Resolution of hepatitis B virus-related membranoproliferative glomerulonephritis after orthotopic liver transplantation

The most well-described renal disease associated with hepatitis B virus (HBV) infection is membranous glomerulonephritis; membranoproliferative glomerulonephritis is described much less frequently. The course of HBV-associated renal disease after liver transplantation has not been described to date. We present a 15-year-old girl with HBV-associated membranoproliferative glomerulonephritis and end-stage liver disease, in whom, after cadaver liver transplantation, clinical and histological resolution of renal disease was observed. Resolution was associated with diminution of circulating HBV surface antigen levels.     

Absence of hepatitis B and C viruses in pediatric idiopathic membranoproliferative glomerulonephritis

The blood-borne hepatitis viruses, hepatitis B virus (HBV) and hepatitis C virus (HCV), have similar epidemiological features. The association of chronic HBV infection and glomerulonephritis is well established, particularly in children. Recent reports have shown an association between HCV infection and glomerulonephritis in adults. In order to assess the role of these hepatotropic viruses in membranoproliferative glomerulonephritis (MPGN) we screened 34 children with idiopathic MPGN for the presence of HBV and HCV infection using highly sensitive polymerase chain reaction techniques for the detection of HBV DNA and HCV RNA. Also, enzyme-linked immunosorbent assays were used to detect the presence of antibody to hepatitis B surface antigen and antibody to HCV. No evidence of HBV or HCV infection was demonstrated in any of the patients. We conclude that HBV and HCV are not significant causes of idiopathic MPGN in children in the United States.     

Hepatitis C and glomerulonephritis

Summary: Several systemic viral infections have been associated with the development of glomerular lesions. of the viruses that cause liver disease hepatitis B was the first to be recognized. the recent availability of serologic tests for the hepatitis C virus (HCV) has uncovered an association between HCV infection and renal disease. the principal glomerular lesion that develops is that of a membranoproliferative glomerulonephritis (MPGN), usually in association with antigenaemia and circulating immune complexes that have the characteristics of mixed cryoglobulinaemia represented by polyclonal IgG and monoclonal IgM with rheumatoid factor activity. the presence of a very high percentage of anti-HCV seropositivity in cryoglobulinaemic forms of MPGN suggests that the virus plays an important role in the pathogenesis of the associated immune complex glomerulonephritis. Precipitates containing HCV-RNA and circulating anti-HCV IgG and IgM have been found in the majority of such cases. the course of the renal disease that develops is progressive. Treatment with interferon alpha appears to attenuate the progression of the renal lesions, and the response to treatment appears to be closely related to the clearance of hepatitis C viraemia. Renal lesions also occur in the absence of clinical evidence of liver disease or mixed cryoglobulinaemia. In addition to MPGN, membranous glomerulonephropathy, IgA nephropathy and focal segmental glomerulosclerosis have been reported in these cases of HCV infection. the prevalence of glomerular lesions in patients with HCV infection remains to be determined. the available serologic tests for HCV are still in evolution. In the meantime, all patients presenting with glomerular disease should be screened for HCV.     

Treatment of hepatitis C-associated glomerular disease

Hepatitis C virus (HCV) infection can lead to chronic active hepatitis, cirrhosis, and liver failure; however it is also associated with a wide range of extrahepatic features. Renal manifestations include cryoglobulinemic membranoproliferative glomerulonephritis and membranous nephropathy. Treatment of HCV with alpha-interferon is only moderately effective and suffers from a high relapse rate. More recently, combination therapy with ribavirin has led to improved suppression of HCV RNA levels. In this review we briefly describe the features of renal disease associated with HCV infection and discuss the therapeutic options.     

Nephropathy associated with heroin abuse in Caucasian patients.

