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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2008  |  Volume : 19  |  Issue : 5  |  Page : 775-780
Effect of Antiviral Therapy on Hepatitis C Virus Related Glomerulopathy

Nephrology Department, Sheikh Zayed Hospital, Lahore, Punjab, Pakistan

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To determine the efficacy of antiviral therapy in hepatitis C virus associated glome­rulopathy, we studied 30 patients with HCV-associated glomerulopathy at Sheikh Zayed Hospital, Lahore, Pakistan from June 2004 to February 2007. Membranoproliferative glomerulonephritis (MPGN) was the commonest kidney lesion, being reported in 25/30 (83%), followed by membra­nous glomerulonephritis (MGN) in 3/30 (10%) and mesangioproliferative glomerulonephritis (MesGN) in 2/30 (7%). Cryoglobulinaemia was positive in 8/20 (40%) cases. Most common HCV genotype was 3a. All the patients received interferon alpha combined with ribavirin therapy for 6-12 months based on viral genotypes and doses were adjusted according to renal function. Anti-viral response was achieved in the form of aviremia at completion of 6 months treatment in 8/30 (26.6%), decreased transaminases levels from a mean of 96.4 ± 72.2 to 60.1 ± 44.3 IU/L, p= 0.005, 24-hour proteinuria decreased significantly from a mean of 4.8 g to 1.20 g, p= 0.001, and complement C3 and C4 concentrations returned to normal in those subjects who responded to treatment. The rate of relapse was 50%. We conclude that though the overall antiviral response of HCV was not high, there was a significant reduction in proteinuria suggesting indirectly an improvement in renal patho­logy. Further studies with large number of patients with follow-up renal biopsies are warranted.

Keywords: HCV nephropathy, glomerulopathy, membranoproliferative glomerulonephritis, interferon, ribavirin

How to cite this article:
Abbas G, Hussain S, Shafi T. Effect of Antiviral Therapy on Hepatitis C Virus Related Glomerulopathy. Saudi J Kidney Dis Transpl 2008;19:775-80

How to cite this URL:
Abbas G, Hussain S, Shafi T. Effect of Antiviral Therapy on Hepatitis C Virus Related Glomerulopathy. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2023 Feb 9];19:775-80. Available from: https://www.sjkdt.org/text.asp?2008/19/5/775/42456

   Introduction Top

Hepatitis C virus (HCV) is an RNA virus, which can be transmitted through intravenous drug abuse and blood products. It is estimated that HCV infects 4 million people in the United States and 170 million people world wide. [1],[2] It primarily infects liver and results in various manifestations such as chronic active hepatitis, cirrhosis and hepatic failure.

However, HCV has a wide range of extra hepatic manifestations including renal disease. Mem­branoproliferative glomerulonephritis (MPGN), with or without cryoglobulinemia is the most common renal manifestation of HCV. [3] Other renal lesions include membranous glomerulo­ nephritis (MGN) and mesangioproliferative glo­merulonephritis (MesGN). [4],[5] Epidemiological surveys demonstrate that HCV is a significant cause of glomerulopathy in the countries where HCV infection is highly prevalent especially in developing countries. However, the incidence of MPGN due to HCV varies from 60% in Japan to 10–20% in the United States. [6]

It is estimated that HCV infection is present in about 7% to 9% of patients with chronic renal failure without undergoing dialysis or any his­tory of blood transfusion. [7],[8] There is strong association between chronic hepatitis C viral infection and glomerular disease, but HCV may cause glomerulonephritis without any clinical evidence of systemic or liver disease. Patho­genesis of HCV associated glomerulopathy is mediated by glomerular deposition of circula­ting immune complexes containing HCV and anti HCV antibodies. [9]

There is successful treatment of HCV related liver disease, along with eradication of HCV infection with antiviral therapy. However, anti­viral therapies for the HCV-related renal di­seases are still controversial. [10] Most often, the main indication for antiviral therapy in HCV- associated glomerulopathy is moderate to se­vere progressive disease. The treatment of choice for chronic HCV infection is interferon alpha. [11] Although it improves renal disease, clears HCV infection, and reduces the flares up, the effects are temporary and relapse occurs on discontinuation of the treatment. [12] Those patients who do not respond to conventional doses or relapse may achieve sustained response with higher doses of interferon alpha. [13] Combination therapy with recombinant interferon alpha-2b and ribavirin have also attained a sustained response in renal disease. [14],[15]

The aim of our study is to evaluate the effi­cacy of interferon in controlling HCV-asso­ciated glomerulopathies.

