Selection Committee Member: Vineeta Kumar @VineetaKumar8
Vineeta Kumar is Professor of Medicine, Robert and Cutessa Bourge Endowed Professor in Transplant Nephrology, and the Medical Director of the Incompatible Solid Organ Transplant Program for the University of Alabama at Birmingham. She is the lead nephrologist for UAB’s Living Donor Transplant Program and UAB’s Xenotransplantation efforts. Her mission is to improve the care and outcome of living organ donors and the medically complex transplant patient through direct care, education, and clinical research.
Writer: Margaret DeOliveira @MargaretD128
Margaret DeOliveira is a second-year nephrology fellow at Mount Sinai Hospital. She is a graduate of Cooper Medical School of Rowan University in Camden, NJ, and completed her combined residency in internal medicine and pediatrics at Duke University Medical Center in Durham, NC. She is interested in transitions of care and glomerular disease. She is currently a Fellow Editor for Renal Fellow Network.
Writer: Jeffrey Kott @jrkott27
Jeffrey Kott is a second-year clinical nephrology fellow at Mount Sinai Hospital. He completed his Residency and Chief year at Stony Brook Medicine. His interests include critical care nephrology, transplant nephrology, improving access to medical care, and medical education. He is a 2021 graduate of the NSMC.
Competitors for the Access to Kidney Transplantation Region
After another one-year break, kidney transplantation (KT) is back in the tournament and ready to rumble! In 2020, Biomarkers in Rejection advanced to the Effluent 8 but could not keep up with Consumable Waste in Hemodialysis (and we still haven’t forgotten that KT was the inaugural NephMadness champion in 2013). This year, two teams representing KT have suited up and come to the tournament with one shared goal: timely and successful KT for all patients who need them.
Team 1: Journey to the Wait List
Currently, there are more than 100,000 patients on the deceased donor kidney transplant (DDKT) wait list in the United States (US), with an average wait list time of 3-5 years (longer in some parts of the US). Like the journey of the basketball into the hoop from the 3-point line, so is the journey for the patient with advanced chronic kidney disease (CKD) to the wait list, and ultimately to a successful KT. Before one can even attempt the shot, the player must get on the court. Let’s start at the beginning.
Referral to Kidney Transplantation
Primary care providers and nephrologists both play pivotal roles in the referral of eligible patients to transplant clinics evaluation. Why kidney transplant? Most individuals living with end-stage kidney disease (ESKD) who receive a KT live longer and have a better quality of life compared to those who do not.
Early referral is key to educate potential KT recipients about living donors and wait list options. Per the Organ Procurement and Transplantation Network (OPTN) guidelines, the optimal timing of referrals to a transplant center is when estimated glomerular filtration rate (eGFR) is less than 30 mL/min/1.73 m2. Wait list time accrual begins once a patient is registered on the kidney transplant wait list and the eGFR is less than or equal to 20 mL/min/1.73 m2, or once the patient initiates dialysis, whichever comes first (Figure 1). The race-free eGFR calculation for transplant candidate listing has been adopted and was approved in June 2022.
Figure 1. Waiting list time accrual for a deceased donor kidney transplant
Unfortunately, a majority of patients with advanced CKD are not referred to general nephrology for their kidney care, and thus are likely not referred for transplantation either. How can you make the shot if you don’t have access to the court? A large 2020 retrospective study of 1,119 patients with advanced CKD found that 55% of patients had not been referred to general nephrology for evaluation.
In 2014, the National Kidney Allocation System (KAS) redefined parameters for calculating wait list time in an attempt to address disproportionately long wait list times for highly sensitized patients (i.e. those with high calculated panel reactive antibody [cPRA]) and racial and ethnic minorities. A significant change to the existing wait list time calculation was having time accrued on the wait list include the time from dialysis initiation for those actively listed after initiating dialysis. In other words, if an individual was referred and listed for KT after receiving dialysis for 5 years, waitlist time would begin at 5 years. For patients not yet on dialysis, wait list time begins at the time of listing (after evaluation). A cohort of 37,676 incident patients in Georgia, North Carolina, and South Carolina from 2012-2016 found that KAS had increased referrals and evaluation starts, decreased overall wait listing, and lowered rates of active wait listing when compared to the “pre-KAS” era. There was also an increase in the percentage of preemptive transplants after KAS, though there were continued disparities in access, with the rate of preemptive transplants persistently lower in minoritized populations.