BACKGROUND: Renal disease is a complication of heroin addiction. Using renal biopsies in Caucasian patients, we studied the types of nephropathy associated with heroin abuse. METHODS: Nineteen renal biopsies were performed on heroin addicts between January 1993 and December 2001. The indications for renal biopsy included proteinuria with or without renal insufficiency. RESULTS: All 19 patients had serological evidence of hepatitis C virus (HCV) infection, one had hepatitis B virus surface antigen and three were HIV positive. Thirteen patients (68.4%) were found to have membranoproliferative glomerulonephritis (MPGN), 12 with type I and one with type III. Of the remaining patients, two had chronic interstitial nephritis, two had acute proliferative glomerulonephritis, one had amyloidosis and one had granulomatous glomerulonephritis with interstitial nephritis. No apparent decline in the incidence of renal disease was observed. CONCLUSIONS: In this cohort of male Caucasian heroin addicts, HCV-associated MPGN was the most frequent pattern of nephropathy, showing that the nephropathy associated with heroin abuse in Caucasians is not of the focal and segmental glomerulosclerosis type, in contrast to previous reports on African-Americans. This aspect may have important implications for patient management and prognosis.     

Outcome of hepatitis C virus-associated membranoproliferative glomerulonephritis after liver transplantation.

BACKGROUND: Hepatitis C virus was the most frequent cause of liver failure requiring liver transplantation in our series. Hepatitis C virus infection has been associated with glomerulonephritis and, more frequently, type I membranoproliferative glomerulonephritis. Renal disease in patients with liver failure is often clinically silent and difficult to diagnose; thus, biopsy is required to establish the diagnosis. Our aim was to study the evolution of six patients diagnosed with membranoproliferative glomerulonephritis some months before liver transplantation. METHODS: Liver transplantation alone was performed in four patients and combined liver-kidney transplantation in the remaining two, who were on hemodialysis for kidney failure. These patients were followed for a mean of 38.3+/-7.8 months. Evolution of proteinuria, renal function, hepatic function, and hepatitis C virus activity was studied. RESULTS: In the four patients who underwent liver transplantation alone, proteinuria became negative initially and renal function remained stable. Proteinuria reappeared and renal function was altered in two of these patients at 17 and 36 months of follow-up, respectively, coinciding with a recurrence of active chronic hepatitis. In the two patients who received a combined liver-kidney transplant, proteinuria became negative, and their renal grafts currently maintain normal renal function. CONCLUSIONS: Membranoproliferative glomerulonephritis does not constitute an absolute contraindication for liver transplantation alone; combined liver-kidney transplantations are reserved for patients with end-stage kidney failure. Proteinuria is reversed after liver transplantation, and recurrence seems to be associated with severe hepatitis C virus hepatic allograft disease relapse.     

Effect of combination therapy (ribavirin and interferon) in HCV-related glomerulopathy.

BACKGROUND: Hepatitis C virus (HCV) is a major cause of acute and chronic hepatitis throughout the world. Several extrahepatic manifestations, including glomerulonephritis, have been reported to be associated with this type of infection. Cryoglobulinaemic and non-cryoglobulinaemic membranoproliferative glomerulonephritis (MPGN) and membranous nephropathy (MN) are the commonest lesions associated with HCV. Results of treatment of these patients with interferon therapy have been disappointing, since relapse of the viraemia and subsequent relapse of the renal disease are major problems. Combination of interferon with ribavirin in patients with chronic liver disease has been shown to increase the rate of sustained response. METHODS: In this work, 20 patients with HCV-associated glomerulopathy were subjected to an in-depth evaluation of their kidney lesions and HCV involvement. Laboratory, histopathological, immunohistochemical, and electron-microscopy techniques were used. The patients received interferon therapy for 12 months; in interferon-resistant subjects, interferon was combined with ribavirin. RESULTS: MPGN was the commonest kidney lesion, being reported in 85% of these cases, followed by MN and mesangioproliferative glomerulonephritis (10 and 5% respectively). Mixed cryoglobulinaemia was encountered in 60% of the cases. Twelve months' anti-viral treatment resulted in aviraemia in 25% of cases, while liver enzymes were normalized in 75%, 24-h proteinuria significantly decreased (from median 4 g to 1.10 g, P=0.001), serum albumin increased (from median 2.50 to 3.55 g/dl, P=0.012), lower viral titres (from median 1.15 to 0.53 mega-Eq/ml, P=0.049), and C3 and C4 concentrations returned to normal. Basal serum creatinine and viral titres were important determinants of response to treatment. CONCLUSION: This study supports the relationship between HCV and glomerulonephritis, especially MPGN, and the use of a combination of interferon and ribavirin in the treatment of selected cases of HCV-related glomerulopathy.     

