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INTRODUCTION/BACKGROUND:Direct acting antiviral (DAA) therapeutics have ushered in an era in which transplanting organs from donors infected with hepatitis C virus (HCV+) into recipients without (HCV-) is an increasingly common practice. Rare but potentially life-threatening events have been reported in recipients of HCV+ organs. METHODS:Since 2018 at our institution, 182 HCV- patients have received HCV+ donor organs. Here, we retrospectively reviewed cases in which recipients' family member caregivers reported sustaining needlestick exposures at home following discharge of the transplant recipient from the hospital. RESULTS:Caregiver needlestick exposures were passively reported in three cases of HCV+ into HCV- transplants (1.64% of such cases at our center). In all instances, the exposed individuals were aiding in diabetic management and the exposure occurred via lancets or insulin needles. In one case, the recipient viral load was undetectable at the time of the exposure but in the other two, recipients were viremic, putting their family members at risk to contract HCV infection. Surveillance for the exposed individuals was undertaken and no transmissions occurred. DISCUSSION/CONCLUSIONS:For centers performing HCV+ into HCV- transplants, it is important that informed consent includes discussion of potential secondary risks to family members and caregivers. Further, protocols for post-exposure surveillance and for the acquisition of DAA treatment in the event of a secondary transmission should be in place. This article is protected by copyright. All rights reserved.

Imlifidase is a cysteine proteinase which specifically cleaves IgG, inhibiting Fc-mediated effector function within hours of administration. Imlifidase converts a positive crossmatch to a potential donor (T cell, B cell, or both), to negative, enabling transplantation to occur between previously HLA incompatible donor-recipient pairs. To date, 39 crossmatch positive patients received imlifidase prior to a kidney transplant in four single-arm, open-label, phase 2 studies. At 3 years, for patients who were AMR+ compared to AMR-, death-censored allograft survival was 93% vs 77%, patient survival was 85% vs 94%, and mean eGFR was 49 ml/min/1.73 m² vs 61 ml/min/1.73 m² , respectively. The incidence of AMR was 38% with most episodes occurring within the first month post-transplantation. Sub-analysis of patients deemed highly sensitized with cPRA ≥ 99.9%, and unlikely to be transplanted who received crossmatch-positive, deceased donor transplants had similar rates of patient survival, graft survival, and eGFR but a higher rate of AMR. These data demonstrate that outcomes and safety up to 3 years in recipients of imlifidase-enabled allografts is comparable to outcomes in other highly sensitized patients undergoing HLA-incompatible transplantation. Thus, imlifidase is a potent option to facilitate transplantation among patients who have a significant immunologic barrier to successful kidney transplantation. Clinical Trial: ClinicalTrials.gov (NCT02790437), EudraCT Number: 2016-002064-13.

Transplanting hepatitis C viremic donor organs into hepatitis C virus (HCV)-negative recipients is becoming increasingly common; however, practices for posttransplant direct-acting antiviral (DAA) treatment vary widely. Protracted insurance authorization processes for DAA therapy often lead to treatment delays.

The current kidney allocation system (KAS) preferentially allocates kidneys from blood type A2 or A2B (A/A2B) donors to blood type B candidates. We used national data to evaluate center-level performance of A2/A2B to B transplants, and organ procurement organization (OPO) reporting of type A or AB donor subtyping, in 5-year time periods prior to (2009-2014) and following (2015-2019) KAS implementation. The number of centers performing A2/A2B to B transplants increased from 17 pre-KAS to 76 post-KAS, though this still represents only a minority of centers (7.3% pre-KAS and 32.6% post-KAS). For high-performing centers, the median net increase in A2/A2B to B transplants was 19 cases (range -2-72) per center in the 5 years post-KAS. The median net increase in total B recipient transplants was 21 cases (range -17-119) per center. Despite requirements for performance of subtyping, in 2019 subtyping was reported on only 56.4% of A/AB donors. This translates into potential missed opportunities for B recipients, and even post-KAS up to 2322 A2/A2B donor kidneys may have been allocated for transplantation as A/AB. Further progress must be made both at center and OPO levels to broaden implementation of A2/A2B to B transplants for the benefit of underserved recipients.

