Rituximab or cyclosporine a for the treatment of membranous nephropathy: Economic evaluation of the MENTOR trial.

BACKGROUND AND HYPOTHESIS: The MENTOR trial (MEmbranous Nephropathy Trial Of Rituximab) showed that rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria and was superior in maintaining proteinuria remission. However, the cost of rituximab may prohibit first-line use for some patients and health care payers. METHODS: A Markov model was used to determine the incremental cost-effectiveness ratio (ICER) of rituximab compared with cyclosporine for the treatment membranous nephropathy from the perspective of a health care payer with a life-time time horizon. The model was informed by data from the MENTOR trial where possible; additional parameters including cost and utility inputs were obtained from the literature. Sensitivity analyses were performed to evaluate the impact of reduced cost biosimilar rituximab. RESULTS: Rituximab for the treatment of membranous nephropathy was cost-effective (assuming a willingness-to-pay threshold of ${\$}$50 000 per quality adjusted life year (QALY) gained; ${\$}$US 2021) compared with cyclosporine, with an ICER of ${\$}$8 373/QALY over a lifetime time horizon. The incremental cost of rituximab therapy was ${\$}$28 007 with an additional 3.34 QALYs compared with cyclosporine. Lower cost of rituximab biosimilars resulted in a more favourable ICER, and in some cases resulted in rituximab being dominant (lower cost and great benefit) compared to cyclosporine. CONCLUSIONS: Despite the greater cost of rituximab, it may be a cost-effective option for the treatment of membranous nephropathy when compared with cyclosporine. The cost-effectiveness of rituximab is further improved with the use of less expensive biosimilars.

The living kidney donor profile index fails to discriminate allograft survival: implications for its use in kidney paired donation programs.

The inclusion of blood group- and human leukocyte antigen-compatible donor and recipient pairs (CPs) in kidney paired donation (KPD) programs is a novel strategy to increase living donor (LD) transplantation. Transplantation from a donor with a better Living Donor Kidney Profile Index (LKDPI) may encourage CP participation in KPD programs. We undertook parallel analyses using data from the Scientific Registry of Transplant Recipients and the Australia and New Zealand Dialysis and Transplant Registry to determine whether the LKDPI discriminates death-censored graft survival (DCGS) between LDs. Discrimination was assessed by the following: (1) the change in the Harrell C statistic with the sequential addition of variables in the LKDPI equation to reference models that included only recipient factors and (2) whether the LKDPI discriminated DCGS among pairs of prognosis-matched LD recipients. The addition of the LKDPI to reference models based on recipient variables increased the C statistic by only 0.02. Among prognosis-matched pairs, the C statistic in Cox models to determine the association of the LKDPI with DCGS was no better than chance alone (0.51 in the Scientific Registry of Transplant Recipient and 0.54 in the Australia and New Zealand Dialysis and Transplant Registry cohorts). We conclude that the LKDPI does not discriminate DCGS and should not be used to promote CP participation in KPD programs.

ABO-adjusted calculated panel reactive antibody (cPRA): A unified metric for immunologic compatibility in kidney transplantation.

Implementation of the kidney allocation system in 2014 greatly reduced access disparity due to human leukocyte antigen (HLA) sensitization. To address persistent disparity related to candidate ABO blood groups, herein we propose a novel metric termed "ABO-adjusted cPRA," which simultaneously considers the impact of candidate HLA and ABO sensitization on the same scale. An ethnic-weighted ABO-adjusted cPRA value was computed for 190 467 candidates on the kidney waitlist by combining candidate's conventional HLA cPRA with the remaining fraction of HLA-compatible donors that are ABO-incompatible. Consideration of ABO sensitization resulted in higher ABO-adjusted cPRA relative to conventional cPRA by HLA alone, except for AB candidates since they are not ABO-sensitized. Within cPRA Point Group = 99%, 43% of the candidates moved up to ABO-adjusted cPRA Point Group = 100%, though this proportion varied substantially by candidate blood group. Nearly all O and most B candidates would have elevated ABO-adjusted cPRA values above this policy threshold for allocation priority, but relatively few A candidates displayed this shift. Overall, ABO-adjusted cPRA more accurately measures the proportion of immune-compatible donors compared with conventional HLA cPRA, especially for highly sensitized candidates. Implementation of this novel metric could enable the development of allocation policies permitting more ABO-compatible transplants without compromising equity.

