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Tuesday Case. 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,

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Presentation on theme: "Tuesday Case. 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,"— Presentation transcript:

1 Tuesday Case

2 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 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 non-compliance w/meds 2/2 diarrhea for 4 days PTA. Non bloody, yellow-brown 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.

3 PMHx Renal Renal CKD stage 3 CKD stage 3 baseline creatinine of ~1.5 baseline creatinine of ~1.5 Nephrotic syndrome Nephrotic syndrome Heme Heme Normocytic anemia Normocytic anemia CVS CVS HTN HTN CHF (EF 38%, 11/07) CHF (EF 38%, 11/07) CAD s/p PCI 7/06, prox LAD CAD s/p PCI 7/06, prox LAD AVR 2001, porcine AVR 2001, porcine Pulm: asthma Pulm: asthma GI Hep C, gen 1a PUD EGD: erythematous gastropathy Colonoscopy: single polyp, diverticulosis, internal hemorrhoids GU BPH Hematuria - cystoscopy 3/07 neg, 4/06 with inflammation Rheum Skin rash - 11/07 Leukocytoclastic Vasculitis arthalgia

4 SocH: SocH: Lives alone Lives alone tobacco: ex-smoker (1-2 packs/week, quit 4 years ago) tobacco: ex-smoker (1-2 packs/week, quit 4 years ago) ETOH: alcohol 1-2x/wk, quit 4 yrs ago ETOH: alcohol 1-2x/wk, quit 4 yrs ago DRUGS: former crack- cocaine use, several episodes of IVDU 30 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

5 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

6 Lab Data

7 Differential Diagnosis Patient with Patient with active sediment (proteinuria and hematuria) active sediment (proteinuria and hematuria) HTN, edema, … pulmonary edema HTN, edema, … pulmonary edema Nephrotic syndrome Nephrotic syndrome Anasarca, nephrotic proteinuria, hypoalbuminuria Anasarca, nephrotic proteinuria, hypoalbuminuria Low Complement GN Low Complement GN SLE SLE Endocarditis Endocarditis PIGN PIGN Cyroglobulinema (HCV, arthralgia, leukocytoclastic vasculitis) Cyroglobulinema (HCV, arthralgia, leukocytoclastic vasculitis) MPGN (HCV) MPGN (HCV)

8 LM

9 IF

10 EM

11 EM

12 How should we treat this patient?

13 Hepatitis C virus-related cryoglobulinemia and glomerulonephritis pathogenesis and therapeutic strategies

14 Introduction HCV HCV HCV related disease: cryoglobulinemia and MPGN HCV related disease: cryoglobulinemia and MPGN Treatment for our patient Treatment for our patient Standard antiviral (IFN-alpha and Ribavirin)? Standard antiviral (IFN-alpha and Ribavirin)? IFN-alpha? IFN-alpha? CG targeted treatment? CG targeted treatment?

15 HCV virus HCV is an RNA virus of the flaviviridae family HCV is an RNA virus of the flaviviridae family 170 million persons infected worldwide 170 million persons infected worldwide The natural targets of HCV are hepatocytes and, possibly, B lymphocyte The natural targets of HCV are hepatocytes and, possibly, B lymphocyte

16 The HCV Genome and Expressed Polyprotein N Engl J Med, Vol. 345, No. 1 July 5, 2001

17 Genotypes There are at least six major genotypes There are at least six major genotypes 75%

18 HCV-associated 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. 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 MCs are categorized as Type I monoclonal Igs (IgG, IgM, and sometimes IgA) Type I monoclonal Igs (IgG, IgM, and sometimes IgA) 2/2 MM or Waldenström's macroglobulinemia 2/2 MM or Waldenström's macroglobulinemia Type II if the IgM RF is monoclonal Type II if the IgM RF is monoclonal 2/2 persistent viral infection: HCV, HIV 2/2 persistent viral infection: HCV, HIV Type III if polyclonal IgM RF is present Type III if polyclonal IgM RF is present 2/2 connective tissue disease 2/2 connective tissue disease HCV involved in the pathogenesis of MC HCV involved in the pathogenesis of MC Characterized by nonneoplastic proliferation of rheumatoid factor positive B-cell clones => CG production Characterized by nonneoplastic proliferation of rheumatoid factor positive B-cell clones => CG production

