hcv_related_mpgn

hcv_related_mpgn - Tuesday Case Tuesday Case History...

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Unformatted text preview: Tuesday Case Tuesday Case History History Pt is a 70 yo man originally presented to the ER on 12/20/07 c/o SOB x 3 days with increasing LE edema. Pt has a h/o CKD, asthma, HTN, CHF, CAD, AS w/porcine AVR 2001, HCV, chronic normocytic anemia thought 2/2 HCV and CKD. Pt has been admitted several times over the past year for similar reasons, including to the ICU in 11/07 for CHF which required a lasix drip for diuresis. Pt reported non­compliance w/meds 2/2 diarrhea for 4 days PTA. Non bloody, yellow­brown well formed diarrhea x 4 days. No fevers/chills, n/v, melena or brbpr. Denies use of NSAIDs. Pt was diuresed in the ICU, given blood transfusions, and started on vanco for a resistant staph epidermis UTI and was transferred to the floor 12/22. On 12/26/07, renal consulted for patient’s worsening CKD (crt from 1.5 baseline to 2.8) with nephrotic range proteinuria. Renal bx on 1/8/08. PMHx PMHx Renal CKD stage 3 Heme Normocytic anemia HTN CHF (EF 38%, 11/07) CAD s/p PCI 7/06, prox LAD AVR 2001, porcine Pulm: asthma GI baseline creatinine of ~1.5 Nephrotic syndrome CVS GU Hep C, gen 1a PUD EGD: erythematous gastropathy Colonoscopy: single polyp, diverticulosis, internal hemorrhoids BPH Hematuria ­ cystoscopy 3/07 neg, 4/06 with inflammation Rheum Skin rash ­ 11/07 Leukocytoclastic Vasculitis arthalgia SocH: Lives alone tobacco: ex­smoker (1­2 packs/week, quit 4 years ago) ETOH: alcohol 1­2x/wk, quit 4 yrs ago DRUGS: former crack­ cocaine use, several episodes of IVDU 30 yrs ago FamH: all relatives died of "old age" ­ denies liver/renal disease Physical Exam Physical Exam General: elderly, thin, in NAD HEENT: anicteric, perrl NECK: no lad, no jvd HEART: rrr, s1s2, 2/6 systolic murmur LUNGS: mild bibasilar crackles ABDOMEN: nl bs, soft, nt/nd, +hepatomegaly, no splenomegaly, no fluid wave SKIN: no stigmata of cirrhosis EXTREMITIES: 2+ edema with scrotal swelling, chronic stasis changes EXTREMITIES: 1+ edema Lab Data Lab Data Differential Diagnosis Differential Diagnosis Patient with active sediment (proteinuria and hematuria) HTN, edema, … pulmonary edema Nephrotic syndrome Anasarca, nephrotic proteinuria, hypoalbuminuria Low Complement GN SLE Endocarditis PIGN Cyroglobulinema (HCV, arthralgia, leukocytoclastic vasculitis) MPGN (HCV) LM LM IF IF EM EM EM EM How should we treat How should we treat this patient? Hepatitis C virus­related Hepatitis C virus­related cryoglobulinemia and glomerulonephritis pathogenesis and therapeutic strategies Introduction Introduction HCV HCV related disease: cryoglobulinemia and MPGN Treatment for our patient Standard antiviral (IFN­alpha and Ribavirin)? IFN­alpha? CG targeted treatment? HCV virus HCV virus HCV is an RNA virus of the flaviviridae family 170 million persons infected worldwide The natural targets of HCV are hepatocytes and, possibly, B lymphocyte The HCV Genome and Expressed The HCV Genome and Expressed Polyprotein N Engl J Med, Vol. 345, No. 1 July 5, 2001 Genotypes Genotypes 75% There are at least six major genotypes HCV­associated Mixed HCV­associated Mixed Cryoglobulinemia (MC) Mixed cryoglobulins (MCs) are proteins that reversibly precipitate at ≤ 37°C and consist of a mixture of monoclonal or polyclonal IgM that have antiglobulin (rheumatoid factor­ RF) activity and bind to polyclonal IgG. MCs are categorized as Type I monoclonal Igs (IgG, IgM, and sometimes IgA) Type II if the IgM RF is monoclonal 2/2 persistent viral infection: HCV, HIV Type III if polyclonal IgM RF is present 2/2 MM or Waldenström's macroglobulinemia 2/2 connective tissue disease HCV involved in the pathogenesis of MC Characterized by nonneoplastic proliferation of rheumatoid factor positive B­cell clones => CG production 25% Cryoglobulin precipitate in a cryocrit tube Serum protein electrophoresis Sequential steps for managing and treating patients Sequential steps for managing and treating patients with chronic HCV infection, genotype 1 American Association for the Study of Liver Diseases. Hepatology 2004; 39:1147 Sustained virologic response rates with peginterferon alfa­2a (pegIFN) or Sustained virologic response rates with peginterferon alfa­2a (pegIFN) or interferon alfa­2b (IFN) and ribavirin (RBV) according to genotype Contraindications to Treatment with Iterferon Contraindications to Treatment with Iterferon Alfa and Ribavirin Renal Insufficiency (CrCl ~50) Side Effects of Treatmetn with Interferon Alfa and Ribavirin What treatment options are What treatment options are available? HCV related cryoglobulinemia and MPGN Treatment for our patient Standard antiviral (IFN­alpha and Ribavirin)? IFN­alpha? CG targeted treatment? Proposed Mechanisms of Action of Interferon Alfa against HCV Proposed Mechanisms of Action of Interferon Alfa against HCV Influence of Antiviral Therapy in Hepatitis C Virus–Associated Influence of Antiviral Therapy in Hepatitis C Virus–Associated Cryoglobulinemic MPGN (Alric, AJKD, 2004) Patients (n=25) with nephrotoic­range proteinuria, mixed CG, MPGN by biopsy, with HCV Initial phase 2nd phase (not