INFLUENCE OF NEPHRON MASS IN THE DEVELOPMENT OF NEPHROSCLEROSIS AFTER RENAL WARM ISCHEMIA

Abstract

189 Kidney transplantation from non-heart-beating donors when warm ischemia is longer than 45 min is associated to a very poor graft outcome. We evaluated, in the absence of alloresponse, the long-term consequences of prolonged renal warm ischemia in uninephrectomized and non-nephrectomized rats. Male Sprague-Dawley rats (250-300 g) were subjected to 60 minutes of renal warm ischemia and followed for 52 weeks. Animals were organized in four groups: 2NK: sham-operated rats; 1NK: uninephrectomized rats without ischemia; 2WIK: rats with two ischemic kidneys; 1WIK: rats with left renal warm ischemia and right nephrectomy. Additional animals were studied at 24 h (serum creatinine (sCr, mg/dl), renal histology and apoptosis), at 7 days (sCr and renal histology), and at 16th and 32th wk (renal histology and tissue mRNA TGF-β1 (RT-PCR, TGF-β1/β-actin)). In the long-term follow-up until 52 wk, proteinuria (Prot/u, mg/24h), cholesterol and sCr were determined every four weeks. At the end of the study, blood arterial pressure, GFR and RPF (inulin and PAH cl., ml/min/g kidney) were measured and kidneys harvested for renal histology, TGF-β1 immunolocalization and mRNA TGF-β1. Glomerulosclerosis was estimated (%GS, × 100 glomeruli) Twenty-four h after ischemia, rats from 2WIK and 1WIK groups had a similar degree of acute renal failure (ARF), similar histological score of renal injury, and similar number of apoptotic tubular cells in the inner stripe of the outer medulla. Recovery of renal function during the first week after ischemia was faster in rats from 2WIK than in the 1WIK group. As early as 8 wk after ischemia, 1WIK rats developed progressive proteinuria. In contrast, proteinuria profile in 2WIK rats paralleled to that in 1NK rats. Only rats from 1WIK group developed hypercholesterolemia, chronic renal failure, glomerulosclerosis, interstitial fibrosis and from 16th wk, had up-regulation of TGF-β1 gene expression. By immunohistochemistry, TGF-β1 protein was mainly identified in tubular epithelial cells and in areas of mononuclear interstitial cell infiltrate. (Table)TableThis study shows that prolonged warm ischemia on 100% nephron mass is not associated to the development of chronic renal damage in contrast to the severe renal dysfunction observed when renal mass in reduced by 50%. These data may be of interest to improve the poor long-term results of non-heart-beating renal transplants associated to prolonged renal warm ischemia time.