Hepatitis C virus infection in kidney donors

INTRODUCTION — Transplantation of a kidney from a donor with hepatitis C virus (HCV) infection may cause HCV infection in the recipient. Untreated HCV infection has been associated with increased morbidity and possibly mortality in kidney transplant recipients. However, the widespread availability of highly effective direct-acting antiviral (DAA) therapies has opened the possibility of curing HCV infection, even after transplantation, and thereby attenuating the negative impact of receiving a kidney from a donor with HCV infection.

This topic reviews issues surrounding deceased or living kidney donors with HCV infection. HCV infection in kidney transplant recipients, transplant candidates, and nontransplant candidate patients on dialysis is discussed elsewhere:

●(See "Hepatitis C infection in kidney transplant candidates and recipients".)

●(See "Hepatitis C virus infection in patients on maintenance dialysis".)

EPIDEMIOLOGY

Prevalence of HCV among donors — In the United States, the prevalence of HCV infection among deceased organ donors has increased as a result of the ongoing opioid crisis. An analysis of 70,414 deceased organ donors in the United States from 2010 to 2017 using the Organ Procurement and Transplantation Network (OPTN) database reported an overall increase in the prevalence of anti-HCV positivity (4.2 to 7.3 percent from 2010 to 2017) and HCV ribonucleic acid (RNA) positivity (3.9 to 4.9 percent from 2014 to 2017) [1]. While rates of both anti-HCV positivity and HCV RNA positivity increased among increased-risk donors (from 15.9 to 21.6 percent and from 8.6 to 15.7 percent, respectively), they decreased among standard-risk donors (from 3 to 2.2 percent and from 2.2 to 1.1 percent, respectively).

By comparison, the prevalence of HCV among kidney donors is much lower in other countries, ranging from 0.3 percent in the United Kingdom (between 2009 and 2016) [2], 0.9 percent in Germany (between 2017 and 2019) [3], to 2.2 percent in Australia (between 2014 and 2020) [4]. In many Asian countries, anti-HCV positive kidney donors are generally uncommon [5]. There are scarce data on HCV prevalence in organ donors available from any of the African countries performing organ transplantation.

Risk of transmission — The risk of HCV transmission through kidney transplantation depends on the presence or absence of HCV RNA (ie, HCV viremia) in the donor.

From HCV RNA–positive donors — Donors who are positive for HCV RNA have active viremia, which poses a high risk of transmission through transplantation. Among studies of patients without HCV infection who received a kidney from a donor with HCV viremia and did not receive direct-acting antiviral (DAA) therapy before evaluation for posttransplant HCV, viremia was detected in 77 to 100 percent [6-11]. (See 'Approach' below.)

From HCV RNA–negative donors — Donors who have detectable HCV antibody but are HCV RNA–negative are considered to have cleared the infection (either spontaneously or through antiviral treatment) and do not have active viremia. The risk of transmission of HCV from such patients is extremely low [12-14]. In general, kidney transplantation from such donors is considered a safe approach.

Although seroconversion (developing detectable HCV antibody) has been reported in recipients of kidneys from donors who were HCV antibody positive but HCV RNA negative, those recipients did not subsequently develop HCV viremia [12,14]. Thus, although HCV antibody was transmitted, HCV infection was not.

However, rare transmission of HCV from donors who were negative for HCV RNA at the time of organ procurement has been documented, likely because of false-negative HCV RNA results [15,16]. In one analysis of nine such donors associated with new HCV infection in recipients, eight were classified as increased-risk donors; one donor was not initially classified as an increased-risk donor but had evidence of injection drug use in the medical record [16]. Two donors tested positive for HCV RNA from stored specimens during investigation of donor-derived HCV infection.

EVALUATION FOR HCV INFECTION AMONG DONORS — Prior to transplantation, the potential donor should be evaluated for evidence of HCV infection by blood tests (including assays for anti-HCV antibody and HCV RNA according to the United Network for Organ Sharing [UNOS]) and for the risk of HCV infection based on environmental or lifestyle factors.

The approach to evaluating for HCV infection or risk of infection varies slightly between deceased and living donors.

