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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2015  |  Volume : 26  |  Issue : 6  |  Page : 1183-1189
Microalbuminuria and pegylated interferon in hepatitis-C patients


Renal Division, Faculty of Medicine, Ain Shams University, Cairo, Egypt

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Date of Web Publication30-Oct-2015
 

   Abstract 

To determine the relation between hepatitis C virus (HCV) genotype 4 and microalbuminuria in relation to hepatic histology and viremia in the absence of cryoglobulinemia and to examine the effect of treatment on microalbuminuria, we studied 400 HCV genotype-4-infected patients who were tested for microalbuminuria, albumin creatinine ratio (ACR), urea, creatinine and estimated glomerular filtration rate (eGFR). The parameters were measured again in the HCV patients after six months of treatment with pegylated interferon and ribavirin. Microalbuminuria was detected in 56 (14%) HCV-positive patients. There was a highly significant reduction in the microalbuminuria levels among the HCV-positive individuals after six months of therapy (P <0.001). Microalbuminuria was significantly associated with older age [Odds Ratio (OR): 1.1, 95% confidence interval (CI): 1.0-1.2, P = 0.01], elevated creatinine (OR: 0.09, 95% CI: 0.01- 0.7, P = 0.02), high modified Histological Activity Index score (OR: 1.5, 95% CI: 1.1-1.5, P = 0.004) and increased viral load (OR: 2.8, 95% CI: 1.1-6.6, P = 0.01). Sustained virological response (SRV) was achieved in 272 (86%) patients. The individuals with SVR had lower microalbuminuria post-treatment (P = 0.56). We conclude that HCV infection can be associated with microalbuminuria, which can be reduced by the use of a combination therapy of pegylated interferon-ribavirin.

How to cite this article:
Elshahawi Y, Sany D, Abd Elmohsen WA, Tantawi T. Microalbuminuria and pegylated interferon in hepatitis-C patients. Saudi J Kidney Dis Transpl 2015;26:1183-9

How to cite this URL:
Elshahawi Y, Sany D, Abd Elmohsen WA, Tantawi T. Microalbuminuria and pegylated interferon in hepatitis-C patients. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2021 Dec 8];26:1183-9. Available from: https://www.sjkdt.org/text.asp?2015/26/6/1183/168602

   Introduction Top


Hepatitis C virus genotype 4 (HCV-G4) is prevalent in the Middle East and Africa, and has spread to several regions in Europe. [1] HCV infection is associated with several renal diseases, including mixed essential cryoglobulinemia, membranoproliferative glomerulonephritis and, less frequently, membranous nephropathy and crescentic glomerulonephritis. [2],[3],[4] HCV is a significant cause of glomerulopathy in countries with a high prevalence of HCV infection. [3] Several studies have postulated a causal link between HCV infection and renal diseases through the induction of cryoglobulinemia. [4] The affinity for the kidney mesangium appears to be a major factor responsible for the initiation of renal damage. [5]

The principal clinical manifestations of glomerular disease in HCV-infected patients are the presence of proteinuria and microscopic hematuria with or without impaired kidney function. [6] Various approaches have been attempted for the treatment of the HCV-associated glomerulonephritis, including immunosuppressive therapy (corticosteroids and cytotoxic agents), plasma exchange and antiviral agents.

Treatment of HCV chronic hepatitis can be potentially nephrotoxic. [7] Interferon (IFN) has antiviral, anti-proliferative and immuno-modulatory effects, such as increased cytotoxic T cell and natural killer cell as immune response to viral proteins. [8] Reluctance to use IFN in HCV-infected kidney transplant recipients is related to concerns about precipitating acute allograft rejection. [9],[10],[11],[12] Both standard and pegylated (Peg) IFN therapy for chronic hepatitis C have been associated with reports of nephrotoxicity. [13],[14],[15],[16]

Limited data exist regarding antiviral treatment of HCV-associated glomerulonephritis.

