DONOR ACUTE KIDNEY INJURY IN CURRENT PRACTICE
Transplant centers strive to appropriately accept high-quality organs for transplantation while limiting discard of potentially viable organs. Optimizing this decision-making is particularly important in the context of donor organ shortages. Over 90 000 people are on the kidney transplant waitlist in the United States; unfortunately, approximately 5000 people on the waitlist die each year waiting for a transplant.1 Nearly 20% of kidneys are discarded, some of which may be suitable for transplantation.2
When offered an organ from an organ procurement organization, transplant centers and clinicians must make the difficult decision to accept or reject within minutes. Factors that guide decision-making include donor age, history of hypertension or diabetes, serum creatinine, hepatitis C virus serostatus, donation after cardiovascular determination of death, and panel reactive antibody, among others. Surgeons often use the kidney donor profile index (KDPI) as a useful tool to guide decision-making. The KDPI uses 10 donor factors to compute an aggregate score between 0 and 100% that assesses relative risk of failure compared with other reference donors in the past year.3 Although higher KDPI overall correlates with higher risk of graft failure, there is still large variation in outcomes among kidneys with the same KDPI value, even among kidneys with high KDPI.4 The C statistic, which evaluates the discriminatory power of a test and ranges from 0.5 to 1.0, is only 0.60 for KDPI.5,6
Another challenge of the current kidney transplantation process is differentiating donor kidneys with acute kidney injury (AKI) versus chronic kidney disease (CKD). The KDPI only includes terminal creatinine values, which do not clarify whether donor kidneys experienced acute elevations in serum creatinine from baseline. For example, if a donor has a baseline creatinine of 1 mg/dL and a terminal creatinine level of 3 mg/dL, this kidney may have AKI that would make this organ viable for transplantation. However, if the donor’s baseline was approximately 3 mg/dL, then this kidney may have CKD that would not recover from injury the same way an AKI kidney would recover. One creatinine value does not reflect the recent trend of values. Accordingly, transplant surgeons can utilize the patient’s entire chart to interpret how creatinine levels for a donor has changed over an admission or preimplantation biopsy data when available to categorize injury as acute versus chronic and screen for more severe cortical necrosis.7 Transplant surgeons use the KDPI in the context of the full medical chart of the donor, including admission, peak, and terminal creatinine levels from DonorNet and biopsy data when available.
Using donor kidneys with AKI may be a source of additional viable organs. Kidneys with AKI are discarded at a higher rate than donor kidneys without AKI (30% versus 18% discard rate).8 Donor AKI was an independent risk factor for discard in an analysis adjusting for components of kidney donor risk index (eg, age, height, race, death from stroke, history of hypertension) with an adjusted relative risk of discard of 1.55 (95% CI, 1.34-1.79). Higher AKIN stages were associated with greater risk of discard versus no donor AKI, with adjusted relative risks of 1.28 (1.08-1.52), 1.82 (1.45-2.30), 2.74 (2.0-3.75) for stage 1, 2, and 3 AKI, respectively.8 Discard rate by AKI stage is described in Table 1. An analysis of kidney transplants from 1995 to 2007 also showed a 7-fold and 2.7-fold higher discard risk among standard criteria donor kidneys with terminal serum creatinine >2.0 mg/dL and 1.6–2.0 mg/dL relative to those with serum creatinine ≤1.5 mg/dL.9 Discard rate is also associated with KDPI (discard rate = 3.1%, 47.5%, 49.4% for KDPI 0%–20%, 21%–85%, >85%, respectively).2
DEFINING ACUTE KIDNEY INJURY
Clinically, transplant surgeons typically use terminal serum creatinine and urine output values to identify AKI among donors. Various classifications systems were developed to categorize kidneys into stages of injury. In 2004, the Risk, Injury, Failure, Loss, End-stage criteria provided the first consensus definition of acute renal failure and used estimated glomerular filtration rate (eGFR), low urine output, and relative change from baseline serum creatinine within 7 days.10 In 2007, the Acute Kidney Injury Network (AKIN) established a modified consensus definition of AKI using changes in absolute serum creatinine or from baseline within 48 hours and low urine output.11 Finally, in 2012, Kidney Disease Improving Global Outcomes combined the RIFLE and AKIN criteria to incorporate both relative change from baseline serum creatinine within 7 days, changes in absolute serum creatinine within 48 hours, and low urine output.12 In a study evaluating the predictive value of these criteria, short-term and long-term risk of death or need for renal replacement therapy following AKI is greatest when both serum creatinine and urine output criteria are met.13 Kim et al14 also found the Kidney Disease Improving Global Outcomes criteria more effectively predicted delayed graft function (DGF) versus AKIN criteria, but long-term function was comparable between both criteria. Research studies analyzing the association of donor AKI on posttransplant outcomes have primarily used change in creatinine or terminal creatinine values to define AKI.
