An Enhanced Role of Innate Immunity in the Immune Response After Kidney Transplant in People Living With HIV: A Transcriptomic Analysis.

BACKGROUND: Although kidney transplantation (KT) has become the standard of care for people living with HIV (PLWH) suffering from renal failure, early experiences revealed unanticipated higher rejection rates than those observed in HIV- recipients. The cause of increased acute rejection (AR) in PLWH was assessed by performing a transcriptomic analysis of biopsy specimens, comparing HIV+ to HIV- recipients. METHODS: An analysis of 68 (34 HIV+, 34 HIV-) formalin-fixed paraffin-embedded (FFPE) renal biopsies matched for degree of inflammation was performed from KT recipients with acute T cell-mediated rejection (aTCMR), borderline for aTCMR (BL), and normal findings. Gene expression was measured using the NanoString platform on a custom gene panel to assess differential gene expression (DE) and pathway analysis (PA). RESULTS: DE analysis revealed multiple genes with significantly increased expression in the HIV+ cohort in aTCMR and BL relative to the HIV- cohort. PA of these genes showed enrichment of various inflammatory pathways, particularly innate immune pathways associated with Toll-like receptors. CONCLUSIONS: Upregulation of the innate immune pathways in the biopsies of PLWH with aTCMR and BL is suggestive of a unique immune response that may stem from immune dysregulation related to HIV infection. These findings suggest that these unique HIV-driven pathways may in part be contributory to the increased incidence of allograft rejection after renal transplantation in PLWH.

OPTN/SRTR 2022 Annual Data Report: Pancreas.

The postpandemic recovery did not occur in pancreas transplantation as in other organs. The number of pancreas transplants in the United States decreased to 918 in 2022 from 963 in 2021. The number of simultaneous pancreas-kidney transplants decreased to 810 in 2022 from 820 in 2021, but the largest decrease was in pancreas transplant alone: 62 in 2022 compared with 92 in 2021. Pancreas-after-kidney transplants decreased to 46 in 2022 from 51 in 2021. The trend of increasing proportions of pancreas transplants in patients with type 2 diabetes seen over the past few years ended in 2022; there were 22.4% of such transplants in 2022 compared with 25.8% in 2021. The proportion of recipients older than 45 years decreased in 2022 as well. However, the proportions of candidates with type 2 diabetes and older candidates on the waiting list did not decrease. The number of pancreas donors decreased and the pancreas nonuse rate increased in 2022. Outcomes after pancreas transplant continued to improve, with an impressive 8.1% pancreas and 4.3% kidney graft failure rate for simultaneous pancreas-kidney transplant at 1 year in 2022. The proportion of pancreas transplants performed by medium-volume centers (11-24 transplants/year) returned to 37.2% in 2022 from a high of 48.3% in 2021, whereas the proportion of those done by large-volume centers (25 or more transplants/year) returned to 25.3% in 2022 from a low of 15.9% in 2021.

Transplantation in the Context of Migration and Refugees: A Summary of the DICG and TTS Ethics Committee Workshop, Buenos Aires, Argentina, September 2022.

Global conflicts and humanitarian crises have resulted in an unprecedented number of refugees and migrants. This challenges the limited resources of health care systems and jeopardizes the availability of transplant care for these deserving migrants and refugees. This was the basis for a workshop held during the Congress of the Transplantation Society (Buenos Aires, 2022). We elaborate on the proceedings of the workshop entitled "Transplantation in the Context of Migration and Refugees," organized by the Ethics Committee of The Transplantation Society and Declaration of Istanbul Custodian Group. Transplant providers from around the world shared strategies of how each region has responded to providing access to care for refugees and migrants in need of transplant services. The potential exploitation of this vulnerable group leading to illicit organ removal was addressed for each region. The Transplantation Society, Declaration of Istanbul Custodian Group, and global transplant community should continue to focus on the status of refugees and migrants and collaborate on strategies to provide access to transplant care for this deserving population. Global cooperation will be essential to provide vigilant oversight to prevent exploitation of this vulnerable population.

Expanding Access to Organ Transplant for People Living With HIV: Can Policy Catch Up to Outcomes Data?

