INTRODUCTION — Hepatitis C virus (HCV) causes kidney disease in native and transplanted kidneys. Kidney transplant recipients with HCV infection, if HCV is not eradicated after transplantation, have worse patient and allograft survival after transplantation compared with kidney transplant recipients without infection.
Early detection and treatment of HCV infection and HCV-related kidney disease after kidney transplantation improves posttransplant outcomes in this population [1].
This topic reviews HCV infection in the kidney transplant recipient. HCV infection among dialysis patients, in the kidney transplant donor, and in the general population is discussed elsewhere:
●(See "Hepatitis C virus infection in kidney donors".)
●(See "Hepatitis C virus infection in patients on maintenance dialysis".)
●(See "Clinical manifestations and natural history of chronic hepatitis C virus infection".)
●(See "Screening and diagnosis of chronic hepatitis C virus infection".)
●(See "Overview of the management of chronic hepatitis C virus infection".)
EPIDEMIOLOGY — The reported prevalence of HCV infection among kidney transplant recipients is approximately 1.8 to 8 percent [2-6] and appears to be decreasing over time [7]. Most transplant recipients with HCV infection acquired infection prior to transplant, while on dialysis [5]. The transmission of HCV through kidney transplantation is rare due to screening of donors [5], although organs from donors with HCV infection are increasingly being used for recipients without infection with the availability of highly effective treatments for HCV. (See "Hepatitis C virus infection in kidney donors".)
HCV EVALUATION OF TRANSPLANT CANDIDATES
Assessment for HCV infection — Consistent with other expert guidelines, we assess for HCV infection in all kidney transplant candidates [1]. Transplant candidates who receive hemodialysis at a center should be reassessed every six months.
Initial evaluation is typically with an HCV antibody test. In countries or dialysis centers with a low prevalence of HCV, a negative antibody test is likely sufficient to rule out HCV infection [1]; positive antibody tests should be followed by HCV RNA testing. In areas with a high prevalence of HCV, transplant candidates should be evaluated by HCV RNA testing because false-negative HCV antibody tests have been reported to be as high as 17.9 percent in dialysis units in such areas [8]. The blood samples for testing should preferably be drawn before hemodialysis, as hemodialysis reduces plasma viral levels [9]. For transplant candidates who were previously treated for HCV infection (and therefore have existing HCV antibodies), ongoing evaluation is performed with HCV RNA testing. Detectable HCV RNA is indicative of HCV infection. The diagnosis of HCV infection is discussed in detail elsewhere. (See "Screening and diagnosis of chronic hepatitis C virus infection", section on 'Diagnosis'.)
The reason to evaluate patients is that, with advances in HCV antiviral therapy, HCV infection can be successfully cured in the majority of patients, either before or after transplant. In addition, transplant candidates with HCV infection may have the opportunity to shorten the waiting time by accepting a kidney from a donor with HCV infection, if available and offered by their transplant center.
HCV infection in the potential recipient is not a contraindication to kidney transplantation. Although HCV infection prior to transplantation, when not successfully treated, increases posttransplant morbidity and mortality, even in the absence of cirrhosis, patients with HCV infection have a lower mortality with transplantation compared with remaining on dialysis. (See 'Prognosis' below.)
We do not test patients who are negative for HCV RNA for occult HCV infection. Occult HCV infection is defined as the detection of HCV RNA in peripheral blood mononuclear cells and/or hepatocytes in the absence of positive HCV RNA in the serum. The prevalence of occult HCV infection has been found to be very low in kidney transplant recipients; therefore, routine evaluation for this is not warranted in these patients [6].
Staging of liver disease — Staging of liver disease (ie, assessing extent of fibrosis) is a standard component of the evaluation of patients with HCV infection, including those who are kidney transplant candidates. Staging is initially performed with noninvasive testing, which may include blood tests and imaging tests; we perform transient elastography (TE) or a combination of TE and a serum marker test, such as the aspartate aminotransferase (AST)-to-platelet ratio index (APRI). (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations".)
Imaging tests such as TE, which uses shear wave imaging to estimate liver stiffness, have been shown to be reasonably accurate for the evaluation of liver fibrosis in patients with end-stage kidney disease (ESKD) [10,11]. In one study of 284 patients on hemodialysis with chronic HCV infection, TE was found to be superior to the APRI (area under the receiver operating characteristic [ROC] curve 0.96 versus 0.84) in assessing the severity of hepatic fibrosis [10]. TE should only be performed after a dialysis session since liver stiffness measurements have been shown to decrease significantly after hemodialysis [12-15].
If a blood test is used, we prefer using the APRI because it is easy to calculate in the routine clinical setting and has been shown to have a higher predictive ability to detect fibrosis in patients with ESKD than other blood tests such as the Fibrosis-4 (FIB-4) score, hyaluronic acid, and the human cartilage glycoprotein YKL-40 [16-18]. However, in the setting of chronic kidney disease (CKD) and ESKD, the APRI or FIB-4 score may yield a false-negative result, as transaminase levels in patients on dialysis tend to fall within the lower end of the range of normal values (see "Serum enzymes in patients with kidney failure", section on 'Aminotransferases'). Nonetheless, both APRI and FIB-4 scores can accurately exclude significant fibrosis or cirrhosis in patients on hemodialysis when using TE as the reference standard [19]. Commercial blood tests such as the FibroTest and ActiTest have not been shown to be reliable noninvasive markers for the prediction of fibrosis in patients with HCV on hemodialysis [20]. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations", section on 'Serologic tests'.)
