Suggested Patient Selection Criteria For Initial Clinical Trials Of Pig Kidney Xenotransplantation In The United States

INTRODUCTION More than 80 000 patients with end-stage renal disease (ESRD) are on the waitlist for kidney transplantation in the United States,1 most of whom are receiving chronic hemodialysis. The 5-year mortality of waitlisted patients is approximately 40%,2-5 whereas the median waiting time to receive a deceased human donor kidney is 4 years.6 Many patients will not live long enough to undergo kidney allotransplantation. Chronic dialysis is associated with relatively high mortality and increased comorbidities that may render the patient unsuitable for renal transplantation. Furthermore, the quality of life is inferior to that of a patient with a functioning kidney allograft.7-9 Prolonged dialysis may have adverse economic implications for the patient and his/her family.10,11 Xenotransplantation using genetically engineered pigs as sources of kidneys has several advantages over allotransplantation (Table 1) and is a potential option for patients on chronic dialysis, either as a bridge to allotransplantation or as destination therapy. Life-supporting genetically modified pig kidney transplantation in nonhuman primates is currently associated with substantial success, with recipient survival extending for many months or even more than a year.12-17 It is therefore becoming important to determine which patients could be considered as potential recipients in the first clinical trials. TABLE 1. - Potential advantages of pig kidney xenotransplantation over allotransplantation (if the immunological challenges can be successfully overcome) 1. Unlimited supply of “donor” organs. 2. Organs available electively. (Patients with ESRD will no longer require chronic dialysis. 3. Avoids the detrimental effects of brain death on the organs. 4. The “donors” will be exogenous infection-free. 5. “Borderline” transplant candidates, ie, those with health problems that may be detrimental to prolonged patient survival, eg, poorly controlled diabetes, severe peripheral, or cerebrovascular disease, will be more acceptable (as they will no longer be competing for scarce organs with other potential transplant candidates). 6. Avoids the cultural barriers to deceased human organ donation. ESRD, end-stage renal disease. The present report discusses factors influencing the selection of patients for pig kidney xenotransplantation. Before addressing these topics, several points have to be made. (i) The patients being considered for the clinical trial will be those for whom a living donor is not an option. (ii) The results of studies in the pig-to-nonhuman primate kidney transplant model will suggest that there is a realistic probability of achieving a clinically useful period of dialysis-free survival in a patient, for example, a minimum of 12 months and hopefully much longer. (iii) The immunosuppressive regimens that have proved successful in pig-to-nonhuman primate models include agents that block the CD40/CD154 costimulation pathway that are not yet FDA-approved, and it seems likely that at least 1 of these agents will be essential.17 (iv) The risk of an adverse outcome, for example, death, is small; if the graft is rejected or a life-threatening infection proves uncontrollable, the graft will be excised, all immunosuppressive therapy will be discontinued, and the patient will return to dialysis. (v) The risk of a zoonotic infection is uncertain but considered to be small.18 For the first clinical trial of pig kidney transplantation it would be wise to select patients who have not had a prolonged period on dialysis (eg, >1 y), who do not have diabetes, have not had a previous organ transplant, and are not very old. Significant comorbidities are likely to increase posttransplant morbidity or mortality. However, we suggest that the patients should have been initiated on chronic hemodialysis (and should not undergo preemptive kidney xenotransplantation, ie, before requiring dialysis) because the patient and his/her family should be convinced that kidney failure has progressed to the point where death would have occurred if dialysis had not been initiated. We also suggest that the patient should be of an age where it is unlikely that he/she will survive until a deceased donor becomes available. Patients in their late 50s (or possibly early 60s), if in a good physiological state and without comorbidities, may prove to be the candidates who are most likely to benefit from a pig kidney transplant. In 2018, of the 92 906 patients on the waitlist in the United States, 4193 died and 4240 were removed from the waitlist for being considered no longer suitable for kidney transplantation (eg, too frail or too sick).1 Based on retrospective data from 163 636 patients (aged >18 y) between January 1, 2007, and December 31, 2011, Hart et al found multiple parameters that affect the outcome of patients on the waitlist. From these data, they developed an original competing risk model (the system was subsequently modified with the introduction of a new kidney allocation system in 2014), which is available on the Scientific Registry of Transplant Recipients (SRTR) website. At present, the SRTR’s kidney transplant decision aid calculator is based on candidates listed between October 2018 and September 2019.19,20 Several factors have been found to affect the outcome adversely, most notably (i) advanced age, (ii) male sex, (iii) a high calculated panel-reactive antibody, (iv) comorbid conditions (eg, diabetes, hypertension, cardiovascular pathology, high body mass index), and (v) the length of the waiting period (eg, related to ABO blood group or UNOS region).21-23 The SRTR’s kidney transplant decision aid calculator is equally suitable to predict outcome of patients on the kidney transplant