Treatment of chronic hepatitis C infection in adults with kidney function impairment

INTRODUCTION — Chronic hepatitis C virus (HCV) infection is frequently present in patients with kidney function impairment. There is a strong and likely causal association between chronic HCV infection and glomerular disease, including mixed cryoglobulinemia, membranoproliferative glomerulonephritis, and possibly membranous nephropathy [1]. HCV has also been associated with proteinuria, incident chronic kidney disease (CKD), progressive CKD, and end-stage kidney disease (ESKD) in general population cohorts [2]. In addition, the prevalence of anti-HCV antibody is higher among patients on hemodialysis compared with healthy populations, suggesting that dialysis patients may be at higher risk of acquiring HCV infection. (See "Hepatitis C virus infection in patients on maintenance dialysis", section on 'Epidemiology'.)

The management of HCV in adults with significant kidney disease (ie, estimated glomerular filtration rate <30 mL/min per 1.73 m²) has undergone substantial changes with the availability of new direct-acting antiviral agents. New HCV medications have allowed for interferon-free and, in almost all cases, ribavirin-free treatment regimens.

This topic will discuss the approach to antiviral therapy of patients with HCV infection and kidney function impairment. Other management issues, such as consideration for immunosuppressive therapy of HCV-associated renal disease as well as treatment of proteinuria and hypertension or other complications, may also be important in such patients. Discussions of renal disease associated with HCV infection, the epidemiology and prevention of HCV infection among dialysis patients, and HCV infection associated with kidney transplantation are found in detail elsewhere:

●(See "Overview of kidney disease associated with hepatitis C virus infection".)

●(See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis" and "Mixed cryoglobulinemia syndrome: Treatment and prognosis".)

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

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

ANTIVIRAL TREATMENT

Rationale for antiviral treatment — The primary rationale for antiviral treatment in patients with chronic HCV infection is to prevent liver-related morbidity and mortality. In the patient with advanced chronic kidney disease (CKD) who is a potential kidney transplant candidate, an additional reason is to prevent kidney transplant-related complications specific to HCV infection. In the less common scenario of HCV-associated vasculitis and/or glomerulonephritis (such as mixed cryoglobulinemia), an additional objective is to eradicate the immunologic stimulus (ie, HCV itself) for the vasculitis and/or glomerulonephritis.

The main sequelae of chronic HCV infection usually develop over the span of decades and include cirrhosis and hepatocellular carcinoma. Eradication of HCV prior to the development of decompensated cirrhosis results in decreased all-cause mortality, liver-related death, need for liver transplantation, hepatocellular carcinoma rates, and liver-related complications [3-8]. This is discussed in detail elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Benefits of treatment'.)

For patients with HCV-associated renal disease, cure of HCV confers additional benefits. As examples, in several earlier studies of patients with HCV-associated membranoproliferative glomerulonephritis and/or mixed cryoglobulinemia, improvements in the cutaneous vasculitis, cryoglobulin titers, proteinuria, and the plasma creatinine concentration were observed in the majority patients who achieved HCV viral suppression during interferon-based treatment [9-23]. In one study of 14 patients, protein excretion fell among viral responders from 6.1 to 1.3 g/day, while there was a lesser, non-statistically significant reduction in protein excretion in nonresponders (6.1 versus 4.2 g/day) [12]. Cessation of interferon therapy resulted in recurrence of viremia, which coincided with recurrent vasculitis, in most patients in these studies, suggesting that the efficacy of interferon was directly related to its antiviral activity [9,11,12,14,24]. In general, when patients with mixed cryoglobulinemia and HCV are treated for HCV and achieve a sustained virologic response, the mixed cryoglobulinemia and its renal manifestations usually (but not always) resolve [25]. As the treatment paradigm for HCV infection has moved away from interferon-containing regimens in all patients, including those with kidney disease and mixed cryoglobulinemia, case reports and series have emerged demonstrating the efficacy of newer direct-acting antiviral (DAA) agents in the treatment of HCV and mixed cryoglobulinemia [26-29].