Deceased donors — Most organ procurement organizations (OPOs) have a policy for testing all deceased organ donors for evidence of HCV infection. In the United States, the screening of deceased donors is regulated by the Public Health Service (PHS) through the Organ Procurement and Transplantation Network (OPTN). The PHS issued guidelines for screening deceased donors for HCV in 2020 [17]. The screening process includes an assessment of risk criteria associated with HCV infection and blood tests that indicate previous or current HCV infection.

●Assessment of risk criteria associated with HCV infection – This is done through confidential interviews with next of kin, a life partner, a cohabitant, or a primary treating clinician. Risk criteria are listed in the table (table 1).

●Blood tests – All deceased donors should be tested for the presence of anti-HCV antibodies and for HCV RNA (by nucleic acid testing) within 96 hours before procurement of the kidney [18]. To ensure accuracy, testing should be performed on donor blood that is not hemodiluted (as among deceased donors who received blood products or crystalloid prior to death). (See "Screening and diagnosis of chronic hepatitis C virus infection", section on 'Initial testing' and "Evaluation of the potential deceased organ donor (adult)", section on 'Infectious disease testing'.)

Test results should be made available prior to transplantation. Although the HCV RNA result may not be known prior to transplant, data may be subsequently used to guide treatment of the recipient. The OPO is advised to archive blood samples for at least 10 years.

Both antibody and HCV RNA testing are important for evaluation. The immunoassay tests for HCV antibodies only detect evidence of prior infection. This test does not indicate whether active transmissible infection is present, which is indicated by a positive HCV RNA test. False-positive immunoassays are also possible, but the contemporary tests used for donor screening are more sensitive and specific than earlier tests and minimize the rate of false-positive antibody results [19].

However, immunoassays may not identify donors who were recently infected (ie, within eight weeks prior to death), since it takes at least eight weeks for detectable antibodies to develop [20]. HCV RNA testing closes the window of a false-negative anti-HCV antibody result in the early phase of HCV infection. The average window period between exposure and HCV RNA detectability is approximately three to five days, and the estimated risk for undetected HCV infection has been reported to be less than 1 per million donors after seven days from the time of most recent potential exposure to the day of a negative RNA test [16]. HCV RNA testing is mandatory in the United States but may not yield a result quickly enough to be useful for the valuation of deceased donors with an unknown status of HCV infection [21]. HCV RNA testing can be falsely negative in infected, deceased individuals who received blood products or crystalloid just prior to death, or who became infected just before death, since HCV first replicates in target cells (ie, hepatocytes) before it appears in blood [17]. A single negative HCV RNA test may thus not exclude the possibility of HCV infection and transmission risk [12,16,22].

If a deceased donor is identified as being at risk for or known to have HCV infection, the OPO should notify both the OPTN and transplant center. The transplant center team should include this information in discussion of risk with the transplant candidate or medical decision maker. However, donors with HCV infection are not excluded from donation. (See 'Use of kidneys from donors with HCV infection' below.)

Living donors — The screening of living potential donors is closely regulated by PHS/OPTN in the United States. (See "Kidney transplantation in adults: Evaluation of the living kidney donor candidate", section on 'Medical evaluation'.)

As per the 2020 PHS guidelines, all living-donor candidates should be interviewed regarding risk criteria (table 1). (See 'Deceased donors' above.)

All living-donor candidates should be tested for anti-HCV antibodies and for HCV RNA. The tests should be performed within at least 28 days prior to surgery and as close to the time of surgery as possible. If an HCV RNA–positive donor is identified, the transplant center should be notified and risk discussed with the potential recipient. If a kidney from an HCV RNA–positive donor is used, OPTN should be notified.

HCV RNA–positive living donors should be assessed for liver fibrosis, as the presence and extent of fibrosis may impact their eligibility to donate a kidney. While liver disease is not defined as an absolute contraindication by OPTN, it may be a relative contraindication beyond OPTN requirements at some centers. The presence of significant liver disease with synthetic and functional abnormalities is considered an absolute contraindication for donation. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations".)