A liver biopsy can be performed when noninvasive test results are discordant or when liver comorbidities are suspected [1]. Although liver biopsy was previously considered a gold standard to evaluate all transplant candidates with HCV infection for the presence of cirrhosis, advances in HCV therapy and noninvasive testing for liver fibrosis have reduced the need for this invasive procedure, which carries risk of severe complications [1].
Results of these staging tests inform liver-related prognosis, selection of HCV treatment regimen, and the decision on kidney versus combined kidney-liver transplantation. Patients with cirrhosis detected clinically or on staging tests should undergo evaluation for portal hypertension. (See 'Kidney versus combined liver-kidney' below and "Portal hypertension in adults", section on 'Diagnosis'.)
Although the presence of cirrhosis on biopsy was previously associated with a poor prognosis following transplantation [21], the availability of safe and effective antiviral therapy has enabled the vast majority of kidney transplant candidates with HCV infection and cirrhosis to be successfully treated, and a resultant improvement in liver-related morbidity can be expected [22]. Furthermore, kidney transplantation alone is now feasible for patients with compensated cirrhosis in the absence of major complications of portal hypertension. (See 'Antiviral treatment' below.)
TYPE OF TRANSPLANTATION
Use of kidneys from HCV-seropositive donors — Accepting a kidney from a donor with chronic HCV infection may substantially reduce waiting times on the transplant list and improve long-term outcomes [23,24]. Transplantation of a kidney from a donor with chronic HCV infection had historically been associated with increased morbidity and possibly mortality in kidney transplant recipients without HCV, with a less clear impact on recipients with preexisting HCV infection. However, these data were from the pre-direct-acting antiviral (DAA) therapy era, when the risk of rejection with interferon-based regimens precluded posttransplant HCV treatment. Historical data are furthermore limited by the inability to distinguish viremic from nonviremic donors and recipients since serologic testing was used without HCV RNA testing to identify HCV infection in most of these older studies.
The increasing availability of DAA therapy that is effective and safe for transplant recipients has opened up the possibility of transplanting a kidney from an HCV RNA-positive donor into an HCV RNA-positive recipient followed by posttransplant antiviral therapy. Furthermore, with the high cure rates achieved with DAA therapy, several trials have investigated the feasibility of allocating kidneys from HCV RNA-positive donors to HCV RNA-negative patients, followed by antiviral treatment of the ensuing HCV infection [25-33]. Most of these trials have reported 100 percent cure rates of HCV with excellent short-term graft function and safety profile [28]. A retrospective United States-based cohort study using Organ Procurement and Transplantation Network (OPTN) data showed similar graft survival even at five years for recipients of HCV-RNA–positive versus HCV-RNA-negative donor kidneys in the DAA era [34]. The approach to use of kidneys from donors with HCV infection is discussed in detail elsewhere. (See "Hepatitis C virus infection in kidney donors", section on 'Use of kidneys from donors with HCV infection'.)
Kidney versus combined liver-kidney — For patients with cirrhosis, the decision to perform a kidney transplantation alone versus combined liver-kidney transplantation usually depends upon whether the patient has compensated or decompensated liver disease [1]. Decompensated cirrhosis is characterized by ascites, hepatic encephalopathy, prolonged prothrombin time, decreased serum albumin, and/or hyperbilirubinemia (see "Cirrhosis in adults: Overview of complications, general management, and prognosis" and "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Major complications'):
●Patients with HCV infection and decompensated cirrhosis should not receive a kidney transplant alone but should be considered for combined liver-kidney transplantation [1]. Patients with compensated cirrhosis but severe portal hypertension should also be considered for combined liver-kidney transplantation.
●Patients with HCV infection and compensated liver cirrhosis (ie, those with well-preserved liver function) without portal hypertension may receive a kidney transplantation alone. However, approaches differ among transplant centers. When sustained virologic response (SVR) has been achieved after HCV treatment and no other comorbidities are present, it is possible that liver function will remain stable over a long period of time.
Decompensated cirrhosis is a standard indication for liver transplantation. A 2008 American consensus conference proposed that combined liver-kidney transplantation should be performed if patients have severe portal hypertension (defined as a hepatic venous pressure gradient [HVPG] ≥10 mmHg) even with compensated cirrhosis since HVPG predicts clinical decompensation in patients with compensated cirrhosis and is directly related to mortality [35] (see "Portal hypertension in adults"). Some retrospective studies have reported successful kidney transplantation alone in patients with compensated cirrhosis and portal hypertension, but invasive measurement of HVPG in recipients was not performed in these studies [7,36]. Under the existing allocation policy using the Model for End-Stage Liver Disease (MELD) score, a patient with HCV infection and end-stage kidney disease (ESKD), compensated cirrhosis, and portal hypertension, but with no bleeding diathesis, will have a very low chance of receiving a liver, especially in countries with higher demand for MELD scores for liver transplantation. Thus, the medical eligibility criteria for allocation of liver-kidney need to be revised to provide prioritization to such patients for combined liver-kidney transplantation.
