Long-Term Health Long-Term Health ImplicationsImplications

Hemolytic Uremic Syndrome (HUS)(HUS)

Normal Kidney Structure Normal Kidney Structure and Functionand Function

Renal Artery Takes blood into kidneyTakes blood into kidney

Renal Vein Takes blood from kidneyTakes blood from kidney

Ureter Takes urine to the bladderTakes urine to the bladder

Normal KidneyNormal Kidney

From “The Human Body, Dorling Kindersly Limited, London 1995

Blood In

Blood Out

Urine Out

Renal Cortex Where the Where the

blood is blood is filtered filtered into urineinto urine

The Human Body, Dorling Kindersly Limited, London 1995

GlomerulusGlomerulus The structure which The structure which

filters blood into urinefilters blood into urine

Normal KidneyNormal Kidney

Courtesy of JC Jennette, MD, UNC-Chapel Hill

Normal KidneyNormal Kidney

The Human Body, Dorling Kindersly Limited, London 1995

Measuring Kidney Measuring Kidney Structure and FunctionStructure and Function

StructureStructure– Renal ultrasoundRenal ultrasound

– Renal biopsyRenal biopsy

FunctionFunction– Glomerular filtration rateGlomerular filtration rate

– Blood and urine creatinineBlood and urine creatinine

– UrinalysisUrinalysis

Courtesy S. Williamson MD, U of New Mexico

Structure: Renal UltrasoundStructure: Renal Ultrasound

Provides Provides information information about:about:– Size Size

– Echogenicity Echogenicity

– Stones/ScarsStones/Scars

– ObstructionObstruction

Provides Provides informationinformationabout functionabout function

Normal Glomerulus Acute HUS Glomerulus

Courtesy of JC Jennette, MD, UNC-Chapel Hill

Structure: Kidney BiopsyStructure: Kidney Biopsy

*GFR is usually expressed in terms of average adult body surface area: meters squared

Function: Function: Glomerular Filtration Rate (GFR)Glomerular Filtration Rate (GFR)

The rate at which blood The rate at which blood is filtered by the kidneyis filtered by the kidney

Normal GFR = Normal GFR = 90–150 ml/min/1.73m2*90–150 ml/min/1.73m2*

The most accurate measure The most accurate measure of kidney functionof kidney function

CreatinineCreatinine

A by-product of normal A by-product of normal muscle metabolismmuscle metabolism

Blood or 24-hour urine levels Blood or 24-hour urine levels are used to estimate GFRare used to estimate GFR– Most commonMost common

– Easily obtainedEasily obtained

– Overestimates actual kidney Overestimates actual kidney function (GFR)function (GFR)

A Window Into the Kidney’s A Window Into the Kidney’s HealthHealth

Blood

UrinalysisUrinalysis

Normal Value

Protein

24-Hr Protein

Protein/Cr ratio

None (< 4 rbc/hpf)

None or trace

< 150 mg/day

< 0.2 (mg/mg)

What Goes Wrong During HUS?What Goes Wrong During HUS?

At the cell and organ levelAt the cell and organ level– Pathology and PathophysiologyPathology and Pathophysiology

At the patient level At the patient level – Clinical findingsClinical findings

Thrombotic Microangiopathy (TMA)Thrombotic Microangiopathy (TMA)

The pathologic lesion of HUSThe pathologic lesion of HUS E. Coli Shigatoxin damages endothelial cellsE. Coli Shigatoxin damages endothelial cells

– Endothelial swelling narrows Endothelial swelling narrows vessel lumenvessel lumen

– Platelet/fibrin clots form blocking Platelet/fibrin clots form blocking blood flowblood flow

Poor blood flowPoor blood flow– Low tissue oxygen (hypoxia)Low tissue oxygen (hypoxia)

HypoxiaHypoxia– Cell dysfunctionCell dysfunction

– Cell necrosis (death)Cell necrosis (death)

