EXPERIMENTAL AND CLINICAL TRANSPLANTATION

The expanded criteria donor is any donor over the age of 60 years or a donor over the age of 50 years with 2 of the following 3 items: (1) history of high blood pressure, (2) serum creatinine ≥1.5 mg/dL, and (3) death due to stroke. To accept an expanded criteria donor kidney may significantly decrease the amount of time a person waits for transplant but requires written informed consent from the recipient. Although expanded criteria donor kidneys have predictably shorter outcomes than standard criteria donors, the exact risk is unknown. At 5 years follow-up, 50% of expanded criteria donor kidneys are still working. Regardless of donor status of these kidneys as expanded criteria or standard criteria, the transplant recipients have higher survival rates compared with candidates who remain on the wait list. The success rate may be increased when a perfusion pump is used to preserve the kidneys. Sometimes the function of a single kidney from an expanded criteria donor is deemed insufficient. In this situation, a pair of marginally functioning kidneys may be transplanted as a dual-kidney transplant. This dual transplant option offers acceptable outcomes as good as a single-kidney transplant with normal function and can effectively address the shortage of donor organs. The use of a perfusion pump allows the clinician to decide whether or not to use a particular expanded criteria donor kidney. Expanded criteria donors may be justified by meticulous selection of each donor for recipients, along with more sophisticated surgical techniques to maximize the kidney donor pool.

Key words : Deceased donors, Dual-kidney transplant, Marginal kidneys, Waiting list

As the number of patients on the wait list for deceased donor organs is increasing faster than the very modest growth in their availability, the need for deceased kidney donors is growing around the world, and various efforts have been made to increase the donor pool. Although kidneys procured from deceased donors older than 55 to 60 years of age are known to be associated with inferior graft survival compared with kidneys from younger donors, these older kidneys yield a substantial survival advantage over maintenance on dialysis.¹ The term “expanded criteria donor” (ECD) originated from the study of Port and colleagues.¹ They collected data for 29 068 transplanted kidneys recorded in the Organ Procurement and Transplantation Network between March 6 and November 30, 1995. They concluded that 4 donor characteristics were independently associated with a significantly increased risk for graft failure, including age older than 60 years, impaired renal function by creatine greater than 1.5 mg/dL, history of hypertension, and cerebrovascular accident as the cause of donor death. It has been shown that about 10% more kidneys could be transplanted from ECD.

Thereafter, the ECD has been defined by a deceased donor older than 60 years, or any deceased donor aged 50 to 59 years plus at least 2 of the following characteristics: (1) history of hypertension, (2) serum creatinine level > 1.5 mg/dL, and (3) cerebrovascular cause of death.

An effective allocation scheme for ECD should have the following 3 major characteristics: increase the number of kidneys from older donors actually used, shorten the longer wait time for older recipients, and do not negatively affect graft and patient survival. An allocation system with these characteristics will allow the ECD option to be more popular around the world.

We suggest that the best recipients for ECD grafts are those with longer times on the wait list, older candidates, and candidates with comorbid conditions likely to lead to a degraded condition without transplant (ie, severe problems in hemodialysis such as frequent hypotension or muscle cramps during hemodialysis). Because the cold ischemia time (CIT) is an important issue for ECD, we prefer local recipients, which can limit CIT.

Physiological Changes of Older Kidneys in Expanded Criteria Donors

Age-related manifestations of the kidney are composed of broad-spectrum changes from macroscopic to microscopic anatomic structural changes.² On the macroscopic scale, renal aging manifests as roughness of the kidney surface and increased formation and size of simple renal cysts. Renal volume is an important indicator of renal impairment. It was estimated that the parenchymal thickness of a kidney will decrease 10% for each additional decade of age regardless of patient sex.³ Assessed kidney volume by magnetic resonance imaging has shown that the kidney volume declines by about 16 mL per decade after 60 years of age. Although renal cortical volume progressively declines with age, medullary volume increases until 50 years of age, resulting in a net decline in total kidney volume after 50 years of age in normal individuals. Ten percent of a kidney’s weight and 0.5 cm of a kidney’s length are reduced normally per decade after 50 years of age.

