Probable antibody-mediated rejection in kidney transplantation is a rare and challenging phenotype to define: Findings from a single-center study.

The Banff 2022 consensus introduced probable antibody-mediated rejection (AMR), characterized by mild AMR histologic features and human leukocyte antigen (HLA) donor-specific antibody (DSA) positivity. In a single-center observational cohort study of 1891 kidney transplant recipients transplanted between 2004 and 2021, 566 kidney biopsies were performed in 178 individual HLA-DSA-positive transplants. Evaluated at time of the first HLA-DSA-positive biopsy of each transplant (N = 178), 84 of the 178 (47.2%) of first biopsies were scored as no AMR, 22 of the 178 (12.4%) as probable AMR, and 72 of the 178 (40.4%) as AMR. The majority (77.3%) of probable AMR cases were first diagnosed in indication biopsies. Probable AMR was associated with lower estimated glomerular filtration rate (mL/min/1.73m2) than no AMR (20.2 [8.3-32.3] vs 40.1 [25.4-53.3]; P = .001). The one-year risk of (repeat) AMR was similar for probable AMR and AMR (subdistribution hazard ratio (sHR), 0.99; 0.42-2.31; P = .97) and higher than after no AMR (sHR, 3.05; 1.07-8.73; P = .04). Probable AMR had a higher five-year risk of transplant glomerulopathy vs no AMR (sHR, 4.29; 0.92-19.98; P = 06), similar to AMR (sHR, 1.74; 0.43-7.04; P = .44). No significant differences in five-year risk of graft failure emerged between probable AMR and AMR (sHR, 1.14; 0.36-3.58; P = .82) or no AMR (sHR, 2.46; 0.78-7.74; P = .12). Probable AMR is a rare phenotype, however, sharing significant similarities with AMR in this single-center study. Future studies are needed to validate reproducible diagnostic criteria and associated clinical outcomes to allow for defining best management of this potentially relevant phenotype.

Long-term persistence of seroprotection against measles following measles-mumps-rubella vaccination administered before and after pediatric liver transplantation.

Liver transplantation (LT) recipients are susceptible to infections, including measles. Concerns about the safety and efficacy of live-attenuated vaccines, such as the measles-mumps-rubella (MMR) vaccine, have led to hesitancy among providers in administering them to immunocompromised patients. This 9-year interventional study assessed seroprotection against measles following MMR vaccination in pediatric LT recipients. Of 119 participants enrolled, 60 (50%) were seroprotected against measles after transplantation. Among the 59 nonseroprotected participants, 56 fulfilled safety criteria and received MMR vaccination with a seroprotection rate of 90% (95% confidence interval [CI], 73%-98%) after a first dose, 95% (95% CI, 85%-99%) after primary vaccination with 1 to 3 doses, comparable to nonimmunocompromized populations. However, measles antibodies declined over time, suggesting the need for regular monitoring, and booster doses. Half of the vaccinees (26/53, 49%) subsequently lost seroprotection. Among them, 23 received additional doses of MMR, with a high seroconversion rate. At their last follow-up (median, 6.1 years; interquartile range, 3.0-8.1 after inclusion), 63% (95% CI, 49%-75%) of all vaccinees were seroprotected against measles. In conclusion, MMR vaccination in pediatric LT recipients offers seroprotection against measles, but long-term immunity should be monitored closely.

Short-course early outpatient remdesivir prevents severe disease due to COVID-19 in organ transplant recipients during the omicron BA.2 wave.

Solid organ transplant recipients (SOTr) remain at risk of severe COVID-19. Several previous early therapies are no longer effective against new circulating variants. We performed a prospective cohort study in outpatient adult SOTr during the omicron BA.2 wave (April-May 2022), to determine the effectiveness of 3 doses of remdesivir given within 7 days of symptoms onset. Patients were followed for at least 30 days. The primary outcome was hospitalization. Of 210 SOTr that had COVID-19, we included 192. The median age was 54.5 years and 61.5% were men. The most common transplants were kidney (41.7%), lung (19.3%), liver (18.8%), and heart (6.3%). Most patients (90.1%) had previously received ≥3 COVID-19 vaccine doses. Fifteen (7.8%) were hospitalized, 5(2.6%) required supplemental oxygen, 3(1.6%) ICU admission, and 2(1%) mechanical ventilation with 2(1%) deaths. Age, the number of comorbidities, prednisone chronic treatment, and lung transplant were risk factors for hospitalization. Early remdesivir significantly decreased the hospitalization rate: adjusted hazard ratio 0.12 (95% CI: 0.03-0.57). The adjusted number needed to treat to prevent one hospitalization was 15.2 (95% CI: 13.6-31.4). No patient that received early remdesivir needed ICU admission or died. In a cohort of SOTr with COVID-19 infection, administration of 3-dose early remdesivir independently reduced the disease severity.

