Christopher E. Simpkins

Desensitization in HLA-Incompatible Kidney Recipients and Survival

BACKGROUND More than 20,000 candidates for kidney transplantation in the United States are sensitized to HLA and may have a prolonged wait for a transplant, with a reduced transplantation rate and an increased rate of death. One solution is to perform live-donor renal transplantation after the depletion of donor-specific anti-HLA antibodies. Whether such antibody depletion results in a survival benefit as compared with waiting for an HLA-compatible kidney is unknown. METHODS We used a protocol that included plasmapheresis and the administration of low-dose intravenous immune globulin to desensitize 211 HLA-sensitized patients who subsequently underwent renal transplantation (treatment group). We compared rates of death between the group undergoing desensitization treatment and two carefully matched control groups of patients on a waiting list for kidney transplantation who continued to undergo dialysis (dialysis-only group) or who underwent either dialysis or HLA-compatible transplantation (dialysis-or-transplantation group). RESULTS In the treatment group, Kaplan-Meier estimates of patient survival were 90.6% at 1 year, 85.7% at 3 years, 80.6% at 5 years, and 80.6% at 8 years, as compared with rates of 91.1%, 67.2%, 51.5%, and 30.5%, respectively, for patients in the dialysis-only group and rates of 93.1%, 77.0%, 65.6%, and 49.1%, respectively, for patients in the dialysis-or-transplantation group (P<0.001 for both comparisons). CONCLUSIONS Live-donor transplantation after desensitization provided a significant survival benefit for patients with HLA sensitization, as compared with waiting for a compatible organ. By 8 years, this survival advantage more than doubled. These data provide evidence that desensitization protocols may help overcome incompatibility barriers in live-donor renal transplantation. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Charles T. Bauer Foundation.).

Plasmapheresis, CMV hyperimmune globulin, and anti-CD20 allow ABO-incompatible renal transplantation without splenectomy

The majority of preconditioning protocols developed to allow ABO‐incompatible (ABOi) renal transplantation include concurrent splenectomy as a prerequisite to successful engraftment. Our center has developed a preconditioning protocol that includes plasmapheresis (PP), low‐dose CMV hyperimmune globulin (CMVIg), and anti‐CD20 monoclonal antibody (rituximab) to allow ABOi renal transplantation without splenectomy. Our initial experience has included treatment of six recipients and successful transplantation from blood group A1, A2, and group B living donors. Mean (± SD) serum creatinine was 1.3 ± 0.1 mg/dL among the six recipients and no episodes of antibody‐mediated rejection (AMR) occurred at a median follow‐up of 12 months. ABO antibody titers have remained below pretreatment levels. The absence of AMR and stable allograft function in this series show the potential of this preconditioning protocol to increase ABOi renal transplantation. The use of rituximab, allowing avoidance of splenectomy, may further remove one of the significant disincentives to ABOi transplantation, and eliminate the risk of post‐splenectomy infections.

C4d and C3d staining in biopsies of ABO- and HLA-incompatible renal allografts: correlation with histologic findings.

Biopsies of ABO‐incompatible and positive crossmatch (HLA‐incompatible) renal allografts were retrospectively examined to compare results of C4d and C3d staining, and the correlation between such staining and histologic findings suggestive of antibody‐mediated rejection (AMR). A total of 75 biopsies (55 protocol, 17 for graft dysfunction, 3 for other indications) of 24 ABO‐incompatible grafts and 244 biopsies (103 protocol, 129 for graft dysfunction, 12 for other indications) of 66 HLA‐incompatible grafts were examined; all were stained for C4d and ∼40% for C3d.

ABO incompatible renal transplantation: A paradigm ready for broad implementation

The requirements for potent immunosuppression coupled with the formidable risk of irreversible antibody-mediated rejection (AMR) have thus far limited the expansion of ABO incompatible (ABOi) kidney transplantation. We present a retrospective review of our single-center experience with 60 consecutive ABOi kidney transplants and describe the evolution of our treatment protocol to one that consists only of a brief escalation in immunosuppression without long-term B-cell suppression from splenectomy or anti-CD20. The 1-, 3-, and 5-year graft survival rates for the cohort were 98.3%, 92.9%, and 88.7%, respectively, which is comparable with United Network for Organ Sharing data for compatible live donor transplants. No instances of hyperacute rejection were observed, and no grafts were lost secondary to AMR. In fact, fewer than 15% of the patients experienced a clinical episode of AMR, and rejections were mild. Elimination of B-cell ablative therapies did not result in an increased incidence of AMR. Excellent graft function persists with a current median creatinine clearance of 60 mL/min. The findings of this study and the relatively simple therapeutic regimen used should facilitate widespread application of ABOi kidney transplantation resulting in one of the most rapid escalations in access to organs in the modern era of kidney transplantation.

