Transplantation
Chronic Allograft Injury Graham Towns1
and Venkat Ramanathan2 1. Fellow; 2. Associate Professor of Medicine, Division of Nephrology, Michael E DeBakey VA Medical Center, Baylor College of Medicine
Abstract
A significant proportion of transplanted kidneys are lost due to chronic allograft injury. Chronic allograft injury may represent the cumulative burden of various alloantigen-dependent and -independent insults on the allograft over time. The resultant interstitial fibrosis and tubular atrophy (IF/TA) may actually represent non-specific repair processes in response to these injuries. To differentiate various aetiologies, Banff classification has defined morphologic clues to link specific histologic findings with clinical conditions that are associated with IF/TA, including chronic hypertension, calcineurin inhibitor toxicity, chronic obstruction, bacterial pyelonephritis and viral infection. This classification has helped pathologists and clinicians to better define the disorder and understand the pathogenesis of fibrosis and eventual graft loss. Angiotensin II and transforming growth factor-β appear to play a prominent pro-fibrotic role in this disorder.
Keywords Chronic allograft injury, chronic rejection, chronic antibody-mediated rejection, kidney transplantation, interstitial fibrosis
Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: The authors gratefully acknowledge Dr Luan D Truong, Renal Pathologist at The Methodist Hospital in Houston, for providing pathology pictures. Received: 22 March 2011 Accepted: 4 May 2011 Citation: European Nephrology, 2011;5(2):155–9 Correspondence: Venkat Ramanathan, Associate Professor of Medicine, Division of Nephrology, Michael E DeBakey VA Medical Center, Baylor College of Medicine, 1709 Dryden, 9th floor, Houston, TX 77030, US. E:
ramanath@bcm.edu
As a result, patients with allograft failure represent an expanding pool of patients who either return to dialysis or are listed for re-transplantation. Approximately 5 % of incident dialysis patients and 17 % of patients on the active waiting list for deceased donor kidney transplantation have a history of previous kidney or kidney–pancreas transplantation.1
Kidney transplantation is the best renal replacement therapy option for patients with end-stage kidney disease. However, the allograft function deteriorates with time and, according to the Organ Procurement and Transplantation Network (OPTN)/Scientific Registry of Transplant Recipients (SRTR) 2009 annual data report, the unadjusted 10-year graft survival for patients with living donor and deceased donor kidney transplantation is 59 % and 43 %, respectively.1
antibody-mediated. Even though Banff classification attempts to differentiate them into distinct histologic categories, chronic injury to the allograft may in fact be a composite endpoint and may represent a cumulative burden of insults on the allograft over time.
Definitions
Despite this knowledge, studies on chronic allograft injury are limited. Most studies in kidney transplantation have short-term study endpoints, including rate of acute rejection, one-year patient or graft survival rate, and change in serum creatinine or estimated glomerular filtration rate (eGFR) at one year of follow-up after implementation of various drug withdrawal or drug avoidance protocols. While we have made significant strides in reducing acute rejection rates to less than 10 %, we have not noted a proportionate increment in long-term graft survival rate.
provided an elaborate description and gradation of histologic changes, and also shed light on whether injury was T-cell- or
Chronic graft dysfunction is probably a result of both alloantigen- dependent and -independent factors. The older term ‘chronic allograft nephropathy’ was a generic clinical definition and did not adequately differentiate various aetiologies of graft dysfunction. Subsequent Banff classification2
© TOUCH BRIEFINGS 2011
Nephrology has witnessed a wave of nomenclature changes and chronic allograft injury is no exception. Definitions such as ‘chronic rejection’, ‘chronic allograft nephropathy’, ‘interstitial fibrosis/tubular atrophy’ (IF/TA) and ‘chronic injury’ have been used to define this clinical entity, characterised by a slow decline in kidney function accompanied by various degrees of proteinuria. Chronic rejection implies that the injury is primarily related to immunologic mechanisms. The term ‘chronic allograft nephropathy’ (CAN) does not indicate a specific aetiology and hence was ‘can’ned. IF/TA is a histologic diagnosis, purely explaining the pathologic picture. In the Banff 2005 meeting report, the term CAN was eliminated from the Banff classification and the morphology of specific conditions that are associated with IF/TA – including chronic hypertension, calcineurin inhibitor (CNI) toxicity, chronic obstruction, bacterial pyelonephritis and viral infection – was defined (see Table 1).2
According to the Banff classification, chronic active antibody-mediated rejection is defined by the presence of:
• • •
complement fragment deposition (C4d) in peritubular capillaries; circulating donor-specific antibodies (DSAs); and
histological evidence of chronic tissue injury including glomerular double contours, peritubular capillary basement membrane multilayering, IF/TA, or fibrous intimal thickening in arteries.3,4
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