Introduction 

Hepatitis C virus (HCV) remains a public health challenge. HCV is typically asymptomatic until major complications supervene. Detection had been based on screening patients with acknowledged risk factors, but more recently the focus has been on screening individuals born between 1945 - 1965 given the high prevalence of HCV infection in this age group. The advent of highly effective and well tolerated HCV therapies has made virological cure feasible for the vast majority of HCV infected patients, including those with chronic kidney disease (CKD).

Prevalence and Associations of HCV and CKD

HCV persists as the most common chronic blood-borne infection in the United States (U.S.). An estimated 2.7 - 3.9 million people in the United States have chronic HCV infection, which is associated with increased risk of liver fibrosis or cirrhosis, development of hepatocellular carcinoma, and is a common indication for liver transplant in the U.S.1,2 The majority (75% - 85%) of newly infected individuals will develop chronic infection. The incidence of HCV infection is likely under-reported; most people infected are asymptomatic and it is estimated that only half of those infected have been tested and diagnosed.3

HCV infection is a potentially life-threatening condition. The number of HCV-associated deaths increased 10.9% from 2011 through 2014 and decreased 0.2% in 2015.4 Approximately one-half of all deaths in 2015 occurred among persons aged 55 - 64 years.4 An observational cohort study of mortality data showed that 19% of decedents had HCV listed on the death certificate, despite 63% having medical record evidence of chronic liver disease, suggesting that HCV is under-reported even in people with liver disease.5 

In addition to hepatic complications (i.e., cirrhosis, hepatocellular carcinoma), HCV infection has been implicated in other extrahepatic manifestations, including cardiovascular disease, diabetes, neurocognitive dysfunction, systemic vasculitis, and B cell non-Hodgkin lymphoma (Figure 1). 6,7,8,9,10,11 HCV infection has also been linked to higher incidence and faster progression of CKD as well as higher rates of end-stage renal disease (ESRD, also known as kidney failure).

Figure 1: Extrahepatic Manifestations of Chronic HCV Infection

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HCV is more prevalent among patients with CKD than in the general population.12,13 HCV infection is a recognized cause of progression to kidney failure, and is associated with reduced survival in the CKD population.14,15 A study by Molnar et al found that HCV infection is associated with a higher mortality risk, incidence of decreased kidney function, and progressive loss of kidney function (Figure 2).16 Multivariate adjusted models showed HCV infection independently was associated with a 2.2 - fold higher mortality (adjusted hazard ratio (aHR), 95% confidence interval (CI): 2.13; 2.21), and a 15% higher incidence of decreased kidney function (aHR, 95% CI: 1.12; 1.17).

Figure 2: Associations with HCV Infection, Mortality, and Decreased Kidney Function

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A 6-year cohort study by Chen et al compared individuals newly diagnosed with HCV without traditional CKD risk factors to randomly selected matched controls without HCV infection.17 HCV-infected patients had a significantly higher rate of CKD compared with the control group (aHR 3.42 vs 2.48 per 1,000 person-years, P = 0.02) and had a significantly greater risk for CKD (aHR 1.75, 95% CI: 1.25; 2.43, P=0.0009). The authors concluded that this association between HCV and CKD may indicate a causative role for HCV in kidney injury.

The prevalence of HCV infection is higher among CKD patients of all stages compared with rates in the general population, but is particularly high among patients receiving hemodialysis.18,19,20 A study by Goodkin et al evaluated data from the Dialysis Outcomes and Practice Patterns Study (DOPPS).20 The study reviewed the HCV status of 76,689 adults enrolled between 1996 – 2015 and found that 7.5% of patients were HCV-positive at enrollment. HCV infection among patients receiving hemodialysis was associated with higher risk of death, hospitalization, and worse quality-of life scores. Cardiovascular and infectious hospitalizations are also greater among patients infected with Hepatitis C.20 A meta-analysis of 14 observational studies by Fabrizi et al observed an independent and significant relationship between anti-HCV seropositivity in patients receiving hemodialysis and mortality risk (relative risk (RR) 1.35; 95% CI, 1.25; 1.47).21 Mortality in HCV-infected patients receiving hemodialysis is most often related to progression of liver disease (RR 3.82; 95% CI, 1.92; 7.61), with the cause of death attributed to cirrhosis and hepatocellular carcinoma in most cases.21 HCV was also associated with increased risk for cardiovascular mortality in patients receiving hemodialysis (RR 1.26; 95% CI, 1.10; 1.45).21 The role of HCV in cardiovascular risk is believed to be related to inflammation of chronic disease and atherogenesis mediated by the metabolic syndrome and dyslipidemia.9

Patients with CKD can be at increased risk for acquiring HCV infection due to factors directly related to the treatment of their renal disease. For example, patients receiving hemodialysis are at elevated risk for acquiring HCV due to their increased exposure to factors implicated in viral transmission. Risk factors that relate to HCV risk among patients receiving hemodialysis include duration and mode of dialysis, and prevalence of HCV in the hemodialysis unit.22 In 2016 a report by the Centers for Disease Control and Prevention (CDC), highlighted an increased number of reports of newly acquired HCV infection in patients on maintenance hemodialysis.23 Additional risks factors include intravenous drug use and a history of kidney transplantation.24 