Patient selection for treatment — We agree with the guidelines from the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) that recommend treatment for all patients with chronic HCV infection who have access to DAA therapies, including those who have kidney function impairment and/or are on dialysis; the main exceptions to universal treatment are patients with short life expectancies due to comorbidities [30].

Specific considerations regarding life expectancy are warranted for patients with HCV-related renal disease and those with severe renal impairment (ie, with estimated glomerular filtration rate [eGFR] <30 mL/min per 1.73 m² or on dialysis):

●For patients with HCV-related renal disease, successful antiviral treatment is likely to result in improved renal function and symptoms related to renal failure. Thus, we believe that antiviral treatment is warranted in such patients, even if life expectancy may otherwise be limited due to other comorbidities. Some of these patients may also warrant immunosuppressive therapy, and timing of antiviral therapy in relation to immunosuppression is an important management consideration. (See 'Timing of treatment' below and 'Rationale for antiviral treatment' above.)

●For patients who have severe renal impairment or are on dialysis and have incidental HCV infection (ie, the renal disease is not associated with HCV), the decision on antiviral treatment should be undertaken on a case-by-case basis and take into account the potential for kidney transplant candidacy in addition to the anticipated benefits of HCV therapy, comorbidities, and life expectancy. In many cases, such individuals have significant comorbidities, including cardiovascular disease. With advanced CKD and competing comorbidities, it can be difficult to determine whether treatment of chronic HCV infection would actually provide the patient with a meaningful benefit. HCV treatment is warranted for most patients who are kidney transplant candidates, although the timing of treatment in relation to transplantation depends on various factors that are discussed in detail elsewhere. (See "Hepatitis C infection in kidney transplant candidates and recipients", section on 'Timing of treatment'.)

Decisions to treat patients with severe renal impairment and decompensated cirrhosis (eg, ascites, hepatic synthetic dysfunction, or hepatic encephalopathy) are further complicated, as most treatment trials of patients with decompensated cirrhosis have excluded those with eGFR <40 mL/min per 1.73 m² [31]. Furthermore, antiviral options are more limited in this population. Specifically, HCV protease inhibitors are contraindicated in decompensated cirrhosis. These patients should be managed by an expert in the care of such patients, preferably at a transplant center. (See 'Hepatorenal syndrome' below.)

The approach to deciding on antiviral treatment for patients with kidney disease has evolved. Prior to the availability of DAA agents that could be safely used in patients with kidney disease, including those on dialysis, deciding to treat these patients represented a management challenge. With non-DAA-based regimens (ie, standard or pegylated interferon with or without ribavirin), the efficacy of antiviral therapy was suboptimal, and the potential toxicity of therapy was high, depending on the extent of renal impairment and the comorbid conditions. With the growing availability of DAAs that can be used safely in patients with kidney disease, including those on dialysis, the decision to treat HCV infection in these patients has become less challenging.

Timing of treatment — The timing of antiviral therapy is relevant for patients who have HCV-associated renal disease as well as for patients with advanced CKD awaiting transplant.

Patients with HCV-associated renal disease — For patients with severe, acute vasculitic manifestations associated with HCV infection, immunosuppressive therapy may be warranted in addition to antiviral therapy. We initiate immunosuppressive therapy first and delay antiviral therapy for one to four months. This approach is in agreement with the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) and the Italian Group for the Study of Cryoglobulinemias guidelines [32-34]. Immunosuppressive therapy is discussed in detail elsewhere. (See "Overview of kidney disease associated with hepatitis C virus infection" and "Mixed cryoglobulinemia syndrome: Treatment and prognosis", section on 'Moderate to severe disease'.)