19 Cryoglobulin precipitate in a cryocrit tube Serum protein electrophoresis25%

20 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

21 Sustained virologic response rates with peginterferon alfa-2a (pegIFN) or interferon alfa-2b (IFN) and ribavirin (RBV) according to genotype

22 Contraindications to Treatment with Iterferon Alfa and Ribavirin Side Effects of Treatmetn with Interferon Alfa and Ribavirin Renal Insufficiency (CrCl ~50)

23 What treatment options are available? HCV related cryoglobulinemia and MPGN HCV related cryoglobulinemia and MPGN Treatment for our patient Treatment for our patient Standard antiviral (IFN-alpha and Ribavirin)? Standard antiviral (IFN-alpha and Ribavirin)? IFN-alpha? IFN-alpha? CG targeted treatment? CG targeted treatment?

24 Proposed Mechanisms of Action of Interferon Alfa against HCV

25 Influence of Antiviral Therapy in Hepatitis C Virus–Associated Cryoglobulinemic MPGN (Alric, AJKD, 2004) Patients (n=25) with nephrotoic-range proteinuria, mixed CG, MPGN by biopsy, with HCV Patients (n=25) with nephrotoic-range proteinuria, mixed CG, MPGN by biopsy, with HCV Initial phase Initial phase All treated for nephrotic proteinuria with lasix, acei, plasma exchanges, and steroid All treated for nephrotic proteinuria with lasix, acei, plasma exchanges, and steroid 2 nd phase (not randomized) 2 nd phase (not randomized) Group 1, (n=18) after 4-12 weeks of initial treatment receive antiviral treatment for minimal 6 mos Group 1, (n=18) after 4-12 weeks of initial treatment receive antiviral treatment for minimal 6 mos Group 2, (n=7) maintenance with low dose lasix Group 2, (n=7) maintenance with low dose lasix Follow up Follow up Initial eval, end of antiviral tx, and 6 mos after discontinuation Initial eval, end of antiviral tx, and 6 mos after discontinuation

26 Influence of Antiviral Therapy in Hepatitis C Virus–Associated Cryoglobulinemic MPGN (Alric, AJKD, 2004)

27 All 6 nonresponders were genotype 1

28 Conclusion Promising but not appropriate for our patient Promising but not appropriate for our patient Anemia requiring frequent transfusions prohibits the use of Ribavirin Anemia requiring frequent transfusions prohibits the use of Ribavirin As per GI: ½ dose PEG-IFN As per GI: ½ dose PEG-IFN Response seen is genotype dependent: Response seen is genotype dependent: For full dose PEG-IFN: 1b ~20% vs 2b ~40% For full dose PEG-IFN: 1b ~20% vs 2b ~40% Interferon Alfa-2a Therapy in Cryoglobulinemia Associated with Hepatitis C Virus (Misiani, NEJM, 1994) Interferon Alfa-2a Therapy in Cryoglobulinemia Associated with Hepatitis C Virus (Misiani, NEJM, 1994)

29 Interferon Alfa-2a Therapy in Cryoglobulinemia Associated with Hepatitis C Virus (Misiani, NEJM, 1994) prospective randomized, controlled trial prospective randomized, controlled trial 53 patients with HCV-associated type II cryoglobulinemia. 53 patients with HCV-associated type II cryoglobulinemia. 27 patients received recombinant interferon alfa-2a 27 patients received recombinant interferon alfa-2a 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. 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 26 control patients did not receive anything apart from previously prescribed treatments All patients were then followed for an additional 24 to 48 weeks. All patients were then followed for an additional 24 to 48 weeks.