Disparities in Referrals & Wait Listing
2020 NephMadness champion Inequities Region describes in-depth the factors that contribute to disparities in kidney care, including referrals to KT and subsequent wait listing. Figure 2 illustrates the history of citizenship-based access policies and the evolution of the “5% guideline.” In 1986, OPTN released a policy recommending that at each transplant center’s kidney transplant recipients (KTR) who were non-US citizens be less than 10% of all KTR. In 1994, 10% was lowered to 5%, and a policy was implemented to potentially audit transplant centers in violation. In 2012, the 5% guideline was replaced with a review of US citizenship and US residency data of KTR.
Race-Based eGFR Calculations
As eGFR determines active wait listing eligibility, it is not surprising that race-based eGFR calculations have been a driver of disparities. In September 2021, a National Kidney Foundation/American Society of Nephrology Task Force released a special report urging the elimination of race-based eGFR equations and adoption of the 2021 CKD-EPI equation, which does not include race. The report also recommended national efforts to increase the use of cystatin C as a biomarker, as consideration of both creatinine and cystatin C is more accurate than creatinine alone. Calculation of eGFR using the 2009 CKD-EPI equation with a race coefficient increases the eGFR by 16% for those labeled as “Black.” A 2021 cohort study of self-identified Black adults with CKD (Figure 3) found that estimation of kidney function without a race coefficient was significantly associated with a shorter time to referral and DDKT wait list eligibility. As Black patients have been shown to have faster progression of kidney disease, a recent study proposed a higher eGFR listing threshold for Black patients that could potentially improve racial disparities.
Obesity can delay patients from being listed, although body mass index (BMI) cut-offs vary from center to center. The “obesity paradox”) tells us there is a reverse association between BMI and survival in patients receiving hemodialysis. (Figure 4), with improved survival for the rest. Together, these data underscore that it may not always be prudent to require weight loss in potential recipients of KT on dialysis, especially in older patients who are greater than 65 years of age.
A study of the Scientific Registry of Transplant Recipients (SRTR) from 2015-2020 found significant variation in the proportion of recipients with BMI greater than 35 kg/m2 at transplant centers; 11% of transplant centers had more than 20% of recipients with BMI greater than 35 kg/m2 while 14% of centers had fewer than 5% (Figure 5). For patients with BMI greater than 35 kg/m2, center-specific cut-offs may significantly impact access. Similarly, living donor evaluation may be restricted to those with a BMI less than 30-35 kg/m2.
A 2021 meta-analysis of UNOS data (Figure 6) with adults that were first-time deceased donor kidney transplant recipients from 2000-2016 compared BMI categories (less than 25 kg/m2, greater than 25-30 kg/m2, greater than 30-35 kg/m2 and greater than 35 kg/m2). There was an increase in delayed graft function in patients with BMI greater than 35 kg/m2 and those BMI greater than 30-35 kg/m2. Though allograft outcomes were better for those with BMI less than 30 kg/m2 compared to those greater than 35 kg/m2, there was no difference in graft or patient outcomes between BMI greater than 30-35 kg/m2 and BMI > 35 kg/m2. There was no difference in patient survival or hospital length of stay following transplant across BMI categories. This study supports the idea of greater flexibility in BMI inclusion criteria for potential KT recipients.
Once a potential KT recipient has been referred for evaluation, the journey has really just begun. The pre-transplant evaluation seeks to assess not only if the individual can safely undergo the surgical procedure and then subsequently tolerate immunosuppression, but also if KT is the best treatment option for that individual. The evaluation process begins with a large, multidisciplinary team of nurse coordinators, social workers, dieticians, financial coordinators, pharmacists, nephrologists, and surgeons. In addition to the laundry list of screening and diagnostic tests patients must complete (and subsequent follow-up assessments, pending the results), assessment of cardiac health is a critical step in the evaluation process, given the high burden of cardiovascular disease in patients with CKD, though it is not so clear whether intervention (eg, percutaneous coronary intervention) in patients without symptoms and good functional status improves outcomes. Pre-KT cardiac evaluation guidelines differ slightly among organizations, though some suggest using a non-invasive cardiac stress test in asymptomatic, “high-risk” individuals. A recent United Kingdom study even suggested that non-invasive cardiac stress tests, often a mainstay of the pre-transplant evaluation process, may not provide any benefit while increasing the time to wait listing. If a patient who has been able to successfully complete their evaluation makes it to the wait list, some of the pre-evaluation testing may need repeating as they wait, driven by either screening guidelines (eg, mammography, colonoscopy) or changes in clinical status.