Characterizing the risk of human leukocyte antigen-incompatible living donor kidney transplantation in older recipients.

Older compatible living donor kidney transplant (CLDKT) recipients have higher mortality and death-censored graft failure (DCGF) compared to younger recipients. These risks may be amplified in older incompatible living donor kidney transplant (ILDKT) recipients who undergo desensitization and intense immunosuppression. In a 25-center cohort of ILDKT recipients transplanted between September 24, 1997, and December 15, 2016, we compared mortality, DCGF, delayed graft function (DGF), acute rejection (AR), and length of stay (LOS) between 234 older (age ≥60 years) and 1172 younger (age 18-59 years) recipients. To investigate whether the impact of age was different for ILDKT recipients compared to 17 542 CLDKT recipients, we used an interaction term to determine whether the relationship between posttransplant outcomes and transplant type (ILDKT vs CLDKT) was modified by age. Overall, older recipients had higher mortality (hazard ratio: 1.632.072.65, P < .001), lower DCGF (hazard ratio: 0.360.530.77, P = .001), and AR (odds ratio: 0.390.540.74, P < .001), and similar DGF (odds ratio: 0.461.032.33, P = .9) and LOS (incidence rate ratio: 0.880.981.10, P = 0.8) compared to younger recipients. The impact of age on mortality (interaction P = .052), DCGF (interaction P = .7), AR interaction P = .2), DGF (interaction P = .9), and LOS (interaction P = .5) were similar in ILDKT and CLDKT recipients. Age alone should not preclude eligibility for ILDKT.

Subphenotypes of frailty in lung transplant candidates.

Heterogeneous frailty pathobiology might explain the inconsistent associations observed between frailty and lung transplant outcomes. A Subphenotype analysis could refine frailty measurement. In a 3-center pilot cohort study, we measured frailty by the Short Physical Performance Battery, body composition, and serum biomarkers reflecting causes of frailty. We applied latent class modeling for these baseline data. Next, we tested class construct validity with disability, waitlist delisting/death, and early postoperative complications. Among 422 lung transplant candidates, 2 class model fit the best (P = .01). Compared with Subphenotype 1 (n = 333), Subphenotype 2 (n = 89) was characterized by systemic and innate inflammation (higher IL-6, CRP, PTX3, TNF-R1, and IL-1RA); mitochondrial stress (higher GDF-15 and FGF-21); sarcopenia; malnutrition; and lower hemoglobin and walk distance. Subphenotype 2 had a worse disability and higher risk of waitlist delisting or death (hazards ratio: 4.0; 95% confidence interval: 1.8-9.1). Of the total cohort, 257 underwent transplant (Subphenotype 1: 196; Subphenotype 2: 61). Subphenotype 2 had a higher need for take back to the operating room (48% vs 28%; P = .005) and longer posttransplant hospital length of stay (21 days [interquartile range: 14-33] vs 18 days [14-28]; P = .04). Subphenotype 2 trended toward fewer ventilator-free days, needing more postoperative extracorporeal membrane oxygenation and dialysis, and higher need for discharge to rehabilitation facilities (P ≤ .20). In this early phase study, we identified biological frailty Subphenotypes in lung transplant candidates. A hyperinflammatory, sarcopenic Subphenotype seems to be associated with worse clinical outcomes.

Lymphopenia at the time of transplant is associated with short-term mortality after deceased donor liver transplantation.

