Challenges & Controversies in Kidney Transplantation Sandip Kapur
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1 SECTION
1Maximizing Transplant Opportunities2

Utilization of Marginal, Pediatric and HCV+ Deceased Donor OrgansCHAPTER 1

Jim Kim

ABSTRACT

The disparity between organ supply and demand continues to grow, resulting in an ever-growing need to increase the donor pool. As a result, the utilization of suboptimal or marginal donors has become a common strategy to lessen this organ shortage. Although these donors serve as valuable resources, increased rates of delayed graft function and primary nonfunction and inferior graft survival rates highlight the importance of appropriate donor selection and recipient matching. By maximizing these marginal donors, access to transplantation can be optimized without compromising outcomes.
 
INTRODUCTION
Extraordinary breakthroughs in the realm of transplantation have been made since the first successful kidney transplant by Joseph Murray and his team in 1954. Advancements in immunosuppressive drug therapies, enhanced understandings of immunology, and changes in public policy have all led to significantly improved outcomes over the past six decades. According to data compiled by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Health (NIH), the 5-year patient survival rate for transplant recipients is 85.5% compared to 35.8% for dialysis patients (Fig. 1.1).1 The landmark paper by Wolfe and colleagues in 1999 also showed a doubling of life expectancy in renal transplant patients as compared to those who were wait-listed and remained on dialysis.2 This study demonstrated the long-term mortality (>18 months) was reduced by 68% in recipients of deceased donor renal transplants. These findings have led to an explosion in the number of patients with end-stage renal disease (ESRD) being listed for kidney transplants. What was once considered “a respite from the real treatment of dialysis”3 is now the accepted therapeutic approach for those with kidney failure.
As of November 1, 2013, there were over 98,000 candidates listed for a kidney transplant.4 Despite the increasing numbers of people with ESRD in need of a transplant, there has not been a concordant rise in the number of organ donors.4
zoom view
Fig. 1.1: Patient survival rates by dialysis and transplant.Source: NIH Publication No. 12-3895 June 2012 (National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health).
Table 1.1   Kidney transplants by donor type in the United States.
Donor type
2001
2011
All deceased donors
8234 (100)
11,043 (100)
Standard criteria donor
7033 (85.41)
9,374 (84.89)
Expanded criteria donor (ECD)
1201 (14.59)
1,669 (15.11)
Donation after cardiac death, non-ECD
227 (2.76)
1,592 (14.42)
Donation after cardiac death, ECD
16 (0.19)
106 (0.96)
Data from 2011 OPTN & SRTR Annual Data Report. Values expressed as number (percent).
This has resulted in a steady decline in the rate of transplants for adult candidates on the waiting list. The rate of deceased donor renal transplants performed in 1998 was 20.6 transplants per 100 wait-list years as compared to 11.4 transplants per 100 wait-list years in 2011.5 With this growing disparity between supply and demand, there is an imperative to expand the pool of donors. One strategy is to use organs previously thought to be unacceptable (Table 1.1). A growing body of evidence has shown promising results using kidney allografts from marginal and pediatric donors, as well as from donors with hepatitis C.4,6–8 Despite inferior outcomes compared to standard criteria donors (SCD), these donors may help to alleviate the organ shortage because the negative impact of dialysis is far worse than the 5negative impact of “inferior” grafts. Key factors in successful utilization of these donors include selecting appropriate donor traits, weighing recipient characteristics and managing variable risk factors to optimize outcomes.
 
