Addressing sex-based disparities in solid organ transplantation in the United States - a conference report.

Solid organ transplantation provides the best treatment for end-stage organ failure, but significant sex-based disparities in transplant access exist. On June 25, 2021, a virtual multidisciplinary conference was convened to address sex-based disparities in transplantation. Common themes contributing to sex-based disparities were noted across kidney, liver, heart, and lung transplantation, specifically the existence of barriers to referral and wait listing for women, the pitfalls of using serum creatinine, the issue of donor/recipient size mismatch, approaches to frailty and a higher prevalence of allosensitization among women. In addition, actionable solutions to improve access to transplantation were identified, including alterations to the current allocation system, surgical interventions on donor organs, and the incorporation of objective frailty metrics into the evaluation process. Key knowledge gaps and high-priority areas for future investigation were also discussed.

Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes.

Allogeneic islet transplant offers a minimally invasive option for ß cell replacement in the treatment of type 1 diabetes (T1D). The CIT consortium trial of purified human pancreatic islets (PHPI) in patients with T1D after kidney transplant (CIT06), a National Institutes of Health-sponsored phase 3, prospective, open-label, single-arm pivotal trial of PHPI, was conducted in 24 patients with impaired awareness of hypoglycemia while receiving intensive insulin therapy. PHPI were manufactured using standardized processes. PHPI transplantation was effective with 62.5% of patients achieving the primary endpoint of freedom from severe hypoglycemic events and HbA1c  ≤ 6.5% or reduced by ≥ 1 percentage point at 1 year posttransplant. Median HbA1c declined from 8.1% before to 6.0% at 1 year and 6.3% at 2 and 3 years following transplant (P < .001 for all vs baseline), with related improvements in hypoglycemia awareness and glucose variability. The improved metabolic control was associated with better health-related and diabetes-related quality of life. The procedure was safe and kidney allograft function remained stable after 3 years. These results add to evidence establishing allogeneic islet transplant as a safe and effective treatment for patients with T1D and unstable glucose control despite intensive insulin treatment, supporting the indication for PHPI in the post-renal transplant setting.

Transplant Radical Nephrectomy and Transplant Radical Nephroureterectomy for Renal Cancer: Postoperative and Survival Outcomes.

BACKGROUND The treatment of complex tumors in non-functioning renal transplants requiring surgical extirpation is challenging. Here, we report the largest series of patients who underwent transplant radical nephrectomy for renal cell carcinoma (RCC) and transplant radical nephroureterectomy for urothelial cell carcinoma (UCC) in their transplanted kidneys. MATERIAL AND METHODS From 2004 to 2018, 10 patients underwent transplant radical nephrectomy (7 patients) and nephroureterectomy (3 patients). Retrospective analyses, in terms of complications, oncological recurrence, and survival, of peri-operative and long-term outcomes, were performed. RESULTS Out of the 10 patients, 7 had RCC and 3 had UCC. No intraoperative mortality occurred. Three patients presented with Clavien-Dindo grade IIIa or greater within 30 days of surgery. Two patients died within 60 days of surgery, both due to vascular events: one due to myocardial infarction and one due to stroke. Two other patients died: one after 2.9 years, due to myocardial infarction, and the other after 6 years, due to unknown reasons. At the 7-year follow-up, there was a 60% overall survival rate. For all patients, average survival post-nephrectomy was approximately 4.5 years, including the 6 living patients and 4 deceased patients. Importantly, there was no observed cancer recurrence. CONCLUSIONS This study reports outcomes of the largest series of transplant radical nephrectomy and nephroureterectomy for malignancies of renal allografts. In the optimized setting, extirpative surgeries appear safe, with favorable long-term oncological and survival outcomes.

Outcomes of donor-derived superinfection screening in HIV-positive to HIV-positive kidney and liver transplantation: a multicentre, prospective, observational study.

