One size does not fit all: Differential benefits of simultaneous liver-kidney transplantation by eligibility criteria.

Standard eligibility criteria for simultaneous liver-kidney transplantation (SLK) are in place in the United States. We hypothesize that the benefit associated with SLK over liver transplant alone differs by patient, depending on the specific SLK criteria met. We analyzed a retrospective US cohort of 5446 adult liver transplant or SLK recipients between January 1, 2015, and December 31, 2018, who are potentially qualified for SLK. Exposure was a receipt of SLK. We tested effect modification by the specific SLK eligibility criteria met (end-stage kidney disease, acute kidney injury, chronic kidney disease, or unknown). The primary outcome was death within 1 year of a liver transplant. We used a modified Cox regression analysis containing an interaction term of SLK * time from transplant. Two hundred ten (9%) SLK recipients and 351 (11%) liver-alone recipients died in 1 year. In the overall population, SLK was associated with a mortality benefit over liver transplant on the day of the transplant, without adjustment [HR: 0.59 (95% CI, 0.46-0.76)] and with adjustment [aHR: 0.50 (95% CI, 0.35-0.71)]. However, when SLK eligibility criteria were included, only in patients with end-stage kidney disease was SLK associated with a sustained survival benefit at day 0 [HR: 0.17 (0.08-0.35)] up to 288 (95% CI, 120-649) days post-transplant. Benefit within the first year post-transplant associated with SLK over liver-alone transplantation was only pronounced in patients with end-stage kidney disease but not present in patients meeting other criteria for SLK. A "strict SLK liberal Safety Net" strategy may warrant consideration at the national policy level.

Daratumumab Use Prior to Kidney Transplant and T Cell-Mediated Rejection: A Case Report.

There is growing interest in daratumumab in the solid organ transplant realm owing to the potential immunomodulatory effects on CD38-expressing cells, primarily plasma cells, as they have a key role in antibody production. In particular there is interest in use of daratumumab for desensitization and potential treatment for antibody-mediated rejection. However, ongoing investigation with daratumumab has shown potential immunologic concerns in vitro, with a significant increase in populations of CD4-positive cytotoxic T cells and CD8-positive helper T cells in both peripheral blood and bone marrow that could lead to acute T cell-mediated rejection in the solid organ transplant patient. To date, there are no published reports of an association with daratumumab use and T cell-mediated rejection in vivo. In this case report we present what is to our knowledge the first documented case of an early severe T cell-mediated rejection in a low-immunologic-risk living-donor kidney transplant recipient who received daratumumab for multiple myeloma maintenance prior to transplant.

Attitudes of patients with renal disease on xenotransplantation: A systematic review.

BACKGROUND: Recent years have seen major advancements in xenotransplantation: the first pig-to-human heart transplant, the development of a brain-dead recipient model for kidney xenotransplantation, and the registration of the first xenokidney clinical trial. The attitudes of patients with kidney disease or transplants on xenotransplantation and an assessment of their reservations and considerations regarding the technology are crucial to successful clinical translation and eventual widespread implementation. METHODS: This systematic review was registered through PROSPERO (CRD42022344581) prior to initiation of the study and reported using the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. We included studies that evaluated attitudes towards and willingness to undergo xenotransplantation in patients with end-stage renal disease (ESRD), including those who had already undergone transplantation. MEDLINE (via Ovid), Embase (via Elsevier), and Web of Science (via Clarivate) were searched from database inception to July 15, 2022 by an experienced medical librarian for studies on xenotransplantation and attitudes. Abstracts and full text were screened using Covidence software and data items regarding study methodology, patient demographics, and attitudes regarding xenotransplantation were extracted using Microsoft Excel. Risk of bias assessments were performed using the Critical Appraisal Skills Programmed and National Institute of Health study quality assessment tools. RESULTS: Of 1992 studies identified, 14 studies met the inclusion criteria. These studies were conducted across eight countries, four in the United States, for a total of 3114 patients on the kidney waitlist or with a kidney transplant. All patients were over 17 years old and 58% were male. Acceptance of a xenotransplant was assessed using surveys in 12 studies. Sixty-three percent (n = 1354) of kidney patients reported that they would accept a xenotransplant with function comparable to that of an allotransplant. Acceptance of xenografts with inferior function to allografts (15%) or as bridge organs (35%) to allotransplantation was lower. Specific concerns expressed by patients included graft function, infection, social stigma, and animal rights. Subgroup analyses showed higher acceptance in already transplanted compared to waitlist patients and white compared to Black Americans. CONCLUSION: An understanding of patient attitudes and reservations is key to the successful execution of the first xenotransplantation clinical trials. This study compiles important factors to consider, such as patient concerns, attitudes regarding practical clinical scenarios for the use of xenotransplantation, and the impact of demographic factors on acceptance of this emerging technology.