MARGINAL DONORS
 
Expanded Criteria Donor
 
Donor Criteria and Outcomes
An analysis of the Scientific Registry of Transplant Recipients (SRTR) was undertaken to study “expanded” qualities of donors.9 A consensus definition for expanded criteria donors (ECDs) was developed to describe basic characteristics that were associated with a 70% greater likelihood of graft loss [relative risk (RR) >1.7] as compared to SCD.6,10 These factors included age and three statistically significant risk factors: history of arterial hypertension, cause of death from cerebrovascular accident, and preretrieval serum creatinine >1.5 mg/dL. Consequently, ECD was implemented as policy starting October 31, 2002 and was defined as donor age over 60 or over age 50 plus any 2 of the 3 cited risk factors.11
A landmark paper by Ojo et al. associated certain clinical features, which included advanced age, long-standing hypertension, diabetes mellitus, and prolonged cold ischemic time (CIT), with inferior outcomes compared to ideal kidney donors.12 However, the authors determined a substantial survival advantage using these ‘marginal’ donors over those wait-listed patients maintained on dialysis, showing an average increase of 5 years in life expectancy. Prior to this study, no accepted definition of a “marginal” donor had existed and the SRTR study soon afterwards defined ECD to standardize this type of kidney.
In another important study, Merion et al. demonstrated the adjusted risk of death at 3 years for recipients of an ECD kidney was 60% lower than for wait-listed transplant candidates.13 For non-ECD transplants, the mortality reduction was even greater at 72%. Overall, the relative long-term mortality was found to be 17% lower for ECD recipients than those who had standard therapy (wait-listed for transplant, maintained on dialysis or receiving SCD).
The long-term graft outcomes of ECD may be worse in comparison to SCD, but the overall mortality is significantly reduced compared with those remaining on dialysis.14 ECD was shown to have similar early graft survival compared to SCD, but this was shown to be significantly less after a mean follow-up of 50 months. Regardless, using ECD kidneys was still found to be more cost-effective than maintenance on dialysis.15 An earlier study by Stratta et al. determined that the estimated half-lives of ECD kidneys were 6–8 years compared to 10–12 years in SCD kidneys,16 and both far exceeded established patient survival on dialysis.6
Table 1.2   Recipient characteristics for ECD kidneys.13,17
Benef icial
Disadvantageous
Age >40 years
Age <40 years
Diabetes or hypertension as cause of ESRD
Short waiting time
Listed in OPO with long waiting time (>1350 days)
Retransplantation
Non-hispanic
OPO, organ procurement organizations
The adjusted patient survival for ECD as compared to non-ECD at 1 and 5 years was found to be 90.6% and 69% vs 94.5% and 81.2%, respectively.10 The overall patient survival for those remaining on dialysis at 5 years was < 40%.1
 
