Hemolytic Uremic SyndromeHemolytic Uremic Syndrome

Beatrice Goilav, M.D.Beatrice Goilav, M.D.

Pediatric NephrologyPediatric Nephrology

Children’s Hospital at MontefioreChildren’s Hospital at Montefiore

Albert Einstein College of MedicineAlbert Einstein College of Medicine

DisclosuresDisclosures

Nothing to disclose.Nothing to disclose.

OutlineOutline

Background/Epidemiology and other Background/Epidemiology and other things to know on “classical” diarrhea-things to know on “classical” diarrhea-associated HUSassociated HUS

The “funky” types of HUSThe “funky” types of HUS Atypical, non-diarrhea associated, recurrent, Atypical, non-diarrhea associated, recurrent,

familialfamilial

What you should know about atypical HUS What you should know about atypical HUS and what to do with that informationand what to do with that information

THE HISTORY OF HUSTHE HISTORY OF HUS

Gasser C, Gasser C, et alet al. 1955. 1955

First descriptionFirst description Self-limited illness associated with a Self-limited illness associated with a

prodrome of diarrhea that results in prodrome of diarrhea that results in spontaneous recovery spontaneous recovery I was born here

Einstein’s first job was here

Conrad Gasser (1912-1982)

DIAGNOSTIC COMPONENTS DIAGNOSTIC COMPONENTS ANDAND

HISTOPATHOLOGYHISTOPATHOLOGY

Hemolytic Uremic Syndrome (HUS)Hemolytic Uremic Syndrome (HUS)TriadTriad Microangiopathic hemolytic anemiaMicroangiopathic hemolytic anemia

ThrombocytopeniaThrombocytopenia

Acute kidney injuryAcute kidney injury

Thrombotic Microangiopathy (TMA)Thrombotic Microangiopathy (TMA)Hemolytic Uremic SyndromeHemolytic Uremic SyndromeThrombotic Thrombocytopenic PurpuraThrombotic Thrombocytopenic Purpura

HemolyticHemolytic AnemiaAnemia

Microangiopathic hemolytic anemia with erythrocyte Microangiopathic hemolytic anemia with erythrocyte fragmentationfragmentation

Coombs negativeCoombs negative

Plasma LDH elevatedPlasma LDH elevated

Haptoglobin decreasedHaptoglobin decreasedMost sensitive marker to track resolution of intravascular Most sensitive marker to track resolution of intravascular hemolysishemolysis

Severity does not correlate with clinical outcomeSeverity does not correlate with clinical outcome Red cell production increasedRed cell production increased

ThrombocytopeniaThrombocytopenia

Variable and transientVariable and transient May be missedMay be missed

Consumption of plateletsConsumption of platelets

Majority of platelets removed in Majority of platelets removed in reticuloendothelial systemreticuloendothelial system

Significant bleeding rare!Significant bleeding rare! Slightly pro-thrombotic stateSlightly pro-thrombotic state

Acute Kidney InjuryAcute Kidney Injury

AbruptAbrupt

OligoanuriaOligoanuria

ProteinuriaProteinuria

HypertensionHypertension Severe and difficult to control in atypical formsSevere and difficult to control in atypical forms Absent or mild in infection-associated form – Absent or mild in infection-associated form –

delayed to recovery perioddelayed to recovery period

Thrombotic Microangiopathy Thrombotic Microangiopathy (TMA)(TMA)

Histopathological termHistopathological term

Characterized by presence ofCharacterized by presence ofPlatelet-fibrin thrombi within the vascular lumenPlatelet-fibrin thrombi within the vascular lumen

Injury to endothelial cells with separation from Injury to endothelial cells with separation from underlying basement membraneunderlying basement membrane

Deposition of eosinophilic materialDeposition of eosinophilic material

Risk Factors for Development of HUSRisk Factors for Development of HUS

Female genderFemale genderSevere colitisSevere colitisFeverFeverLeukocytosisLeukocytosisAlso:Also: Younger ageYounger age Antimotility agentsAntimotility agents AntibioticsAntibiotics Alterations in gene for factor HAlterations in gene for factor H

Implicated in pathophysiology of atypical HUSImplicated in pathophysiology of atypical HUS

Some Statistical DataSome Statistical Data

Most common cause of acute kidney injury in Most common cause of acute kidney injury in childhoodchildhood Incidence: 3-5/100,000 population in children age 1-Incidence: 3-5/100,000 population in children age 1-

1818Gradual decline from early childhood to adolescenceGradual decline from early childhood to adolescence

Significant morbidity and mortality in acute Significant morbidity and mortality in acute phasephase