Center variations in patient selection for simultaneous heart-kidney transplantation.

There are no established regulations governing patient selection for simultaneous heart-kidney (SHK) transplantation, creating the potential for significant center-level variations in clinical practice. METHODS: Using the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research (STAR) file, we examined practice trends and variations in patient selection for SHK at the center level between January 1, 2004 and March 31, 2019. RESULTS: Overall, SHK is becoming more common with most centers performing heart transplants also performing SHK. Among patients who underwent heart transplant who were receiving dialysis, the rate of SHK varied from 22% to 86% at the center level. Among patients not on dialysis, the median estimated glomerular filtration rate (eGFR) of patients receiving SHK varied between 19 and 59 mL/min/1.73 m2 . When adjusting for other factors, the odds of SHK varied 57-fold between the highest and lowest SHK performing centers. CONCLUSION: Variation in SHK at the center level suggests the need for national guidelines around the selection of patients for SHK.

Need for improvements in simultaneous heart-kidney allocation: The limitation of pretransplant glomerular filtration rate.

The incidence of simultaneous heart-kidney transplant (SHK) has increased markedly in the last 15 years. There are no universally agreed upon indications for SHK vs. heart alone (HA) transplant, and center evaluation processes vary widely. We utilized Scientific Registry of Transplant Recipients data from 2003 to 2017 to quantify changes in the practice of SHK, examine the survival of SHK vs. HA, and identify patients with marginal benefit from SHK. We used Kaplan-Meier curves and Cox proportional hazards to assess differences in survival. The incidence of SHK increased more than fourfold between 2003 and 2017 from 1.6% to 6.6% of total hearts transplanted, while the proportion of dialysis-dependent patients undergoing SHK has remained constant. SHK was associated with increased survival in dialysis-dependent patients (Median Survival SHK: 12.6 vs. HA: 7.1 years p < .0001) but not with nondialysis-dependent patients (Median Survival SHK: 12.5 vs. HA 12.3, p = .24). The marginal effect of SHK in decreasing the hazard of death diminished with increasing eGFR. Delayed graft function occurred in 26% of SHK recipients. Posttransplant chronic dialysis was similar for both operations (6.4% of HA and 6.0% of SHK). Further study is needed to define patients who benefit from SHK.

The Impact of the 2017 Kidney Allocation Policy Change on Simultaneous Liver-Kidney Utilization and Outcomes.

