Hepatitis: Messa P

Fabrizi F, Messa P, Martin P. · Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS Foundation, Milano, Italy. · Int J Artif Organs. · Pubmed #19241358 No free full text.

Abstract: Hepatitis C Virus (HCV) infection remains prevalent in patients receiving regular dialysis all over the world. The adverse impact of anti-HCV serologic status on mortality in the dialysis population has been documented. Antiviral therapy for hepatitis C in chronic kidney disease (CKD) patients, including the dialysis population, is still unsatisfactory. Several findings support a different course of HCV in dialysis patients versus the non-uremic population. The HCV viral load appears lower in hemodialysis patients with HCV despite the immune compromise caused by chronic uremia; the histologic abnormalities seem milder, and a severe clinical course of chronic hepatitis C is unusual in most hemodialysis (HD) patients. It appears that the HD procedure per se can preserve patients from an aggressive course of HCV by reducing the viral load (HCV RNA). The mechanisms by which the HD procedure lowers HCV viremia remain largely speculative: the passage of viral particles into the dialysate, the trapping of the virus on the surface of the dialyzer membrane, and an indirect host-mediated mechanism have been cited. The latter hypothesis implicates the production of interferon-alpha, hepatocyte growth factor, or other cytokines provided with antiviral activities during the hemodialysis sessions. Clinical trials aimed at clarifying this issue are under way.

Fabrizi F, Messa P, Martin P. · Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS Foundation, Milano, Italy. · Int J Artif Organs. · Pubmed #19115192 No free full text.

Abstract: A variety of epidemiological data provides evidence for the occurrence of nosocomial transmission of hepatitis C virus (HCV) infection to hemodialysis (HD) patients. The most important factor implicated in HCV transmission between patients treated in the same dialysis unit is cross-contamination from supplies and surfaces as a result of failure of staff to follow infection control procedures. Parts of the HCV genome are highly variable and lend themselves to fingerprinting of each isolate using nucleic acid testing (NAT) and sequencing. This approach has permitted investigation of possible transmission routes within HD units. A systematic review of molecular virology papers revealed transmission of HCV via internal fluid pathways of the dialysis machines in a minority of reports only. Dialyzer reuse was not identified as a risk factor for HCV acquisition in multicenter databases. No randomized controlled trials exist on the impact of isolation on the risk of transmission of HCV to hemodialysis patients. A Belgian prospective multicenter study showed a reduction from 1.4% to 0% in the annual incidence of seroconversion for HCV without any isolation measures, by implementation of strict infection control procedures designed to prevent transmission of blood-borne pathogens, including HCV. However, an isolation policy for HCV-infected dialysis patients should be considered in dialysis units where nosocomial transmission of HCV persists despite reinforcement and audit of hygienic precautions for hemodialysis. Routine audit precautions (general and for dialysis machines) are recommended on a regular basis within HD units.

Fabrizi F, Lunghi G, Messa P, Martin P. · Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS Foundation, Milan - Italy. · J Nephrol. · Pubmed #19034865 links to  free full text

Abstract: The most frequent kidney disease associated with chronic hepatitis C virus (HCV) infection is type I membranoproliferative glomerulonephritis (MPGN) in patients with type II mixed cryoglobulinemia. 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. Various approaches have been tried for the treatment of HCV-associated glomerulonephritis, including immunosuppressive therapy (corticosteroids and cytotoxic agents), plasma exchange and antiviral agents. Limited data exist regarding antiviral treatment of HCV-associated glomerulonephritis, whereas immunosuppressive agents have been suggested for cryoglobulinemic kidney disease. A recent meta-analysis of controlled clinical trials (CCTs) suggested that standard interferon (IFN) doses were more effective than immunosuppressive agents in lowering proteinuria of patients with HCV-related cryoglobulinemic glomerulonephritis (odds ratio 3.86; 95% confidence interval, 1.44-10.33; p=0.007). However, data for follow-up were not given. Two distinct approaches should be considered for the treatment of HCV-associated cryoglobulinemic glomerulonephritis according to the level of proteinuria and kidney failure. Preliminary studies with rituximab therapy of HCV-related cryoglobulinemic glomerulonephritis have given encouraging results, even if a point of caution is important, because rituximab use may be associated with activation of various infections, including HCV.

Fabrizi F, Messa P, Martin P, Takkouche B. · Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS, Milan, Italy. · Int J Artif Organs. · Pubmed #18825640 No free full text.