Mortality: 3-5%, usually associated with severe extra-renal Mortality: 3-5%, usually associated with severe extra-renal diseasedisease

Primary diagnosis for up to 4.5% of children on Primary diagnosis for up to 4.5% of children on chronic renal replacement therapychronic renal replacement therapy

M & MM & M

MortalityMortality 3-5%3-5%

Serious extra-renal complicationsSerious extra-renal complications 20%20%

Need for acute dialysisNeed for acute dialysis 40%40%

Persistent renal injuryPersistent renal injury 20%; hypertension, proteinuria, reduced GFR20%; hypertension, proteinuria, reduced GFR

Terminology/CategoriesTerminology/CategoriesTermTerm CommentComment

D+ HUSD+ HUS Patient presents with prodrome of diarrhea in past 2 Patient presents with prodrome of diarrhea in past 2 weeksweeks

Typical HUSTypical HUS D+ HUS, diagnosis made in retrospect; single, self-D+ HUS, diagnosis made in retrospect; single, self-limited eventlimited event

Atypical HUSAtypical HUS Any pattern of clinical presentation Any pattern of clinical presentation other thanother than D+ D+ HUS – implies complement dysregulationHUS – implies complement dysregulation

Recurrent or relapsing HUSRecurrent or relapsing HUS Repeat episode of same clinical features, implies Repeat episode of same clinical features, implies repeat injury to kidneys – strongly suggests genetic repeat injury to kidneys – strongly suggests genetic or autoimmune risk factoror autoimmune risk factor

Thrombotic microangiopathy, glomerular Thrombotic microangiopathy, glomerular thrombotic microangiopathythrombotic microangiopathy

Pathological descriptive termsPathological descriptive terms

Familial HUSFamilial HUS Unclear term. Not distinguishing betweenUnclear term. Not distinguishing between

Synchronous Synchronous HUS = several family members HUS = several family members infected with EHEC at the same time;infected with EHEC at the same time;

andand

AsynchronousAsynchronous HUS = implies inherited risk factor HUS = implies inherited risk factor

D+ HUSD+ HUS

DiagnosisDiagnosisClinical - Abrupt onset of illnessClinical - Abrupt onset of illness

Recognized within 24 hours of onsetRecognized within 24 hours of onset LethargyLethargy PallorPallor OliguriaOliguria

Laboratory abnormalities:Laboratory abnormalities:Coombs-negative anemia and thrombocytopeniaCoombs-negative anemia and thrombocytopenia

Rising BUN/CreatinineRising BUN/Creatinine

Elevated LDHElevated LDH

Low haptoglobinLow haptoglobin

Clinical Time CourseClinical Time Course

Ingestion of bacteriaIngestion of bacteria

Enterocolitis within 2-3 daysEnterocolitis within 2-3 daysBloody stools in >85%Bloody stools in >85%

FeverFever

Severe abdominal painSevere abdominal pain

Most cases: self-limited, complete resolutionMost cases: self-limited, complete resolution5-10% progress to HUS5-10% progress to HUS

Monophasic illnessMonophasic illness

Route of InfectionRoute of Infection

Most Common Etiology WorldwideMost Common Etiology Worldwide

Enterohemorrhagic Enterohemorrhagic E. coliE. coli (EHEC) (EHEC) O157:H7O157:H7

DD+ + HUS (typical)HUS (typical)

Produces Shiga toxin (Stx) 1 and/or 2Produces Shiga toxin (Stx) 1 and/or 2 Encoded on a phageEncoded on a phage

Other Other E. coliE. coli strains also produce Stx strains also produce Stx Called Stx-producing Called Stx-producing E. coliE. coli (STEC) (STEC) Over 400 seropathotypesOver 400 seropathotypes

PathogenesisPathogenesis

Shiga toxin (Stx)-induced injury to Shiga toxin (Stx)-induced injury to endothelial cellsendothelial cells

Activation of prothrombotic coagulation Activation of prothrombotic coagulation cascadecascade

Release of inflammatory mediators and Release of inflammatory mediators and chemokineschemokines

Molecular Risk AssessmentMolecular Risk Assessment

Association of virulence genes with severity of Association of virulence genes with severity of diseasedisease

Presence or absence of genes (binary typing) Presence or absence of genes (binary typing) produces genetic fingerprint for each isolateproduces genetic fingerprint for each isolate

Identify strains that have greater potential to cause Identify strains that have greater potential to cause harm = harm = molecular risk assessmentmolecular risk assessment

Binary Typing of Virulence Genes Binary Typing of Virulence Genes

Distribution of 41 virulence genes in STEC Distribution of 41 virulence genes in STEC isolatesisolates ““Virulence bar code” for each isolateVirulence bar code” for each isolate Integrated epidemiological dataIntegrated epidemiological data

Allows some prediction of clinical courseAllows some prediction of clinical course

Brandt SM et al. Appl Environ Microbiol. 2011 Apr;77(7):2458-70.