Although recommendations from these expert groups were formulated prior to the availability of newer DAA agents, there are still limited data on the efficacy and safety of these agents with concomitant use of potent immunosuppressive therapy. Thus, we continue to favor initiation of immunosuppression for severe vasculitic sequelae and/or HCV-related renal disease before starting antiviral medications.

The rationale for delaying antiviral therapy by one to four months in patients who require immunosuppressive therapy is as follows:

●Immunosuppressive therapy can rapidly improve inflammation and resolve target organ damage. Clinical improvements due to antiviral therapy are gradual.

●High-dose immunosuppressive therapy and antiviral therapy each have side effects. Thus, patients may not be able to tolerate both treatments simultaneously. This rationale is less important for interferon-free and ribavirin-free regimens.

●CD19+ B cell depletion with rituximab reduces the viral "reservoir" in CD19+ B cells.

Kidney transplant candidates — Whether to treat HCV infection in kidney transplant candidates prior to or after transplantation is a major management decision, and the optimal approach is uncertain. Kidney transplant should not be withheld from candidates with untreated HCV infection, as post-transplantation treatment with DAA therapy is effective and safe.

Decisions on timing of antiviral treatment depend upon several factors, including severity of liver disease, extrahepatic complications of HCV infection, anticipated wait time on the transplant list, and accessibility of HCV-positive donor organs. This is discussed in detail elsewhere. (See "Hepatitis C infection in kidney transplant candidates and recipients", section on 'Timing of treatment'.)

Regimen selection and dosing — The selection of the antiviral regimen among patients with renal disease is largely the same as that among patients without renal disease and depends on genotype, extent of underlying liver disease, and treatment history.

In general, glecaprevir-pibrentasvir and sofosbuvir-velpatasvir are the main pangenotypic options for initial HCV treatment (algorithm 1). Details on regimen specifics (eg, the duration of therapy), treatment of relapsed infections, and alternative regimens are found elsewhere. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults" and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults".)

Dose adjustments of the DAAs that can be used in advanced renal disease and hemodialysis are not necessary. 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.

However, in the uncommon case that ribavirin is used for treatment in such patients, the dose is adjusted depending on renal function (see 'Ribavirin' below):

●For patients with an eGFR <50 but ≥30 mL/min per 1.73 m², it is given orally at alternating doses of 200 and 400 mg every other day.

●For patients with an eGFR <30 mL/min per 1.73 m² or on dialysis, use of ribavirin is controversial because of the risk of hemolysis. We use it with caution and at an initial low dose of 200 mg three times weekly. Additionally, for patients with a pre-treatment hemoglobin level <10 g/dL, we pre-emptively administer adjunctive erythropoietin therapy during the course of ribavirin if the patient is not already taking it. For patients without pre-existing anemia, a reasonable alternative is to start ribavirin therapy without adjunctive erythropoietin but have a low threshold to initiate it if there is any decrease in hemoglobin. (See 'Ribavirin' below.)

The eGFR can be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [35]. This equation is discussed in detail separately. (See "Assessment of kidney function".)

Although there is an overall paucity of data on anti-HCV therapy in patients with renal disease, there is growing evidence on the use of various regimens in such patients. In general, contemporary antiviral regimens have high efficacy in patients with renal disease, similar to that in the general population, and are safe overall. (See 'Antiviral efficacy and safety' below.)

Care team — A multidisciplinary approach, with a nephrologist and a hepatologist who have experience treating these complex issues, may improve care for patients with HCV and renal impairment. If HCV-associated cryoglobulinemic vasculitis (such as mixed cryoglobulinemia) is present, the care team may also include a rheumatologist.

ANTIVIRAL EFFICACY AND SAFETY

Direct-acting antivirals — Data evaluating the use of direct-acting antiviral (DAA) agents in patients with significant renal impairment are accumulating, although these remain more limited than for the general population. Furthermore, there are no data directly comparing the efficacy of antiviral therapy in patients with and without significant renal impairment. Nevertheless, available evidence in patients with eGFR <30 mL/min per 1.73 m² or on dialysis suggests comparably high efficacy as seen in the general population. Many DAAs also largely appear safe in patients with renal impairment, including those on dialysis. In the absence of direct safety data for certain agents, assumptions about expected safety can also be made based on the mechanism of metabolism.

