Hemolytic Uremic Syndrome: A Dangerous Complication of E. coli

Long-Term Health Implications Hemolytic Uremic Syndrome (HUS)

Normal Kidney Structure and Function

Normal Kidney
Renal Artery
Takes blood into kidney
Renal Vein
Takes blood from kidney
Ureter
Takes urine to the bladder

From “The Human Body, Dorling Kindersly Limited, London 1995 Blood In Blood Out Urine Out
Renal Cortex
Where the blood is filtered into urine

Normal Kidney The Human Body, Dorling Kindersly Limited, London 1995
Glomerulus
The structure which filters blood into urine

Normal Kidney Courtesy of JC Jennette, MD, UNC-Chapel Hill The Human Body, Dorling Kindersly Limited, London 1995

Measuring Kidney Structure and Function
Structure
Renal ultrasound
Renal biopsy
Function
Glomerular filtration rate
Blood and urine creatinine
Urinalysis

Structure: Renal Ultrasound
Provides information about:
Size
Echogenicity
Stones/Scars
Obstruction
Provides information about function
Courtesy S. Williamson MD, U of New Mexico

Structure: Kidney Biopsy Normal Glomerulus Acute HUS Glomerulus Courtesy of JC Jennette, MD, UNC-Chapel Hill

Function: Glomerular Filtration Rate (GFR)
The rate at which blood is filtered by the kidney
Normal GFR = 90–150 ml/min/1.73m2*
The most accurate measure of kidney function
*GFR is usually expressed in terms of average adult body surface area: meters squared

Creatinine
A by-product of normal muscle metabolism
Blood or 24-hour urine levels are used to estimate GFR
Most common
Easily obtained
Overestimates actual kidney function (GFR)

A Window Into the Kidney’s Health
Urinalysis Blood 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?
At the cell and organ level
Pathology and Pathophysiology
At the patient level
Clinical findings

Thrombotic Microangiopathy (TMA)
The pathologic lesion of HUS
E. Coli Shigatoxin damages endothelial cells
Endothelial swelling narrows vessel lumen
Platelet/fibrin clots form blocking blood flow
Poor blood flow
Low tissue oxygen (hypoxia)
Hypoxia
Cell dysfunction
Cell necrosis (death)

HUS Pathogenesis Adapted from Stewart CL, Pediatr Rev, 1993 A: Normal Glomerular blood vessel B: (-) charged endothelial cell (+) charged Platelet ( ) C: Loss of (-) charge and PGI 2 due to endothelial damage D: Fibrin/platelet thrombi formation A B C D

The Kidney in HUS Courtesy of P Tarr MD, Univ of Washington Normal Capillary TMA Capillary Thrombus Expanded subendothelial zone Narrowed lumen Toxin causing injury to endothelial cells

Micrograph of TMA in Glomerulus Courtesy of JC Jennette, MD, UNC-Chapel Hill Glomerular Light Microscopy Normal Capillary TMA Capillary Lumen Subendothelial Expansion

Micrograph of TMA in Renal Artery Courtesy of JC Jennette, MD, UNC-Chapel Hill Normal Artery TMA Artery Arterial Intimal Thickening Lumen Intimal Expansion Obliterating Lumen

Electron Micrograph of Fibrin Clot and Red Blood Cells Fibrin Strands Red Blood Cells Courtesy of P Tarr MD, Univ of Washington

Tissue Damage vs Necrosis
HUS induced hypoxia: “Cell Suffocation”
Tissue injury without loss of structure
Repairable
Tissue death (necrosis*) leads to:
Scar formation
Permanent injury
Loss of function
* Acute Tubular Necrosis (ATN) is an exception to this

Clinical Findings in Acute HUS
Serum creatinine level
GFR
Blood pressure
Urine protein
Urine output

Normal Kidney
Serum 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

Acute HUS
Abnormalities
- Areas of HUS Activity 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 Output)
Clinical Findings in Acute HUS Renal Frequency (of patients) Dialysis Blood Transfusion Platelet Transfusion Hypertension Death 70% 50% 70% 30% 30% 4%

Other Organs Involved in Acute HUS Siegler RL, Spectrum of involvement in post-diarrheal hemolytic-uremic syndrome. J Pediatrics, 125(4): 511-518, 1994 Intestine Liver Brain Pancreas Heart / Lung / Other 100 % 40 % 20 % 20 % < 1 % Frequency

Why the Kidney? Why Children?
Children get E. coli O157 infections:
Peak age = 1-6 years
The cell receptor for Shigatoxin: Gb3
Gb3 concentrations are:
Higher in the Kidney
Higher in Children

What Happens to the Kidney as HUS Resolves?
Areas of Cell Hypoxia repair to normal
Areas of TMA mostly repair to normal
Areas of Necrosis form Scar tissue

What Happens to the Kidney as HUS Resolves?
Kidney compensation for scar tissue:
Normal areas work harder: Hyperfiltration
Excessive Hyperfiltration leads to:
Progressive Glomerular Scarring!!!

