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.

Diminished Met Signaling in Podocytes Contributes to the Development of Podocytopenia in Transplant Glomerulopathy

“…1 Although interstitial fibrosis and tubular atrophy (IFTA) is multifactorial in origin, transplant vasculopathy and transplant glomerulopathy (TxG) are considered specific lesions of chronic allograft rejection. [2][3][4][5][6][7] The prevalence of TxG increases over time after transplantation from 5% at 1 year to 20% at 5 years. 8 Early, subdiagnostic findings include an "activated" aspect of glomerular endothelial cells (GECs), with accumulation of mitochondria, Golgi apparati, and ribosomes, and a transition from fenestrated to continuous endothelium.…”

Immunogenicity and Immune-Modulating Properties of Human Stem Cells

“…In spite of improved immunosuppressants (see below, section 7), chronic rejection is still the leading cause of graft failure and happens in >50% of solid organ transplants within 10 years (Orlando et al, 2011a). During the first year after transplantation, the survival rates of the grafts are well above 90%, but the long-term survival of the graft is compromised (Li & Yang, 2009;Meier-Kriesche et al, 2004). Thus, immunological tolerance does not establish in practice.…”

“…The purpose of deliberately induced immunosuppression in a host recipient is to prevent rejection during transplantation of nonhistocompatible (allogeneic) cells, tissues or organs, and to treat GvHD. However, the use of immunosuppresants increases the vulnerability of the individual to opportunistic infections, nephrotoxicity, cancer and even accelerated aging (Li & Yang, 2009;Nehlin and Barington, 2009). Several families of immunosuppressants have been developed such as glucocorticoids, cytostatics, therapeutic monoclonal antibodies, and many others (Duncan & Wilkes, 2005).…”

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“…They further cause renal ischemia that in the final analysis results in the fibrosis. 7,10 Calcineurin inhibitors also promote transforming growth factor-β and up-regulate apoptotic genes, which further leads to interstitial fibrosis. Furthermore, CNIs give unmediated tubular toxicity, kindling tubular atrophy.…”