Faculty Bibliography

BACKGROUND AND HYPOTHESIS/OBJECTIVE:Hepatitis C virus (HCV) positive-to-negative kidney transplants (KT) require direct acting antiviral therapy, but the optimal timing and duration remain unclear. We hypothesized that 14-day prophylactic course of glecaprevir/pibrentasvir 300/120 mg (GLE/PIB) would be safe and effective at treating donor-derived HCV viremia. METHODS:This was a prospective, single-center, single-arm, open-label pilot study. 20 adult HCV negative recipients of HCV nucleic acid amplification test positive deceased-donor kidneys (HCV positive-to-negative) received a 14-day course of GLE/PIB, with the first dose pre-transplant. HCV RNA viral loads (VL) were monitored on post-operative days (POD) 1, 3, 7, and 13. If VL was undetectable on POD 13, GLE/PIB was stopped, and if detectable, GLE/PIB was continued to complete an 8-week course. Surveillance monitoring continued after treatment to ensure sustained viral response (SVR). The primary outcome was efficacy of 14-day prophylactic GLE/PIB. Secondary outcomes included patient and allograft survival, the incidence, timing, and clearance of HCV viremia, and safety events. RESULTS:7/20 subjects (35%) never developed detectable HCV viremia. Only one subject had a detectable, but nonquantifiable, VL on POD 13 and completed an 8-week course. All subjects achieved SVR 12 weeks post-treatment with no relapses through 1-year follow-up. Mean time to undetectable HCV RNA VL was 10.5 (±4.7) days and mean peak VL was 371 (±715) copies/mL. 6-month and 1-year patient and allograft survival were 100% and 95%. CONCLUSION/CONCLUSIONS:A 14-day course of prophylactic GLE/PIB is safe and effective for HCV positive-to-negative KT and may prevent HCV transmission or significantly reduce the VL for those with detectable transmission allowing for rapid clearance within 2 weeks.

INTRODUCTION/BACKGROUND:Dietary restrictions for patients with end-stage kidney disease (ESKD) are burdensome. Kidney transplantation (KT) candidates who lack neighborhood resources and are burdened by dietary restrictions may have decreased access to KT. METHODS:In our two-center prospective cohort study (2014-2023), 2471 ESKD patients who were evaluated for KT (candidates) reported their perceived burden of dietary restrictions (not at all, somewhat/moderately, or extremely bothered). Neighborhood-level socioeconomic factors were derived from residential ZIP codes. We quantified the association of perceived burden of the dietary restrictions with a chance of listing using Cox models and risk of waitlist mortality using competing risks models. Then we tested whether these associations differed by neighborhood-level socioeconomic factors. RESULTS: = 0.02). The association between dietary burden and waitlist mortality did not differ by neighborhood-level healthy food access. CONCLUSION/CONCLUSIONS:The perceived burden of dietary restrictions is associated with a lower chance of listing for KT, and higher waitlist mortality only among candidates residing in neighborhoods with high food insecurity. Transplant centers should identify vulnerable patients and support them with nutrition education and access to food assistance programs.

Among patients awaiting kidney transplantation (KT), sexual dysfunction is common owing to end-stage kidney disease, but may improve post-KT. Leveraging a 2-center prospective study, 2422 adult KT candidates and 490 adult KT recipients (May 2014 to December 2023) were identified. Using the Kidney Disease Quality of Life Short Form, participants reported on the negative impact of sexual dysfunction due to end-stage kidney disease (ie, sexual bother) at KT evaluation, admission, and post-KT follow-ups. Using mixed-effect logistic regression models, we estimated odds and trajectories for odds of sexual bother. At evaluation, 46.1% of male and 29.6% of female candidates reported sexual bother; 39.0% and 34.5%, respectively, had been sexually active in the past 4 weeks. At admission, 53.8% male and 27.0% female recipients reported sexual bother; 41.6% and 41.8%, respectively, had been sexually active in the past 4 weeks. The estimated prevalence of sexual bother decreased during the first 3 years post-KT (odds ratio per year: 0.39; 95% CI: 0.25-0.60). Sexual activity increased and peaked 1-year post-KT. At 3 years post-KT, 48.9% of male and 50.0% of female recipients were sexually active. Sexual bother is common pre-KT and improves post-KT, and sexual activity increases post-KT. Sexual health is important and should be considered during KT management.