De novo glomerulonephritis in renal allografts with hepatitis C virus infection

The purpose of this study was to examine the influence of hepatitis C virus (HCV) infection on the occurrence of posttransplant de novo glomerulonephritis (GN). Of 165 patients selected for the study, 44 were HCV positive and 121 HCV negative. Light and immunofluorescence microscopy were performed on all biopsies and clinical and laboratory findings reviewed. Fifteen (34%) of the 44 HCV positive patients showed de novo GN (4 membranous, 11 membranoproliferative) at a mean of 47 +/- 22 months. But only 8 (6.6%) of 121 HCV negative patients showed de novo GN (5 anti-glomerular basement membrane nephritis in recipients with Alport's disease, 2 membranous GN, 1 membranoproliferative GN) at a mean of 60 +/- 39 months. The risk of development of de novo GN was higher among patients with HCV infection (P < .001). The presence of de novo GN in HCV positive patients impaired graft survival compared with HCV positive patients without de novo GN (P < .01). The incidence of recurrence of primary disease, mainly focal segmental glomerulosclerosis, membranous glomerulonephritis, membranoproliferative glomerulonephritis, and IgA nephropathy, was higher in HCV negative patients (29%) compared with HCV positive patients (6.8%; P = .001), namely, 50%, 57.6%, 25%, and 69%, respectively. In conclusion, HCV infection showed a strong influence on the development of de novo GN. For this reason, it is important to follow HCV positive recipients with a renal biopsy even when there are no significant clinical or laboratory findings.     

Hepatitis B virus associated focal and segmental glomerular sclerosis: report of two cases and review of literature

The hepatitis B virus (HBV) is estimated to have infected about 350 million people worldwide, making it one of the most common human pathogens. Renal involvement is among its most common extra hepatic manifestations and usually manifests in the form of immune complex mediated glomerulopathy, such as membranous glomerulonephritis (MGN), membranoproliferative glomerulonephritis (MPGN), mesangioproliferative glomerulonephritis and immunoglobulin A (IgA) nephropathy. Occurrence of focal and segmental glomerular sclerosis (FSGS) with HBV infection is rare and only five cases have been reported earlier. We report two cases of hepatitis B associated FSGS. In both the cases, HBsAg was demonstrated in the renal tissue and both the cases showed response to treatment with lamivudine, thus indicating a possible causal association between the viral infection and occurrence of nephrotic syndrome.     

Hepatitis serology predicts tumor and liver-disease characteristics but not prognosis after resection of hepatocellular carcinoma

The impact of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection on survival rates after resection of hepatocellular carcinoma (HCC) is controversial. The objective of this study was to determine whether serologic evidence of HBV or HCV infection ("hepatitis serology") can predict underlying liver disease, tumor factors, and survival rates in patients with HCC. Using a multicenter international database, we identified 446 patients with complete HBV and HCV serology. One hundred twenty-six patients were negative for HBV and HCV, 163 patients had HBV infection only, 79 patients had HCV infection only, and 78 patients had coinfection with HBV and HCV. Patients with hepatitis were more likely to have tumors smaller than 5 cm and bilateral HCC involvement. Hepatitis status (negative vs. HBV vs. HCV vs. coinfection with HBV and HCV) did not predict tumor grade or the presence of multiple tumor nodules. Patients with HCV or coinfection with HBV and HCV exhibited a lower incidence of vascular invasion, but worse fibrosis than patients with negative serology or HBV. The median survival rate was 47.9 months. The presence of hepatitis did not significantly affect the survival rate, but hepatic fibrosis and vascular invasion predicted a decreased survival rate. The prognosis after resection of HCC is influenced by tumor factors and liver disease, but not by HBV or HCV infection. The treatment for HCC should be dictated by the extent of underlying liver disease rather than by hepatitis serology. Presented at the Forty-Fifth Annual Meeting of the Society for Surgery of the Alimentary Tract, New Orleans, Louisiana, May 15–19, 2004 (oral presentation).     