Advances in antiretroviral and immunosuppressive regimens have improved outcomes following solid organ transplantation in people living with HIV (PLWH). The HIV Organ Policy and Equity Act was conceived to reduce the discard of HIV-positive organs and improve access to transplant for PLWH. Nevertheless, PLWH continue to experience disproportionately low rates of transplant. This overview examines the hurdles to transplantation in PLWH with end-organ disease, the potential and realized impact of the HIV Organ Policy and Equity Act, and changes that could permit expanded access to organ transplant in this population.

Wait Time Advantage for Transplant Candidates With HIV Who Accept Kidneys From Donors With HIV Under the HOPE Act.

BACKGROUND: Kidney transplant (KT) candidates with HIV face higher mortality on the waitlist compared with candidates without HIV. Because the HIV Organ Policy Equity (HOPE) Act has expanded the donor pool to allow donors with HIV (D + ), it is crucial to understand whether this has impacted transplant rates for this population. METHODS: Using a linkage between the HOPE in Action trial (NCT03500315) and Scientific Registry of Transplant Recipients, we identified 324 candidates listed for D + kidneys (HOPE) compared with 46 025 candidates not listed for D + kidneys (non-HOPE) at the same centers between April 26, 2018, and May 24, 2022. We characterized KT rate, KT type (D + , false-positive [FP; donor with false-positive HIV testing], D - [donor without HIV], living donor [LD]) and quantified the association between HOPE enrollment and KT rate using multivariable Cox regression with center-level clustering; HOPE was a time-varying exposure. RESULTS: HOPE candidates were more likely male individuals (79% versus 62%), Black (73% versus 35%), and publicly insured (71% versus 52%; P < 0.001). Within 4.5 y, 70% of HOPE candidates received a KT (41% D + , 34% D - , 20% FP, 4% LD) versus 43% of non-HOPE candidates (74% D - , 26% LD). Conversely, 22% of HOPE candidates versus 39% of non-HOPE candidates died or were removed from the waitlist. Median KT wait time was 10.3 mo for HOPE versus 60.8 mo for non-HOPE candidates ( P < 0.001). After adjustment, HOPE candidates had a 3.30-fold higher KT rate (adjusted hazard ratio = 3.30, 95% confidence interval, 2.14-5.10; P < 0.001). CONCLUSIONS: Listing for D + kidneys within HOPE trials was associated with a higher KT rate and shorter wait time, supporting the expansion of this practice for candidates with HIV.

A Multi-Modal Approach to Islet and Pancreas Transplantation With Calcineurin-Sparing Immunosuppression Maintains Long-Term Insulin Independence in Patients With Type I Diabetes.

Long-term success in beta-cell replacement remains limited by the toxic effects of calcineurin inhibitors (CNI) on beta-cells and renal function. We report a multi-modal approach including islet and pancreas-after-islet (PAI) transplant utilizing calcineurin-sparing immunosuppression. Ten consecutive non-uremic patients with Type 1 diabetes underwent islet transplant with immunosuppression based on belatacept (BELA; n = 5) or efalizumab (EFA; n = 5). Following islet failure, patients were considered for repeat islet infusion and/or PAI transplant. 70% of patients (four EFA, three BELA) maintained insulin independence at 10 years post-islet transplant, including four patients receiving a single islet infusion and three patients undergoing PAI transplant. 60% remain insulin independent at mean follow-up of 13.3 ± 1.1 years, including one patient 9 years after discontinuing all immunosuppression for adverse events, suggesting operational tolerance. All patients who underwent repeat islet transplant experienced graft failure. Overall, patients demonstrated preserved renal function, with a mild decrease in GFR from 76.5 ± 23.1 mL/min to 50.2 ± 27.1 mL/min (p = 0.192). Patients undergoing PAI showed the greatest degree of renal impairment following initiation of CNI (56% ± 18.7% decrease in GFR). In our series, repeat islet transplant is ineffective at maintaining long-term insulin independence. PAI results in durable insulin independence but is associated with impaired renal function secondary to CNI dependence.

OPTN/SRTR 2021 Annual Data Report: Pancreas.