Brandt SM et al. Appl Environ Microbiol. 2011 Apr;77(7):2458-70.

Virulence FactorsVirulence Factors

Seropathotype (SPT) classification identifies STEC Seropathotype (SPT) classification identifies STEC serotypes linked to outbreaks and/or serious serotypes linked to outbreaks and/or serious diseasedisease

SPT ASPT A (O157:H7, (O157:H7, O157:NM) and O157:NM) and SPT BSPT B (O26:H11/NM, O103:H2, (O26:H11/NM, O103:H2, O111:H8/NM, O121:H19, O145:NM) associated with O111:H8/NM, O121:H19, O145:NM) associated with outbreaks outbreaks and HUSand HUS

SPT CSPT C (e.g., O5:NM, (e.g., O5:NM, O91:H21, O113:H21, O121:NM, O128:H2) O91:H21, O113:H21, O121:NM, O128:H2) associated with associated with sporadic cases of HUS but not sporadic cases of HUS but not with with outbreaksoutbreaks

SPT DSPT D includes remainder of STEC serotypes that have been includes remainder of STEC serotypes that have been reported to cause reported to cause sporadic disease sporadic disease and association with and association with diarrhea diarrhea but not HUSbut not HUS

SPT ESPT E notnot associated with associated with human illnesshuman illness

TherapyTherapy

Nothing provenNothing provenIntensive, supportive medical careIntensive, supportive medical careDialysis if:Dialysis if:

Anuria x 24 hAnuria x 24 hOliguria (urine output <0.5ml/kg/h) x 48-72 hOliguria (urine output <0.5ml/kg/h) x 48-72 h

pRBC Transfusion if:pRBC Transfusion if:Hemoglobin <6 g/dlHemoglobin <6 g/dl

Ineffective treatments are:Ineffective treatments are: Antiplatelet drugs, fibrinolytic agents, IVIG, high-dose Antiplatelet drugs, fibrinolytic agents, IVIG, high-dose

steroids, plasmapheresis, and oral Stx-binding agentssteroids, plasmapheresis, and oral Stx-binding agents

Careful MonitoringCareful Monitoring

Electrolyte abnormalitiesElectrolyte abnormalities HyponatremiaHyponatremia HypocalcemiaHypocalcemia

LDH, serum creatinine, Hgb, plateletsLDH, serum creatinine, Hgb, platelets

Watch out for :Watch out for :SeizuresSeizures

PancreatitisPancreatitis

Myocardial dysfunctionMyocardial dysfunction

Adult respiratory distress syndromeAdult respiratory distress syndrome

Sudden neurologic deteriorationSudden neurologic deterioration

Prevention of HUS – Prevention of HUS – The Scientific ApproachThe Scientific Approach

Subcutaneous mouse vaccine against stx Subcutaneous mouse vaccine against stx and intestinal zonula occludens toxinsand intestinal zonula occludens toxins Decreased shedding of E. coli O157:H7Decreased shedding of E. coli O157:H7 Good news: mice TOLERATED vaccine Good news: mice TOLERATED vaccine

WELLWELL Bad news: MICE tolerated vaccine wellBad news: MICE tolerated vaccine well

Prevention of HUS – Prevention of HUS – The Useful ApproachThe Useful Approach

Changes in feed provided to cattleChanges in feed provided to cattle

Tighter regulation of meat processing plantsTighter regulation of meat processing plants

Irradiation of food and beveragesIrradiation of food and beverages

No antibiotics in children with bloody diarrheaNo antibiotics in children with bloody diarrhea

Prompt hospitalization and administration of Prompt hospitalization and administration of isotonic parenteral fluidsisotonic parenteral fluids

Prevent vascular injury in glomerular microcirculationPrevent vascular injury in glomerular microcirculation

Isolate sick individual from other family membersIsolate sick individual from other family members

D- HUSD- HUS

Atypical, Sporadic, Non-Familial Atypical, Sporadic, Non-Familial HUSHUS

Pneumococcus-related diseasePneumococcus-related disease

Younger childrenYounger children

Number of cases requiring dialysis is higherNumber of cases requiring dialysis is higher

Worse prognosis compared with STEC-related Worse prognosis compared with STEC-related HUSHUS