More Sensitive Markers of AKI
Although serum creatinine is frequently used clinically to define AKI, serum creatinine is not the most sensitive marker of AKI. Therefore, using serum creatinine as a measure of AKI can sometimes miss kidney injury, with an estimated rate of false negatives between 15% and 20%.15 The term subclinical AKI reflects the presence of injury biomarkers in the absence of serum creatinine-defined AKI.15,16 To estimate the rate of subclinical AKI, Moledina et al17 analyzed histological samples of kidneys that did not have serum creatinine-defined AKI. This study found that 18% and 9% of these kidneys from hospitalized deceased donors had histological mild and severe acute tubular injury (ATI), respectively. However, categorization of ATI differs by pathologist which may also influence the relationship between histology and AKI.18
Urine Injury Biomarkers Have Emerged as More Sensitive Markers of AKI
Urine injury biomarkers, such as microalbumin, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), interleukin (IL)-18, and liver-type fatty acid–binding protein, are present within 1 to 4 hours of ATI.19,20 As a result, research studies have utilized these markers to study kidney injury and transplant outcomes. How to appropriately integrate more sensitive markers of AKI into clinical practice remains an area for investigation.
Biomarker investigations have broadened to capture the effects of injury on kidneys and to predict and study the responses of kidney to injury. For example, YKL-40 and uromodulin are being measured for assessing kidney response to injury. YKL-40 is a glycoprotein found in a variety of white blood cells that is involved in inflammation and repair and is associated with repair from AKI and DGF.21 However, these biomarkers are not clinically available, and future studies can consider how to accurately incorporate repair biomarkers into the evaluation of recovery from AKI in renal transplantation.
DONOR AKI AND POSTTRANSPLANT OUTCOMES
We identified 37 studies that compared posttransplant outcomes of kidneys with donor AKI versus no AKI. To compile these studies, we searched “donor acute kidney injury graft failure” in PubMed on August 7, 2019, and included studies that compared outcomes of a donor AKI group versus a nondonor AKI group. Of the 37 studies, 13 used cohorts from the United States.
A summary of results is provided in Table 2.
Delayed Graft Function
We identified 23 studies that showed the association between donor AKI and DGF, defined as need for renal replacement therapy within 1 week of transplantation.8,14,24-44 DGF can add days to a recipient’s hospital stay and increase total cost of care. For this reason, some centers have moved treatment of DGF to the outpatient setting, which has yielded comparable outcomes.22,23 In a meta-analysis of 14 cohort studies and 15 345 donors, Zheng et al57 estimate the RR of DGF to be 1.76 (95% CI, 1.52-2.04) for recipients of kidneys with AKI versus without AKI.
We identified 9 studies that analyzed donor AKI and 6-month or 1-year acute rejection, primarily using posttransplant biopsies categorized by the Banff58 criteria. Studies found no difference in acute rejection rates between AKI donor kidneys versus non-AKI donor kidneys.27,37,41-43,45-48 In their meta-analysis, Zheng et al57 estimated the relative risk of acute rejection to be 0.87 (95% CI, 0.66-1.15) for AKI donors versus non-AKI donors.
