Identifying Specific Causes of Kidney Allograft Loss
El-Zoghby ZM, Stegall MD, Lager DJ, et al
Am J Transplant. 2009;9:527-535. Epub 2008 Feb 3
Probability, Predictors, and Prognosis of Posttransplantation Glomerulonephritis
Chailimpamontree W, Dmitrienko S, Li G, et al; Genome Canada Biomarkers in Transplantation Group
J Am Soc Nephrol. 2009;20:843-851. Epub 2009 Feb 4
In the first study, El-Zoghby and colleagues performed a retrospective, single-center analysis of the specific causes of graft loss among 1317 kidney transplant recipients between January 1, 1996 and July 1, 2006. The patient group included 90% primary transplants, 89.5% white recipients, 72.5% from living donors, and 60% male recipients. During a mean follow-up of 50 months, 330 (25%) of the grafts were lost, including 138 (42%) due to death with a functioning graft, 39 (12%) from primary nonfunction, and 153 (46%) due to other causes.
Kidney graft biopsies were performed in 150 (98%) cases of this latter group, which was further subdivided by cause: glomerular diseases (n = 56, 37%), fibrosis/atrophy (n = 47, 31%), medical/surgical conditions (n = 25, 16%), acute rejection (n = 18, 12%), and unclassifiable (n = 7, 5%). Glomerular pathologies leading to graft failure included recurrent disease (n = 23), transplant glomerulopathy (n = 23), and presumed nonrecurrent disease (n = 10).
In cases with fibrosis/atrophy, a specific cause was identified in 81%, including 11 cases of polyomavirus nephropathy, and rarely was it attributed to calcineurin inhibitor (CNI) toxicity alone (n = 1, < 1%). Other causes of fibrosis/atrophy included acute and chronic rejection as well as recurrent pyelonephritis. Graft loss due to glomerular diseases or fibrosis/atrophy usually occurred much later compared with the other subcategories.
On the basis of these findings, the authors concluded that, contrary to current concepts, most cases of kidney graft loss have an identifiable cause that is not merely idiopathic fibrosis/atrophy or CNI toxicity. These identifiable causes include recurrent disease and antibody-mediated graft injury, which represent targets for intervention.
The second report is a Canadian epidemiologic study of 2026 primary kidney transplants (37% living donor, 56% deceased donor, and 7% unknown donor source) performed between January 1, 1990 and December 31, 2005 in patients whose original renal disease resulted from biopsy-proven glomerulonephritis (GN, 36%), presumed GN (8%), or from disorders other than GN (56%).
During a mean follow-up of 80 months, 144 patients (7%) were diagnosed with posttransplant GN. The cumulative probability of posttransplant GN in the whole population was 5.5%, 10.1%, and 15.7% at 5, 10, and 15 years post transplant, respectively. Posttransplant GN was diagnosed in 24.3% of patients whose original renal disease was GN, compared with an 11.8% incidence in patients with presumed GN and 10.5% in patients without pretransplant GN (de novo GN). Principal predictors of posttransplant GN were the presence of biopsy-proven pretransplant GN, male sex, younger age, and nonwhite ethnicity. Specific immunosuppressive modalities did not influence the probability of developing posttransplant GN. In patients with posttransplant GN, the estimated 15-year graft survival was reduced from 70% to 10% (hazard ratio, 7.45).
On the basis of these findings, the authors concluded that posttransplant GN is an important cause of graft loss following kidney transplantation and is associated with a dramatic reduction in graft survival despite the use of modern immunosuppressive regimens.
With advances in selective immunosuppression, the incidences of acute rejection and graft loss due to refractory acute rejection have decreased dramatically in the past 2 decades, resulting in current 1-year rejection-free rates above 80%, 1-year graft survival rates exceeding 90%, and 1-year patient survival rates above 95%. However, these advances have not resulted in dramatic improvements in long-term graft survival rates. The reasons for this lack of improvement remain unclear and are probably multifactorial, although it is generally believed that CNIs, which remain the mainstay of contemporary immunosuppressive regimens, are a major contributor to chronic graft loss due to nephrotoxicity.
In recent years, death with a functioning graft has become a more frequent if not the most common cause of graft loss in many series, particularly with the aging end-stage renal disease population of adults who are now candidates for transplantation. However, one of the goals of transplantation is for the allograft to outlive the patient, provided that the requisite immunosuppression does not lead to premature mortality. Modern immunosuppression, by achieving control of early graft loss due to acute rejection, has unmasked other causes of graft loss that occur later and may not be influenced by current immunosuppressive agents.
Both of the above studies highlight the importance of either recurrent/de novo glomerular disease or antibody-mediated graft injury as causes of late graft loss that are probably not susceptible to conventional immunosuppressive manipulations. Although immunologic mechanisms continue to be a major threat to the allograft, new paradigms need to be investigated on the basis of a better understanding of the patterns and pathogenesis of the various causes of death-censored graft loss.