background. Chronic allograft nephropathy (CAN) is a major cause of loss of renal allografts. Mechanisms postulated to be involved include sequelae of rejection, warm ischaemia time, drug toxicity, ongoing hypertension and dyslipidaemia. Plasminogen activator inhibitor-1 (PAI-1) is implicated not only in thrombosis, but also in fibrosis, by inhibiting matrix degradation, and is expressed in renal parenchymal cells as well as in macrophages. Peroxisome proliferator-activated receptor-
(PPAR-) is a member of the steroid receptor superfamily, and plays a major beneficial role in lipid regulation, insulin sensitivity and macrophage function, factors that may play a role in CAN. We therefore studied the expression of these molecules in CAN.
Methods. All renal biopsy/nephrectomy files from Vanderbilt and Nashville VAMC from a 6 year period were reviewed to identify all renal transplant biopsies or nephrectomies more than 6 months after transplant with CAN. CAN was defined as fibrosis in the graft, vascular, interstitial or glomerular. All cases were scored for severity of fibrosis in vasculature (0–3 scale), glomeruli (% affected with either segmental and/or global sclerosis) and interstitial fibrosis (% of sample affected). PAI-1 and PPAR- immunostaining was assessed on a 0–3 scale in glomeruli, vessels and tubules.
Results. Eighty-two patients with a total of 106 samples met entry criteria. The population consisted of 59 Caucasians and 23 African-Americans; 49 males, 33 females with average age 37.9±1.7 years. Average time after transplant at time of biopsy was 60.5±4.9 months (range 7–229). Glomerulosclerosis extent in CAN was on average 26.5±2.4% compared with 3.6±1.2% in normal control kidneys from native kidney cancer nephrectomies and 0% in transplanted kidney biopsies from patients obtained 
6 months after transplantation without CAN. Native control kidneys showed mild interstitial fibrosis (8.0±1.2%), whereas transplant controls showed very minimal fibrosis (2.0±2.0%). Interstitial fibrosis in CAN kidneys was on average 47.9±2.4%. Glomerular PAI-1 and PPAR- staining scores were markedly increased in CAN (1.8±0.1, 2.3±0.1, respectively) compared with normal control kidneys from native kidney cancer nephrectomies (PAI-1 0.2±0.2 and PPAR- 0.4±0.2, P<0.001) and transplanted kidney biopsies from patients obtained 6 months after transplantation without CAN (PAI-1 0 and PPAR- 0, P<0.001). Tubular PAI-1 and PPAR- staining scores were 1.9±0.1 and 1.9±0.1, respectively, and also increased over both native and transplant kidney controls (0.8±0.2 for both categories for PAI-1, 1.2±0.2 for both categories for PPAR-, respectively). Vascular sclerosis in CAN was 1.0±0.1 with increased PAI-1 and PPAR- scores (1.7±0.1, 1.2±0.1, respectively) compared with controls. Infiltrating macrophages were increased in CAN, and were positive for both PAI-1 and PPAR-. Biopsies with less sclerosis overall showed a trend for less PAI-1 and PPAR- staining.
Conclusion. PAI-1 and PPAR- are both increased in CAN compared with non-scarred native or transplant control kidneys. We speculate that altered matrix metabolism and macrophage function might be involved in the development of CAN.
Keywords: chronic allograft nephropathy; macrophage; peroxisome proliferator-activated receptor-; plasminogen activator inhibitor-1
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