The aim of our study was to determine the prevalence of microalbuminuria in the HCVG4 patients and the effect of viral load on liver histology, microalbuminuria and renal function in addition to the effect of antiviral therapy with Peg IFN and ribavirin on microalbuminuria and other parameters of renal insufficiency.


   Materials and Methods Top


In this prospective study, 512 consecutive eligible subjects who attended the gastroenterology clinic in the Ain-Shams University Hospital were recruited in the period between January 2011 and 2013. Of these, 112 (21.9%) patients dropped out from the study due to miscellaneous causes, including side-effects of treatment, lack of virological response and other causes. Accordingly, 400 patients completed the study. These patients received antiviral therapy for 12 months. All the study participants were seen two to three times to provide repeated blood samples at baseline and were also seen periodically to assess the response to treatment. All the patients provided written informed consent as stated in the Declaration of Helsinki of 1979, and the ethics research committee of the Ain Shams University Hospital provided ethical approval.

Chronic HCV infection was evidenced by persistently increased alanine aminotransferase (ALT) levels, positive serology for anti-HCV, active virus replication by detection of HCV RNA in serum and histological findings of chronic active hepatitis according to the modified Histological Activity Index (HAI) described by Ishak et al. [17] Hepatic fibrosis was assessed by the Metavir scoring system on a scale of F0-F4: F0, no fibrosis; F1, portal tract expansion by fibrosis; F2, <50% bridging fibrosis; F3, >50% bridging fibrosis without cirrhosis; F4, established cirrhosis. [18] The patients were excluded if they had (1) concurrent hepatitis B or human immunodeficiency virus infections, autoimmune hepatitis, hemochromatosis, or Wilson's disease, (2) systemic hypertension or if they reported current use of antihypertensive medication, (3) diabetes mellitus or if they reported current use of oral hypoglycemic medication, (4) active alcohol consumption, (5) chronic renal disease or history of dialysis, (6) congestive heart failure, (7) leukopenia (<3000/ mm 3 ), neutropenia (<1500/mm 3 ), anemia (<11 g/dL) and thrombocytopenia (<100,000/mm 3 ).

The HCV patients who were candidates for treatment received 180 μg of Peg IFN α-2a (Pegasys ®; Hoffmann-LaRoche, Basel, Switzerland) subcutaneously once weekly and ribavirin (Copegus ® ; Hoffmann-La Roche) at a daily oral dose of 1000 mg (body weight <75 kg) or 1200 mg (body weight >75 mg) for 48 weeks.

Testing for anti-HCV antibodies was carried out using a commercial enzyme-linked immunosorbent assay kit (Axsym HCV version 3.0; Abbott Laboratories, Chicago, IL, USA). All the patients were HCV-G4 as detected by the Inno-LiPA HCV II assay (Innogenetics Inc., Alpharetta, GA, USA). Monitoring serum HCV-RNA levels was performed with Amplicor (version 2.0, Hoffmann-LaRoche), which had a minimum detection limit of 50 IU/mL. Microalbuminuria was measured on the morning second spot urine after an overnight fast and the mean of at least two samples collected for each subject was calculated. Urine albumin measurements were obtained by an automated immunoturbidometric assay (Roche Hitachi 902, Roche Diagnostics, Indianapolis, IN 46250 USA). For quantitative determination of creatinine in serum or urine, creatinine blanked kinetic Jaffé (Roche Diagnostics, Hitachi 917, Modulator P analyzer Roche Diagnostics) was used. We determined the estimated glomerular filtration rate (eGFR) using the abbreviated Modification of Diet in Renal Disease (MDRD) equation.

Three parameters of renal insufficiency were examined, namely eGFR, microalbuminuria and serum creatinine. The presence of microalbuminuria was tested using (1) albuminuria level; or categories of microalbuminuria, defined as individuals with an albuminuria level higher than the upper tertile of the albuminuria level among controls and (2) albumin- creatinine ratio (ACR): to adjust for the variation in urine concentration, microalbuminuria was assessed by ACR. Gender-specific normal values for the ACR were 22 mg/g for males and 28 mg/g for females. High levels of serum creatinine were defined as >1.2 mg/dL for males and >1.1 mg/dL for females.

