Subthreshold rejection activity in many kidney transplants currently classified as having no rejection.

Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. To examine this question, we studied genome-wide microarray results from 5086 kidney transplant biopsies (from 4170 patients). An updated molecular archetypal analysis designated 56% of biopsies as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower estimated glomerular filtration rate, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR, respectively, diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.

First successful ovarian cortex allotransplant to a Turner syndrome patient requiring immunosuppression: wide implications.

OBJECTIVE: To determine whether we can safely and successfully transplant an ovary tissue allograft from a nonidentical donor to her Turner syndrome sister. DESIGN: Transplantation of cryopreserved ovary tissue, as well as fresh transplantation of ovarian tissue between identical twins, is now well established with numerous reported successful cases. However, there have not yet been any ovary transplants between nonidentical women requiring immunosuppression (ovary allotransplant). This could be a much more common indication for ovary tissue transplantation if safe and reliable immunosuppression were available. SETTING: Infertility Center of St. Louis. PATIENT(S): A 20-year-old amenorrheic woman with nonmosaic 45-XO Turner syndrome requested ovary tissue transplantation from her fertile 22-year-old 46-XX sister. They were an human leukocyte antigens match but were ABO incompatible, a well-known contra-indication to solid tissue or organ transplantation. The Turner syndrome sister strongly preferred to be able to become pregnant naturally without donor egg in vitro fertilization and to avoid hormone replacement therapy. In her religious group, that would also be important for finding a marital match. Despite the poor prognosis associated with ABO incompatibility, an ovary from her 22-year-old nonidentical fertile sister was transplanted to her employing the immunosuppression protocol now used for kidney transplant patients in our centers at Washington University and Johns Hopkins. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Post operatively at 5 months she developed normal monthly menstrual ovarian function, and she became spontaneously pregnant with a normal infant girl. The relation between her postoperation follicle stimulating hormone and antimüllerian hormone levels continue to support the theory that tissue pressure controls primordial follicle recruitment. The fact that ABO incompatibility did not prevent success suggests that diffusion and not revascularization may be all that is required for successful long-term ovarian cortex transplant survival with spontaneous pregnancy. RESULT(S): Ovary allotransplantation with safe immunosuppression allows natural conception, and also normal hormone function obviates the need for hormone replacement therapy. Orthotopic placement of the graft and surgical technique is critical for natural conception and a higher pregnancy rate. CONCLUSION(S): Allotransplantation requiring safe immunosuppression, if successful, maybe a much more commonly used indication for ovary transplantation in the future than frozen ovary grafts or grafts between identical twins.

Longitudinal alterations in the urinary virome of kidney transplant recipients are influenced by BK viremia and patient sex.

Little is known about the urinary virome and how it interacts with the host, particularly in renal transplant diseases. Using metagenomic sequencing, we characterized the urinary virome of 23 kidney transplant recipients longitudinally (11 BKV+ patients and 12 BKV- patients). We applied linear mixed effects models, PERMANOVA, k-means clustering, and MaAsLin2 algorithms to determine virome signatures associated with post-transplant time, BK viremia status, and patient sex. We found that the richness and alpha diversity of urinary virome were significantly different in renal transplant recipients with BKV+ over time in comparison to BKV- (richness P = 0.012, alpha P < 0.0001). Female BKV- patients had significantly higher virome richness than males (P = 0.0063). Virome beta diversity was significantly different between patients by BKV status (P < 0.001). Additionally, we identified underlying interactions between patient sex and BKV status, in terms of virome beta diversity (P = 0.008). BK polyomavirus infections were primarily of subtypes IA, IB1, and IB2. The non-BK dominant samples clustered into six urinary virome community states. BKV- samples had more anelloviruses than BKV+ samples though this difference was not statistically significant. Lastly, we identified specific viruses, associated with BKV+ and time in our samples. Our results indicate that dynamic alterations in the urinary virome over the post-transplant period in kidney transplant recipients can be shaped by BK viremia and patient sex. These findings advance our fundamental understanding of the urinary virome and support a new line of investigation in renal disease and transplantation. IMPORTANCE: The urinary microbiome is increasingly implicated in renal health and disease. While most research focuses on bacteria communities of the microbiome, factors that influence the urinary virome are not understood. Here, we investigated the urinary virome of 23 adult kidney transplant recipients longitudinally over 14 weeks post-transplant. We show that alterations in the urinary virome are associated with kidney transplant recipients with BK polyomavirus viremia that can lead to BK nephropathy and allograft rejection. By modeling the temporal dynamics post-transplant, we delineated specific profiles of the urinary virome associated with patient sex and urinary community states. These findings reveal fundamental aspects of the urinary virome that can be leveraged to better manage kidney diseases.