Adapted from Stewart CL, Pediatr Rev, 1993

A: Normal Glomerular blood vessel

B: (-) charged endothelial cell (+) charged Platelet ( )

C: Loss of (-) charge and PGI2 due to endothelial damage

D: Fibrin/platelet thrombi formation

HUS PathogenesisHUS Pathogenesis

A B

C D

Courtesy of P Tarr MD, Univ of Washington

The Kidney in HUSThe Kidney in HUS

Normal Capillary

TMA Capillary

ThrombusExpanded subendothelial zone

Narrowed lumen

Toxin causing injury to endothelial cells

Courtesy of JC Jennette, MD, UNC-Chapel Hill

Micrograph of TMA Micrograph of TMA in Glomerulusin Glomerulus

Glomerular Light Microscopy

Normal Capillary TMA Capillary

Lumen Subendothelial Expansion

Micrograph of TMA Micrograph of TMA in Renal Arteryin Renal Artery

Courtesy of JC Jennette, MD, UNC-Chapel Hill

Normal Artery TMA Artery

Arterial Intimal Thickening

Lumen Intimal Expansion Obliterating Lumen

Fibrin Strands

Red Blood Cells

Courtesy of P Tarr MD, Univ of Washington

Electron Micrograph of Fibrin Electron Micrograph of Fibrin Clot and Red Blood CellsClot and Red Blood Cells

* Acute Tubular Necrosis (ATN) is an exception to this

Tissue Damage vs Necrosis Tissue Damage vs Necrosis

HUS induced hypoxia: HUS induced hypoxia: “Cell Suffocation”“Cell Suffocation”

Tissue injury without loss of structureTissue injury without loss of structure– RepairableRepairable

Tissue death (necrosis*) leads to: Tissue death (necrosis*) leads to: – Scar formationScar formation

– Permanent injury Permanent injury

– Loss of functionLoss of function

Clinical Findings in Acute HUSClinical Findings in Acute HUS

Serum creatinine levelSerum creatinine level GFRGFR Blood pressureBlood pressure Urine proteinUrine protein Urine outputUrine output

Normal KidneyNormal Kidney

Serum CrSerum Cr

4-year Old with Normal Kidneys

GFR

BP

Urine Protein

Urine Prot/Cr

Urine Output

0.5 mg/dl

120 ml/min/1.73m2

100/60

none

0.09 (nl < 0.2)

1000 ml/day

- Areas of HUS Activity

Acute HUSAcute HUS

AbnormalitiesAbnormalities

2.5 mg/dl

23 ml/min/1.73m2

140/90

300 mg/dl

1.8

125 ml

High

Low

High

High

High

Low

Serum Cr

GFR

BP

Urine Protein

Urine Prot/Cr

Urine Output

Oliguria (Low Urine Oliguria (Low Urine Output)Output)

Frequency (of patients)

Dialysis

Blood Transfusion

Platelet Transfusion

Hypertension

Death

70%

50%

70%

30%

30%

4%

Clinical Findings Clinical Findings in Acute HUS Renalin Acute HUS Renal

Siegler RL, Spectrum of involvement in post-diarrheal hemolytic-uremic syndrome. J Pediatrics, 125(4): 511-518, 1994

Other Organs InvolvedOther Organs Involvedin Acute HUSin Acute HUS

Intestine

Liver

Brain

Pancreas

Heart / Lung / Other

100 %

40 %

20 %

20 %

< 1 %

Frequency

Why the Kidney? Why the Kidney? Why Children?Why Children?

Children get E. coli O157 infections:Children get E. coli O157 infections:– Peak age = 1-6 yearsPeak age = 1-6 years

The cell receptor for Shigatoxin: Gb3The cell receptor for Shigatoxin: Gb3– Gb3 concentrations are:Gb3 concentrations are:

– Higher in the KidneyHigher in the Kidney

– Higher in ChildrenHigher in Children

What Happens to the Kidney What Happens to the Kidney as HUS Resolves?as HUS Resolves?