Graft Function (eGFR and Creatinine Clearance)
In 22 analyses of graft function using eGFR or creatinine clearance, there was overall no significant difference in long-term function.8,27,33-42,45-54 Two studies differed in findings. Boffa et al33 studied 11 219 kidneys in a UK cohort and found worse eGFR among kidneys with donor AKI. This study differed from other cohorts with higher sample size and percentage of donor kidneys with severe AKI and donation after circulatory death. This cohort also had higher rates of primary nonfunction of donor kidneys. This study may have been better powered to observe differences in outcomes among donor kidneys with higher levels of injury. Kolonko et al49 who studied a specific population of 61 deceased donors from 1 intensive care unit (ICU), also observed overall lower graft function for donor AKI versus non-AKI kidneys over an 84-month posttransplant period. Zheng et al57 estimated the weighted mean difference of 1-year eGFR between AKI and non-AKI donors to be −1.53 (95% CI, −3.54 to 0.49).
Within a cohort of recipients who received AKI kidneys, increased Kidney Donor Risk Index was associated with lower graft function.59
We found 29 studies that analyzed the association between donor AKI and graft failure. Overall, donor AKI was not associated with graft failure over time in 25 studies.7,9,14,24,25,27,28,30-32,34,36-41,44-48,53,55,56 Histologic criteria of ATI at implantation in the absence of donor demographics or clinical information do not provide sufficient predictability in outcomes after transplantation. On the other hand, histologic assessment of chronic injury correlated with GFR and overall survival.45
As described above, Boffa et al33 found worse graft survival overall with 20% greater risk of all-cause graft failure within 1 year for kidneys with donor AKI.33 The difference in all-cause graft failure was not as severe at 5 years (78% versus 76%, P = 0.009). The difference was primarily driven by donor kidneys with stage 3 AKI, which suggests that donor kidneys with more severe AKI should be transplanted more cautiously. Kolonko et al49 also found higher rates of graft failure in a single-center study of ICU patients.49 Two other studies found higher rates of graft failure only among the expanded-criteria donors with AKI.26,29 A recent analysis by Heilman et al7 which included over 400 donor kidneys with stage 3 AKI and excluded donor kidneys with >10% cortical necrosis or more than mild chronic injury found no effect on long-term survival. Another recent analysis of over 6500 deceased donors with AKI in the United States found that deceased donor AKI status was not associated with graft failure across AKI stages after adjusting for recipient and transplant characteristics.44
Overall, graft survival is comparable between AKI and non-AKI donors, especially among stage 1 and stage 2 AKI donors. Stage 3 AKI donors in the United States may be considered for transplantation. Although Boffa et al33 found higher rates of all-cause graft failure among stage 3 AKI kidneys, discard rate in the United Kingdom is approximately 10% versus 25% in the United States, which may reflect a currently more conservative approach to accepting organs in the United States.
URINE INJURY BIOMARKERS AND POSTTRANSPLANT OUTCOMES
We have studied the relationship between the following donor urine injury biomarkers (collected immediately before transplantation) and posttransplant outcomes: microalbumin (mg/dL), NGAL (ng/dL), KIM-1 (pg/mL), IL-18 (pg/mL), and liver-type fatty acid–binding protein (pg/mL). Our group showed that these donor urine injury biomarkers were associated with higher rates of DGF but not higher graft failure at 6 months posttransplant.34 A recent analysis of the same cohort showed that, at median 4 years posttransplant, donor urine injury biomarkers were not associated with long-term risk of graft failure and graft function. As urine injury biomarkers are more sensitive than serum creatinine for defining AKI, this analysis was able to more accurately assess the association between donor injury and posttransplant outcomes. A subanalysis also implied that subclinical donor AKI was not associated with long-term kidney transplant outcomes, as creatinine-defined AKI did not modify the relationship between donor injury biomarker concentration and outcomes.53
HYPOTHESIZED MECHANISMS OF SIMILAR OUTCOMES BETWEEN AKI AND NON-AKI DONORS
Graft survival from living kidney donors remains higher than deceased donors, regardless of the degree of HLA mismatch.60 Advances like induction therapy agents (eg, rabbit antithymocyte globulin) during transplantation have narrowed the gap in graft survival among living versus deceased donors. Understanding the mechanisms of similar outcomes between AKI and non-AKI deceased donors may help further reduce the gap between living and deceased donor graft survival.
