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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2020  |  Volume : 31  |  Issue : 1  |  Page : 109-117
Ribavirin as a beneficial treatment option for hepatitis C virusassociated glomerular disease


1 Division of Nephrology, Maggiore Hospital and IRCCS Foundation, Milano, Italy
2 Division of Pathology, Maggiore Hospital and IRCCS Foundation, Milano, Italy
3 Division of Gastroenterology, Maggiore Hospital and IRCCS Foundation, Milano, Italy
4 Division of Gastroenterology, Maggiore Hospital and IRCCS Foundation; Deparment of Medicine, University School of Medicine, Milano, Italy
5 Division of Nephrology, Maggiore Hospital and IRCCS Foundation; Deparment of Medicine, University School of Medicine, Milano, Italy

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Date of Submission04-Sep-2018
Date of Acceptance10-Oct-2018
Date of Web Publication3-Mar-2020
 

   Abstract 


The management of hepatitis C virus (HCV)-induced glomerular disease remains unsatisfactory despite novel advances in antiviral and immunosuppressive therapy. Recent evidence highlighted the role of ribavirin, a drug provided with immunomodulatory properties, in the treatment of glomerular diseases associated with chronic HCV. We administered low-dose ribavirin (200 mg/day or 200 mg twice a week or 200 mg thrice weekly) in a prospective fashion to a group of patients with HCV-associated glomerular disease (n = 7). Ribavirin monotherapy was given in most (n = 6) patients and was accompanied by erythropoietin therapy in all. The primary endpoint was reduction of 24-h proteinuria after treatment ended; the secondary end-points were decrease in serum creatinine and amelioration of urinary abnormalities. We collected data on on-treatment adverse events (AEs), serious AEs, and laboratory abnormalities. Many patients (n = 6) had inactive HCV infection as they had shown HCV RNA clearance from serum after antiviral therapy with direct-acting antivirals. Some patients (n = 4) had membranoproliferative glomerulo- nephritis, the diagnosis being confirmed by kidney histology in three cases; others (n = 2) received diagnosis of diabetic glomerulosclerosis, confirmed in one by kidney biopsy. We observed consistent reduction of 24-h proteinuria in two individuals after ribavirin therapy; another patient reported disappearance of microscopic hematuria. We found severe AE (hemolytic anemia) in three patients which required discontinuation of ribavirin treatment in two patients, one required hospitalization. Other AEs were cutaneous rash (n = 1), dyspepsia (n = 1), and fatigue (n = 1). Low-dose ribavirin was able to give consistent reduction of 24-h proteinuria in two patients; tolerance to ribavirin was unsatisfactory. We need further studies aimed to expand our knowledge on ribavirin therapy of HCV-associated glomerular disease. The low incidence of the disease hampers the conduction of clinical trials on this aim.

How to cite this article:
Fabrizi F, Cresseri D, Moroni G, Passerini P, Pallotti F, Donato FM, Lampertico P, Messa P. Ribavirin as a beneficial treatment option for hepatitis C virusassociated glomerular disease. Saudi J Kidney Dis Transpl 2020;31:109-17

How to cite this URL:
Fabrizi F, Cresseri D, Moroni G, Passerini P, Pallotti F, Donato FM, Lampertico P, Messa P. Ribavirin as a beneficial treatment option for hepatitis C virusassociated glomerular disease. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Apr 4];31:109-17. Available from: http://www.sjkdt.org/text.asp?2020/31/1/109/279930



   Introduction Top


Hepatitis C virus (HCV) infection is a common infectious disease, which has been recently estimated a prevalence of 71 million infected individuals all over the world.[1] In addition to hepatic damage, HCV infection has been recently found to be involved in a variety of extrahepatic diseases; chronic HCV infection is associated with increased nonliver-related mortality compared to noninfected individuals.[2]

Kidneys are an important target of chronic HCV infection, and HCV can cause tubulo- interstitial injury in a large case-control study;[3] however, the most frequent kidney disease associated with HCV remains HCV- associated glomerular disease. Despite recent achievements on the pathogenesis and natural history, the management of HCV-associated glomerular diseases remains a challenge to clinicians.[4],[5],[6] Interferon-based regimens have been given with some benefit.[7],[8] The advent of all-oral, interferon (IFN)-free combinations of direct-acting antiviral agents (DAAs) gives us the possibility to make clearance of the virus with high efficacy, tolerability, and short treatment duration.[9] Unfortunately, the HCV RNA clearance is sometimes insufficient to improve the outcome of the disease,[4] and conventional (steroids, cyclophosphamide and azathioprine) or selective (rituximab) immunosuppression[10] is required to target the inflammation at glomerular level.