BACKGROUND: One of the primary risks of HIV-positive to HIV-positive organ transplantation is loss of virological control because of donor-derived HIV superinfection, which occurs when an HIV-positive individual becomes infected with a new distinct HIV strain. In this study, as part of the larger HIV Organ Policy Equity pilot study, HIV-positive to HIV-positive kidney and liver transplant recipients in the USA were examined for evidence of sustained donor-derived HIV superinfection. METHODS: In this multicentre, prospective, observational study, HIV-positive to HIV-positive kidney and liver transplant recipients were followed in three hospitals in the USA. Candidates with well controlled HIV infection on ART, no active opportunistic infections, and minimum CD4 T-cell counts (>100 cells per µL for liver and >200 cells per µL for kidney per federal guidelines) were eligible to receive a kidney or liver from deceased HIV-positive donors without active infections or neoplasm. Peripheral blood mononuclear cells were collected from donor-recipient pairs at the time of transplantation, and from recipients at several timepoints up to 3 years after transplantation. Donor samples were assessed for HIV RNA viral load, CD4 cell count, and antiretroviral drug-resistant mutations. Donor and recipient HIV proviral DNA, and viral RNA from the viraemic timepoint were sequenced using a site-directed next-generation sequencing assay for the reverse transcriptase and gp41 genes. Neighbour-joining phylogenetic trees and direct sequence comparison were used to detect the presence of HIV superinfection. This study is registered with ClinicalTrials.gov, NCT02602262. FINDINGS: 14 HIV-positive to HIV-positive kidney and eight liver transplant recipients were followed from March, 2016, to July, 2019. 17 recipients had adequate viral sequences allowing for HIV superinfection assessment. Eight donors were suppressed (viral load <400 copies per mL), and none had multiclass drug-resistant mutations detected. None of the recipients examined had evidence of HIV superinfection. One recipient had a viraemic episode (viral load of 2 080 000 copies per mL) 3 years after transplantation as a result of non-adherence to ART. Only recipient viral sequences were detected during the viraemic episode, suggesting that the donor virus, if present, was not reactivated despite temporary withdrawal of ART. INTERPRETATION: These findings suggest that loss of HIV suppression due to donor-derived HIV superinfection might not be a significant clinical concern in carefully monitored ART suppressed HIV-positive organ recipients. FUNDING: US National Institute of Allergy and Infectious Diseases and National Cancer Institute.

Organs from deceased donors with false-positive HIV screening tests: An unexpected benefit of the HOPE act.

Organs from deceased donors with suspected false-positive HIV screening tests were generally discarded due to the chance that the test was truly positive. However, the HIV Organ Policy Equity (HOPE) Act now facilitates use of such organs for transplantation to HIV-infected (HIV+) individuals. In the HOPE in Action trial, donors without a known HIV infection who unexpectedly tested positive for anti-HIV antibody (Ab) or HIV nucleic acid test (NAT) were classified as suspected false-positive donors. Between March 2016 and March 2018, 10 suspected false-positive donors had organs recovered for transplant for 21 HIV + recipients (14 single-kidney, 1 double-kidney, 5 liver, 1 simultaneous liver-kidney). Median donor age was 24 years; cause of death was trauma (n = 5), stroke (n = 4), and anoxia (n = 1); three donors were labeled Public Health Service increased infectious risk. Median kidney donor profile index was 30.5 (IQR 22-58). Eight donors were HIV Ab+/NAT-; two were HIV Ab-/NAT+. All 10 suspected false-positive donors were confirmed to be HIV-noninfected. Given the false-positive rates of approved assays used to screen > 20 000 deceased donors annually, we estimate 50-100 HIV false-positive donors per year. Organ transplantation from suspected HIV false-positive donors is an unexpected benefit of the HOPE Act that provides another novel organ source.

National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities.

Eight manufacturing facilities participating in the National Institutes of Health-sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed.

Pancreas transplantation in unconventional recipients.

PURPOSE OF REVIEW: Advances in surgical technique and immunosuppression have significantly improved outcomes after pancreas transplantation, and as a result pancreas transplants increasingly are being performed for indications other than type 1 diabetes mellitus. This review summarizes the current literature on pancreas transplantation in unconventional recipient populations. RECENT FINDINGS: An increasing body of work suggests that pancreas transplantation can be performed with good outcomes in patients with type 2 diabetes mellitus and those 50 years of age and older. Obesity appears detrimental to patient and pancreas graft survival, and bariatric surgery prior to transplantation may be of increasing interest and relevance. There are limited data yielding mixed outcomes on pancreas transplantation in patients with HIV or hepatitis C virus. However, rapidly improving antiviral therapies are prolonging survival in patients with HIV and chronic hepatitis C virus infections and may increase the number of candidates available for pancreas transplantation in these populations in the future. SUMMARY: Despite limited literature in these patient populations, pancreas transplantation may be a viable treatment option for endocrine pancreas failure in appropriately selected patients regardless of disease cause or age.

Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia.

OBJECTIVE: Impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50-80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment. RESEARCH DESIGN AND METHODS: This multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA1c <7.0% (53 mmol/mol) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant. RESULTS: The primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA1c level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients. CONCLUSIONS: Transplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.