The number of pancreas transplants in the United States was largely unchanged in 2021 at 963 transplants compared with 962 in 2020, showing that recovery from the COVID-19 pandemic was not as pronounced in pancreas transplantation as in other organs. The number of simultaneous pancreas-kidney transplants (SPKs) decreased from 827 to 820, whereas the number of pancreas-after-kidney transplants and pancreas transplants alone increased marginally to compensate. The proportion of patients with type 2 diabetes on the waiting list increased to 22.9% in 2021, compared with 20.1% in 2020. Consequently, the proportion of transplants in patients with type 2 diabetes increased from 21.3% in 2020 to 25.9% in 2021. The proportion of transplants in older recipients (aged 55 years or older) also increased to 13.5% in 2021 from 11.7% in 2020. Outcomes after SPK continue to be the best of the three categories of pancreas transplants: 1-year graft failure for kidney at 5.7% and pancreas at 10.5% for transplants performed in 2020. The proportion of pancreas transplants performed by medium-volume centers (11-24 transplants per year) increased sharply to 48.3% in 2021 from 35.1% in 2020, with a corresponding decrease in transplants in large-volume centers (25 or more transplants per year) to 15.9% in 2021 from 25.7% in 2020.

COVID-19 infection and vaccination rarely impact HLA antibody profile in waitlisted renal transplant candidates- a multicenter cohort.

Although rare, infection and vaccination can result in antibodies to human leukocyte antigens (HLA). We analyzed the effect of SARS-CoV-2 infection or vaccination on HLA antibodies in waitlisted renal transplant candidates. Specificities were collected and adjudicated if the calculated panel reactive antibodies (cPRA) changed after exposure. Of 409 patients, 285 (69.7 %) had an initial cPRA of 0 %, and 56 (13.7 %) had an initial cPRA > 80 %. The cPRA changed in 26 patients (6.4 %), 16 (3.9 %) increased, and 10 (2.4 %) decreased. Based on cPRA adjudication, cPRA differences generally resulted from a small number of specificities with subtle fluctuations around the borderline of the participating centers' cutoff for unacceptable antigen listing. All five COVID recovered patients with an increased cPRA were female (p = 0.02). In summary, exposure to this virus or vaccine does not increase HLA antibody specificities and their MFI in approximately 99 % of cases and 97 % of sensitized patients. These results have implications for virtual crossmatching at the time of organ offer after SARS-CoV-2 infection or vaccination, and these events of unclear clinical significance should not influence vaccination programs.

The John S. Najarian symposium: The past, present, and future of surgery and transplantation, May 20, 2022, Minneapolis, MN.

Dr John S Najarian (1927-2020), chairman of the Department of Surgery at the University of Minnesota from 1967 to 1993, was a pioneer in surgery, clinical immunology and transplantation. A Covid-delayed Festschrift was held in his honor on May 20, 2022. The speakers reflected on his myriad contributions to surgery, transplantation, and resident/fellow training, as well as current areas of ongoing research to improve clinical outcomes. Of note, Dr Najarian was a founder of the journal Clinical Transplantation.

Impact of Donor Liver Macrovesicular Steatosis on Deceased Donor Yield and Posttransplant Outcome.

BACKGROUND: The Scientific Registry of Transplant Recipients (SRTR) had not traditionally considered biopsy results in risk-adjustment models, yet biopsy results may influence outcomes and thus decisions regarding organ acceptance. METHODS: Using SRTR data, which includes data on all donors, waitlisted candidates, and transplant recipients in the United States, we assessed (1) the impact of macrovesicular steatosis on deceased donor yield (defined as number of livers transplanted per donor) and 1-y posttransplant graft failure and (2) the effect of incorporating this variable into existing SRTR risk-adjustment models. RESULTS: There were 21 559 donors with any recovered organ and 17 801 liver transplant recipients included for analysis. Increasing levels of macrovesicular steatosis on donor liver biopsy predicted lower organ yield: ≥31% macrovesicular steatosis on liver biopsy was associated with 87% to 95% lower odds of utilization, with 55% of these livers being discarded. The hazard ratio for graft failure with these livers was 1.53, compared with those with no pretransplant liver biopsy and 0% to 10% steatosis. There was minimal change on organ procurement organization-specific deceased donor yield or program-specific posttransplant outcome assessments when macrovesicular steatosis was added to the risk-adjustment models. CONCLUSIONS: Donor livers with macrovesicular steatosis are disproportionately not transplanted relative to their risk for graft failure. To avoid undue risk aversion, SRTR now accounts for macrovesicular steatosis in the SRTR risk-adjustment models to help facilitate use of these higher-risk organs. Increased recognition of this variable may also encourage further efforts to standardize the reporting of liver biopsy results.