Absolute lymphocyte count (ALC) is considered a surrogate marker for nutritional status and immunocompetence. We investigated the association between ALC and post-liver transplant outcomes in patients who received a deceased donor liver transplant (DDLT). Patients were categorized by ALC at liver transplant: low (<500/µL), mid (500-1000/µL), and high ALC (>1000/µL). Our main analysis used retrospective data (2013-2018) for DDLT recipients from Henry Ford Hospital (United States); the results were further validated using data from the Toronto General Hospital (Canada). Among 449 DDLT recipients, the low ALC group demonstrated higher 180-day mortality than mid and high ALC groups (83.1% vs 95.8% and 97.4%, respectively; low vs mid: P = .001; low vs high: P < .001). A larger proportion of patients with low ALC died of sepsis compared with the combined mid/high groups (9.1% vs 0.8%; P < .001). In multivariable analysis, pretransplant ALC was associated with 180-day mortality (hazard ratio, 0.20; P = .004). Patients with low ALC had higher rates of bacteremia (22.7% vs 8.1%; P < .001) and cytomegaloviremia (15.2% vs 6.8%; P = .03) than patients with mid/high ALC. Low ALC pretransplant through postoperative day 30 was associated with 180-day mortality among patients who received rabbit antithymocyte globulin induction (P = .001). Pretransplant lymphopenia is associated with short-term mortality and a higher incidence of posttransplant infections in DDLT patients.

Preliminary safety and efficacy of laser stricturotomy for treatment of refractory biliary anastomotic strictures following liver transplantation.

Biliary anastomotic stricture (BAS) is a frequent complication of liver transplantation and is associated with reduced graft survival and patient morbidity. Existing treatments for BAS involve dilation of the stricture though placement of 1 or more catheters for 6 to 24 months yielding limited effectiveness in transplant patients. In this case series, we present preliminary safety and efficacy of a novel percutaneous laser stricturotomy treatment in a cohort of 5 posttransplant patients with BAS refractory to long-term large bore catheterization. In all patients, holmium or thulium laser was used to excise the stricture and promote biliary re-epithelization. There were no periprocedural complications. Technical success was 100% and at mean follow-up time of 22 months, there have been no recurrences. In conclusion, percutaneous laser stricturotomy demonstrates preliminary safety and efficacy in treatment of refractory BAS following liver transplantation.

Impact of Omicron BA.1 infection on BA.4/5 immunity in transplant recipients.

Mutations in the spike protein of SARS-CoV-2 have allowed Omicron subvariants to escape neutralizing antibodies. The degree to which this occurs in transplant recipients is poorly understood. We measured BA.4/5 cross-neutralizing responses in 75 mostly vaccinated transplant recipients who recovered from BA.1 infection. Sera were collected at 1 and 6 months post-BA.1 infection, and a lentivirus pseudovirus neutralization assay was performed using spike constructs corresponding to BA.1 and BA.4/5. Uninfected immunized transplant recipients and health care worker controls were used for comparison. Following BA.1 infection, the proportion of transplant recipients with neutralizing antibody responses was 88.0% (66/75) against BA.1 and 69.3% (52/75) against BA.4/5 (P = .005). The neutralization level against BA.4/5 was approximately 17-fold lower than that against BA.1 (IQR 10.6- to 45.1-fold lower, P < .0001). BA.4/5 responses declined over time and by ≥0.5 log10 (approximately 3-fold) in almost half of the patients by 6 months. BA.4/5-neutralizing antibody titers in transplant recipients with breakthrough BA.1 infection were similar to those in immunized health care workers but significantly lower than those in uninfected triple-vaccinated transplant recipients. These results provide evidence that transplant recipients are at ongoing risk for BA.4/5 infection despite vaccination and prior Omicron strain infection, and additional mitigation strategies may be required to prevent severe disease in this cohort.

Preemptive treatment of de novo donor-specific antibodies in lung transplant patients reduces subsequent risk of chronic lung allograft dysfunction or death.