Patients with less severe portal hypertension (ie, HVPG <10 mmHg) may have acceptable outcomes with kidney transplantation alone. In two series with 9 and 18 patients with HCV and biopsy-proven cirrhosis and HVPG <10 mmHg who underwent kidney transplantation alone, there was no difference in patient and graft survival rates at three years compared with recipients without cirrhosis [37,38]. Larger prospective studies are needed to determine whether HVPG may be used as a criterion to identify patients who are acceptable for kidney transplantation alone.
ANTIVIRAL TREATMENT — We recommend antiviral treatment for all kidney transplant candidates and recipients with HCV infection. The advent of safe and highly effective direct-acting antiviral (DAA)-based interferon-free treatment regimens has changed the landscape of HCV treatment in kidney transplant candidates and recipients. As an example, in a study performed four years after DAA introduction in the United States, DAAs were associated with a 57 percent reduction in the risk of death among HCV-seropositive transplant recipients who received a kidney from an HCV-seropositive donor (adjusted hazard ratio [HR] 0.43, 95% CI 0.19-0.93) compared with mortality rates prior to the DAA era [39].
The decision of when and how to treat kidney transplant candidates and recipients with HCV infection should be tailored on an individual basis, in close collaboration with specialists in transplant and HCV management.
Guidelines for the management of HCV infection by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) are updated on a regular basis, following availability of new medications or presentation of major treatment trials. These guidelines can be accessed on the internet [40]. The discussion in this section is generally consistent with these guidelines.
Other available guidelines include treatment recommendations from the European Association for the Study of the Liver (EASL) [41] and the Asian Pacific Association for the Study of the Liver (APASL) [42].
Timing of treatment — Whether to treat HCV infection prior to or after transplantation is a major management decision for kidney transplant candidates, and the optimal approach is uncertain.
With the availability of several DAA regimens, including pangenotypic regimens, that have established safety and efficacy in the setting of severe kidney function impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) and/or dialysis, the majority of transplant candidates could be successfully treated with minimal side effects prior to transplantation. However, posttransplant antiviral therapy is also highly effective and safe, and delaying treatment until after transplant may open up the possibility of receipt of an organ from a donor with HCV infection, which could decrease waiting times and waitlist mortality, improve organ utilization, and even improve graft survival [43-46]. However, this approach depends on national HCV prevalence in the donor pool and thus the effect on the consequent waiting time advantage. In the United States, for example, the waiting time could be reduced significantly to less than one year (even as low as a median of 58 days) for an organ from a donor with HCV infection as compared with more than five years for one from a donor without HCV infection [24,44-46]; by contrast, there may not be a substantial waiting time advantage in countries with lower HCV prevalence. The wait time advantage may be further reduced if expanded use of organs from donors with HCV infection increases competition.
Decisions on timing of antiviral treatment therefore depend upon several factors, including severity of liver disease, extrahepatic complications of HCV infection, anticipated wait time on the transplant list, and accessibility of organs from donors with HCV infection:
●For kidney transplant candidates with decompensated cirrhosis, a combined kidney-liver transplantation is recommended [1]. The decision to treat before or after combined kidney-liver transplantation should be individualized, taking into account the short-term prognosis and Model for End-Stage Liver Disease (MELD) score, the likelihood of meaningful response to therapy and expected virologic response, access to transplantation, and treatment options. (See "Hepatitis C virus infection in liver transplant candidates and recipients".)
●For kidney transplant candidates who have advanced or rapidly progressive liver fibrosis (but not decompensated cirrhosis) or severe extrahepatic manifestations (eg, cryoglobulinemic vasculitis), prompt antiviral therapy is generally warranted, and we typically do not postpone treatment until after transplantation. (See 'Regimen selection before transplantation' below.)
●For kidney transplant candidates who do not have decompensated, advanced, or rapidly progressive liver fibrosis or severe extrahepatic manifestations, treatment considerations depend upon whether they are on the deceased-donor waiting list or are receiving an organ from a living donor:
•For those on the deceased-donor waiting list, the decision to treat prior to transplantation or after transplantation is informed by the anticipated wait time and whether organs from donors with HCV infection are available to potentially decrease that wait time. If they are available, postponing HCV treatment in a patient with no significant hepatic fibrosis or extrahepatic manifestations so that the patient can receive an organ earlier may be a valuable option. Even if receipt of an organ from a donor with HCV infection results in two different HCV genotypes posttransplant, the infections could still be easily treatable. (See 'Regimen selection after transplantation' below.)