waitlist who might be considered for a pig kidney transplant. SELECTION OF PATIENTS FOR PIG KIDNEY XENOTRANSPLANTATION On the basis that the period on the waitlist might be so long that they may die before being allocated a deceased human donor organ, we have suggested that older age patients (55–60 y or possibly 55–65 y), but with good physiology and with no comorbidities, particularly of blood group O (as these patients tend to spend longer on the waitlist), should be considered as potential candidates for the first clinical trial.2 As the anticipated period of pig graft survival remains uncertain, younger patients, who are more likely to survive until a suitable allograft becomes available, should perhaps be excluded from the initial trials. One important factor that needs consideration is the rate of kidney allotransplantation in the donor service area or UNOS region in which the patient is waitlisted. In the United States, the likelihood of receiving a kidney within 5 years of listing varies between <20% and almost 80% depending on the UNOS region in which the patient is listed.1 We therefore suggest that in a UNOS region with a low rate of kidney transplantation or a high ESRD burden, where waitlisted patients are at a disadvantage, there is an added need to consider xenotransplantation. Geographic variation in patient access to transplantation between UNOS regions could be reduced or avoided when xenotransplantation is introduced as a routine procedure. Other factors could also be considered, for example patients (i) who no longer have vascular access to enable hemodialysis, or (ii) with recurrent kidney disease after allotransplantation,24 but we suggest that these patients are less suitable for the initial clinical trial because it is likely that they have been on dialysis for a long period of time (and, therefore, have possibly developed comorbidities) or have undergone previous kidney allotransplantation, both of which would complicate the management of a patient in an initial clinical trial.2 Patients with a high calculated panel-reactive antibody, for whom it will be difficult to identify an acceptable deceased human donor, may be candidates for xenotransplantation. However, there is some evidence that anti-HLA antibodies can cross-react with swine leukocyte antigens and therefore may increase the risk of antibody-mediated rejection of a pig organ.25 Although these patients may ultimately benefit most from the availability of pig kidney xenografts, we suggest that they should not be considered for the first clinical trial. Considering these factors, we suggest exclusion criteria for the first clinical xenotransplantation trial (Table 2). These are based largely on the equivalent criteria for kidney allotransplantation, although some xenotransplantation-specific exclusion criteria are included. Because this would be the first clinical trial, the criteria may be rather more rigorous than for clinical allotransplantation today but, in the light of initial experience in renal xenotransplantation, they could subsequently be relaxed. There are currently no hard data on how many patients in the suggested age range might meet these strict criteria. However, if they are already on the waitlist for an allograft, some will very likely meet these more rigorous criteria. Whether these specific patients would accept a xenograft is unknown, but small surveys have indicated that patients might well accept a pig kidney graft.30 Furthermore, if they are provided with realistic information on their prognosis on the waitlist (see below), we suggest that some will be prepared to accept the potential risks of pig kidney xenotransplantation. TABLE 2. - Suggested exclusion criteria for patient selection for the first clinical trial of pig kidney transplantation Age <55 or >65 y. Body mass index <18 or >30 kg/m2 (possibly 35 kg/m2). Metabolic equivalents in exercise testing <4.26 On dialysis <12 mo. Comorbidities Heart disease or dysfunction (ejection fraction <50%). Poorly controlled chronic hypertension. Severe hypotension during hemodialysis, requiring vasopressors. Peripheral occlusive vascular disease, including previous endarterectomy, bypass grafting, stenting, or limb amputation. Cerebrovascular disease, eg, previous stroke, or multiple transient ischemic attacks Chronic lung disease. Severe pulmonary hypertension. Chronic liver disease. Severe, unstable insulin-requiring diabetes mellitus. History of cancer within the past 5 y, except for nonmelanoma skin cancer, unless recurrent. Active autoimmune disease. Calciphylaxis (calcified uremic arteriolopathy). History of psychosis. Severe psychological problems. Cognitive impairment (dementia). Infectious contraindications Documented HIV infection Documented hepatitis B or C Active untreated infections. History of active tuberculosis or systemic fungal infection. Presence of an intestinal stoma (ostomy). Social contraindications Active alcohol or drug abuse, including tobacco. History of noncompliance with medical therapy, including dialysis. Dependence on nursing home or other long-term provider Resources deemed inadequate to support necessary posttransplant care. Because of the potential transfer of pig endogenous retroviruses to future offspring: 1. Female patients should not be of child-bearing age, ie, they should be postmenopausal (unless they have previously undergone hysterectomy or tubal ligation). 2. Male patients will be excluded unless they agree to use birth control methods with their sexual partner(s) to prevent pregnancy. Immunological/inflammatory contraindications Sensitization to HLA (ie, panel-reactive antibodies >5%). Sensitization to TKO pig cells, based on evidence of: 1. Serum natural IgM or IgG antibody binding to TKO pig RBCs. 2. Serum natural IgM or IgG antibody binding to TKO pig PBMCs. 