The development of donor-specific antibodies after lung transplantation is associated with downstream acute cellular rejection, antibody-mediated rejection (AMR), chronic lung allograft dysfunction (CLAD), or death. It is unknown whether preemptive (early) treatment of de novo donor-specific antibodies (dnDSAs), in the absence of clinical signs and symptoms of allograft dysfunction, reduces the risk of subsequent CLAD or death. We performed a multicenter, retrospective cohort study to determine if early treatment of dnDSAs in lung transplant patients reduces the risk of the composite endpoint of CLAD or death. In the cohort of 445 patients, 145 patients developed dnDSAs posttransplant. Thirty patients received early targeted treatment for dnDSAs in the absence of clinical signs and symptoms of AMR. Early treatment of dnDSAs was associated with a decreased risk of CLAD or death (hazard ratio, 0.36; 95% confidence interval, 0.17-0.76; P < .01). Deferring treatment until the development of clinical AMR was associated with an increased risk of CLAD or death (hazard ratio, 3.00; 95% confidence interval, 1.46-6.18; P < .01). This study suggests that early, preemptive treatment of donor-specific antibodies in lung transplant patients may reduce the subsequent risk of CLAD or death.

Endovascular transatrial stenting of pulmonary vein stenosis after lung transplantation.

Pulmonary vein stenosis (PVS) and pulmonary vein occlusion (PVO) represent rare complications after lung transplantation (LTx), with limited therapeutic options and a high risk of graft loss. We present 2 cases of successful endovascular transatrial stenting following double LTx. A 60-year-old woman with chronic obstructive pulmonary disease who underwent double lobar LTx was diagnosed at postoperative day 72 with a high-grade PVS on the left side. A 22-year-old woman with idiopathic pulmonary arterial hypertension who underwent double LTx was diagnosed 9 days later with PVO of the left upper lobe vein. To avoid surgical reintervention, endovascular transatrial dilatation and stenting were performed successfully in both cases. Transatrial endovascular stenting of PVS or PVO after LTx seems an effective and safe treatment option that should be considered for these life-threatening complications and executed with care.

Clinical recommendations for posttransplant assessment of anti-HLA (Human Leukocyte Antigen) donor-specific antibodies: A Sensitization in Transplantation: Assessment of Risk consensus document.

Although anti-HLA (Human Leukocyte Antigen) donor-specific antibodies (DSAs) are commonly measured in clinical practice and their relationship with transplant outcome is well established, clinical recommendations for anti-HLA antibody assessment are sparse. Supported by a careful and critical review of the current literature performed by the Sensitization in Transplantation: Assessment of Risk 2022 working group, this consensus report provides clinical practice recommendations in kidney, heart, lung, and liver transplantation based on expert assessment of quality and strength of evidence. The recommendations address 3 major clinical problems in transplantation and include guidance regarding posttransplant DSA assessment and application to diagnostics, prognostics, and therapeutics: (1) the clinical implications of positive posttransplant DSA detection according to DSA status (ie, preformed or de novo), (2) the relevance of posttransplant DSA assessment for precision diagnosis of antibody-mediated rejection and for treatment management, and (3) the relevance of posttransplant DSA for allograft prognosis and risk stratification. This consensus report also highlights gaps in current knowledge and provides directions for clinical investigations and trials in the future that will further refine the clinical utility of posttransplant DSA assessment, leading to improved transplant management and patient care.

Living donor liver paired exchange between pediatric and adult recipients due to donor graft size mismatch.

Living donor liver transplantation is an effective means to decrease organ shortage. However, many potential living donors are currently being denied due to ABO incompatibility or inadequate donor liver volume. Liver paired exchange (LPE) provides a practical solution to overcome these obstacles, and yet the first case of LPE in the United States was only recently reported in 2020. Here, we report world's first case of LPE involving pediatric and adult recipients to avoid surgical complexity of the pediatric recipient and to increase the graft-to-recipient weight ratio of the adult recipient between 2 ABO compatible pairs. As living donor liver transplantation becomes more widely adopted, the need for pair exchange to improve surgical safety and postoperative outcomes between 2 ABO compatible pairs is likely to increase.

Nonskeletal and skeletal effects of high doses versus low doses of vitamin D3 in renal transplant recipients: Results of the VITALE (VITamin D supplementation in renAL transplant recipients) study, a randomized clinical trial.