BACKGROUND:Patients with calculated panel reactive antibody (cPRA) ≥80.00%, particularly those with cPRA ≥99.90%, are considered highly sensitized and underserved by the Kidney Allocation System. Desensitization removes circulating reactive antibodies and/or suppresses antibody production to increase chances of a negative crossmatch. CD38 is expressed highly on plasma cells, thus is a potential target for desensitization. METHODS:This was an open-label single-arm Phase 1/2 study investigating the safety, pharmacokinetics, and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. There were two cohorts, Cohorts A and B, which enrolled cPRA ≥99.90% and 80.00%-<99.90%, respectively. RESULTS:23 patients (12 Cohort A, 11 Cohort B) received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks. Isatuximab was well tolerated with pharmacokinetic and pharmacodynamic profiles that indicated similar exposure to multiple myeloma trials. It resulted in decreases in CD38+ plasmablasts, plasma cells, and NK cells; and significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate, based on a pre-defined composite desensitization end-point, was 83.3% and 81.8% in Cohorts A and B. Most responders had decreases in anti-HLA antibodies that were maintained for 26 weeks after the last dose. Overall cPRA values were minimally impacted, however, with only 9/23 patients (39%) having cPRA decreases to target levels. By study cut-off (median follow-up 68 weeks), 6 patients received transplant offers, of which 4 were accepted. CONCLUSIONS:In this open-label trial, isatuximab was well tolerated and resulted in a durable decrease in anti-HLA antibodies with partial desensitization activity.

BACKGROUND:Understanding immunogenicity and alloimmune risk following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in kidney transplant recipients is imperative to understanding the correlates of protection and to inform clinical guidelines. METHODS:We studied 50 kidney transplant recipients following SARS-CoV-2 vaccination and quantified their anti-spike protein antibody, donor-derived cell-free DNA (dd-cfDNA), gene expression profiling (GEP), and alloantibody formation. RESULTS:Participants were stratified using nucleocapsid testing as either SARS-CoV-2-naïve or experienced prior to vaccination. One of 34 (3%) SARS-CoV-2 naïve participants developed anti-spike protein antibodies. In contrast, the odds ratio for the association of a prior history of SARS-CoV-2 infection with vaccine response was 18.3 (95% confidence interval 3.2, 105.0, p < 0.01). Pre- and post-vaccination levels did not change for median dd-cfDNA (0.23% vs. 0.21% respectively, p = 0.13), GEP scores (9.85 vs. 10.4 respectively, p = 0.45), calculated panel reactive antibody, de-novo donor specific antibody status, or estimated glomerular filtration rate. CONCLUSIONS:SARS-CoV-2 vaccines do not appear to trigger alloimmunity in kidney transplant recipients. The degree of vaccine immunogenicity was associated most strongly with a prior history of SARS-CoV-2 infection.

Genetically modified xenografts are one of the most promising solutions to the discrepancy between the numbers of available human organs for transplantation and potential recipients. To date, a porcine heart has been implanted into only one human recipient. Here, using 10-gene-edited pigs, we transplanted porcine hearts into two brain-dead human recipients and monitored xenograft function, hemodynamics and systemic responses over the course of 66 hours. Although both xenografts demonstrated excellent cardiac function immediately after transplantation and continued to function for the duration of the study, cardiac function declined postoperatively in one case, attributed to a size mismatch between the donor pig and the recipient. For both hearts, we confirmed transgene expression and found no evidence of cellular or antibody-mediated rejection, as assessed using histology, flow cytometry and a cytotoxic crossmatch assay. Moreover, we found no evidence of zoonotic transmission from the donor pigs to the human recipients. While substantial additional work will be needed to advance this technology to human trials, these results indicate that pig-to-human heart xenotransplantation can be performed successfully without hyperacute rejection or zoonosis.