Abstract: OBJECTIVE: To examine the association between HCV infection and the occurrence of post-transplant diabetes mellitus (PTDM) among renal transplant patients. DESIGN: Meta-analysis of observational studies. DATA SOURCES: We retrieved studies published in any language by systematically searching Medline, and Embase and by manually examining the references of the original articles, reviews, and monographs retrieved. REVIEW METHODS: We included cohort and case-control studies reporting relative risk estimates and 95% confidence intervals (CIs) for PTDM occurrence with HCV after renal transplantation. Thirteen studies providing information on a total of 30,099 unique patients were included in our meta-analysis. RESULTS: Study-specific relative risks were weighted by the inverse of their variance to obtain fixed and a 95% confidence interval (CI) of 1.94; 3.83 (10 studies). In a stratified analysis including only large studies (2 studies), the pooled RR was 1.36 (95% CI, 1.21; 1.54). Egger's regression test showed some evidence of publication bias (p=0.0001), but our sensitivity analysis showed that this issue did not meaningfully change the results. CONCLUSIONS: Our study shows a marked increase of the risk of post-transplant diabetes mellitus in anti-hepatitis C virus-positive renal transplant recipients. The excess risk of death in hepatitis C virus-positive renal transplant recipients may be at least partially attributed to post-transplant diabetes mellitus with its attendant complications.

Fabrizi F, Marzano A, Messa P, Martin P, Lampertico P. · Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS, Milan - Italy. · Int J Artif Organs. · Pubmed #18609511 No free full text.

Abstract: One of the major advances in the management of patients on regular dialysis has been the control of the spread of hepatitis B virus (HBV) infection in dialysis units. The rate of HBsAg positive patients on regular dialysis in the developed world is currently low, but outbreaks of HBV continue to occur. The diffusion of HBV in dialysis units in developing countries is higher, although available information is not abundant. There are limited data on the natural history of HBV in the dialysis population; they support a detrimental effect of HBV on survival in dialysis patients. The HBV viral load in HbsAg-positive dialysis patients appears low and stable over time and numerous mechanisms have been posited to explain it. Several assays for detecting HBV DNA in serum are available but they should not be used for purposes of routine screening within dialysis units. The epidemiology and clinical significance of occult HBV infection in the dialysis population needs to be addressed adequately - this remains an area of active research. Recent recommendations for the management of HBsAg chronic carriers on maintenance dialysis have been issued. No controlled trials for the treatment of hepatitis B with either interferon or lamivudine in dialysis patients are currently available.

Fabrizi F, Messa P, Martin P. · Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS, Milan, Italy. · Semin Dial. · Pubmed #18397202 No free full text.

Abstract: Prevention of nosocomial transmission of hepatitis B virus (HBV) has been a signal achievement in the management of chronic kidney disease. The rate of serum hepatitis B surface antigen (HBsAg) seropositivity in patients on maintenance hemodialysis in the developed world is currently low (0-10%) but outbreaks of acute HBV infection continue to occur in this setting. The prevalence of HBV infection within dialysis units in developing countries appears higher (2-20%) based on relatively few reports. Although data are limited, HBV infection in dialysis population diminishes survival; HBV viral load in HBsAg-positive dialysis patients is reportedly low and stable over time. Updated recommendations for the management of HBsAg chronic carriers on maintenance dialysis have been issued. No rigorously controlled treatment trials for treatment of hepatitis B with either interferon or lamivudine therapy in dialysis patients are currently available.

Fabrizi F, Lunghi G, Ganeshan SV, Martin P, Messa P. · Division of Nephrology, Maggiore Hospital, IRCCS, Milan, Italy. · Semin Dial. · Pubmed #17897248 No free full text.

Abstract: Hepatitis C virus (HCV) remains common in patients undergoing regular dialysis and is an important cause of liver disease in this population both during dialysis and after renal transplantation (RT). Anti-HCV screening of blood products has almost eliminated posttransfusion HCV infection but acquisition of HCV continues to occur in dialysis patients because of nosocomial spread. The natural history of HCV in dialysis population is not completely understood though recent data show that HCV infection has a detrimental role on survival of chronic dialysis patients. Several clinical trials have suggested that the response rate to conventional interferon (IFN) is higher in dialysis patients than those with normal kidney function but tolerance is lower. There are only limited data about pegylated IFN alone or in association with ribavirin for hepatitis C in dialysis population. IFN remains contraindicated post-RT because of concern about precipitating graft dysfunction; however, preliminary evidence shows the durability of sustained response to antiviral therapy pre-RT after renal transplant. Successful pretransplant therapy is associated with several benefits after RT including reduced incidence of posttransplant diabetes mellitus and de novo glomerulonephritis in HCV-infected recipients.

