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,

Tuesday CaseTuesday Case

HistoryHistory Pt is a 70 yo man originally presented to the ER on 12/20/07 c/o SOB x 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, 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 CHF, CAD, AS w/porcine AVR 2001, HCV, chronic normocytic anemia thought 2/2 HCV and CKD. thought 2/2 HCV and CKD.

Pt has been admitted several times over the past year for similar 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 reasons, including to the ICU in 11/07 for CHF which required a lasix drip for diuresis. drip for diuresis.

Pt reported non-compliance w/meds 2/2 diarrhea for 4 days PTA. Non 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, bloody, yellow-brown well formed diarrhea x 4 days. No fevers/chills, n/v, melena or brbpr. Denies use of NSAIDs.n/v, melena or brbpr. Denies use of NSAIDs.

Pt was diuresed in the ICU, given blood transfusions, and started on Pt was diuresed in the ICU, given blood transfusions, and started on vanco for a resistant staph epidermis UTI and was transferred to the vanco for a resistant staph epidermis UTI and was transferred to the floor 12/22. floor 12/22.

On 12/26/07, renal consulted for patient’s worsening CKD (crt from 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 1.5 baseline to 2.8) with nephrotic range proteinuria. Renal bx on 1/8/08. 1/8/08.

PMHxPMHx RenalRenal

CKD stage 3 CKD stage 3 baseline creatinine of baseline creatinine of

~1.5~1.5 Nephrotic syndromeNephrotic syndrome

HemeHeme Normocytic anemiaNormocytic anemia

CVSCVS HTNHTN CHF (EF 38%, 11/07)CHF (EF 38%, 11/07) CAD s/p PCI 7/06, prox CAD s/p PCI 7/06, prox

LADLAD AVR 2001, porcineAVR 2001, porcine

Pulm: asthmaPulm: asthma

GIGI Hep C, gen 1aHep C, gen 1a PUDPUD EGD: erythematous EGD: erythematous

gastropathygastropathy Colonoscopy: single polyp, Colonoscopy: single polyp,

diverticulosis, internal diverticulosis, internal hemorrhoidshemorrhoids

GUGU BPHBPH Hematuria - cystoscopy Hematuria - cystoscopy

3/07 neg, 4/06 with 3/07 neg, 4/06 with inflammation inflammation

RheumRheum Skin rash - 11/07 Skin rash - 11/07

Leukocytoclastic Leukocytoclastic VasculitisVasculitis

arthalgiaarthalgia

SocH: SocH: Lives aloneLives alone tobacco: ex-smoker tobacco: ex-smoker

(1-2 packs/week, (1-2 packs/week, quit 4 years ago)quit 4 years ago)

ETOH: alcohol 1-ETOH: alcohol 1-2x/wk, quit 4 yrs ago2x/wk, quit 4 yrs ago

DRUGS: former DRUGS: former crack-cocaine use, crack-cocaine use, several episodes of several episodes of IVDU 30 yrs agoIVDU 30 yrs ago

FamH: FamH: all relatives died of all relatives died of

"old age" - denies "old age" - denies liver/renal diseaseliver/renal disease

Physical ExamPhysical ExamGeneral: elderly, thin, in NADGeneral: elderly, thin, in NADHEENT: anicteric, perrlHEENT: anicteric, perrlNECK: no lad, no jvdNECK: no lad, no jvdHEART: rrr, s1s2, 2/6 systolic HEART: rrr, s1s2, 2/6 systolic

murmurmurmurLUNGS: mild bibasilar LUNGS: mild bibasilar

cracklescracklesABDOMEN: nl bs, soft, nt/nd, ABDOMEN: nl bs, soft, nt/nd,

+hepatomegaly, no +hepatomegaly, no splenomegaly, no fluid splenomegaly, no fluid wavewave

SKIN: no stigmata of SKIN: no stigmata of cirrhosiscirrhosis

EXTREMITIES: 2+ edema EXTREMITIES: 2+ edema with scrotal swelling, with scrotal swelling, chronic stasis changeschronic stasis changes

