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Volume: 22 Issue: 3 March 2024

FULL TEXT

ARTICLE
Outcomes of Kidneys Transplanted From Hepatitis C Viremic Donors to Naive Recipients From an Appalachian Rural Kidney Transplant Program

Abstract

Objectives: Before the advent of direct-acting antiviral therapy for hepatitis C virus, a large proportion of kidneys from donors with hepatitis C viremia were discarded. Hepatitis C virus is now amenable to effective treatment with excellent seronegativity rates. In this study, we review the outcomes of hepatitis C viremic kidneys transplanted into hepatitis C-naive recipients.
Materials and Methods: In this retrospective obser-vational study, we examined 6 deceased donor kidneys with hepatitis C viremia that were transplanted into hepatitis C-naive recipients between March 2020 and April 2021 at a single center. Because of health insurance constraints, patients were treated for hepatitis C virus with glecaprevir/pibrentasvir for 8 weeks following seroconversion posttransplant. Primary outcome measured was viral seroconversion; secondary outcomes included graft function, posttransplant complications, and all-cause mortality.
Results: On average, patients seroconverted 6 days (range, 4-10 d) after transplant and began treatment 26 days (range, 15-37 d) after seroconversion. An 8-week course of antiviral treatment was successful in preventing acute hepatitis C virus infection in all patients. Posttransplant median creatinine was 1.96 mg/dL (range, 1-4.55 mg/dL), whereas median estimated glomerular filtration rate was 41.33 mL/min/1.73 m2 (range, 17-85 mL/min/1.73 m2). Patient survival rate was 66.7%, and death-censored graft survival rate was 100%. Two patients died from unrelated reasons: 1 from acute respiratory failure secondary to SARS-CoV-2 infection and 1 from posttransplant lymphoproliferative disorder. Two patients developed allograft rejection posttransplant (1 developed antibody mediated rejection, 1 developed borderline T-cell-mediated cellular rejection). Other major complications included neutropenia, fungal rash, SARS-CoV-2 infection, cytomegalovirus, BK virus, and Epstein-Barr virus reactivation.
Conclusions: Use of hepatitis C-viremic donor kidneys for transplant is a safe option and has great potential to increase the kidney donor pool, as long as high index of suspicion is maintained for allograft rejection and opportunistic infections.


Key words : Complications, Direct-acting antiviral therapy, Renal transplant

Introduction

Before the advent of direct-acting antiviral therapy (DAAT) for hepatitis C virus (HCV), a large proportion of kidneys from donors with HCV viremia were discarded. After the introduction and availability of DAAT, HCV is now amenable to effective treatment with excellent seronegativity rates.1 Although organs from such donors can now be utilized safely, reluctance remains among transplant programs to adopt this practice. The prevalence of hepatitis C in the United States is 2.4 million (range, 2.5-4.2 million), and West Virginia ranks first in the nation for the highest rate of newly reported cases of chronic hepatitis C, with 151.4 cases per 100 000 population (https://www.cdc.gov/).2 Intertwined with the high prevalence of opioid use in West Virginia, this is a large population of potential donors. In this study, we present our experience with transplanting HCV viremic kidneys into naive recipients.

Materials and Methods

In this retrospective observational study, we examined 6 hepatitis C-viremic deceased donor kidneys transplanted into hepatitis C-naive recipients between March 2020 and April 2021 at a single center. We use a rigorous consenting process to ensure adequate information exchange between the transplant team and the potential recipient relating to the definitive risk of contracting HCV after the transplant, protocol to treat HCV infections, and rates of cure posttransplant. Because of health insurance constraints, patients were not treated for HCV until seroconversion was proven with quantitative polymerase chain reaction (qPCR). Treatment included 300 mg/120 mg of glecaprevir/pibrentasvir daily for 8 weeks post-transplant. Induction immunosuppression included thymoglobulin and methylprednisolone; maintenance immunosuppression was achieved with tacrolimus and mycophenolate mofetil. All patients had baseline liver function and HCV qPCR testing on post-transplant days 1 and 3 and subsequently at weeks 1, 2, 3, 4, 12, and 24. Other laboratory investigations (including immunosuppression levels) were tested per routine protocol. We retrospectively analyzed outcomes in these patients through review of medical records.