Other causes:Other causes:HIV infection, use of calcineurin inhibitors, OCP, SLE HIV infection, use of calcineurin inhibitors, OCP, SLE (usually in presence of antiphospholipid syndrome), and (usually in presence of antiphospholipid syndrome), and HELLP syndromeHELLP syndrome

Atypical HUSAtypical HUS

Atypical HUSAtypical HUS

Annual incidence of genetic forms of aHUS:Annual incidence of genetic forms of aHUS:10% of D10% of D++HUSHUS

3-5 cases per 1 million3-5 cases per 1 million

Strong association between aHUS and Strong association between aHUS and mutations and/or polymorphisms in complement mutations and/or polymorphisms in complement gene (regulatory and activation proteins)gene (regulatory and activation proteins)

50% of cases linked to genetic mutations in 50% of cases linked to genetic mutations in alternate cascadealternate cascade

Modulators of Alternate Modulators of Alternate Complement CascadeComplement Cascade

Loss-of-function mutations in regulatory proteins Loss-of-function mutations in regulatory proteins or gain-of-function mutations in factor B and or gain-of-function mutations in factor B and complement 3complement 3Three most common defects:Three most common defects:

Mutation in factor H: 25-35% Mutation in factor H: 25-35% not to be confused withnot to be confused with

Mutation in factor I: 5-10%Mutation in factor I: 5-10%Mutation in membrane co-factor protein (MCP = CD46): 3-5%Mutation in membrane co-factor protein (MCP = CD46): 3-5%

Deficiency in factor H-related proteins (CFHR1-5)Deficiency in factor H-related proteins (CFHR1-5) Polymorphic delCFHR1/3 deletion strongly associated with CFH auto-Polymorphic delCFHR1/3 deletion strongly associated with CFH auto-

antibodies antibodies aHUS due to CFH auto-antibodies more common in children aHUS due to CFH auto-antibodies more common in children

Clinical Course of aHUSClinical Course of aHUS

Onset of syndrome frequently preceded by Onset of syndrome frequently preceded by environmental insult (e.g., infection)environmental insult (e.g., infection)

Typically infants/young childrenTypically infants/young children

C3 level may be normalC3 level may be normal CFH mutations predominantly result in CFH mutations predominantly result in

impaired ability of CFH to interact with cell impaired ability of CFH to interact with cell surfaces, but ability to regulate plasma C3 surfaces, but ability to regulate plasma C3 preservedpreserved

Clinical Relevance of Clinical Relevance of Genetic TestingGenetic Testing

Important to test for CFH auto-antibodies - Important to test for CFH auto-antibodies - strategies to reduce auto-antibody titer (e.g. strategies to reduce auto-antibody titer (e.g. plasma exchange)plasma exchange)

Higher relapse rateHigher relapse rate

Increased likelihood of progression to end-stage Increased likelihood of progression to end-stage kidney diseasekidney disease

High rate of recurrence after kidney transplantHigh rate of recurrence after kidney transplantFactor H or I mutation >> MCP mutationFactor H or I mutation >> MCP mutation

MCP present in transplanted kidney – prevents MCP present in transplanted kidney – prevents complement-mediated injury to allograftcomplement-mediated injury to allograft

Therapy of Genetic aHUSTherapy of Genetic aHUS

PlasmaPlasmaIntermittent infusions or Intermittent infusions or viavia plasmapheresis plasmapheresis

Treatment intensity guided by disease activity:Treatment intensity guided by disease activity:Platelet countPlatelet count

LDH levelLDH level

Serum creatinine concentrationSerum creatinine concentration

If suspecting genetic form of aHUS, initiate daily If suspecting genetic form of aHUS, initiate daily plasma therapy promptlyplasma therapy promptly

Combined kidney/liver transplantCombined kidney/liver transplantFor cases with factor H and factor I mutationsFor cases with factor H and factor I mutations

Hepatic production of normal complement regulatorsHepatic production of normal complement regulators

Plasma TherapyPlasma Therapy

Not THIS one!

Plasma TherapyPlasma Therapy

Complement 5 ProteinComplement 5 Protein

Critical role in development of aHUSCritical role in development of aHUS

CFH-deficient animals expressing mutant CFHD16–20 protein CFH-deficient animals expressing mutant CFHD16–20 protein develop spontaneous aHUSdevelop spontaneous aHUS

C5 knockout in this model results in resistance to aHUS.C5 knockout in this model results in resistance to aHUS.