Glecaprevir-pibrentasvir and sofosbuvir-containing regimens are the primary treatment options for most patients with HCV infection.

●Glecaprevir-pibrentasvir – Both glecaprevir and pibrentasvir undergo hepatic metabolism and clearance, and levels are largely unaffected by renal impairment. In a study (EXPEDITION-4) of 104 patients with genotypes 1 through 6 infection and estimated glomerular filtration rate (eGFR) <30 mL/min per 1.73 m², 82 percent of whom were on dialysis, 98 percent achieved sustained virologic response (SVR) with glecaprevir-pibrentasvir for 12 weeks [36]. Twenty percent had compensated cirrhosis. The regimen was generally well tolerated. None of the severe adverse events were considered drug related, but four percent of patients discontinued the regimen because of adverse events.

●Sofosbuvir-containing combinations – The major elimination pathway for sofosbuvir is renal, so exposure to the drug is increased in patients with severe renal impairment [37]. Because of this and some data suggesting worsening renal function with sofosbuvir, sofosbuvir-containing regimens were previously only recommended for patients with eGFR >30 mL/min per 1.73 m². However, based on subsequent evidence indicating safety, the US Food and Drug Administration approved sofosbuvir-containing regimens for use in severe renal impairment and dialysis in 2019 [38]. It does not appear that the dose of sofosbuvir needs to be adjusted for renal function. Other antiviral agents that are used in combination with sofosbuvir (eg, velpatasvir, ledipasvir, and voxilaprevir) are all hepatically cleared, and their levels are largely unaffected by renal impairment.

In a study of 59 patients with end-stage kidney diseases on dialysis and genotypes 1 to 6 HCV infection, sofosbuvir-velpatasvir (400 mg to 100 mg) for 12 weeks resulted in an SVR rate of 95 percent [39]. Serious adverse events were reported in 19 percent, but all were thought to be unrelated to the treatment; the only renal adverse events were urinary frequency in one patient and an episode of renal colic. Although ledipasvir-sofosbuvir and sofosbuvir-velpatasvir-voxilaprevir have not been specifically studied in trials of patients with renal impairment, their safety is thought to be comparable to that of sofosbuvir-velpatasvir because of the pharmacodynamics.

Observational studies have also suggested generally safe use of various sofosbuvir-containing regimens in patients with renal impairment [40-44]. Some, however, have suggested that advanced chronic kidney disease is associated with a higher risk of acute kidney injury with sofosbuvir-containing regimens [45-47].

Other regimens that are less frequently used but have documented efficacy and safety in the setting of renal impairment include:

●Elbasvir-grazoprevir – Several studies have documented that elbasvir-grazoprevir safely results in high SVR rates in patients with renal impairment [48,49]. As an example, in a study (C-SURFER) that included 122 genotype 1-infected patients with eGFR <30 mL/min per 1.73 m², three-quarters of whom were on dialysis, 94 percent achieved SVR with elbasvir-grazoprevir for 12 weeks [48]. The regimen was generally well tolerated, and the frequency of adverse events was comparable to that in a placebo control group. None of the participants who received elbasvir-grazoprevir discontinued therapy for adverse effects, although one episode of congestive heart failure was ultimately attributed to the drug. The role of elbasvir-grazoprevir in the treatment of genotype 1 infection is discussed in detail elsewhere.