HCV infection is a concern in kidney transplantation, as it has been implicated in diminished patient and graft survival. A meta-analysis by Fabrizi et al showed that HCV-positive patients after kidney transplantation have an increased risk of mortality and graft loss.25 The study identified 18 observational studies (n=133,530) of kidney transplant recipients. The summary estimate for adjusted relative risk (aRR) of all-cause mortality was 1.85 (95% CI, 1.49; 2.31, P < 0.0001) and; for all-cause graft loss was 1.76 (95% CI, 1.46; 2.11, P < 0.0001).25 HCV infection also increases the likelihood of posttransplant diabetes in kidney transplant recipients.26 

There is an association between chronic HCV infection and glomerular diseases, including mixed cryoglobulinemia, membranoproliferative glomerulonephritis (MPGN), membranous nephropathy, and polyarteritis nodosa (PAN).27,28,29 Among patients with HCV-related glomerulonephritis, rapid deterioration in kidney function has been observed in 20% - 25% of patients, moderate renal insufficiency in 50% of patients, and hypertension in 80% of patients.29 When biopsied, patients most often are found to have a MPGN pattern of injury on light microscopy with immunofluorescence microscopy demonstrating granular staining for IgG, IgM, C3 and C1q. Electron microscopy shows electron dense deposits in subendothelial locations.30 

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1 Centers for Disease Control and Prevention. Hepatitis C information. https://www.cdc.gov/hepatitis/hcv/index.htm. Accessed October 10, 2017.

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3 Holmberg S, Spradling P, Moorman A, Denniston M. Hepatitis C in the United States. N Engl J Med. 2013;367:1859-1861.

4 Centers for Disease Control and Prevention. Surveillance for Viral Hepatitis – United States, 2015. https://www.cdc.gov/hepatitis/statistics/2015surveillance/commentary.htm. Accessed October 10, 2017.

5 Mahajan R, Xing J, Liu S, et al. Mortality among persons in care with Hepatitis C virus infection: the Chronic Hepatitis Cohort Study (CHeCS), 2006-2010. Clin Infect Dis. 2014;58:1055-1061.

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11 Vannata B, Arcaini L, Zucca E. Hepatitis C virus-associated B-cell non-Hodgkin’s lymphomas: what do we know? Ther Adv Hematol. 2016;7:94-107.

12 Ladino M, Pedraza F, Roth D. Hepatitis C virus infection in chronic kidney disease. J Am Soc Nephrol. 2016;27:2238-2246.

13 Jadoul M, Martin P. Hepatitis C treatment in chronic kidney disease patients: The Kidney Disease Improving Global Outcomes Perspective. Blood Purif. 2017;43:206-209.

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17 Chen Y-C, Chiou W-Y, Hung S-K, Su Y-C, Hwang S-J. Hepatitis C virus itself is a causal risk factor for chronic kidney disease beyond traditional risk factors: a 6-year nationwide cohort study across Taiwan. BMC Nephrol. 2013;14:187-195.

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19 Kalantar-Zadeh K, Kilpatrick R, McAllister C, et al. Hepatitis C virus and death risk in hemodialysis patients. J Am Soc Nephrol. 2007;18:1584-1593.

20 Goodkin D, Bieber B, Jadoul M, et al. Mortality, hospitalization, and quality of life among patients with Hepatitis C infection on hemodialysis. Clin J Am Soc Nephrol. 2017;12:287-297.

21 Fabrizi F, Dixit V, Messa P. Impact of Hepatitis C on survival in dialysis patients: a link with cardiovascular mortality? J Viral Hepat. 2012;19:601-607.

22 Yu Y-C, Wang Y, He C-L, Wang M-R, Wang Y-M. Management of Hepatitis C virus infection in hemodialysis patients. World J Hepatol. 2014;6:419-425.

23 Centers for Disease Control and Prevention (CDC). CDC urging dialysis providers and facilities to assess and improve infection control practices to stop Hepatitis C virus transmission in patients undergoing hemodialysis. http://emergency.cdc.gov/han/han00386.asp. Accessed October 10, 2017.

24 Fabrizi F. Hepatitis C virus infection and dialysis: 2012 update. ISRN Nephrol. 2012;2013:159760.

25 Fabrizi F, Martin P, Dixit V, et al. Meta-analysis of observational studies: Hepatitis C and survival after renal transplant. J Viral Hepat. 2014;21:314-324.

26 Bloom R, Rao V, Weng F, et al. Association of Hepatitis C with posttransplant diabetes in renal transplant patients on tacrolimus. J Am Soc Nephrol. 2002;13:1374-1380.

27 Kamar N, Rostaing L. Glassock R, Hirsch M, Lam A (Eds). Overview of renal disease associated with Hepatitis C virus infection. UptoDate, Waltham MA. Accessed October 10, 2017.

28 McGuire B, Julian B, Bynon J, et al. Glomerulonephritis in patients with Hepatitis C virus cirrhosis undergoing liver transplantation. Ann Intern Med. 2006;144:735.

29 Tarantino A, Campise M, Banfi G, et al. Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Int.1995;47:618.

30 Alpers C, Kowalewska J. Emerging paradigms in the renal pathology of viral diseases. Clin J Am Soc Nephrol. 2007;2(Suppl 1):S6-S12.