Vitamin D sufficiency is associated with a reduced risk of fractures, diabetes mellitus, cardiovascular events, and cancers, which are frequent complications after renal transplantation. The VITALE (VITamin D supplementation in renAL transplant recipients) study is a multicenter double-blind randomized trial, including nondiabetic adult renal transplant recipients with serum 25-hydroxy vitamin D (25(OH) vitamin D) levels of <30 ng/mL, which is randomized 12 to 48 months after transplantation to receive high (100 000 IU) or low doses (12 000 IU) of cholecalciferol every 2 weeks for 2 months and then monthly for 22 months. The primary outcome was a composite endpoint, including diabetes mellitus, major cardiovascular events, cancer, and death. Of 536 inclusions (50.8 [13.7] years, 335 men), 269 and 267 inclusions were in the high-dose and low-dose groups, respectively. The serum 25(OH) vitamin D levels increased by 23 versus 6 ng/mL in the high-dose and low-dose groups, respectively (P < .0001). In the intent-to-treat analysis, 15% versus 16% of the patients in the high-dose and low-dose groups, respectively, experienced a first event of the composite endpoint (hazard ratio, 0.94 [0.60-1.48]; P = .78), whereas 1% and 4% of patients in the high-dose and low-dose groups, respectively, experienced an incident symptomatic fracture (odds ratio, 0.24 [0.07-0.86], P = .03). The incidence of adverse events was similar between the groups. After renal transplantation, high doses of cholecalciferol are safe but do not reduce extraskeletal complications (trial registration: ClinicalTrials.gov; identifier: NCT01431430).

A comparison of deprivation indices and application to transplant populations.

The choice of deprivation index can influence conclusions drawn regarding the extent of deprivation within a community and the identification of the most deprived communities in the United States. This study aimed to determine the degree of correlation among deprivation indices commonly used to characterize transplant populations. We used a retrospective cohort consisting of adults listed for liver or kidney transplants between 2008 and 2018 to compare 4 deprivation indices: neighborhood deprivation index, social deprivation index (SDI), area deprivation index, and social vulnerability index. Pairwise correlation between deprivation indices by transplant referral regions was measured using Spearman correlations of population-weighted medians and upper quartiles. In total, 52 individual variables were used among the 4 deprivation indices with 25% overlap. For both organs, the correlation between the population-weighted 75th percentile of the deprivation indices by transplant referral region was highest between SDI and social vulnerability index (liver and kidney, 0.93) and lowest between area deprivation index and SDI (liver, 0.19 and kidney, 0.15). The choice of deprivation index affects the applicability of research findings across studies examining the relationship between social risk and clinical outcomes. Appropriate application of these measures to transplant populations requires careful index selection based on the intended use and included variable relevance.

Donor and recipient human leukocyte antigen-G polymorphisms modulate the risk of adverse immunologic events following lung transplantation.

The long-term benefits of lung transplantation (LTx) are limited by pathogenic alloimmune responses that drive injury, inflammation, and chronic dysfunction. Human leukocyte antigen-G (HLA-G) plays a key role in the modulation of these pathways. This study assesses the impact of the HLA-G genotype on immunologic risk and survival following LTx. This retrospective cohort study included 289 bilateral LTx. Recipient and donor HLA-G genotypes were analyzed to identify associations with de novo donor-specific antibodies, acute rejection, chronic lung allograft dysfunction, and allograft survival. We further assessed these associations, both individually and in paired analysis, based on a grouped haplotype classification of HLA-G expression. Donor HLA-G single nucleotide polymorphisms were associated with allograft injury, the onset of chronic lung allograft dysfunction following injury, and allograft survival. Recipient HLA-G single nucleotide polymorphisms were associated with allograft injury, cellular rejection, and donor-specific antibody formation. "Low HLA-G expression" donor haplotypes were associated with impaired allograft survival, as were "low HLA-G expression" donor-recipient haplotype pairs. This study provides compelling evidence for the role of HLA-G in modulating immunologic risk after LTx. Our results highlight the importance of both donor and recipient HLA-G genotypes on the overall risk profile and underscore the lasting influence of donor genotype on lung transplant outcomes.

The minimum weight and age of kidney donors: en bloc kidney transplantation from preterm neonatal donors weighing less than 1.2 kg to adult recipients.

