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Deceased Donor Issues in Kidney Transplantation: Identifying Barriers and Defining New Limits of Acceptability

Posted to the Web: Friday, August 08 , 2008
Introduction

Based on Organ Procurement Transplantation Network (OPTN) data as of June 20, 2008, the United Network for Organ Sharing (UNOS) national waiting list for solid organ transplantation approached 107,000 registrations, including nearly 81,000 patients awaiting kidney transplantation. Despite concerted efforts, such as the Organ Donor Breakthrough Collaborative, to increase the donor organ supply the waiting list continues to grow disproportionately because of the relative shortage of donors and transplantable organs. Any increase in the number of donors or expansion of previous limits defining acceptable donors could favorably affect the organ shortage but adversely affect transplant outcomes because current efforts to increase donor utilization target potential donors that historically were considered marginal. The burgeoning crisis in the donor organ supply fuels initiatives to expand the limited use of the deceased-donor pool. The purpose of this article is to highlight data from selected studies on expanding the organ pool and optimizing outcomes in deceased-donor kidney transplantation presented at the American Transplant Congress 2008.

Splitting Pediatric "En Bloc" Kidneys for Adult Renal Transplantation Historically, transplantation of an en bloc kidney allograft (both kidneys transplanted as a single allograft) from small pediatric donor kidneys (≤ 15 kg body weight) into 1 adult recipient has been associated with excellent results. However, some centers do not perform pediatric en bloc kidney transplants at all, whereas other centers transplant kidneys en bloc from donors up to 5 years of age. Moreover, most centers will not even consider performing pediatric en bloc kidney transplants for very small (< 9 kg body weight) donors. If the majority of pediatric donor kidneys were transplanted separately vs en bloc and the minimum safe weight limit for acceptable pediatric kidney donors was further lowered, then in theory the number of patients who could receive kidneys from small pediatric donors would almost double. Based on OPTN data as of June 20, 2008, the number of kidney donors younger than 1 year of age and ages 1-5 years in 2007 were 68 and 175, respectively.

An analysis of the cumulative experience with transplanting kidneys from small (≤ 15 kg) pediatric donors either en bloc (n = 19) or as a single kidney transplant (SKT) (n = 14) into recipients older than15 years of age at the University of Pittsburgh between 2002 and 2006 revealed that many of the SKTs were performed because of damage that prevented en bloc reconstruction.[1] Mean donor age was 15 +/- 10 months and donor weight ranged from 4 to 15 kg. Although SKTs had a higher incidence (25% vs 0%, P =.025) of delayed graft function (DGF) compared with en bloc-kidney transplants, 1-year graft survival rates were similar (86% for SKT vs 79% for en bloc-kidney transplant recipients). There were 2 cases of primary nonfunction with SKT vs 1 case with en blockidney transplantation. No differences were noted in the incidence of graft thrombosis, donor age, donor or recipient weight, cold ischemia time, or incidence of acute rejection. However, renal function was slightly better in en bloc kidney transplant recipients compared with SKT recipients.

The preliminary (first-year) experience of a novel pilot program at Weill-Cornell Medical College in New York of intentionally splitting small pediatric donor kidneys (< 60 months of age) for transplantation into 2 adult recipients was reported.[2] Donor exclusion criteria were age younger than 2 months or single kidney size < 5 cm. Twelve pediatric SKT allografts (median donor age 24 months, range 8-58 months) were transplanted into 12 adults (median age 46 years, range 24-67 years) and results were compared with 86 consecutive recipients of adult SKT allografts from standard criteria donors (SCD). Both groups received the same immunosuppression protocol. Although the incidence of DGF was higher in recipients of pediatric SKTs (67% vs 21% in SCD kidneys, P =.0001), 1-year graft survival rates were similar (100% vs 96% in SCDs).