Mycotic pseudoaneurysms are a rare, life-threatening complication after pancreas transplant. There have been limited reports of endovascular treatment of mycotic pseudoaneurysms in pancreas transplant recipients. Herein, we report on a case of a mycotic pseudoaneurysm from Pseudomonas aeruginosa after pancreas transplant. A 53-year-old male recipient underwent an uneventful simultaneous pancreas and kidney transplant. He was readmitted 48 days posttransplant with fevers and rigors. Pan-cultures were performed and broad-spectrum antibiotics were initiated. Imaging studies demonstrated a large mycotic pseudoaneurysm arising from the right common iliac artery adjacent to the arterial Y-graft anastomosis of the transplant pancreas. Endovascular stent placement was used to exclude the pseudoaneurysm prior to transplant pancreatectomy. During pancreatectomy, the lateral wall of the common iliac artery was found to be necrotic with significant exposure of the endovascular stent. After ligation and excision of the common iliac artery, a femorofemoral bypass was performed to revascularize the lower extremity. This case report highlights the advantage of a staged endovascular and surgical management strategy for complex mycotic pseudoaneurysms after pancreas transplant.

OBJECTIVE:Transplant renal artery stenosis (TRAS) after renal transplantation is a common cause of graft dysfunction and failure. Endovascular intervention in the form of percutaneous transluminal angioplasty (PTA) and stenting has rapidly become the dominant treatment modality for the TRAS. There is a paucity of clinical data on use of drug-eluting stent (DES) for TRAS. We investigated the outcomes of patients with clinically significant TRAS undergoing DES placement. METHODS:A retrospective review of patients with clinically significant TRAS undergoing PTA with DES placement from June 2014 to April 2021 was conducted. Patients treated for TRAS exhibited uncontrolled hypertension and/or unexplained allograft dysfunction. Patient demographics, procedural details, and follow-up outcomes were collected. Primary endpoints were the in-stent primary patency and graft survival. Secondary endpoints were freedom from reintervention, primary-assisted patency and access-related complications. RESULTS:Thirteen TRAS in twelve patients with graft function alteration were treated with DES. The median age was 57 years (interquartile range (IQR), 48-63 years), and nine (70%) patients were male (Table). The median follow-up was 9 months (IQR, 4-52 months). The most common comorbidity was hypertension (100%), coronary artery disease (83%) and diabetes. The median time from deceased donor transplant to intervention was 5.8 months (IQR, 3.5-6.7 months). TRAS was most commonly found at the juxta-ostial segment (77%). The procedure was performed with carbon dioxide angiography with minimal amount of iodinated contrast (median, 3 mL) under local anesthesia in nine (69%) and general anesthesia in four (31%) patients. The median stent diameter was 4.5 mm (IQR, 4-5 mm), and the median stent length was 15 mm (IQR, 15-18 mm). No intraoperative complications occurred. The rates of stenosis-free primary patency of the DES and graft survival were 76% and 100%, respectively. All three reinterventions for restenosis resulted from the kinking of the transplant renal artery proximal to the DES, which were treated by extending the stent more proximally 1-2 mm into the external iliac artery. There were no access-related complications. The median time to reintervention was 0.9 months (range, 0.23-2 months). Freedom from reintervention and primary-assisted patency were 76% and 100%, respectively. CONCLUSIONS:Our study demonstrates that DES is a safe and effective treatment modality in patients with TRAS at short to mid-term follow-up. As all reinterventions after DES were performed due to kinking of the transplant renal artery proximal to the stent, bridging of the DES 1-2 mm into the external iliac artery is recommended.

BACKGROUND:Xenografts from genetically modified pigs have become one of the most promising solutions to the dearth of human organs available for transplantation. The challenge in this model has been hyperacute rejection. To avoid this, pigs have been bred with a knockout of the alpha-1,3-galactosyltransferase gene and with subcapsular autologous thymic tissue. METHODS:We transplanted kidneys from these genetically modified pigs into two brain-dead human recipients whose circulatory and respiratory activity was maintained on ventilators for the duration of the study. We performed serial biopsies and monitored the urine output and kinetic estimated glomerular filtration rate (eGFR) to assess renal function and xenograft rejection. RESULTS:in Recipient 2. In both recipients, the creatinine level, which had been at a steady state, decreased after implantation of the xenograft, from 1.97 to 0.82 mg per deciliter in Recipient 1 and from 1.10 to 0.57 mg per deciliter in Recipient 2. The transplanted kidneys remained pink and well-perfused, continuing to make urine throughout the study. Biopsies that were performed at 6, 24, 48, and 54 hours revealed no signs of hyperacute or antibody-mediated rejection. Hourly urine output with the xenograft was more than double the output with the native kidneys. CONCLUSIONS:Genetically modified kidney xenografts from pigs remained viable and functioning in brain-dead human recipients for 54 hours, without signs of hyperacute rejection. (Funded by Lung Biotechnology.).