Association between Pre-Kidney Transplant Elevated Parathyroid Hormone and Post-Transplant Graft Loss.

BACKGROUND: Prior to kidney transplantation (KT) most patients have an elevated parathyroid hormone (PTH). However, the impact of PTH on post-KT mortality and graft loss is unclear. We quantified the association between PTH levels measured at transplant and adverse post-KT outcomes. STUDY DESIGN: A prospective longitudinal cohort of 1,136 KT recipients from a single tertiary care center between 12/2008 and 2/2020. Pre-KT PTH levels were abstracted retrospectively. Adjusted multivariable Cox proportional hazards models were used to estimate the association between pre-KT PTH levels and mortality and death-censored graft loss (DCGL). RESULTS: Of 1,136 recipients, pre-KT PTH levels were ≤300pg/mL in 62.3% and >600pg/mL in 12.5%. Compared to those with a pre-KT PTH≤300pg/mL, patients with a pre-KT PTH>600pg/mL were more likely to be Black (51.4% vs. 34.6%) and have a longer dialysis vintage (4.8y vs. 1.7y) (p<0.001). Those with a pre-KT PTH>600pg/mL had a higher 10-year cumulative incidence of DCGL than those with PTH≤300pg/mL (31.7% vs. 15.4%, p<0.001). After adjusting for confounders, pre-KT PTH>600pg/mL was associated with a 1.76-fold increased risk of DCGL (95% CI: 1.16-2.65). The magnitude of this association differed by race (pinteraction=0.011) and by treatment (pinteraction=0.018). Among non-Black patients, a PTH>600pg/mL was associated with a 3.21-fold increased risk of DCGL compared to those with PTH≤300pg/mL (95%CI: 1.77-5.81). Among untreated patients, those with PTH>600pg/mL had a 2.54-fold increase in DCGL (95%CI: 1.44-4.47). There was no association between pre-KT PTH and mortality risk. CONCLUSIONS: PTH >600pg/mL prior to KT increased the risk of DCGL by 76%, demonstrating the importance of treating PTH prior to KT to prevent graft loss in a contemporary era with the introduction and widespread availability of medical therapy.

The Second International Consensus Guidelines on the Management of BK Polyomavirus in Kidney Transplantation.

BK polyomavirus (BKPyV) remains a significant challenge after kidney transplantation. International experts reviewed current evidence and updated recommendations according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Risk factors for BKPyV-DNAemia and biopsy-proven BKPyV-nephropathy include recipient older age, male sex, donor BKPyV-viruria, BKPyV-seropositive donor/-seronegative recipient, tacrolimus, acute rejection, and higher steroid exposure. To facilitate early intervention with limited allograft damage, all kidney transplant recipients should be screened monthly for plasma BKPyV-DNAemia loads until month 9, then every 3 mo until 2 y posttransplant (3 y for children). In resource-limited settings, urine cytology screening at similar time points can exclude BKPyV-nephropathy, and testing for plasma BKPyV-DNAemia when decoy cells are detectable. For patients with BKPyV-DNAemia loads persisting >1000 copies/mL, or exceeding 10 000 copies/mL (or equivalent), or with biopsy-proven BKPyV-nephropathy, immunosuppression should be reduced according to predefined steps targeting antiproliferative drugs, calcineurin inhibitors, or both. In adults without graft dysfunction, kidney allograft biopsy is not required unless the immunological risk is high. For children with persisting BKPyV-DNAemia, allograft biopsy may be considered even without graft dysfunction. Allograft biopsies should be interpreted in the context of all clinical and laboratory findings, including plasma BKPyV-DNAemia. Immunohistochemistry is preferred for diagnosing biopsy-proven BKPyV-nephropathy. Routine screening using the proposed strategies is cost-effective, improves clinical outcomes and quality of life. Kidney retransplantation subsequent to BKPyV-nephropathy is feasible in otherwise eligible recipients if BKPyV-DNAemia is undetectable; routine graft nephrectomy is not recommended. Current studies do not support the usage of leflunomide, cidofovir, quinolones, or IVIGs. Patients considered for experimental treatments (antivirals, vaccines, neutralizing antibodies, and adoptive T cells) should be enrolled in clinical trials.

Cytomegalovirus Treatment in Solid Organ Transplantation: An Update on Current Approaches.

