ESRD Management of Atypical
Hemolytic-Uremic Syndrome (HUS)
Jeffrey M. Saland, M.D.
Department of Pediatrics
Mount Sinai School of Medicine
Conflicts / Disclosures
Will discuss off label uses
No financial interests in any agents discussed
No financial interest in any healthcare-related entity
Overview
• A significant percentage of cases of atypical HUS are
due to disorders of complement regulation.
Overview
• A significant percentage of cases of atypical HUS are
due to disorders of complement regulation.
• Empiric plasma therapy can delay or prevent ESRD in
many of those cases
Overview
• A significant percentage of cases of atypical HUS are
due to disorders of complement regulation.
• Empiric plasma therapy can delay or prevent ESRD in
many of those cases
• Risk of post-transplant recurrence depends on the
specific disorder of complement regulation.
Overview
• A significant percentage of cases of atypical HUS are
due to disorders of complement regulation.
• Empiric plasma therapy can delay or prevent ESRD in
many of those cases
• Risk of post-transplant recurrence depends on the
specific disorder of complement regulation.
• Emerging therapy may expand ESRD options
Typical HUS
Triad of :
Microangiopathic hemolytic anemia
Thrombocytopenia
Acute renal failure
Generally diarrhea-associated
Shiga toxin produced by E coli serotype O157:H7
Shigella, Salmonella, others also
Food borne disease: uncooked / unpasteurized
products contaminated by animal wastes
Or other infections (respiratory):
Invasive S. Pneumoniae or viral infections
Typical HUS
A severe condition:
acutely 2.5% mortality, often significant morbidity
Long term results (10-20 years after HUS*)
63% Complete recovery
12% Recovery with proteinuria
6%
Recovery with proteinuria and HTN
16% Recovery with low GFR ± proteinuria or HTN
3%
ESRD
* Diarrheal or URI- related only, pediatric
Spizzirri et al. Pediatric Nephrology 1996
Atypical HUS
Clinically very severe
15% died
25% ESRD
15% renal insufficiency
60% major sequelae
1/3 recover without significant renal disease
most (75%) of these had a single episode
few (25%) of these had recurrent aHUS
(a pediatric series)
Taylor et al Ped Neph 2004
A Classification of TMA
(Thrombotic Microangiopathy)
Typical / diarrheal
(HUS or TTP)
Complement defects
Atypical HUS
von Willebrand proteinase
(ADAMSTS13) defeciency
Generally TTP
Cobalamin-C deficiency
TMA + multiorgan failure
Quinine-related
Abrupt TMA, exposure related
Post transplantation
De-novo renal TMA
(calcineurin inhibitior related) May be renal “isolated”
Others:
HIV, radiation, chemotherapy HELLP,
antiphospholipid Ab syndrome, unclassified
Besbas et al. Kidney International 2006
Complement and Atypical HUS
Since the early 1970’s alternative pathway complement
activation (low C3), has been recognized in some cases of
atypical HUS
1981: 1st case of HUS
with factor H
deficiency described
1998: Linkage analysis in 3
families with HUS provided
clear association with CFH
Clin. Exp. Immunol. (1981), Kidney International (1998)
Complement and Atypical HUS
About 50%-60% of aHUS cases are associated with a
mutation in a complement-related gene
Protein
Gene
Source
Location
% of
aHUS
Factor H
CFH
Liver
circulates
~ 15-30%
Factor I
CFI
Liver
circulates
~ 5-10%
Membrane
Cofactor Protein
MCP
Widespread
Membrane
bound
~ 10-15%
Factor B
CFB
Liver, ?
circulates
<5%
C3
Liver, ?
circulates
~ 5-10%
CFHR1/
CFHR3
Lymphocyte
circulates
~ 10%
C3
Anti-FH-Ab
Unknown
~ 40-50%
Jozsi et al. Blood 2008, Frémeaux-Bacchi V et al. Blood 2008, Goicoechea de Jorge
2007, Caprioli, et al Blood 2006, Kavanagh Curr Opin Nephrol Hypertens, 2007
C3 Levels By Mutation
Sellier-Leclerc, A.-L. et al. J Am Soc Nephrol 2007;18:2392-2400
Recommended Initial Evaluation of HUS
Because infections trigger both typical and atypical
HUS, initial evaluation should encompass both
Testing should include C3 level as well as classic
evaluation (stool culture, LDH, smear, etc.)
ADAMSTS13 / auto-Ab analysis if TTP not ruled out
Save some plasma for later analysis
Plasma Therapy
Fluid phase complement proteins reside in plasma
and are therefore subject to plasma therapy
Caprioli, et al. Blood. 2006
Plasma Therapy
Fluid phase complement proteins reside in plasma
and are therefore subject to plasma therapy
Plasma Infusion:
• Repletes but does not remove mutant protein
Plasma Exchange:
• Removes mutant protein and repletes
Caprioli, et al. Blood. 2006
Plasma Therapy
Fluid phase complement proteins reside in plasma
and are therefore subject to plasma therapy
Plasma Infusion:
• Repletes but does not remove mutant protein
Plasma Exchange:
• Removes mutant protein and repletes
There are MANY anecdotes of prolonged preservation
of kidney function in patients with CFH mutation,
though most eventually suffer ESRD.