BACKGROUND:Highly HLA sensitized patients have limited access to life-saving kidney transplantation because of a paucity of immunologically suitable donors. Imlifidase is a cysteine protease that cleaves IgG leading to a rapid decrease in antibody level and inhibition of IgG-mediated injury. This study investigates the efficacy and safety of imlifidase in converting a positive crossmatch test to negative, allowing highly sensitized patients to be transplanted with a living or deceased donor kidney. METHODS:This open-label, single-arm, phase 2 trial conducted at 5 transplant centers, evaluated the ability of imlifidase to create a negative crossmatch test within 24 h. Secondary endpoints included postimlifidase donor-specific antibody levels compared with predose levels, renal function, and pharmacokinetic/pharmacodynamic profiles. Safety endpoints included adverse events and immunogenicity profile. RESULTS:Of the transplanted patients, 89.5% demonstrated conversion of baseline positive crossmatch to negative within 24 h after imlifidase treatment. Donor-specific antibodies most often rebounded 3-14 d postimlifidase dose, with substantial interpatient variability. Patient survival was 100% with graft survival of 88.9% at 6 mo. With this, 38.9% had early biopsy proven antibody-mediated rejection with onset 2-19 d posttransplantation. Serum IgG levels began to normalize after ~3-7 d posttransplantation. Antidrug antibody levels were consistent with previous studies. Seven adverse events in 6 patients were classified as possibly or probably related to treatment and were mild-moderate in severity. CONCLUSIONS:Imlifidase was well tolerated, converted positive crossmatches to negative, and enabled patients with a median calculated panel-reactive antibody of 99.83% to undergo kidney transplantation resulting in good kidney function and graft survival at 6 mo.

Purpose: Utilization of HCV viremic donor kidneys for transplant into HCV naive recipients has become more widespread, yet best practices governing the initiation, timing or duration of direct acting antiviral (DAA) therapy are lacking. Most published series describe DAA initiation weeks to months after transplant. However, fibrosing cholestatic hepatitis has been reported with delayed DAA initiation. Herein we report our center practice utilizing donor blood for HCV genotyping to expedite DAA insurance approval and minimize the duration of recipient viremia.
Method(s): Patients received education and DAA insurance benefits were ensured prior to listing for HCV+ organs. At the time of transplant, donor blood accompanying the kidney was used for HCV genotyping. Results were received within one week of transplant. Recipients were screened for HCV RNA by POD#4, and weekly for 12 weeks. Insurance authorization for DAA coverage was sought after both recipient viremia and donor HCV genotyping resulted. In 3 cases, donor viral load was insufficient for genotyping, and these recipients were genotyped once viremic.
Result(s): 80 hepatitis C naive patients received hepatitis C positive donor kidneys between July, 2018 and October, 2020. 17 donors were HCV Ab+/NAT-and 63 donors were HCV Ab+/NAT+. All recipients of NAT+ donor organs became viremic; 89% were genotype 1a or 3. The median time to DAA initiation was 10 days for cases with donor genotyping (IQR 8-13). In contrast, the median time to DAA initiation was 20 days for the 3 cases with recipient genotyping (IQR 18-24). Median time from transplant to clearance of HCV viremia was 38 days (IQR 30-47) (Table 1). SVR12 was achieved in all patients, and no cases of fibrosing cholestatic hepatitis have been observed. There were 2 needlestick exposures of patient family members, though no HCV transmission occurred.
Conclusion(s): Early HCV genotyping using donor blood results in expedited initiation of DAA therapy for recipients of HCV+ kidneys. Compared to published reports, our patients are clearing viremia at the time that most other centers' patients are initiating DAA therapy. Whether duration of viremia or peak viral load are associated with adverse allograft events such as acute rejection is not known. The advantages to a shortened duration of HCV viremia remain to be characterized, but may include a lower risk of fibrosing cholestatic hepatitis and lower risk of HCV exposure to family members and caregivers. Our practice of expedited genotyping using donor blood is immediately implementable at all centers performing these transplants. (Table Presented)