OBJECTIVE: The article reviews the safety and efficacy of treatments for cytomegalovirus (CMV) in solid organ transplantation. DATA SOURCES: A literature review was conducted in PubMed, MEDLINE, and Clinicaltrials.gov from database inception through January 2024, using terms CMV, therapy, and solid organ transplantation. STUDY SELECTION AND DATA EXTRACTION: Clinical trials, meta-analyses, cohort studies, case reports, and guidelines were included. Letters to the editor, reviews, and commentaries were excluded. DATA SYNTHESIS: After abstract screening and full-text review of 728 citations for eligibility, 53 were included. Valganciclovir and intravenous ganciclovir are drugs of choice for CMV management and, until recently, the availability of alternative options has been restricted due to toxicity. For instance, foscarnet and cidofovir serve as second-line agents due to potential bone marrow and renal toxicity. In patients with refractory or resistant CMV, maribavir, a novel oral agent, has proven efficacy and a lower adverse effect profile. However, in refractory or resistant CMV, foscarnet and cidofovir are preferred in invasive disease (CMV gastritis, CMV retinitis, and CMV encephalitis), high viral loads, and inability to tolerate oral preparations. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Consensus guidelines have not been revised since approval of novel antivirals in solid organ transplantation. Valganciclovir and ganciclovir remain drugs of choice for initial CMV therapy. Foscarnet, cidofovir, and maribavir are treatments for refractory or resistant-CMV. CONCLUSIONS: Selection of CMV antiviral treatment should be determined by patient-specific factors, including severity of illness, resistant or refractory disease, dose-limiting adverse effects, and the preferred route of administration.

A multicenter prospective study to define the natural history of BK viral infections in kidney transplantation.

BACKGROUND: BK polyomavirus (BKV) can cause permanent loss of allograft function due to BKV-associated nephropathy (BKVN) in kidney transplant recipients. Besides immunosuppression reduction, there are no consistently effective interventions for BKV infection. Study purpose was to define natural history of BKV infection, identify risk factors for BKV reactivation and BKVN in kidney transplant recipients, and inform the design/conduct of future clinical trials of BKV-targeted therapeutics. METHODS: We conducted a multicenter prospective observational study of incident kidney transplant recipients at six U.S. transplant centers. Participants were monitored every 4 weeks for BKV reactivation and followed for up to 24 months post-transplant. We used regression models (logistic, survival, mixed models) to study relationships between BK viremia/BKVN, clinical characteristics, and allograft function. RESULTS: We enrolled 335 participants. Fifty-eight (17%) developed BK viremia, 6 (2%) developed biopsy-proven BKVN, and 29 (9%) developed suspected/presumed BKVN (defined as BKV viral load > 10,000 copies/mL without biopsy). Male donor sex was associated with lower odds for BK viremia, whereas recipient Black race was associated with two-fold increased odds for BK viremia. Recipient female sex was associated with more rapid clearance of BK viremia. Persistent BK viremia/BKVN was associated with poorer allograft function by 24 months post-transplant. CONCLUSIONS: We identified multiple donor and recipient demographic factors associated with risk for BKV infection and poorer allograft function by 24 months post-transplant. This may help design future clinical trials of therapies to prevent or mitigate the deleterious impact of BKV reactivation on kidney transplant outcomes.

Outcomes and management of kidney transplant recipients with Fabry disease: a review.

Fabry disease is an X-linked inheritable lysosomal storage disease caused by various mutations of the galactosidase α gene resulting in α-galactosidase deficiency. Chronic kidney disease (CKD) is one of the most significant consequences of Fabry disease, with risk of end-stage kidney disease (ESKD) in this population. Like for other patients with ESKD, kidney transplant is the optimal treatment for Fabry disease patients with ESKD. However, enzyme replacement therapy and newer Fabry disease treatments remain important to mitigate other end organ damage such as cardiomyopathy post transplantation. This review is a primer on Fabry disease, which examines the outcomes of disease in the context of kidney transplant prior to, and during, the enzyme replacement treatment era, medical treatment of kidney transplant recipients with Fabry disease, and progress in screening studies.

Twenty years in the making: tolerance in a living-related kidney transplant recipient.

Kidney transplant recipients require lifelong immunosuppression to prevent graft rejection. However, immunosuppression is associated with adverse effects. A minority of kidney transplant recipients can be weaned off immunosuppression and maintain their graft function, a situation referred to as "functional or operational tolerance". We describe a case of a 70-year-old man who received a haploidentical hematopoietic cell transplant for lymphoma 22 years before receiving a kidney transplant from the same donor and was weaned off all immunosuppression by four months post-transplant. Tolerance was present, and there has been no graft rejection or graft vs. host disease. This case demonstrates successful long-term hematopoietic chimerism and functional tolerance after receiving a kidney transplant from the same donor.