   Patients and Methods Top

A total of 30 outpatients with positive anti HCV antibodies and evidence of glomerulo­pathy as proteinuria were enrolled in the study at Shaikh Zayed Hospital, Lahore, Pakistan from June 2004 to February 2007. Informed consent was obtained from each patient. We excluded from the study patients with severe renal failure or patients in which interferon was contraindicated such as advance cirrhosis, and psychosis.

All study patients underwent a detailed clinical history and physical examination. Laboratory investigations measured at baseline before star­ting therapy included serum creatinine, 24–hour creatinine clearance, liver function tests, and 24–hour proteinuria. HCV RNA with poly chain reaction (PCR) and HCV genotype were per­formed to confirm Hepatitis C virus infection and to decide about duration of therapy.

Renal biopsies were obtained to document the type of glomerular lesion in the study patients. In our center, only light microscopy was per­formed for renal pathology as immunoflou­rescence facility was not present in our set up. Once renal pathology was determined, all anti­proteinuric medications were discontinued two weeks prior to starting the antiviral therapy to abolish crossover effect. In hypertensive pa­tients, only calcium channel blockers of Dihy­droperidine groups (Amlodipine) were used to control blood pressure.

For treatment of HCV infection, standard interferon (IFN) alpha (3 million units 3 times/ wk) and ribavirin (200 to 1,000 mg/d) were administered in combination for at least 6 months.

We followed the study patients in the out­patient clinic initially every two weeks for two months and then monthly to monitor the side effects of therapy. The efficacy of therapy was assessed by ALT, HCV RNA by PCR, serum creatinine levels, creatinine clearance, comple­ments levels, and quantification of proteinuria at three and six months of the treatment.

   Statistical Analysis Top

Data were analyzed by using computer soft­ware SPSS13 (Statistical Package for Social Sciences). The sociodemographic, clinical and adverse effects profiles are presented as frequency tables. The outcome of therapy both quantitative, e.g. differences in serum creatinine level and urine protein level, and qualitative, e.g. recovery and complications, is described in comparative tables and expressed as mean ± standard deviation (SD). Chi-square method and Fisher's exact test were used to compare dichotomous variables. Differences in means of continuous variables were assessed by means of Student's paired t-test and P value < 0.05 is considered significant for all analysis.

   Results Top

The clinical characteristics of the study pa­ tients are given in [Table 1]. The mean age was 36 ± 9 years with predominant male gender. Most common presenting symptoms were peri­pheral edema and generalized weakness. Labo­ratory evaluation revealed HCV antibodies and HCV-RNA in the serum of all patients. Mixed cryoglobulinemia was detected in 8 out of 20 (40%) tested cases. Of those with cryoglobu­linemia, extra-renal manifestations were repor­ted in only 6 (75%) patients, mainly in the form of purpura and arthralgia. The most common HCV genotype was 3a.

Light microscopy of kidney sections revealed MPGN in 25 cases, MGN in 3 cases and MesGN in 2 cases. Light microscopy of liver sections obtained from four patients revealed chronic active hepatitis in 3 patients and chro­nic persistent hepatitis in 1 case. Three patients were lost to follow-up.

At 3 months after initiation of interferon and ribavirin treatment, 8 of the 30 treated patients achieved negative HCV-RNA-PCR, while others disclosed persistent viremia.

[Table 2] demonstrates the effect of anti-viral treatment on laboratory and serological parame­ters of the 27 patients who completed the course of therapy. Proteinuria, and complement com­ponents C3 and C4 levels significantly improved after treatment. A long follow-up after anti-HCV treatment withdrawal was available on 8 pa­tients. Sustained virological response, defined as negative HCV RNA PCR at least 6 months after the end of antiviral treatment, was recor­ded in 4 of the 8 (50%) patients. Those patients who did not respond, were offered prolong treatment with higher doses or pegylated inter­feron but none of them accepted this treatment due to cost implication. They were maintained on treatment for nephrotic range proteinuria i.e.furosemide and angiotensin-converting enzyme inhibitor. Antiviral treatment was well tole­rated, except for ribavirin. Anemia occurred due to the combination therapy in 7 patients. Riba­virin dosage was decreased to 400 mg/day and erythropoietin was administered for a short period.

[Table 3] illustrates the adverse effects of anti­HCV treatment. Anemia was clinically the most significant adverse event. Fever, the most fre­quent symptom, occurred early in the treatment period.