Six months after HUS 0.5 - 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

5 Years After HUS: Possible Outcomes III. Significant Hyperfiltration I. None/Minimal Hyperfiltration II. Moderate Hyperfiltration

10-30 Years After HUS Chronic Renal Failure 4.0 NO Maybe? Probable Serum Cr 28 GFR U Prot Elevated BP High

How Do We Study the Effects (Sequelae) of HUS?
Glomerular Filtration Rate (GFR)
Urinalysis: Proteinuria
Blood Pressure
Renal Biopsy

GFR After HUS
The most accurate method of following actual renal function
Methods
Iothalamate, Inulin, Cr Clearance, EDTA, or DPTA
Time consuming
Require either an IV line and/or long urine collection

Proteinuria After HUS
Causes in general
Infection, renal inflammation, fever, etc.
After HUS: Proteinuria
Hyperfiltration

Proteinuria and ACE Inhibitors
ACE Inhibitors (ACEIs)
Blood Pressure Medications
ACEIs also decrease Renal Hyperfiltration
ACEIs slow damage due to Hyperfiltration

Blood Pressure
New High Blood Pressure after HUS may be a sign of permanent kidney damage
Renal scars cause high blood pressure through
Renin
ACEIs block Renin action

Renal Biopsy
To evaluate structural damage after HUS
Useful in predicting future problems
Does not provide information about function
Rarely done in the U.S. (except in research)

Why Is It Difficult to Interpret Outcome Studies in HUS?
Rarity of Disease
Variation in
Disease Severity and E. Coli virulence
Measuring Outcomes
Lack of long term follow-up by patients

Rarity of Disease
Incidence
(cases/100,000 children/yr)
HUS ALL (Leukemia) Congenital Heart Disease Urinary Tract Infection 2 13 100 225

Evaluation of HUS Outcomes
Renal Function
GFR by serum Cr, urine CrCl, Iothalamate, EDTA, etc.
Renal Plasma Flow
Renal Concentrating Ability
Proteinuria
Dipstick
U Prot / Cr ratio
24 hr urine protein
Renal Biopsy

A Word About Study Size
Number Followed
Number Abnormal Percentage Abnormal 1 1 10 100 1000 1 10% 1% 0.1%

What Do The Outcome Studies Show So Far?
Measures used most consistently
Hypertension
Proteinuria
Low GFR
ESRD (End Stage Renal Disease)

Outcome Studies of Note
E. coli associated patients only
Follow-up > 5 years
Study Assessed
Hypertension
Proteinuria
Renal Function
Evaluated outcome predictors

9 Outcome Studies on E. coli- related HUS Published 1988–1998
# Patients Followed
Years of Follow-up Renal Sequelae (Yes / No) Hypertension Proteinuria Low GFR ESRD 478 (73%) 0.5 - 28 yrs 35 %/65% 0 - 20 % 8 - 31 % 1 - 28 % 5 %

Renal Sequelae May Develop After a 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 in HUS
1) Elevated WBC count at presentation
2) Prolonged Oliguria or Anuria (or Dialysis)
3) Severe tissue damage on HUS biopsy
Extensive TMA (> 50% of gloms)
Cortical necrosis
4) Low GFR at > 2 year follow-up

Common Symptoms with Renal Damage after HUS
Most common: NONE
High Blood Pressure, Low GFR, Proteinuria usually cause no noticeable signs or symptoms

How Will You Know If Your Child Is at Risk of Future Kidney Damage?
Yearly follow-up with a Pediatric Nephrologist
Yearly blood pressure and urinalysis
GFR and creatinine every few years
1, 3, 5, 10, 15 yrs, …etc.

For More Information See Links Below
Hemolytic Uremic Syndrome
Food Poisoning Law
Food Poison News and Updates

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Hemolytic Uremic Syndrome: A Dangerous Complication of E. coli

by Bill Marler on Jun 03, 2011

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