Identification of novel HLA alleles discovered in 2022-2023.

In this paper, we describe 10 novel HLA alleles discovered, submitted and officially named in the calendar years 2022 through the end of 2023.

Transplanting FVIII/ET3-secreting cells in fetal sheep increases FVIII levels long-term without inducing immunity or toxicity.

Hemophilia A is the most common X-linked bleeding disorder affecting more than half-a-million individuals worldwide. Persons with severe hemophilia A have coagulation FVIII levels <1% and experience spontaneous debilitating and life-threatening bleeds. Advances in hemophilia A therapeutics have significantly improved health outcomes, but development of FVIII inhibitory antibodies and breakthrough bleeds during therapy significantly increase patient morbidity and mortality. Here we use sheep fetuses at the human equivalent of 16-18 gestational weeks, and we show that prenatal transplantation of human placental cells (107-108/kg) bioengineered to produce an optimized FVIII protein, results in considerable elevation in plasma FVIII levels that persists for >3 years post-treatment. Cells engraft in major organs, and none of the recipients mount immune responses to either the cells or the FVIII they produce. Thus, these studies attest to the feasibility, immunologic advantage, and safety of treating hemophilia A prior to birth.

Simultaneous pancreas-kidney transplantation in Caucasian versus African American patients: Does recipient race influence outcomes?

The influence of African American (AA) recipient race on outcomes following simultaneous pancreas-kidney transplantation (SPKT) is uncertain. METHODS: From 11/01 to 2/19, we retrospectively studied 158 Caucasian (C) and 57 AA patients (pts) undergoing SPKT. RESULTS: The AA group had fewer patients on peritoneal dialysis (30% C vs. 14% AA), more patients with longer dialysis duration (28% C vs. 51% AA), more sensitized (PRA ≥20%) patients (6% C vs. 21% AA), and more patients with pretransplant C-peptide levels ≥2.0 ng/ml (11% C vs. 35% AA, all P < .05). With a mean 9.2 year follow-up, patient survival (65% C vs. 77% AA, P = .098) slightly favored the AA group, whereas kidney (55% C vs. 60% AA) and pancreas (48% C vs. 54% AA) graft survival rates (GSRs) were comparable. Death-censored kidney (71% C vs. 68% AA) and pancreas (both 62%) GSRs demonstrated that death with a functioning graft (DWFG) was more common in C vs. AA patients (23% C vs. 12% AA, P = .10). The incidence of death-censored dual graft loss (usually rejection) was 7% C versus 21% AA (P = .005). CONCLUSIONS: Following SPKT, AA patients are at a greater risk for dual immunological graft loss whereas C patients are at greater risk for DWFG.

Do pretransplant C-peptide levels predict outcomes following simultaneous pancreas-kidney transplantation? A matched case-control study.

Following simultaneous pancreas-kidney transplantation (SPKT), survival outcomes are reported as equivalent in patients with detectable pretransplant C-peptide levels (Cp+) and a "type 2″ diabetes mellitus (DM) phenotype compared to type 1 (Cp negative [Cp-]) DM. We retrospectively compared 46 Cp+ patients pretransplant (≥2.0 ng/mL, mean 5.4 ng/mL) to 46 Cp- (level < 0.5 ng/mL) case controls matched for recipient age, gender, race, and transplant date. Early outcomes were comparable. Actual 5-year patient survival (91% versus 94%), kidney graft survival (69% versus 86%, p = .15), and pancreas graft survival (60% versus 86%, p = .03) rates were lower in Cp+ versus Cp- patients, respectively. The Cp+ group had more pancreas graft failures due to insulin resistance (13% Cp+ versus 0% Cp-, p = .026) or rejection (17% Cp+ versus 6.5% Cp-, p = .2). Post-transplant weight gain > 5 kg occurred in 72% of Cp+ versus 26% of Cp- patients (p = .0001). In patients with functioning grafts, mean one-year post-transplant HbA1c levels (5.0 Cp+ versus 5.2% Cp-) were comparable, whereas Cp levels were higher in Cp+ patients (5.0 Cp+ versus 2.6 ng/mL Cp-). In this matched case-control study, outcomes were inferior in Cp+ compared to Cp- patients following SPKT, with post-transplant weight gain, insulin resistance, and rejection as potential mitigating factors.

Identification of novel HLA alleles discovered in 2019-2021.

In this paper, we describe 15 novel HLA alleles discovered and officially named in the calendar years 2019 through the first half of 2021.

Recipient age and outcomes following simultaneous pancreas-kidney transplantation in the new millennium: Single-center experience and review of the literature.