Some articles have underlined the efficacy of ribavirin monotherapy in the management of glomerular diseases associated with HCV[11],[12],[13],[14] and hepatitis E virus[15] infections. We report in this article our experience (a prospective case series) on the efficacy and safety of ribavirin for HCV-associated glomerular disease.


   Material and Methods Top


Patients

This was a study (prospective case series) of patients with HCV-associated glomerular disease recruited consecutively at our outpatient clinic between May 2010 and June 2018.

Inclusion criteria were the (1) evidence of chronic and active HCV infection and (2) presence of renal (glomerular) disease. Renal disease was defined either by the histologic finding of chronic glomerulonephritis (GN) at kidney biopsy or by the presence of at least two of the following clinical signs: proteinuria and hematuria and reduced glomerular filtration rate (<60 mL/min/1.73 m2) without alternative cause of chronic kidney disease (CKD). Cases with symptomatic mixed cryoglobulinemia syndrome are defined as showing HCV RNA levels >1000 IU/mL at baseline and circulating cryoglobulins associated with clinical manifestations including purpura, cutaneous ulcers, Raynaud’s phenomenon, arthralgias, sicca syndrome, gastrointestinal vasculitis, neurologic (peripheral neuropathy and/or central nervous system), or renal involvement. In this article, patients were included irrespective of their liver fibrosis stage, genotype, or prior HCV treatment status.

Exclusion criteria were as follows: conditions that might be associated with secondary cryo- globulinemia such as hematologic neoplastic disorders, autoimmune diseases, and acute or chronic infectious diseases not related to HCV; serious medical illnesses other than liver disease that might preclude completion of the study; hepatic failure, characterized by a history of bleeding esophageal varices, and a prothrombin time that was more than three times longer than normal; and cytopenia, as indicated by a platelet count below 3000/mm3 or a hemoglobin level below 10 g/dL.

Laboratory assessments

HCV infection was assessed in the form of a positive test for anti-HCV antibody; active (or viremic) HCV infection was defined by the presence of anti-HCV antibody and HCV viremia (detectable HCV RNA in serum) by the polymerase chain reaction (PCR). Circulating anti-HCV antibody was detected by third- generation enzyme-linked immunosorbent assay. HCV RNA levels were tested using Abbott real-time HCV PCR assay (Abbott, Wiesbaden, Germany) according to the manufacturer’s protocol (detection limit of 12 IU/mL). Detection of HCV genotypes was performed using Versant HCV genotype assay kit (LiPA) 2.0 (Siemens Medical Solutions Diagnostics, Germany). This kit is a reverse hybridization line probe assay designed to identify HCV genotypes 1-6 in the 5’ untranslated regions and core regions of HCV genome. The estimated glomerular filtration rate (eGFR) was assessed by the Modification of Diet in Renal Disease 4-variable GFR equation. All measurements of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma- glutamyl transpeptidase (GGT) were made by spectrophotometric method using the same automate. Proteinuria was measured by the ratio of urine protein to urine creatinine on a spot urine sample, when available. Otherwise, proteinuria was quantified by measuring the total quantity of protein in a 24-h urine collection test. Microscopic hematuria, dysmorphic red cells, and red cell casts were evaluated by examination of urine sediment by phase- contrast microscopy. Serum creatinine and urinary proteins were measured by standard methods. The serum concentrations of immuno- globulins, rheumatoid factor, and C3 and C4 complement components were measured by routine nephelometric assays. Normal ranges of biochemistries were as follows: albumin (3.4-4.8 g/dL), ALT (5-40 U/L), AST (5-38 U/L), C3 (90-180 mg/dL), C4 (10-40 mg/dL), creatinine (0.5-1.2 mg/dL), GGT (8-61 U/L), hemoglobin (13.5-17.5 g/dL), rheumatoid factor (1-14 IU/mL), total bilirubin (0.12-1.1 mg/dL), and total proteins (6.6-8.7 g/dL).