All pediatric renal allografts experienced significant hypertrophy (median increase in size of 35% by 3 months), which was associated with a progressive increase in measured creatinine clearance (CrCl) over time. At 6 months after transplantation, the measured CrCl in recipients of pediatric SKTs was 53.5 mL/min compared with 61 mL/min in SCD kidney recipients (P =.54). The authors concluded that adoption of a policy to routinely split all pediatric en bloc renal allografts for adult recipients is safe and successful with 1-year outcomes comparable with SCD adult kidney recipients. In addition, pediatric renal hypertrophy provides allograft function nearly equivalent to adult SCD kidneys by 6 months after transplantation.

It is important to note that both of these studies were from centers quite experienced in pediatric donor kidney transplantation. In addition, both centers excluded pediatric recipients from consideration for pediatric donor kidneys and thus, avoided the temptation of nephron-matching between donor and recipient. Donation after cardiac death (DCD) may be a relative contraindication to splitting small pediatric kidneys, particularly if the life support withdrawal or agonal phases are prolonged. Both centers utilized antibody induction to minimize or prevent rejection, especially in the setting of DGF. Finally, recipient selection is imperative and ideally should include only patients with low-immunologic risk (ie, primary transplant, low panel reactive antibody level, good human leukocyte antigen match) low body mass index , favorable vascular anatomy, the absence of severe hypertension, and predicted ability to tolerate a variable period of DGF or even a prolonged period of suboptimal function until renal hypertrophy occurs. In spite of these caveats, the initial experiences reported herein are quite favorable and exciting.

Adult Dual Kidney Transplantation From Elderly Donors: The "Flip Side" of the Other Extreme

The use of expanded criteria donors (ECDs) has become a viable way to use organs from older donors with multiple comorbidities, but concerns have been raised regarding limited nephron mass and the lower expected life span of these organs. One approach to offset this dilemma has been the use of DKT from marginal adult deceased donors. In an effort to utilize ECD kidneys that were not considered suitable for SKT due to insufficient nephron mass, the concept of DKT evolved in lieu of organ discard. In the last decade, the use of DKT from marginal, older donors has become increasingly accepted as a method to increase the organ supply. Unlike pediatric donor kidneys that have the capacity to undergo compensatory hypertrophy, DKTs from older donors may have a fixed nephron mass due to senescence that stabilizes over time at approximately 80% of the calculated donor CrCl. DKT has been shown to be effective when appropriate donors and recipients are chosen, but this procedure may involve greater anesthetic and surgical risks. Without the benefit of DKT however, many patients would likely remain on the waiting list untransplanted. It should be noted that the specific indications for and optimal utilization of DKTs are controversial.

A 2-center, prospective cohort experience from France comparing SKT with DKT from ECDs 65 years of age or older from August 2003 to August 2007 was reported.[3] If the highest estimated donor CrCl (by Cockcroft-Gault formula) was < 60 mL/min, then the kidneys were transplanted as a DKT into a single recipient. A total of 70 DKTs and 65 SKTs were performed. Donors were significantly older (mean 74 vs 71 years, P =.02) and the estimated CrCl level was significantly lower (mean 48 vs 87 mL/min, P <.0001) in DKT compared with SKTs, respectively. Recipients were older (mean 69 vs 60 years, P <.0001) and waiting times were shorter (mean 33 vs 58 months, P <.0001) in DKT compared with SKTs, respectively. One-year actuarial patient (99% vs 98%) and kidney graft survival (96% vs 89%) rates were similar as were 12-month calculated CrCl levels (mean 47 vs 48 mL/min) in the DKT and SKT groups, respectively. Length of initial hospital stay was similar in the 2 groups, whereas the readmission rate was lower in the DKT group (mean 1.3 DKT vs 2.3 readmissions in SKT recipients, P <.005. The investigators concluded that short-term results are comparable in DKT and SKTs from older donors, despite the significantly older age of donors and recipients in the DKT group.

