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Commentaries

Hepatitis C Infection in Kidney Donors

A Call to Reexamine Its Relevance As a Predictor of Transplant Outcomes

Huang, Edmund MD1

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doi: 10.1097/TP.0000000000002950
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Considerable data have described hepatitis C virus (HCV) infection as a risk factor for mortality in patients with end-stage kidney disease, both in transplanted patients and those maintained on dialysis.1,2 However, the majority of outcome data in the end-stage kidney disease population were derived from older cohorts before the development of direct-acting antiviral (DAA) therapy for HCV. DAA have revolutionized care for hepatitis C, with reported sustained virologic response rates achieved in over 90% of patients, and have dramatically improved the prognosis for patients infected with HCV.

Historically, kidneys from HCV-seropositive donors were mostly transplanted into recipients infected with HCV. Despite data indicating that post transplant mortality and graft failure were higher among HCV-positive recipients, HCV infection was considered advantageous for a transplant candidate because it allowed transplantation from an HCV-seropositive donor with a shorter waiting time than would be expected from an HCV-seronegative donor. More recently, some transplant centers have taken advantage of shorter waiting times by transplanting kidneys from aviremic donors with prior HCV infection (HCV-seropositive/nucleic acid testing [NAT] negative) and viremic donors into HCV-uninfected recipients.3-5

Donor HCV seropositivity is one parameter included in the Kidney Donor Profile Index (KDPI) used for donor kidney allocation in the United States and is associated with a 27% increased hazard of graft failure compared to HCV-seronegative donors after adjusting for other relevant factors.6 This association was derived from a cohort of United States transplant recipients from 1995 to 2005, an era well before the development of DAA therapy. It should be noted that the association does not account for whether the donor is viremic or aviremic. Additionally, because many centers have only recently considered transplanting kidneys from HCV-seropositive donors into HCV-uninfected recipients, residual confounding due to recipient HCV infection, a known risk factor for death and graft loss, was not accounted for in the original Kidney Donor Risk Index (KDRI) model. As a result, it is possible that the relative association of donor HCV seropositivity on graft failure may have been overestimated in the KDRI model and could attenuate as survival improves with the introduction of DAA agents.

In this issue of Transplantation, Cannon et al7 investigated the impact of donor HCV on patient and allograft survival in the modern era of DAA. Using matching by propensity scores, the authors demonstrated in a well-balanced cohort that there was no difference in all-cause graft loss, death-censored graft loss, and death between recipients of HCV-seropositive and HCV-seronegative donors despite a higher mean KDPI among HCV-seropositive donors (58.2% versus 38.8%; standardized difference = 0.89). These findings suggest that KDPI might not reliably predict graft survival among HCV-seropositive donors in the current era. In a subgroup analysis of recipients of kidneys from HCV NAT-positive donors (approximately 75% of HCV-seropositive donors) and HCV-seronegative donors, however, there was a higher risk of graft loss and death over the first 10–14 months post transplant among recipients of HCV NAT-positive donors. With follow-up to 36 months, there was a trend toward lower graft survival (log-rank P = 0.09) and higher mortality among HCV NAT-positive recipients (log-rank P = 0.08).

How can we reconcile the disparate findings in the main and subgroup analyses? It is possible that the survival differences observed in the subgroup analysis of HCV NAT-positive recipients may have been influenced by residual confounding. In contrast to the main analysis, where baseline characteristics were well balanced, the subjects in the subgroup analysis were not balanced on several covariates. On the other hand, it may be that only viremic donors are associated with a higher risk for graft loss and death and that the association is nonsignificant when aviremic and viremic donors are considered together.

The findings from the subgroup analysis of NAT-positive donors are consistent with other studies demonstrating that donor HCV infection is a risk factor for graft loss, including a reanalysis of the KDRI model using a more recent cohort of recipients from 2000 to 2016.8 Additionally, in a propensity score-matched analysis of HCV-positive recipients, donor HCV seropositivity was associated with a higher risk of death and graft loss compared to donor HCV-negative serostatus.9 It is possible that survival differences in the current study could develop with a longer duration of follow-up. Cohen et al9 reported nearly identical graft survival among HCV-infected recipients of HCV-seropositive and HCV-seronegative donors over the first 2 years post transplant, with survival differences only emerging thereafter with follow-up to 8 years. Longer-term follow-up, particularly among recipients of HCV NAT-positive donors, will be informative.

The extent to which the introduction of DAA in recent years will affect the association of donor HCV on survival is unclear, and whether wider utilization of DAA in the future will eventually diminish the impact of donor HCV on graft outcomes will need to be studied. It is likely that the negative association of donor HCV on death and graft survival is at least driven, in part, by recipient HCV infection, as recipient HCV infection has historically been associated with higher risks of death and graft failure, even with transplantation from HCV-negative donors.2,10 Given this, one would anticipate that improving recipient outcomes with DAA will ultimately improve transplant outcomes associated with donor HCV. However, this hypothesis will need to be tested going forward.

Although one cannot conclude from the current study that donor HCV seropositivity is no longer a risk factor for graft failure in the current era, the data is provocative and raises the question of whether HCV NAT would be a better predictor of graft loss than HCV serostatus. Although longer-term data is necessary, this study at least raises the question of whether the inclusion of HCV serostatus as a covariate in the KDRI should be reexamined.

References

1. Sawinski D, Forde KA, Lo Re V 3rd, et al. Mortality and kidney transplantation outcomes among hepatitis C virus-seropositive maintenance dialysis patients: a retrospective cohort study. Am J Kidney Dis. 2019; 73:815–826
2. Abbott KC, Bucci JR, Matsumoto CS, et al. Hepatitis C and renal transplantation in the era of modern immunosuppression. J Am Soc Nephrol. 2003; 14:2908–2918
3. de Vera ME, Volk ML, Ncube Z, et al. Transplantation of hepatitis C virus (HCV) antibody positive, nucleic acid test negative donor kidneys to HCV negative patients frequently results in seroconversion but not HCV viremia. Am J Transplant. 2018; 18:2451–2456
4. Reese PP, Abt PL, Blumberg EA, et al. Twelve-month outcomes after transplant of hepatitis C-infected kidneys into uninfected recipients: a single-group trial. Ann Intern Med. 2018; 169:273–281
5. Molnar MZ, Nair S, Cseprekal O, et al. Transplantation of kidneys from hepatitis C-infected donors to hepatitis C-negative recipients: single center experience. Am J Transplant. 2019
6. Rao PS, Schaubel DE, Guidinger MK, et al. A comprehensive risk quantification score for deceased donor kidneys: the kidney donor risk index. Transplantation. 2009; 88:231–236
7. Cannon RM, Locke JE, Orandi BJ, et al. Impact of donor hepatitis C virus on kidney transplant outcomes for hepatitis C positive recipients in the direct acting antiviral era: time to revise the kidney donor risk index? Transplantation. 2020; 104:1215–1228
8. Zhong Y, Schaubel DE, Kalbfleisch JD, et al. Reevaluation of the kidney donor risk index. Transplantation. 2019; 103:1714–1721
9. Cohen JB, Eddinger KC, Shelton B, et al. Effect of kidney donor hepatitis C virus serostatus on renal transplant recipient and allograft outcomes. Clin Kidney J. 2017; 10:564–572
10. Fabrizi F, Martin P, Dixit V, et al. Meta-analysis of observational studies: hepatitis C and survival after renal transplant. J Viral Hepat. 2014; 21:314–324
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