HCV RNA–positive living donors who do not have evidence of liver fibrosis may be acceptable for kidney donation. For such living donors, we suggest antiviral therapy prior to transplantation rather than after transplantation. The vast majority of HCV infections can be successfully treated with short (8- to 12-week) direct-acting antiviral (DAA) regimens. Successful antiviral treatment results in sustained virologic response at 12 weeks, which is considered a marker for cure of HCV infection. If transplantation cannot be delayed for the 8 to 12 weeks of treatment and if a timely transplant would be highly beneficial for the recipient, antiviral treatment can be delayed until after transplantation. This approach is largely consistent with the 2022 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [23]. The selection of a DAA regimen is discussed in detail elsewhere. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults".)

USE OF KIDNEYS FROM DONORS WITH HCV INFECTION

Approach — When an eligible kidney becomes available from a donor with HCV viremia, potential options for the transplant candidate include proceeding with transplantation with early direct-acting antiviral (DAA) therapy versus remaining on the wait list. For transplant candidates (regardless of their HCV status) who can receive DAA therapy posttransplant, we suggest proceeding with transplantation. This is consistent with the 2022 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, which recommend that kidneys from donors with HCV infection be considered regardless of the HCV status of the transplant recipients, provided that national or regional laws and regulations allow this practice and that the recipient is guaranteed DAA therapy in the early posttransplant period [23]. In all such cases, the recipient should receive detailed information about the advantages and potential risks of transplantation in order to provide informed consent. Policies on use of HCV RNA–positive organs vary by country and institution. (See 'Institutional policies' below and 'Advantages' below and 'Potential risks' below.)

The precise timing of antiviral therapy in the setting of kidney transplantation from an HCV viremic donor is uncertain and varies by institution. In the United States, the joint guidelines from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend that antiviral therapy be initiated immediately pretransplant, on the day of transplant, or within the first week posttransplant, as soon as the patient is clinically stable [24]. In some locations, antiviral therapy can only be started once HCV viremia has been confirmed in the recipient; in those cases, antiviral therapy as early as possible posttransplant is also recommended.

Since the HCV genotype of the donor is often unknown, we recommend a pangenotypic antiviral regimen for recipients of HCV RNA–positive kidneys. The optimal duration in this setting is also uncertain; the joint AASLD/IDSA guidelines recommend [24]:

●Sofosbuvir-velpatasvir for 12 weeks.

●Glecaprevir-pibrentasvir for 8 weeks if administered within the first week after transplant or 12 weeks if administered later. In contrast to the AASLD/IDSA guidelines, we suggest glecaprevir-pibrentasvir for 8 weeks unless treatment is postponed for more than three months posttransplant, in which case we suggest 12 weeks, in accordance with European guidelines [25]. In some locations, payers may not cover glecaprevir-pibrentasvir for a full 12 weeks, which limits access to this regimen. Use of glecaprevir-pibrentasvir may also be limited by potential interactions with immunosuppressive agents (table 2) and is contraindicated in patients with decompensated cirrhosis (Child-Pugh score B or C). (See "Hepatitis C infection in kidney transplant candidates and recipients", section on 'Interactions with immunosuppressive agents'.)

Multiple studies have demonstrated the safety of transplanting kidneys from deceased donors with HCV into recipients without HCV when the recipient is treated with early or preemptive DAA therapy [6-8,26-35], supporting the use of kidneys from donors with HCV infection in patients without infection. Early trials found that the administration of elbasvir-grazoprevir for 12 weeks, either initiated prophylactically (first dose given pretransplant) or upon detection of HCV RNA after transplantation, prevented chronic HCV infection in all recipients, and patients maintained overall good kidney allograft function without experiencing acute rejection [6,26-28]. Subsequent studies have reported successful transplantation with the use of other DAA regimens (eg, glecaprevir-pibrentasvir, sofosbuvir-velpatasvir, and sofosbuvir-ledipasvir) and with shorter durations of treatment (eg, four or eight weeks) with DAA therapy [7,8,29-31,33,34]. However, antiviral prophylaxis alone prior to transplant is not sufficient to prevent transmission; in studies where the antiviral regimen was initiated prior to transplantation, the rate of HCV viremia in the few days after transplant ranged from 0 to 88 percent [26,28,30,31]. Thus, a treatment course of antiviral therapy is generally used.