Ischemic Injury and Inflammatory Response
AKI can be due to prerenal, intrarenal, or postrenal causes. In the ICU, sepsis is the predominant cause of AKI, and subsequent ischemic injury and acute tubular necrosis is common.61,62 Experiments show that ischemic kidney injury activates innate immune cells systemically and affects remote organs like the heart (eg, increased myocardial tumor necrosis factor-a and IL-1) and lungs (eg, IL-1, IL-6, IL-12). AKI increases future mortality and morbidity, including CKD.
Innate Immunity in Graft Rejection
Land et al63 have described the role of innate immunity response to oxidative stress and reactive oxygen species in activating the adaptive immune system that is eventually responsible for long-term graft failure. For example, ischemic injury induces ligands like heat shock proteins that activate Toll-like receptors (ie, Toll-like receptor 4) on dendritic cells that facilitate adaptive immunity response and alloatherosclerosis in chronic rejection. Studies are investigating therapies to block this activation of dendritic cells, including prevention of further oxidative allograft injury that promotes toleragenic dendritic cells and alloprotective T regulatory cells.64 Ischemic injury before transplantation may limit the subsequent posttransplant innate immune response.
Despite the destructive effects of AKI immediately postinjury, AKI may be protective against future ischemia. Several experiments over the past decade have demonstrated that ischemic injury to a kidney (and other organs) protects the organ from a second insult (like during transplantation). In these experiments, timing and frequency of ischemia influenced the degree of future protection provided by the original ischemic injury.65 One experiment found that optimal ischemic and reperfusion timing for preconditioning and future protection was 15 minutes of warm ischemia followed by 10 minutes of reperfusion on Sprague-Dawley rats, and the protective effect was modulated by nitrous oxide concentration.66 The mechanism for ischemic preconditioning still requires investigation.
Renal ischemic preconditioning may change humoral, neuronal, and systemic communication pathways and protein kinase and transcription factor production.67 Initial ischemic injury may alter protein expression to promote protection against future injury. For example, during second ischemic injury, less jun N-terminal kinase and p38 are produced versus first time ischemic states. However, extracellular signal-regulated kinase 1/2 are not changed in second versus first time ischemic injury. This ratio of jun N-terminal kinase and p38 to extracellular signal-regulated kinase helps determine whether neurons and kidney cells survive or undergo apoptosis. Postischemic heat shock proteins that are upregulated following initial ischemic injury also may stabilize actin cytoskeleton and contribute to altered kinase expression. Several other examples of changes in protein expression have been described in mice.65
Initial ischemia also influences the amount of future inflammation after second ischemia. For example, after second ischemic injury in mice 8 days after initial insult, there was no outer medullary inflammatory congestion that is typically present after ischemia. Less leukocyte adhesion molecules and cytokine production after secondary injury may contribute to this observation.68 Ogawa et al69 attribute some leukocyte resistance in the preconditioned kidney to increased nitrous oxide. Decreased nitrous oxide production reduced future ischemic protection.70 Adenosine, which increases following short ischemic periods, also limits leukocyte adhesion and reduces neutrophil density in the outer medulla and cortex.71 In humans, the predominant studies and randomized-controlled trials demonstrating the effectiveness of ischemic preconditioning are on hearts.72
Future studies can evaluate whether preconditioning can be induced in humans before kidney transplantation to improve outcomes. Donor AKI may reduce host innate immune response in the recipient in a process similar to ischemic preconditioning.