A Canadian, single-center study of DKT from 1999-2007 as an alternative for use of very marginal donors compared 63 DKTs with concurrent selected control groups of SKTs from ECDs (n = 66) and ideal SCDs (n = 63, donors aged 10-39 years).[4] Indications for DKT were donor age older than 60 years, ≥ 15% glomerulosclerosis on preimplantation biopsy, and surgeon refusal to use the kidneys for SKT. DKT donors were significantly older (mean 69 years DKT vs 62 years ECD vs 24 years SCD), and by design, so were DKT recipients (mean 60 years DKT vs 50 years ECD vs 44 years SCD). Delayed graft function (in the absence of pulsatile perfusion preservation) was more common in DKT (27%) and ECD (29%) compared with SCD (11%) transplant recipients (all P <.05). Surgical complications and operating time were higher in DKT recipients. However, 36-month CrCl levels were similar in DKT (mean 54 mL/min) and ECD (mean 60 mL/min) compared with SCD (mean 82 mL/min) transplant recipients. Actuarial patient and kidney graft survival as well as death-censored kidney graft survival rates were similar among the 3 groups with follow-up out to 84 months. The authors concluded that DKT is associated with acceptable long-term outcomes and has permitted a 19% increase in volume of transplant activity while facilitating shorter waiting times for elderly recipients.

Predicting and Preventing Delayed Graft Function in Deceased-Donor Kidney Transplantation

Delayed graft function is usually defined as the need for dialysis in the first week after kidney transplantation. It is well established that DGF is a risk factor not only for graft dysfunction, acute rejection, and poorer intermediate-term graft survival, but is also directly related to deceased donor age and donor organ quality. Based on OPTN data as of June 20, 2008, the incidence of DGF is highest with DCD donor kidneys (44%), intermediate with ECD kidneys (33%), and lowest with SCD kidneys (21%). The presence of DGF is an early marker of organ quality and preservation that represents a combined response to a series of ischemic, reperfusion, inflammatory, and immunologic injuries. The incidence of DGF has not changed appreciably in the past decade and the major risk factors for DGF appear to be warm and cold ischemia. Other risk factors for DGF include donor, procurement, preservation, transplant, and recipient variables. Each of these areas represents a potential opportunity for minimizing, preventing, or reversing the manifestations of ischemia-reperfusion injury. Expanded-criteria donor kidneys are uniquely susceptible to ischemia-reperfusion injury because of older donor age, comorbidities such as hypertension and vascular disease, and the terminal effects of brain death on kidneys with limited functional reserve that due to senescence have lost the ability to undergo compensatory hypertrophy.

The presence of DGF doubles the rate of graft loss at 5 years after kidney transplantation compared with recipients with immediate graft function. This is associated with a reduction in graft half-life from 11.5 to 7.2 years, which is eerily similar to the difference in graft half-life between recipients of SCD and ECD kidneys. In addition, DGF increases the risk of acute and chronic rejection, such that the presence of DGF and acute rejection further reduces graft half-lives to 9.4 and 6.2 years for patients with immediate and DGF, respectively. Moreover, DGF increases length of initial hospital stay, is more resource-intensive, increases initial hospital charges, and has adverse psychological and medical effects on the patient. Consequently, efforts directed at minimizing DGF can be expected to have a number of beneficial effects.

Irish and colleagues[5] presented an update of their original nomogram for predicting DGF based on a retrospective analysis of UNOS data on adult, solitary, nonpreemptive, nonmachine-perfused, deceased-donor kidney transplants performed from 2003 to 2005. Grafts lost within the first 24 hours (n = 245) were excluded and the remaining 18,276 kidney transplants were analyzed in a multivariable logistic regression model that was validated using a dataset of 3601 patients transplanted in 2006. The incidence of DGF was 25.8% and the overall accuracy of the updated model was 70.4%. A total of 16 variables contributed to the updated nomogram, which provides a tool for developing a pretransplant index of DGF. The most significant variables predictive of DGF included:

-Donor factors: DCD donor, older age, history of hypertension, higher terminal serum creatinine (SCr) level, nontraumatic cause of death;
-Preservation factors: longer cold ischemia time;
-Recipient factors: history of pretransplant dialysis, African-American race, male gender, history of diabetes; and
-Immunologic factors: retransplantation, higher panel reactive antibody level, greater human leukocyte antigen mismatch.

