ESRD Management of Atypical Hemolytic-Uremic Syndrome (HUS) Jeffrey M. Saland, M.D. Department of Pediatrics Mount Sinai School of Medicine

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


• Empiric plasma therapy can delay or prevent ESRD in many of those cases

Overview



• Risk of post-transplant recurrence depends on the specific disorder of complement regulation.

Overview



• 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 Infusion:• Repletes but does not remove mutant protein

Plasma Exchange:• Removes mutant protein and repletes



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


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


C3 levels should be part of every HUS evaluationSave blood from before plasma exchange

Summary #1



Patients with aHUS should undergo genotyping for the most up-to-date list of complement-related disorders:

Summary #1




CFH, CFI, MCP, C3, CFB, anti-FH-Ab – CFHR1/CFHR3 (more likely to be added)

Summary #1




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*


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.


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


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




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


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


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


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


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

Documents

ESRD Management of Atypical Hemolytic-Uremic Syndrome (HUS) Jeffrey M. Saland, M.D. Department of Pediatrics Mount Sinai School of Medicine