EculizumabEculizumab

Recombinant, humanized, monoclonal Ab produced from Recombinant, humanized, monoclonal Ab produced from mouse myeloma cellsmouse myeloma cells

Approved for treatment of paroxysmal nocturnal Approved for treatment of paroxysmal nocturnal hemoglobinuria (PNH)hemoglobinuria (PNH)

Reduces intravascular hemolysis, anemia, thrombotic Reduces intravascular hemolysis, anemia, thrombotic events, and transfusion requirements in PNHevents, and transfusion requirements in PNH

Targets complement protein C5 and prevents generation Targets complement protein C5 and prevents generation of proinflammatory peptide C5a and cytotoxic membrane of proinflammatory peptide C5a and cytotoxic membrane attack complex C5b-9attack complex C5b-9

RegimenRegimen

Weekly infusions with gradual increase in dosing with Weekly infusions with gradual increase in dosing with biweekly maintenance therapybiweekly maintenance therapy

Shown to completely block complement activityShown to completely block complement activity

Complement blockade confirmed by CH50 Complement blockade confirmed by CH50 measurementsmeasurements

Dosing and pharmacokinetics in children are underway Dosing and pharmacokinetics in children are underway in international multi-center study – Children’s Hospital at in international multi-center study – Children’s Hospital at Montefiore to be added as site within next 2 monthsMontefiore to be added as site within next 2 months

Thrombotic Thrombocytopenic Thrombotic Thrombocytopenic PurpuraPurpura

TTP – Moschcowitz SyndromeTTP – Moschcowitz Syndrome

An acute febrile pleiochromic anemia with hyaline thrombosis of terminal arterioles and capillaries: An undescribed disease. Archives of Internal Medicine, Chicago, 1925, 36: 89.

Deficiency of von Willebrand Protease Deficiency of von Willebrand Protease (ADAMTS13) (ADAMTS13) = = a disintegrin and metalloproteinase with a thrombospondin type 1 motif, a disintegrin and metalloproteinase with a thrombospondin type 1 motif,

member 13member 13

ThrombocytopeniaThrombocytopenia

Microangiopathic hemolytic anemiaMicroangiopathic hemolytic anemia

Neurological symptomsNeurological symptoms

Renal dysfunctionRenal dysfunction

FeverFever

Role of ADAMTS13 Role of ADAMTS13 (or (or a disintegrin and a disintegrin and

metalloproteinase with a thrombospondin type 1 motif, member 13)metalloproteinase with a thrombospondin type 1 motif, member 13)

ADAMTS13 ADAMTS13 (you know what is supposed to be written (you know what is supposed to be written

here)here)DeficiencyDeficiencyCause:Cause:

Rare: loss-of-function mutation (Congenital TTP)Rare: loss-of-function mutation (Congenital TTP)

Acquired inhibitor: IgG auto-antibodyAcquired inhibitor: IgG auto-antibody Associated with use of Clopidogrel and TiclopidineAssociated with use of Clopidogrel and Ticlopidine

Effect:Effect:Ultra-large vWF multimersUltra-large vWF multimers

ADAMTS13 ADAMTS13 (guess what?) (guess what?) DeficiencyDeficiency

Enzyme activity of <5% is primary cause of Enzyme activity of <5% is primary cause of microvascular thrombosismicrovascular thrombosisEnzyme activity <30% in several disease and Enzyme activity <30% in several disease and physiological statesphysiological states

Thrombi found at arteriolar-capillary junction – area of Thrombi found at arteriolar-capillary junction – area of high shear stresshigh shear stressAffected organs:Affected organs:

Brain, heart, spleen, kidney, pancreas, adrenals, lungs, and eyesBrain, heart, spleen, kidney, pancreas, adrenals, lungs, and eyes

Outcome of TTPOutcome of TTP

Mortality:Mortality:Historically: 95%Historically: 95%

Today: 20%Today: 20%

What made the difference?What made the difference?Plasma therapy Plasma therapy

The Weird OnesThe Weird Ones

HUS can be also caused by:HUS can be also caused by: Cobalamin deficiencyCobalamin deficiency

Defect in methylmalonic aciduria and homocystinuria Defect in methylmalonic aciduria and homocystinuria gene (gene (MMACHCMMACHC))

Quinine/QuinidineQuinine/Quinidine Found in tonic water and tablets that prevent muscle Found in tonic water and tablets that prevent muscle

crampscramps Autoantibodies to ? Autoantibodies to ?

Really rare ones:Really rare ones: Use of anti-VEGF monoclonal antibodiesUse of anti-VEGF monoclonal antibodies Disseminated adenocarcinomaDisseminated adenocarcinoma

Questions?Questions?

Not related to me, no idea who he is, but love his hair