A meta-analysis of 51 studies of long-term outcomes (> 6 months) in the setting of DGF showed that compared with patients without DGF, patients with DGF > 6 months after transplantation had an increased risk of graft loss (relative risk [RR] = 1.63).[6] The RR of graft loss persisted (RR = 1.50) in studies with longer follow-up (> 4 years). When studies that clearly excluded acute rejection in the DGF group were pooled, the RR of graft loss increased to 2.11. Delayed graft function did not have a significant effect on patient survival at 1 year (RR = 1.06), but patients with DGF experienced a mean increase of 0.65 mg/dL in SCr at 1 year compared with patients without DGF.

The United States Renal Data Systems database was analyzed for adult deceased-donor kidney recipients transplanted from 1995 to 2004 who had Medicare as their primary payer.[7] A total of 41,049 transplants were analyzed, including 83.2% from SCDs, 14.2% from ECDs, and 2.6% from DCD donors. The incidences of DGF were 23.6% for SCD, 35.9% for ECD, and 44.2% for DCD donor recipients. The occurrence of DGF was associated with an average $20,000 increase in cost during the first year after transplantation, regardless of deceased-donor category. For patients who did not experience graft failure, DGF was most costly for ECD followed by DCD and then SCD kidney recipients (additional cost of $12,145, $11,692, and $9648, respectively).

A randomized, prospective trial of 336 consecutive deceased-donor kidney pairs was performed. Kidney pairs were randomly assigned to either static cold storage or hypothermic machine perfusion (MP).[8] MP significantly reduced the risk of DGF (odds ratio [OR] = 0.63, P = .02) as well as the incidence of primary nonfunction after transplantation (2.1% vs 4.8%, P = .04) compared with cold storage preservation. In addition, the risk of graft failure in the first 6 months after transplantation was lower with MP (OR = 0.46, P = .05). In patients in whom DGF developed, the 6-month kidney graft survival rate was improved by MP (87% MP vs 76% with cold storage, P = .05). By contrast, in another study of paired kidneys exclusively from DCD donors that were randomly assigned to either static cold storage or MP preservation, study recruitment was discontinued after enrollment of 46 donors when data analysis concluded that there was no difference in the incidence of DGF according to method of preservation (56% MP vs 53% static cold storage).[9] However, mean cold ischemia times were short, < 15 hours in both groups.

The UNOS database was analyzed for adult deceased-donor kidney transplants performed from 2002-2005. Transplant centers were stratified into 3 categories based on utilization of MP preservation: (1) low-MP centers (0% to 10%), (2) medium-MP centers (10% to 30%), and (3) high-MP centers (> 30%) utilization of PP.[10] Although MP was used by 97% of centers, 70.7% of centers used MP < 10% of the time. The overall incidence of DGF was lowest in high-MP centers (13.5%) compared with medium-MP (24.7%) and low-MP (24.8%) centers. In ECD kidney transplants, the use of MP was associated with lower rates of DGF in all 3 center categories. However, the impact of MP on SCD and DCD-donor kidney transplants was less significant and varied across centers according to MP use. The authors concluded that when stratified by donor type and transplant center category, only ECD kidney transplants demonstrate a consistent reduction in DGF when MP is compared with cold storage preservation.

Summary

In summary, the critical organ shortage poses a formidable challenge to maximize the utilization and optimize the function of all recovered kidneys. Prevention of DGF may have beneficial short- and long-term consequences, and the results above suggest that the use of MP can reduce the incidence of DGF in ECD kidney transplantation. In addition, MP provides an ex vivo assessment of marginal donor kidneys and may rescue some kidneys that were doomed to either failure or nonuse. On the basis of the studies highlighted, one might surmise that ECD kidneys should be routinely managed with MP to improve outcomes, promote sharing, safely extend cold ischemia times when necessary, and reduce organ discard. However, the role of MP in SCD and DCD donor kidney preservation remains uncertain. Ultimately, understanding the factors that determine outcome and longer-term follow-up are necessary to fully delineate the benefits and risks of various management strategies in deceased-donor kidney transplantation.