Historically in the United States, kidneys for simultaneous liver-kidney transplantation (SLKT) candidates were allocated with livers, prioritizing SLKT recipients over much of the kidney waiting list. A 2017 change in policy delineated renal function criteria for SLKT and implemented a safety net for kidney-after-liver transplantation. We compared the use and outcomes of SLKT and kidney-after-liver transplant with the 2017 policy. United Network for Organ Sharing Standard Transplant Analysis and Research files were used to identify adults who received liver transplantations (LT) from August 10, 2007 to August 10, 2012; from August 11, 2012 to August 10, 2017; and from August 11, 2017 to June 12, 2019. LT recipients with end-stage renal disease (ESRD) were defined by dialysis requirement or estimated glomerular filtration rate <25. We evaluated outcomes and center-level, regional, and national practice before and after the policy change. Nonparametric cumulative incidence of kidney-after-liver listing and transplant were modeled by era. A total of 6332 patients received SLKTs during the study period; fewer patients with glomerular filtration rate (GFR) ≥50 mL/min underwent SLKT over time (5.8%, 4.8%, 3.0%; P = 0.01 ). There was also less variability in GFR at transplant after policy implementation on center and regional levels. We then evaluated LT-alone (LTA) recipients with ESRD (n = 5408 from 2012-2017; n = 2321 after the policy). Listing for a kidney within a year of LT increased from 2.9% before the policy change to 8.8% after the policy change, and the rate of kidney transplantation within 1 year increased from 0.7% to 4% (P < 0.001). After the policy change, there was no difference in patient survival rates between SLKT and LTA among patients with ESRD. Implementation of the 2017 SLKT policy change resulted in reduced variability in SLKT recipient kidney function and increased access to deceased donor kidney transplantation for LTA recipients with kidney disease without negatively affecting outcomes.

BK virus nephropathy in non-renal solid organ transplant recipients: Are we looking hard enough?

We retrospectively examined the clinical characteristics, pathological features, and outcomes of BK viremia and nephropathy in a population of non-renal solid organ transplant patients (NRSOT) referred for outpatient nephrology consultation over a period of 5 years. In the entire cohort of liver, heart, and lung transplant recipients referred to this clinic, 14% percent were found to have BK viremia with a median peak serum BK viral load of 35 500 copies/ml (range 250 to 21 100 000 copies/ml). BK viremia resolved in six of the seventeen patients (35%). Four out of five patients biopsied showed BK virus (BKV) nephropathy. Eleven out of seventeen patients with BK viremia developed advanced (stage 4 or 5) chronic kidney disease. Four patients developed rejection of their solid organ transplant within the first year post detection of BK viremia after immunosuppression reduction. We conclude that a multi-center study is required to evaluate whether implementation of a systematic BK screening program would be effective in early detection and management of this problem in the NRSOT population.

Definition and Analysis of Textbook Outcome: A Novel Quality Measure in Kidney Transplantation.

BACKGROUND: "Textbook outcome" (TO) is a novel composite quality measure that encompasses multiple postoperative endpoints, representing the ideal "textbook" hospitalization for complex surgical procedures. We defined TO for kidney transplantation using a cohort from a high-volume institution. METHODS: Adult patients who underwent isolated kidney transplantation at our institution between 2016 and 2019 were included. TO was defined by clinician consensus at our institution to include freedom from intraoperative complication, postoperative reintervention, 30-day intensive care unit or hospital readmission, length of stay > 75th percentile of kidney transplant patients, 90-day mortality, 30-day acute rejection, delayed graft function, and discharge with a Foley catheter. Recipient, operative, financial characteristics, and post-transplant patient, graft, and rejection-free survival were compared between patients who achieved and failed to achieve TO. RESULTS: A total of 557 kidney transplant patients were included. Of those, 245 (44%) achieved TO. The most common reasons for TO failure were delayed graft function (N = 157, 50%) and hospital readmission within 30 days (N = 155, 50%); the least common was mortality within 90 days (N = 6, 2%). Patient, graft, and rejection-free survival were significantly improved among patients who achieved TO. On average, patients who achieved TO incurred approximately $50,000 less in total inpatient charges compared to those who failed TO. CONCLUSIONS: TO in kidney transplantation was associated with favorable post-transplant outcomes and significant cost-savings. TO may offer transplant centers a detailed performance breakdown to identify aspects of perioperative care in need of process improvement.

Lymphocyte depletion and risk of acute rejection in renal transplant recipients at increased risk for delayed graft function.