Transplantation of Patients With Long Dialysis Vintage in the Current Deceased Donor Kidney Allocation System (KAS).

RATIONALE & OBJECTIVE: In 2014 the wait-time calculation for deceased donor kidney transplantation in the United States was changed from the date of first waitlisting to the date of first maintenance dialysis treatment with the aim of minimizing disparities in access to transplantation. This study examined the impact of this policy on access to transplantation, patient survival, and transplant outcomes among patients treated with maintenance dialysis for a prolonged duration before waitlisting. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Patients identified in the US Renal Data System between 2008 and 2018 aged 18-70 years and in the 95th percentile of dialysis treatment duration (≥6.5 years) before waitlisting. EXPOSURE: Waitlisting for transplantation before versus after implementation of the policy. OUTCOME: Time from date of waitlisting to deceased donor transplantation and death, and from date of transplantation to all cause graft loss. ANALYTICAL APPROACH: Univariate and multivariable time to event analyses. RESULTS: Patients waitlisted after the policy change had a higher likelihood of deceased donor transplantation (HR, 3.12 [95% CI, 2.90-3.37]) and lower risk of death (HR, 0.74 [95% CI, 0.63-0.87]). The risk of graft loss was lower in the post-kidney allocation system (KAS) cohort (HR, 0.66 [95% CI, 0.55-0.80]). The proportion of adult patients treated with dialysis ≥6.5 years who were never waitlisted for transplantation remained high (73%) and did not decrease after the policy implementation. LIMITATIONS: Cannot determine causality in this observational study. CONCLUSIONS: The policy change was associated with an increase in deceased donor transplantation and marked improvement in patient survival for patients waitlisted after long periods of dialysis treatment without decreasing the utility of available deceased donor kidney supply. The policy was not associated with increased waitlisting of this disadvantaged population.

Economic Evaluation of Extending Medicare Immunosuppressive Drug Coverage for Kidney Transplant Recipients in the Current Era.

BACKGROUND: Kidney transplant recipients must take immunosuppressant drugs to prevent rejection and maintain transplant function. Medicare coverage of immunosuppressant drugs for kidney transplant recipients ceases 36 months after transplantation, potentially increasing the risk of transplant failure. A contemporary economic analysis of extending Medicare coverage for the duration of transplant survival using current costs of immunosuppressant medications in the era of generic equivalents may inform immunosuppressant drug policy. METHODS: A Markov model was used to determine the incremental cost and effectiveness of extending Medicare coverage for immunosuppressive drugs over the duration of transplant survival, compared with the current policy of 36-month coverage, from the perspective of the Medicare payer. The expected improvement in transplant survival by extending immunosuppressive drug coverage was estimated from a cohort of privately insured transplant recipients who receive lifelong immunosuppressant drug coverage compared with a cohort of Medicare-insured transplant recipients, using multivariable survival analysis. RESULTS: Extension of immunosuppression Medicare coverage for kidney transplant recipients led to lower costs of -$3077 and 0.37 additional quality-adjusted life years (QALYs) per patient. When the improvement in transplant survival associated with extending immunosuppressant coverage was reduced to 50% of that observed in privately insured patients, the strategy of extending drug coverage had an incremental cost-utility ratio of $51,694 per QALY gained. In a threshold analysis, the extension of immunosuppression coverage was cost-effective at a willingness-to-pay threshold of $100,000, $50,000, and $0 per QALY if it results in a decrease in risk of transplant failure of 5.5%, 7.8%, and 13.3%, respectively. CONCLUSIONS: Extending immunosuppressive drug coverage under Medicare from the current 36 months to the duration of transplant survival will result in better patient outcomes and cost-savings, and remains cost-effective if only a fraction of anticipated benefit is realized.

