Acute rejection-associated tubular basement membrane defects and chronic allograft nephropathy

Background Acute rejection is a major risk factor for chronic allograft nep hropathy, although the link(s) between these events is not understood. The hypothesis of this study is that alterations in tubular basement membranes (TBMs) that occur during acute rejection may be irreversible and thereby pl ay a role in the development of chronic allograft nephropathy. Methods. Fourteen renal transplant patients were selected, each having had two or more biopsies performed (42 total). All biopsies were scored for acu te and chronic rejection using Banff 1997 criteria. The initial biopsy show ed only acute interstitial rejection (type I rejection). No biopsies contai ned significant chronic arterial lesions of chronic vascular rejection. The entire cortex was examined on Jones methenamine silver-stained sections at X400 for interruption in TBM staining. The number of tubules with TBM abno rmalities was counted, and the renal cortical area was measured by image an alysis. Periodic acid-Schiff/immunoperoxidase stain was performed on 12 acu te rejection biopsies stained for laminin, cytokeratin 7, CD3, CD20, and CD 68. Controls consisted of 11 biopsies (s negative for rejection and 3 acute tubular necrosis). Results. Numerous TBM alterations in silver staining were identified as bei ng associated with acute rejection and tubulitis, consisting of abrupt TBM discontinuities and/or extreme attenuation with segmental or complete absen ce of TBM. A loss of TBM matrix proteins was confirmed by absent laminin st aining in areas of acute rejection and tubulitis. There was herniation of t ubular cells into the interstitium through TBM defects confirmed by cytoker atin staining. The TBM defects were spatially associated with inflammatory cells, particularly macrophages. When the biopsies were divided into two gr oups, <10 and >10 TBM breaks/mm(2), there were statistically significant mo rphologic and clinical correlations. The number of TBM disruptions correlat ed with the serum creatinine at the time of biopsy, a combined Banff t + i score, the difference in tubular atrophy between the initial and most recen t biopsy and the difference between the nadir creatinine and most recent cr eatinine. Conclusion. Damage to TBM develops in acute rejection as a consequence of i nterstitial inflammation and tubulitis. These lytic events correlate with t he later development of clinical and morphologic evidence of chronic injury in the absence of arterial injury of chronic rejection. We suggest that ch ronic allograft nephropathy may have an inflammatory interstitial origin.