Delayed graft function (DGF) is a risk factor for acute rejection (AR) in renal transplant recipients, and KDIGO guidelines suggest use of lymphocyte-depletion induction when DGF is anticipated. We analyzed the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) database to assess the impact of induction immunosuppression on the risk of AR in deceased kidney recipients based on pretransplant risk of DGF using a validated model. Recipients were categorized into 4 groups based upon the induction immunosuppression: (1) Rabbit anti-thymocyte globulin (rATG); (2) Alemtuzumab (C1H); (3) IL2-receptor antagonists (IL2-RA; basiliximab or daclizumab), and (4) No antibody induction. The primary endpoint for analysis was a composite endpoint of treated AR or graft failure by 1-year posttransplantation. Compared to no antibody induction, rATG and C1H had consistently lower adjusted odds of the composite endpoint across all risk strata for DGF risk, whereas IL2-Ra was associated with increased adjusted odds of the composite endpoint with increasing DGF risk. When the induction agents were compared, rATG and C1H were associated with decreasing adjusted odds for the composite endpoint with increasing risk of DGF, especially at the higher risk spectrum of DGF. Consideration must be given to use of lymphocyte-depletion induction when the anticipated risk of DGF is increased.

Improving Health Equity in Living Donor Kidney Transplant: Application of an Implementation Science Framework.

BACKGROUND: Interventions to improve racial equity in access to living donor kidney transplants (LDKT) have focused primarily on patients, ignoring the contributions of clinicians, transplant centers, and health system factors. Obtaining access to LDKT is a complex, multi-step process involving patients, their families, clinicians, and health system functions. An implementation science framework can help elucidate multi-level barriers to achieving racial equity in LDKT and guide the implementation of interventions targeted at all levels. METHODS: We adopted the Pragmatic Robust Implementation and Sustainability Model (PRISM), an implementation science framework for racial equity in LDKT. The purpose was to provide a guide for assessment, inform intervention design, and support planning for the implementation of interventions. RESULTS: We applied 4 main PRISM domains to racial equity in LDKT: Organizational Characteristics, Program Components, External Environment, and Patient Characteristics. We specified elements within each domain that consider perspectives of the health system, transplant center, clinical staff, and patients. CONCLUSION: The applied PRISM framework provides a foundation for the examination of multi-level influences across the entirety of LDKT care. Researchers, quality improvement staff, and clinicians can use the applied PRISM framework to guide the assessment of inequities, support collaborative intervention development, monitor intervention implementation, and inform resource allocation to improve equity in access to LDKT.

Therapeutic apheresis in kidney transplantation: a review of renal transplant immunobiology and current interventions with apheresis medicine.

Transplantation is the treatment of choice for end stage renal disease. Kidney transplants convey both a significant survival advantage to the individual recipient as well as cost savings to the medical system. Circulating alloantibodies directed against donor human leukocyte antigens and blood group antigens are fairly common among potential recipients. They are known to injure allografts, shorten allograft survival, and limit access to kidney transplantation. Hence, screening for pretransplant alloantibodies using complement dependent cytotoxic cross-matching and more sensitive techniques such as the solid phase assays, have become routine in an attempt to avoid incompatible donor-recipient pairs and risk stratify those with donor specific antibodies (DSA). By removing harmful antibodies, therapeutic apheresis (TA) has become a critical tool for improving access to transplantation in cases where the immunologic risk had previously been considered unacceptable. It has also allowed us to transplant across the barrier of ABO blood group incompatibility and expand the pool of donors with reasonable success. Furthermore, it is an important tool in the treatment of antibody-mediated rejection. Advanced apheresis technologies, such as immunoadsorption, and the use of TA in combination with innovative paired-donor exchange programs, offer the potential to further improve access and outcomes, minimizing the short comings of one single form of therapy alone.

Evaluation of Weight-Based Dose During Transition From Immediate-Release to Extended-Release Tacrolimus in Kidney Transplant Recipients.