3. Serum complement-dependent cytotoxicity to TKO pig PBMCs. 4. Response of patient’s PBMCs (on MLR) to stimulation by TKO pig PBMCs greater than to wild-type or GTKO pig PBMCs, and greater than the median MLR to PBMCs from the pig that will be the source of the kidney. CRP ≥8 mg/L (CRP levels ≥8 mg/L are consistently associated with increased risk of death of patients on chronic dialysis).27-29 Surgical contraindications No previous major abdominal surgical procedures that would complicate kidney transplantation CRP, C-reactive protein; MLR, mixed lymphocyte reaction; PBMC, peripheral blood mononuclear cell; RBC, red blood cells; TKO, triple-knockout. PROVISION OF REALISTIC INFORMATION ON PROGNOSIS FOR WAITLIST PATIENTS The median waiting time for a deceased human kidney (approximately 4 years) indicates the time it will take for half of the potential recipients to undergo kidney transplantation. Patients removed from the waitlist are not included in the calculation. Importantly, information on median waiting time obscures the fact that, because of death while on the waitlist or being removed from the waitlist because they are no longer considered to be acceptable recipients, a significant percentage of candidates on the waitlist never receive an allograft. We suggest that patients on hemodialysis, as well as their physicians, overestimate their likelihood of survival,31,32 though this will vary from patient to patient. Probably because physicians do not wish to provide the patient with a pessimistic prognosis (which they are unable to improve), most patients, therefore, do not receive realistic prognostic information about their likely outcome while on the waitlist.33 We recommend that, as part of their counseling, patients should be informed of their likely outcome on the waitlist based on the SRTR’s kidney transplant decision aid calculator. Without this information, a patient will be unable to make an informed decision as to whether to take the risk of accepting a pig kidney graft.30 IMMUNOLOGIC ASPECTS OF PATIENT SELECTION In preclinical models of pig kidney transplantation, graft survival of 6 months or longer is increasingly being obtained in nonhuman primates with low anti-pig antibody levels, particularly if the organ-source pig expresses human complement- and coagulation-regulatory protein, and effective immunosuppressive therapy is administered to suppress the adaptive immune response.12-17 It should be noted that all Old World nonhuman primates express antibodies to cells from “triple-knockout” pigs (the basis of the optimal pigs currently available),34 whereas approximately 30% of humans have no or minimal antibodies binding to these cells.35 In the light of these results, potential human recipients should be selected who do not have (i) antiglycan IgM/IgG anti-pig antibodies (with no evidence of cytotoxicity to the organ-source pig cells), (ii) anti-HLA antibodies (that may cross-react with swine leukocyte antigens),36 and (iii) a strong response on mixed lymphocyte reaction (compared with the median response of a panel of potential recipients) (Table 2). The current (limited) evidence suggests that sensitization to pig antigens, should it develop after pig organ transplantation, would not be detrimental to the outcome of a subsequent allotransplant.37 If confirmed, this is an important point as it would not preclude subsequent successful allotransplantation after an initial xenotransplant. A patient undergoing pig kidney transplantation could remain on the waitlist for a deceased human allograft and, at least for a period of time (as yet uncertain), avoid the medical and social disadvantages of chronic dialysis and enjoy the benefits of a functioning kidney graft. In clinical trials, therefore, although intended as destination therapy, the pig kidney graft may initially act as a bridge to allotransplantation. Furthermore, the immunosuppressive therapy required to maintain a pig xenograft, though with some differences from that used in allotransplantation,17 is not significantly more intensive than conventional immunosuppressive therapy. CONCLUSIONS With the increasing success of preclinical genetically engineered pig kidney xenotransplantation in nonhuman primates, it is time to consider kidney xenotransplantation as renal replacement therapy for patients with ESRD. Patient selection can be based on the parameters currently used for allotransplantation. SIGNIFICANCE STATEMENT Life-supporting pig kidney transplantation in nonhuman primates is now associated with survival of several months, suggesting that clinical trials might soon be justified. Patients who are unlikely to survive until a deceased human donor kidney becomes available could be offered a pig kidney graft. In some US states, patients aged 55–65 years, particularly if of blood group O, may wait >5 years for a donor organ, by which time >50% are likely to have died or removed from the waitlist because they are no longer acceptable for transplantation. They might accept the opportunity of early pig kidney xenotransplantation. LAY SUMMARY There is a critical shortage of kidneys for transplantation into patients with kidney failure. Genetically engineered pigs could provide an additional source. Increasing success is being reported of the transplantation of pig kidneys in nonhuman primates. Consideration is now being given to the selection of patients for the first clinical trial of pig kidney transplantation. In some US states, patients aged 55–65 years, particularly if of blood group O, may wait >5 years for a donor organ, by which time >50% are likely to have died or removed from the waitlist because they are no longer acceptable for transplantation. We suggest that these patients, if otherwise healthy, might accept the opportunity of early pig kidney transplantation.