title: Does the antiviral therapy of patients with chronic hepatitis exert nephrotoxic effects?
abstract: BACKGROUND
  HBV and HCV chronic hepatitis can be accompanied by secondary renal disease. In addition, these patients receive antiviral drugs with potential nephrotoxicity. It is known that interferon (IFN) therapy in HCV-infected kidney transplant recipients is followed by rejection of the transplant in 50% of the cases. Ribavirin is contraindicated in hemodialyzed patients and in patients with a GFR <50 ml/min/1.73 m(2). IFN therapy requires dosage reduction and close monitoring in patients with a GFR <50 ml/min/1.73 m(2) and in patients with end stage renal disease. The aim of our study was to assess the nephrotoxicity of antiviral drugs in patients with chronic hepatitis by measuring three renal biomarkers: urinary albumin, N-acetyl-β-D-glucosaminidase (NAG) and α 1-microglobulin, as well as glomerular filtration rate (GFR-MDRD4) before and at 6 months of therapy.
  
  
  METHODS
  Fifty-five patients (28 male and 27 female, with a mean age of 47.85 ± 12.03 years) with chronic hepatitis (40 patients with HCV, 13 patients with HBV, 1 patient with HBV+HCV, and 1 patient with HBV+HDV) were enrolled into the study. Different antiviral drug associations were used on a case-by-case basis. The 40 patients with HCV chronic hepatitis received either Peg-IFN-α 2a+Ribavirin (37 patients) or Peg-IFN-α 2b+Ribavirin (3 patients). The 13 patients with HBV chronic hepatitis received Peg-IFN-α 2a (9 patients), Lamivudine (2 patients), Entecavir (1 patient), or Adefovir (1 patient). The patient with HBV+HCV chronic hepatitis received Peg-IFN-α 2a+Ribavirin. The patient with HBV+HDV chronic hepatitis received IFN-α 2a. Urinary albumin (ELISA), NAG (colorimetrical method), α 1-microglobulin (ELISA), and serum creatinine were measured before and at 6 months of antiviral therapy. Urinary markers were expressed as either mg/gCr (for albumin and α 1-microglobulin) or U/gCr (for NAG). Statistical analysis (Pearson's correlation coefficient, paired t-test and χ(2)-test) was performed.
  
  
  RESULTS
  At 6 months of therapy urinary albumin/gCr did not increase significantly: 16.58 ± 23.39 vs. 15.85 ± 24.96 mg/gCr before therapy, p = 0.87. Urinary NAG/gCr did not increase significantly: 4.21 ± 3.37 vs. 3.83 ± 3.2 U/gCr before therapy, p = 0.53. Urinary α 1-microglobulin/gCr was almost unchanged: 4.38 ± 4.47 vs. 4.38 ± 3.57 mg/gCr before therapy, p = 0.99. The GFR did not decline significantly: 92.41 ± 22.21 vs. 94.59 ± 36.1 ml/min/1.73 m(2) before therapy, p = 0.7. Ten patients (18.18%) were albuminuric before therapy, and 14 patients (25.45%) were albuminuric at 6 months of therapy, a non-significant increase (p = 0.35). We found a correlation between urinary albumin/gCr and NAG/gCr and between urinary albumin/gCr and α 1-microglobulin/gCr both at baseline and at 6 months of therapy: r = 0.54, p = 0.0005; r = 0.29, p = 0.03; r = 0.51, p = 0.0005; and r = 0.4, p = 0.002, respectively. In the patient receiving Adefovir, a known nephrotoxic drug, two of the three biomarkers (urinary albumin/gCr and NAG/gCr) increased, most notably NAG/gCr. Both HCV and HBV chronic hepatitis therapy were associated with non-significant changes in renal biomarker excretion and GFR.
  
  
  CONCLUSIONS
  With the exception of Adefovir, all of the drug associations used in this study were safe.
authors.affiliation: Division of Nephrology, University of Medicine and Pharmacy V. Babes Timisoara, Romania. gluhovschi@yahoo.com
authors.forename: Cristina
authors.initials: C
authors.lastname: Gluhovschi
authors.forename: Florica
authors.initials: F
authors.lastname: Gadalean
authors.forename: Adriana
authors.initials: A
authors.lastname: Kaycsa
authors.forename: Manuela
authors.initials: M
authors.lastname: Curescu
authors.forename: Ioan
authors.initials: I
authors.lastname: Sporea
authors.forename: Gheorghe
authors.initials: G
authors.lastname: Gluhovschi
authors.forename: Ligia
authors.initials: L
authors.lastname: Petrica
authors.forename: Silvia
authors.initials: S
authors.lastname: Velciov
authors.forename: Gheorghe
authors.initials: G
authors.lastname: Bozdog
authors.forename: Flaviu
authors.initials: F
authors.lastname: Bob
authors.forename: Corina
authors.initials: C
authors.lastname: Vernic
authors.forename: Daniel
authors.initials: D
authors.lastname: Cioca
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000328:Adult; D000419:Albuminuria / Q000097:blood / Q000139:chemically induced* / Q000652:urine; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects*; D004359:Drug Therapy, Combination / Q000009:adverse effects / Q000379:methods; D005260:Female; D019694:Hepatitis B, Chronic / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage / Q000009:adverse effects*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects*; D013997:Time Factors
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D063065:Organophosphonates; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C053001:adefovir; D000225:Adenine; C100416:peginterferon alfa-2a