Natural leukocyte interferon alfa for the treatment of chronic viral hepatitis in heart transplant recipients

BACKGROUND: A more rapid and aggressive course of hepatitis B virus (HBV)-related and hepatitis C virus (HCV)-related infection in organ transplant recipients has been described. Interferon alfa is the most accepted drug for treating HBV and HCV chronic infections. However, the use of interferon alfa-N3 has been contraindicated in heart transplant (HTx) recipients because of the hypothesized greater risk of triggering acute cellular rejection. The aim of this clinical pilot study was to evaluate tolerability, safety, and efficacy of natural leukocyte interferon alfa in the treatment of chronic HBV and HCV in HTx recipients. METHODS: Seven HTx recipients were enrolled in the study: two with HBV, four with HCV, and one with combined HBV-HCV chronic infection. The patients had a mean follow-up after heart transplantation of 8.5+/-3 years, before starting interferon alfa-N3 treatment at a dose of 6 MU three times per week, intramuscularly for 12 months. RESULTS: All patients completed the treatment with no major side effects. No unexpected episodes of acute cellular rejection were observed during the treatment. Mean aminotransferase serum levels were significantly lower than before transplantation at 3 (P<0.03), 6 (P<0.02), and 12 (P<0.02) months of treatment and at the 12-month follow-up (P<0.02). A complete and sustained response was achieved in all subjects with HBV-related chronic hepatitis, whereas sustained virologic response was observed in one of four HCV patients. CONCLUSIONS: The preliminary data emerging from our study indicate that natural leukocyte interferon alfa-N3 can be safely administered in HTx recipients with chronic HBV or HCV viral hepatitis. Further studies with larger numbers of patients are needed to assess the efficacy of interferon alfa-N3 on HCV virologic response.     

Hepatitis C virus infection and renal disease after renal transplantation

Hepatitis C virus (HCV) infection is the main cause of chronic liver disease after renal transplantation (RT). It is considered in some series to be a risk factor for graft loss and patient death. Also, HCV has been implicated in the pathogenesis of glomerular diseases in native and transplanted kidneys. The presence of membranoproliferative (MP) or membranous (M) glomerulonephritis (GN) in HCV-positive patients has been well documented after RT, but there is no clear data concerning the real prevalence of HCV-induced glomerulonephritis. MPGN with or without cryoglobulinemia and MGN have been described in HCV RNA-positive patients in general without severe liver disease. Also, there is a possible association between HCV infection and acute/chronic transplant glomerulopathy. Renal thrombotic microangiopathy has been described in HCV-positive patients with positive anti-cardolipin antibodies. The pathogenesis of MPGN and MGN in HCV patients after RT seems to be similar to that which occurs in native kidneys: the deposition of immune complexes containing HCV proteins in the glomeruli. Renal biopsy, using light microscopy, immunofluorescence techniques, and electron microscopy, is useful to achieve a correct diagnosis. Unfortunately, interferon is not recommended due to the significant risk of rejection. The possibility of pegylated interferon needs to be tested. Ribavirin can improve proteinuria but HCV RNA remains positive. Finally, recent data suggest that the use of interferon in HCV patients on dialysis can negate HCV RNA and prevent associated glomerulonephritis after RT.     