BACKGROUND: Manufacturer recommendations for conversion from immediate-release to extended-release tacrolimus, Envarsus XR®, suggests 80% of the total daily dose of the immediate-release formulation. This conversion has not consistently achieved therapeutic levels in the kidney transplant population. OBJECTIVES: To determine if a reliable weight-based dosing strategy could be utilized to transition kidney transplant patients from immediate-release to extended-release tacrolimus. This may help establish a safe protocol to guide transition between formulations. METHODS: Retrospective, single-center study of adult kidney transplant recipients between July 2015 and December 2018. Excluded patients received dual organs, lacked appropriately drawn tacrolimus levels, or were prescribed interacting medications. Patients were identified by querying prescriptions for extended-release tacrolimus and chart review was performed to exclude any patients without sufficient follow-up after transition. RESULTS: 30 patients who transitioned from immediate-release tacrolimus to tacrolimus XR were included in the final analysis. The median weight-based dose of tacrolimus XR that achieved a therapeutic level among the cohort was 0.158 mg/kg/day (Q1-Q3: 0.0587-0.221), which was about 80% of the original median weight-based immediate-release tacrolimus dose. Therapeutic dosing strategies were widely variable, represented by an R2 of 0.33 on linear regression. There was a statistically significant difference in median weight-based dosing strategies among patients of various racial backgrounds (p = 0.0148). CONCLUSIONS: A weight-based dose of tacrolimus XR could not reliably predict a therapeutic level among the total cohort due to the wide inter-patient variability. The median weight-based rate of conversion from immediate-release to extended-release tacrolimus was 80%.

Translation of therapeutic strategies to modulate B cell reponses from non-human primate models to human kidney transplantation.

Using novel drugs targeting lymphocyte costimulation, cytokines, antibody, complement, and plasma cells, we have developed strategies in a non-human primate model to modulate the B cell response to incompatible kidney transplants. After more than two decades of research supported by mechanistic studies, this has resulted in clinically relevant approaches that are currently enrolling in clinical trials or preparing for such. In this manner, we aim to address the problems of HLA sensitization for very highly sensitized patients awaiting transplantation and the unmet need of effective treatment for antibody-mediated rejection.

Transcriptional responses define dysregulated immune activation in Hepatitis C (HCV)-naïve recipients of HCV-infected donor kidneys.

Renal transplantation from hepatitis C (HCV) nucleic acid amplification test-positive (NAAT-positive) donors to uninfected recipients has greatly increased the organ donation pool. However, there is concern for adverse outcomes in these recipients due to dysregulated immunologic activation secondary to active inflammation from acute viremia at the time of transplantation. This includes increased rates of cytomegalovirus (CMV) DNAemia and allograft rejection. In this study, we evaluate transcriptional responses in circulating leukocytes to define the character, timing, and resolution of this immune dysregulation and assess for biomarkers of adverse outcomes in transplant patients. We enrolled 67 renal transplant recipients (30 controls, 37 HCV recipients) and performed RNA sequencing on serial samples from one, 3-, and 6-months post-transplant. CMV DNAemia and allograft rejection outcomes were measured. Least absolute shrinkage and selection operator was utilized to develop gene expression classifiers predictive of clinical outcomes. Acute HCV incited a marked transcriptomic response in circulating leukocytes of renal transplant recipients in the acute post-transplant setting, despite the presence of immunosuppression, with 109 genes significantly differentially expressed compared to controls. These HCV infection-associated genes were reflective of antiviral immune pathways and generally resolved by the 3-month timepoint after sustained viral response (SVR) for HCV. Differential gene expression was also noted from patients who developed CMV DNAemia or allograft rejection compared to those who did not, although transcriptomic classifiers could not accurately predict these outcomes, likely due to sample size and variable time-to-event. Acute HCV infection incites evidence of immune activation and canonical antiviral responses in the human host even in the presence of systemic immunosuppression. After treatment of HCV with antiviral therapy and subsequent aviremia, this immune activation resolves. Changes in gene expression patterns in circulating leukocytes are associated with some clinical outcomes, although larger studies are needed to develop accurate predictive classifiers of these events.

Real-world Experiences in the Transplantation of Hepatitis C-NAAT-positive Organs.