Outcomes of kidneys from donors after cardiac death: Implications for allocation and preservation

Although donation after cardiac death (DCD) kidneys have a high incidence of delayed graft function (DGF) and have been considered marginal, no tool for stratifying risk of graft loss nor a specific policy governing their allocation exist. We compared outcomes of 2562 DCD, 62 800 standard criteria donor (SCD) and 12 812 expanded criteria donor (ECD) transplants reported between 1993 and 2005, and evaluated factors associated with risk of graft loss and DGF in DCD kidneys. Donor age was the only criterion used in the definition of ECD kidneys that independently predicted graft loss among DCD kidneys. Kidneys from DCD donors <50 had similar long‐term graft survival to those from SCD (RR 1.1, p = NS). While DGF was higher among DCD compared to SCD and ECD, limiting cold ischemia (CIT) to <12 h decreased the rate of DGF 15% among DCD <50 kidneys. These findings suggest that DCD <50 kidneys function like SCD kidneys and should not be viewed as marginal or ECD, and further, limiting CIT <12 h markedly reduces DGF.

Domino paired kidney donation: a strategy to make best use of live non-directed donation

Current models for allocation of kidneys from living non-directed donors Living non-directed (LND) donors, also known as altruistic, good Samaritan, anonymous, or benevolent community donors, are a new and rapidly growing source of solid organs for transplantation. The willingness of individuals to donate organs without a designated recipient has been unexpected, but has probably developed as a societal response to the growing crisis in organ availability. In the context of this shortage, health professionals have attempted to make the best use of kidneys from LND donors. We present a novel application of paired donation that has the potential to multiply the number of recipients who can benefi t from each LND donation. At present, there is no universally accepted system for allocation of organs from LND donors. Selection of recipients has been at the discretion of the transplant centres where LND donors have presented and has generally been guided by one of three models: donorcentric, recipient-centric, or sociocentric allocation. Each of these models is supported by valid ethical arguments. The main goal of donor-centric allocation is to ensure a successful outcome for the recipient. A good outcome provides justifi cation for medical professionals to assist a person who is not ill to put themselves in harm’s way to aid another. A positive result also gives an LND donor a sense that their eff ort was fruitful and worthwhile. However, this model dictates allocation to the healthiest patient on the transplant waiting list. These recipients are the most likely to have good outcomes on dialysis or with organs from deceased donors, and therefore are arguably the least in need. Recipient-centric allocation is based on the belief that society has a responsibility to protect its most vulnerable and disadvantaged members. Under this model, organs from LND donors are given to those patients in the greatest need, those for whom a kidney transplant might be truly life saving, or those disadvantaged under the existing system for allocation of kidneys from deceased donors. This model mainly benefi ts children, patients who have no vascular access, highly sensitised patients, and those with life-threatening medical illnesses related to dialysis. However, because the recipient-centric model accords priority to such patients, it tends to yield unacceptably poor transplant outcomes, and could lead to a negative public perception of LND donation. Under the third model, of sociocentric allocation, the LND donated organ is treated as a public resource that should be allocated in the fairest and most equitable way, irrespective of outcome or need. This rationale dictates that the recipient should be the patient at the top of the transplant waiting list administered by the United Network of Organ Sharing (UNOS). UNOS oversees the allocation of deceased donor organs in the USA, using a so-called match run algorithm that ranks potential recipients according to agreed criteria. The limitations of this model are that a patient at the top of the list will probably receive a kidney from a deceased donor in the near future, and that they will have already incurred the costs, and exposure to comorbidity, that result from a long period on dialysis. The waiting list for deceased donor kidneys can be circumvented by patients who fi nd a willing live donor. But direct donation might be complicated by diff erences in blood type and by HLA sensitivity. Some incompatible donor-recipient pairs enter into programmes that facilitate paired donation, also known as kidney paired donation. A donor and recipient who have incompatible blood groups or HLA sensitivity can be matched with another incompatible pair, to result in two compatible transplants (fi gure). Although there are many ways to match up a pool of incompatible pairs, the mathematical technique of optimisation helps to fi nd out which matches will yield the best results. Nevertheless, even in paired-donation programmes in which mathematical optimisation is applied, more than 50% of the incompatible pairs in the pool remain unmatched. In many cases, pools of incompatible donor-recipient pairs have a high proportion of patients with blood types that are hard to match and those with HLA sensitisation.