The influence of recipient age on outcomes following simultaneous pancreas-kidney transplantation (SPKT) in the modern era is uncertain. METHODS: We retrospectively studied 255 patients undergoing SPKT from 11/01 to 8/20. Recipients were stratified according to age group: age <30 years (n = 16); age 30-39 years (n = 91); age 40-49 years (n = 86) and age ≥50 years (n = 62 [24.3%], including 9 patients ≥60 years of age). RESULTS: Three-month and one-year outcomes were comparable. The eight-year patient survival rate was lowest in the oldest age group (47.6% vs 78% in the 3 younger groups combined, p < .001). However, eight-year kidney and pancreas graft survival rates were comparable in the youngest and oldest age groups combined (36.5% and 32.7%, respectively), but inferior to those in the middle 2 groups combined (62% and 50%, respectively, both p < .05). Death-censored kidney and pancreas graft survival rates increased from youngest to oldest recipient age category because of a higher incidence of death with functioning grafts (22.6% in oldest group compared to 8.3% in the 3 younger groups combined, p = .005). CONCLUSIONS: Recipient age did not appear to significantly influence early outcomes following SPKT. Late outcomes are similar in younger and older recipients, but inferior to the middle 2 age groups.

Early Graft Loss after Deceased-Donor Kidney Transplantation: What Are the Consequences?

BACKGROUND: Decreasing kidney discards continues to be of paramount importance for improving organ transplant access, but transplantation of nonideal deceased donor kidneys may have higher inherent risks of early graft loss (EGL). Patients with EGL (defined as graft failure within 90 days after transplant) are allowed reinstatement of waiting time according to United Network for Organ Sharing (UNOS) policy. The purpose of this study was to examine outcomes for patients experiencing EGL. STUDY DESIGN: We performed a single center retrospective review of adult deceased donor kidney transplant (DDKT)-alone recipients from 2001 to 2018, comparing those with EGL (including primary nonfunction [PNF]) to those without. RESULTS: EGL occurred in 103 (5.5%) of 1,868 patients, including 57 (55%) PNF, 25 (24%) deaths, 16 (16%) thrombosis, 3 (3%) rejection, and 2 (2%) disease recurrence. Kidney Donor Profile Index (KDPI) > 85% and donation after circulatory death (DCD) DDKTs did not increase risk of either EGL or PNF unless combined with prolonged cold ischemic time (CIT). For KDPI >85% with CIT >24 hours, the risk of EGL or PNF was tripled (EGL odds ratio [OR] 2.9, 95% CI 1.6-5.2; PNF OR3.6, 95% CI1.7-7.7). For DCD with CIT > 24 hours, increased risks were likewise seen for EGL (OR 2.4, 95% CI 1.3-4.3), and PNF (OR 3.2, 95% CI 1.5-7). One-year and 5-year patient survival rates were 60% and 50% after EGL, 80% and 73% after PNF, and 99% and 87% for controls, respectively. Only 24% of either EGL or PNF patients underwent retransplantation. CONCLUSIONS: EGL and PNF were associated with low retransplantation rates and inferior patient survival. Prolonged CIT compounds risks associated with KDPI > 85% and DCD donor kidneys. Therefore, policies promoting rapid allocation and increased local use of these kidneys should be considered.

NGS and HLA: The long road ahead.

This manuscript is a continuation of this laboratory's journey to identifying novel HLA alleles while performing routine clinical HLA laboratory testing. Since our last paper, we have identified an additional 28 novel HLA alleles that are identified and described herein. One novel allele was found in two unrelated patients that were HLA typed for different reasons at two different times, suggesting that novel alleles may be much more frequent than previously expected. If the rate of identification is hindered by bioinformatics challenges, there is a great potential for our patients to suffer needlessly from incomplete information in either diagnostics or unrecognized incompatibilities with potential donors.

APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO): Design and Rationale.

INTRODUCTION: Much of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (APOL1). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)-sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes. METHODS: APOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys. RESULTS: The United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses. CONCLUSION: This article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of APOL1 genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation.

New HLA alleles discovered by next generation sequencing in routine histocompatibility lab work in a medium-volume laboratory.

The immunogenetics research and clinical communities are undergoing a revolution in the way that Human Leukocyte Antigens (HLA) alleles are typed, thanks to the introduction and increasing acceptance of next-generation sequencing into laboratory practice. With the ability to sequence all exons of each allele, instead of the previously routine typing of exons 2 and 3 of class I and exon 2 of class II, the sequencing of previously unsequenced areas of HLA alleles is causing a host of new alleles to be discovered through the course of routine laboratory testing. In the first 4 months of routine next generation sequencing, we have identified 10 novel alleles that have been discovered through laboratory testing for all facets of HLA typing, i.e. solid organ transplantation, hematopoietic stem cell transplantation, disease association typing and pharmacogenomics testing. The advent of NGS HLA typing in routine clinical practice, and the concomitant routine typing of exons outside the norm, opens the window for rapid discovery of new HLA alleles and a potential for overwhelming the current HLA nomenclature naming conventions.