The association of pretransplant dialysis exposure with transplant failure is dependent on the state-specific rate of dialysis mortality.

Longer pretransplant dialysis exposure is associated with a higher risk of transplant failure. Whether patients who receive dialysis in a region with a higher rate of dialysis mortality are a higher risk for transplant failure is unknown. Adjusted state-specific hemodialysis mortality rates were determined in 3-year intervals among prevalent dialysis patients in the United States between 1995 and 2012. The effect of state- and period-specific dialysis mortality on the association of pretransplant dialysis exposure with transplant survival through December 2017 was determined using multivariable models. Dialysis mortality within states ranged from 128 deaths/1000 patient-years to 330 deaths/1000 patient-years. Each additional year of dialysis was associated with a 4% higher risk of transplant failure in states within the lowest quartile of dialysis mortality, compared with an 8% higher risk in states within the highest quartile of dialysis mortality. Patients who received pretransplant dialysis treatment in a state with a high rate of dialysis mortality are at a higher risk for transplant failure compared with patients with the same duration of pretransplant dialysis treatment in a state with a lower mortality rate. The findings may have implications for dialysis care in transplant candidates and the design of future outcome metrics.

The Change in Living Kidney Donation in Women and Men in the United States (2005-2015): A Population-Based Analysis.

The factors underlying the decline in living kidney donation in the United States since 2005 must be understood to inform strategies to ensure access to this option for future patients. Population-based estimates provide a better assessment of donation activity than do trends in the number of living donor transplants. Using data from the Scientific Registry of Transplant Recipients and the United States Census, we determined longitudinal changes in living kidney donation between 2005 and 2015, focusing on the effect of sex and income. We used multilevel Poisson models to adjust for differences in age, race, the incidence of ESRD, and geographic factors (including population density, urbanization, and daily commuting). During the study period, the unadjusted rate of donation was 30.1 and 19.3 per million population in women and men, respectively, and the adjusted incidence of donation was 44% higher in women (incidence rate ratio [IRR], 1.44; 95% confidence interval [95% CI], 1.39 to 1.49). The incidence of donation was stable in women (IRR, 0.95; 95% CI, 0.84 to 1.07) but declined in men (IRR, 0.75; 95% CI, 0.68 to 0.83). Income was associated with longitudinal changes in donation in both sexes, yet donation was stable in the highest two population income quartiles in women but only in the highest income quartile in men. In both sexes, living related donations declined, irrespective of income. In conclusion, living donation declined in men but remained stable in women between 2005 and 2015, and income appeared to have a greater effect on living donation in men.

Cost-effectiveness of using kidneys from hepatitis C nucleic acid test-positive donors for transplantation in hepatitis C-negative recipients.

Kidneys from deceased donors who are hepatitis C virus (HCV) nucleic acid test positive are infrequently used for transplantation in HCV-negative patients due to concerns about disease transmission. With the development of direct-acting antivirals (DAAs) for HCV, there is now potential to use these kidneys in HCV-negative candidates. However, the high cost of DAAs poses a challenge to adoption of this strategy. We created a Markov model to examine the cost-effectiveness of using deceased donors infected with HCV for kidney transplantation in uninfected waitlist candidates. In the primary analysis, this strategy was cost saving and improved health outcomes compared to remaining on the waitlist for an additional 2 or more years to receive a HCV-negative transplant. The strategy was also cost-effective with an incremental cost-effectiveness ratio of $56 018 per quality-adjusted life year (QALY) from the payer perspective, and $4647 per QALY from the societal perspective, compared to remaining on the waitlist for 1 additional year. The results were consistent in 1-way and probabilistic sensitivity analyses. We conclude that the use of kidneys from deceased donors with HCV infection is likely to lead to improved clinical outcomes at reduced cost for HCV-negative transplant candidates.

Cold ischemia time up to 16 hours has little impact on living donor kidney transplant outcomes in the era of kidney paired donation.

