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

Hemolytic Uremic Syndrome: A Dangerous Complication of E. coli

More Related Content

What's hot

Similar to Hemolytic Uremic Syndrome: A Dangerous Complication of E. coli

More from Bill Marler

Recently uploaded

Hemolytic Uremic Syndrome: A Dangerous Complication of E. coli