Benefit is not clear for MCP mutations– most (single)
episodes seem to recover with or without exchange
Caprioli, et al. Blood. 2006
Detecting Complement-related HUS
(Trying to Prevent ESRD)
Criteria for empiric plasma therapy treatment of aHUS
Presence of any of the following or
Absence of the
Following
Patient age < 6 months
Slow or insidius onset of HUS
Multiple HUS Episodes or relapses
Asynchronous family history of HUS
Previous unexplained anemia
HUS after any type of organ
transplantation
Prodromal diarhhea
Invasive S.
pneumoniae infection
Saland, et al. JASN 2009, Ariceta et al. Ped Neph 2008
Diagnosis of HUS
Atypical presentation
Empiric Plasma
Exchange
Clinical
Exceptions
Plasma Exchange within 24 hrs
1.5 Volumes (60-75 ml/kg) per session
FFP or Octaplas®
Repeat Plasma Exhange Daily x 5
Then 5 sessions/week for 2 weeks
Then 3 sessions/week for 2 weeks
Assess Outcome at Day 33
Ariceta et al. Ped Neph 2009
Withdrawal
Alternate Diagnosis
Plasma Exchange Complication
Early remission
Summary #1
Key atypical features require empiric plasma exchange.
Summary #1
Key atypical features require empiric plasma exchange.
C3 levels should be part of every HUS evaluation
Save blood from before plasma exchange
Summary #1
Key atypical features require empiric plasma exchange.
C3 levels should be part of every HUS evaluation
Save blood from before plasma exchange
Patients with aHUS should undergo genotyping for the
most up-to-date list of complement-related disorders:
Summary #1
Key atypical features require empiric plasma exchange.
C3 levels should be part of every HUS evaluation
Save blood from before plasma exchange
Patients with aHUS should undergo genotyping for the
most up-to-date list of complement-related disorders:
CFH, CFI, MCP, C3, CFB, anti-FH-Ab – CFHR1/CFHR3
(more likely to be added)
Summary #1
Key atypical features require empiric plasma exchange.
C3 levels should be part of every HUS evaluation
Save blood from before plasma exchange
Patients with aHUS should undergo genotyping for the
most up-to-date list of complement-related disorders:
CFH, CFI, MCP, C3, CFB, anti-FH-Ab – CFHR1/CFHR3
(more likely to be added)
Contacting one of the major registries is prudent
ESRD Management of aHUS
ESRD Management
Do not diagnose ESRD too soon.
Renal recovery may occur if TMA is halted.
In dialysis dependent patients, native
nephrectomy should be considered for:
• Ongoing HUS (clinical or biochemical)
• Severe hypertension
ESRD Management: Dialysis
aHUS is generally quiescent during ESRD
Rare findings reported during dialysis:
• Angioedema, complement activation (hemodialysis)
• Hemolysis / thrombocytopenia
• Subclinical hepatic (or other organ) involvement
Jalanko, et al. AJT 2007, Saland, et al. CJASN 2009
Subclinical Hepatic Involvement
Saland et al. CJASN 2009
ESRD Management: Dialysis
Due to a high rate of transplant failures, aHUS patients
have been faced with extremely long dialysis duration
and its accompanying risks.
Transplant Considerations
Gray, Henry. Anatomy of the Human Body. Philadelphia: Lea & Febiger, 1918; Bartleby.com,
2000. www.bartleby.com/107/.
Complement and Atypical HUS
Risk of recurrence after “unmodified” kidney transplant
Protein
Gene
Source
Location
Recurrence
Rate
Factor H
CFH
Liver
circulates
> 80%
Factor I
CFI
Liver
circulates
> ~ 80%
MCP
MCP
Widespread
Membrane
bound
~ 20%
Factor B
CFB
Liver, ?
circulates
?
C3
Liver, ?
circulates
?
CFHR1/
CFHR3
Lymphocyte
circulates
?
C3
Anti-FHAb
No known mutation
Loirat, C et al. Pediatric Transplantation 2008, Saland et al. JASN 2009
30%
Post-Transplant HUS Recurrence
Most are within 1 month
Plasma responsiveness of the underlying defect is
often retained.
If untreated, most result in graft loss
Chronic plasmapheresis may be required
Seitz, B et al. Transplantation Proceedings 2007,
Options for Transplantation
Kidney transplantation*
Options for Transplantation
Kidney transplantation*
Combined liver-kidney transplantation*
Complement and Atypical HUS
Risk of recurrence after “unmodified” kidney transplant
Protein
Gene
Source
Location
Recurrence
Rate
Factor H
CFH
Liver
circulates
> 80%
Factor I
CFI
Liver
circulates
> ~ 80%
MCP
MCP
Widespread
Membrane
bound
~ 20%
Factor B
CFB
Liver, ?
circulates
?
C3
Liver, ?
circulates
?
CFHR1/
CFHR3
Lymphocyte
circulates
?