Areas of Cell Hypoxia repair to normalAreas of Cell Hypoxia repair to normal Areas of TMA mostly repair to normalAreas of TMA mostly repair to normal Areas of Necrosis form Scar tissueAreas of Necrosis form Scar tissue

What Happens to the Kidney What Happens to the Kidney as HUS Resolves?as HUS Resolves?

Kidney compensation for scar tissue:Kidney compensation for scar tissue:– Normal areas work harder: HyperfiltrationNormal areas work harder: Hyperfiltration

Excessive Hyperfiltration leads to:Excessive Hyperfiltration leads to:– Progressive Glomerular Scarring!!!Progressive Glomerular Scarring!!!

0.5

Six months after HUSSix months after HUS

- Areas of scar formation

115 ml/min/1.73m2

100/60

10 mg/dl

0.2

NL

NL

NL

NL

NL

Serum Cr

GFR

BP

Urine Protein

Urine Prot/Cr

III. Significant Hyperfiltration

I.None/Minimal Hyperfiltration

II.Moderate Hyperfiltration

5 Years After HUS:5 Years After HUS:Possible OutcomesPossible Outcomes

Chronic Renal Failure

4.0

10-30 Years After HUS10-30 Years After HUS

NO

Maybe?

Probable

Serum Cr

28GFR

U Prot Elevated

BP High

How Do We Study the Effects How Do We Study the Effects (Sequelae) of HUS?(Sequelae) of HUS?

Glomerular Filtration Rate (GFR)Glomerular Filtration Rate (GFR) Urinalysis: ProteinuriaUrinalysis: Proteinuria Blood PressureBlood Pressure Renal BiopsyRenal Biopsy

GFR After HUSGFR After HUS

The most accurate method of The most accurate method of following actual renal functionfollowing actual renal function

MethodsMethods– Iothalamate, Inulin, Cr Clearance, Iothalamate, Inulin, Cr Clearance,

EDTA, or DPTAEDTA, or DPTA

– Time consumingTime consuming

– Require either an IV line and/or long Require either an IV line and/or long urine collectionurine collection

Proteinuria After HUSProteinuria After HUS

Causes in general Causes in general – Infection, renal inflammation, fever, etc.Infection, renal inflammation, fever, etc.

After HUS: Proteinuria After HUS: Proteinuria – HyperfiltrationHyperfiltration

Proteinuria and ACE InhibitorsProteinuria and ACE Inhibitors

ACE Inhibitors (ACEIs) ACE Inhibitors (ACEIs) – Blood Pressure MedicationsBlood Pressure Medications

ACEIs also decrease ACEIs also decrease Renal HyperfiltrationRenal Hyperfiltration

ACEIs slow damage due ACEIs slow damage due to Hyperfiltrationto Hyperfiltration

Blood PressureBlood Pressure

New High Blood Pressure after HUS may New High Blood Pressure after HUS may be a sign of permanent kidney damagebe a sign of permanent kidney damage

Renal scars cause high blood pressure Renal scars cause high blood pressure throughthrough– ReninRenin

ACEIs block Renin actionACEIs block Renin action

Renal BiopsyRenal Biopsy

To evaluate structural damage after HUSTo evaluate structural damage after HUS Useful in predicting future problemsUseful in predicting future problems Does not provide information about functionDoes not provide information about function Rarely done in the U.S. Rarely done in the U.S.

(except in research)(except in research)

Why Is It Difficult to Interpret Why Is It Difficult to Interpret Outcome Studies in HUS?Outcome Studies in HUS?