Management of chronic viral hepatitis before and after renal transplantation

Hepatitis C virus (HCV) infection is present in 2-50% of renal transplant recipients and patients receiving hemodialysis. Renal transplantation confers an overall survival benefit in HCV positive (HCV+) hemodialysis patients, with similar 5-year patient and graft survival to those without HCV infection. However, longer-term studies have reported increased liver-related mortality in HCV-infected recipients. Unfortunately, attempts to eradicate HCV infection before transplant have been disappointing. Interferon is poorly tolerated in-patients with end-stage renal disease and ribavirin is contraindicated because reduced renal clearance results in severe hemolysis. Antiviral therapy following renal transplantation is also poorly tolerated, because of interferon-induced rejection and graft loss. Although the prevalence of hepatitis B virus (HBV) infection has declined in hemodialysis patients and renal transplant recipients since the introduction of routine vaccination and other infection control measures, it remains high within countries with endemic HBV infection (especially Asia-Pacific and Africa). Renal transplantation is associated with reduced survival in HBsAg+ hemodialysis patients. Unlike interferon, lamivudine is a safe and effective antiviral HBV treatment both before and after renal transplantation. Lamivudine therapy commenced at transplantation should prevent early posttransplant reactivation and subsequent progression to cirrhosis and late liver failure. This preemptive therapy should also eradicate early liver failure from fibrosing cholestatic hepatitis. Because cessation of treatment may lead to severe lamivudine-withdrawal hepatitis, most patients require long-term therapy. The development of lamivudine-resistance will be accelerated by immunosuppression and may result in severe hepatitis flares with decompensation. Regular monitoring with liver function tests and HBV DNA measurements should enable early detection and rescue with adefovir. Chronic HCV and HBV infections are important causes of morbidity and mortality in renal transplant recipients. The best predictor for liver mortality is advanced liver disease at the time of transplant, and liver biopsy should be considered in all potential HBsAg+ or HCV+ renal transplant candidates without clinical or radiologic evidence of cirrhosis. Established cirrhosis with active viral infection should be considered a relative contraindication to isolated renal transplantation.     

Virus-related glomerular diseases: histological and clinical aspects

Viral infections can be the causative agent in many glomerular diseases, and diagnostic criteria include clinical and laboratory data and tissue molecular analysis. Hepatitis B virus (HBV) is a well known cause of membranous glomerulonephritis (MGN), membranoproliferative GN (MPGN) and IgA nephropathy (IgAN), frequently in Asian populations. Hepatitis C virus (HCV), besides cryoglobulinemia-mediated glomerulonephritis (GN), is reported to cause other forms of GN. Human immunodeficiency virus (HIV) infection is closely related to a collapsing focal segmental glomerulosclerosis (FSGS), a distinct disease that affects mainly Africans and African-Americans. In the course of HIV infection other immune complex (IC) GN can occur, most frequently in whites. Nephrotic syndrome and progression to renal insufficiency are the main clinical manifestations. HIV-HCV co-infection is related to an IC glomerular disease, sometimes with immunotactoid deposits. Recent reports emphasize the role of parvovirus B19 (PV B19) for "idiopathic" collapsing FSGS and ICGN, and of Coxsackie B virus for IgAN. Renal biopsy is useful for defining virus-related glomerular lesions and a guide for prognostic and therapeutic evaluation.     

Hepatitis C virus-related kidney disease: an overview

Hepatitis C virus (HCV)-infection leads to chronic liver disease, but also to extra-hepatic manifestations, including kidney disease. We provide an overview of HCV-related kidney diseases in non-transplanted and in kidney transplant patients, and their therapies. Membranoproliferative glomerulonephritis, associated with Type 2 cryoglobulinemia, is the predominant Type of HCV-related glomerulonephritis. Membranous glomerulonephritis and focal segmental glomerular sclerosis are less commonly described. HCV infection seems to be linked to Type 2 diabetes mellitus, and might alter the progression of diabetic-related nephropathy. Patients infected by HCV should be annually screened for markers of kidney disease and, similarly, patients with membranoproliferative or membranous glomerulonephritis should be screened for HCV infection. After transplantation, cryoglobulinemia is frequent and is associated with HCV markers. HCV-related kidney disease requires specific treatment. In non-kidney-transplant patients, treatment relies on either only anti-HCV therapy in cases of moderate renal disease, or combined anti-viral and immunosuppressive therapies in cases of severe renal disease, i.e., nephrotic syndrome and/or progressive renal failure, and in diseases that are refractory to anti-HCV therapy. In kidney transplant patients, ribavirin monotherapy could be used cautiously, whereas rituximab might be a treatment of choice in the presence of cryoglobulinemia. In liver-transplant patients, in addition to anti-HCV therapy, rituximab might be also used.     