●Ombitasvir-paritaprevir-ritonavir plus dasabuvir – This regimen also appears effective and safe in severe renal impairment. In a study (RUBY-1) of genotype 1-infected patients with eGFR <30 mL/min per 1.73 m², including those on dialysis and without cirrhosis, a 12-week regimen of ombitasvir-paritaprevir-ritonavir plus dasabuvir (with ribavirin added for subtype 1a infection) resulted in an SVR12 of 90 percent [50]. Most adverse events were mild or moderate, and there were no regimen discontinuations. However, as expected, the genotype 1a-infected patients who received ribavirin had more frequent side effects that were likely directly related to the ribavirin, including anemia and fatigue (see 'Ribavirin' below). The role of ombitasvir-paritaprevir-ritonavir plus dasabuvir in the treatment of genotype 1 infection is discussed in detail elsewhere.

●Daclatasvir – Daclatasvir is primarily metabolized by the liver, and renal elimination is minor. A pharmacologic analysis did not identify clinically important increases in daclatasvir levels among patients with eGFR ≤30 mL/min per 1.73 m² or on dialysis [51]. Daclatasvir is usually given with sofosbuvir in locations with limited access to more commonly used regimens.

Ribavirin — Ribavirin is not commonly used in HCV antiviral therapy, although there are rare indications for adding it to a DAA regimen. (See 'Regimen selection and dosing' above.)

The main adverse effect of ribavirin is hemolytic anemia, and the risk is predicted by ribavirin plasma concentration [52]. Since ribavirin is cleared mainly via the kidney, and very little ribavirin is removed with hemodialysis, the drug accumulates and can cause severe anemia in patients with renal insufficiency [53]. Even at lower doses, ribavirin may result in catastrophic anemia in patients with renal impairment.

Thus, the use of ribavirin in moderate to severe renal insufficiency is controversial. The manufacturer of one brand of ribavirin (Rebetol) has issued warnings for patients with renal dysfunction and contraindicated its use with creatinine clearance <50 mL/min [54,55]. However, a different brand of ribavirin (Copegus) is approved in the United States for patients with end-stage kidney disease and those on hemodialysis [56].

We cautiously use ribavirin in patients with moderate to severe renal impairment, including those on hemodialysis, with low starting doses, closer monitoring of the hemoglobin level, aggressive ribavirin dose reductions for anemia, and adjunctive use of erythropoietic growth factors. (See 'Regimen selection and dosing' above.)

This practice is supported by several studies that have reported overall safe use of ribavirin despite anemia in patients with moderate to severe renal insufficiency when such measures are taken, although treatment interruptions may be necessary. In a trial of ombitasvir-paritaprevir-ritonavir plus dasabuvir among patients with eGFR <30 mL/min per 1.73 m², ribavirin dosed at 200 mg daily was added in 13 patients [50]. Ribavirin use was suspended for meeting prespecified hemoglobin criteria (>2 g/dL drop in four weeks or a level <10 g/dL) in 69 percent (9 patients). Four patients required erythropoietin-stimulating agents, but none required blood transfusions, and there were no serious adverse events deemed associated with therapy. Three patients were able to restart ribavirin.

Earlier trials had also suggested relatively safe, cautious use of ribavirin in this population, despite the higher rate of anemia. In a randomized trial of peginterferon with ribavirin (200 mg daily) versus peginterferon alone in 205 Asian patients with HCV on hemodialysis, patients receiving peginterferon and ribavirin were more likely to have significant anemia (defined as hemoglobin <8.5 g/dL) that warranted reduction of ribavirin dose (72 versus 6 percent) and used a higher mean erythropoietin dose (13,946 versus 6449 international units) compared with those who received only peginterferon [18,57-59]. Eleven patients who received combination therapy had nadir hemoglobin concentrations <7.5 g/dL, although only one patient in each group required transfusion. The difference in adverse event-related withdrawal rates (7 percent for combination therapy versus 4 percent for monotherapy) was not statistically significant.