Optimizing Outcomes
To achieve the maximum benefit from ECD, it becomes increasingly important to identify the best possible setting in which to use these donors (Table 1.2). No standard protocol has been established, but several studies have highlighted the significance of appropriate donor selection to match recipient characteristics. There are considerable differences across organ procurement organizations (OPOs) in the proportion of candidates wait-listed for ECD.18 In OPOs where median waiting times are prolonged (>1350 days), the risk of death was 27% lower for ECD recipients. However, in OPOs where wait times were shorter, an ECD survival benefit was only shown for diabetic recipients. In addition, a subgroup, consisting of patients over age 40 years, those with hypertension or diabetes, non-Hispanics, and unsensitized patients, were shown to have significant survival benefit with ECD kidney transplants.13 Older recipients have been shown to be good candidates for ECD kidneys because graft survival typically exceeds patient survival on dialysis. Patients over age 60 years who were recipients of ECD kidneys had a 62% greater death rate at 1 year than recipients of SCD, but had a significant survival advantage over patients remaining on dialysis.19 Another study demonstrated increased survival in recipients over the age of 60 years receiving kidneys from donors over the age of 70 years as compared to recipients aged 41–60 years.20 For patients over age 40 years, the benefits conferred by an SCD kidney were negated by the additional years on dialysis. There appeared to be no upper age limit; even patients exceeding age 75 years attained a survival benefit. For diabetics aged 18–39 years, receiving kidneys from ECD after 2 years had a similar life expectancy compared to those waiting 4 years for SCD.21 However, cumulative survival of ECD recipients did not equilibrate with patients waiting for a transplant until 3.5 years posttransplantation due to the excess ECD recipient mortality.137
One of the most common indications for transplantation is failure of an existing allograft.22 Although repeat kidney transplantation has been shown to improve patient survival over dialysis therapy, using ECD kidneys may not be a cost-effective strategy23 because retransplantation with ECD kidneys has poor outcomes. This subgroup of patients likely has better outcomes remaining on dialysis until an SCD or living donor become available.17 A review of the SRTR database demonstrated a 56% decrease in mortality with repeat transplants using SCD. However, similar survival was found between those remaining on the waiting list compared to repeat transplant with ECD.24
Stroke as the cause of death in the donor also portends a worse outcome, with inferior graft half-life, patient survival, and a RR of 2.2 for graft loss.6,25,26 ECDs have also been associated with increased urinary complications, but did not result in increased graft loss.27 ECDs were also noted to have higher rates of delayed graft function (DGF), primary nonfunction (PNF), and lower creatinine clearance at 5 years. However, in comparing ECD to SCD, 5-year graft (70.4% vs 76.7%) and patient survival (88.2% vs 88.9%) were not significantly different.28
Especially because of intrinsic disease and loss of nephron mass that occurs with normal aging, careful selection of ECD is important to successful outcomes. In fact, over 50% of all procured kidneys that were discarded were from ECD.5 Perioperative mortality risk for ECD kidney transplantation has been shown to be 5.2-fold higher within the first 2 weeks compared to standard therapy. This risk decreases and only becomes equal at 33 weeks post-transplant.13 Several factors determine whether ECD would be suitable to use for transplant. Donor creatinine clearance (CrCl) can serve as a surrogate for projected kidney function from single or dual kidney (both kidneys from same donor) transplants. Single kidneys were used with a CrCl >65 mL/min, dual kidneys were used for CrCl 40–65 mL/min, and kidneys were discarded if CrCl was <40 mL/min.16 The use of donor biopsies are controversial, but can also potentially be a useful tool in selecting appropriate ECD kidneys. Glomerulosclerosis >20% has been identified to be a risk factor for early graft failure.29 Remuzzi et al. devised a scoring system centered on histological evaluation prior to kidney allocation.30 This study suggested similar outcomes using dual ECD kidneys compared to SCD based on four histological factors: glomerulosclerosis, arteriosclerosis, tubular atrophy, and interstitial fibrosis (Table 1.3). The current UNOS (United Network of Organ Sharing) guidelines considers dual kidney allocation if any two of the following criteria exist: donor age >60 years, estimated donor CrCl <65 mL/min, rising serum creatinine (>2.5 mg/dL) at time of procurement, donor history of long-standing hypertension or diabetes mellitus, or adverse donor kidney histology (defined as glomerulosclerosis of 15–50%).
Another strategy to improve outcomes with ECD is to limit the CIT, which appears to have a more deleterious effect than for SCD.12,16,318
Table 1.3   Pretransplant biopsy factors and allocation of dual kidney transplant.30
0
1+
2+
3+
Glomerulosclerosis
None
<20%
20–50%
>50%
Tubular atrophy
Absent
<20%
20–50%
>50%
Interstitial fibrosis
Absent
<20%
20–50%
>50%
Arterial/arteriolar narrowing
Absent
<Luminal diameter
≥Luminal diameter
Extreme narrowing or occlusion
Total score
0–3 (mild)
4–6 (moderate)
7–12 (severe)
Use for transplant
Single kidney
Dual kidney
Discard kidneys
The prevalence of DGF, which has been associated with impaired long-term graft survival,12,32,33 can be partly attributed to the increased sensitivity of ECD to the effects of cold ischemia.34 However, the impact of CIT has also been called into question in a recent analysis of the SRTR database. Despite DGF rates being higher for CIT >15 h and significantly more likely between pairs with greater CIT (35% vs 31%, P <0.001), graft and patient survival were similar.35 The authors noted no association with acute rejection. A safe conclusion from these conflicting studies would be to minimize CIT when possible, but it is not advisable to automatically discard ECD solely based on prolonged CIT. Minimizing CIT also relates to how these kidneys are stored. Although multiple studies have evaluated the effects of static cold storage (CS) and pulsatile machine perfusion (MP), their individual merits can be debatable.36,37 In regards to ECD, there appears to be a significant reduction in DGF using MP over CS.37–39 The long-term patient and graft survival rates do not seem markedly improved, but still appear to be a cost-effective strategy.40,41
 