   Discussion Top

The high prevalence of MPGN in our series is consistent with what was reported in literature. Schifferli and his colleagues reported from accu­mulating epidemiological evidence that there was an association between HCV infection and the histological lesions of MPGN and MGN. [16] These findings were also reported by others. [17]

The optimal treatment strategy for HCV­associated renal disease remains to be defined. Johnson et al. reported that oral steroids with HCV-associated nephritis had no effect on renal function, although it improved the purpura. While pulse steroids improved renal function, these patients remained HCV-RNA positive. One problem with such therapy is the increase in HCV-RNA levels with its possible conse­quences on the underlying liver disease. [18] Fur­thermore, cyclophosphamide was used success­fully for the treatment of HCV-infected patients with cryoglobulinemia and progressive renal insufficiency caused by MPGN. Unfortunately, HCV-RNA levels also increased in this patients. [19]

Only a few studies, involving small number of patients, have examined the response of MPGN associated with chronic HCV infection to inter­feron (IFN) treatment. Results of these studies have been inconsistent. [20] In our study, 6 months treatment with IFN combined with ribavirin resulted in a significant reduction of protei­nuria, a rise in serum albumin levels, stabili­zation of serum creatinine, and normalization of complements C3 and C4. Beneficial effects of IFN therapy on the clinical and biochemical manifestations of type II essential mixed cryo­globulinemia in some uncontrolled studies and in two controlled trials had been reported even before the demonstration of the pathogenetic role of HCV infection in this disease. [21],[22],[23] More recently, Alric et al [10] treated 18 patients who had HCV related cryoglobulinemic MPGN with a combined therapy of standard or pegylated IFN and ribavirin. Fourteen out of the 18 were treated with standard a-IFN 3 MU three times weekly plus ribavirin at 600 to 1000 mg/day, and the four other patients received pegylated IFN at 1.5 mg/kg weekly with the same dose of ribavirin. The mean duration of anti-HCV the­rapy was 18 ± 10 months (range 6–24 months), and the mean duration of follow-up after com­pleting anti-HCV treatment was 16.7 ± 17.7 months. A sustained virological response was observed in 67% of patients. After anti-HCV treatment, proteinuria and cryoglobulins levels decreased. In addition, serum albumin level in­creased significantly in the responders com­pared to non-responders or control patients. In contrast, serum creatinine level remained stable in all three groups. The authors suggested that the anti-viral therapy should be given for a long period, and also recommended to treat the patients for at least 48 weeks, and to continue the anti-viral therapy even in the absence of a decrease in HCV RNA concentration of 2 logs at week 12. After HCV RNA clearance, cryo­globulinemia persisted for a long period. [10] Al-though our findings are more or less similar with theirs finding, our response rate was less and we treated for short period maximum of six months. In view of the poor response rate, we agree with the recommendations of Alric et al [10] of prolonged treatment with IFN to achieve maximum and sustained response.

Antiviral treatment was well tolerated in our patients except few cases of anemia in which we had to reduce the ribavirin dose. We agree with Kamar et al [23] that in patients with impaired renal function, ribavirin should be administered with caution because its clearance correlates with creatinine clearance, and its accumulation indu­ces hemolytic anemia. Severe chronic hemo­lysis is responsible for iron overload, liver iron deposition and accelerated progression of liver fibrosis. [23]

The limitations in our study include the small number of study patients and absence of a control group. In addition, we could not obtain cryoglobulin levels in all the study patients due to cost implications. Although we were inte­rested to prolong the duration of treatment to achieve better response, it could not be attained due to cost involved. Furthermore, we could not repeat the renal biopsies to reveal the changes in the renal pathology but permission was not granted by ethical committee. Unfortunately three (10%) of our patients were lost to follow­up which may have affected the response rate.

We conclude that although the virological res­ponse of the HCV patients with GN to antiviral therapy was poor in our study, the effect on proteinuria was significant. We recommend, like other studies, to treat patients with HCV asso­ciated GN with prolonged antiviral therapy to improve their overall prognosis and survival. Further larger studies using higher doses and prolonged periods with standard or pegylated interferon on HCV-related glomerulopathy are required.

   Acknowledgment Top

The authors wish to thank all patients for their cooperation during the study. The authors are also grateful to the Gastroenterology depart­ment at Sheikh Zayed hospital for their help in sample collections and treatment guidance. In addition, the authors are grateful to all the staff of nephrology department for their continuous help, support and guidance for the completion of this study.