EXTREMITIES: 1+ edemaEXTREMITIES: 1+ edema

Lab DataLab Data

Differential DiagnosisDifferential Diagnosis

Patient with Patient with active sediment (proteinuria and hematuria)active sediment (proteinuria and hematuria) HTN, edema, … pulmonary edemaHTN, edema, … pulmonary edema Nephrotic syndromeNephrotic syndrome

Anasarca, nephrotic proteinuria, hypoalbuminuriaAnasarca, nephrotic proteinuria, hypoalbuminuria Low Complement GNLow Complement GN

SLESLE EndocarditisEndocarditis PIGNPIGN Cyroglobulinema (HCV, arthralgia, leukocytoclastic Cyroglobulinema (HCV, arthralgia, leukocytoclastic

vasculitis)vasculitis) MPGN (HCV) MPGN (HCV)

LMLM

IFIF

EMEM

EMEM

How should we How should we treat this treat this patient?patient?

Hepatitis C virus-related Hepatitis C virus-related cryoglobulinemia and cryoglobulinemia and glomerulonephritisglomerulonephritis

pathogenesis and therapeutic pathogenesis and therapeutic strategiesstrategies

IntroductionIntroduction

HCVHCV HCV related disease: HCV related disease:

cryoglobulinemia and MPGNcryoglobulinemia and MPGN Treatment for our patientTreatment for our patient

Standard antiviral (IFN-alpha and Standard antiviral (IFN-alpha and Ribavirin)?Ribavirin)?

IFN-alpha?IFN-alpha? CG targeted treatment?CG targeted treatment?

HCV virusHCV virus

HCV is an RNA virus of the HCV is an RNA virus of the flaviviridae familyflaviviridae family

170 million persons infected 170 million persons infected worldwideworldwide

The natural targets of HCV are The natural targets of HCV are hepatocytes and, possibly, B hepatocytes and, possibly, B lymphocytelymphocyte

The HCV Genome and The HCV Genome and Expressed PolyproteinExpressed Polyprotein

N Engl J Med, Vol. 345, No. 1 July 5, 2001

GenotypesGenotypes

There are at least six major There are at least six major genotypesgenotypes

75%

HCV-associated Mixed HCV-associated Mixed Cryoglobulinemia (MC)Cryoglobulinemia (MC)

Mixed cryoglobulins (MCs) are proteins that Mixed cryoglobulins (MCs) are proteins that reversibly precipitate at ≤ 37°C and consist of a reversibly precipitate at ≤ 37°C and consist of a mixture of monoclonal or polyclonal IgM that mixture of monoclonal or polyclonal IgM that have antiglobulin (rheumatoid factor-RF) activity have antiglobulin (rheumatoid factor-RF) activity and bind to polyclonal IgG. 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 monoclonalType II if the IgM RF is monoclonal

2/2 persistent viral infection: HCV, HIV2/2 persistent viral infection: HCV, HIV Type III if polyclonal IgM RF is presentType III if polyclonal IgM RF is present

2/2 connective tissue disease2/2 connective tissue disease HCV involved in the pathogenesis of MCHCV involved in the pathogenesis of MC

Characterized by nonneoplastic proliferation of Characterized by nonneoplastic proliferation of rheumatoid factor positive B-cell clones => CG rheumatoid factor positive B-cell clones => CG productionproduction

Cryoglobulin precipitate in a cryocrit tube

Serum protein electrophoresis25%

Sequential steps for managing and Sequential steps for managing and treating patients with chronic HCV treating patients with chronic HCV

infection, genotype 1infection, genotype 1

American Association for the Study of Liver Diseases. Hepatology 2004; 39:1147

Sustained virologic response rates with peginterferon Sustained virologic response rates with peginterferon alfa-2a (pegIFN) or interferon alfa-2b (IFN) and alfa-2a (pegIFN) or interferon alfa-2b (IFN) and

ribavirin (RBV) according to genotype ribavirin (RBV) according to genotype

Contraindications to Treatment Contraindications to Treatment with Iterferon Alfa and Ribavirinwith Iterferon Alfa and Ribavirin

Side Effects of Treatmetn Side Effects of Treatmetn with Interferon Alfa and with Interferon Alfa and

RibavirinRibavirin

Renal Insufficiency (CrCl ~50)

What treatment options are What treatment options are available?available?