Sustained virological response (SVR) was defined as loss of detectable serum HCV RNA at the end of treatment. Normal ALT was defined as ALT ≤31 U/L for women and ≤40 U/L for men.


   Statistical Analysis Top


Statistical analysis was performed using Statistical Package for Social Sciences, Version 17.0 (SPSS Inc., Chicago, IL, USA) for Windows. Continuous variables were analyzed as mean values ± standard deviation (SD) or median (range) as appropriate. Rates and proportions were calculated for categorical data. For categorical variables, differences were analyzed with the χ[2] (chi-square) test. Differences among continuous variables with normal distribution before and after treatment were analyzed by the paired T-test, and we used the Wilcoxon signed rank test for those not normally distributed. For comparison between two independent groups regarding continuous variables without normal distribution, we used non-parametric tests and differences were analyzed by the Mann-Whitney U-test. Step-wise logistic regression was carried out to evaluate the adjusted Odds Ratio (OR) and the measure magnitude of the effect of different factors for development of microalbuminuria in hepatitis C patients. A P-value of ≤0.05 was considered statistically significant and a P-value <0.001 was considered as being highly significant.


   Results Top


The study population consisted of 400 subjects who were HCV-positive. The majority of the study participants [337(84.3%)] were males. The median age of the study patients was 45 years (interquartile range, 21-49 years). The histopathological changes of the liver in the patients were classified according to the Metavir Fibrosis staging system and fibrotic changes of Stages I, II, III and IV were illustrated in 102 (25.5%), 107 (26.7%), 131 (32.7%) and 60 (15%) patients, respectively. The necro-inflammatory changes were determined with the Ishak score (modified HAI) median 9.5 (inter-quartile range, 7-12). A median microalbuminuria of 13 mg/g (interquartile range, 3-270 mg/g) was observed, while the median eGFR was 101 mL/min/1.73 m 2 (inter-quartile range, 90-114 mL/min/1.73 m 2 ). Fiftysix (14%) patients revealed microalbuminuria at the start of the study. Of all the patients, 272 (68%) showed an SVR. [Table 1] demonstrates the characteristics of the study patients and status after six months of therapy.
Table 1: Data of the study patients by microalbuminuric state at 6 months of therapy.

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There was a highly significant reduction in microalbuminuria levels after six months of therapy (P <0.001). However, the patients with persistent microalbuminuria at the end of therapy had significantly older age (P = 0.029), higher creatinine levels (P = 0.043), higher modified HAI score (P = 0.024) and significant viral load (P = 0.05). No difference was detected among other variables [Table 1], [Table 2] and [Table 3]. To adjust for potential confounders and important covariates, we employed multivariate regression to test for the predictors of micro-albuminuria. Microalbuminuria was significantly associated with older age (OR: 1.1, 95% CI: 1.0-1.2, P = 0.01), higher creatinine (OR: 0.09, 95% CI: 0.01-0.7, P = 0.02), higher modified HAI score (OR: 1.5, 95% CI: 1.1- 1.5, P = 0.004) and more viral load (OR: 2.8, 95% CI: 1.1-6.6, P = 0.01) [Table 4].
Table 2: Laboratory characteristics of individuals with and without microalbuminuria at 6 months of therapy.

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Table 3: Study subjects viral load and Metavir score by microalbuminuric state at 6 months of therapy.

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Table 4: Multivariate analysis for the variables associated with microalbuminuria in hepatitis C-positive patients.

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The mean ACR was 33.8 ± 61.2 mg/g among the study patients with SVR versus 37.7 ± 64.6 mg/g (P = 0.56) among patients who failed to achieve SVR, and the difference was not statically significant.

There was a significant reduction in the eGFR post therapy (101.8/1.73 m 2 vs. 100.7/1.73 m 2 , P = 0.02). Multivariate regression analysis revealed that with adjustment for age, gender and other variables, persistence of microalbuminuria at the end of therapy was significantly associated with reduced eGFR (OR: 0.09, 95% CI: 1.01-1.1) [Table 4].