Safety evaluation

The patients were monitored on a regular basis for treatment efficacy and side effects. Patients underwent outpatient visits according to the following schedule: at the start of the study (baseline), and in the following weeks (week 2, 4, 6, 8, 12, 16, 20 and 24 after the start of therapy). The patients were seen at the end of therapy and on a regular basis (each month) post treatment. Each visit consisted of a query on medical history and side effects, check of concomitant medications, physical examination, laboratory analyses, and drug delivery. Laboratory analyses included blood chemistry, urine examination, and 24-h proteinuria.

The structure of recordings of adverse events (AEs) was as follows: any AEs or severe AE which included any event requiring hospitali- zation, life-threatening event, or death, and the relationship with the administered medication was also assessed.

Ethical standard

All procedures during the study were conducted in accordance with the International Conference on Harmonization guidelines and ethical principles that have their origin in the Declaration of Helsinki. All patients enrolled in the study had given their informed consent in a written manner and received the drug on an off-label basis according to the local regulation. The study was reported according to the Enhancing the QUAlity and Transparency Of health Research Network.[16],[17]


   Results Top


Baseline patient demographics

The baseline demographic and clinical characteristics of patients included in the study group are shown in [Table 1]. The baseline clinical and biochemical characteristics of patients are reported in [Table 2]. All patients were male and Caucasian. Most patients had achieved clearance of HCV RNA from serum by DAAs two patients had received antiviral therapy with sofosbuvir (SOF) + ribavirin and three SOF + ledipasvir + ribavirin.
Table 1: Demographic and clinical patients' characteristics at baseline.

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Table 2: Adverse events experienced during treatment with direct-acting antiviral agents. Six of seven patients experienced at least adverse event.

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In the subset of orthotopic liver transplant (OLT) recipients, the mean time between OLT and initiation of ribavirin therapy was 58.7 ± 51.8 months. Treatment duration with ribavirin ranged between three and 53 months. The duration of follow-up after the end of ribavirin therapy was 20.8 ± 13.4 months. Ribavirin therapy was accompanied by subcutaneous administration of erythropoietin-stimulating agents (ESAs) in all patients. At the beginning of ESA therapy, low dose was administered and subsequently increased according to hemoglobin levels.

Kidney biopsy was performed in four patients - we observed membranoproliferative GN (n = 3) and diabetic glomerulopathy (n = 1). Cryoglobulinemic disease with typical clinical and biochemical manifestations occurred in patient 2 and patient 5.

Three additional patients were recruited during the study period but were not included as refused treatment with ribavirin. The latest update shows that all patients are alive with the exception of patient 6 (as reported below).

Efficacy outcomes

One patient (patient 1) did not show changes in proteinuria and serum creatinine during a 15-month ribavirin therapy [Figure 1]. Percutaneous kidney biopsy had shown histological features of membranoproliferative (increased glomerular size, mesangial hypercellularity, and glomerular lobulated aspect) and chronic (tubular atrophy and glomerulosclerosis) GN.
Figure 1: Efficacy outcome: Patient number 1.
No impact of ribavirin on proteinuria or kidney function.


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Two patients obtained reduction of pro- teinuria with ribavirin therapy. One patient (patient 2) lowered proteinuria, but this rebounded the following months after the end of ribavirin therapy [Figure 2]. The proteinuria decrease was accompanied with amelioration of urine abnormalities (lower microscopic hematuria, dysmorphic cells, and red cell casts) and normalization of complement levels. He did not undergo kidney biopsy as he showed characteristic (biochemical and urinary) signs of membranoproliferative GN with clinical manifestations of cryoglobulinemic disease (purpuric rash and ulcers at the legs). Another patient (patient 3) had remission of proteinuria after combined antiviral therapy (pegylated IFN plus ribavirin) without viral response; he continued ribavirin monotherapy with some benefit [Figure 3]. The patient had the histologic signs of membranoproliferative GN (large glomeruli with accentuation of lobules and irregular thickening of glomerular basement membrane by interposition of mesangial cells between endothelium and basement membrane) without crescents.
Figure 2: Efficacy outcome: Patient number 2.
Lowered proteinuria after ribavirin monotherapy.