Rarity of DiseaseRarity of Disease Variation inVariation in

– Disease Severity and E. Coli virulenceDisease Severity and E. Coli virulence

– Measuring OutcomesMeasuring Outcomes

Lack of long term follow-up by patientsLack of long term follow-up by patients

Rarity of DiseaseRarity of Disease

IncidenceIncidence (cases/100,000 children/yr)(cases/100,000 children/yr)

HUS

ALL (Leukemia)

Congenital Heart Disease

Urinary Tract Infection

2

13

100

225

Evaluation of HUS OutcomesEvaluation of HUS Outcomes

Renal FunctionRenal Function– GFR by serum Cr, urine CrCl, Iothalamate, GFR by serum Cr, urine CrCl, Iothalamate,

EDTA, etc.EDTA, etc.

– Renal Plasma FlowRenal Plasma Flow

– Renal Concentrating AbilityRenal Concentrating Ability

ProteinuriaProteinuria– DipstickDipstick

– U Prot / Cr ratioU Prot / Cr ratio

– 24 hr urine protein24 hr urine protein

Renal BiopsyRenal Biopsy

A Word About Study SizeA Word About Study Size

NumberNumberFolloweFollowedd

Number Abnormal

PercentageAbnormal

1

1

10

100

1000 1

10%

1%

0.1%

What Do The Outcome Studies What Do The Outcome Studies Show So Far?Show So Far?

Measures used most consistently Measures used most consistently – Hypertension Hypertension

– ProteinuriaProteinuria

– Low GFRLow GFR

– ESRD (End Stage Renal Disease)ESRD (End Stage Renal Disease)

Outcome Studies of NoteOutcome Studies of Note

E. coli associated patients onlyE. coli associated patients only Follow-up > 5 yearsFollow-up > 5 years Study AssessedStudy Assessed

– HypertensionHypertension

– ProteinuriaProteinuria

– Renal FunctionRenal Function

– Evaluated outcome predictorsEvaluated outcome predictors

9 Outcome Studies on E. coli-9 Outcome Studies on E. coli-related HUS Published 1988–1998related HUS Published 1988–1998

# Patients Followed# Patients Followed

Years of Follow-up

Renal Sequelae (Yes / No)

HypertensionProteinuriaLow GFRESRD

478 (73%)

0.5 - 28 yrs

35 %/65%

0 - 20 %8 - 31 %1 - 28 %5 %

Renal Sequelae May Develop After Renal Sequelae May Develop After a Period of Normal Renal Testsa Period of Normal Renal Tests

Siegler, Utah, 1991

Gagnadoux, France, 1996

“Abnormalities sometimes appeared after an interval of apparent recovery.” (proteinuria)

“...4 had reached end-stage renal failure (ESRF) 16-24 years after onset; 2 of these latter 4 had a normal GFR at 10-year examination.”

Predictors of Renal Damage Predictors of Renal Damage in HUSin HUS

1) Elevated WBC count at presentation1) Elevated WBC count at presentation 2) Prolonged Oliguria or Anuria (or Dialysis)2) Prolonged Oliguria or Anuria (or Dialysis) 3) Severe tissue damage on HUS biopsy3) Severe tissue damage on HUS biopsy

– Extensive TMA (> 50% of gloms)Extensive TMA (> 50% of gloms)

– Cortical necrosisCortical necrosis

4) Low GFR at > 2 year follow-up4) Low GFR at > 2 year follow-up

Common Symptoms with Renal Common Symptoms with Renal Damage after HUS Damage after HUS

Most common: NONEMost common: NONE High Blood Pressure, Low GFR, High Blood Pressure, Low GFR,

Proteinuria usually cause no Proteinuria usually cause no noticeable signs or symptomsnoticeable signs or symptoms

How Will You Know If Your Child Is How Will You Know If Your Child Is at Risk of Future Kidney Damage?at Risk of Future Kidney Damage?

Yearly follow-up with a Pediatric Yearly follow-up with a Pediatric NephrologistNephrologist

Yearly blood pressure and urinalysisYearly blood pressure and urinalysis GFR and creatinine every few years GFR and creatinine every few years

– 1, 3, 5, 10, 15 yrs, …etc.1, 3, 5, 10, 15 yrs, …etc.

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