If the anticipated wait time for kidney transplantation is long and receipt of an organ from a donor with HCV infection is not feasible or is not expected to meaningfully reduce that wait time by ≥9 months, proceeding with antiviral therapy prior to transplant is appropriate. However, in patients with no fibrosis (F0), outcomes might be the same with pre- and posttransplant treatment [47]. (See 'Regimen selection before transplantation' below.)
•For those who are receiving an organ from a living donor, we typically treat with antiviral therapy prior to transplant unless there are limiting circumstances (eg, drug-drug interactions or the inability to delay transplant for the 8 to 12 weeks of treatment). If antiviral therapy is started prior to transplantation, the decision can be individualized whether to delay transplantation for another 12 weeks until the completion of therapy to determine if a sustained virologic response at 12 weeks (SVR12) is achieved. Although cure rates with DAA are very high, retreatment following DAA failure may be more difficult in the posttransplant period because of potential drug interactions, and data on the regimens used for retreatment are limited for transplant recipients [48]. Eradicating HCV prior to transplantation would avoid these issues.
Our approach differs from the 2018 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, which propose delaying therapy in such patients until after transplantation if it is expected to occur within 24 weeks [1]. The 2018 guidelines were written when DAA options for patients with ESKD were limited to a regimen active against genotypes 1 and 4 only. Since pangenotypic regimens for patients with ESKD are widely available [9], we believe that there is no benefit to postponing treatment until after transplantation. (See 'Regimen selection before transplantation' below.)
All patients with ongoing HCV infection following kidney transplantation warrant antiviral therapy, irrespective of the kidney function. (See 'Regimen selection after transplantation' below.)
Cost-effectiveness studies support the concept that the timing of DAA therapy relative to transplant primarily depends upon the waiting list advantage and the impact of delay on HCV-associated mortality, particularly in those with advanced fibrosis or cirrhosis [47,49]. In one model, posttransplant treatment was more cost effective, except in patients with advanced fibrosis in long wait time areas, who risked liver disease progression while awaiting transplantation [47].
Pretreatment evaluation — The evaluation of kidney transplant candidates and recipients in expectation of HCV antiviral therapy is generally the same as for the general population. This is discussed in detail elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Evaluation'.)
Regimen selection before transplantation — Regimen selection for chronic HCV infection depends upon genotype, extent of underlying liver disease, and antiviral treatment history, as well as potential drug interactions and availability and costs of comparable regimens. The treatment of patients with reduced GFR, including patients on dialysis, is discussed elsewhere. (See "Treatment of chronic hepatitis C infection in adults with kidney function impairment", section on 'Regimen selection and dosing'.)
Regimen selection after transplantation — Posttransplant antiviral therapy should be administered by or in consultation with experts in the management of transplant recipients with HCV infection. For kidney transplant recipients, major considerations in drug selection are the presence and extent of kidney function impairment, evidence supporting the particular regimen in transplant populations, and potential interactions with the immunosuppressive agent. (See 'Interactions with immunosuppressive agents' below.)
Ample data are now available on the safety and efficacy of various DAA regimens in kidney transplant recipients, which show good tolerability and high SVR rates, consistent with those in the general population [50-60]. Moreover, indirect evidence from studies in liver transplant recipients has also suggested promising results with various regimens for the posttransplant population. (See "Hepatitis C virus infection in liver transplant candidates and recipients", section on 'Post-transplant regimen selection'.)
Although interferon-free regimens are the most effective for most patients with chronic HCV infection, they may not be accessible in resource-limited countries. However, even in such cases, interferon should not be used for transplant recipients, since it is associated with an increased risk of acute rejection of the allograft [61-66]. Symptomatic acute rejection due to interferon has been experienced even in nonfunctional grafts (ie, in patients back on dialysis) [67,68]. This recommendation is consistent with the guidelines from EASL [41] and WHO [69].
Suggested regimens — Our approach to regimen selection depends on prior exposure to DAA therapy:
●DAA naïve – For patients who have not previously received DAA therapy for the current HCV infection, we suggest:
•Sofosbuvir-velpatasvir for 12 weeks for all genotypes – Direct data are limited to several observational studies in which a handful of kidney transplant recipients received sofosbuvir-velpatasvir for 12 weeks [24,33,70-73]. All achieved SVR while maintaining good allograft function.
or
•Ledipasvir-sofosbuvir for 12 weeks for genotypes 1 or 4, 5, and 6 – In a trial of 114 kidney transplant recipients with genotype 1 or 4 infection who were treatment naïve or had failed prior treatment with interferon, ledipasvir-sofosbuvir for 12 or 24 weeks resulted in an SVR rate of 100 percent [52]. Compensated cirrhosis was present in 15 percent.
Glecaprevir-pibrentasvir for 12 weeks is an equally effective alternative option for all genotypes, but it carries a higher likelihood of needing immunosuppressive drug dose adjustments compared with the sofosbuvir-containing regimens (eg, cannot be given with cyclosporine doses >100 mg), and it should not be administered in patients with decompensated liver cirrhosis (Child-Pugh class B or C) (see 'Interactions with immunosuppressive agents' below). In a trial that included 20 kidney transplant recipients who were HCV treatment naïve or had failed prior treatment with interferon, glecaprevir-pibrentasvir for 12 weeks resulted in an SVR rate of 100 percent [57]. Most patients had genotype 1 infection and no or minimal fibrosis. No kidney transplant recipients experienced adverse events related to transplant rejection.