Donation After Cardiac Death
Since the criteria for brain death was defined in 1968, most transplants have resulted from donation after brain death (DBD).42 However, rates of donation after cardiac death (DCD) have increased from 1.4% in 1998 to 15.8% in 2011.5 In other countries, such as Japan, DCD comprises the majority of organ donors. Unlike in brain dead donors, organs from DCD donors are procured after cardiopulmonary arrest and face warm ischemic injury until cold preservation solution is perfused. Concerns about poor graft function arose due to this additional ischemic insult, especially with higher rates of DGF and PNF being reported.43 However, follow-up studies over the past two decades demonstrate similar long-term patient and graft survival compared to DBD donors.44 Increasing numbers of DCD organs can contribute to expansion of the donor pool and help alleviate the shortage of organs.9
Despite a higher incidence of DGF and PNF, these complications do not appear to have a negative effect on long-term outcomes.45 One large study from the University of Wisconsin demonstrated higher rates of DGF and discharge creatinine with the use of DCD kidneys, but no difference was found in long-term graft survival. DBD renal transplants had a 5–, 10–, and 15-year graft survival of 71.3%, 48.3%, and 33.8%, while DCD renal transplants had graft survival of 64.8%, 44.8%, and 27.8%, respectively.46 In another study, 45% of DCD renal transplants experienced DGF, but that had no effect on graft and patient survival or kidney function.47 This study also suggested that increased donor age was associated with higher risk of poor kidney function with the highest observed risk being donors older than 45 years (RR 4.81, p=0.001). Other clinical features, such as CIT >12 hour, have also been shown to increase rates of DGF in kidney transplants using DCD donors. However, both DCD and DBD donors under age 50 years old had similar graft survival.48
Attention to clinical features also impact successful outcomes for DCD donors. Warm ischemia time, donor age, length of CIT, and method of preservation have been studied and optimizing these variables can lead to liberal use of kidneys from these donors.49 Techniques, such as mechanical chest compression devices and extracorporeal membrane oxygenation, have been suggested to help reduce the effects of warm ischemic time.50 Contradicting studies regarding the potential benefits of MP over CS have been reported.36,51 Overall, MP appears to reduce DGF, but its implication to long-term graft survival remains controversial.52 As previously cited, multiple studies have also shown donor age to be correlated with DGF. An analysis of the SRTR database demonstrated ECD status did not adversely affect the outcomes of DCD kidney transplant (hazard ratio 1.04; 95% CI, 1.01–1.15) compared to non-ECD (hazard ratio 1.21; 95% CI, 1.04–1.40). The study suggested ECD-DCD donor kidneys could be a valuable source of potential donors.53 At the other end of the age spectrum, kidneys from pediatric DCD donors (aged 2–17) had similar patient and graft survival compared to their DBD counterparts.54 Multiple studies support the conclusion that DCD kidneys can safely be utilized to expand the donor pool without detrimental consequences and can even be allocated in a similar fashion to DBD kidneys.
 