Our primary outcome measured was viral seroconversion and subsequent qPCR load. Secondary outcomes measured included graft function (median creatinine and estimated glomerular filtration rate [eGFR] at baseline and then monthly posttransplant), any complications either directly related to HCV seroconversion or activation of other viruses including cytomegalovirus, BK virus (BKV), or Epstein-Barr virus, and all-cause mortality.

Results

We examined outcomes of 6 kidneys transplanted from hepatitis C-viremic donors to hepatitis C-naive recipients. Male-to-female ratio was 2:1, and median age was 55.67 years (range, 42-73 y). Median follow-up was 10 months (range, 2-12 mo). The average time on dialysis for this cohort was 2.92 years, and median time on dialysis was 2.75 years (range, 1-6 y); 67% of patients were on hemodialysis and 33% on peritoneal dialysis. Patients waited an average of 5.57 months on transplant wait list, with median wait time of 3.46 months (range, 1.18-13.2 mo). Average total time on a transplant wait list was 31.84 months, with median time of 31.24 months (range, 0-68.24 mo). The most common cause of end-stage renal disease was diabetes mellitus (40%) and hypertensive neph-rosclerosis (40%), followed by lupus nephritis, calcineurin inhibitor toxicity, and nonsteroidal anti-inflammatory drug-induced nephropathy (each with rate of occurrence of 20%). Median creatinine level was 1.96 mg/dL at last follow-up posttransplant (range, 1-4.55 mg/dL). Median eGFR was 41.33 mL/-min/1.73 m2 at last follow-up posttransplant (range, 17-85 mL/min/1.73 m2).

Because of health insurance constraints, no patient received treatment for HCV until serocon-version was documented with a positive qPCR. On average, patients seroconverted 6 days after transplant (range, 4-10 d). Patients began treatment about 26 days after a positive qPCR (range, 15-37 d). In all patients, 8 weeks of antiviral treatment was successful in preventing acute HCV infection. All patients seroconverted and had undetectable levels of viral RNA at 24 weeks after treatment initiation.

All patients developed a posttransplant compli-cation. One patient developed several complications, skewing cohort analysis. Two patients developed allograft rejection posttransplant: 1 patient deve-loped antibody-mediated rejection at 2 weeks posttransplant, which was successfully treated with steroids and intravenous immunoglobulin, and the other patient developed borderline T-cell-mediated cellular rejection 1 week posttransplant, which was treated with optimizing baseline immunosup-pression. Patient survival rate was 66.67%, and death-censored graft survival rate was 100%. Two patients died from unrelated reasons: 1 from acute respiratory failure secondary to SARS-CoV-2 infection and 1 from posttransplant lymphoproliferative disorder, which can be attributed to long-term pretransplant immunosuppressive treatment for lupus and previous Epstein-Barr virus infection.

Among our recipients, the most common complication was SARS-CoV-2 infection (50%) followed by neutropenia (33%). Other complications included pleural effusion, fungal rash, peritransplant hematoma, wound infection, dehydration from diarrhea and vomiting requiring admission to hospital, posttransplant diabetes mellitus type 2, and mitral regurgitation. Cytomegalovirus and BKV reactivation occurred in 1 patient (16.7%), with subsequent BK viremia. Epstein-Barr virus reactivated once in a different patient (16.7%). Reactivation of BKV progressed to BKV nephropathy and was treated with intravenous immunoglobulin. For all infections, immunosuppression was reduced as per institutional protocol, and each infection resolved (Table 1).