Background: Hepatitis C virus (HCV) nucleic acid amplification test (NAAT)-positive donors have increased the organ pool. Direct-acting antivirals (DAAs) have led to high rates of treatment success and sustained virologic response (SVR) in recipients with donor-derived HCV infection without significant adverse effects, although variability remains in the timing and duration of antivirals. Methods: This retrospective study analyzed all adult HCV-NAAT-negative transplant recipients who received an organ from HCV-NAAT-positive donors from November 24, 2018, to March 31, 2022, at Duke University Medical Center with protocolized delay of DAA initiation until after hospital discharge, with at least 180-d follow-up on all patients. Transplant and HCV-related outcomes were analyzed. Results: Two hundred eleven transplants (111 kidneys, 41 livers, 34 hearts, and 25 lungs) were performed from HCV-NAAT-positive donors to HCV-NAAT-negative recipients. Ninety percent of recipients became viremic within 7 d posttransplant. Ninety-nine percent of recipients were initiated on pangenotypic DAAs in the outpatient setting a median of 52 d posttransplant, most commonly with 12-wk courses of sofosbuvir-velpatasvir (lungs) and glecaprevir-pibrentasvir (heart, kidney, and liver). Ninety-seven percent of recipients had SVR after a first-line DAA; all ultimately achieved SVR at 12 wk after subsequent treatment courses. The median peak HCV RNA for all organ systems was 2 436 512 IU/mL; the median time from antiviral to undetectable RNA was 48 d, although differences were noted between organ groups. No patient deaths or graft losses were directly attributable to HCV infection. Conclusions: One hundred percent of transplant recipients of HCV-NAAT-positive organs ultimately developed SVR without significant adverse effects when HCV antivirals were initiated in the outpatient setting after transplant hospitalization, suggesting that this real-world treatment pathway is a viable option.

The role of therapeutic apheresis in high immunologic risk renal transplantation: a review of current trends.

Immunologic sensitization, defined by the presence of antibodies directed against donor human leukocyte antigen (or so called donor-specific antibodies [DSA]), is common among those awaiting kidney transplantation, and is associated with worse outcomes following transplant. Existing DSA have historically been screened for pretransplant using complement-dependent cytotoxic crossmatching and their risk circumnavigated through policies that prohibit transplants between incompatible donor-recipient pairs. This risk avoidance strategy maximizes outcomes following transplant, but at the expense of limiting access to transplant for sensitized individuals. Over the last decade, the field of kidney transplantation has moved to actively modify the risks posed by DSA, rather than to simply avoid them. More sensitive detection methods have provided detailed immunologic risk stratification of potential donor-recipient pairs. Desensitization protocols, in which therapeutic aphaeresis plays a central role, have been used to reduce the potential harms posed by DSA. More recently, desensitization and paired donor exchange programs have been used in combination to expand transplantation to highly sensitized patients with incompatible living donors. It is likely that this combination of risk mitigation and avoidance strategies will be used together more often to both maximize individuals' access to transplant, and optimize patient and graft outcomes.

Therapeutic apheresis before and after kidney transplantation.

Kidney transplantation is considered the treatment of choice for most individuals with end-stage kidney disease, as well as the most cost-effective renal replacement therapy for the health care system that serves them. Immunologic sensitization, defined by the presence of antibodies directed against foreign HLA (or so called, donor specific antibodies, or DSA), is a significant barrier to kidney transplantation. Further, the presence of DSA is associated with an increase in the incidence of antibody-mediated rejection and decreased graft survival following transplantation. Therapeutic plasma exchange, an extracorporeal therapy directed at removing plasma proteins, including DSA, has proven to be an important part of a comprehensive strategy to minimize the effect of sensitization before, and following kidney transplantation. As such, it offers the promise of increasing access to transplantation, as well as improving outcomes following transplantation. In this concise narrative review, we describe more specifically the benefits of kidney transplantation, the epidemiology of kidney transplantation in the United States, the clinical significance of anti-HLA antibodies, and the evidence supporting a role for therapeutic plasma exchange before and after kidney transplantation.