Delta Analysis of Posttransplantation Tubulointerstitial Damage

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Abstract
Chronic interstitial fibrosis (CIF) is an adverse prognostic feature of chronic allograft nephropathy. We evaluated the evolution, onset, potential causes, and outcomes of tubulointerstitial damage using 959 protocol kidney biopsy specimens obtained regularly until 10 years after transplantation. Specimens were scored by the Banff schema and analyzed for time-specific change or “delta damage” from sequential biopsy-pairs (n=839). Substantial CIF occurred within 1 year after transplantation, comprising 67.6% of the total burden accumulated during the study period. The maximal intensity of CIF formation occurred within the first 3 months, as a result of acute tubular necrosis and acute and subclinical rejection (all P<0.05), where fibrosis rates exceeded loss from tubular atrophy. By 1 year, diminished CIF formation was accompanied by declining low-level subclinical inflammation (P<0.001) and increasingly prevalent calcineurin inhibitor nephrotoxicity (P<0.01). Banff CIF correlated with tubular atrophy (r=0.82, P<0.001), with tubulointerstitial damage showing a cumulative and irreversible pattern. Mononuclear cell infiltration within areas of tubulointerstitial damage correlated with CIF (r=0.49, P<0.001), tubular atrophy (r=0.43, P<0.001), and Banff i scores (r=0.34, P<0.001) and, most importantly, heralded histologic progression (P<0.001). CIF formation preceded and correlated with glomerulosclerosis (r=0.40, P<0.001), although isotopic glomerular filtration rates underestimated the severity of tubular damage. Cyclosporine (vs. tacrolimus, P<0.001) increased delta CIF, and mycophenolate was protective (vs. azathioprine, P<0.001), independent of their immunosuppressive and nephrotoxic properties when assessed by multivariate analysis of biopsy-pairs (n=849). CIF was a result of early ischemia-reperfusion injury, acute, subacute or persistent interstitial inflammation occurring in a time-dependent manner and was considerably modified by immunosuppressive therapy.