Recipient Factors Contribute More Than Donor Factors
Although donor conditioning via AKI may play a role in future ischemic protection and similar long-term graft survival versus non-AKI donors, it is important to consider an additional hypothesis that may contribute to similar outcomes: the host response may be the predominant contributor to graft failure. Thus, differences in donor graft condition may be relatively minor in overall graft survival as posttransplant complications such as side effects of immunosuppression medication, acute rejection, infection (BK virus, cytomegalovirus), chronic recipient immune response, and hospitalizations may be larger determinants of graft survival.
We believe donor protective factors in donor AKI kidneys play some role in explaining the similar long-term graft survival versus non-AKI donors. Our group found that among recipients with DGF, higher levels of injury biomarkers was associated with higher 6-month eGFR.34 DGF is a result of ischemic-reperfusion injury with the generation of excess oxygen radicals during both ischemic injury and subsequent reperfusion, eventually leading to tubular cell apoptosis and loss of function.73 It is possible that AKI helps kidneys with DGF recover through some of the mechanisms of ischemic preconditioning described above. Further investigation into graft recovery and molecular markers of repair is necessary to elucidate how donor injury relates to long-term graft survival.
Demographics and Selection Bias Among AKI Donor Kidneys
It is important to note that the studies of donor AKI and posttransplant outcomes are observational and do not imply causation. Selection bias is a major consideration in these studies, as those donor kidneys with AKI that were transplanted may differ from donor kidneys with AKI that were not transplanted in ways that were not captured by the data. Donors with AKI that are transplanted (versus discarded) may come from a healthier population demographically (eg, younger age, better health status). Adjusting for KDPI may not be sufficient in capturing overall health status of kidneys; thus, there may be residual confounding.
However, a recent study better addressed this selection bias and confounding by using propensity-based matching of donors with AKI to donors without AKI. This study did not see any effect of donor AKI on graft failure, even among donors with stage 3 AKI.44
LIMITATIONS IN USING DONOR AKI KIDNEYS
It would be helpful for transplant centers to know the duration of AKI for a potential donor and consider whether the AKI was prerenal or progressed to acute tubular necrosis. Type of AKI may help appropriately select viable donors with AKI that will not progress to chronic histologic changes faster than non-AKI donors. Heilman et al7 saw comparable long-term graft survival for donor AKI versus nondonor AKI recipients after excluding donors with cortical necrosis >10% and more than mild chronic injury.
Given the context of a major shortage of viable kidneys for transplantation and high discard rate of kidneys with AKI, transplant centers may be able to find a more appropriate balance between discarding and transplanting kidneys with AKI. A growing body of literature suggests current practices result in similar graft survival but higher discard rates of donor AKI kidneys versus non-AKI donor kidneys. Reducing the number of kidneys with AKI that are inappropriately discarded may increase the number of life-saving transplants available for people on the waitlist. An estimated 500–600 kidneys per year could be transplanted if centers accepted organs with AKI at the same rate as organs without AKI (Table 1). Even reducing the gap in discard rate between AKI and no AKI donor kidneys by half would yield an additional 300 viable organs. Systemic changes with payments, report cards, and allocation algorithms can incentivize transplant centers to take on this risk and accept kidneys with donor AKI.5 Currently, there is large regional variation in organ procurement organization and transplant center procurement and acceptance of donor AKI kidneys, as demonstrated in the allocation of kidneys with AKI map in Liu et al.44
Although increased biomarkers of donor AKI-like NGAL and KIM-1 do not affect long-term recipient outcomes, they may be helpful in identifying donor AKI kidneys most likely to have DGF so that care teams can prepare appropriately. Since these biomarkers are more sensitive than serum creatinine in measuring AKI and appear within 1–4 hours of injury, they may be helpful in other contexts, such as limiting ongoing injury to kidneys among deceased donors in the ICU. Since donor AKI (measured using biomarkers or serum creatinine) does not affect long-term recipient outcomes, current biomarkers of AKI do not provide additional clinical utility for evaluating outcomes of recipients with donor AKI kidneys.
The existing literature suggests more deceased donors with stage 1 and stage 2 AKI can be used for transplantation. Stage 3 AKI donors may also be a viable source for additional kidneys.
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