In living donor transplantation, cold ischemia time is a concern in transplants involving kidney paired donation. The impact of cold ischemia time over eight hours is unknown. Here we examined the association of cold ischemia time with delayed graft function and allograft loss among 48,498 living recipients in the Scientific Registry of Transplant Recipients registry. The incidence of delayed graft function was low but significantly higher among patients with longer cold ischemia times (0-2.0 hours: 3.3%; 2.1-4.0 hours: 3.9%; 4.1-8.0 hours: 4.3%; 8.1-16.0 hours: 5.5%). In multivariate analyses, only those with cold ischemia times of 8.1-16.0 hours had increased odds of delayed graft function (odds ratio 1.47; 95% confidence interval 1.05-2.05) compared to patients with times of 0-2.0 hours. In multivariate time-to-event analyses, cold ischemia times of 16 hours or less were not associated with allograft loss from any cause including death or death-censored graft loss with hazard ratios for cold ischemia times between 8.0-16.0 hours of 0.97 (95% confidence interval 0.74-1.26) and 1.09 (0.81-1.48) compared to patients with times of 0-2.0 hours). The results were consistent in paired and non-kidney paired donation transplants and in those with living donors over 50 years of age. In subgroup analysis restricted to kidney paired donation recipients, there was no difference in the risk of delayed graft function with an odds ratio of 1.40 (0.88, 2.40) or all-cause graft loss with a hazard ratio of 0.89 (0.62, 1.30) in transplant recipients who received kidneys that were shipped versus not shipped. Thus, a cold ischemia time up to 16 hours has limited impact on living donor outcomes. These findings may help expand living donor transplantation through kidney paired donation.

Predicting Progression in CKD: Perspectives and Precautions.

Predicting outcomes to guide clinical care, decision making, and resource allocation is a challenging undertaking in chronic kidney disease (CKD). Many prediction models have been developed, but few have been appropriately externally validated and even fewer have been assessed to be usable in the clinical setting. This contributes to the currently infrequent use of existing prediction models. Patients with CKD are a particularly heterogeneous group with significant biological variability, making the development of useful prediction models even more challenging. This article explores the different challenges in the development, validation, and application of prediction models in CKD. We explore the notion that newer biomarkers offer potential for enhancing existing and future prediction models and that modern technology is an opportunity to make prediction models more accessible and less cumbersome to use in clinical practice. Despite the challenges associated with their development and implementation, clinical prediction models have the potential to be a powerful tool for clinicians, researchers, and policy makers alike.

Clinical relevance of HLA-DQ eplet mismatch and maintenance immunosuppression with risk of allosensitization after kidney transplant failure.

The optimal immunosuppression management in patients with a failed kidney transplant remains uncertain. This study analyzed the association of class II HLA eplet mismatches and maintenance immunosuppression with allosensitization after graft failure in a well characterized cohort of 21 patients who failed a first kidney transplant. A clinically meaningful increase in cPRA in this study was defined as the cPRA that resulted in 50% reduction in the compatible donor pool measured from the time of transplant failure until the time of repeat transplantation, death, or end of study. The median cPRA at the time of failure was 12.13% (interquartile ranges = 0.00%, 83.72%) which increased to 62.76% (IQR = 4.34%, 99.18%) during the median follow-up of 27 (IQR = 18, 39) months. High HLA-DQ eplet mismatches were significantly associated with an increased risk of developing a clinically meaningful increase in cPRA (p = 0.02) and de novo DQ donor-specific antibody against the failed allograft (p = 0.02). We did not observe these associations in patients with high HLA-DR eplet mismatches. Most of the patients (88%) with a clinically meaningful increase in cPRA had both a high DQ eplet mismatch and a reduction in their immunosuppression, suggesting the association is modified by immunosuppression. The findings suggest HLA-DQ eplet mismatch analysis may serve as a useful tool to guide future clinical studies and trials which assess the management of immunosuppression in transplant failure patients who are repeat transplant candidates.

High-Functioning Deceased Donor Kidney Transplant System Characteristics: The British Columbia Experience With an Opt-In System.