Observational data also suggest that kidney function and rates of rejection at one year and graft survival at five years are similar for recipients of HCV RNA–positive and HCV RNA–negative deceased-donor kidneys [36-38]. The results of these studies suggest that transplantation of HCV RNA–positive kidneys into HCV RNA–negative recipients, in conjunction with DAA therapy, could provide well-functioning allografts and cure HCV infection. Additional studies are required to assess the optimal timing of DAA treatment, long-term graft and patient outcomes, and potential risks of transplanting HCV RNA–positive kidneys into HCV RNA–negative recipients.

The safety of transplanting a kidney from an HCV antibody–positive living donor who has undergone successful antiviral treatment into an HCV-negative recipient or into an HCV RNA–positive recipient with a different HCV genotype is unknown, as data are limited [39]. However, extrapolating from data on transplantation of anti-HCV antibody–positive/HCV RNA–negative deceased-donor organs into HCV-negative recipients, the risk seems to be low.

Advantages — The use of HCV RNA–positive kidneys could help expand the donor pool and reduce the waiting time for receiving a kidney transplant. Kidneys from deceased donors with HCV are presently an underused resource [40-42], and the use of such kidneys could help reduce wasting these organs. Although the discard rate of HCV RNA–positive kidneys is decreasing, it continues to be higher than that of kidneys from donors without HCV [43-45]. Discarded kidneys from HCV RNA–positive donors are more likely to be from younger donors with a lower kidney-donor profile index compared with kidneys from discarded kidneys from donors without HCV [45]. (See "Kidney transplantation in adults: Organ sharing", section on 'Kidney donor profile index (KDPI)'.)

Data on long-term graft and patient outcomes following transplantation of HCV RNA–positive kidneys in the DAA-therapy era are limited (see 'Approach' above). However, even before the introduction of DAA therapy, there appeared to be a survival advantage associated with receiving a kidney from an HCV-seropositive donor compared with remaining on the deceased-donor waitlist [46-48]. Among nearly 40,000 United States Renal Data System (USRDS) patients awaiting transplantation, transplantation with such a kidney was associated with improved survival versus remaining on a transplant waitlist (adjusted hazard ratio 0.76) [46]. These results were supported by another retrospective analysis of data from the national Organ Procurement and Transplant Network (OPTN) registry from 1994 to 2014 [48]. In this study, although five-year graft and patient survival were worse among HCV-seronegative recipients receiving HCV-seropositive kidneys compared with those receiving HCV-seronegative kidneys, the five-year patient survival from the time of waitlisting was superior when compared with waitlisted controls. One limitation of these data is that they did not distinguish survival outcomes among recipients of HCV-seropositive but RNA-negative kidneys versus recipients of HCV-seropositive and RNA-positive kidneys.

Potential risks

Recipients without HCV — Transplantation of an HCV RNA–positive kidney is associated with a high risk of viral transmission from the donor to the recipient. However, this risk can be mitigated by early or preemptive treatment of the recipient with DAA therapy. (See 'Risk of transmission' above and 'Approach' above.)

A delay in initiation of DAA therapy may be associated with an increased incidence of cytomegalovirus and BK polyomavirus viremia, de novo donor-specific antibodies, and fibrosing cholestatic hepatitis [7,8]. These unexpected consequences may be seen in the real-world setting, where it often may not be possible to initiate preemptive/early therapy, as access to DAA therapy may be complicated by issues with insurance approval or lack of resources. Thus, any center performing kidney transplantation from an HCV RNA–positive donor to an HCV-negative recipient should confirm availability of DAA therapy in the early posttransplant period [23].

Prior to the advent of DAA therapy in 2014, when HCV could not be easily treated posttransplant, receipt of an HCV-seropositive kidney rather than an HCV-seronegative kidney was associated with increased morbidity, decreased survival, and higher rates of liver disease among HCV-seronegative recipients [47,49,50]. Cure of HCV infection could only be achieved by the administration of interferon-alpha, which had low response rates and was contraindicated after kidney transplantation. Thus, kidneys from donors with HCV were almost exclusively transplanted into recipients with HCV infection.