Nivolumab + Tacrolimus + Prednisone ± Ipilimumab for Kidney Transplant Recipients With Advanced Cutaneous Cancers.

PURPOSE: Cancer-related mortality rates among kidney transplant recipients (KTR) are high, but these patients have largely been excluded from trials of immune checkpoint inhibitors because of immunosuppression and risk of treatment-related allograft loss (TRAL). We conducted a prospective clinical trial testing nivolumab (NIVO) + tacrolimus (TACRO) + prednisone (PRED) ± ipilimumab (IPI) in KTR with advanced cutaneous cancers. METHODS: Adult KTR with advanced melanoma or basal, cutaneous squamous, or Merkel cell carcinomas were eligible. Immunosuppression was standardized to TACRO (serum trough 2-5 ng/mL) + PRED 5 mg once daily. Patients then received NIVO 480 mg IV once every 4 weeks. The primary composite end point was partial or complete (tumor) response (CR) or stable disease per RECIST v1.1 without allograft loss at 16W. Patients with progressive disease (PD) could receive IPI 1 mg/kg IV + NIVO 3 mg/kg once every 3 weeks × 4 followed by NIVO. Donor-derived cell-free DNA (dd-cfDNA) levels were measured approximately once every 2 weeks as a potential predictor of allograft rejection. RESULTS: Among eight evaluable patients, none met the trial's primary end point. All eight patients experienced PD on NIVO + TACRO + PRED; TRAL occurred in one patient. Six patients then received IPI + NIVO + TACRO + PRED. Best overall responses: two CR (one with TRAL) and four PD (one with TRAL). In total, 7 of 8 pre-NIVO tumor biopsies contained a paucity of infiltrating immune cells. In total, 2 of 5 on-NIVO biopsies demonstrated moderate immune infiltrates; both patients later experienced a CR to IPI + NIVO. In 2 of 3 patients with TRAL, dd-cfDNA elevations occurred 10 and 15 days before increases in serum creatinine. CONCLUSION: In most KTR with advanced skin cancer, TACRO + PRED provides insufficient allograft protection and compromises immune-mediated tumor regression after administration of NIVO ± IPI. Elevated dd-cfDNA levels can signal treatment-related allograft rejection earlier than rises in serum creatinine.

Development and Validation of an Abridged Physical Frailty Phenotype for Clinical Use: A Cohort Study Among Kidney Transplant Candidates.

BACKGROUND: Frailty is associated with poor outcomes in surgical patients including kidney transplant (KT) recipients. Transplant centers that measure frailty have better pre- and postoperative outcomes. However, clinical utility of existing tools is low due to time constraints. To address this major barrier to implementation in the preoperative evaluation of patients, we developed an abridged frailty phenotype. METHODS: The abridged frailty phenotype was developed by simplifying the 5 physical frailty phenotype (PFP) components in a two-center prospective cohort of 3 220 KT candidates and tested for efficiency (time to completion) in 20 candidates evaluation (January 2009 to March 2020). We examined area under curve (AUC) and Cohen's kappa agreement to compare the abridged assessment with the PFP. We compared waitlist mortality risk (competing risks models) by frailty using the PFP and abridged assessment, respectively. Model discrimination was assessed using Harrell's C-statistic. RESULTS: Of 3 220 candidates, the PFP and abridged assessment identified 23.8% and 27.4% candidates as frail, respectively. The abridged frailty phenotype had substantial agreement (kappa = 0.69, 95% CI: 0.66-0.71) and excellent discrimination (AUC = 0.861). Among 20 patients at evaluation, abridged assessment took 5-7 minutes to complete. The PFP and abridged assessment had similar associations with waitlist mortality (subdistribution hazard ratio [SHR] = 1.62, 95% CI: 1.26-2.08 vs SHR = 1.70, 95% CI: 1.33-2.16) and comparable mortality discrimination (p = .51). CONCLUSIONS: The abridged assessment is an efficient and valid way to identify frailty. It predicts waitlist mortality without sacrificing discrimination. Surgical departments should consider utilizing the abridged assessment to evaluate frailty in patients when time is limited.

Measures to Increase Immunogenicity of SARS-CoV-2 Vaccines in Solid Organ Transplant Recipients: A Narrative Review.