Dual Kidney Transplantation from Donors at the Extremes of Age.

BACKGROUND: The study purpose was to analyze outcomes in recipients of pediatric dual en bloc (PEB) kidneys from small pediatric donors (SPDs, age ≤ 3 years) and dual kidney transplants (KTs) from adult marginal deceased donors (DDs) in the context of the Kidney Donor Profile Index (KDPI). STUDY DESIGN: This was a single center retrospective review. Recipient selection included primary transplant, low BMI, low immunologic risk, and informed consent. All patients received antibody induction with FK/MPA/± prednisone. RESULTS: From 2002 to 2015, we performed 34 PEB and 73 adult dual KTs. Mean donor ages were 17 months for the PEB and 59 years for the dual KTs; mean KDPIs were 73% for PEB and 83% for dual KT, and mean cold ischemia times were 21.0 hours for PEB and 26.5 hours for dual KT. Adult dual KT recipients were older (mean age 38 years for PEB and 60 years for dual KT) and had shorter waiting times (mean 25 months for PEB and 12 months for dual KT). With a mean follow-up of 7.6 years, actual patient survival (88% for PEB and 62% for dual KT) and graft survival (71% for PEB and 44% for dual KT) rates were higher in PEB compared with dual KT. Death-censored kidney graft survival rates were 77% for PEB and 58% for dual KT. Delayed graft function (DGF) rates were 15% for PEB and 23% for dual KT; incidences of DGF in single kidney transplantations from SPDs and adult nonmarginal DDs were 20% and 32%, respectively. Based on actual 5-year graft survival rates, the adjusted KDPIs for dual PEB and dual KTs were 3% and 60%, respectively. CONCLUSIONS: Acceptable mid-term outcomes are associated with PEB and adult dual KTs, which may expand the donor pool and prevent kidney discard. The KDPI is inaccurate for predicting outcomes from either PEB from SPDs or dual KT from adult marginal DDs, which may prevent acceptance of these organs.

The Pathology Workforce and Clinical Licensure: The Role of the PhD Clinical Laboratorian in the United States.

There has been a recent recognition of the need to prepare PhD-trained scientists for increasingly diverse careers in academia, industry, and health care. The PhD Data Task Force was formed to better understand the current state of PhD scientists in the clinical laboratory workforce and collect up-to-date information on the training and certification of these laboratorians. In this report, we summarize the findings of the PhD Data Task Force and discuss the relevance of the data collected to the future supply of and demand for PhD clinical laboratory scientists. It is clear that there are multiple career opportunities for PhD scientists in academic medical centers, commercial clinical laboratories, biotechnology and pharmaceutical companies, and the federal government. Certified PhD scientists have and will continue to form an important resource for our technologically advancing field, bringing training in scientific methods, and technologies needed for modern laboratory medicine. The data gathered by the PhD Data Task Force will be of great interest to current and future PhD candidates and graduate PhD scientists as they make decisions regarding future career directions.

Is prolonged cold ischemia a contraindication to using kidneys from acute kidney injury donors?

To determine the impact of prolonged cold ischemia time (CIT) on the outcome of acute kidney injury (AKI) renal grafts, we therefore performed a single-center retrospective analysis in adult patients receiving kidney transplantation (KT) from AKI donors. Outcomes were stratified according to duration of CIT. A total of 118 patients receiving AKI grafts were enrolled. Based on CIT, patients were stratified as follows: (i) <20 hours, 27 patients; (ii) 20-30 hours, 52 patients; (iii) 30-40 hours, 30 patients; (iv) ≥40 hours, nine patients. The overall incidence of delayed graft function DGF was 41.5%. According to increasing CIT category, DGF rates were 30%, 42%, 40%, and 78%, respectively (P = .03). With a mean follow-up of 48 months, overall patient and graft survival rates were 91% and 81%. Death-censored graft survival (DCGS) rates were 84% and 88% for patients with and without DGF (P = NS). DCGS rates were 92% in patients with CIT <20 hours compared to 85% with CIT >20 hours (P = NS). In the nine patients with CIT >40 hours, the 4-year DCGS rate was 100%. We conclude that prolonged CIT in AKI grafts may not adversely influence outcomes and so discard of AKI kidneys because of projected long CIT is not warranted when donors are wisely triaged.