C3
Anti-FHAb
No known mutation
Loirat, C et al. Pediatric Transplantation 2008, Saland et al. JASN 2009
30%
Combined Liver Kidney Transplant
For aHUS Secondary to CFH Mutation
First 3 Experiences not Encouraging
Auxiliary liver, several month function followed by
acute decompensation, death
Hepatic graft failure* with neurological deficits, 2nd
liver transplant at 1 month
Primary hepatic non-function*, death
* Complement mediated injury to liver vasculature
Cheong HI. (Abstract) ASN/ISN World Congress 2001, Remuzzi G, et al. Lancet
2002, Remuzzi G, et al. AJT 2005, Cheong HI et al. Pediatr Nephrol 2004
Surgery is a trigger for complement activation
Preparative plasma exchange before transplant
followed by serial plasma exchange is recommended
Liver-Kidney Transplant Protocol
Modified by Plasma Exchange
•
•
•
•
•
•
•
Hemodialysis (if needed) session no heparin
Plasma exchange with FFP (minimum 1.5 volumes)
< 6 hours of surgery
10- 20 ml/kg FFP intraoperatively
Additional FFP if clinically indicated
Post-operative LMW heparin prophylaxis
Low dose aspirin prophylaxis
Plasma exchange removes mutant FH, replaces normal
LMW heparin used empirically
Hold anticoagulation for bleeding or coagulopathy
Saland, J et al. JASN 2009
Combined Liver Kidney Transplant
For aHUS Secondary to CFH Mutation
A Modified* Approach is Potentially Successful, Though Risky.
1.
2.
3.
4.
5.
6.
7.
8.
9.
NYC #1: whole liver
Helsinki #1: whole liver
Helsinki #2: whole liver
NYC #2: split liver
Helsinki #3: adult, whole liver
UK #1: whole liver*
Boston #1: whole liver
NYC #3: split liver, death (hepatic artery thrombosis)
NYC #4: split liver, death (SVC syndrome complication))
* Native kidney function preserved, liver tx only
Saland et al, AJT 2006, Jalanko et al. AJT 2008, Saland et al. CJASN 2009 and
verbal communications: Jalanko 2007, Milford 2008, Milner 2008
Options for Transplantation
Kidney transplantation*
Combined liver-kidney transplantation*
Kidney transplantation*
followed by chronic plasma exchange prophylaxis
Not yet …
followed by chronic anti-complement therapy
followed by specific factor replacement (eg. FH)
Transplant Decisions
MCP
Mutation
Transplantation Reasonable
Current consensus for now is
to provide pre-operative
plasma exchange and at least
one month of tapering plasma
exchange protocol
LMW heparin anticoagulation
Loirat, C et al. Pediatric Transplantation 2008, Saland,et al. JASN 2009
Transplant Decisions
MCP Combined
with other
Mutations
No consensus, isolated
kidney may be reasonable
If transplanted, provide preoperative plasma exchange
and at least one month of
tapering plasma exchange
protocol
LMW heparin anticoagulation
Loirat, C et al. Pediatric Transplantation 2008, Saland,et al. JASN 2009
Transplant Decisions
CFH or CFI
Mutation*
Wait for new Rx
• FH
concentrate
• Complement
inhibitors
Combined
Liver-Kidney Tx
Pre-operative
Plasma
exchange
LMW heparin
anticoagulation
Renal Tx *
Plasma exchange
before and
chronically after
LMW heparin anticoagulation
* Especially if kidney transplant in family
members with same mutation was
successful
Loirat, C et al. Pediatric Transplantation 2008, Saland,et al. JASN 2009
Transplant: Anti-FH-Autoantibodies
One Successful Case Reported
Pretransplant preparation using:
plasma exchanges over several weeks
(the response was not complete)
4 weekly doses of rituximab added
Anti-FH
Autoantibodies
Anti-FH-Ab levels were monitored
Fairly routine transplant protocol:
Basiliximab, prednisone, cyclosporine
Resulted in sustained antibody supression
for over 4 months
Kwon et al, NDT 2008
Transplant Decisions
CFB, C3
Mutations
Case by Case:
Unclear impact of:
Non-hepatic protein sources
Complement activating potential of residual protein
Therapeutic potential of future anti-complement Rx
Saland et al. JASN 2009
Transplant Decisions
No Known
Mutation
Transplantation Reasonable
Current consensus for now is
to provide pre-operative
plasma exchange and at least
one month of tapering plasma
exchange protocol
LMW heparin anticoagulation
Loirat, C et al. Pediatric Transplantation 2008
Saland, J et al. JASN 2009
Final Summary
Atypical HUS has a high risk of ESRD
Transplantation options depend on the specific cause
Transplant surgery triggers complement activation
For high-recurrence risk conditions:
Current options are risky and limited
Emerging treatments are promising
Acknowledgments
Foundation for Children with Atypical HUS
Censensus Group, Liver-Kidney Transplantation for HUS
Bergamo: Drs. Giussepe Remuzzi & Piero Ruggenenti
Newcastle: Dr. Timothy Goodship
U. Iowa: Dr. Richard Smith