HCV related cryoglobulinemia and HCV related cryoglobulinemia and MPGNMPGN

Treatment for our patientTreatment for our patient Standard antiviral (IFN-alpha and Standard antiviral (IFN-alpha and

Ribavirin)?Ribavirin)? IFN-alpha?IFN-alpha? CG targeted treatment?CG targeted treatment?

Proposed Mechanisms of Action of Interferon Alfa against HCVProposed Mechanisms of Action of Interferon Alfa against HCV

Influence of Antiviral Therapy in Hepatitis C Influence of Antiviral Therapy in Hepatitis C Virus–AssociatedVirus–Associated

Cryoglobulinemic MPGN (Alric, AJKD, 2004)Cryoglobulinemic MPGN (Alric, AJKD, 2004)

Patients (n=25) with nephrotoic-range Patients (n=25) with nephrotoic-range proteinuria, mixed CG, MPGN by biopsy, with proteinuria, mixed CG, MPGN by biopsy, with HCVHCV

Initial phaseInitial phase All treated for nephrotic proteinuria with lasix, All treated for nephrotic proteinuria with lasix,

acei, plasma exchanges, and steroidacei, plasma exchanges, and steroid 22ndnd phase (not randomized) phase (not randomized)

Group 1, (n=18) after 4-12 weeks of initial Group 1, (n=18) after 4-12 weeks of initial treatment receive antiviral treatment for minimal 6 treatment receive antiviral treatment for minimal 6 mosmos

Group 2, (n=7) maintenance with low dose lasixGroup 2, (n=7) maintenance with low dose lasix Follow upFollow up

Initial eval, end of antiviral tx, and 6 mos after Initial eval, end of antiviral tx, and 6 mos after discontinuationdiscontinuation





All 6 nonresponders were genotype 1

ConclusionConclusion

Promising but not appropriate for our Promising but not appropriate for our patientpatient Anemia requiring frequent transfusions Anemia requiring frequent transfusions

prohibits the use of Ribavirinprohibits the use of Ribavirin As per GI: ½ dose PEG-IFNAs 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 Interferon Alfa-2a Therapy in Cryoglobulinemia Associated with Cryoglobulinemia Associated with Hepatitis C Virus (Misiani, NEJM, 1994)Hepatitis C Virus (Misiani, NEJM, 1994)

Interferon Alfa-2a Therapy in Interferon Alfa-2a Therapy in Cryoglobulinemia Associated with Cryoglobulinemia Associated with

Hepatitis C Virus (Misiani, NEJM, 1994)Hepatitis C Virus (Misiani, NEJM, 1994)

prospective randomized, controlled trialprospective randomized, controlled trial 53 patients with HCV-associated type II 53 patients with HCV-associated type II

cryoglobulinemia. cryoglobulinemia. 27 patients received recombinant interferon alfa-27 patients received recombinant interferon alfa-

2a 2a thrice weekly at a dose of 1.5 million units for a week and thrice weekly at a dose of 1.5 million units for a week and

then 3 million units thrice weekly for the following 23 then 3 million units thrice weekly for the following 23 weeks. weeks.

26 control patients did not receive anything apart 26 control patients did not receive anything apart from previously prescribed treatmentsfrom previously prescribed treatments

All patients were then followed for an All patients were then followed for an additional 24 to 48 weeks. additional 24 to 48 weeks.