Time on the Wait List
What is the “wait list” anyway? It’s not really a linear list, per se. It is a pool of candidates waiting for an organ based on different characteristics. When a donor becomes available, a list is generated and that dynamically created list determines how organs are allocated. The more donors we have, the more lists we can generate, and the more offers we can make. Dialysis has the biggest impact on wait list time, along with sensitization from previous blood transfusions, and blood type (B and O have the longest wait list times). There are regional variations in wait times as well. The cPRA is used to determine a percentage score estimating the amount of antibodies a patient has in their blood. The higher the percentage, the harder it will be for a patient to find a suitable match (without high levels of donor-specific antibodies), leading to longer wait times. Since the implementation of KAS, sensitized candidates (those that have a cPRA greater than 98%) have been given increased priority. The net impact of the KAS in the highly sensitized group varied across cPRA categories, such that candidates with cPRA 80%-89% received fewer kidneys than those with cPRA 98%-100%. Interestingly, the same study found that KAS implementation was associated with decreased rates of living donor KT (both for kidney paired donation [KPD], and non-KPD) in highly sensitized patients.
A 2022 National Academies of Sciences, Engineering, and Medicine report found the US organ transplant system to be “demonstrably inequitable.” OPTN has also recently stated the need for increased transparency in wait list selection and described a need for autonomy, procedural justice, equity, and utility. Transparency is a must as we strive toward a more equitable transplantation system.
In an effort to improve equitable access to kidney transplant, the Board of Directors of the Organ Procurement and Transplantation Network (OPTN) unanimously approved a new policy, effective January 5, 2023, whose goal is to backdate waiting times for those Black kidney transplant candidates who were disadvantaged by previous use of a race-inclusive eGFR. For Black candidates registered on the kidney transplant wait list, this change back dates wait list time to the earliest documentation of a race-neutral eGFR less than or equal to 20 mL/min/1.73 m2.
So what happens during the long timeout between wait listing and the KT? Each center’s care of the pre-transplant patient varies, with many centers seeing patients yearly prior to transplantation to evaluate potential clinical changes. Pre-transplant care costs (initial evaluation, wait list management, evaluations of living donors, and donor aftercare) are funded via the Organ Acquisition Cost Center (OACC). The costs per transplant have increased from $81,000 to $100,000 between 2012 and 2017 due to increasing wait list pools and comorbidities.
In summary, the journey to the wait list is long and arduous, with numerous defenders protecting the hoop. Though the transplant community has made some progress in improving this process by encouraging transparency and beginning to address disparities through the use of race-free eGFR for wait listing eligibility, several barriers remain to making this journey easier to navigate for those who need to undertake it.
Check out this podcast episode of Core IM:
Team 2: Organ Pool
Given the more than 100,000 individuals waiting on the KT list in the United States alone, to paraphrase Steven Speilberg’s 1975 “Jaws”: “We’re gonna need a bigger pool.” The paucity of organs has led to lower percentages of individuals transplanted within 5 years of being listed for organ transplant. Expanding the available organ pool has become a priority for many involved in kidney transplantation. This team will review the current deficiencies as well as developments aimed at making KT more accessible.
Throwing away organs that can potentially be used is essentially a technical foul. Discard or non-utilization of organs has been high, recently reaching a peak percentage of 21.3% in 2020. To meet the demands of an increased KT list, there has been a need to use conventionally “less ideal” organs, including those from donors with complex medical comorbidities, surgical complication, or histologic findings.
In the mid-1990s, the idea of using “expanded or extended donor” criteria for organs from donors thought to be suboptimal candidates (compared to standard criteria donors [SCD]) was proposed, and in 2002 “expanded-criteria kidneys” donors (ECD) were defined as in Figure 1 in an effort to increase the organ pool.
