Chronic allograft nephropathy: current concepts and future directions.
The paradigm that chronic rejection causes all progressive late allograft failure has been replaced by a hypothesis of cumulative damage, where a series of time-dependent immune and nonimmune mechanisms injure the kidney and lead to chronic interstitial fibrosis and tubular atrophy, representing a final common pathway of injury and its consequent fibrotic healing response. Allograft damage is common, progressive, time-dependent, clinically important and modified by immunosuppression. Early after transplantation, tubulointerstitial damage is predominantly related to ischemia reperfusion injury, acute tubular necrosis, acute and subclinical rejection and/or calcineurin inhibitor nephrotoxicity, superimposed on preexisting donor disease. Later, cellular inflammation lessens and is replaced by microvascular and glomerular injury from calcineurin inhibitor nephrotoxicity, hypertension, immune-mediated fibrointimal vascular hyperplasia, transplant glomerulopathy and capillary injury, polyoma virus and/or recurrent glomerulonephritis. Additional mechanisms of injury include internal architectural disruption of the kidney, cortical ischemia, persistent chronic inflammation, replicative senescence, cytokine excess and fibrosis induced by epithelial-to-mesenchymal transition. Current understanding of the etiology, pathophysiology and evolution of pathological changes are detailed. An approach to histological assessment of the individual failing graft are presented and a series of postulates are defined for future studies of chronic allograft nephropathy.
Nankivell
Brian J
BJ
Department of Renal Medicine, University of Sydney, Westmead Hospital, Sydney, Australia. brian_nankivell@wsahs.nsw.gov.au
Chapman
Jeremy R
JR
D005544:Forecasting; D005921:Glomerulonephritis / Q000209:etiology / Q000276:immunology / Q000473:pathology; D006084:Graft Rejection / Q000209:etiology* / Q000473:pathology* / Q000628:therapy; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology* / Q000276:immunology / Q000473:pathology*; D016030:Kidney Transplantation / Q000473:pathology*; D012008:Recurrence