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Figure 3: Efficacy outcome: Patient number 3.
Proteinuria reduction after combined antiviral therapy (pegIFN plus RBV) before and RBV monotherapy after.


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One patient (patient 4) prematurely abandoned ribavirin monotherapy due to important decrease in hemoglobin levels (he discontinued therapy with ESA prematurely and on his own initiative). He was, therefore, hospitalized, received two units of concentrated red blood cells, and initiated maintenance hemodialysis (HD) in a few months [Figure 4]. A few months after OLT (and immunosuppression with steroids, calcineurin inhibitors, and mycophenolate mofetilhad remission of proteinuria), he had developed a clinical picture of diabetic nephropathy that had been confirmed by kidney biopsy (diffuse and nodular marked expansion of the mesan- gium and increased glomerular basement membrane width). He is now doing well while on thrice-weekly maintenance HD.
Figure 4: Efficacy outcome: Patient number 4.
No impact of ribavirin on proteinuria or kidney function.


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Patient 5 had histologic and clinical (purpura) signs of cryoglobulinemic membranoprolife- rative GN; he achieved clinical benefit with high-dose intravenous steroids. Then, he received a course (11 months) of ribavirin therapy with poor benefit on serum creatinine and 24-h proteinuria [Figure 5]. He is currently a liver transplant recipient and receives oral corticosteroids, mycophenolate mofetil, and tacrolimus.
Figure 5: Efficacy outcome: Patient number 5.
No impact of ribavirin on proteinuria or kidney function.


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Patient 6 did not undergo kidney biopsy due to decompensated cirrhosis (HCV genotype 1b, HCV RNA titers 12,565,653 IU/mL). He showed typical signs of chronic nephritic syndrome - proteinuria (<1 g/day), stable kidney failure (serum creatinine 1.8 mg/dL), repeat urine sediment with microscopic hema- turia (10-20 erythrocytes/microscopic field), many dysmorphic erythrocytes, and casts (hyaline, granular, and red cell casts). He assumed ribavirin (very low doses, 200 mg twice weekly) due to his baseline hemoglobin values. No impact of ribavirin monotherapy occurred on serum creatinine and proteinuria, but a significant improvement of urine changes was found (disappearance of hematuria and red cell casts). Ribavirin monotherapy was interrupted due to low hemoglobin levels when he began the first cycle of evacuative paracentecis. He died due to complications related to the onset of HCC [Figure 6].
Figure 6: Efficacy outcome: Patient number 6.
No impact of ribavirin on proteinuria or kidney function.


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Patient 7 showed an important increase of 24- h proteinuria (up to 12.7 g/day) immediately after OLT (serum creatinine increased to 2.5 mg/dL). He did not perform kidney biopsy due to the presence of an established clinical picture of diabetic nephropathy. He underwent monotherapy with low-dose ribavirin (200 mg thrice weekly) without apparent benefit on renal function or urine abnormalities; he suspended on its own initiative ribavirin (at week 13) while kidney function has shown progres- sive worsening (serum creatinine: 4.2 mg/dL). He was transferred to a nephrological unit near the home in order to initiate maintenance HD.

Safety outcomes

As listed in [Table 2], AEs were recorded in almost all (6/7 = 86%) patients during treatment with ribavirin. Many AEs were mild, the most common being anemia (n = 3) despite all patients used ESA during RBV therapy. One patient required hospitalization, ribavirin therapy was prematurely interrupted, and two units of packed red blood cells were administered - of note, he had not been compliant with erythropoietin therapy. Another dropout was again related to anemia (no hospitalization requested). One patient suffered from myo- cardial infarction, but this was not related to ribavirin therapy.


