Yukimasa Hisada

Exacerbation of glomerulonephritis in subjects with chronic hepatitis C virus infection after interferon therapy

We previously reported the glomerular deposition of hepatitis C virus (HCV) core antigen (Ag) in HCV-related nephropathy. In this study, we analyzed 23 HCV-positive subjects with exacerbation of proteinuria and/or hematuria during interferon (IFN) therapy and measured urinary protein selectivity. We also examined the involvement of HCV-related Ag using anti-HCV core (capside) Ag murine monoclonal antibody (Ab) and anti-core2 rabbit polyclonal Abs in nine subjects. Of 17 subjects, 13 (78%) showed low selective proteinuria. We found mesangial proliferative glomerulonephritis in 9 subjects, membranoproliferative glomerulonephritis in 1 subject, and nephrosclerosis in 1 subject. Immunofluorescence study showed the glomerular deposition of immunoglobulin G (IgG) or IgA and complements in all 9 subjects examined. Trace amounts only of HCV core Ag were detected along the glomerular capillary wall in 3 of 9 subjects (33%). Electron microscopy showed subendothelial or mesangial electron-dense deposits and also foot process effacement (20% to 72.5% of glomerular capillary walls) in all subjects and endothelial swelling in 4 subjects. In conclusion, IFN therapy for HCV may exacerbate the underlying glomerulopathies, unrelated to HCV Ags, through direct or indirect effects on glomerular endothelial and epithelial cells. Physicians should carefully distinguish HCV-related nephropathy from other glomerular diseases when they administer IFN therapy to HCV-positive subjects.

Risk Factors for Infection and Immunoglobulin Replacement Therapy in Adult Nephrotic Syndrome

Infection has been recognized as an important cause of morbidity and mortality in children with nephrotic syndrome. However, the incidence and severity of infection and the mechanisms responsible for the increased susceptibility to infection are still unclear in adults. We studied 86 consecutive adult patients with nephrotic syndrome but no diabetic nephropathy. Risk factors for infection were evaluated by logistic regression analysis. Infections were found in 16 patients (19%), of whom six died of infection and two developed end-stage renal failure associated with infection. The relative risk for bacterial infection among patients with serum immunoglobulin G (IgG) levels below 600 mg/dL was 6.74 compared with that for patients with serum IgG levels over 600 mg/dL (95% confidence interval, 1.22 to 36.32; P = 0.029). In patients with serum creatinine levels over 2.0 mg/dL, the relative risk of bacterial infection was 5.31 compared with patients with serum creatinine levels below 2.0 mg/dL (95% confidence interval, 1.08 to 26.09; P = 0.040). Intravenous immunoglobulin (10 to 15 g) was administered prospectively every 4 weeks to 18 patients with serum IgG levels below 600 mg/dL until serum IgG levels increased to over 600 mg/dL. Administration of immunoglobulin resulted in a decreased rate of bacterial infections to a level equal to that in patients with endogenous levels over 600 mg/dL. These data indicate that hypogammaglobulinemia and renal insufficiency are independent risk factors for bacterial infection in adult patients with nephrotic syndrome. The effects of intravenous immunoglobulin suggest that maintenance of serum IgG levels over 600 mg/dL may reduce the risk of infection.

Glomerular ICAM-1 Expression Related to Circulating TNF-α in Human Glomerulonephritis

To clarify the in vivo involvement of cellular adhesion molecules and cytokines in human glomerulonephritis, we have investigated the glomerular and interstitial expression of intercellular adhesion m

Matrix metalloproteinase-2 (MMP-2) and membrane-type 1 MMP (MT1-MMP) affect the remodeling of glomerulosclerosis in diabetic OLETF rats

BACKGROUND We reported previously that diabetic glomerular nodular-like lesions were formed during the reconstruction process of mesangiolysis. However, the precise mechanism has yet to be elucidated. Here, we investigated the roles of matrix metalloproteinase (MMP)-2, which is activated from proMMP-2 by membrane-type (MT)-MMP in the sclerotic and endothelial cell injury process of a type II diabetic model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. METHODS Monocrotaline (MCT) or saline only was injected three times every 4 weeks in 36-week-old OLETF rats and control Long-Evans Tokushima Otsuka rats. Glomerular expression and enzymatic activity of MMP-2 and MT1-MMP were assessed by immunohistochemistry, gelatin zymography of cultured glomerular supernatants, in situ enzymatic detection and reverse transcription-polymerase chain reaction. RESULTS Mesangial matrix increased in OLETF rats. In addition, mesangiolysis and nodular-like mesangial expansion were observed only in MCT-injected endothelial injured OLETF rats. MMP-2 and MT1-MMP proteins increased in the expanded mesangial lesions in OLETF rats. Gelatin zymography revealed an increase in 62-kDa activated MMP-2 in the culture supernatants of isolated glomeruli from OLETF rats. In situ enzymatic activity of MMP in the mesangial areas was also detected in 50-week-old MCT-injected OLETF rats. CONCLUSION These results suggest that MMP-2 and MT1-MMP are produced and activated in glomeruli through the progression of diabetic nephropathy and may have some effect on the remodeling of the glomerular matrix in diabetic nephropathy.

Clinicopathologic features of glomerular lesions associated with hepatitis C virus infection in Japan

BackgroundWe determined the incidence of hepatitis C virus (HCV)-related glomerulonephritis in Japan and the glomerular localization of HCV-related antigens in this disorder.MethodsWe analyzed urinalysis findings in 100 consecutive Japanese patients with HCV chronic liver disease from 1993 to 1994. Immunohistochemical analysis using monoclonal or polyclonal antibodies to HCV-core antigen and polyclonal antibodies to HCV-envelope antigen was done on kidney specimens from 11 of 29 patients with antibody to HCV (anti-HCV-Ab).ResultsEight of 100 patients had proteinuria, but only 2 cases (2%) were related to HCV nephropathy. Pathohistologic analysis showed 10 patients to have hepatic glomerulosclerosis, and 9 patients had mesangial proliferative glomerulonephritis involving primary immunoglobulin A nephropathy. Membranoproliferative glomerulonephritis was seen in 4 biopsy specimens that showed subendothelial electron-dense deposits and annular structures with characteristic cryogloblin. HCV core antigen was detected along the capillary walls with the same pattern as that of immunoglobulin G deposition and electron-dense deposits in 5 of 6 specimens from patients with both anti-HCV-Ab and HCV ribonucleic acid positive in the sera, but could not be detected in any of 3 specimens, from patients with anti-HCV-Ab but no HCV ribonucleic acid. Envelope antigen was not detected in the glomeruli of any specimens.ConclusionsGlomerular lesions associated with HCV infection were characterized by deposition of immune complexes containing HCV core antigen and immunoglobulin G, and by the subendothelial deposition of cryoglobulin. These HCV-related glomerular diseases are rare in Japan (2% incidence), and these lesions should be distinguished from hepatic glomerulosclerosis related to advanced liver disease and other primary glomerular diseases.