Microstructural changes, including nephrosclerosis, glomerular basement membrane thickening, mesangial broadening, and increased accumulation of extracellular matrix, are observed in older kidneys. The pathologic hallmark of older kidneys is nephrosclerosis, accompanied by hypertrophy of remaining nephrons and arteriosclerosis. Tubular atrophy and interstitial fibrosis are other hallmarks of older kidneys. After 30 years of age, approximately 6000 to 6500 nephrons will be lost every year due to nephrosclerosis, or more specifically glomerulosclerosis.²

Following these macrostructural and microstructural changes, functional alterations are anticipated such as decreased glomerular filtration rate of 1 mL per year, decreased tubular sodium resorption, decreased urinary concentration, and reduced renal plasma flow. All of these conditions predispose the donated kidneys to decreased functional reserve, susceptibility to acute kidney injury (AKI) secondary to longstanding CIT, susceptibility to drug toxicity, and susceptibility to allograft rejection.

A close association between AKI and older donors was demonstrated more than half of a century ago.4 It was shown in Italy that patients older than 65 years had 10 times the rate of incidence of AKI compared with patients younger than 65 years of age.⁵ Many risk factors have been considered to predispose older patients to AKI secondary to ischemic reperfusion injury,⁶ including limited antioxidant defense of the older kidneys, reduced regenerative capacity in the older kidneys, compromised mitochondrial ability in the older kidneys, and impaired vascular microcirculation of the older kidneys.

The immunosuppression regimen is a big challenge for a transplant team, as a correct regimen can prevent adverse effects such as nephrotoxicity and higher risk of infections or cancer in a population already at risk. Although older kidneys are prone to ischemic and nephrotoxic AKI, these organs could be easily rejected7 or are predisposed to calcineurin inhibitor (CNI) toxicity.⁸

Kidneys from older donors present more antigens to the recipient T cells, express more major histocompatibility complex (HLA/MHC) antigens, and increase local inflammation.7 In general, a nonspecific injury induces proinflammation that, in turn, may activate recipient immune responsiveness. Inflammatory cytokines released after ischemia-reperfusion injury in older organs may aggravate the innate and adaptive immune responses of the recipient. Increased immunogenicity and cause of graft loss of older donor kidneys were evaluated by Fijter and colleagues, and factors that determined the failure of kidney transplants from older donors were evaluated among 663 consecutive first deceased donor renal transplants that were performed at the Leiden University Medical Center between 1983 and 1997.9 Kidneys from older donors were more likely to undergo acute rejection episodes in the early posttransplant period compared with kidneys from younger donors. They concluded that older donor kidneys are more immunogenic than kidneys from young donors. The prognostic effect of an acute interstitial rejection episode was also worse in the older kidneys.

In the latter scenario,⁸ clinicians encounter the increased risk of CNI nephrotoxicity, increased incidence of infections, cardiovascular risk, and malignancies. Older recipients of ECD kidney transplants are a special group who require a tailored immunosuppression regimen. As the older recipients of ECD kidneys often are excluded from transplant trials, the optimized induction and maintenance immunosuppression regimens for them are not known. Presently, data suggest that antithymocyte globulin might be the preferred induction agent for older recipients of ECD kidneys. Maintenance regimens that spare CNIs, or with belatacept, have been advocated for older recipients of ECD kidneys without any significant advantages for belatacept.¹⁰ Such CNI-free regimens are not universally recommended for ECD transplant recipients because of occasionally high rejection rates. However, reduced CNI exposure and CNI-free regimens based on mechanistic target of rapamycin (mTOR) inhibitors have shown acceptable outcomes in appropriately selected ECD transplant recipients.

Expanded Criteria Donors Versus Standard Criteria Donors

In the past 2 decades, the kidney transplant landscape has deeply evolved. The median age of recipients of a deceased donor kidney increased from 45 years in 1990 to 56 years in 2016. Accordingly, with this higher median age, current transplant recipients are more likely to have more pretransplant comorbidities.¹¹ Despite the higher comorbidities, mortality and graft loss have decreased substantially for this older recipient population, although the ECD kidneys have shown inferior graft survival compared with those from standard criteria donors (SCD), with a relative risk of graft failure of >1.7.¹ In a recent study,¹² survival data for adults awaiting a first deceased donor kidney transplant in Belgium were reported. They divided the population into 3 age groups and compared survival with either SCD or ECD transplant versus continued dialysis. For this purpose, they linked wait list and donor data sources. In all age groups, transplant was associated with an increased risk of death in the first months after transplant but with a lower risk of death later in the follow-up period. The mortality risk was consistently higher with ECD than with SCD transplant in all age groups, with a peak at 3 months after transplant. Correspondingly, the period of increased mortality risk in transplant recipients versus patients who remained on dialysis was consistently longer for ECD kidney recipients versus SCD kidney recipients, which was, respectively, 7 versus 4 months for patients aged 20 to 44 years, 18 versus 7 months for patients aged 45 to 60 years, and 26 versus 8 months in the 65-year-old age group. They concluded that older patients might gain a survival benefit with SCD transplant versus dialysis, but any survival benefit with ECD transplant versus dialysis may be small.