Fabrizi F, Bruchfeld A, Mangano S, Dixit V, Messa P, Martin P. · Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS, Via Commenda 15, 20122 Milan, Italy. · Int J Artif Organs. · Pubmed #17417760 No free full text.

Abstract: BACKGROUND: A relationship between hepatitis C virus (HCV) infection and chronic glomerulonephritis (GN) has been asserted on the grounds of epidemiological and experimental data. Although this suggests a role for an antiviral approach to HCV-associated GN instead of the more conventional immunosuppressive (or supportive) therapy, the optimal management of HCV related glomerulonephritis remains controversial. OBJECTIVE: To compare antiviral with immunosuppressive therapy for HCV-associated GN. DESIGN: Meta-analysis of controlled clinical trials (CCTs) of the two treatments (antiviral versus immunosuppressive) of HCV-associated GN. METHODS: We used the fixed or random effects model of DerSimonian and Laird, with heterogeneity and sensitivity analyses. The rate of proteinuria and serum creatinine decrease after therapy for HCV-associated GN were regarded as the most reliable outcome end-points. RESULTS: We identified six studies involving 145 unique patients with HCV-associated GN. Pooling of study results demonstrated that proteinuria decreased more commonly after IFN than corticosteroid therapy (OR 1.92 (95% CI, 0.39; 9.57), NS), P-test for heterogeneity, 0.06 (I2=52.9%). In a sensitivity analysis including only CCTs using standard IFN-doses, OR was 3.86 (95% CI, 1.44; 10.33, (P=0.007)), P-test for heterogeneity, 0.18 (I2=35.9%). No improvement of serum creatinine after IFN compared to immunosuppressive therapy was noted (OR, 0.59 (95% CI, 0.21; 1.65), NS), P-test for heterogeneity, 0.76 (I2=0%). Only three CCTs gave information on the rate of proteinuria decrease over follow-up (OR, 5.08 (95% CI, 0.69; 37.31), NS). A few major side effects were noted after IFN administration. CONCLUSIONS: Our meta-analysis indicates that standard IFN-doses were more effective than immunosuppressive therapy in lowering proteinuria of patients with HCV-related glomerulonephritis. However, no significant improvement in serum creatinine was seen by IFN or steroid therapy across the studies. Also, information on proteinuria recurrence after the completion of antiviral therapy was not sufficient. Prospective, randomized trials based on combined antiviral therapy (pegylated IFN plus ribavirin) with adequate dose and follow-up are required to assess the efficacy and safety of antiviral treatment of HCV-associated glomerulonephritis.

Fabrizi F, Messa P, Martin P. · Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS Foundation, Milan - Italy and Division of Hepatology, School of Medicine, University of Miami, Miami, FL - USA. · Int J Artif Organs. · Pubmed #19569034 No free full text.

Abstract: Hepatitis C virus (HCV) infection remains frequent among renal transplant (RT) recipients and has a detrimental effect on patient and graft survival. accelerated progression of liver disease due to HCV has been implicated in increased mortality after kidney transplantation but additional outcomes have been related to HCV after RT. all HCV-infected kidney transplant candidates should be considered for liver biopsy before RT. HCV infection should not be considered an absolute contraindication to renal transplantation, although the course of HCV-related liver disease is often progressive. Numerous organ procurement organizations have introduced the policy of accepting kidneys from HCV-positive donors for HCV-positive recipients, but this is still controversial. Single-center experiences have not reported adverse effects on the short-term patient and graft survival, however information from large databases has suggested that RT recipients of HCV-positive donors are independently at risk of mortality even in the modern era of immunosuppression. Renal transplantation should be considered using HCV-seropositive grafts for qualified patients with chronic kidney disease (CKD) stage 5 and HCV infection since good information indicates that the transplantation of kidneys from HCV-infected donors results in improved survival compared to wait-listed and dialysis-dependent candidates. a potential risk related to the use of donor HCV-positive kidneys cannot be excluded, and kidneys from HCV-infected donors should be restricted to recipients with evidence of active viremia at the time of kidney transplantation.

Fabrizi F, Dixit V, Messa P, Martin P. · Division of Nephrology, Maggiore Hospital, IRCCS, Milan, Italy. · J Viral Hepat. · Pubmed #18184190 No free full text.