   Discussion Top


HCV infection can cause glomerular disease in both native kidneys and after kidney or liver transplant. The most common type of HCV- related glomerular disease is type 1 membrano- proliferative GN usually, but not invariably, in the context of type II cryoglobulinemia. HCV- infected patients show less common glome- rular diseases including membranoprolife- rative GN without cryoglobulinemia, membranous nephropathy, diabetic glomerulosclerosis, and others.[14],[18]

Recent evidence had suggested the adoption of ribavirin therapy for patients with HCV- associated glomerular disease.[11],[12],[13],[14] The results of our prospective case series confirm in part the results obtained in previous series - two patients experienced consistent reduction of proteinuria by ribavirin and three dropouts were observed.

Ribavirin was administered at low doses; monotherapy was adopted in most cases. We adopted low-dose ribavirin to avoid ribavirin accumulation and consequent hemolytic anemia as many patients in the current case series had impaired kidney function at baseline. Hemolytic anemia can be particularly dangerous in CKD patients as they often have anemia as well as other comorbidities (for example, cardiac ischemia) at baseline.

Two patients interrupted the treatment with ribavirin due to an important reduction of hemoglobin levels; one of them required hospitalization and recovered after transfusions with red blood cells. Of note, this patient discontinued erythropoietin therapy which had been prescribed at the time of ribavirin initiation. Thus, the side effect profile of our case series gives emphasis to the recommendations made by the KDIGO HCV Work Group. It had been suggested low-dose ribavirin, frequent monitoring of hemoglobin levels, and therapy with ESA to prevent anemia induced RBV.[19]

We suggest that the antiproteinuric activity of ribavirin was related to its immunomodulatory activities. Ribavirin is a guanosine (ribonucleic) analog that produces broad-spectrum activity against several RNA or DNA viruses. Although originally approved for the treatment of severe respiratory syncytial virus, RBV has been used in the treatment of various viruses including HCV.[20] Ribavirin’s antiviral activity has been postulated to result from four pathways; the last is given by immunomodulation of shifting a Th2 response in favor of a Th1 phenotype. In humans, ribavirin has been seen to enhance HCV-specific Th1 response by increasing IFN-gamma and tumor necrosis factor-alpha (TNF-α) production by peripheral blood mononuclear cell (PBMC) in patients with chronic HCV. In addition, ribavirin increased Th1 cytokine production [IFN- gamma, interleukin 2 (IL-2), and IL-12] and TNF-alpha production in PBMC of patients with chronic HCV.[20]

We need randomized clinical trials (RCTs) in order to clarify the efficacy and safety of ribavirin in the treatment of HCV-associated glomerular disease; the low incidence of the disease prevents the conduction of clinical studies on this point. We need to clarify several points - as an example, it remains unclear if the impact of ribavirin on protei- nuria is dose dependent or not. The duration of ribavirin monotherapy and the predictors of response to ribavirin are still unknown.

In conclusion, our prospective case series confirms partially those obtained previously by other authors on the management of HCV- associated glomerular disease. The safety profile was unsatisfactory in our study; a careful monitoring of hemoglobin values and renal function is suggested. We need further studies, both RCTs and “real-life” cohorts, to evaluate the efficacy and safety of immuno- modulatory agents such as RBV in the treatment of glomerular disease-associated with HCV.

Conflict of interest: Dr. Fabrizio Fabrizi is a consultant or advisor to AbbVie, Merck & Co.



 
   References Top

1.
WHO. Hepatitis C. Fact sheet Number 164. Available from: http://www.who.int/mediacentre/ factsheets/fs164/en.  Back to cited text no. 1
    
2.
Lee MH, Yang HI, Lu SN, et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: A community-based long-term prospective study. J Infect Dis 2012;206:469-77.  Back to cited text no. 2
    
3.
Kasuno K, Ono T, Matsumori A, et al. Hepatitis C virus-associated tubulointerstitial injury. Am J Kidney Dis 2003;41:767-75.  Back to cited text no. 3
    
4.
Fabrizi F, Plaisier E, Saadoun D, Martin P, Messa P, Cacoub P. Hepatitis C virus infection, mixed cryoglobulinemia, and kidney disease. Am J Kidney Dis 2013;61:623-37.  Back to cited text no. 4
    