Use of older donor kidneys for young recipients leads to increased organ wastage due to early graft failure, which results in return to hemodialysis or a second transplant. These patients do not have a great chance for a functioning older allograft for their whole life; hence, they are exposed to the risks of sensitization and to a return to dialysis with its increased morbidity and mortality. On the other hand, older recipients who receive younger kidneys will die with functioning grafts, thereby reducing the potential lifespan of the transplanted kidney given to a younger recipient. With regard to the theory that donor-recipient age matching would improve patient survival, many studies have been published. In one of these studies,¹³ the effect of donor age on patient survival after first deceased donor renal transplant was examined to better understand how donor-recipient age matching might affect patient outcomes. To determine the difference between the actual and random donor and recipient age distribution of kidneys, data from 50 320 kidney transplants in the database between 1990 and 1997 were used from the United Network for Organ Sharing (UNOS) files. To determine the 10-year survival rates based on different donor-recipient age matches, the recipients were divided into 3 groups on the basis of recipient age (0 to 40 years, 41 to 54 years, and 55 years or older). For each recipient age group, the adjusted 10-year survival rates were plotted on the basis of the donor age category to determine the expected rate of survival at 10 years, and they found that the donor-recipient age matching improved survival, especially in younger recipients; interestingly, the effect of age matching was even greater than that seen with HLA/MHC antigen matching.

In another study,¹⁴ the benefit of using ECD kidney grafts rather than remaining on the wait list and continuing dialysis for patients aged 60 years and older was assessed. To assess kidney graft survival of ECD and non-ECD recipients and survival of patients remaining on the wait list, patients registered on a French wait list between 1996 and 2004 were evaluated. A total of 3001 patients aged 60 years and older were registered on the French kidney transplant wait list. Patients on this wait list had an adjusted risk of death 2.5 times higher than that of transplant recipients of the same age regardless of the type of graft (3.78 times greater than transplants from SCD and 2.31 times greater than transplants from ECD). The investigators found that the increased risk linked to transplants from donors more than 60 years of age remained significant but was smaller after adjustment for other donor characteristics, such as diabetes mellitus and hypertension. The study concluded that, in the older patients, transplant with an ECD kidney was associated with higher survival rates than remaining on the wait list; also, the identification and use of ECD kidney grafts should be optimized by the respective risk factors for recipients.

In a comparison of mortality after ECD kidney transplant versus mortality shown in patients who have had standard deceased donor transplant and patients still on hemodialysis,15 Merion and colleagues showed that the ECD recipients had a 27% lower risk of death versus patients on dialysis after 3 years of follow-up. The study used UNOS data of more than 100 000 patients on the wait list from 1995 to 2002. Average time to equal cumulative mortality for ECD kidney recipients versus patients receiving standard therapy was 3.5 years. The recipients listed for long wait times benefited the most from ECD transplants, since the longer a patient remains on the wait list, the more likely that the patient will die. Longer wait times for non-ECD kidneys increased the benefit of ECD transplants even more. Nearly 42% of all kidney transplant candidates in the United States were listed for ECD kidney transplant, and it was concluded that ECD kidney transplants should be offered principally to candidate recipients older than 40 years and to candidates with diabetes.

Although the ECD transplant has been shown to confer a survival benefit for patients with end-stage renal disease compared with remaining on dialysis and on the wait list, the precise financial costs for transplant centers and the long-term benefits of transplanting these kidneys remain unknown. To solve this problem, the financial costs and the long-term benefits of ECD transplant were evaluated among 271 deceased donor transplants from 1998 to 2005 at Massachusetts General Hospital.¹⁶ The ECD group was composed of 44 patients with a follow-up duration of 50 months. The ECD group had a significantly higher incidence of delayed graft function (DGF), longer length of stay, and more readmissions compared with the SCD group. These factors resulted in a higher financial cost for the ECD group compared with the classic SCD group. Although early graft survival rates were comparable among all groups, after a mean follow-up of 50 months, graft survival was significantly less in the ECD group. A higher rate of graft loss was noted in the ECD group after 2 years. Whereas graft survival was lower in the ECD group, patient survival was comparable to the SCD group in long-term follow-up. Conditions such as the more frequent need for hemodialysis, longer hospitals stays, more hospital readmissions due to poor or late-onset graft function, and more cytomegalovirus infections in recipients of ECD transplant caused around 1.5 times higher financial cost than SCD transplant ($70 304 vs $47 462, respectively).