The effect of induction immunosuppression for kidney transplant on the latent HIV reservoir.

The HIV latent viral reservoir (LVR) remains a major challenge in the effort to find a cure for HIV. There is interest in lymphocyte-depleting agents, used in solid organ and bone marrow transplantation to reduce the LVR. This study evaluated the LVR and T cell receptor repertoire in HIV-infected kidney transplant recipients using intact proviral DNA assay and T cell receptor sequencing in patients receiving lymphocyte-depleting or lymphocyte-nondepleting immunosuppression induction therapy. CD4+ T cells and intact and defective provirus frequencies decreased following lymphocyte-depleting induction therapy but rebounded to near baseline levels within 1 year after induction. In contrast, these biomarkers were relatively stable over time in the lymphocyte-nondepleting group. The lymphocyte-depleting group had early TCRß repertoire turnover and newly detected and expanded clones compared with the lymphocyte-nondepleting group. No differences were observed in TCRß clonality and repertoire richness between groups. These findings suggest that, even with significant decreases in the overall size of the circulating LVR, the reservoir can be reconstituted in a relatively short period of time. These results, while from a relatively unique population, suggest that curative strategies aimed at depleting the HIV LVR will need to achieve specific and durable levels of HIV-infected T cell depletion.

A Worldwide Survey of Activities and Practices in Clinical Islet of Langerhans Transplantation.

A global online survey was administered to 69 islet transplantation programs, covering 84 centers and 5 networks. The survey addressed questions on program organization and activity in the 2000-2020 period, including impact on activity of national health care coverage policies. We obtained full data from 55 institutions or networks worldwide and basic activity data from 6 centers. Additional data were obtained from alternative sources. A total of 94 institutions and 5 networks was identified as having performed islet allotransplantation. 4,365 islet allotransplants (2,608 in Europe, 1,475 in North America, 135 in Asia, 119 in Oceania, 28 in South America) were reported in 2,170 patients in the survey period. From 15 centers active at the start of the study period, the number of simultaneously active islet centers peaked at 54, to progressively decrease to 26 having performed islet allotransplants in 2020. Notably, only 16 centers/networks have done >100 islet allotransplants in the survey period. Types of transplants performed differed notably between North America and the rest of the world, in particular with respect to the near-absence of simultaneous islet-kidney transplantation. Absence of heath care coverage has significantly hampered transplant activity in the past years and the COVID-19 pandemic in 2020.

Pancreas Transplantation for Type 2 Diabetes: A Systematic Review, Critical Gaps in the Literature, and a Path Forward.

Pancreas transplantation in patients with type 2 diabetes (T2D) remains relatively uncommon compared with pancreas transplantation in patients with type 1 diabetes (T1D); however, several studies have suggested similar outcomes between T2D and T1D, and the practice has become increasingly common. Despite this growing interest in pancreas transplantation in T2D, no study has systematically summarized the data to date. We systematically reviewed the literature on pancreas transplantation in T2D patients including patient and graft survival, glycemic control outcomes, and comparisons with outcomes in T2D kidney transplant alone and T1D pancreas transplant recipients. We searched biomedical databases from January 1, 2000, to January 14, 2021, and screened 3314 records, of which 22 full texts and 17 published abstracts met inclusion criteria. Full-text studies were predominantly single center (73%), whereas the remaining most often studied the Organ Procurement and Transplantation Network database. Methodological quality was mixed with frequent concern for selection bias and concern for inconsistent definitions of both T2D and pancreas graft survival across studies. Overall, studies generally reported favorable patient survival, graft survival, and glycemic control outcomes for pancreas transplantation in T2D and expressed a need to better characterize the T2D patients who would benefit most from pancreas transplantation. We suggest guidance for future studies, with the aim of supporting the safe and evidence-based treatment of end-stage T2D and judicious use of scarce resources.

