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The pathogenesis and treatment of chronic allograft nephropathy

Abstract

Despite improvements in immunosuppressive therapy, long-term allograft survival after kidney transplantation remains as low as 50%. Chronic allograft nephropathy (CAN) is a major cause of late graft loss in renal transplant recipients. The histopathologic signs of CAN—interstitial fibrosis, tubular atrophy, glomerulopathy and vasculopathy—are nonspecific; therefore, the 2007 Banff classification dispensed with the term CAN in favor of 'interstitial fibrosis and tubular atrophy without evidence of any specific etiology'. In this Review, however, the term CAN is used to describe a clinical syndrome that is characterized by progressive decline in renal function from 3 months after transplantation, accompanied by the development of proteinuria and hypertension. The pathogenesis of CAN is complex and incompletely understood, and involves several immunological and non-immunological factors. We discuss the contributory roles of acute rejection, donor age, anti-human-leukocyte-antigen antibodies, calcineurin inhibitor nephrotoxic effects, viral infection, hypertension and hyperlipidemia. The prevention and treatment of CAN needs multidisciplinary strategies. Early detection by means of protocol biopsy and calculation of glomerular filtration rate is the first step, followed by management of modifiable risk factors.

Key Points

  • Chronic allograft nephropathy (CAN) is characterized by declining graft function, hypertension and proteinuria; the accompanying pathology is defined as 'interstitial fibrosis and tubular atrophy without evidence of any specific etiology'

  • Acute rejection, donor age, anti-human-leukocyte-antigen antibodies, viral infection, hypertension, hyperlipidemia and use of calcineurin inhibitors contribute to CAN

  • Prolonged endoplasmic reticulum stress caused by the calcineurin inhibitor ciclosporin induces apoptotic cell death in renal allografts by depleting molecular chaperones

  • Protocol biopsy and calculation of glomerular filtration rate are recommended to facilitate early diagnosis of CAN, and reduction of exposure to calcineurin inhibitors (for example, by substitution of non-nephrotoxic drugs) is advisable

  • Angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers are recommended to treat hypertension and proteinuria, and ezetimibe, a novel inhibitor of intestinal cholesterol absorption, can be used in cases of statin-resistant hyperlipidemia

  • CAN in grafted kidneys mirrors chronic kidney disease in native kidneys; therefore, patients with CAN should be managed according to their stage of chronic kidney disease

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Figure 1: Histopathology of chronic allograft nephropathy.
Figure 2: Pathways of chronic ciclosporin-induced renal injury.

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Li, C., Yang, C. The pathogenesis and treatment of chronic allograft nephropathy. Nat Rev Nephrol 5, 513–519 (2009). https://doi.org/10.1038/nrneph.2009.113

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