Figure 1. Criteria used to define expanded criteria donor (ECD) vs those used to calculate the kidney donor risk index (KDRI)
Retrospective analyses of the ECD program found that the most common reason for discard of these organs was due to biopsy findings. However, at the time the rationale for rejecting biopsy findings (>20% glomerulosclerosis) was based on data that was felt to be insufficient in determining long-term function of an allograft, especially as subsequent data found that biopsies of organs with >25% glomerulosclerosis has a 3-year graft survival rate of 75%. Not surprisingly, graft survival of ECD kidneys was lower compared to non-expanded criteria kidneys (Table), with prior sensitization contributing to this outcome.
Table. Graft Survival of Expanded Criteria Kidneys versus Non-Expanded Criteria Kidneys. Adapted from American Journal of Transplant
Though the ECD program had strengths, ECD organs only accounted for 17% of kidney transplantations by 2005. The consensus became that a more concrete means of discussing risk would be beneficial for physicians, patients, and health policymakers. This movement culminated in the development of the Kidney Donor Risk Index (KDRI), which is used to graph the now more commonly known Kidney Donor Profile Index (KDPI). Though the KDRI initially combined 10 donor characteristics and 4 transplant characteristics (cold ischemia time, degree of HLA mismatch, en bloc transplant, and double kidney transplant), the KDPI excluded the transplant characteristics due to their uncertainty at the time of organ offer (Figure 1). KDPI has since become the preeminent tool used in discussing risk of organ survival and has an inverse relationship with graft survival (Figure 2). The full KDPI calculator is available here.
Figure 2. Survival of deceased donor kidney-alone transplants, by kidney donor profile index (KPDI). Figure adapted from OPTN
Organ discard may occur for several reasons, including characteristics of donated organs, failure to convert potential organ donors (with conversion meaning that a deceased individual actually becomes an organ donor), or just because it’s the weekend! Organs procured during the weekend were 20% more likely to be discarded, even though these organs were of higher quality than those procured and used Monday-Friday. Organs from donors older than 55 years old or with diabetes mellitus, hypertension, or obesity are discarded at higher rates. Organs for which biopsies were obtained continue to have high rates of organ discard, and high KDPI kidneys (>85%) are also more frequently discarded compared to others. Based on these figures, despite efforts to reduce organ discard, there remains work to be done to more effectively expand the organ pool. This need has now become a part of United States governmental policy, as an ambitious target of doubling available organs by 2030 was signed into law in the Advancing American Kidney Health Initiative in 2019.
While the KDPI was introduced to help provide a more accessible means of categorizing risk for donor organs in both centers and individuals, it has its flaws. Compared to the ECD vs SCD categorization, KDPI may introduce a bias when an organ is quantified as worse than some percentage, leading to further organ discard. One study, for instance, found that organs categorized as SCD (but with KDPI >85%) were rejected at higher rates once only KDPI was presented, despite use of these organs lowering risk of mortality at 2 years. Mortality benefit of high KDPI organs has since been replicated in additional studies (which include the elderly, though notably not the pediatric population). To maximize the use of high KDPI organs, systems have been proposed to improve informed decisions and mitigate bias introduced by KDPI, and OPTN changed the Kidney Allocation System to increase the geographic area in which high KDPI organs are offered. Still despite these efforts, there remains significant discard of high KDPI organs.
Additionally, variables that increase KDPI though may not ultimately impact allograft function have come into question:
- Race: Though the discard rates vary between races, Black is the only race that increases KDPI, more than medical conditions, donation after cardiac death (DCD) status, or cerebrovascular accident (CVA). As race is a social construct, rather than a biological variable, it has already been removed from eGFR questions. Further, removal of race from the KDPI has repeatedly demonstrated restratification of high-risk organs to the lower-risk categories (and thus likely decreased organ discard). Some have proposed that APOL1 genotype should be included in KDPI, as donor high-risk APOL1 genotypes are associated with poorer allograft outcomes in kidney recipients.