Islet cell xenotransplantation: a serious look toward the clinic.

Type I diabetes remains a significant clinical problem in need of a reliable, generally applicable solution. Both whole organ pancreas and islet allotransplantation have been shown to grant patients insulin independence, but organ availability has restricted these procedures to an exceptionally small subset of the diabetic population. Porcine islet xenotransplantation has been pursued as a potential means of overcoming the limits of allotransplantation, and several preclinical studies have achieved near-physiologic function and year-long survival in clinically relevant pig-to-primate model systems. These proof-of-concept studies have suggested that xenogeneic islets may be poised for use in clinical trials. In this review, we examine recent progress in islet xenotransplantation, with a critical eye toward the gaps between the current state of the art and the state required for appropriate clinical investigation.

Improvement in outcomes of clinical islet transplantation: 1999-2010.

OBJECTIVE: To describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010. RESEARCH DESIGN AND METHODS: A total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999-2002), mid (2003-2006), or recent (2007-2010) transplant era based on annual follow-up to 5 years. RESULTS: Insulin independence at 3 years after transplant improved from 27% in the early era (1999-2002, n = 214) to 37% in the mid (2003-2006, n = 255) and to 44% in the most recent era (2007-2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA(1c) and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007-2010 vs. 60-65% in 1999-2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001). CONCLUSIONS: The CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007-2010 compared with those in 1999-2006, with fewer islet infusions and adverse events per recipient.

The impact of renal function on outcomes of bariatric surgery.

The effect of CKD on the risks of bariatric surgery is not well understood. Using the American College of Surgeons National Surgical Quality Improvement Program Participant Use File, we analyzed 27,736 patients who underwent bariatric surgery from 2006 through 2008. Before surgery, 34 (0.12%) patients were undergoing long-term dialysis. Among those not undergoing dialysis, 20,806 patients (75.0%) had a normal estimated GFR or stage 1 CKD, 5011 (18.07%) had stage 2 CKD, 1734 (6.25%) had stage 3 CKD, 94 (0.34%) had stage 4 CKD, and 91 (0.33%) had stage 5 CKD. In an unadjusted analysis, CKD stage was directly associated with complication rate, ranging from 4.6% for those with stage 1 CKD or normal estimated GFR to 9.9% for those with stage 5 CKD (test for trend, P<0.001). Multivariable logistic regression demonstrated that CKD stage predicts higher complication rates (odds ratio for each higher CKD stage, 1.30) after adjustment for diabetes and hypertension. Although patients with higher CKD stage had higher complication rates, the absolute incidence of complications remained <10%. In conclusion, these data demonstrate higher risks of bariatric surgery among patients with worse renal function, but whether the potential benefits outweigh the risks in this population requires further study.

B cells and transplantation tolerance.

Transplantation tolerance is a state of immune unresponsiveness (or benign responsiveness) to the presence of specific, nonself antigens in the absence of chronic immunosuppressive therapy. Renal transplant tolerance remains a desired yet generally unattained goal that would enable transplantation to be performed without the risk of graft rejection or the need for broadly immunosuppressive drugs, which can have toxic effects. Studies published in the past few years have provided evidence that B cells have an important role in both graft rejection and transplantation tolerance. Indeed, antibody-dependent and antibody-independent functions of B cells account for both tolerogenic and rejection-promoting immune responses in transplant recipients. This Review comprises a discussion of the mechanisms involved in the induction of B-cell tolerance and a survey of current and emerging therapies that target the effects of B cells in transplant recipients.

Differential effects of donor-specific alloantibody.

Alloantigen exposure typically provokes an adaptive immune response that can foster rejection of transplanted organs, and these responses present the most formidable biological barrier to kidney transplantation. Although most cellular alloimmune responses can be therapeutically controlled with T-cell-specific immunosuppressants, humoral alloimmune responses remain relatively untamed. Importantly, humoral immunity, typically manifesting as allospecific antibody production, is increasingly recognized for its variable appearance after kidney transplantation. Indeed, the appearance of alloantibody can herald the onset of rapid and destructive antibody-mediated rejection or have no demonstrable acute effects. The factors determining the end result of alloantibody formation remain poorly understood. This review will discuss the breadth of alloantibody responses seen in clinical kidney transplantation and provide an overview of potential factors explaining the phenotypic variability associated with humoral alloimmunity. We propose several avenues ripe for future investigation including the influence of innate immune components and the potential influence of heterologous immune responses in determining the ultimate clinical import of an alloantibody response.