   References Top

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3.D'Amico G. Renal involvement in Hepatitis C infection: cryoglobulinemic glomerulonephritis. Kidney Int 1998;54(2):650-71.  Back to cited text no. 3    
4.Sabry AA, Sobh MA, Irving WL, et al. A comprehensive study of the association between hepatitis C virus and glomerulopathy. Nephrol Dial Transplant 2002;17(2):239-45.  Back to cited text no. 4    
5.Daghestani L, Pomeroy C. Renal manifestations of hepatitis C infection. Am J Med 1999;106 (3):347-54.  Back to cited text no. 5    
6.Yamabe H, Johnson RJ, Gretch DR, et al. Hepatitis C virus infection and membranopro­liferative glomerulonephritis in Japan. J Am Soc Nephrol 1995;6(2):220-3.  Back to cited text no. 6    
7.Garcia-Valdecasas J, Bernal C, Garcia F, et al. Epidemiology of hepatitis C virus infection in patients with renal disease. J Am Soc Nephrol 1994;5(2):186-92.  Back to cited text no. 7    
8.Shafiq F, Akram S, Hashmat N. Prevalence of hepatitis C in patients with end stage renal disease before and during hemodialysis. Pak J Gastroenterol 2002;16:17-20.  Back to cited text no. 8    
9.Barhiono G, Ferrario F. Membranoproliferative Glomerulonephritis. In: Schrier RW (ed). Diseases of the kidney and Urinary tract.7 th ed. Philadelphia, Lippincot William and Wilkins, 2001;1717-35.  Back to cited text no. 9    
10.Alric L, Plaisier E, Thebault S, et al. Influence of antiviral therapy in hepatitis C virus asso­ciated cryoglobulinemic MPGN. Am J Kidney Dis 2004;43(4):617-23.  Back to cited text no. 10    
11.Zukrman E, Keren D, Slobodin G, et al. Treatment of refractory, symptomatic, Hepatitis C Virus related mixed cryoglobulinemia with ribavirin and interferon alpha. J Rheumatol 2000;27(9):2172-8.  Back to cited text no. 11    
12.Johnson RJ, Gretch DR, Couser WG, et al. Hepatitis C virus associated glomerulonephritis: Effect of alpha interferon therapy. Kidney Int 1994;46(6):1700-4.  Back to cited text no. 12    
13.Misiani R, Bellavita P, Fenili D, et al. Interferon alpha-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 1994;330 (11):751-6.  Back to cited text no. 13    
14.Poynard T, Bedossa P, Chevallier M, et al. A comparison of three interferon alpha-2b regimens for the long term treatment of chronic non-A, non-B hepatitis. N Engl J Med 1995; 332(22):1457-62.  Back to cited text no. 14    
15.Bruchfeld A, Lindahi K, Stahle L, Soderberg M, Schvarcz R. Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and renal insufficiency. Nephrol Dial Transplant 2003;18(8):1573-80.  Back to cited text no. 15    
16.Schifferli JA, French LE, Tissat JD. HCV infection, cryoglobulinemia and glomerulo­nephritis. Adv Nephrol Necker Hosp 1995;24: 107-29.  Back to cited text no. 16    
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18.Diamond AD, Davis GL, Qian KP, Lau JY.Detection of hepatitis C viral sequences in formalin-fixed, paraffin-embedded liver tissue: Effect of interferon Alpha therapy. J Med Virol 1994;42(3):294-8.  Back to cited text no. 18    
19.Quigg RJ, Brathwaite M, David FG. Successful cyclophosphamide treatment of cryoglobulinemic membranoproliferative glomerulonephritis asso­ciated with hepatitis C virus infection. Am J Kidney Dis 1995;25(5):798-800.  Back to cited text no. 19    
20.Johnson RJ, Gretch DR, Yamabe H. Membrano­proliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 1993; 328(7):465-70.  Back to cited text no. 20    
21.Agnello V, Chung RT, Kaplan LM. A role for heaptitis C virus infection in type II cryoglobu­linemia. N Engl J Med 1992;327(21):1490-5.  Back to cited text no. 21    
22.Kamar N, Rostaing L, Alric L. Treatment of hepatitis C-virus-related glomerulonephritis. Kidney Int 2006;69(3):436-9.  Back to cited text no. 22    
23.Kamar N, Chatelut E, Manolis E. Ribavirin pharmacokinetics in renal and liver transplant patients: evidence that it depends on renal function. Am J Kidney Dis 2004;43(1):140-6.  Back to cited text no. 23    

Correspondence Address:
Ghulam Abbas
Nephrology Department, Sheikh Zayed Hospital, Lahore, Punjab
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Source of Support: None, Conflict of Interest: None

PMID: 18711294

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  [Table 1], [Table 2], [Table 3]

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