Tuesday Case

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Tuesday Case
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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 patients
  worsening CKD (crt from 1.5 baseline to 2.8) with
  nephrotic range proteinuria. Renal bx on 1/8/08.
  

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PMHx

• 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

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• 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

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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

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Lab Data
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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)

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LM
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IF
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EM
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EM
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How should we treat this patient?
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Hepatitis C virus-related cryoglobulinemia and
glomerulonephritis

• pathogenesis and therapeutic strategies

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Introduction

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

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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

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The HCV Genome and Expressed Polyprotein
N Engl J Med, Vol. 345, No. 1 July 5, 2001
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Genotypes
75

• There are at least six major genotypes

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HCV-associated Mixed Cryoglobulinemia (MC)

• Mixed cryoglobulins (MCs) are proteins that
  reversibly precipitate at 37C 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 gt CG
  production

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Serum protein electrophoresis
25
Cryoglobulin precipitate in a cryocrit tube
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Sequential steps for managing and treating
patients with chronic HCV infection, genotype 1
American Association for the Study of Liver
Diseases. Hepatology 2004 391147
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Sustained virologic response rates with
peginterferon alfa-2a (pegIFN) or interferon
alfa-2b (IFN) and ribavirin (RBV) according to
genotype
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Contraindications to Treatment with Iterferon
Alfa and Ribavirin
Side Effects of Treatmetn with Interferon Alfa
and Ribavirin
Renal Insufficiency (CrCl 50)
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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?

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Proposed Mechanisms of Action of Interferon Alfa
against HCV
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Influence of Antiviral Therapy in Hepatitis C
VirusAssociatedCryoglobulinemic MPGN (Alric,
AJKD, 2004)

• Patients (n25) 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, (n18) after 4-12 weeks of initial
  treatment receive antiviral treatment for minimal
  6 mos
• Group 2, (n7) maintenance with low dose lasix
• Follow up
• Initial eval, end of antiviral tx, and 6 mos
  after discontinuation

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Influence of Antiviral Therapy in Hepatitis C
VirusAssociatedCryoglobulinemic MPGN (Alric,
AJKD, 2004)
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Influence of Antiviral Therapy in Hepatitis C
VirusAssociatedCryoglobulinemic MPGN (Alric,
AJKD, 2004)
All 6 nonresponders were genotype 1
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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)

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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.

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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
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Peg-IFN

• We dont know the genotype of responders in NEJM
  study
• Even with response, 100 relapsed in six months

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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?

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Rituximab? Why not?
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Pathogenesis of Mixed Cryoglobulinemia
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Pathogenesis of cryoglobulinaemic nephritis and
rationale for Rituximab treatment
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Mechanism of rituximab

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

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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

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

• No increase in VL detected

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Efficacy and safety of rituximab in type II mixed
cryoglobulinemia, Zaja, Blood, 2003

• N15, 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)

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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
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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