Rationale & Objective: A high level of cooperation between organ procurement organizations and transplant programs may help maximize use of deceased donor kidneys. The practices that are essential for a high functioning organ donation and transplant system remain uncertain. We sought to report metrics of organ donation and transplant performance in British Columbia, Canada, and to assess the association of specific policies and practices that contribute to the system's performance. Study Design: A retrospective observational study. Setting & Participants: Referred deceased organ donors in British Columbia were used in the study from January 1, 2016, to December 31 2019. Exposures: Provincial, organ procurement organization, and center level policies were implemented to improve donor referral and organ utilization. Outcomes: Assessment of donor and kidney utilization along steps of the critical pathway for organ donation. Analytical Approach: Deceased donors were classified according to the critical pathway for organ donation and key donation and transplant metrics were identified. Results: There were 1,948 possible donors referred. Of 1,948, 754 (39%) were potential donors. Of 754 potential donors, 587 (78%) were consented donors. Of 587 consented donors, 480 (82%) were eligible kidney donors. Of 480 eligible kidney donors, 438 (91%) were actual kidney donors. And of 438 actual kidney donors, 432 (99%) were utilized kidney donors. One-year all-cause allograft survival was 95%. Practices implemented to improve the system's performance included hospital donor coordinators, early communication between the organ procurement organization and transplant nephrologists, dedicated organ recovery and implant surgeons, aged-based kidney allocation, and hospital admission of recipients before kidney recovery. Limitations: Assignment of causality between individual policies and practices and organ donation and utilization is limited in this observational study. Conclusions: In British Columbia, consent for donation, utilization of donated kidneys, and transplant survival are exceptionally high, suggesting the importance of an integrated deceased donor and kidney transplant service.

Optimization of all possible opportunities for deceased donor kidney donation and transplantation is essential to meet the need for transplantation. We examined the performance of organ procurement and transplant in a deceased organ donor system in British Columbia, Canada, and reviewed policies and practices that may contribute to the system's performance. We found a high level of donation, transplantation, and survival of donated kidneys and identified policies and practices that likely contribute to the system's performance.

The Benefits of Preemptive Transplantation Using High-Kidney Donor Profile Index Kidneys.

BACKGROUND: The Kidney Donor Profile Index (KDPI) is a percentile score summarizing the likelihood of allograft failure: A KDPI ≥85% is associated with shorter allograft survival, and 50% of these donated kidneys are not currently used for transplantation. Preemptive transplantation (transplantation without prior maintenance dialysis) is associated with longer allograft survival than transplantation after dialysis; however, it is unknown whether this benefit extends to high-KDPI transplants. The objective of this analysis was to determine whether the benefit of preemptive transplantation extends to recipients of transplants with a KDPI ≥85%. METHODS: This retrospective cohort study compared the post-transplant outcomes of preemptive and nonpreemptive deceased donor kidney transplants using data from the Scientific Registry of Transplant Recipients. 120,091 patients who received their first, kidney-only transplant between January 1, 2005, and December 31, 2017, were studied, including 23,211 with KDPI ≥85%. Of this cohort, 12,331 patients received a transplant preemptively. Time-to-event models for the outcomes of allograft loss from any cause, death-censored graft loss, and death with a functioning transplant were performed. RESULTS: Compared with recipients of nonpreemptive transplants with a KDPI of 0%-20% as the reference group, the risk of allograft loss from any cause in recipients of a preemptive transplant with KDPI ≥85% (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.39 to 1.64) was lower than that in recipients of nonpreemptive transplant with a KDPI ≥85% (HR, 2.39; 95% CI, 2.21 to 2.58) and similar to that of recipients of a nonpreemptive transplant with a KDPI of 51%-84% (HR, 1.61; 95% CI, 1.52 to 1.70). CONCLUSIONS: Preemptive transplantation is associated with a lower risk of allograft failure, irrespective of KDPI, and preemptive transplants with KDPI ≥85% have comparable outcomes with nonpreemptive transplants with KDPI 51%-84%.

