Jeanne Kamal @jeanne_kamal
Jeanne Kamal is an assistant professor of medicine at the University of Virginia where she is involved in the day to day care of kidney transplant patients. She is currently the associate program director of the transplant fellowship, and works closely with Dr. Sudipa Chowdhury, a general nephrology fellow in the program.
Sudipa Chowdhury completed her internal medicine residency and gravitated towards specializing in nephrology. She is currently a second year nephrology fellow at the University of Virginia. Her interests include acute kidney injury, hypertension, and medical education.
Kidney transplantation is the gold standard treatment for patients with advanced kidney disease. In fact, increasing access to kidney transplants is one of the goals of the Advancing American Kidney Health initiative launched in 2019. The initiative specifically strives to double the number of kidneys available for transplant by 2030. However, a sharp disparity between supply and demand of organs in kidney transplantation exists. And while increasing the number of living donors is one way to increase the available organs, there has been increased interest in using kidneys from marginal donors including those with acute kidney injury (AKI) to help address organ shortage.
Most transplant centers use the kidney donor profile index (KDPI) to assist with the selection of deceased donor kidney. KDPI ranks the relative quality of a donor by looking at a total of ten variables of clinical parameters and demographic characteristics at organ procurement. A major limitation of the KDPI is its poor predictive power with a C-statistic of 0.6, roughly not much better than a coin flip in which C-statistic would be 0.5.
AKI is common in deceased kidney donors. Deceased organ donors can develop AKI in the setting of brain or cardiac death due to significant hemodynamic changes or as a sequela from intrinsic tissue injury. Transplant centers are more likely to decline donor kidneys with AKI than those without AKI. In fact, the discard rate is 30% for donor AKI kidneys compared to 18% for donor without AKI. Additionally, increasing severity of donor AKI as defined by increasing stages in AKI Network (AKIN) criteria is associated with greater risk of discard with adjusted relative risks of 1.28 (1.08-1.52) for stage 1, 1.82 (1.45-2.30) for stage 2, and 2.74 (2.0-3.75) for stage 3. The higher discard rate of donor AKI kidney may be due to a perception that having donor AKI can lead to adverse transplant outcomes.
Urinary biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1) and interleukin- 18 (Il-18) have emerged as sensitive markers of structural kidney damage. These markers help detect early stages of acute tubular injury and thus subclinical AKI. They could potentially serve as a way to judge allograft quality especially considering the scarcity of available tools. A prospective study in 1304 deceased kidney donors and 2441 respective recipients found that urinary biomarkers were strongly associated with donor AKI. However, they added minimal value in predicting delayed graft function (DGF) or early allograft function after transplant (Reese et al. in JASN). So why is donor AKI not associated with worse allograft outcomes?
The “injury hypothesis” suggests that the reperfusion injury caused by reactive oxygen species stimulates the innate immunity of donor and recipient as well as the adaptive immune response via Toll-like receptors increasing the risk for T and B-cell mediate rejection. The latter is mediated by the formation of donor specific anti-human leukocyte antigen (HLA) antibodies (DSA). Prolonged immunological injury caused by DSA leads to chronic rejection, fibrosis and allograft loss. AKI-induced tissue injury is caused by multiple inflammatory pathways similar to those encountered in the ischemia reperfusion injury (IRI). So could donor AKI cause similar immunological outcomes to those encountered in IRI?
Post-transplant immunological outcomes, associated with the use of kidneys from donors with AKI were analyzed by Reese et al. in AJKD 2022. This is a multicenter, prospective cohort that included 1,137 deceased-donor kidney transplant recipients from 13 transplant centers (5 organ procurement organizations). Donor kidney injury was assessed by terminal serum Cr, or the elevation in urinary biomarkers (IL-18, KIM-1, NGAL).
