Faculty Bibliography

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.

Transplantation benefits from appropriate regulation by ensuring adherence to quality and safety standards. However, Dr. Andreoni highlights in his Personal Viewpoint the unintended consequences of heightened regulatory control¹ . While the article has a US perspective, its message is global. For example, in the UK any center with statistical deviation in actual-versus-expected 30-day survival outcomes can be investigated. US data show that discard rates have risen and the number of patients waiting for transplants has flattened in the era of enhanced regulation; suggesting we are providing fewer transplant opportunities for patients who could potentially benefit.

Data describing the clinical progression of coronavirus disease 2019 (COVID-19) in transplant recipients are limited. In New York City during the surge in COVID-19 cases, a systematic approach to monitoring and triaging immunocompromised transplant patients was required in the context of strained healthcare resources, limited outpatient testing, and heightened hospital exposure risks. Public health guidance at the onset of the COVID-19 outbreak recommended outpatient monitoring of mildly symptomatic patients without specific recommendations for special populations such as transplant recipients. We developed and implemented a systematic monitoring algorithm for kidney transplant recipients at our transplant center who reported mild symptoms suggestive of COVID-19. We describe the outcomes of the first 44 patients monitored through this algorithm. A total of 44 kidney transplant recipients thought to be symptomatic for COVID-19 disease were followed for a minimum of 14 days. The majority of mildly symptomatic patients (34/44) had clinical progression of disease and were referred to the emergency department where they all tested PCR positive and required hospitalization. More than half of these patients presented with hypoxia requiring supplemental oxygen, 39% were intubated within 48 hours, and 53% developed acute kidney injury but did not require dialysis. There were 6 deaths. During surge outbreaks, kidney transplant patients with even mild symptoms have a high likelihood of COVID-19 disease and most will worsen requiring hospitalization for supportive measures. Earlier outpatient testing and hospitalization may improve COVID-19 outcomes among transplant recipients.

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low level evidence. The number of prospective randomized trials for the treatment of AMR is small and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated.At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes and outcomes were discussed. The evidence for different treatments was reviewed and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented.Whilst it was agreed that the aims of treatment are to preserve renal function, reduce histological injury and reduce the titer of donor specific antibody (DSA), there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.

Rationale & Objectives/UNASSIGNED:Recent data demonstrate that center volume is not a factor in the outcomes of adult kidney transplant recipients. This study assessed whether center volume affects graft survival in pediatric patients who received a kidney transplant. Study Design/UNASSIGNED:Case-cohort study. Setting & Participants/UNASSIGNED:Kidney transplantation centers, recipients younger than 18 years. Results/UNASSIGNED: = 0.02. Although outcomes for deceased donor kidney recipients were similar in the 3 volume categories, outcomes in patients who received a living kidney donation were better in the high-volume centers. Low household income was associated with poorer outcomes. However, 3-year graft survival was similar in the 3 center volume categories in high and low mean household income states. Limitations/UNASSIGNED:Lack of information for complications and individual family household income of recipients. Conclusions/UNASSIGNED:Transplantation outcomes are worse in pediatric patients treated at lower-volume centers. The difference was more pronounced for patients receiving living versus deceased donor kidneys. The distribution of household income in pediatric transplant recipients may also be a factor that contributes to lower 3-year graft survival in low-volume centers.

Background: Clinical trials have demonstrated the safety of utilizing hepatitis C viremic donors (HCV+) to expand the donor pool through transplantation into hepatitis C naive recipients (HCV-). However, there has been a lack of enthusiasm to of er HCV+ pancreas grafts to HCV- recipients. We of ered HCV- pancreas patients the option to list for HCV+ donor organs.
Material(s) and Method(s): Patients undergoing pancreas transplant evaluation had informed consent by a transplant physician to receive HCV+ donor organs. We ensured patients had pharmacy coverage for post-transplant HCV anti-retroviral therapy prior to listing. In our early experience, 4 of our 8 transplant recipients elected to list for HCV+ donor organs.
Result(s): In the first 8 months, the average time to transplant from listing was 41 days for patients with standard listing and 21 days for patients listing for HCV+ organs (p<0.05). Of note, 2 of the 4 HCV- recipients were blood type AB and had shorter match time due to their blood type. For all HCV+ donors, COD was anoxia/drug OD, all were HCV antibody and NAT positive, PHS IR, and national imports, with average rank of 3 on the match run. All HCV- donors were local donors with average rank of 21 on the match run. HCV+ donors were younger (28 years) in contrast to HCV- donors (35 years). All recipients have excellent graft function with no signif cant dif erences in complications, LOS, or readmissions.
Conclusion(s): Utilization of HCV+ pancreas donors has allowed our patients increased access to high quality pancreas donors with signif cantly shorter wait times

Desensitization using plasma exchange can remove harmful antibodies prior to transplantation and mitigate risks for hyperacute and severe early acute antibody-mediated rejection. Traditionally, the use of plasma exchange requires a living donor so that the timing of treatments relative to transplant can be planned. Non-HLA antibody is increasingly recognized as capable of causing antibody-mediated renal allograft rejection and has been associated with decreased graft longevity. Our patient had high-strength non-HLA antibody deemed prohibitive to transplantation without desensitization, but no living donors. As the patient was eligible to receive an A2 ABO blood group organ and was willing to accept a hepatitis C positive donor kidney, this afforded a high probability of receiving an offer within a short enough time frame to attempt empiric desensitization in anticipation of a deceased donor transplant. Fifteen plasma exchange treatments were performed before the patient received an organ offer, and the patient was successfully transplanted. Hepatitis C infection was treated posttransplant. No episodes of rejection were observed. At one-year posttransplant, the patient maintains good graft function. In this case, willingness to consider nontraditional donor organs enabled us to mimic living donor desensitization using a deceased donor.

Kidney paired donation (KPD) and the new kidney allocation system (KAS) in the United States have led to improved transplantation rates for highly sensitized candidates. We aimed to assess the potential need for other approaches to improve the transplantation rate of highly sensitized candidates such as desensitization. Using the UNOS STAR file, we analyzed transplant rates in a prevalent active waiting-list cohort as of June 1, 2016, followed for 1 year. The overall transplantation rate was 18.9% (11 129/58769). However, only 9.7% (213/2204) of candidates with a calculated panel reactive antibody ≥99.9% received a transplant, and highly sensitized candidates were less likely to receive a living donor transplant. Among candidates with a CPRA ≥ 99.5% (ie. 100%), only 2.5% of transplants were from living donors (13 total, 7 from KPD). Nearly 4 years after KAS (6/30/2018), 1791 actively wait-listed candidates had a CPRA of ≥99.9% and 34.6% (620/1791) of these had ≥5 years of waiting time. Thus, despite KPD and KAS, many sensitized candidates have not been transplanted even with prolonged waiting time. We conclude that candidates with a CPRA ≥ 99.9% and sensitized candidates with an incompatible living donor and prolonged waiting time may benefit from desensitization to improve their ability to receive a transplant.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.