Optimization of Extended Criteria Donor Program

We could optimize ECD transplant programs by at least 4 strategies: (1) old-for-old program, (2) biopsy of the marginal kidneys, (3) reduction of CIT for these vulnerable kidneys, and (4) minimization of drug toxicity, such as from CNI inhibitors.

The old-for-old program
The Eurotransplant Senior Program (ESP) was developed to allocate kidneys from donors ≥65 years old to recipients ≥65 years old regardless of HLA/MHC antigen matching. In an analysis, the effects of the ESP on wait time, graft survival, and patient survival were studied.¹⁷ The ESP group (n = 1406, old-to-old) was compared with 2 groups allocated via the Eurotransplant Kidney Allocation System with either similar donor age (old-to-any, donor age ≥65 years; n = 446) or recipient age (any-to-old, recipient age 60-64 years; n = 1687). All patients received transplants between 1999 and 2004. Since initiation of the ESP, availability of older donors doubled and wait time for ESP patients decreased. Local allocation led to shorter CIT (11.9 vs >17.0 hours; P < .001) and less DGF (ESP 29.7% vs old donor to any recipient 36.2%; P = .047) but 5% to 20% higher rejection rates. Graft and patient survival rates were not negatively affected by the ESP allocation compared with the standard allocation. It was concluded that the ESP age matching of older donors and recipients is an effective allocation system for organs from older donors. Age matching could potentially increase the number of older patients whoreceive transplants and result in longer life compared with dialysis.

Biopsy of the marginal kidneys

In marginal donors such as ECD, or in donors with diabetes or renal abnormalities, the long-term graft survival is influenced by progressive scarring of the allograft. The poor graft outcomes with such kidneys may sometimes be the result of the disparity between the number of viable nephrons supplied and the metabolic demand of an average recipient, a gap that becomes wider when diseased kidneys or kidneys from older donors are transplanted after prolonged CIT.

One of the most important questions about an ECD program is, “How could we improve utilization of the organ donor pool and avoid unnecessary discard of ECD?”

To answer this question, we go back to around 20 years ago,¹⁸ when Gridelli and Remuzzi noted that kidneys from very old donors could be used successfully when a pretransplant biopsy shows a small degree of glomerular injury. Kidneys from older donors, which are currently not accepted for single-kidney transplant, function well when transplanted together.

At least theoretically, on the basis of the biopsy findings, the transplant strategy could be planned to allow the allocation of kidneys to single transplants or dual transplants. Hence, pretransplant biopsy may be used as a reliable tool to discard or accept ECD kidneys.¹⁹

A comparison of deceased donor kidney scoring systems and correlations with graft outcomes²⁰ has shown that ECD kidneys with a low score (<3) could be used for single-kidney transplants, ECD kidneys with a score from 4 to 6 could be used as dual-kidney transplants, and, finally, ECD kidneys should be discarded when the score is more than 7 in kidney biopsy. The degree of the score is based on the severities of glomerulosclerosis, tubular atrophy, interstitial fibrosis, and vascular lesions. Graft and patient outcomes for ECD transplants were better for dual-kidney transplant versus single-kidney transplant after 1 year and after 5 years, respectively. Since the mid-1990s, the University of Maryland and Stanford University have adopted the dual-kidney transplant approach for marginal kidneys.²¹

Tan and colleagues published their experience for up to 8 years of follow-up in recipients who had undergone dual-kidney transplant at Stanford University.²² Because older patients with end-stage renal disease have a higher risk of death while awaiting transplant, the researchers preferentially offered the option of dual-kidney transplant, using kidneys that otherwise would have been discarded, to candidates aged 55 years or more. The 5-year graft survival rates for the dual-transplant and single-transplant groups were 79.5% and 67%, respectively, and the 8-year actuarial graft survival rates for the 2 groups were 69.7% and 59.4%, respectively (not significant). They concluded that the long-term patient survival and graft survival rates in recipients aged 55 years or older of dual, marginal kidneys are similar to the rates in contemporary recipients of single kidneys. Dual kidneys can be transplanted to the common iliac arteries and veins bilaterally or ipsilaterally.²³