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Roccatello D, Saddoun D, Ramos-Casals M, et al. Cryoglobulinemia. Nat Rev Dis Primers 2018; 2:11.  Back to cited text no. 5
    
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Tang SC, Lai KN. Hepatitis C virus-associated glomerulonephritis. Contrib Nephrol 2013; 181: 194-206.  Back to cited text no. 6
    
7.
Fabrizi F, Pozzi C, Farina M, et al. Hepatitis C virus infection and acute or chronic glome- rulonephritis: An epidemiological and clinical appraisal. Nephrol Dial Transplant 1998;13: 1991-7.  Back to cited text no. 7
    
8.
Feng B, Eknoyan G, Guo ZS, et al. Effect of interferon-alpha-based antiviral therapy on hepatitis C virus-associated glomerulonephritis: A meta-analysis. Nephrol Dial Transplant 2012;27: 640-6.  Back to cited text no. 8
    
9.
Fabrizi F, Aghemo A, Lampertico P, et al. Immunosuppressive and antiviral treatment of hepatitis C virus-associated glomerular disease: A long-term follow-up. Int J Artif Organs 2018; 41:306-18.  Back to cited text no. 9
    
10.
Fabrizi F, Cresseri D, Fogazzi GB, et al. Rituximab therapy for primary glomerulo- nephritis: Report on two cases. World J Clin Cases 2015;3:736-42.  Back to cited text no. 10
    
11.
Pham HP, Féray C, Samuel D, et al. Effects of ribavirin on hepatitis C-associated nephrotic syndrome in four liver transplant recipients. Kidney Int 1998;54:1311-9.  Back to cited text no. 11
    
12.
Kamar N, Sandres-Saune K, Selves J, et al. Longterm ribavirin therapy in hepatitis C viruspositive renal transplant patients: Effects on renal function and liver histology. Am J Kidney Dis 2003;42:184-92.  Back to cited text no. 12
    
13.
Hu SL, Jaber BL. Ribavirin monotherapy for hepatitis C virus-associated membranous nephro- pathy. Clin Nephrol 2005;63:41-5.  Back to cited text no. 13
    
14.
Donato MF, Fabrizi F, Fogazzi GB, et al. Remission of HCV-associated glomeruloneph- ritis with pegylated ifn and ribavirin therapy after liver transplantation: Case report and literature review. Int J Artif Organs 2013;36:63-8.  Back to cited text no. 14
    
15.
Del Bello A, Guilbeau-Frugier C, Josse AG, Rostaing L, Izopet J, Kamar N. Successful treatment of hepatitis E virus-associated cryoglobuli- nemic membranoproliferative glomerulonephritis with ribavirin. Transpl Infect Dis 2015;17:279- 83.  Back to cited text no. 15
    
16.
UK Equator Centre, Centre for Statistics in Medicine (CSM), NDORMS, University of Oxford. Available from: https://www.equator- network.org/reporting-guidelines/improving-the- reporting-of-clinical-case-series.  Back to cited text no. 16
    
17.
Dekkers OM, Egger M, Altman DG, Vandenbroucke JP. Distinguishing case series from cohort studies. Ann Intern Med 2012;156: 37-40.  Back to cited text no. 17
    
18.
Soma J, Saito T, Taguma Y, et al. High prevalence and adverse effect of hepatitis C virus infection in type II diabetic-related nephropathy. J Am Soc Nephrol 2000;11:690-9.  Back to cited text no. 18
    
19.
Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C Work Group. KDIGO 2018 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease. Kidney Int Suppl 2018;8:91-165.  Back to cited text no. 19
    
20.
Te HS, Randall G, Jensen DM. Mechanism of action of ribavirin in the treatment of chronic hepatitis C. Gastroenterol Hepatol (N Y) 2007;3: 218-25.  Back to cited text no. 20
    

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Correspondence Address:
Fabrizio Fabrizi
Division of Nephrology, Maggiore Hospital and IRCCS Foundation, Milano
Italy
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DOI: 10.4103/1319-2442.279930

PMID: 32129203

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    Figures

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