For patients with genotype 1 and no baseline NS5A resistance-associated substitutions (RASs) who cannot use other options, elbasvir-grazoprevir for 12 weeks is a potential alternative that has been evaluated in small studies of transplant recipients without baseline infection who received kidneys from donors with HCV infection [26,60,74-77]. However, we do not recommend this regimen in patients with cyclosporine use because of significant interactions, and it should not be administered in patients with decompensated liver cirrhosis (Child-Pugh class B or C). (See 'Interactions with immunosuppressive agents' below.)
Other observational data in kidney transplant recipients support the high efficacy of these and other DAA regimens (including sofosbuvir plus daclatasvir, as well as sofosbuvir plus simeprevir and ombitasvir-paritaprevir-ritonavir plus dasabuvir, which are no longer preferred regimens in the general population and for which the sponsor has even withdrawn the marketing authorizations). These are generally used only in regions where access to the fixed-combination regimens mentioned above are limited [48,50,53,54,78,79].
●DAA experienced – For most patients with relapsed HCV infection following DAA therapy, we suggest:
•Sofosbuvir-velpatasvir-voxilaprevir for 12 weeks for all genotypes – However, it should not be administered to patients with decompensated cirrhosis (Child-Pugh class B or C), and drug interactions with certain immunosuppressive agents may complicate management. Data on the use of sofosbuvir-velpatasvir-voxilaprevir in kidney transplant recipients are limited.
Our recommendations are largely consistent with the 2018 EASL guidelines and the joint AASLD/IDSA guidelines [40,41]. Regimen selection is generally the same regardless of eGFR; however the European Medicines Agency (EMA) notes that for patients with eGFR <30 mL/min/1.73 m2, sofosbuvir-based regimens should only be used when there are no other relevant options [80]. In the United States, the FDA has acknowledged that sofosbuvir can be used in all stages of kidney disease, including during dialysis. Growing evidence supports the use of Sofosbuvir in CKD stage 4/5 [74,81-85].
No dose adjustment for kidney function is required in patients for the DAA agents. However, sofosbuvir-containing regimens are cleared by dialysis and should be administered after the session on hemodialysis days. Dosing data among patients on peritoneal dialysis are limited. Moreover, ribavirin, if used, should be dose reduced among patients with eGFR 30 to 50 mL/min/1.73 m2. The manufacturer does not recommend use of ribavirin with a creatinine clearance <50 mL/min because of the risk of severe hemolytic anemia. However, among transplant recipients, after the implementation of safety precautions, alternating doses of 200 and 400 mg every other day with eGFR 30 to 50 mL/min/1.73 m2 can be given [40] (see "Treatment of chronic hepatitis C infection in adults with kidney function impairment"). Safety precautions include close monitoring of hemoglobin levels, initiation of erythropoietin, or increasing the dose of erythropoietin in patients already receiving it.
For patients on specific agents, the immunosuppressive regimen may require modification as described elsewhere. (See 'Interactions with immunosuppressive agents' below.)
Interactions with immunosuppressive agents — The immunosuppressive regimen that an individual patient is on may limit the selection of the antiviral agent or need to be modified (table 1). Relevant drug interactions with the regimens most commonly used in the posttransplant setting are discussed here. Potential drug interactions can also be assessed using the drug interactions program included in UpToDate.
●Glecaprevir-pibrentasvir – Concurrent use with cyclosporine increases the levels of glecaprevir and pibrentasvir, so coadministration is not recommended when the daily cyclosporine dose exceeds 100 mg.
Routine dose modifications are not required with other immunosuppressive agents. Close therapeutic drug monitoring of tacrolimus, sirolimus, and everolimus is advisable; plasma levels of these agents may increase when used with glecaprevir-pibrentasvir and, thus, warrant dose modification. In addition, tacrolimus clearance may increase as HCV replication declines.
Glecaprevir-pibrentasvir has been studied in patients taking tacrolimus, sirolimus, everolimus, azathioprine, mycophenolate mofetil, prednisone/prednisolone <10 mg daily dose, and cyclosporine <100 mg daily dose [57].
●Sofosbuvir – This agent has not been shown to have a significant drug-to-drug interaction with cyclosporine, mycophenolate, or sirolimus. However, clearance of the hepatitis C virus may affect tacrolimus pharmacokinetics, and therefore tacrolimus concentrations should be followed, with dose adjustments as necessary.
●Ledipasvir – There are theoretical concerns that ledipasvir may interact with calcineurin inhibitors or inhibitors of mammalian target of rapamycin (mTOR inhibitors; sirolimus, everolimus) since ledipasvir is both a substrate and inhibitor of P-glycoprotein [86]. However, ledipasvir appears to have a minimal impact on cyclosporine concentrations [87,88]. Tacrolimus clearance may also increase as HCV replication declines.
