"Nature Versus Nurture" Study of Deceased-Donor Pairs in Kidney Transplantation
Louvar DW, Li N, Snyder J, Peng Y, Kasiske BL, Israni AK
J Am Soc Nephrol. 2009;20:1351-1358
Fate of the Mate: The Influence of Delayed Graft Function in Renal Transplantation on the Mate Recipient
Johnson JF, Jevnikar AM, Mahon JL, Muirhead N, House AA
Am J Transplant. 2009;9:1796-1801
Summary
The first study, conducted by Louvar and colleagues, sought to determine the relative influence of donor characteristics ("nature") vs transplant center characteristics ("nurture") on deceased donor paired kidney transplant outcomes. With the United States Renal Data System database, a retrospective analysis was performed of 38,922 primary kidney transplants or 19,461 common donor/recipient pairs. Recipients of en bloc or dual kidney transplants, multiple organ transplants, retransplants, and cases in which only 1 kidney was transplanted were excluded. Logistic and Cox regression were used in multivariable analyses that both included and excluded 4075 transplants in which the recipient experienced allograft failure within 3 months of transplantation. Delayed graft function (DGF) occurred in 9430 (24%) patients.
Expanded criteria donor was a potent risk factor for DGF (odds ratio [OR] 1.51). Both pairs were concordant and developed DGF in 1846 cases (10%), whereas both pairs were concordant for no DGF in 11,877 cases (61%). The remaining 5738 (29%) pairs were discordant for DGF. Within common donor pairs, the unadjusted OR for DGF in the recipient of the contralateral kidney was 2.66. For the 11,894 common donor pairs transplanted at different centers, a recipient was twice as likely to develop DGF when the recipient of the contralateral paired kidney developed DGF (OR 2.05). Similarly, for common donor pairs transplanted at the same center, a recipient was 3 times as likely to develop DGF (OR 3.02).
After adjustment for DGF, the within-pair ORs for allograft failure at 1 year were 1.92 and 1.77 for recipients who underwent transplantation at the same center and different centers, respectively. On the basis of these findings, the authors concluded that there was a significant degree of correlation within pairs of kidneys transplanted from the same donor for the occurrence of DGF and allograft failure, suggesting that unmeasured donor factors (nature) contribute to transplant outcomes. These unmeasured donor factors had a higher attributable risk for DGF than an expanded criteria donor. In addition, there was a transplant center effect (nurture) on DGF but not allograft failure within the first 3 years following transplantation.
The second study, conducted by Johnson and colleagues, is a retrospective cohort review of 55 deceased donor kidneys transplanted at a single center. The primary outcome was the change in glomerular filtration rate (GFR) at 1 year post transplant. The authors compared 26 "mates" to DGF recipients vs 29 mates to non-DGF recipients. In mates to DGF recipients, the unadjusted mean change in GFR at 1 year post transplant was -11.2 mL/minute. In comparison, the mean change in GFR at 1 year post transplant in mates to non-DGF recipients was -0.4 mL/minute (P = .014 in univariate, P = .025 in multivariate analyses). No differences between groups were found in baseline GFR.
On the basis of these findings, the authors concluded that mates to DGF recipients are at significant risk for deterioration in renal function, and strategies that may preserve allograft function in these patients should be developed and implemented early.
Viewpoint
A fascinating issue in deceased donor kidney transplantation is the comparative function and outcomes of paired donor kidneys transplanted into different recipients. When kidney pairs are placed on the pulsatile perfusion pump, the pump numbers are usually concordant in the majority (approximately 80%) of cases. Pump parameters are usually (but not always) predictive of initial graft function. Because donor factors are mostly controlled for when analyzing donor pairs, differential outcomes in this setting can be ascribed to either preservation or recipient factors. With acute rejection rates decreasing to < 20% due to modern immunosuppressive strategies, increasing attention is now focused on DGF. DGF occurs in the immediate posttransplant period and results in oliguria requiring dialysis. Although the clinical severity of DGF varies, it is defined operationally as the need for dialysis in the first 7 days post transplant. Although rates of acute rejection have decreased dramatically over the past 10 years, DGF rates have remained constant. DGF occurs in approximately 25% to 50% of deceased donor kidney transplants in the United States and is directly related to donor classification (standard vs expanded criteria donor) and donor category (brain death vs donation after cardiac death).
The detrimental impact of DGF following kidney transplant is well established. Although the precise contribution of DGF to graft loss is debated, many studies have identified DGF as a predisposing factor for acute rejection and diminished graft survival. The independent contribution of DGF to graft outcome is important because it indicates that eliminating only acute rejection will not ensure optimal graft survival. DGF is also associated with significant costs due to prolonged hospitalization and increased costs of patient management.
The etiology of DGF is not well understood but is believed to have both immunologic and nonimmunologic components. Ischemia/reperfusion injury during the transplant causes a cascade of molecular events, including activation of endothelial adhesion molecules and cytokine release. Leukocyte adherence, diapedesis, and lymphocyte activation induce apoptosis, inflammation, and endothelial injury resulting in organ dysfunction. These events upregulate the immune response, increase organ alloreactivity, and enhance susceptibility to acute rejection.
The above studies highlight the importance of DGF; the relative concordance of kidney function in donor pairs; and the need to develop donor, preservation, or recipient strategies aimed at minimizing or preventing the manifestations of ischemic injury in order to optimize posttransplant outcomes.
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