Abstract: The efficacy of monotherapy with interferon (IFN) (conventional or pegylated IFN) in dialysis patients with chronic hepatitis C remains unclear, although a number of clinical trials have been published addressing this issue. The aim of the study was to evaluate the efficacy and safety of monotherapy by conventional or pegylated IFN in dialysis patients with chronic hepatitis C by performing a systematic review of the literature with a meta-analysis of clinical trials. The primary outcome was sustained virological response (SVR; as a measure of efficacy), and the secondary outcome was drop-out rate (as a measure of tolerability). We used the random-effects model of Der Simonian and Laird, with heterogeneity and sensitivity analyses. We identified 28 clinical trials (645 unique patients), of which six (21.4%) had a controlled design. In the group of trials based on conventional IFN, the summary estimate for SVR and drop-out rate was 39% [95% confidence interval (CI) 32-46] and 19% (95% CI 13-26) respectively. The summary estimate for SVR rate in patients with the hepatitis C virus genotype 1 was 33% (95% CI 19-47). In the subset of trials using pegylated IFN, the summary estimate for SVR and drop-out rate was 31% (95% CI 7-55) and 27% (95% CI 1-52) respectively. The most frequent side-effects requiring interruption of treatment were flu-like symptoms, and gastrointestinal and haematological changes. A relationship between age and drop-out rate was found, even if no statistical significance was reached (P = 0.064). The studies were heterogeneous with regard to SVR and drop-out rate. No publication bias was observed. One-third of dialysis patients with chronic hepatitis C were successfully treated with conventional or pegylated IFN monotherapy. Preliminary evidence does not support additional benefit due to monotherapy with pegylated IFN on the viral response in the chronic kidney disease (CKD) population. Tolerance to IFN monotherapy was unsatisfactory, particularly to pegylated IFN. The optimal antiviral treatment of chronic hepatitis C in dialysis populations is currently under active investigation.

Fabrizi F, Takkouche B, Lunghi G, Dixit V, Messa P, Martin P. · Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS, Milano, Italy. · J Viral Hepat. · Pubmed #17875004 No free full text.

Abstract: The impact of hepatitis C virus (HCV) infection on mortality of patients receiving regular dialysis remains unclear. The assessment of the natural history of HCV in dialysis population is difficult because of the low progression of HCV-related liver disease over time and the reduced life expectancy in patients with end-stage renal disease. The aim of the study was to conduct a systematic review of the published medical literature concerning the impact of HCV infection on the survival of patients undergoing maintenance dialysis. The relative risk of mortality was regarded as the most reliable outcome end-point. Study-specific relative risks were weighted by the inverse of their variance to obtain fixed- and random-effects pooled estimates for mortality with HCV across the published studies. We identified seven studies involving 11 589 unique patients on maintenance dialysis; two (29%) were case-control studies. Pooling of study results demonstrated that presence of anti-HCV antibody was an independent and significant risk factor for death in patients on maintenance dialysis. The summary estimate for adjusted relative risk (aRR) (all-cause mortality) was 1.34 with a 95% confidence interval (CI) of 1.13-1.59. Heterogeneity statistics, R(i) = 0.48 (P-value by Q-test = 0.13). In a sensitivity analysis including only (n = 5) cohort studies, the pooled aRR was 1.38 (95% CI, 1.20-1.59); heterogeneity statistics R(i) = 0.46. As a cause of death, hepatocellular carcinoma and liver cirrhosis were significantly more frequent among anti-HCV-positive than -negative dialysis patients. Our meta-analysis indicates that anti-HCV-positive patients on dialysis have an increased risk of mortality compared with HCV-negative patients. The excess risk of death in HCV-positive patients may be at least partially attributed to chronic liver disease with its attendant complications.

De Feo TM, Grossi P, Poli F, Mozzi F, Messa P, Minetti E, Sandrini S, Boschiero L, Rigotti P, Maresca C, Rolla D, Chiaramonte S, Gotti E, Caldara R, Briano G, Scalamogna M. · Department Trasfusionale e di Riferimento per il Trapianto di Organi e Tessuti, IRCCS Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy. · Transplantation. · Pubmed #16421480 No free full text.

Abstract: BACKGROUND: The risk of transmitting a hepatitis B virus (HBV) infection from donor kidneys with a past HBV serological profile may be negligible. Data on HBV transmission to kidney transplant recipients from donor organs that were anti-HBc/HBsAg in Italy has not been previously reported. Anti-HBc testing in cadaver organ donors has been mandatory in Italy since 2002, when anti-HBc determinations were included in the National Guidelines for donor evaluation. Therefore, prior to that date kidney recipients from anti-HBc/HBsAg donors can be identified retrospectively where stored serum is available for testing. METHODS: The prevalence of anti-HBc Italian organ donors, the incidence of HBV transmission according to the recipients' HBV status (vaccinated, recovered, or naive), and the clinical impact (5-year graft and patient survival rates) in the North Italy Transplant program was evaluated by retrospectively screening for anti-HBc antibodies in the sera of cadaver kidney donors used in transplants from 1997 to 1999. RESULTS: Two hundred and ten donors were found to have been anti-HBc. At the time of the study, no active infection was observed in any of the 344 HBsAg recipients, but 4/140 (2.86%) of the vaccinated recipients were found to have been anti-HBc/HBsAg. None of these patients, however, had any biochemical or clinical history of HBV infection. Patient and graft survival rates of anti-HBc or anti-HBc kidney recipients did not differ statistically. CONCLUSION: Kidney grafts from anti-HBc donors should be considered in all recipients because the benefit obtained from the transplantation out weighs the negligible risk of HBV transmission.