The microalbuminuria pre-treatment mean level was 35.1 ± 62.2 mg/g while the post treatment level was 22.0 ± 42.7 mg/g (P <0.001). Among patients with SVR, 76.6% had no microalbuminuria at the end of treatment versus 46.1% with persistent microalbuminuria (P = 0.01), while in the patients without SVR, 23.4% had no microalbuminuria at the end of treatment versus 53.9% with persistent microalbuminuria (P = 0.01).

The pre-to post-treatment log microalbuminuria difference was significantly correlated with pre-treatment fasting blood sugar (r = 0.125, P <0.012), but was not correlated with age (r = 0.008, P = 0.873), body mass index (r = 0.048, P = 0.339), modified HAI score (r = 0.036, P = 0.471), eGFR (r = 0.010, P = 0.838) or ALT (r = 0.001, P = 0.989).

There was a significant reduction in the Creactive protein mean levels after therapy (10.5 mg/dL) in comparison with that (12.3 mg/dL) before therapy (P <0.001).


   Discussion Top


Studying microalbuminuria in HCV-G4 patients and its relationship to response to treatment is a novel report. In the current study, using the same definition of microalbuminuria as Liangpunsakul et al, [19] the prevalence of microalbuminuria in HCV-G4 was 14%, similar to that reported by the Third National Health and Nutrition Examination Survey (NHANES) (12.4%). In contrast to the limitations of the NHANES III study, we studied the mean of multiple microalbuminuria readings, adjusted for stage of hepatic fibrosis, grade of inflammation and viral load. HCV-induced glomerulonephropathy in the absence of cryoglobulinemia was explained in previous reports by direct or indirect pathways: Deposition in the glomerulus of a monoclonal IgM rheumatoid factor with particular affinity for the glomerular matrix, which is produced by permanent clones of B lymphocytes infected by the virus or immune complexes composed of HCV antigens and anti-HCV IgG antibodies deposit directly in the glomerular structures in the absence of a concomitant type II mixed cryoglobulins. HCV RNA genomic sequences and HCV core protein detected in kidney glomerular and tubular structures point to distinct pathways of HCV-related damage in glomeruli and tubules. [20] Kidney disorders constitute pathoand morphogenesis of systemic infection in HCV. [21] In spite of the HCV-induced microalbuminuria, which was in agreement with Liang Punsakul et al, [19] Moe et al [22] and Tsui et al, [23] but in contrast to Dalrymple et al [24] and Tsui et al, [24] we did not find an increased risk for deterioration of renal function in the HCV-G4-infected patients with persistent high viral load as reflected by undetectable changes in creatinine and eGFR among patients who achieved SVR in comparison with the patients who failed to achieve SVR at the end of therapy. This discrepancy might be explained by the viral genotype. Our findings suggest that the principal clinical manifestation of glomerular disease in the HCV-G4-infected patients is the presence of microalbuminuria without impaired kidney function. [25] We found a significant correlation between microalbuminuria and the necro-inflammatory changes (modified HAI score), but not the fibrotic changes (Metavir score); this represents a relation with viral activity rather than progression of liver disease. Furthermore, we found a significant correlation between microalbuminuria and viral load; therefore, we suggest that HCV infection per se in HCV-G4 is the cause of microalbuminuria. There was a significant reduction in microalbuminuria after the Peg IFN therapy, which was more pronounced in patients with SVR. This posttreatment reduction in microalbuminuria in HCV-G4 indirectly suggest an improvement in renal pathology. [26],[27]

In conclusion, the incidence of microalbuminuria is increased in HCV-G4 infection, especially during older age and in higher viral load, suggesting that HCV independently affects the development of microalbuminuria, which can be reduced by the use of a combination therapy of Peg IFN-ribavirin.

Conflict of interest: None declared.

 
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Correspondence Address:
Yasser Elshahawi
Division of Renal Diseases, Faculty of Medicine, Ain Shams University, Postal Code: 11351, Cairo
Egypt
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DOI: 10.4103/1319-2442.168602

PMID: 26586057

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