Nature and mediators of renal lesions in kidney transplant patients given cyclosporine for more than one year

Background. Cyclosporine (CsA) has improved patients and organ-graft surviv al rates, but its chronic nephrotoxicity is still an issue. Although prolon ged vasoconstriction could contribute to chronic CsA tubulointerstitial cha nges by producing chronic ischemia, this relationship has been difficult to demonstrate thus far, and cellular origin and mediators of these structura l alterations remain ill-defined. Methods. As a part of a clinical trial in kidney transplant recipients on t riple immunosuppressive therapy (CsA, azathioprine and steroid), which incl udes renal biopsy as "per protocol," 22 patients enrolled between 12 and 24 months posttransplantation underwent renal hemodynamic evaluation by measu ring glomerular filtration rate and renal plasma how by the plasma clearanc e of unlabeled iohexol and the renal clearance of para-aminohippuric acid, respectively. In parallel, the CsA pharmacokinetic profile was also determi ned. A week later, a protocol biopsy of kidney graft was performed. Light m icroscopy examination and localization of endothelin-l, RANTES, monocyte ch emoattractant protein-1 gene expression by in situ hybridization in the gra ft specimens were evaluated and related to the pattern of histologic lesion s. Results. Ten out of 22 kidney transplant recipients who underwent the proto col biopsy had CsA nephrotoxicity, eight had chronic rejection, and four ha d no lesions at histological examination. The total daily exposure to CsA w as higher in patients with CsA nephrotoxicity than in those with chronic re jection or no lesions at biopsy. Renal function was preserved in the CsA to xicity group as compared with the chronic rejection group, despite some deg ree of renal hypoperfusion. Tubular atrophy and striped interstitial fibros is were found in all patients with light microscopical evidence of CsA neph rotoxicity, whereas glomerular and arteriolar lesions were less frequent. I ntense staining for endothelin-l, RANTES, and monocyte chemoattractant prot ein-1 mRNAs selectively localized at tubular epithelial cells was found in biopsies taken from patients with CsA nephrotoxicity, but not in the chroni c graft rejection group, whose tubuli had only minimal staining for RANTES mRNA on a few occasions. Conclusion. Long-term CsA administration to kidney allograft recipients lea ds to tubulointerstitial injury independently of its vascular effect. The p ossible contribution to the development of interstitial fibrosis of inflamm atory and growth factors released by tubular cells in which CsA accumulates is proposed.