Kidney Ultrasound for Nephrologists: A Review.

Ultrasound imaging is a key investigatory step in the evaluation of chronic kidney disease and kidney transplantation. It uses nonionizing radiation, is noninvasive, and generates real-time images, making it the ideal initial radiographic test for patients with abnormal kidney function. Ultrasound enables the assessment of both structural (form and size) and functional (perfusion and patency) aspects of kidneys, both of which are especially important as the disease progresses. Ultrasound and its derivatives have been studied for their diagnostic and prognostic significance in chronic kidney disease and kidney transplantation. Ultrasound is rapidly growing more widely accessible and is now available even in handheld formats that allow for bedside ultrasound examinations. Given the trend toward ubiquity, the current use of kidney ultrasound demands a full understanding of its breadth as it and its variants become available. We described the current applications and future directions of ultrasound imaging and its variants in the context of chronic kidney disease and transplantation in this review.

Use and Outcomes of Induction Therapy in Well-Matched Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: The optimal induction treatment in low-immune risk kidney transplant recipients is uncertain. We therefore investigated the use and outcomes of induction immunosuppression in a low-risk cohort of patients who were well matched with their donor at HLA-A, -B, -DR, -DQB1 on the basis of serologic typing. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our study was an observational study of first adult kidney-only transplant recipients in the United States recorded by the Organ Procurement and Transplant Network. RESULTS: Among 2976 recipients, 57% were treated with T cell-depleting antibodies, 28% were treated with an IL-2 receptor antagonist, and 15% were treated without induction. There was no difference in allograft survival, death-censored graft survival, or death with function between patients treated with an IL-2 receptor antagonist and no induction therapy. In multivariable models, patients treated with T cell-depleting therapy had a similar risk of graft loss from any cause, including death (hazard ratio, 1.19; 95% confidence interval, 0.98 to 1.45), compared with patients treated with an IL-2 receptor antagonist or no induction. The findings were consistent in subgroup analyses of Black recipients, patients grouped by calculated panel reactive antibody, and donor source. The incidence of acute rejection at 1 year was low (≤5%) and did not vary between treatment groups. CONCLUSIONS: Use of induction therapy with T cell-depleting therapy or IL-2 receptor antagonists in first kidney transplant recipients who are well matched with their donor at the HLA-A, -B, -DR, -DQB1 gene loci is not associated with improved post-transplant outcomes.

Pretransplant Calculated Panel Reactive Antibody in the Absence of Donor-Specific Antibody and Kidney Allograft Survival.

BACKGROUND AND OBJECTIVES: Panel reactive antibody informs the likelihood of finding an HLA-compatible donor for transplant candidates, but has historically been associated with acute rejection and allograft survival because testing methods could not exclude the presence of concomitant donor-specific antibodies. Despite new methods to exclude donor-specific antibodies, panel reactive antibody continues to be used to determine the choice of induction and maintenance immunosuppression. The study objective was to determine the clinical relevance of panel reactive antibody in the absence of donor-specific antibodies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Retrospective observational study of kidney allograft survival among 4058 zero HLA-A-, B-, DR-, and DQB1-mismatched transplant recipients without antibodies to donor kidney antigens encoded by these HLA gene loci. RESULTS: Among 4058 first and repeat transplant recipients, patients with calculated panel reactive antibody (cPRA) 1%-97% were not at higher risk of transplant failure, compared with patients with cPRA of 0% (death censored graft loss: hazard ratio, 1.07; 95% confidence interval, 0.82 to 1.41). Patients with cPRA ≥98% had a higher risk of graft loss from any cause including death (hazard ratio, 1.39; 95% confidence interval, 1.08 to 1.79) and death censored allograft failure (hazard ratio, 1.78; 95% confidence interval, 1.27 to 2.49). In stratified analyses, the higher risk of graft loss among patients with cPRA ≥98% was only observed among repeat, but not first, transplant recipients. In subgroup analysis, there was no association between cPRA and graft loss among living related transplant recipients. CONCLUSIONS: Calculated panel reactive antibody is poorly associated with post-transplant immune reactivity to the allograft in the absence of donor-specific antibody. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_01_25_CJN13640820_final.mp3.