Recipients with HCV — Even in the absence of DAA therapy, it is uncertain whether transplanting a kidney from an HCV RNA–positive donor into a recipient with preexisting, untreated HCV infection is associated with additional risk. Most data come from the era prior to mandatory HCV RNA testing, when HCV positivity was defined only by HCV seropositivity, without consideration of the patient's viremic status. Such studies suggested that morbidity and mortality of HCV-seropositive recipients were not increased by the transplantation of kidneys from HCV-seropositive donors, despite the possibility of superinfection with HCV [51-57]. One report of 468 HCV-seropositive recipients found comparable 5- and 10-year survival rates between recipients of kidneys from HCV-seropositive and HCV-seronegative donors [54]. Graft survival also appeared comparable; in a case-control study of 205 HCV RNA–negative kidneys transplanted between 2014 and 2016, graft survival of the HCV-seropositive/RNA-negative kidneys transplanted in mostly HCV-seropositive recipients was similar to that of HCV-seronegative kidneys [58].

By contrast, other single-center as well as large registry studies have shown increased mortality, graft loss, and adverse liver outcomes associated with the transplantation of HCV-seropositive kidneys in HCV-seropositive recipients [59-62]. Differences in immunosuppression or superinfection with another genotype may have explained the observed differences in outcomes in different studies. Furthermore, most of these studies tested only for anti-HCV antibodies but not for HCV RNA in both donors and recipients, which could further contribute to the observed differences. As an example, it is possible that some HCV-seropositive recipients may not have had chronic HCV infection at the time of transplant or that some kidneys were seropositive but HCV RNA negative and so had minimal risk of transmitting HCV.

Institutional policies — While kidney transplantation using HCV RNA–positive donors is slowly increasing, institutional practices and policies regarding the use of kidneys from HCV RNA–positive donors vary among transplant centers in the United States and around the world. Many centers do not perform kidney transplantation using HCV RNA–positive donors, whereas some centers may only allow transplantation of HCV RNA–positive kidneys into recipients with HCV [43,63-65].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatitis C infection in solid organ transplant candidates and recipients".)

SUMMARY AND RECOMMENDATIONS

●Overview – Transplantation of a kidney from a donor with hepatitis C virus (HCV) infection may cause HCV infection in the recipient. Untreated HCV infection has been associated with increased morbidity and possibly mortality in kidney transplant recipients. However, the widespread availability of highly effective direct-acting antiviral (DAA) therapies has opened the possibility of curing HCV infection, even after transplantation, and thereby attenuating the negative impact of receiving a kidney from a donor with HCV infection. (See 'Introduction' above.)

●Risk of transmission – The risk of HCV transmission through kidney transplantation depends on the presence of HCV RNA (ie, HCV viremia) in the donor. Donors who are HCV RNA positive have active viremia, which poses a high risk of transmission through transplantation. By contrast, the risk of HCV transmission from patients who are HCV RNA negative is extremely low. (See 'Risk of transmission' above.)

●Donor evaluation for HCV infection – Prior to transplantation, the potential donor should be evaluated for evidence of HCV infection by blood tests (including assays for anti-HCV antibody and HCV RNA according to the United Network for Organ Sharing [UNOS]) and for the risk of HCV infection based on environmental or lifestyle factors. The approach to evaluation varies slightly between deceased and living donors. The potential recipient must be informed of the donor HCV status and the potential risk of infection prior to transplantation. (See 'Evaluation for HCV infection among donors' above.)

●Use of kidneys from donors with HCV infection – When an eligible kidney becomes available from a donor with HCV viremia, potential options for the transplant candidate include proceeding with transplantation with early DAA therapy versus remaining on the wait list. For transplant candidates (regardless of their HCV status) who can receive DAA therapy posttransplant, we suggest proceeding with transplantation (Grade 2C). Early DAA therapy involves administration of a pangenotypic antiviral regimen (either sofosbuvir-velpatasvir or glecaprevir-pibrentasvir) as soon as possible after transplant (ideally within the first week).

In all such cases, the recipient should receive detailed information about the advantages and potential risks of transplantation in order to provide informed consent. (See 'Approach' above.)

●Institutional policies – While kidney transplantation using HCV RNA–positive donors is slowly increasing, institutional practices and policies regarding the use of kidneys from HCV RNA–positive donors vary among transplant centers in the United States and around the world. Many centers do not perform kidney transplantation using HCV RNA–positive donors, whereas some centers may only allow transplantation of HCV RNA–positive kidneys into recipients with HCV. (See 'Institutional policies' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Svetlozar Natov, MD, and Brian JG Pereira, MD, who contributed to earlier versions of this topic review.