- Hepatitis C Virus (HCV): Presence of HCV in the donor significantly increases the KDPI, and thus can increase discard of these organs. The past 10 years have seen significant breakthroughs in anti-virals that induce a sustained virologic response (cure!), so it seems anachronistic that HCV remains in the KDPI. Single–center exploration into the use of donor HCV+ kidneys in combination with administration of the anti-virals (eg, elbasvir/grazoprevir, glecaprevir/pibrentasvir) at the time of transplant have had promising outcomes with respect to both organ function and recipient HCV cure, if transmitted from the donor. Reproduced in larger, multicenter trials (Figure 3), this has led to a decline in the discard of HCV+ organs (from over 40% in 2016 to about 20% in 2020), though we can likely do better by removing HCV from the KDPI.
Figure 3. Multicenter Study to Transplant Hepatitis C-Infected Kidneys (MYTHIC): An Open-Label Study of Combined Glecaprevir and Pibrentasvir to Treat Recipients of Transplanted Kidneys from Deceased Donors with Hepatitis C Virus Infection
Despite all efforts thus far to reduce organ discard and a significant decrease in the discard of HCV+ kidneys, organ discard continues to increase. One solution that has been proposed in Europe is the Eurotransplant Senior Program (older donors for older recipients), which has been shown to be beneficial in the long term with respect to decreasing organ discard and outcomes. While this system can theoretically disadvantage the elderly, who may otherwise receive younger donor organs, it yields a shorter wait time for the elderly and has demonstrated a survival benefit over dialysis. Given its success, this program has been implemented in various countries across Europe, and would be projected to significantly decrease the number of discarded organs in the United States.
Organ Procurement Organization (OPO) Performance
OPOs are non-profit organizations distributed geographically that are responsible for the procurement of organizations for transplantation. They are governed by the provisions laid out in the National Organ Transplant Act (NOTA), which defines the federal oversight by the Center for Medicaid and Medicare Services (CMS) as well as the OPTN, and the Uniform Anatomical Gift Act (UAGA), which defines guidelines by which organ donations occur. There are currently 57 OPOs in the United States which have numerous responsibilities along the entirety of organ allocation.
The CMS governs OPOs, ensuring appropriate adherence through the meeting of certain conditions to maintain reimbursement and certification. Two metrics (donation rate and organ yield rate) have historically been used to evaluate OPO performance, and both rely on the variable known as “eligible deaths” (ED). The donation rate (patients with at least one organ transplanted/ED) and the organ yield rate (organs transplanted/ED) are used to target OPOs outside the top 25% with quality assurance and improvement programs. OPOs deemed not efficient can ultimately be redesignated or de-certified. However, a review of OPO performance from 2011-2018 demonstrated that OPO performance ranking largely did not change despite programs and interventions aimed at rapid improvement.
Unfortunately, donation rate and organ yield rate do not reflect the full potential of donors. ED is used to estimate a potentially deceased donor pool, but does not include all groups those older than 70 years and DCD donors, thus underestimating the true potential donors. CMS quality metrics have attempted to address some of the deficiencies in ED by incentivizing pursuit of single organ donors. Use of the proposed variable ”potential donors” instead of ED, would allow for more uniformity across OPOs, remove self reporting, and also account for geographic differences, all while capturing the actual upper limit of the possible organ pool. A more recent study proposed the incorporation of administrative data on potential donors into OPO performance measures, such as a donation percentage (Actual Donors/Potential Donors) and Organs Transplanted per Potential Donor.
Another point of improvement for OPOs would be identifying patterns in donor authorization, which varies significantly. While OPOs certainly drive organ donation consent, and internal methods such as having an in-house coordinator have shown improvements in donor authorization, external methods, (eg, Organ Donor Breaththrough Collaborative) have shown some short-term success in increasing organ consent rates.
Think of “xeno” as a heave from half-court to beat the buzzer. XT, the human transplantation of organs from non-humans (cross species), is probably the most exciting and innovative prospect for increasing the organ pool. While we have to look back a few thousand years to the earliest documented case report of XT (and subsequent rejection), use of non-human organs has actually been an area of interest since the 1960s, when a series of chimpanzee-to-human kidney transplants were first described, with one organ lasting 9 months! Additional attempts were made using baboon kidneys, due to declining populations of chimpanzees, though all transplanted organs failed quickly. Fast forward to the 1980s, when deceased donor organ supply could not be met by the demand for organs. Advancements in immunosuppression, coupled with the outlawing of use of chimpanzees as organ sources and various issues with other non-human primates (viruses, size, ethics), made it clear that another animal source needed to be found. Enter the pig, whose physiology, immunology, availability, organ size, and breeding profile made them a viable option to become the main organ provider from the animal kingdom. While initially limited by natural antibodies (NAbs) to porcine antigens such as 1-3,Galactose (Gal) leading to hyperacute rejection (HAR), significant progress has been made for the first time to modify the donor (Pig) to be “more human like” through several advances in genetic modification. This may one day make porcine XT the solution to the organ shortage. These advances led to the development of a xenograft with 10 gene edits, to minimize chance of rejection, blood clot formation, inflammation, and organ growth.
