Hepatitis C virus infection and the kidney

INTRODUCTION

Hepatitis C virus (HCV) is the most common chronic viral infection, affecting ∼71 million people worldwide. HCV is a single-stranded ribonucleic acid (RNA) virus belonging to the flavivirus family, with significant sequence diversity categorized into six genotypes. Acute HCV infection is generally asymptomatic or may cause flu-like symptoms and rarely jaundice. Approximately 20% of those infected will mount an immune response that successfully clears the virus, while the remaining 80% develop a chronic infection with persistently elevated HCV RNA that leads to chronic hepatitis. After 20–30 years of infection, patients may develop cirrhosis, which can lead to the need for liver transplantation, hepatocellular carcinoma or death.

HCV AND CHRONIC KIDNEY DISEASE

HCV may also cause mixed cryoglobulinemic syndrome, which is a systemic vasculitis that affects ∼2% of patients with HCV infection, with manifestations including palpable purpura, arthritis, neuropathy and glomerulonephritis. Cryoglobulinemic glomerulonephritis typically has an immune complex–mediated membranoproliferative pattern of injury due to deposition of mesangial and subendothelial immune complexes, leading to glomerular hypercellularity, thickening of the glomerular basement membrane and a ‘double-contoured’ appearance. Curative therapy of HCV infection leads to remission of cryoglobulinemic glomerulonephritis in the majority of patients, however, patients with rapidly progressive glomerulonephritis or nephrotic syndrome typically require up-front immunosuppression to control severe manifestations [1]. While other glomerular diseases, including fibrillary, immunotactoid, membranous nephropathy and immunoglobulin A nephropathy, have been associated with chronic HCV infection, this may be coincidental.

On a population level, HCV infection is associated with an increased incidence of chronic kidney disease (CKD) and speeds progression to end-stage renal disease (ESRD) [2]. Mechanisms explaining this finding include HCV’s ability to promote systemic inflammation and worsen atherosclerotic disease and insulin resistance, leading to subclinical immune-complex deposition in the kidneys of those with long-standing chronic infection.

HCV AND ESRD

The prevalence of HCV infection in patients with ESRD on dialysis ranges from 3 to 70% depending on the country. All dialysis patients should be screened for HCV, either with antibody testing or HCV RNA (viral load testing), at the start of dialysis and every 6 months [3]. Once the HCV antibody is detected, HCV RNA viral load should be measured to confirm the presence of an active infection. HCV-infected dialysis patients have a 15–34% increased risk of mortality compared to those without HCV [4]. A recent analysis also showed that HCV infection is associated with higher hospitalization risk, the need for more blood transfusions and lower quality of life [5]. The risks of HCV infection carry over into the post–kidney transplant period, where HCV is associated with higher rates of acute rejection, new-onset diabetes mellitus, transplant glomerulopathy and de novo glomerulonephritis; meta-analyses have demonstrated a 1.56-fold [95% confidence interval (CI) 1.35–1.80] relative risk of graft loss and 1.79-fold (95% CI 1.57–2.03) relative risk for mortality when compared with uninfected kidney transplant recipients [6].

TREATING HCV INFECTION

Historically, HCV infection was treated with interferon-α and ribavirin-based therapies. These medications were poorly tolerated and ineffective in most patients, thus only 1% of dialysis patients ever received HCV treatment [4]. Direct-acting antiviral therapies (DAAs) have revolutionized the management of HCV, transforming it into a curable illness. The general approach is to target multiple components of the viral replicative machinery with agents from two or more DAA classes and inhibit them for 8–24 weeks. This is sufficient to achieve a cure, defined as sustained virologic response at 12 weeks (SVR12), in the vast majority (>95%) of patients. ‘Pan-genotypic’ therapies that can effectively treat all major viral genotypes have recently been approved by the US Food and Drug Administration. Even the minority of patients that fail first-line DAAs can be re-treated with combinations of newer, more effective agents. Both the recently published clinical practice guidelines from the European Association for the Study of the Liver and HCVguidelines.org, a website with joint guidelines for HCV treatment published by the American Association for the Study of Liver Disease and Infectious Diseases Society of America, are extremely valuable resources for prescribers [7].