Subclinical Acute Antibody‐Mediated Rejection in Positive Crossmatch Renal Allografts

Subclinical antibody‐mediated rejection (AMR) has been described in renal allograft recipients with stable serum creatinine (SCr), however whether this leads to development of chronic allograft nephropathy (CAN) remains unknown.

ABO Incompatible High‐Titer Renal Transplantation without Splenectomy or Anti‐CD20 Treatment

Most successful protocols for renal transplantation across ABO incompatible (ABOi) barriers have utilized splenectomy as part of the pre‐conditioning process. We recently described successful ABOi transplantation using anti‐CD20 monoclonal antibody in lieu of splenectomy. In the current study, we hypothesized that plasmapheresis (PP) and low dose CMV hyper‐immunoglobulin (CMVIg) alone would be sufficient to achieve successful engraftment of ABOi kidneys. We describe four blood type incompatible patients who received live donor renal transplants from A1 (two patients), A2 (one patient), and B (one patient) donors. All patients started with antihuman globulin (AHG) phase titers of 64 or higher and were pre‐conditioned with PP/CMVIg but not splenectomy or anti‐CD20. All 4 patients underwent successful transplantation and have a mean current serum creatinine of 1.1 (range: 0.9–1.2). There were no episodes of antibody mediated rejection. Rapid allograft accommodation may limit the need for long‐term antibody suppression provided by splenectomy or anti‐CD20, thereby eliminating the added infectious risk of these modalities and removing another disincentive to ABOi transplantation.

Obesity Impacts Access to Kidney Transplantation

Current billing practices and mandates to report surgical outcomes are disincentives to surgical treatment of obese patients, who are at increased risk for longer hospital stays and higher complication rates. The objective of this study was to quantify the independent association between body mass index (BMI) and waiting time for kidney transplantation to identify potential provider bias against surgical treatment of the obese. A secondary data analysis was performed of a prospective cohort of 132,353 patients who were registered for kidney transplantation in the United States between 1995 and 2006. Among all patients awaiting kidney transplantation, the likelihood of receiving a transplant decreased with increasing degree of obesity, categorized by ranges of BMI (adjusted hazard ratios 0.96 for overweight, 0.93 for obese, 0.72 for severely obese, and 0.56 for morbidly obese, compared with a reference group of patients with normal BMI). Similarly, the likelihood of being bypassed when an organ became available increased in a graded manner with category of obesity (adjusted incidence rate ratio 1.02 for overweight, 1.05 for obese, 1.11 for severely obese, and 1.22 for morbidly obese). Although matching an available organ with an appropriate recipient requires clinical judgment, which could not be fully captured in this study, the observed differences are dramatic and warrant further studies to understand this effect better and to design a system that is less susceptible to unintended bias.

Factors affecting graft survival after liver transplantation from donation after cardiac death donors

Background. Liver transplantation from donation after cardiac death (DCD) donors is an increasingly common approach for expansion of the donor organ supply. However, transplantation with DCD livers results in inferior graft survival. In this study, we examined donor and recipient characteristics that are associated with poor allograft outcomes and present a set of criteria that permit allograft survival that is comparable to that of donation after brain death (DBD) grafts in both low- and high-risk recipients. Methods. The United Network for Organ Sharing/Organ Procurement and Transplantation Network Liver Transplantation Registry between January 1996 and March 2006 was investigated. Adult DCD liver transplants (n=874) were included. Results. A DCD risk index was developed using the statistically significant factors from a multivariate Cox model: history of previous transplantation, life support status at transplantation, donor age, donor warm ischemia time (DWIT), and cold ischemia time (CIT). Favorable DCD donor criteria were donor age ≤45 years, DWIT ≤15 min, and CIT ≤10 hr. Four risk groups were developed based upon index scores that showed different graft survival. Graft survival of the favorable DCD group (84.9% at 1 year, 75.2% at 3 years, and 69.4% at 5 years) was comparable to that for DBD liver transplantation irrespective of recipient condition. Increasing donor age was more highly predictive of poor outcomes in DCD compared to DBD, especially in recipients in poor preoperative condition. Conclusions. DCD livers from young donors with short DWIT and CIT should be given greater consideration in order to expand the number of available donor organs.