Reduction of cold ischemia time

Various methods to reduce the CIT have been attempted because longer CIT has generally been associated with worse graft survival in many studies. Marginal older kidneys are vulnerable to ischemic damage (as previously described), and so effective strategies should be applied to reduce CIT, including allocation of ECD kidneys to older recipients and preconsented candidates within the local area,²⁴ timely kidney allocation, the use of pulsatile perfusion, and prompt access to operating rooms and recipients.²⁵ The effect of machine perfusion becomes stronger as CIT becomes longer. The role of dynamic preservation and the need for oxygen provision to restore ATP levels, despite the fact that the clinical marginal features had labeled such organs as unsuitable for transplant, remain very important.Hypothermic oxygenated machine perfusion is effective and safe in both liver and kidney transplant and has been reported to demonstrate safety and efficacy in reducing ischemic preservation injuries.²⁶ Organ perfusion with this method is easily performed, and it may be initiated at the time of surgical graft preparation during the back-table procedures, avoiding unnecessary CIT extension. Earlier initiation of hypothermic oxygenated perfusion promotes the reduction of waste products and improves the restoration of mitochondrial function. Hypothermic oxygenation during organ perfusion is able to restore ATP levels in the kidney and accelerate restoration of function after transplant.²⁶ In this procedure, after introduction of the catheter via the femoral artery, the abdominal aorta including the renal arteries can be selectively perfused, flushing and cooling the kidneys.

Immunosuppression therapy in expanded criteria donors

Kidneys from older donors are generally more immunogenic than kidneys from young donors.8 Increased inflammatory response and increased T-cell immunoreactivity in recipients of older donor kidney allografts have been shown. Subsequently, increased incidence of acute interstitial rejection episodes has been observed among ECD kidney transplant recipients in the early posttransplant period. On the other hand, it is well established that the immune response is significantly affected by the aging process. The goal of any immunosuppression protocol should be composed of an adequate immunosuppression level with minimal risk of infection without increasing the risk of rejection. It is suggested that initial CNI doses should be reduced because, at any given dose, higher than normal blood levels result from a decline in cytochrome P450 activity. Moreover, rapid corticosteroid tapering is recommended because corticosteroids have many untoward effects in older adults. On the other hand, ECD transplants are complicated by increased rates of DGF and acute rejection, especially in the early posttransplant period, and an adequate level of immunosuppression is desired under these circumstances. Therefore, optimal management is a challenge in ECD kidney transplant recipients. Generally, in ECD transplant recipients it is recommended to use induction with rabbit antithymocyte globulin to ameliorate preservation injury and, moreover, minimize the state of DGF due to acute tubular necrosis.²⁷

The ECD kidney recipients treated with tacrolimus had a higher median estimated creatinine clearance than those treated without tacrolimus. Graft function from 1 to 3 years was better preserved in ECD recipients treated with tacrolimus compared with those treated without tacrolimus. Compared with recipients of living donor kidneys, recipients of ECD kidneys were at an increased risk of malignancy. Recommendations regarding optimal immunosuppression regimens in this patient population should be made with caution. Reduced CNI exposure regimens or even CNI-free regimens, in selected cases, may improve survival of ECD kidney transplants. In the context of such regimens, the mTOR inhibitor everolimus appears to offer advantages in ECD kidney recipients in terms of both improving outcomes and preserving renal function, as well as in terms of minimizing CNI-associated adverse events, such as cardiovascular morbidity/mortality and malignancies, which are particularly prevalent in this patient population.

In areas with long wait times, ECD kidneys would be suitable for those who are not likely to survive or remain healthy enough to receive an SCD kidney. A decision to decline an offer of an ECD kidney does not preclude a subsequent SCD transplant. Advances in ECD donor management resulting in better outcomes could broaden the categories of suitable ECD candidates. Wait-listed patients on dialysis who are older and hypertensive have poorer survival rates but typically achieve the greatest relative gains in overall survival and quality of life after transplant compared with remaining on dialysis. Special attention should be paid for individualized immunosuppression in this vulnerable group of patients, preferentially to minimize CNI but prevent allograft rejection.

Volume: 20 Issue: 8 August 2022 - Supplement - 4

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