Recipients’ mean age was 54 years old, 61% were male, and 46% were Black. In terms of sensitizing events, 14% received a previous kidney transplant and 15% had a PRA >80. 85% received T-cell depleting induction (83% rabbit antithymocyte globulin (rATG), 3% alemtuzumab) and 15% received basiliximab. Most patients (96% tacrolimus, 1% cyclosporine) had calcineurin-inhibitor based maintenance immunosuppressive regimen. DGF was encountered in 37% of patients. About 73% of the kidneys came from donors without AKI, 16% from donors with stage 1 AKIN, 6% from donors with stage 2 AKIN, and 5% from donors with stage 3 AKIN. In 8% of donors, only one kidney was procured while the mate kidney was discarded; however, there is no information available whether these came from donors with kidney injury.
The primary composite outcome of graft failure or biopsy proven acute rejection (BPAR) at 1 year after transplant was encountered in 159 (14%) patients (107 BPAR). The patients’ risk factors were similar to those previously reported in the literatures including black race (57% vs. 45%, p 0.003), recipients with DGF (54% vs. 35% p <0.001) and those with high immunological risk such as previous transplant (19% vs. 13%, p 0.04), sensitizing events (PRA >80% 21% vs. 14% p 0.05), and more HLA mismatch (4.57 ± 1.23 vs. 4.32 ± 1.34 p 0.02). There was no association between donor AKI or urinary biomarkers and the composite primary outcome (graft failure or BPAR) nor with the secondary composite outcome that included de novo DSA development.
One of the limitations of this study, as mentioned by the authors, was that BPAR was evaluated only on for-cause biopsies. Protocol biopsies were not done, nevertheless subclinical rejection didn’t lead to adverse graft outcomes, owing to a potent immunosuppressive regimen. Genetic expression using donor-derived cell free DNA was not evaluated in this study. It is reassuring that similar outcomes were achieved despite including multiple academic centers with variable clinical protocols. One can conclude that contemporary immunosuppression regimens utilizing rATG induction and tacrolimus and mycophenolic acid maintenance mitigate the potential immunological risk associated with using kidneys with AKI.
Recent studies have shown that good short and long-term outcomes can be achieved with donor kidneys with AKI. The exact mechanism of graft survival despite donor AKI and DGF is unclear. AKI causes tissue inflammation through complement activation and enhanced expression of toll-like receptors. Macrophages and regulatory T cells help repair AKI. While donor AKI may aggravate inflammation in the allograft, advances in surgical techniques, immunosuppression regimens, and post-transplant monitoring protocols may dampen the immunological sequelae of inflammation after kidney transplantation. In addition, the post-transplant complications experienced by recipients (immunosuppression, acute rejection, infections (BK virus, CMV), frequent hospitalizations) may have more impact on graft survival than isolated donor factors. Finally, there has been some speculation that donor AKI may initiate ischemic preconditioning and upregulate mechanisms that protect against IRI during transplantation.
As an increasing number of patients are listed as transplant recipient candidates, the need to expand the donor pool has led to the acceptance of “less-than-perfect kidneys”. The decision to accept a kidney with AKI is complex, involving not only factors related to the donor but also taking in consideration recipient characteristics and transplant center resources. The KDPI score alone has limited value when assessing post-transplant graft viability. While the search for better predictive tools of allograft function continues, current evidence supports the notion that donors with AKI are more likely to have DGF but still retain similar long-term outcomes as donors without AKI. The evidence may point to the fact that ischemic pre-conditioning, advances in transplant medicine, and post-transplant and recipient factors may be exerting a more prominent role in long-term graft survival than donor factors alone. Findings may be skewed by selection bias of transplanting only relatively healthy donor kidneys with AKI. Improving our understanding of the impact of donor AKI on post-transplant outcomes will lead to less discard rates and will eventually expand the availability of life-saving organs for recipients on the waitlist.
– Post prepared by Jeanne Kamal and Sudipa Chowdhury
Title: Deceased-Donor Acute Kidney Injury and Acute Rejection in Kidney Transplant Recipients: A Multicenter Cohort
Authors: Peter P. Reese, Mona D. Doshi, Isaac E. Hall, Behdad Besharatian, Jonathan S. Bromberg, Heather Thiessen-Philbrook, Yaqi Jia, Malek Kamoun, Sherry G. Mansour, Enver Akalin, Meera N. Harhay, Sumit Mohan, Thangamani Muthukumar, Bernd Schröppel, Pooja Singh, Francis L. Weng, and Chirag R. Parikh