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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, HTN, CHF, CAD, AS w/porcine AVR 2001, HCV, chronic normocytic anemia thought 2/2 HCV and CKD.

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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 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.

slide3
Renal

CKD stage 3

baseline creatinine of ~1.5

Nephrotic syndrome

Heme

Normocytic anemia

CVS

HTN

CHF (EF 38%, 11/07)

CAD s/p PCI 7/06, prox LAD

AVR 2001, porcine

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

PMHx
slide4
SocH:

Lives alone

tobacco: ex-smoker (1-2 packs/week, quit 4 years ago)

ETOH: alcohol 1-2x/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
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

Physical Exam
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)
hepatitis c virus related cryoglobulinemia and glomerulonephritis

Hepatitis C virus-related cryoglobulinemia and glomerulonephritis

pathogenesis and therapeutic strategies

introduction
Introduction
  • HCV
  • HCV related disease: cryoglobulinemia and MPGN
  • Treatment for our patient
    • Standard antiviral (IFN-alpha and Ribavirin)?
    • IFN-alpha?
    • 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 polyprotein
The HCV Genome and Expressed Polyprotein

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

genotypes
Genotypes
  • There are at least six major genotypes

75%

hcv associated mixed cryoglobulinemia mc
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.
  • MCs are categorized as
    • Type I monoclonal Igs (IgG, IgM, and sometimes IgA)
        • 2/2 MM or Waldenström's macroglobulinemia
    • 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 connective tissue disease
  • HCV involved in the pathogenesis of MC
    • Characterized by nonneoplastic proliferation of rheumatoid factor positive B-cell clones => CG production
slide19

25%

Serum protein electrophoresis

Cryoglobulin precipitate in a cryocrit tube

sequential steps for managing and treating patients with chronic hcv infection genotype 1
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

slide21

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

contraindications to treatment with iterferon alfa and ribavirin
Contraindications to Treatment with Iterferon Alfa and Ribavirin

Side Effects of Treatmetn with Interferon Alfa and Ribavirin

Renal Insufficiency (CrCl ~50)

what treatment options are available
What treatment options are available?
  • HCV related cryoglobulinemia and MPGN
  • Treatment for our patient
    • Standard antiviral (IFN-alpha and Ribavirin)?
    • IFN-alpha?
    • CG targeted treatment?
slide25
Influence of Antiviral Therapy in Hepatitis C Virus–AssociatedCryoglobulinemic MPGN (Alric, AJKD, 2004)
  • Patients (n=25) with nephrotoic-range proteinuria, mixed CG, MPGN by biopsy, with HCV
  • Initial phase
    • All treated for nephrotic proteinuria with lasix, acei, plasma exchanges, and steroid
  • 2nd phase (not randomized)
    • 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
  • Follow up
    • Initial eval, end of antiviral tx, and 6 mos after discontinuation
slide26
Influence of Antiviral Therapy in Hepatitis C Virus–AssociatedCryoglobulinemic MPGN (Alric, AJKD, 2004)
slide27
Influence of Antiviral Therapy in Hepatitis C Virus–AssociatedCryoglobulinemic 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 PEG-IFN
    • Response seen is genotype dependent:
      • 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
Interferon Alfa-2a Therapy in Cryoglobulinemia Associated with Hepatitis C Virus (Misiani, NEJM, 1994)
  • prospective randomized, controlled trial
  • 53 patients with HCV-associated type II cryoglobulinemia.
    • 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.
    • 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 alfa 2a therapy in cryoglobulinemia associated with hepatitis c virus misiani nejm 19941
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

peg ifn
Peg-IFN
  • We don’t know the genotype of responders in NEJM study
  • Even with response, 100% relapsed in six months
treatment of hcv related cryoglobulinemic glomerulonephritis
Treatment of HCV-related 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?

mechanism of rituximab
Mechanism of rituximab
  • Why Rituximab?
    • Chimeric monocloanl ab
    • Binds to the B-cell surface Ag CD20
    • Stop it before it starts
slide37

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

  • N = 6
      • Two with bone marrow lymphocyte infiltration
      • Four with either intolerance or resistance to standard immunosuppressive tx
    • HCV genotype
      • 1b = 2
      • 2a2c = 2
  • Tx:
    • Rituximab 375 mg/m2
      • 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
slide38

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

slide39

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

slide40

Long-term effects of anti-CD20 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 mixed cryoglobulinemia zaja blood 2003
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 mixed cryoglobulinemia zaja blood 20031
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

conclusion1
Conclusion
  • Optimal strategy for HCV-associated MC nephritis is still undefined
  • For our patient
    • INF/Ribavirin - prohibitive
    • INF-alpha with high relapse
  • Corticosteroid in combination with Rituximab