Current recommended therapies for patients with advanced CKD or ESRD are elbasvir and grazoprevir, which treats genotype 1 or 4 infection, or glecaprevir and pibrentasvir, which treat all genotypes of HCV; the safety and efficacy of these combinations were studied in clinical trials in patients with ESRD [8, 9]. Sofosbuvir, an NS5B polymerase inhibitor commonly prescribed to treat HCV, is renally eliminated and not approved for those with an eGFR <30 mL/min/1.73 m². However, off-label use of sofosbuvir in advanced renal failure has been reported. A recent meta-analysis summarizing DAA use in advanced renal failure demonstrated excellent virologic success with sofosbuvir-based regimens (89% cured) and a reasonable safety profile [10]. Sofosbuvir may be used off-label under the direction of a hepatologist to treat HCV in patients with decompensated cirrhosis.

The risk of reactivation of hepatitis B virus (HBV) infection during DAA therapy applies primarily to hepatitis B surface antigen (HBsAg)-positive patients [11]. Those with HBsAg positivity who meet criteria for antiviral treatment of HBV should begin treatment prior to starting HCV therapy. If they do not meet the criteria for HBV therapy, HBV DNA levels should be monitored monthly during and for up to 3 months after DAA therapy because of the risk that HCV treatment may cause reactivation of HBV infection. In patients with isolated HBV core antibody positivity, the risk of HBV reactivation is very rare, but any increase in liver function tests should prompt evaluation of HBsAg and HBV deoxyribonucleic acid (DNA) levels.

TIMING OF HCV TREATMENT IN KIDNEY TRANSPLANT CANDIDATES

There is increasing data to suggest DAAs are safe and effective after kidney transplant without increasing the risk of acute rejection [12]. Thus a patient’s transplant waitlist status impacts the timing of treatment (Figure 1). In parts of the world where HCV-infected organ donors are common and often discarded, such as the USA, remaining HCV infected to allow a waitlisted patient to accept an organ from an HCV-infected donor may dramatically shorten transplant waiting time. In the USA, because of the opioid epidemic, HCV-infected donors are often younger and less likely to have comorbidities; however, in much of Europe, drug overdose donors make up only a small fraction of the donor population, thus treatment of ESRD patients with HCV infection should not be delayed [13, 14]. In the USA, transplantation of HCV-infected kidneys into HCV-uninfected waitlist recipients followed by immediate DAA therapy to prevent transmission of HCV infection is being actively explored in order to increase the kidney donor pool and decrease the discarding of otherwise healthy HCV-infected donor kidneys. So far, this has been performed successfully in 20 patients [15, 16].

FIGURE 1.

An algorithm for HCV antibody–positive patients with CKD and ESRD. Patients with a positive HCV antibody and negative viral load should be rescreened for infection with HCV RNA testing only; HCV antibody remains positive for life. Risk factors for HCV acquisition include hemodialysis, intravenous drug use, unregulated tattoos, incarceration and males with sexual contact with a male with known HCV infection. ^aFibroscan is the current standard of care for staging liver disease; liver biopsy may be needed if the etiology of liver disease is in question or if noninvasive tests are discordant. ^bPer current national/regional guidelines for simultaneous liver and kidney transplantation. ^cGFR cutoffs for determining which patients should remain untreated depend on the likelihood of needing a deceased donor kidney transplant in the next 1–2 years and the severity of underlying liver disease. ^dIn countries where HCV-infected donors are common and often discarded, most transplant candidates without a living donor will benefit from receiving an HCV-positive deceased donor kidney to shorten their time on the transplant waitlist. Some patients may have a strong personal preference to be treated while on dialysis, which should be discussed with the transplant center. In parts of the world where HCV infection status does not impact waitlist time for kidney transplantation, then patients should have HCV infection treated while they are on dialysis.

CONCLUSION

HCV is common in patients with predialysis CKD, ESRD and kidney transplantation and affects clinical outcomes in these populations. All genotypes of HCV infection are now curable with 8- to 24-week courses of DAAs, which are extremely well tolerated, and there are now straightforward treatment options for all patients on dialysis. More data are needed to determine the effect of curative DAA therapy on outcomes in patients with CKD, ESRD and those who have undergone kidney transplantation.

FUNDING

MES was supported by NIH K23 DK117014.

CONFLICT OF INTEREST STATEMENT

This article has not been published previously in whole or in part. M.E.S. has received grant support from Gilead Sciences, AbbVie and Merck. She has participated in scientific advisory board meetings for AbbVie and Merck and is a scientific consultant for AbbVie. M.E.S. was supported by the National Institutes of Health (K23 DK117014).