These advancements in genetic modification were enough to allow for the first documented XT of a porcine kidney in a deceased human model (Figure 4). Both kidneys from the 10-gene-edited pig were transplanted into a nephrectomized decedent brain-dead for 72 hours. The study was successful in some ways, and porcine xenografts were transplanted without surgical complications, histologic changes of HAR or acute rejection (with correlating negative prospective crossmatch), transmission of porcine viruses, or reperfusion complications (pig blood pressure is significantly lower than human). While the xenografts produced urine, serum creatinine did not improve and there were early histologic changes of thrombotic microangiopathy as well as severe acute tubular injury. A second publication reported similar results following transplantation of a single-gene modified (Gal knockout) pig kidney with autologous subcapsular thymus implantation (to induce a model of tolerance) into a brain dead decedent. This study reported creatinine clearance, though the native kidneys in the decedent were not removed and the xenograft kidney was left outside the body and on top of the thigh.
Given the brevity of these studies, it is impossible to conclude that this model of porcine xenograft will be sufficient to prevent chronic rejection. The establishment of porcine XT as a safe procedure (albeit in a brain-dead decedent) certainly yielded enough promise to serve as a springboard for future research, however many steps still remain. Will these kidneys provide clearance? And in which live patient population can porcine XT be studied safely and ethically?
Though this is NephMadness, we’d be remiss to exclude a heavily documented cardiac XT from a 10-gene-edited pig into a 57-year-old living man with non-ischemic cardiomyopathy. The pig heart lasted 48 days prior to failing (though initially due to a mechanism not related to rejection), and after almost two weeks on veno-arterial extracorporeal membrane oxygenation (ECMO), care was withdrawn. While this was truly momentous as the first living recipient of XT, it did bring forth several ethical concerns. First, as animals are sentient, intelligent, have a capacity for suffering, and lack the ability to give consent, there are clear ethical challenges that must be addressed. Second, there is a possibility that XT may worsen the allocation landscape, as the potential for high cost may lead to easy access to those who are financially well off, ultimately adding another avenue of socioeconomic disparities that already exist in modern-day medicine. Third, there has been a significant ethical discussion categorizing XT recipients as chimeras with potential subsequent negative effects. And finally, the risks of zoonotic infection remain unknown. While porcine viruses have been fairly well-categorized and thus far prevented due to pathogen-free breeding (except for porcine endogenous retroviruses), the unknown long-term effects of potential zoonotic infection remain uncertain. As we have seen in recent zoonotic infections that have undergone human-animal transmission, these effects could spread beyond the recipient. Lastly, there are ethics around the candidates for XT, especially as further advances are made and we move toward clinical trials on living humans. The live recipient of the cardiac XT was ineligible for a human donor. While we have learned from his contribution to science, there certainly is a question as to whether it is ethical to provide an untested medical service to a living human. The Food and Drug Administration allowed for this procedure to proceed as “the outcome of the experimental transplantation was not likely to be inferior to continuation of medical therapy and venoarterial ECMO”. Ultimately, XT has tremendous promise to provide the answer to the organ shortage. However, we’re still far from the championship and have a way to go in terms of both the science and the ethics of XT.
The kidney donor shortage has been and continues to be an insurmountable barrier to providing effective and optimal care for those with end-stage kidney disease. Stemming from increased and potentially unnecessary organ discard and inefficiencies in the obtaining and allocation of deceased donor organs by OPOs, new methods are needed to help optimally allocate organs. Though XT is exciting and has the potential to greatly increase the organ supply, we must first clear medical and ethical hurdles before this can become a strategy to improve access to transplantation—for all.