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ESRD Management of Atypical Hemolytic-Uremic Syndrome
(HUS)
Jeffrey M. Saland, M.D.Department of PediatricsMount 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 HUSTriad of :
Microangiopathic hemolytic anemiaThrombocytopeniaAcute renal failure
Generally diarrhea-associatedShiga toxin produced by E coli serotype O157:H7Shigella, Salmonella, others alsoFood 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 recovery12% Recovery with proteinuria6% Recovery with proteinuria and HTN16% Recovery with low GFR ± proteinuria or HTN3% ESRD
* Diarrheal or URI- related only, pediatric
Spizzirri et al. Pediatric Nephrology 1996
Atypical HUS
Taylor et al Ped Neph 2004
Clinically very severe
15% died25% ESRD 60% major sequelae15% renal insufficiency
1/3 recover without significant renal diseasemost (75%) of these had a single episodefew (25%) of these had recurrent aHUS
(a pediatric series)
A Classification of TMA(Thrombotic Microangiopathy)
Besbas et al. Kidney International 2006
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(calcineurin inhibitior related)
De-novo renal TMAMay be renal “isolated”
Others: HIV, radiation, chemotherapy HELLP, antiphospholipid Ab syndrome, unclassified
Since the early 1970’s alternative pathway complement activation (low C3), has been recognized in some cases of atypical HUS
Complement and Atypical HUS
Clin. Exp. Immunol. (1981), Kidney International (1998)
1981: 1st case of HUS with factor H deficiency described
1998: Linkage analysis in 3 families with HUS provided clear association with CFH
Complement and Atypical HUSAbout 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 C3 Liver, ? circulates ~ 5-10%
Anti-FH-Ab CFHR1/CFHR3
Lymphocyte circulates ~ 10%
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
Sellier-Leclerc, A.-L. et al. J Am Soc Nephrol 2007;18:2392-2400
C3 Levels By Mutation
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 TherapyFluid phase complement proteins reside in plasma and are therefore subject to plasma therapy
Caprioli, et al. Blood. 2006
Plasma TherapyFluid 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 TherapyFluid 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 monthsSlow or insidius onset of HUSMultiple HUS Episodes or relapsesAsynchronous family history of HUSPrevious unexplained anemiaHUS after any type of organ transplantation
Prodromal diarhheaInvasive S. pneumoniae infection
Saland, et al. JASN 2009, Ariceta et al. Ped Neph 2008
Empiric Plasma Exchange
Ariceta et al. Ped Neph 2009
Diagnosis of HUSAtypical presentation
Plasma Exchange within 24 hrs1.5 Volumes (60-75 ml/kg) per
sessionFFP or Octaplas®
Repeat Plasma Exhange Daily x 5Then 5 sessions/week for 2 weeksThen 3 sessions/week for 2 weeks
Assess Outcome at Day 33
Clinical Exceptions
WithdrawalAlternate Diagnosis
Plasma Exchange ComplicationEarly 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 evaluationSave blood from before plasma exchange
Summary #1
Key atypical features require empiric plasma exchange.
C3 levels should be part of every HUS evaluationSave 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 evaluationSave 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 evaluationSave 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
Saland et al. CJASN 2009
Subclinical Hepatic Involvement
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 HUSRisk 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 C3 Liver, ? circulates ?
Anti-FH-Ab
CFHR1/CFHR3
Lymphocyte circulates ?
No known mutation 30%
Loirat, C et al. Pediatric Transplantation 2008, Saland et al. JASN 2009
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 HUSRisk 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 C3 Liver, ? circulates ?
Anti-FH-Ab
CFHR1/CFHR3
Lymphocyte circulates ?
No known mutation 30%
Loirat, C et al. Pediatric Transplantation 2008, Saland et al. JASN 2009
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
Combined Liver Kidney TransplantFor aHUS Secondary to CFH Mutation
First 3 Experiences not Encouraging
Surgery is a trigger for complement activation
Preparative plasma exchange before transplant followed by serial plasma exchange is recommended
• 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
Liver-Kidney Transplant ProtocolModified by Plasma Exchange
Plasma exchange removes mutant FH, replaces normalLMW heparin used empiricallyHold anticoagulation for bleeding or coagulopathy
Saland, J et al. JASN 2009
1. NYC #1: whole liver2. Helsinki #1: whole liver3. Helsinki #2: whole liver4. NYC #2: split liver5. Helsinki #3: adult, whole liver6. UK #1: whole liver*7. Boston #1: whole liver8. NYC #3: split liver, death (hepatic artery thrombosis)9. 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
Combined Liver Kidney TransplantFor aHUS Secondary to CFH Mutation
A Modified* Approach is Potentially Successful, Though Risky.
Options for Transplantation
Kidney transplantation*Combined liver-kidney transplantation*Kidney transplantation*
followed by chronic plasma exchange prophylaxis
Not yet …followed by chronic anti-complement therapyfollowed by specific factor replacement (eg. FH)
Transplant Decisions
MCPMutation
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 Combinedwith otherMutations No consensus, isolated
kidney may be reasonable
If transplanted, 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
CFH or CFI Mutation*
Wait for new Rx• FH
concentrate• Complement
inhibitors
Renal Tx *Plasma exchangebefore andchronically afterLMW heparin anticoagulation* Especially if kidney transplant in family members with same mutation was successful
CombinedLiver-Kidney TxPre-operative Plasma exchangeLMW heparin anticoagulation
Loirat, C et al. Pediatric Transplantation 2008, Saland,et al. JASN 2009
Transplant: Anti-FH-AutoantibodiesOne Successful Case Reported
Pretransplant preparation using:
plasma exchanges over several weeks(the response was not complete)
4 weekly doses of rituximab added
Anti-FH-Ab levels were monitored
Fairly routine transplant protocol:Basiliximab, prednisone, cyclosporine
Resulted in sustained antibody supressionfor over 4 months
Kwon et al, NDT 2008
Anti-FHAutoantibodies
Transplant Decisions
CFB, C3Mutations
Case by Case:Unclear impact of:Non-hepatic protein sourcesComplement activating potential of residual protein
Therapeutic potential of future anti-complement Rx
Saland et al. JASN 2009
Transplant Decisions
No KnownMutation 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 2008Saland, J et al. JASN 2009
Atypical HUS has a high risk of ESRDTransplantation options depend on the specific cause
Transplant surgery triggers complement activation
For high-recurrence risk conditions:Current options are risky and limitedEmerging treatments are promising
Final Summary
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
Acknowledgments