●Velpatasvir – With a similar pharmacokinetic profile to ledipasvir [89,90], velpatasvir shares the same theoretical concerns of interactions with calcineurin and mTOR inhibitors.
MONITORING AFTER TRANSPLANTATION — Routine monitoring after kidney transplantation is discussed in detail elsewhere. (See "Overview of care of the adult kidney transplant recipient", section on 'Routine follow-up and laboratory monitoring'.)
Patients who have achieved SVR — All patients with advanced fibrosis or cirrhosis posttransplant, regardless of whether they achieved sustained virologic response (SVR), require ongoing monitoring because they continue to be at risk of hepatocellular carcinoma and other complications. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Preventing complications'.)
Patients with ongoing HCV infection — All posttransplant patients with chronic HCV infection should be evaluated and considered for antiviral treatment. Until their HCV infection has been successfully treated, kidney transplant recipients should be closely followed for the emergence or recurrence of HCV-related kidney disease and liver disease.
Proteinuria and kidney disease — We agree with the 2018 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines that kidney transplant recipients with chronic HCV infection should be tested for proteinuria by spot urine protein-to-creatinine ratio or by 24-hour urine protein determination every six months [1]. New-onset proteinuria (either urine protein-to-creatinine ratio >1 g/g or 24-hour urine protein greater than 1 g on two or more occasions) or microscopic hematuria without another identifiable cause warrants an allograft biopsy studied with light microscopy, immunofluorescence techniques, and electron microscopy.
Proteinuria should also be treated with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), as tolerated [1]. Although we are not aware of any studies in this population in particular, studies in kidney transplant recipients in general have suggested that ACEIs and ARBs reduce proteinuria and slow down the progression of chronic kidney allograft disease [91-93]. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Renin-angiotensin system inhibitors'.)
Histologic findings characteristic of cryoglobulinemic membranoproliferative glomerulonephritis (MPGN) may require consideration for specific immunosuppressive therapy in addition to direct-acting antiviral (DAA) therapy. This is discussed in more detail elsewhere. (See "Mixed cryoglobulinemia syndrome: Treatment and prognosis".)
Proteinuria is the most common manifestation of kidney disease in kidney transplant recipients with HCV infection and has been used as a marker of disease in the kidney allograft in these patients [94-99]. Kidney disease associated with HCV infection in transplant recipients includes:
●Membranoproliferative glomerulonephritis – MPGN is more common among transplant recipients with HCV infection compared with recipients without infection [94,100]. Both recurrent and de novo MPGN with or without mixed cryoglobulinemia have been described [94,95,100-102]. De novo MPGN is more likely to progress to end-stage kidney disease (ESKD) in recipients with HCV infection [94,95,100-102]. (See "Overview of kidney disease associated with hepatitis C virus infection", section on 'Membranoproliferative glomerulonephritis without cryoglobulins'.)
●Membranous nephropathy – Membranous nephropathy (MN) has been associated with HCV infection in kidney transplant recipients [94,103]. However, it is unclear if there is an etiologic relationship, and not all studies have demonstrated an association [100]. (See "Overview of kidney disease associated with hepatitis C virus infection", section on 'Membranous nephropathy'.)
●Renal thrombotic microangiopathy – A renal thrombotic microangiopathy (TMA) may be more commonly observed in kidney transplant recipients with HCV infection, particularly among those with anticardiolipin antibodies [104,105]. (See "Clinical manifestations of antiphospholipid syndrome".)
●Transplant glomerulopathy – HCV infection appears to be associated with transplant glomerulopathy, which is usually believed to be a glomerular manifestation of chronic rejection [102,105-108]. In one study, the prevalence of HCV infection among patients with transplant glomerulopathy was 36 percent compared with 4.8 percent in the overall kidney transplant population [105]. Transplant glomerulopathy appeared to progress more rapidly to allograft failure among recipients with HCV infection [105].
The diagnosis of HCV-associated glomerular disease is usually established by kidney biopsy. Both MPGN and the MPGN pattern of transplant glomerulopathy present with mesangial cell proliferation and glomerular basement membrane splitting and are often indistinguishable on light microscopy (picture 1). However, electron microscopy typically shows large, electron-dense immune complex deposition in the glomerular basement membrane in MPGN (picture 2) and only subendothelial accumulation of electron-lucent material in transplant glomerulopathy (picture 3) [102]. (See "Kidney transplantation in adults: Chronic allograft nephropathy".)
Among patients with MPGN, there is no way to determine on kidney biopsy whether HCV infection is responsible for the glomerular disease.
Liver disease — For surveillance of liver disease after transplantation, serial transient elastography (TE) measurements may detect fibrosis progression and allow the identification of "rapid fibrosers," though this remains to be evaluated in prospective studies [5].
At our institutions, we evaluate patients without cirrhosis annually with liver ultrasound and TE, although this is not usually required long term following successful cure of HCV infection in patients with no or mild fibrosis. (See "Noninvasive assessment of hepatic fibrosis: Ultrasound-based elastography".)
Patients with cirrhosis require lifelong monitoring with liver ultrasound and TE annually, even after cure of HCV infection, because they are at risk of hepatocellular carcinoma and other complications. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Preventing complications'.)