Expanding the Deceased Donor Pool in Manitoba Using Hepatitis C-Viremic Donors: Program Report.

PURPOSE OF PROGRAM: The ongoing shortage of organs for transplant combined with Manitoba having the highest prevalence of end-stage renal disease (ESRD) in Canada has resulted in long wait times on the deceased donor waitlist. Therefore, the Transplant Manitoba Adult Kidney Program has ongoing quality improvement initiatives to expand the deceased donor pool. This clinical transplant protocol describes the use of prophylactic pan-genotypic direct-acting anti-viral agents (DAA) for transplanting hepatitis C (HCV)-viremic kidneys (HCV antibody positive/nucleic acid [nucleic acid amplification testing, NAT] positive) to HCV-naïve recipients as routine standard of care. We will evaluate the provincial implementation of this protocol as a prospective observational cohort study. SOURCES OF INFORMATION: Scoping literature review and key stakeholder engagement with interdisciplinary health care providers and health system leaders/decision markers. METHODS: Patients will be screened pre-transplant for eligibility and undergo a multilevel education and consent process to participate in this expanded donor program. Incident adult HCV-naïve recipients of an HCV-viremic kidney transplant will be treated prophylactically with glecaprevir-pibrentasvir with the first dose administered on call to the operation. Glecaprevir-pibrentasvir will be used for 8 weeks with viral monitoring and hepatology follow-up. Primary outcomes are sustained virologic response (SVR) at 12 weeks and the tolerability of DAA therapy. Secondary outcomes within the first year post-transplant are patient and graft survival, graft function, biopsy-proven rejection, HCV transmission to recipient (HCV NAT positive), and HCV nonstructural protein 5A (NS5A) resistance. Safety outcomes within the first year post-transplant include fibrosing cholestatic hepatitis, acute liver failure, primary and secondary DAA treatment failure, HCV transmission to a recipient's partner, elevated liver enzymes ≥2-fold, abnormal international normalized ratio (INR), angioedema, anaphylaxis, cirrhosis, and hepatocellular carcinoma. KEY FINDINGS: This program successfully advocated for and obtained hospital formulary, provincial Exceptional Drug Status (EDS), and Non-Insured Health Benefits (NIHB) to provide prophylactic DAA therapy for this indication, and this information may be useful to other provincial transplant organizations seeking to establish an HCV-viremic kidney transplant program with prophylactic DAA drug coverage. LIMITATIONS: (1) Patient engagement was not undertaken during the program design phase, but patient-reported experience measures will be obtained for continuous quality improvement. (2) Only standard criteria donors (optimal kidney donor profile index [KDPI] ≤60) will be used. If this approach is safe and feasible, then higher KDPI donors may be included. IMPLICATIONS: The goal of this quality improvement project is to improve access to kidney transplantation for Manitobans. This program will provide prophylactic DAA therapy for HCV-viremic kidney transplant to HCV-naïve recipients as routine standard of care outside a clinical trial protocol. We anticipate this program will be a safe and effective way to expand kidney transplantation from a previously unutilized donor pool.