PEDIATRIC DONORS
The donor pool can potentially be further expanded with the use of pediatric donors for adult recipients. Much like ECD and DCD, proper matching of donor and recipient characteristics is important for good outcomes, but the optimal use of small pediatric donors has not been clearly determined.55–57 10Suboptimal graft survival rates and higher technical complications have historically contributed to lower utilization rates from these donors, particularly from smaller pediatric donors (age <5 years, weight <20 kg). These organs have been among the highest discarded group. The use of en bloc kidneys, in part, was developed to offset some of these negative consequences, as well as to augment renal size.58 However, transplanting solitary kidneys from these donors would maximize their use and could serve as a valuable resource to combat the organ shortage. Determining the proper situation whether to use solitary or en bloc pediatric kidneys has not been clearly elucidated.
Graft survival of en bloc pediatric donor allografts has been shown to have similar outcomes compared with adult donors.59,60 A major concern, though, was the perceived increased graft loss associated with solitary pediatric kidneys. One analysis of the SRTR database demonstrated a 78% increased risk of graft loss for single kidneys from pediatric donors who weighed <21 kg.56 This risk of early graft loss was theorized to be as a result of the hyperfiltration syndrome, a condition where a donor–recipient size mismatch leads to compensatory changes of hypertension, proteinuria, glomerulosclerosis and, ultimately, inadequate filtration ability.61 Pediatric donor kidneys, though, have also been shown to increase in size and hypertrophy to provide adequate nephron mass to meet adult metabolic requirements.57,62,63
Other studies, however, have demonstrated comparable outcomes using solitary pediatric kidneys. For donors <5 years old, solitary pediatric kidneys were found to have a 2-year graft survival rate of 92.5% as compared to 89.8% for SCD.64 Better 2-year actuarial graft survival rates for solitary pediatric donors of 93% have also been demonstrated compared to 77% after en bloc transplantation.65 Another analysis of the SRTR database demonstrated solitary pediatric kidneys from donors >35 kg had similar graft survival to SCD.66 Outcomes from adult donors between ages 18 and 45 years were found to be equivalent to grafts from these solitary pediatric donors. Actuarial death-censored graft survival at 1 year and 5 years from adult vs pediatric donors was 93% and 85% vs 93% and 84%.67
Mounting evidence shows the efficacy in utilizing pediatric donors for adult recipients. Attention to meticulous surgical technique and proper patient selection can result in excellent long-term outcomes. Despite conflicting data with respect to the superiority of en bloc kidneys, selective use of solitary pediatric kidneys can clearly be justified. Current data suggest donor age likely serves as a surrogate marker for the size of the kidneys. Further studies looking at specific donor and recipient characteristics need to be conducted, but pediatric kidneys can safely be used as solitary kidneys when donors weigh >15 kg and are >6 cm in length.11
 
HEPATITIS C POSITIVE DONORS
Approximately 3.2 million people in the United States are infected with hepatitis C virus (HCV).68 Compared to HCV(–) patients, HCV(+) patients wait-listed for kidney transplantation have a higher risk of death than HCV(–) patients.69 HCV(+) status has also been shown to be an independent risk factor for death and graft loss after kidney transplant.70 However, a significant survival benefit is seen after transplant for HCV(+) recipients compared to those who remain on dialysis.71 Due to their increased rates of morbidity and mortality, it becomes more important to expand the donor pool to make more organs available. HCV(+) patients are a unique population of patients wait-listed for a kidney transplant who can benefit from HCV(+) donors.
For appropriate patients, the use of HCV(+) donors can potentially expand the donor pool and shorten waiting times. The wait-list time for an HCV(+) patient was, on average, 395 days less than for those who were HCV(–). However, only 29% of these patients received kidneys from HCV(+) donors and HCV(+) kidneys had a 2.6 times higher rate of discard than HCV(–) kidneys.8 Most centers will limit the use of HCV(+) donors to recipients with a positive viral load and with the most common genotype 1b. Those patients, who have cleared the virus or have less virulent genotypes, risk activation of viral replication. Poor survival was seen in HCV(–) elderly patients receiving HCV(+) kidneys due to rapid development of HCV infection, liver disease, and infectious complications.72 Even HCV(–) recipients on the waiting list deemed to have poor life expectancy on dialysis had poor patient and graft survival when transplanted with HCV(+) kidneys. In addition, HCV(+) donor status was a negative risk factor for patient survival.73 Regardless of recipient HCV status, an analysis of the SRTR database demonstrated poor patient survival when HCV(+) donor kidneys were utilized and only HCV(+) recipients had worse graft survival.74 Overall patient and graft survival for HCV(+) recipients was lower compared to HCV(–) recipients, but the survival rates at 3 years between HCV(+) and HCV(–) donors were similar.8 Despite inferior outcomes in comparison to HCV(–) patients, kidney transplantation confers a survival benefit over remaining on dialysis.70
 
