Upload
nguyentruc
View
216
Download
1
Embed Size (px)
Citation preview
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 1.5 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. baseline to 2.8) with nephrotic range proteinuria. Renal bx on 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 VasculitisLeukocytoclastic Vasculitis 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 have mixture of monoclonal or polyclonal IgM that have antiglobulin (rheumatoid factor-RF) activity and antiglobulin (rheumatoid factor-RF) activity and bind to polyclonal IgG. 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 productionrheumatoid factor positive B-cell clones => CG production
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, acei, All treated for nephrotic proteinuria with lasix, acei,
plasma exchanges, and steroidplasma exchanges, and steroid 22ndnd phase (not randomized) phase (not randomized)
Group 1, (n=18) after 4-12 weeks of initial treatment Group 1, (n=18) after 4-12 weeks of initial treatment receive antiviral treatment for minimal 6 mosreceive antiviral treatment for minimal 6 mos
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
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)
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)
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 Hepatitis Cryoglobulinemia Associated with Hepatitis C Virus (Misiani, NEJM, 1994)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-2a 27 patients received recombinant interferon alfa-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
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)
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)
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)
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