Aroldi A, Lampertico P, Montagnino G, Passerini P, Villa M, Campise MR, Lunghi G, Tarantino A, Cesana BM, Messa P, Ponticelli C. · Divisione di Nefrologia e Dialisi, Unità Operativa Nefrologia e Dialisi, Ospedale Maggiore IRCCS, Milano, Italy. · Transplantation. · Pubmed #15880056 No free full text.

Abstract: BACKGROUND: In renal allograft recipients, most cases of liver dysfunction are caused by hepatitis B virus and hepatitis C virus (HCV). The natural history of hepatitis C and B was studied in 286 renal allograft recipients who received a kidney allograft between 1972 and 1989 when tests for anti-HCV became available. METHODS: In all patients, hepatitis B (HB) surface (s) antigen (Ag) was tested before and anti-HCV (by enzyme-linked immunosorbent assay II) after transplantation. RESULTS: At enrollment in 1989 (5.5+/-4 years after transplantation), 209 patients were anti-HCV positive (C+), 42 patients were HBsAg-positive (B+), and 35 patients were both B+ and C+ (C+B+). One hundred four patients were receiving azathioprine (AZA) and 182 were on cyclosporine A (CsA). Since transplantation, the median follow-up was 18 years in AZA-treated and 13 years in CsA-treated patients. Liver biopsy showed chronic hepatitis in 73 patients, cirrhosis in 20 patients, and fibrosing cholestatic hepatitis in 2 patients. In 34 patients, liver biopsy was repeated, and progression of fibrosis was observed in 24 patients. The 12-year patient survival rate was similar in B+, C+, and B+C+ patients (67%, 78%, and 71%, respectively; P=not significant). Liver-related death was the first cause of death in B+ and B+C+ infected patients (58% and 72%, respectively), whereas cardiovascular disease was the leading cause of death in C+ patients (40%). Multivariate analysis showed that older age (>40 years) (relative risk [RR], 2.8), B+ status (RR, 2.36), and C+ status (RR, 1.65) were independently associated with a worse patient survival. CONCLUSIONS: In the long term, B+ patients had a higher risk of death related to liver disease than C+ patients, and co-infection did not worsen patient survival.

Moroni G, Tantardini F, Gallelli B, Quaglini S, Banfi G, Poli F, Montagnino G, Meroni P, Messa P, Ponticelli C. · Divisione di Nefrologia e Dialisi, Centro Trasfusionale e di Immunologia dei Trapianti IRCCS, Ospedale Maggiore Milano, Italy. · Am J Kidney Dis. · Pubmed #15861356 No free full text.

Abstract: BACKGROUND: Few data are available about the long-term outcome of renal transplantation in patients with systemic lupus erythematosus (SLE). METHODS: Between June 1982 and 2004, a total of 33 adults with lupus nephritis received 35 kidney allografts. Outcomes of these grafts and those of 70 controls matched for age, sex, and donor source who underwent transplantation during the same period were compared. RESULTS: Mean follow-up after renal transplantation was 91 +/- 59 months for patients with lupus and 90 +/- 64 months for controls. Actuarial 15-year patient (80% versus 83%) and death-censored graft survival rates (69% versus 67%) were not significantly different between patients with lupus and controls. Risks for acute and chronic rejection, arterial hypertension, and infection were not different between the 2 groups. Mean serum creatinine levels also were similar in the 2 groups at the last follow-up visit. Intravascular thrombotic events occurred in 9 patients with SLE (26%) and 6 controls (8.6%; P = 0.038). In the SLE group, 6 of 7 antiphospholipid (aPL) antibody-positive versus 3 of 17 aPL antibody-negative patients experienced thrombotic events ( P = 0.015). Recurrence of lupus nephritis was documented in 3 renal grafts (8.6%), but no graft was lost because of recurrent lupus nephritis. CONCLUSION: Long-term patient and graft survival probabilities were similar in patients with SLE and matched controls. The risk for thrombotic complications was greater in patients with SLE, particularly aPL-positive patients. Nephritis recurred in less than 10% of patients with SLE and did not influence graft survival.