Analysis of local versus imported expanded criteria donor kidneys: A single-center experience with 497 ECD kidney transplants.

BACKGROUND: The value of importing expanded criteria donor (ECD) kidneys is uncertain. METHODS: We retrospectively reviewed our single-center experience with ECD kidney transplants (KT). RESULTS: Over 12.8 years, we performed 497 ECD KTs including 247 local and 250 imported from other donor service areas. The import ECD group had more donors (16% vs 9%) ≥ age 70, more zero human leukocyte antigen mismatches (14% vs 2%), more KTs with a cold ischemia time >30 hours (46% vs 19%), and fewer kidneys managed with pump preservation (78% vs 92%, all P≤.05) compared to the local ECD group. Mean Kidney Donor Profile Index were 80% import vs 84% local. With a mean follow-up of 55 months, actual patient and graft survival rates were 71% and 58% in import vs 76% and 58% in local ECD KTs, respectively. Death-censored graft survival rates were 70% in import vs 69% in local ECD KTs. Delayed graft function occurred in 28% import vs 23% local ECD KTs (P=NS) whereas the incidence of primary nonfunction was slightly higher with import ECD kidneys (4.8% vs 2.4%, P=.23). CONCLUSIONS: Midterm outcomes are remarkably similar for import vs local ECD KTs, suggesting that broader sharing of ECD kidneys may improve utilization without compromising outcomes.

Deceased-Donor Apolipoprotein L1 Renal-Risk Variants Have Minimal Effects on Liver Transplant Outcomes.

BACKGROUND: Apolipoprotein L1 gene (APOL1) G1 and G2 renal-risk variants, common in populations with recent African ancestry, are strongly associated with non-diabetic nephropathy, end-stage kidney disease, and shorter allograft survival in deceased-donor kidneys (autosomal recessive inheritance). Circulating APOL1 protein is synthesized primarily in the liver and hydrodynamic gene delivery of APOL1 G1 and G2 risk variants has caused hepatic necrosis in a murine model. METHODS: To evaluate the impact of these variants in liver transplantation, this multicenter study investigated the association of APOL1 G1 and G2 alleles in deceased African American liver donors with allograft survival. Transplant recipients were followed for liver allograft survival using data from the Scientific Registry of Transplant Recipients. RESULTS: Of the 639 liver donors evaluated, 247 had no APOL1 risk allele, 300 had 1 risk allele, and 92 had 2 risk alleles. Graft failure assessed at 15 days, 6 months, 1 year and total was not significantly associated with donor APOL1 genotype (p-values = 0.25, 0.19, 0.67 and 0.89, respectively). CONCLUSIONS: In contrast to kidney transplantation, deceased-donor APOL1 G1 and G2 risk variants do not significantly impact outcomes in liver transplantation.

Single vs dual (en bloc) kidney transplants from donors ≤ 5 years of age: A single center experience.

AIM: To compare outcomes between single and dual en bloc (EB) kidney transplants (KT) from small pediatric donors. METHODS: Monocentric nonprospective review of KTs from pediatric donors ≤ 5 years of age. Dual EB KT was defined as keeping both donor kidneys attached to the inferior vena cava and aorta, which were then used as venous and arterial conduits for the subsequent transplant into a single recipient. Donor age was less useful than either donor weight or kidney size in decision-making for kidney utilization as kidneys from donors < 8 kg or kidneys < 6 cm in length were not transplanted. Post-transplant management strategies were standardized in all patients. RESULTS: From 2002-2015, 59 KTs were performed including 34 dual EB and 25 single KTs. Mean age of donors (17 mo vs 38 mo, P < 0.001), mean weight (11.0 kg vs 17.4 kg, P = 0.046) and male donors (50% vs 84%, P = 0.01) were lower in the dual EB compared to the single KT group, respectively. Mean cold ischemia time (21 h), kidney donor profile index (KDPI; 73% vs 62%) and levels of serum creatinine (SCr, 0.37 mg/dL vs 0.49 mg/dL, all P = NS) were comparable in the dual EB and single KT groups, respectively. Actuarial graft and patient survival rates at 5-years follow-up were comparable. There was one case of thrombosis resulting in graft loss in each group. Delayed graft function incidence (12% dual EB vs 20% single KT, P = NS) was slightly lower in dual EB KT recipients. Initial duration of hospital stay (mean 5.4 d vs 5.6 d) and the one-year incidences of acute rejection (6% vs 16%), operative complications (3% vs 4%), and major infection were comparable in the dual EB and single KT groups, respectively (all P = NS). Mean 12 mo SCr and abbreviated MDRD levels were 1.17 mg/dL vs 1.35 mg/dL and 72.5 mL/min per 1.73 m(2) vs 60.5 mL/min per 1.73 m(2) (both P = NS) in the dual EB and single KT groups, respectively. CONCLUSION: By transplanting kidneys from young pediatric donors into adult recipients, one can effectively expand the limited donor pool and achieve excellent medium-term outcomes.