30 Interferon Alfa-2a Therapy in Cryoglobulinemia Associated with Hepatitis C Virus (Misiani, NEJM, 1994) Percent Changes in the Protein Concentration of Cryoprecipitate in Patients Receiving Interferon Alfa-2a, According to Whether Viremia Persisted or Disappeared by the End of the Treatment Period

31 Peg-IFN We don’t know the genotype of responders in NEJM study We don’t know the genotype of responders in NEJM study Even with response, 100% relapsed in six months Even with response, 100% relapsed in six months

32 Treatment of HCV-related Cryoglobulinemic Glomerulonephritis Benefit of antiviral treatment is often transient and restricted to patients with mild and/or quiescent renal disease 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 INF tx may be associated with worsening GN Ribavirin may be contraindicated in the presence on renal failure and anemia Ribavirin may be contraindicated in the presence on renal failure and anemia Is there no hope for our patient?

33 Rituximab? Why not?

34 Pathogenesis of Mixed Cryoglobulinemia

35 Pathogenesis of cryoglobulinaemic nephritis and rationale for Rituximab treatment

36 Mechanism of rituximab Why Rituximab? Why Rituximab? Chimeric monocloanl ab Chimeric monocloanl ab Binds to the B-cell surface Ag CD20 Binds to the B-cell surface Ag CD20 Stop it before it starts Stop it before it starts

37 Long-term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinemic glomerulonephritis (CGGN) (Roccatello_Nephrol Dial Transplant_2004) N = 6 N = 6 Two with bone marrow lymphocyte infiltration Two with bone marrow lymphocyte infiltration Four with either intolerance or resistance to standard immunosuppressive tx Four with either intolerance or resistance to standard immunosuppressive tx HCV genotype HCV genotype 1b = 2 1b = 2 2a2c = 2 2a2c = 2 Tx: Tx: Rituximab 375 mg/m2 Rituximab 375 mg/m2 days 1, 8, 15, and 22. Two additional doses were given 1 and 2 months later. days 1, 8, 15, and 22. Two additional doses were given 1 and 2 months later. No other immunosuppressive drugs No other immunosuppressive drugs Endpoints Endpoints Laboratory parameters Laboratory parameters Proteinuria, ESR, cryocrit, HCV VL Proteinuria, ESR, cryocrit, HCV VL Clinical sxs and symptoms Clinical sxs and symptoms Skin ulcers, purpura, arthralgia, weakness, praesthesia and fever Skin ulcers, purpura, arthralgia, weakness, praesthesia and fever

38 Long-term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinemic glomerulonephritis (CGGN) (Roccatello_Nephrol Dial Transplant_2004)

39

40 No increase in VL detected No increase in VL detected

41 Efficacy and safety of rituximab in type II mixed cryoglobulinemia, Zaja, Blood, 2003 N=15, with type II MC unresponsive to conventional treatments N=15, with type II MC unresponsive to conventional treatments 11/15 were HCV related 11/15 were HCV related one with Sjogren syn and two were essential one with Sjogren syn and two were essential F/U for 6 months F/U for 6 months Tx: Rituximab (days 1, 8, 15, 22) Tx: Rituximab (days 1, 8, 15, 22)

42 Efficacy and safety of rituximab in type II mixed cryoglobulinemia, Zaja, Blood, 2003 Median values (with standard error bars) at baseline and during the 6- month follow-up in the studied patients The course of rheumatoid factor, cryoglobulin, and immunoglobulin serum levels in the studied patients after rituximab therapy

43 Conclusion Optimal strategy for HCV-associated MC nephritis is still undefined Optimal strategy for HCV-associated MC nephritis is still undefined For our patient For our patient INF/Ribavirin - prohibitive INF/Ribavirin - prohibitive INF-alpha with high relapse INF-alpha with high relapse Corticosteroid in combination with Rituximab Corticosteroid in combination with Rituximab


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