Effects of Multi-stage Procurement on the Viability and Function of Human Donor Parathyroid Glands.

INTRODUCTION: Parathyroid allotransplantation is an emerging treatment for severe hypoparathyroidism. Ensuring the viability and functional integrity of donor parathyroid glands following procurement is essential for optimal transplantation outcomes. METHODS: Cellular viability, calcium-responsive hormone secretion, and gland xenograft survival were assessed in a series of deceased donor parathyroid glands following a two-stage procurement procedure recently developed by our group (en bloc cadaveric dissection with subsequent gland isolation after transport to the laboratory). RESULTS: Parathyroid glands resected in this manner and stored up to 48 h in 4°C University of Wisconsin (UW) media retained in vitro viability with no induction of hypoxic stress (HIF-1α) or apoptotic (caspase-3) markers. Ex vivo storage did not significantly affect parathyroid gland calcium sensing capacity, with comparable calcium EC50 values and suppression of parathyroid hormone secretion at high ambient calcium concentrations. The isolated glands engrafted readily, vascularizing rapidly in vivo following transplantation into mice. CONCLUSIONS: Parathyroid tissue retains viability, calcium-sensing capacity, and in vivo engraftment capability after en bloc cadaveric resection, ex vivo dissection, and extended cold storage.

HBV-positive and HIV-positive organs in transplantation: A clinical guide for the hepatologist.

Organ transplantation is a life-saving treatment for patients with end-stage organ disease, a severe condition associated with a high risk of waitlist mortality. It is primarily limited by a shortage of available organs. Maximising available donors can increase access to transplantation. Transplantation from donors positive for HBV and HIV has increased in many countries. However, antiviral therapies need to be readily available for recipients after transplantation to prevent possible reactivation of the virus following the administration of immunosuppressive therapies. Furthermore, the intentional transmission of a virus has practical, ethical, and clinical implications. In this review, we summarise the current research, focusing on grafts from donors positive for the HBV surface antigen, antibodies against the HBV core antigen, and HIV, to help hepatologists and physicians interested in transplantation to select the best antiviral and/or prophylactic regimens for after transplantation.

Procurement of Deceased Donor Parathyroid Glands With the Aid of Near-infrared Autofluorescence Imaging.

Parathyroid allotransplantation is a burgeoning treatment for severe hypoparathyroidism. Deceased donor parathyroid gland (PTG) procurement can be technically challenging due to lack of normal intraoperative landmarks and exposure constraints in the neck of organ donors. In this study, we assessed standard 4-gland exposure in situ and en bloc surgical techniques for PTG procurement and ex vivo near-infrared autofluorescence (NIRAF) imaging for identification of PTGs during organ recovery. Methods: Research tissue consent was obtained from organ donors or donor families for PTG procurement. All donors were normocalcemic, brain-dead, solid organ donors between 18 and 65 y of age. PTGs were procured initially using a standard 4-gland exposure technique in situ and subsequently using a novel en bloc resection technique after systemic organ preservation flushing. Parathyroid tissue was stored at 4 °C in the University of Wisconsin solution up to 48 h post-procurement. Fluoptics Fluobeam NIRAF camera and Image J software were utilized for quantification of NIRAF signal. Results: Thirty-one brain-dead deceased donor PTG procurements were performed by abdominal transplant surgeons. In the initial 8 deceased donors, a mean of 1.75 glands (±1.48 glands SD) per donor were recovered using the 4-gland in situ technique. Implementation of combined en bloc resection with ex vivo NIRAF imaging in 23 consecutive donors yielded a mean of 3.60 glands (±0.4 SD) recovered per donor (P < 0.0001). Quantification of NIRAF integrated density signal demonstrated >1-fold log difference in PTG (2.13 × 105 pixels) versus surrounding anterior neck structures (1.9 × 104 pixels; P < 0.0001). PTGs maintain distinct NIRAF signal from the time of recovery (1.88 × 105 pixels) up to 48 h post-procurement (1.55 × 105 pixels) in organ preservation cold storage (P = 0.34). Conclusions: The use of an en bloc surgical technique with ex vivo NIRAF imaging significantly enhances the identification and recovery of PTG from deceased donors.