randomized) All treated for nephrotic proteinuria with lasix, acei, plasma exchanges, and steroid Group 1, (n=18) after 4­12 weeks of initial treatment receive antiviral treatment for minimal 6 mos Group 2, (n=7) maintenance with low dose lasix Follow up Initial eval, end of antiviral tx, and 6 mos after discontinuation Influence of Antiviral Therapy in Hepatitis C Virus–Associated Influence of Antiviral Therapy in Hepatitis C Virus–Associated Cryoglobulinemic MPGN (Alric, AJKD, 2004) Influence of Antiviral Therapy in Hepatitis C Virus–Associated Influence of Antiviral Therapy in Hepatitis C Virus–Associated Cryoglobulinemic MPGN (Alric, AJKD, 2004) All 6 nonresponders were genotype 1 Conclusion Conclusion Promising but not appropriate for our patient Anemia requiring frequent transfusions prohibits the use of Ribavirin As per GI: ½ dose PEG­IFN Response seen is genotype dependent: For full dose PEG­IFN: 1b ~20% vs 2b ~40% Interferon Alfa­2a Therapy in Cryoglobulinemia Associated with Hepatitis C Virus (Misiani, NEJM, 1994) Interferon Alfa­2a Therapy in Cryoglobulinemia Interferon Alfa­2a Therapy in Cryoglobulinemia Associated with Hepatitis C Virus (Misiani, NEJM, 1994) prospective randomized, controlled trial 53 patients with HCV­associated type II cryoglobulinemia. 27 patients received recombinant interferon alfa­2a thrice weekly at a dose of 1.5 million units for a week and then 3 million units thrice weekly for the following 23 weeks. 26 control patients did not receive anything apart from previously prescribed treatments All patients were then followed for an additional 24 to 48 weeks. Interferon Alfa­2a Therapy in Cryoglobulinemia Interferon Alfa­2a Therapy in Cryoglobulinemia Associated with Hepatitis C Virus (Misiani, NEJM, 1994) Percent Changes in the Protein Concentration of Cryoprecipitate in Patients Receiving Interferon Alfa­2a, According to Whether Viremia Persisted or Disappeared by the End of the Treatment Period Peg­IFN Peg­IFN We don’t know the genotype of responders in NEJM study Even with response, 100% relapsed in six months Treatment of HCV­related Treatment of HCV­related Cryoglobulinemic Glomerulonephritis Benefit of antiviral treatment is often transient and restricted to patients with mild and/or quiescent renal disease INF tx may be associated with worsening GN Ribavirin may be contraindicated in the presence on renal failure and anemia Is there no hope for our patient? Rituximab? Why not? Rituximab? Why not? Pathogenesis of Mixed Pathogenesis of Mixed Cryoglobulinemia Pathogenesis of Pathogenesis of cryoglobulinaemic nephritis and rationale for Rituximab treatment Mechanism of rituximab Mechanism of rituximab Why Rituximab? Chimeric monocloanl ab Binds to the B­cell surface Ag CD20 Stop it before it starts Long­term effects of anti­CD20 monoclonal antibody Long­term effects of anti­CD20 monoclonal antibody treatment of cryoglobulinemic glomerulonephritis (CGGN) (Roccatello_Nephrol Dial Transplant_2004) N = 6 HCV genotype Tx: 1b = 2 2a2c = 2 Rituximab 375 mg/m2 Two with bone marrow lymphocyte infiltration Four with either intolerance or resistance to standard immunosuppressive tx days 1, 8, 15, and 22. Two additional doses were given 1 and 2 months later. No other immunosuppressive drugs Endpoints Laboratory parameters Proteinuria, ESR, cryocrit, HCV VL Clinical sxs and symptoms Skin ulcers, purpura, arthralgia, weakness, praesthesia and fever Long­term effects of anti­CD20 monoclonal antibody Long­term effects of anti­CD20 monoclonal antibody treatment of cryoglobulinemic glomerulonephritis (CGGN) (Roccatello_Nephrol Dial Transplant_2004) Long­term effects of anti­CD20 monoclonal antibody Long­term effects of anti­CD20 monoclonal antibody treatment of cryoglobulinemic glomerulonephritis (CGGN) (Roccatello_Nephrol Dial Transplant_2004) Long­term effects of anti­CD20 monoclonal antibody Long­term effects of anti­CD20 monoclonal antibody treatment of cryoglobulinemic glomerulonephritis (CGGN) (Roccatello_Nephrol Dial Transplant_2004) No increase in VL detected Efficacy and safety of rituximab in type II Efficacy and safety of rituximab in type II mixed cryoglobulinemia, Zaja, Blood, 2003 N=15, with type II MC unresponsive to conventional treatments 11/15 were HCV related one with Sjogren syn and two were essential F/U for 6 months Tx: Rituximab (days 1, 8, 15, 22) Efficacy and safety of rituximab in type II Efficacy and safety of rituximab in type II mixed cryoglobulinemia, Zaja, Blood, 2003 Median values (with standard error bars) at baseline and during the 6­month follow­up in the studied patients The course of rheumatoid factor, cryoglobulin, and immunoglobulin serum levels in the studied patients after rituximab therapy Conclusion Conclusion Optimal strategy for HCV­associated MC nephritis is still undefined For our patient INF/Ribavirin ­ prohibitive INF­alpha with high relapse Corticosteroid in combination with Rituximab ...
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This note was uploaded on 12/24/2011 for the course STEP 1 taught by Professor Dr.aslam during the Fall '11 term at Montgomery College.

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