Purpose of review: To review the data on the immunogenicity of COVID-19 vaccines, administered by different strategies, in solid organ transplant recipients (SOTRs). Recent findings: COVID-19 booster vaccines were given to SOTRs as a widespread practice in many transplant centers, mostly as the third and/or fourth dose in an extended vaccine series, with a significantly improved humoral response compared with the initial two-dose scheme. However, one-third of SOTRs remained unresponsive, despite these boosters. Next steps: Vaccination with standard dosing remains the most feasible strategy for attaining protection against COVID-19. Additional booster doses and temporarily holding or reducing mycophenolate mofetil/mycophenolic acid may provide immunogenicity to vaccines, according to recent studies demonstrating some efficacy with these measures. Preexposure prophylaxis with monoclonal antibodies showed benefit in immunocompromised patients but is no longer recommended by the National Institutes of Health (NIH) due to diminished efficacy against Omicron and recent variants. Screening for the presence and titers of SARS-CoV-2-specific antibodies in SOTRs is not recommended in most clinical settings. T cell-based techniques are needed to evaluate vaccine efficacy and risk of infection. As SARS-CoV-2 continues to evolve, new vaccines based on conservative protein component/complexes of the COVID virus, in addition to its spike protein, are warranted to offer prolonged protection.

Spatiotemporal profile of atrophy in the first year following moderate-severe traumatic brain injury.

Traumatic brain injury (TBI) triggers progressive neurodegeneration resulting in brain atrophy that continues months-to-years following injury. However, a comprehensive characterization of the spatial and temporal evolution of TBI-related brain atrophy remains incomplete. Utilizing a sensitive and unbiased morphometry analysis pipeline optimized for detecting longitudinal changes, we analyzed a sample consisting of 37 individuals with moderate-severe TBI who had primarily high-velocity and high-impact injury mechanisms. They were scanned up to three times during the first year after injury (3 months, 6 months, and 12 months post-injury) and compared with 33 demographically matched controls who were scanned once. Individuals with TBI already showed cortical thinning in frontal and temporal regions and reduced volume in the bilateral thalami at 3 months post-injury. Longitudinally, only a subset of cortical regions in the parietal and occipital lobes showed continued atrophy from 3 to 12 months post-injury. Additionally, cortical white matter volume and nearly all deep gray matter structures exhibited progressive atrophy over this period. Finally, we found that disproportionate atrophy of cortex along sulci relative to gyri, an emerging morphometric marker of chronic TBI, was present as early as 3 month post-injury. In parallel, neurocognitive functioning largely recovered during this period despite this pervasive atrophy. Our findings demonstrate msTBI results in characteristic progressive neurodegeneration patterns that are divergent across regions and scale with the severity of injury. Future clinical research using atrophy during the first year of TBI as a biomarker of neurodegeneration should consider the spatiotemporal profile of atrophy described in this study.

Dual-Organ Transplantation: Indications, Evaluation, and Outcomes for Heart-Kidney and Heart-Liver Transplantation: A Scientific Statement From the American Heart Association.

Although heart transplantation is the preferred therapy for appropriate patients with advanced heart failure, the presence of concomitant renal or hepatic dysfunction can pose a barrier to isolated heart transplantation. Because donor organ supply limits the availability of organ transplantation, appropriate allocation of this scarce resource is essential; thus, clear guidance for simultaneous heart-kidney transplantation and simultaneous heart-liver transplantation is urgently required. The purposes of this scientific statement are (1) to describe the impact of pretransplantation renal and hepatic dysfunction on posttransplantation outcomes; (2) to discuss the assessment of pretransplantation renal and hepatic dysfunction; (3) to provide an approach to patient selection for simultaneous heart-kidney transplantation and simultaneous heart-liver transplantation and posttransplantation management; and (4) to explore the ethics of multiorgan transplantation.

A Systematic Review and Meta-analysis of Optimized CMV Preemptive Therapy and Antiviral Prophylaxis for CMV Disease Prevention in CMV High-Risk (D+R-) Kidney Transplant Recipients.