ASSESSING RISK
Not all kidneys within a specific subgroup are the same. The designation for the type of kidney, i.e. SCD vs ECD, is based on a binary (yes/no) indicator and has been used to assess risk of graft failure. Due to the wide variability within these subgroups (e.g. high risk SCD vs low risk ECD), more recent studies have looked at incorporating specific donor factors 12in a continuous scoring system. The Kidney Donor Risk Index (KDRI) was developed to assess the RR of graft failure based on 10 donor characteristics in comparison to reference deceased donors at the median, 50th percentile from the previous year. A higher KDRI value corresponds to a higher risk of graft failure compared to an “average” donor.75 Among the various factors, the KDRI includes donor age (pediatric vs SCD vs ECD) as well as HCV status (Table 1.4). Woodside et al. analyzed the SRTR database for utilization and outcomes for kidneys designated as ECD. Because the terms ECD and SCD do not account for donor quality within each category, higher discard rates were seen for biopsied kidneys. Although overall graft survival of ECD was worse than SCD, no difference was seen within specific KDRI intervals. The authors concluded that the ECD designation conferred no increased risk of graft failure beyond that predicted by KDRI.76 To simplify the risk assessment, the Kidney Donor Profile Index (KDPI) converts the KDRI from a RR scale to a cumulative percentage scale. In other words, a higher KDPI confers a greater risk of graft failure. For example, a donor with a KDPI of 90% can be interpreted as being a low-quality donor because it has a KDRI >89% and at most 90% of donors in the chosen reference population.77 In March 2012, the OPTN began including the KDPI in DonorNetSM along with the SCD and ECD designations, but has not yet used it as a tool for allocating kidneys. Eventually, though, the OPTN Kidney Committee plans to use KDPI for “longevity matching”–attempting to minimize life years lost following death with a functioning graft while maximizing the number of life years gained with each utilized organ.78
Table 1.4   KDRI donor factors age (in years)
Donor characteristics
Applies to
Model coefficients
All donors
Age <18
0.0128
−0.0194
Age >50
0.0107
Height (cm)
All donors
−0.0464
Weight (kg)
Weight <80 kg
−0.0199
Ethnicity
African American donors
0.1790
History of hypertension
Hypertensive donors
0.1260
History of diabetes
Diabetic donors
0.0881
Cause of death (COD)
Cerebrovascular accident
0.0881
Serum creatinine (mg/dL)
All donors Creatinine >1.5
0.2200
−0.2090
HCV status
HCV (+) donors
0.2400
DCD status
DCD donors
0.1330
KDRI, Kidney Donor Risk Index; HCV, hepatitis C virus; DCD, donation after cardiac death
13
 
CONCLUSION
The growth of the waiting list continues to outpace the number of available donors, and severely limits the number of patients from receiving the benefits of transplantation. Kidneys from ECD, DCD, pediatric, and HCV(+) donors have been a valuable resource in trying to offset the disparity between supply and demand. Studies have shown good outcomes from these donors, especially when carefully selected based on a variety of characteristics and limiting negative factors such as cold ischemia time. Over the past decade, the number of transplants from ECD has tripled and has increased nearly 10-fold from DCD donors. The lack of available organs continues to challenge the transplant community, but expansion of the donor pool can help to alleviate the shortage while maintaining efficacy.
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