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.
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.
PMHx
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Renal
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CKD stage 3
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baseline creatinine of ~1.5
Nephrotic syndrome
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Normocytic anemia
CVS
HTN
CHF (EF 38%, 11/07)
CAD s/p PCI 7/06, prox LAD
AVR 2001, porcine
Pulm: asthma
GI
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Heme
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GU
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Hep C, gen 1a
PUD
EGD: erythematous gastropathy
Colonoscopy: single polyp,
diverticulosis, internal
hemorrhoids
BPH
Hematuria - cystoscopy 3/07 neg,
4/06 with inflammation
Rheum
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Skin rash - 11/07 Leukocytoclastic
Vasculitis
arthalgia
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SocH:
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Lives alone
tobacco: ex-smoker (1-2
packs/week, quit 4 years
ago)
ETOH: alcohol 1-2x/wk,
quit 4 yrs ago
DRUGS: former crackcocaine use, several
episodes of IVDU 30 yrs
ago
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FamH:
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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
Lab Data
Differential Diagnosis
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Patient with
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active sediment (proteinuria and hematuria)
HTN, edema, … pulmonary edema
Nephrotic syndrome
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Anasarca, nephrotic proteinuria, hypoalbuminuria
Low Complement GN
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SLE
Endocarditis
PIGN
Cyroglobulinema (HCV, arthralgia, leukocytoclastic vasculitis)
MPGN (HCV)
LM
IF
EM
EM
How should we treat
this patient?
Hepatitis C virus-related
cryoglobulinemia and
glomerulonephritis
pathogenesis and therapeutic strategies
Introduction
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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
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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
N Engl J Med, Vol. 345, No. 1 July 5, 2001
Genotypes
75%
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There are at least six major genotypes
HCV-associated Mixed
Cryoglobulinemia (MC)
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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
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Type I monoclonal Igs (IgG, IgM, and sometimes IgA)
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Type II if the IgM RF is monoclonal
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2/2 persistent viral infection: HCV, HIV
Type III if polyclonal IgM RF is present
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2/2 MM or Waldenström's macroglobulinemia
2/2 connective tissue disease
HCV involved in the pathogenesis of MC
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Characterized by nonneoplastic proliferation of rheumatoid factor
positive B-cell clones => CG production
25%
Cryoglobulin precipitate in a cryocrit tube
Serum protein electrophoresis
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
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
Renal Insufficiency (CrCl ~50)
Side Effects of Treatmetn with
Interferon Alfa and Ribavirin
What treatment options are
available?
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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
Influence of Antiviral Therapy in Hepatitis C Virus–Associated
Cryoglobulinemic MPGN (Alric, AJKD, 2004)
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Patients (n=25) with nephrotoic-range proteinuria,
mixed CG, MPGN by biopsy, with HCV
Initial phase
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2nd phase (not randomized)
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All treated for nephrotic proteinuria with lasix, acei, plasma
exchanges, and steroid
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
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Initial eval, end of antiviral tx, and 6 mos after
discontinuation
Influence of Antiviral Therapy in Hepatitis C Virus–Associated
Cryoglobulinemic MPGN (Alric, AJKD, 2004)
Influence of Antiviral Therapy in Hepatitis C Virus–Associated
Cryoglobulinemic MPGN (Alric, AJKD, 2004)
All 6 nonresponders were genotype 1
Conclusion
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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:
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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)
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prospective randomized, controlled trial
53 patients with HCV-associated type II
cryoglobulinemia.
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27 patients received recombinant interferon alfa-2a
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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, 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
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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
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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?
Rituximab? Why not?
Pathogenesis of Mixed
Cryoglobulinemia
Pathogenesis of
cryoglobulinaemic nephritis and
rationale for Rituximab treatment
Mechanism of rituximab
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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)
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N=6
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HCV genotype
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1b = 2
2a2c = 2
Tx:
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Rituximab 375 mg/m2
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Two with bone marrow lymphocyte infiltration
Four with either intolerance or resistance to standard immunosuppressive tx
days 1, 8, 15, and 22. Two additional doses were given 1 and 2 months later.
No other immunosuppressive drugs
Endpoints
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Laboratory parameters
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Proteinuria, ESR, cryocrit, HCV VL
Clinical sxs and symptoms
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Skin ulcers, purpura, arthralgia, weakness, praesthesia and fever
Long-term effects of anti-CD20 monoclonal antibody
treatment of cryoglobulinemic glomerulonephritis (CGGN)
(Roccatello_Nephrol Dial Transplant_2004)
Long-term effects of anti-CD20 monoclonal antibody
treatment of cryoglobulinemic glomerulonephritis (CGGN)
(Roccatello_Nephrol Dial Transplant_2004)
Long-term effects of anti-CD20 monoclonal antibody
treatment of cryoglobulinemic glomerulonephritis (CGGN)
(Roccatello_Nephrol Dial Transplant_2004)
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No increase in VL detected
Efficacy and safety of rituximab in type II
mixed cryoglobulinemia, Zaja, Blood, 2003
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N=15, with type II MC unresponsive to
conventional treatments
11/15 were HCV related
 one with Sjogren syn and two were essential
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F/U for 6 months
Tx: Rituximab (days 1, 8, 15, 22)
Efficacy and safety of rituximab in type II
mixed cryoglobulinemia, Zaja, Blood, 2003
Median values
(with standard error bars)
at baseline and during the 6month follow-up in the
studied patients
The course of
rheumatoid factor,
cryoglobulin, and
immunoglobulin serum levels
in the studied patients after
rituximab therapy
Conclusion
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Optimal strategy for HCV-associated MC
nephritis is still undefined
For our patient
INF/Ribavirin - prohibitive
 INF-alpha with high relapse
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Corticosteroid in combination with Rituximab