Interferon Alfa-2a Therapy in Interferon Alfa-2a Therapy in Cryoglobulinemia Associated with Cryoglobulinemia Associated with

Hepatitis C Virus (Misiani, NEJM, 1994)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

Peg-IFNPeg-IFN

We don’t know the genotype of We don’t know the genotype of responders in NEJM studyresponders in NEJM study

Even with response, 100% relapsed Even with response, 100% relapsed in six monthsin six months

Treatment of HCV-related Treatment of HCV-related Cryoglobulinemic Cryoglobulinemic

GlomerulonephritisGlomerulonephritis Benefit of antiviral treatment is often Benefit of antiviral treatment is often

transient and restricted to patients with transient and restricted to patients with mild and/or quiescent renal diseasemild and/or quiescent renal disease

INF tx may be associated with worsening INF tx may be associated with worsening GNGN

Ribavirin may be contraindicated in the Ribavirin may be contraindicated in the presence on renal failure and anemiapresence on renal failure and anemia

Is there no hope for our Is there no hope for our patient?patient?

Rituximab? Why not?Rituximab? Why not?

Pathogenesis of Mixed Pathogenesis of Mixed CryoglobulinemiaCryoglobulinemia

Pathogenesis of Pathogenesis of cryoglobulinaemic cryoglobulinaemic

nephritis and rationale nephritis and rationale for Rituximab treatmentfor Rituximab treatment

Mechanism of rituximabMechanism of rituximab

Why Rituximab?Why Rituximab? Chimeric monocloanl ab Chimeric monocloanl ab Binds to the B-cell surface Ag CD20Binds to the B-cell surface Ag CD20 Stop it before it startsStop it before it starts

Long-term effects of anti-CD20 monoclonal Long-term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinemic antibody treatment of cryoglobulinemic

glomerulonephritis (CGGN) glomerulonephritis (CGGN) (Roccatello_Nephrol Dial Transplant_2004)(Roccatello_Nephrol Dial Transplant_2004) N = 6N = 6

Two with bone marrow lymphocyte infiltrationTwo with bone marrow lymphocyte infiltration Four with either intolerance or resistance to standard Four with either intolerance or resistance to standard

immunosuppressive tximmunosuppressive tx HCV genotype HCV genotype

1b = 21b = 2 2a2c = 22a2c = 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 days 1, 8, 15, and 22. Two additional doses were given 1 and 2 months later.months later.

No other immunosuppressive drugsNo other immunosuppressive drugs EndpointsEndpoints

Laboratory parametersLaboratory parameters Proteinuria, ESR, cryocrit, HCV VLProteinuria, ESR, cryocrit, HCV VL

Clinical sxs and symptomsClinical sxs and symptoms Skin ulcers, purpura, arthralgia, weakness, praesthesia and feverSkin ulcers, purpura, arthralgia, weakness, praesthesia and fever


glomerulonephritis (CGGN) glomerulonephritis (CGGN) (Roccatello_Nephrol Dial Transplant_2004)(Roccatello_Nephrol Dial Transplant_2004)





No increase in VL detectedNo increase in VL detected

Efficacy and safety of rituximab in Efficacy and safety of rituximab in type II mixed cryoglobulinemia, type II mixed cryoglobulinemia,

Zaja, Blood, 2003Zaja, Blood, 2003 N=15, with type II MC unresponsive N=15, with type II MC unresponsive

to conventional treatmentsto conventional treatments 11/15 were HCV related11/15 were HCV related one with Sjogren syn and two were one with Sjogren syn and two were

essentialessential F/U for 6 monthsF/U for 6 months Tx: Rituximab (days 1, 8, 15, 22)Tx: Rituximab (days 1, 8, 15, 22)

Efficacy and safety of rituximab in Efficacy and safety of rituximab in type II mixed cryoglobulinemia, type II mixed cryoglobulinemia,

Zaja, Blood, 2003Zaja, Blood, 2003Median 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

ConclusionConclusion

Optimal strategy for HCV-associated Optimal strategy for HCV-associated MC nephritis is still undefinedMC nephritis is still undefined

For our patientFor our patient INF/Ribavirin - prohibitiveINF/Ribavirin - prohibitive INF-alpha with high relapseINF-alpha with high relapse

Corticosteroid in combination with Corticosteroid in combination with RituximabRituximab

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,

Documents

hcv virus hcv

edema slide

hcv genome

em slide

lm slide

case slide

flaviviridae family

natural targets of hcv