Expanding deceased donor kidney transplantation

Ruck, Jessica M.; Segev, Dorry L.

doi:10.1097/mnh.0000000000000456

Cited by 12 publications

(5 citation statements)

References 61 publications

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“…Other potential utilities of AvFc may be found in pre-exposure prophylaxis against HIV/HCV co-infection in high-risk populations, as well as in the context of transplantation of organs from HCV-infected donors to HCV-negative recipients, which may help alleviate the severe shortage of donor organs available for transplantation. 45 , 46 Further studies are warranted to determine a dose-response relationship, therapeutic window, and feasibility of intravenous or subcutaneous dosing routes, as well as to assess the efficacy of AvFc against established infection.…”

Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of Avaren-Fc Lectibody Targeting HCV High-Mannose Glycans in a Human Liver Chimeric Mouse Model

Dent¹,

Hamorsky²,

Vausselin³

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Hepatitis C virus (HCV) infection remains a major cause of end-stage liver disease. Here, we show the efficacy and safety of a novel biotherapeutic targeting a HCV glycobiomarker in a mouse model, providing a foundation for a new anti-HCV strategy. BACKGROUND & AIMS: Infection with hepatitis C virus (HCV) remains a major cause of morbidity and mortality worldwide despite the recent advent of highly effective direct-acting antivirals. The envelope glycoproteins of HCV are heavily glycosylated with a high proportion of high-mannose glycans (HMGs), which serve as a shield against neutralizing antibodies and assist in the interaction with cell-entry receptors. However, there is no approved therapeutic targeting this potentially druggable biomarker. METHODS: The anti-HCV activity of Avaren-Fc (AvFc Q7) was evaluated through the use of in vitro neutralization assays as well as an in vivo challenge in the PXB Q8 chimeric human liver mouse model. Drug toxicity was assessed by histopathology, serum alanine aminotransferase, and mouse body weights. RESULTS: AvFc was capable of neutralizing cell culture-derived HCV in a genotype-independent manner, with 50% inhibitory concentration values in the low nanomolar range. Systemic administration of AvFc in a histidine-based buffer was well tolerated; after 11 doses every other day at 25 mg/kg there were no significant changes in body or liver weights or in blood human albumin or serum alanine aminotransferase activity. Gross necropsy and liver pathology confirmed the lack of toxicity. This regimen successfully prevented genotype 1a HCV infection in all animals, although an AvFc mutant lacking HMG binding activity failed. CONCLUSIONS: These results suggest that targeting envelope HMGs is a promising therapeutic approach against HCV infection, and AvFc may provide a safe and efficacious means to prevent recurrent infection upon liver transplantation in HCVrelated end-stage liver disease patients.

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Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of Avaren-Fc Lectibody Targeting HCV High-Mannose Glycans in a Human Liver Chimeric Mouse Model

Dent¹,

Hamorsky²,

Vausselin³

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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“…20,21 Taken together, efforts to safely expand the deceased kidney pool using HCV-positive donors have been undertaken by a number of programs to improve outcomes for patients with ESRD. 9,22…”

Section: Changing Perspective On Hcv-positive Organ Donorsmentioning

confidence: 99%

“…6 Manitoba has the highest prevalence and rate of ESRD in Canada, resulting in some of the longest wait times for transplant despite similar rates of transplantation. 7,8 Therefore, efforts are ongoing to expand the donor pool, 6,9 such as expanding the donation after circulatory death (DCD) 10 and accepting marginal 6,11,12 or higher infectious risk donors. 6,9,13…”

Section: Introductionmentioning

confidence: 99%

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

Cuvelier

Caeseele²,

Kadatz

et al. 2021

Can J Kidney Health Dis

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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.

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“…Age is a further limiting factor; age is often associated with comorbidity and the prevalence of patients who can be waitlisted obviously decreases with age. Besides comorbidity, although the age limit has progressively risen and has now reached 80 in many Western European countries, tighter limits are usually present in developing countries or in settings where the availability of organs for transplantation from cadaveric and living donors is limited [27,28,29,30,31,32,33]. As a result, the prevalence of potential candidates for kidney transplantation ranges from 30% to 70% of the overall RRT population; even in the most favourable cases, access to kidney transplantation is not always immediate and, even with a wise combination of resources (cadaveric and living kidney donors, preemptive kidney transplantation), waiting lists are long and most patients experience a period of dialysis [32,34,35,36,37].…”

Section: Introductionmentioning

confidence: 99%

Dialysis Reimbursement: What Impact Do Different Models Have on Clinical Choices?

Piccoli

Cabiddu

Breuer

et al. 2019

JCM

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Allowing patients to live for decades without the function of a vital organ is a medical miracle, but one that is not without cost both in terms of morbidity and quality of life and in economic terms. Renal replacement therapy (RRT) consumes between 2% and 5% of the overall health care expenditure in countries where dialysis is available without restrictions. While transplantation is the preferred treatment in patients without contraindications, old age and comorbidity limit its indications, and low organ availability may result in long waiting times. As a consequence, 30–70% of the patients depend on dialysis, which remains the main determinant of the cost of RRT. Costs of dialysis are differently defined, and its reimbursement follows different rules. There are three main ways of establishing dialysis reimbursement. The first involves dividing dialysis into a series of elements and reimbursing each one separately (dialysis itself, medications, drugs, transportation, hospitalisation, etc.). The second, known as the capitation system, consists of merging these elements in a per capita reimbursement, while the third, usually called the bundle system, entails identifying a core of procedures intrinsically linked to treatment (e.g., dialysis sessions, tests, intradialyitc drugs). Each one has advantages and drawbacks, and impacts differently on the organization and delivery of care: payment per session may favour fragmentation and make a global appraisal difficult; a correct capitation system needs a careful correction for comorbidity, and may exacerbate competition between public and private settings, the latter aiming at selecting the least complex cases; a bundle system, in which the main elements linked to the dialysis sessions are considered together, may be a good compromise but risks penalising complex patients, and requires a rapid adaptation to treatment changes. Retarding dialysis is a clinical and economical goal, but the incentives for predialysis care are not established and its development may be unfavourable for the provider. A closer cooperation between policymakers, economists and nephrologists is needed to ensure a high quality of dialysis care.

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Expanding deceased donor kidney transplantation

Abstract: Critical reexamination of deceased donor organs that were previously discarded has resulted in greater utilization of these organs, an increased number of deceased donor transplants, and the provision of life-saving treatment to more transplant waitlist candidates.

Cited by 12 publications

References 61 publications

Safety and Efficacy of Avaren-Fc Lectibody Targeting HCV High-Mannose Glycans in a Human Liver Chimeric Mouse Model

Safety and Efficacy of Avaren-Fc Lectibody Targeting HCV High-Mannose Glycans in a Human Liver Chimeric Mouse Model

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

Dialysis Reimbursement: What Impact Do Different Models Have on Clinical Choices?

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