HCV infection is a major cause of liver disease following kidney transplantation [5]. A survey of studies published prior to the availability of effective antiviral treatment indicated a higher rate of posttransplant liver disease among recipients with HCV infection compared with recipients without infection (19 to 64 percent versus only 1 to 30 percent among recipients without anti-HCV, with a relative risk of 5.0 in one study) [109-114].
The major form of liver disease is chronic hepatitis. In addition, fibrosing cholestatic hepatitis, characterized by prominent cholestasis and rapidly progressive liver failure, has been described following kidney transplantation [115,116]. While some studies have suggested that HCV-related liver disease progresses more rapidly to cirrhosis among kidney transplant recipients compared with nontransplant patients [117], others have suggested slower progression posttransplantation compared with kidney transplant candidates [118,119].
Differences in outcome among studies have been attributed to differences in the severity and duration of HCV infection and comorbidities at the time of transplantation and to different immunosuppressive regimens [5]. The impact of various immunosuppression on the natural history of HCV infection in kidney transplant recipients remains unclear [120].
Other complications
●Posttransplant diabetes mellitus – Posttransplant screening for posttransplant diabetes mellitus is recommended for kidney transplant recipients regardless of HCV infection. (See "Kidney transplantation in adults: Posttransplantation diabetes mellitus", section on 'Evaluation for PTDM'.)
HCV infection among transplant recipients is associated with a further increase in posttransplant diabetes mellitus risk, as in the general population. This was best shown in a meta-analysis that included 10 studies and 2502 transplant recipients, among whom HCV seropositivity conferred a fourfold higher odds of posttransplant diabetes mellitus [121]. Furthermore, successful antiviral therapy prior to transplant is associated with a lower risk of posttransplant diabetes mellitus as well as improved insulin sensitivity [122,123]. Insulin resistance has been found to be the central mechanism associated with abnormalities in glucose metabolism in patients with HCV infection both in transplant and nontransplant settings [123-125]. (See "Extrahepatic manifestations of hepatitis C virus infection", section on 'Diabetes mellitus' and "Kidney transplantation in adults: Posttransplantation diabetes mellitus", section on 'Modifiable risk factors'.)
●Posttransplant lymphoproliferative disease (PTLD) – HCV infection may increase the risk of PTLD. In one study of 1011 liver, heart, and kidney transplant recipients, the prevalence of PTLD was higher among HCV-seropositive recipients compared with HCV-seronegative recipients (3.6 versus 1.2 percent, respectively) [126]. Moreover, in a case report, disappearance of PTLD due to suppression of HCV viremia, together with a reduction of immunosuppression, was observed [127]. Among patients with PTLD, HCV infection is associated with a higher mortality [128]. The clinical features and diagnosis of PTLD are discussed elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders".)
PROGNOSIS — Most studies in the pre-direct-acting-antiviral (DAA) therapy era with extended follow-up demonstrated that an ongoing HCV infection increased mortality and the risk of graft loss following kidney transplantation [129-131]. However, compared with remaining on the transplant waiting list, transplantation was associated with better survival among patients with HCV infection.
Compared with recipients without HCV — Compared with recipients without infection, transplant recipients with ongoing HCV infection following transplantation have decreased patient and allograft survival. The most useful information comes from two meta-analyses [130,131].
●In one meta-analysis that included 18 observational studies (133,530 individuals), the HCV-associated relative risk of all-cause mortality was 1.85 (95% CI 1.49-2.31) [130]. The adjusted HCV-associated relative risk of graft loss was 1.76 (95% CI 1.46-2.11). In an analysis of nine and four studies, both liver- and cardiovascular-related mortality were higher among HCV-positive recipients.
●In a meta-analysis that included 16 studies, the combined hazard ratio (HR) for mortality in recipients with HCV infection was 1.69 (95% CI 1.33-1.97). The risk of graft loss was also higher for recipients with HCV infection (HR 1.56, 95% CI 1.22-2.00) [131].
However, the outcomes of kidney transplant recipients with HCV infection who achieve virologic clearance appear to be comparable to those of recipients without infection. In one retrospective study of 31,433 kidney transplant recipients between 1993 and 2010, of whom 1060 (3.4 percent) had chronic HCV infection, patients with HCV and undetectable HCV RNA had higher 10-year patient survival (87 versus 78 percent) and similar 10-year graft survival (64 versus 62 percent) compared with matched controls without infection [132].
Although it will take several more years to have sufficient data, it is anticipated that patient and graft survival may substantially improve with the ability to treat transplant recipients with DAA therapy, and evidence for improved survival is already accumulating [39]. In a retrospective analysis of data from the United States Organ Procurement and Transplantation Network (OPTN) that evaluated outcomes of mate kidneys from the same donor that were transplanted into HCV-discrepant recipients (ie, one recipient had HCV infection and the other did not), HCV infection in the recipient was associated with worse patient and graft survival in the pre-DAA era (before December 2013) but not in the post-DAA era [133].