Papillitis and vasculitis of the arteria spinalis anterior as complications of hepatitis C reinfection after liver transplantation

It is well known that hepatitis C virus (HCV)-related chronic liver disease may be associated with various immunological disorders including mixed cryoglobulinemia, which is accompanied by cutaneous vasculitis, arthralgias, membranoproliferative glomerulonephritis, and neuropathy in association with cryoprecipitable immune complexes in serum. We describe here the first case of central nervous system HCV infection with evidence of the virus in the cerebrospinal fluid in association with cryoglobulinemia in a patient who developed recurrent episodes of papillitis and vasculitis of the arteria spinalis anterior after liver transplantation. Received: 3 September 1996 Received after revision: 13 November 1996 Accepted: 6 December 1996     

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

Background We determined the incidence of hepatitis C virus (HCV)-related glomerulonephritis in Japan and the glomerular localization of HCV-related antigens in this disorder. Methods We 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). Results Eight 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. Conclusions Glomerular 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.     

Type I membranoproliferative glomerulonephritis in an HIV-infected individual without hepatitis C co-infection

Type I membranoproliferative glomerulonephritis (MPGN) is an uncommon manifestation of human immunodeficiency virus (HIV)-associated renal disease in patients co-infected with hepatitis C virus (HCV). We describe a case of Type I MPGN in an HIV-positive diabetic man with nephrotic-range proteinuria and renal insufficiency who was not co-infected with HCV. Tubuloreticular inclusions were present but there was no evidence for either cryoglobulinemia or cryoglobulin deposits in the kidney. This finding suggests that Type I MPGN may represent a reaction of the kidney to HIV independent of the effects of HCV co-infection. Clinical suspicion must be maintained for Type I MPGN in all HIV infected patients presenting with significant proteinuria regardless of HCV infection status.     

Hepatitis C virus-associated glomerular disease in patients with human immunodeficiency virus coinfection.

Chronic infection with hepatitis C virus (HCV) has been linked to the development of glomerular disease. HCV infection is highly prevalent among intravenous drug users, a population that is also at risk for HIV coinfection. This study reports the clinical-pathologic features and outcome of HCV-associated glomerular disease (HCV-GD) in 14 patients with HIV coinfection. All were intravenous drug users and all but one were African-Americans. Renal presentations included renal insufficiency, microscopic hematuria with active urine sediment, hypertension, and nephrotic syndrome or nephrotic-range proteinuria without hypercholesterolemia. Hypocomplementemia and cryoglobulinemia were present in 46 and 33% of patients, respectively. The predominant renal biopsy findings were membranoproliferative glomerulonephritis type 1 or type 3 (Burkholder subtype) in 79% of patients and membranous glomerulopathy with atypical features in 21% (including overlap with collapsing glomerulopathy in one patient). The clinical course was characterized by rapid progression to renal failure requiring dialysis. The overall morbidity and mortality were high with median time of 5.8 mo to dialysis or death. Although most patients died in renal failure, cause of death was primarily attributable to long-term immunosuppression and advanced AIDS. Patients with AIDS had shorter survival than those without (median survival time of 6.1 mo versus 45.9 mo, log-rank test P = 0.02). Only two patients were alive with stable renal function at follow-up of 28.5 mo. In patients with HCV-GD, coinfection with HIV leads to an aggressive form of renal disease that can be easily confused with HIV-associated nephropathy. Although hypocomplementemia, cryoglobulinemia, and more prominent hypertension and microscopic hematuria may provide clues to the presence of HCV-GD, renal biopsy is essential to differentiate HCV-GD from HIV-associated nephropathy.