MONITORING OF PATIENTS ON ANTIVIRAL THERAPY — The frequency of monitoring patients on antiviral treatment is dependent upon multiple variables including, but not limited to:

●The HCV treatment regimen selected

●The severity of renal impairment

●The presence of HCV-associated renal disease (such as cryoglobulinemia) and its severity

●The presence of cirrhosis

●The presence of other comorbidities (including hepatitis B virus coinfection)

The specific monitoring parameters for patients with renal impairment are largely the same as those for the general population, which are discussed in detail elsewhere. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Monitoring during antiviral therapy'.)

There are a few additional considerations for patients with renal impairment:

●For patients using a sofosbuvir-containing regimen, we check blood urea nitrogen (BUN) and creatinine every two weeks throughout the course of therapy because of the possibility of acute kidney injury in patients with chronic kidney disease [45,46]. We consider discontinuing the sofosbuvir-containing regimen if the eGFR decreases by more than 25 percent in the absence of other cause. (See 'Direct-acting antivirals' above.)

●For patients on hemodialysis receiving ribavirin, we check a weekly complete blood count throughout the course of therapy because of the greater risk of anemia in such patients. (See 'Ribavirin' above.)

●For patients who have mixed cryoglobulinemia, blood specimens for viral load testing may require special handling to prevent falsely low measurements. HCV viral particles may be incorporated into the cryoprecipitate and centrifuged during preparation of serum samples or may precipitate from the serum during storage. To ensure accurate quantitation of the HCV viral load, specimens should be kept at 37 degrees centigrade during serum preparation, and any cryoprecipitate should be dissolved or suspended into the serum before measuring the viral load.

RECOMMENDATIONS OF OTHERS — Several guidelines are available that discuss management of chronic HCV infection in patients with kidney disease.

In 2014, guidelines for the diagnosis and management of HCV infection were released jointly by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) [60]. These are continuously updated and can be accessed at www.hcvguidelines.org [60].

The Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines for hepatitis C in chronic kidney disease were updated in 2022 [61]. These recommend that all patients with chronic kidney disease and HCV infection be evaluated for antiviral therapy, and they recommend an interferon-free regimen for treatment.

Links to these and other guidelines are found below. (See 'Society guideline links' below.)

SPECIFIC CONSIDERATIONS

Kidney transplant recipients — Any antiviral treatment for HCV infection in renal transplant recipients should only be undertaken by clinicians with experience in caring for such patients. Management of such patients is discussed in detail elsewhere. (See "Hepatitis C infection in kidney transplant candidates and recipients", section on 'Monitoring after transplantation'.)

Hepatorenal syndrome — Patients with cirrhosis who develop hepatorenal syndrome (I or II) with MELDNa scores ≥20 are generally not candidates for HCV antiviral therapy, and it is not recommended at this time. Patients with hepatorenal syndrome type 1 should be considered for liver transplantation referral. Patients with either form of hepatorenal syndrome generally have advanced liver disease with portal hypertensive complications and a poor prognosis. While data from trials (SOLAR-1,SOLAR-2, and ASTRAL-4) support the efficacy and safety of ledipasvir-sofosbuvir and velpatasvir-sofosbuvir in patients with Child-Pugh B and C cirrhosis, these trials excluded patients with creatinine clearance <40 mL/min per 1.73 m² [62-64]. Patients who are transplant candidates should have their HCV infection treated post-liver transplantation. (See 'Liver transplant recipients' below.)

The hepatorenal syndrome is discussed in detail elsewhere. (See "Hepatorenal syndrome".)

Liver transplant recipients — Liver transplant recipients are at risk for declining renal function over time. In the largest study on this topic, 18 percent of liver transplant recipients had renal dysfunction (estimated glomerular filtration rate [eGFR] <30 mL/min per 1.73 m²) five years after transplantation [65]. Risk factors for post-liver transplant renal disease include pre-transplant renal dysfunction, perioperative renal failure, early allograft dysfunction, infections, and most importantly, calcineurin inhibitors. The management of renal disease in such patients is discussed elsewhere. (See "Liver transplantation in adults: Long-term management of transplant recipients", section on 'Acute and chronic renal disease'.)