En bloc kidney transplantation (EBKT) to adults from preterm neonates following donation after circulatory death has not been described in the literature. We report 2 successful cases of EBKT from preterm neonatal donation after circulatory death donors weighing <1.2 kg to adult recipients. The first case was a preterm female infant born at 29 weeks' gestational age, weighing 1.07 kg. The recipient was a 34-year-old woman weighing 75 kg. At the 9-month follow-up, the patient demonstrated excellent graft function with a creatinine concentration of 1.48 mg/dL. The second donor was a preterm female infant born at 29 weeks and 5 days' gestation, weighing 1.17 kg. The recipient was a 25-year-old woman weighing 46 kg. By 5 months post surgery, the serum creatinine level had gradually decreased to 1.47 mg/dL. In our experience, EBKT from preterm neonates <30 weeks' gestation and weighing <1.2 kg has demonstrated acceptable short- to medium-term results.

Development and validation of the lung donor (LUNDON) acceptability score for pulmonary transplantation.

There is a chronic shortage of donor lungs for pulmonary transplantation due, in part, to low lung utilization rates in the United States. We performed a retrospective cohort study using data from the Scientific Registry of Transplant Recipients database (2006-2019) and developed the lung donor (LUNDON) acceptability score. A total of 83 219 brain-dead donors were included and were randomly divided into derivation (n = 58 314, 70%) and validation (n = 24 905, 30%) cohorts. The overall lung acceptance was 27.3% (n = 22 767). Donor factors associated with the lung acceptance were age, maximum creatinine, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen, mechanism of death by asphyxiation or drowning, history of cigarette use (≥20 pack-years), history of myocardial infarction, chest x-ray appearance, bloodstream infection, and the occurrence of cardiac arrest after brain death. The prediction model had high discriminatory power (C statistic, 0.891; 95% confidence interval, 0.886-0.895) in the validation cohort. We developed a web-based, user-friendly tool (available at https://sites.wustl.edu/lundon) that provides the predicted probability of donor lung acceptance. LUNDON score was also associated with recipient survival in patients with high lung allocation scores. In conclusion, the multivariable LUNDON score uses readily available donor characteristics to reliably predict lung acceptability. Widespread adoption of this model may standardize lung donor evaluation and improve lung utilization rates.

BK DNAemia and native kidney polyomavirus nephropathy following lung transplantation.

BK virus DNAemia (BKPyV) and nephropathy are common after kidney transplant; however, there are limited data on BK infections in nonrenal solid organ transplant recipients. We examined the frequency, clinical and pathologic features, and kidney and lung outcomes of BKPyV and BK virus native kidney nephropathy (BKVN) in lung transplant recipients at our center. Among 878 recipients transplanted from 2003 to 2019, 56 (6%) developed BKPyV at a median of 30.1 months after transplant (range, 0.6-213) and 11 (1.3%) developed BKVN at a median of 46 months after transplant (range, 9-213). The incidence of end-stage kidney disease was significantly higher in patients with peak viral load ≥10 000 copies/mL (39% vs 8%, P < .001). All cases of BKVN were in patients with peak viral load of ≥10 000 copies/mL, and 55% of these patients developed end-stage kidney disease. Despite the reduction of immunosuppression to treat BKVN, only 1 patient developed acute rejection, and lung function was stable >1 year. BKPyV and nephropathy are more common after lung transplantation than previously reported. Routine screening for BKPyV should be considered in all lung transplant recipients.

Can remote endarterectomy expand access to kidney transplantation in patients with severe iliac calcification?

Severe iliac artery calcification in patients with end-stage renal disease is a common barrier to listing for kidney transplant. While few surgical solutions to iliac calcification have been reported, improving treatment may thus improve access to transplant care. Here we present two cases of a novel application of remote endarterectomy of the external iliac artery to facilitate listing for renal transplant. Both patients were listed following remote endarterectomy, followed by successful renal transplants using the treated vessels.

Sensitization in transplantation: Assessment of Risk 2022 Working Group Meeting Report.

The Sensitization in Transplantation: Assessment of Risk workgroup is a collaborative effort of the American Society of Transplantation and the American Society of Histocompatibility and Immunogenetics that aims at providing recommendations for clinical testing, highlights gaps in current knowledge, and proposes areas for further research to enhance histocompatibility testing in support of solid organ transplantation. This report provides updates on topics discussed by the previous Sensitization in Transplantation: Assessment of Risk working groups and introduces 2 areas of exploration: non-human leukocyte antigen antibodies and utilization of human leukocyte antigen antibody testing measurement to evaluate the efficacy of antibody-removal therapies.