Dual kidney transplants from adult marginal donors successfully expand the limited deceased donor organ pool.

BACKGROUND: The need to expand the organ donor pool remains a formidable challenge in kidney transplantation (KT). The use of expanded criteria donors (ECDs) represents one approach, but kidney discard rates are high because of concerns regarding overall quality. Dual KT (DKT) may reduce organ discard and optimize the use of kidneys from marginal donors. STUDY DESIGN: We conducted a single-center retrospective review of outcomes in adult recipients of DKTs from adult marginal deceased donors (DD) defined by limited renal functional capacity. If the calculated creatinine clearance in an adult DD was <65 mL/min, then the kidneys were transplanted as a DKT. RESULTS: Over 11.5 yr, 72 DKTS were performed including 45 from ECDs, 17 from donation after cardiac death (DCD) donors, and 10 from standard criteria donors (SCD). Mean adult DD and recipient ages were both 60 yr, including 29 DDs and 26 recipients ≥65 yr of age. Mean pre-DKT waiting and dialysis vintage times were 12 months and 25 months, respectively. Actual patient and graft survival rates were 84.7% and 70.8%, respectively, with a mean follow-up of 58 months. One yr and death-censored graft survival rates were 90% and 80%, respectively. Outcomes did not differ by DD category, recipient age, or presence of delayed graft function (DGF). Eleven patients died at a mean of 32 months post-DKT (eight with functioning grafts) and 13 other patients experienced graft losses at a mean of 33 months. The incidence of DGF was 25%; there were two cases (2.8%) of primary non-function. Mean length of initial hospital stay was 7.2 d. Mean serum creatinine and glomerular filtration rate levels at 12 and 24 months were 1.5 and 53 and 1.5 mg/dL and 51 mL/min/1.73 m(2) , respectively. DKT graft survival and function were superior to concurrent single ECD and similar to concurrent SCD KTs. Two patients underwent successful kidney retransplantation, so the dialysis-free rate in surviving patients was 87%. The proportion of total renal function transplanted from adult DD to DKT recipients was 77% compared to 56% for patients receiving single KTs. CONCLUSIONS: Dual kidney transplantation using kidneys from adult marginal DDs that otherwise might be discarded offer a viable option to counteract the growing shortage of acceptable single kidneys. Excellent medium-term outcomes can be achieved and waiting times can be reduced in a predominantly older recipient population.

APOL1 Genotype and Kidney Transplantation Outcomes From Deceased African American Donors.

BACKGROUND: Two apolipoprotein L1 gene (APOL1) renal-risk variants in donors and African American (AA) recipient race are associated with worse allograft survival in deceased-donor kidney transplantation (DDKT) from AA donors. To detect other factors impacting allograft survival from deceased AA kidney donors, APOL1 renal-risk variants were genotyped in additional AA kidney donors. METHODS: The APOL1 genotypes were linked to outcomes in 478 newly analyzed DDKTs in the Scientific Registry of Transplant Recipients. Multivariate analyses accounting for recipient age, sex, race, panel-reactive antibody level, HLA match, cold ischemia time, donor age, and expanded criteria donation were performed. These 478 transplantations and 675 DDKTs from a prior report were jointly analyzed. RESULTS: Fully adjusted analyses limited to the new 478 DDKTs replicated shorter renal allograft survival in recipients of APOL1 2-renal-risk-variant kidneys (hazard ratio [HR], 2.00; P = 0.03). Combined analysis of 1153 DDKTs from AA donors revealed donor APOL1 high-risk genotype (HR, 2.05; P = 3 × 10), older donor age (HR, 1.18; P = 0.05), and younger recipient age (HR, 0.70; P = 0.001) adversely impacted allograft survival. Although prolonged allograft survival was seen in many recipients of APOL1 2-renal-risk-variant kidneys, follow-up serum creatinine concentrations were higher than that in recipients of 0/1 APOL1 renal-risk-variant kidneys. A competing risk analysis revealed that APOL1 impacted renal allograft survival, but not recipient survival. Interactions between donor age and APOL1 genotype on renal allograft survival were nonsignificant. CONCLUSIONS: Shorter renal allograft survival is reproducibly observed after DDKT from APOL1 2-renal-risk-variant donors. Younger recipient age and older donor age have independent adverse effects on renal allograft survival.