The optimal strategy for cytomegalovirus (CMV) disease prevention in CMV donor/recipient kidney transplant recipients remains uncertain. Conclusions of prior meta-analyses that CMV disease rates with preemptive therapy (PET) and universal prophylaxis (UP) were comparable may have been affected by inclusion of studies lacking key determinants of efficacy of the respective strategies. Methods: We conducted a systematic review and meta-analysis of PET with weekly CMV polymerase chain reaction monitoring for ≥3 mo and UP with 6 mo of valganciclovir. PubMed and Embase databases were reviewed from January 1, 2010, to April 1, 2022. Risk of bias was assessed with 3 instruments (Cochrane RoB, Cochrane RoBINS-I, and an instrument for assessing risk in observational studies). The primary outcome was CMV disease incidence by 1-y posttransplant. Secondary outcomes by 1-y were graft loss, acute allograft rejection, and mortality. Results were synthesized using generalized linear mixed model meta-analysis. PET studies were stratified into low-threshold (LT) and high-threshold (HT) PET based on the viral load threshold for initiation of antiviral therapy. Results: Twenty-five studies met inclusion criteria (6 PET, 19 UP). CMV disease incidence was significantly higher in HT (0.30 [95% confidence interval (CI), 0.22-0.39]) versus LT PET (0.06 [95% CI, 0.03-0.12]). LT PET was associated with a significantly lower CMV disease incidence (0.06 [95% CI, 0.03-0.12]) versus UP (0.21 [95% CI, 0.17-0.27]). Incidence of graft loss, acute allograft rejection, or mortality was not significantly different between LT PET and UP (P > 0.05 for all comparisons). Receipt of lymphocyte-depleting antibodies was not associated with a significant difference in CMV disease incidence (odds ratio = 1.34 [95% CI, 0.80-2.25]). Conclusions: LT PET is associated with a significantly lower incidence of CMV disease compared to UP with similar rates of other clinical outcomes. These findings provide rationale and preliminary data for a randomized superiority trial of optimized LT-PET versus UP in donor seropositive recipient seronegative kidney transplant recipients.

Prospective Assessment of the Prevalence of Enter Hyperoxalosis in Kidney Transplant Candidates.

Enteric hyperoxalosis (EH) is an emerging cause of kidney transplantation (KT) dysfunction. We sought to determine the prevalence of EH and factors that affect plasma oxalate (POx) among at-risk KT candidates. Methods: We prospectively measured POx among KT candidates evaluated at our center from 2017 to 2020 with risk factors for EH namely bariatric surgery, inflammatory bowel disease, or cystic fibrosis. EH was defined by a POx ≥10 µmol/L. Period-prevalence of EH was calculated. We compared mean POx across 5 factors: underlying condition, chronic kidney disease (CKD) stage, dialysis modality, phosphate binder type, and body mass index. Results: Of 40 KT candidates screened, 23 had EH for a 4-y period prevalence of 58%. Mean POx was 21.6 ± 23.5 µmol/L ranging from 0 to 109.6 µmol/L. 40% of screened had POx >20 µmol/L. Sleeve gastrectomy was the most common underlying condition associated with EH. Mean POx did not differ by underlying condition (P = 0.27), CKD stage (P = 0.17), dialysis modality (P = 0.68), phosphate binder (P = 0.58), and body mass index (P = 0.56). Conclusions: Bariatric surgery and inflammatory bowel disease were associated with a high prevalence of EH among KT candidates. Contrary to prior studies, sleeve gastrectomy was also associated with hyperoxalosis in advanced CKD. POx concentrations observed in EH reached levels associated with tissue and potentially allograft deposition. Concentrations can be as high as that seen in primary hyperoxaluria. More studies are needed to assess if POx is indeed a modifiable factor affecting allograft function in patients with EH.

Master protocol to assess the long-term safety in kidney transplant recipients who previously received Medeor's cellular immunotherapy products: the MDR-105-SAE.

BACKGROUND: Immunosuppression in transplantation continues to be associated with a multitude of adverse effects. Induction of immune tolerance may be a viable strategy to reduce dependence on immunosuppression. Various trials are currently underway to assess the efficacy of this strategy. However, long-term safety data for these immune tolerance regimes has yet to be established. METHODS/DESIGN: At the completion of primary follow-up of various Medeor kidney transplant studies, subjects receiving cellular immunotherapy products will be followed annually as per protocolized schedule for up to an additional 84 months (7 years) to evaluate long-term safety. Long-term safety will be assessed by summarizing incidence of serious adverse events, adverse events leading to study withdrawal and hospitalization rates. DISCUSSION: This extension study will be an important step in evaluating safety issues pertaining to immune tolerance regimens, long-term effects of which are largely unknown. These data are essential for furthering an unrealized goal of kidney transplantation- graft longevity without the adverse effects from long-term immunosuppression. The study design utilizes the methodology of a master protocol, wherein multiple therapies can be assessed simultaneously with accompanied gathering of long-term safety data.