OBJECTIF DU PROGRAMME: La pénurie actuelle d'organes à transplanter, combinée au fait que le Manitoba est la province qui présente la plus forte prévalence d'insuffisance rénale terminale au Canada, entraîne de longs délais sur la liste d'attente d'un organe provenant d'un donneur décédé. Le programme de transplantation rénale pour les adultes du Manitoba (Transplant Manitoba Adult Kidney Program) a mis en place des initiatives d'amélioration continue de la qualité afin d'élargir le bassin de donneurs décédés. Ce protocole clinique de transplantation décrit l'emploi, comme traitement habituel, d'agents antiviraux directs (AAD) pan-génotypiques prophylactiques pour la transplantation de reins provenant de donneurs infectés par le virus de l'hépatite C (VHC) (individus positifs pour les anticorps VHC et acides nucléiques [NAT]) à des receveurs naïfs pour VHC. La mise en œuvre provinciale de ce protocole sera évaluée en tant qu'étude de cohorte prospective et observationnelle. SOURCES: Examen de la documentation et évaluation de l'engagement des principaux intervenants avec les fournisseurs de soins de santé interdisciplinaires et les dirigeants/décideurs du système de santé. MÉTHODOLOGIE: L'admissibilité au programme sera évaluée avant la greffe. Pour participer à ce programme élargi de donneurs, les patients devront se soumettre à un processus d'information et de consentement à plusieurs niveaux. Les adultes incidents naïfs pour VHC devant recevoir un rein virémique-VHC seront traités de façon prophylactique par glécaprévir+pibrentasvir; la première dose administrée au moment de l'appel pour l'opération. Le traitement par glécaprévir+pibrentasvir sera administré pendant 8 semaines avec surveillance virale et suivi hépatologique. Les principaux résultats évalués seront une réponse virologique prolongée (RVP) à 12 semaines et la tolérance au traitement par AAD. Les résultats secondaires mesurés dans la première année suivant la greffe seront la survie du patient et du greffon; la fonction du greffon; le rejet avéré par biopsie; la transmission du VHC au receveur (positif pour VHC et NAT) et la résistance aux protéines non structurelles 5A (NS5A) du VHC. Les résultats relatifs à l'innocuité dans la première année suivant la greffe comprennent la cholestase hépatique fibrosante; l'insuffisance hépatique aiguë; l'échec primaire et secondaire du traitement par AAD; la transmission du VHC au partenaire d'un receveur; une élévation supérieure à 2 fois du taux d'enzymes hépatiques; un INR anormal; un angio-œdème; l'anaphylaxie; une cirrhose ou un carcinome hépatocellulaire. PRINCIPAUX RÉSULTATS: Le programme a recommandé et obtenu l'inscription du traitement prophylactique par AAD sur la liste de médicaments des hôpitaux pour cette indication, en plus du statut de médicament d'exception provincial et de son ajout au Programme des services de santé non assurés (SSNA). Ces renseignements pourraient être utiles à d'autres organismes provinciaux de transplantation qui cherchent à mettre en œuvre un programme de transplantation rénale virémique-VHC avec un traitement prophylactique par AAD. LIMITES: (1) La participation des patients n'a pas été entreprise pendant la phase de conception du programme, mais des mesures de l'expérience des patients seront obtenues pour l'amélioration continue de la qualité. (2) Seuls les donneurs satisfaisant aux critères standards (Kidney Donor Profile Index [KDPI] ≤ 60) seront inclus. Si cette approche est sécuritaire et faisable, des donneurs de KDPI plus élevés pourront être inclus. CONCLUSION: L'objectif de ce projet d'amélioration de la qualité est d'améliorer l'accès aux transplantations rénales pour les Manitobains. Ce programme offrira un traitement prophylactique aux AAD pour les greffes de reins virémiques-VHC à des receveurs naïfs pour VHC comme traitement de référence habituel en dehors d'un protocole d'essai clinique. Nous pensons que ce programme sera un moyen sûr et efficace d'étendre la transplantation rénale à partir d'un bassin de donneurs auparavant non utilisés.

Comprehensive Immune Profiling of a Kidney Transplant Recipient With Peri-Operative SARS-CoV-2 Infection: A Case Report.

To date there is limited data on the immune profile and outcomes of solid organ transplant recipients who encounter COVID-19 infection early post-transplant. Here we present a unique case where the kidney recipient's transplant surgery coincided with a positive SARS-CoV-2 test and the patient subsequently developed symptomatic COVID-19 perioperatively. We performed comprehensive immunological monitoring of cellular, proteomic, and serological changes during the first 4 critical months post-infection. We showed that continuation of basiliximab induction and maintenance of triple immunosuppression did not significantly impair the host's ability to mount a robust immune response against symptomatic COVID-19 infection diagnosed within the first week post-transplant.