Discussion

All 6 HCV-naive recipients who received HCV NAT-positive kidney transplants were cured of HCV following an 8-week course of glecaprevir/pibren-tasvir therapy without developing acute hepatitis, with patients showing rapidly declining viral loads with initiation of antiviral therapy and excellent allograft function. Viral loads have remained undetectable at last follow-up. However, we had a high complication rate related to immunosuppression. Two of 6 patients experienced an episode of allograft rejection, which was adequately treated without any sequalae. Our cohort also had a high readmission rate of 3.67 per person-year and a patient survival rate of 66.7%. These results can be attributed to our small study size and multiple admissions for a single patient with complications that skewed the results. We believe it is prudent to do aggressive surveillance for allograft rejection in this population given the high incidence of allograft rejection in our study. We also recom-mend immune surveillance to avoid overim-munosuppression, given the high incidence of opportunistic infections in our study.

The landmark THINKER trial evaluated 20 HCV-negative patients after kidney transplant from HCV genotype 1 viremic donors. Patients received 12 weeks of elbasvir/grazoprevir starting on posttransplant days 3 to 5, and all patients achieved HCV cure. Complications included development of donor-specific antibodies in 3 patients and de novo focal segmental glomerulosclerosis in 1 patient that was successfully treated. At last follow-up, the titer of de novo donor-specific antibodies was either transient, resolved, or weakly positive.3,4 In the EXPANDER trial, 10 HCV-negative patients received elbasvir/grazoprevir before transplant of an HCV viremic kidney. Elbasvir/grazoprevir was continued for 12 weeks posttransplant, and all patients achieved HCV cure.5 In the MYTHIC trial, 30 HCV-negative patients underwent transplant with HCV viremic kidneys and received glecaprevir/pibrentasvir for 8 weeks, starting 2 to 5 days posttransplant, and all patients achieved HCV cure. Complications included 3 episodes of acute cellular rejection; however, all patients had good graft function at 6-month follow-up. Importantly, the MYTHIC trial proved HCV cure persisted at 1-year posttransplant with excellent kidney and liver function.6,7

Similar to our study, Reese and colleagues completed 20 renal transplants of HCV-infected kidneys into seronegative recipients with patients first receiving transplant, followed by close monitoring for seroconversion, and treatment with elbasvir/grazoprevir after seroconversion. All 20 patients were cured of HCV infection 12 weeks after initiation of elbasvir/grazoprevir and remained negative over the 12-month posttransplant follow-up. In addition, they found that eGFR was significantly improved in patients who received an HCV-infected kidney compared with matched recipients of HCV-negative kidneys with similar kidney donor profile index scores.4 In addition, Jandovitz and colleagues found similar results with use of ledipasvir/sofosbuvir or velpatasvir/sofosbuvir after transplant of 25 HCV-positive kidneys into seronegative recipients.8 In conjunction with our present study, use of HCV infected kidneys did not cause decreased allograft function.

Jandovitz and colleagues reported death-censored graft survival of 96% with no development of rejection and reported no adverse events attributable to DAAT.8 In addition, Reese and colleagues reported only 1 adverse effect that could be attributed to DAAT, which was development of focal segmental glomeru-losclerosis treated with angiotensin receptor blocker. No patients experienced allograft rejection.4 Neither study reported other adverse events or outcomes unrelated to DAAT.

Conclusions

In the current era of DAAT offering a cure from HCV, use of HCV NAT-positive donor kidneys for transplant from both seropositive and seronegative donors is a safe option with a great potential to increase the kidney pool available for transplantation. Based on our experience, we believe it is prudent to do aggressive surveillance for allograft rejection in this population. At the same time, we recommend immune surveillance to avoid overimmunosup-pression, given the high incidence of opportunistic infections in our study.


References:

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Volume : 22
Issue : 3
Pages : 185 - 188
DOI : 10.6002/ect.2024.0034


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From the Departments of 1Transplant Surgery, 2Transplant Infectious Disease, 5Transplant Nephrology, 4Transplant Pharmacy, and 3Transplamt Alliance, West Virginia University School of Medicine, Morgantown, West Virginia, USA
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Rajeev Sharma, 1 Medical Center Drive, PO Box 9238, HSS Suite 700, Morgantown, WV 26505, USA
Phone: +1 3042930283
E-mail: Rajeev.Sharma@hsc.wvu.edu