Unique changes in interstitial extracellular matrix composition are associated with rejection and cyclosporine toxicity in human renal allograft biopsies

Renal allograft loss from chronic rejection or cyclosporine toxicity (CsAT) is characterized by progressive interstitial fibrosis, yet the protein com position of these lesions is unknown, The normal tubular basement membrane (TBM) contains laminin (LM), collagen IV (containing collagen IV alpha chai n 1 [COL4A1] and COL4A2), thrombospondin (TSP), and fibronectin (FN), Only TSP and FN extend beyond the TBM into the interstitial space, Very scanty a mounts of interstitial collagens (I and III) are detected in the interstiti um, In a pilot study of human renal allograft biopsy specimens, three patte rns of extracellular matrix (ECM) composition were identified. Pattern 1 sh owed no change in ECM composition; pattern 2 showed generalized accumulatio n of collagens I and III in the interstitium; and pattern 3 showed new expr ession of COL4A3 and LM-beta 3 in the proximal TBM, Criteria were establish ed for the clinicopathological diagnosis of CsAT and rejection, These diagn oses were correlated with the ECM composition in 22 renal allograft biopsy specimens. Control groups were examined in a similar manner and included na tive kidney biopsy specimens from patients with other allografts (n = 7), r enal biopsy specimens from patients with glomerular disease (n = 9), and re nal allograft biopsy specimens from patients without clinicopathological ev idence of renal disease. These data show that rejection is associated with pattern 3 and CsAT is associated with pattern 2, Thus, detection of ECM com position may be a useful adjunct to standard microscopy in distinguishing r ejection from CsAT in renal allograft biopsy specimens. These data suggest that interstitial fibrosis associated with rejection and CsAT result from d ifferent pathogenic mechanisms. This is a US government work, There are no restrictions on its use.