Post-liver transplant antiviral treatment should be performed by experienced providers at a transplant center. We agree with the joint guidelines from the American Association for the Study of Liver Disease (AASLD) and the Infectious Diseases Society of America (IDSA) that recommend a direct-acting antiviral-based regimen for liver transplant recipients [60]. The specific regimens depend on HCV genotype and are discussed elsewhere. (See "Hepatitis C virus infection in liver transplant candidates and recipients", section on 'Post-transplant antiviral therapy'.)

However, certain dose or regimen modifications may be warranted in liver transplant recipients who also have renal impairment. Those who have eGFR between 30 and 50 mL/min per 1.73 m² can be treated with the same regimens recommended for the general liver transplant population, although if ribavirin is used, the daily dose should be 200 mg alternating with 400 mg.

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 virus infection".)

SUMMARY AND RECOMMENDATIONS

●Rationale for antiviral treatment – The primary rationale for antiviral treatment in patients with chronic hepatitis C virus (HCV) infection is to prevent liver-associated morbidity and mortality. Additional reasons specific to patients with renal impairment are to prevent subsequent graft complications in kidney transplant candidates and to eradicate the immunologic stimulus in those who have HCV-related vasculitis or glomerulonephritis. (See 'Rationale for antiviral treatment' above and "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Benefits of treatment'.)

●Indications for treatment – We recommend antiviral treatment for all patients with chronic HCV infection, including those with severe renal impairment, who have access to direct-acting antiviral (DAA) therapies and do not have short life expectancies due to comorbidities (Grade 1A). For patients with HCV-related renal disease (eg, mixed cryoglobulinemia), we suggest antiviral treatment even if life expectancy is limited to improve renal function and symptoms (Grade 2C). In other patients with limited life expectancies, the decision to treat should be individualized and depends on comorbidities and the potential for kidney transplant candidacy. (See 'Patient selection for treatment' above and 'Rationale for antiviral treatment' above.)

●Timing of treatment in selected populations – For patients with severe, acute, HCV-associated vasculitic manifestations that warrant immunosuppressive therapy, we suggest initiating immunosuppressive therapy first and delaying antiviral therapy (Grade 2C). We typically delay antiviral therapy for one to four months. (See 'Timing of treatment' above.)

For kidney transplant candidates, the timing of antiviral treatment relative to transplant depends upon several factors, including severity of liver disease, extrahepatic complications of HCV infection, anticipated wait time on the transplant list, and accessibility of HCV-positive donor organs. (See 'Kidney transplant candidates' above and "Hepatitis C infection in kidney transplant candidates and recipients", section on 'Timing of treatment'.)

●Antiviral selection – The selection of the antiviral regimen among patients with renal disease is largely the same as that among patients without renal disease. In general, glecaprevir-pibrentasvir and sofosbuvir-velpatasvir are the preferred pangenotypic options for initial treatment (algorithm 1). Accumulating data suggest that commonly used DAA regimens are safe and have high efficacy among patients with severe renal impairment. (See 'Regimen selection and dosing' above and 'Antiviral efficacy and safety' above.)

●Dosing considerations – No dose adjustments are warranted for DAA agents in patients with severe renal impairment or on dialysis. Ribavirin is rarely warranted, but if indicated, it is dose-reduced for renal function and used with close monitoring for anemia; patients with more severe renal impairment may additionally warrant adjunctive erythropoietic stimulating agents. (See 'Regimen selection and dosing' above and 'Ribavirin' above.)

●Monitoring – We check blood urea nitrogen (BUN) and creatinine every two weeks in patients with renal impairment taking a sofosbuvir-containing regimen. Otherwise, monitoring during antiviral treatment is largely the same as for the general population. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Monitoring during antiviral therapy'.)