Compared with dialysis — Kidney transplantation results in better survival than dialysis among anti-HCV-positive patients [118,134-138]. A meta-analysis that included nine studies and 1734 patients showed that patients with HCV infection on a transplant waiting list had a 2.19 times higher relative risk of death compared with patients with HCV infection who received a kidney transplant (95% CI 1.5-3.2) [137]. Compared with the transplant group, the waitlisted patients had a higher risk of cardiovascular disease, a lower risk of infection, and a similar risk of liver disease.
Effect of HCV genotype on survival after kidney transplantation — There are limited data concerning the impact of different HCV genotypes on survival after kidney transplantation. Data from the New England Organ Bank revealed that patient survival did not vary significantly with genotype [139]. However, the genotype distribution and the number of patients evaluated were small. (See "Characteristics of the hepatitis C virus".)
In the general population, infection with HCV genotype 3 has been associated with an increased risk for cirrhosis [140]. After liver transplantation, recipients with HCV genotype 1 were found to have the highest risk of advanced fibrosis [141]. Nevertheless, no association has been found to date between the HCV genotype and patient survival.
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" and "Society guideline links: Hepatitis C virus infection".)
SUMMARY AND RECOMMENDATIONS
●Overview – Hepatitis C virus (HCV) causes kidney disease in native and transplanted kidneys. Kidney transplant recipients with untreated HCV infection have worse patient and allograft survival after transplantation compared with transplant recipients without infection. However, transplantation is still associated with lower mortality than dialysis among patients with HCV infection. HCV infection is not considered a contraindication to transplantation. (See 'Introduction' above and 'Prognosis' above.)
●Evaluation of transplant candidates
•Assessment for HCV infection – Consistent with other expert groups, we assess for HCV infection in all kidney transplant candidates. HCV antibody testing can be used for screening in low-prevalence countries, with the caveat that impaired antibody production in dialysis patients may result in false negatives. In high-prevalence countries, transplant candidates should be evaluated by testing for HCV RNA. (See 'Assessment for HCV infection' above.)
•Liver staging – Transplant candidates with HCV should undergo assessment for liver fibrosis and, if cirrhosis is present, assessment for portal hypertension prior to transplantation. Liver staging is initially performed with noninvasive testing, such as elastography. Liver biopsy is generally reserved for discordant noninvasive test results or suspected liver comorbidities. (See 'Staging of liver disease' above.)
●Type of transplantation – Decompensated cirrhosis and cirrhosis with severe portal hypertension are associated with a very poor prognosis following transplantation and exclude transplantation of a kidney alone in most centers. These patients should be considered for combined kidney-liver transplantation. (See 'Type of transplantation' above.)
●Antiviral therapy – For all kidney transplant recipients with HCV infection, we recommend antiviral treatment (Grade 1B). HCV infection increases mortality and morbidity after kidney transplantation, and the treatment of HCV infection is effective and safe in such patients.
•Timing – Timing of antiviral treatment (before or after transplantation) depends on several factors, including severity of liver disease (and especially decompensated cirrhosis) and estimated waiting time on the kidney transplant list. In locations where receiving an organ from a donor with HCV infection reduces the waiting time substantially, deferring antiviral treatment until after transplantation to maintain eligibility for that organ (which is generally reserved for recipients with HCV infection) is a reasonable strategy as long as disease severity does not warrant earlier treatment. (See 'Timing of treatment' above.)
•Regimen selection
-Pretransplant – Pretransplant antiviral regimen selection in kidney transplant candidates with HCV infection depends on extent of underlying liver disease, comedications, and antiviral treatment history. This is discussed in detail elsewhere. (See "Treatment of chronic hepatitis C infection in adults with kidney function impairment", section on 'Regimen selection and dosing'.)
-Posttransplant – For antiviral therapy of HCV infection after kidney transplantation, we suggest sofosbuvir-velpatasvir or, for genotype 1 or 4, 5, 6 infection, ledipasvir-sofosbuvir, each for 12 weeks (Grade 2C). Glecaprevir-pibrentasvir for 12 weeks is an equally effective and safe option but may have interactions with the immunosuppressive regimen (table 1). Elbasvir-grazoprevir should only be used if the other options are not available. (See 'Regimen selection after transplantation' above.)
●Monitoring after transplantation – In addition to standard posttransplant monitoring, kidney transplant recipients with HCV infection warrant close monitoring for HCV-related kidney disease and liver disease until their HCV has been treated. All patients with advanced fibrosis or cirrhosis posttransplant, regardless of whether they were successfully treated for HCV, continue to be at risk of hepatocellular carcinoma and other complications and warrant continued monitoring for these. (See 'Monitoring after transplantation' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Svetlozar Natov, MD, Brian JG Pereira, MD, and Martin S Hirsch, MD, who contributed to earlier versions of this topic review.
10 : Transient elastography to assess hepatic fibrosis in hemodialysis chronic hepatitis C patients.
38 : Equal 3-Year Outcomes for Kidney Transplantation Alone in HCV-Positive Patients With Cirrhosis.
39 : The impact of direct-acting antiviral agents on liver and kidney transplant costs and outcomes.
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