Hemolytic Uremic Syndrome: A Dangerous Complication of E. coli

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In this presentation provided by the nation's foremost food poison law firm - Marler Clark, Hemolytic Uremic Syndrome (HUS) is explained. HUS is a rare and highly dangerous result of an E. coli infection and can result in acute kidney failure

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Hemolytic Uremic Syndrome: A Dangerous Complication of E. coli

  1. 1. Long-Term Health Implications Hemolytic Uremic Syndrome (HUS)
  2. 2. Normal Kidney Structure and Function
  3. 3. Normal Kidney <ul><li>Renal Artery </li></ul><ul><li>Takes blood into kidney </li></ul><ul><li>Renal Vein </li></ul><ul><li>Takes blood from kidney </li></ul><ul><li>Ureter </li></ul><ul><li>Takes urine to the bladder </li></ul>
  4. 4. From “The Human Body, Dorling Kindersly Limited, London 1995 Blood In Blood Out Urine Out <ul><li>Renal Cortex </li></ul><ul><li>Where the blood is filtered into urine </li></ul>
  5. 5. Normal Kidney The Human Body, Dorling Kindersly Limited, London 1995 <ul><li>Glomerulus </li></ul><ul><li>The structure which filters blood into urine </li></ul>
  6. 6. Normal Kidney Courtesy of JC Jennette, MD, UNC-Chapel Hill The Human Body, Dorling Kindersly Limited, London 1995
  7. 7. Measuring Kidney Structure and Function <ul><li>Structure </li></ul><ul><ul><li>Renal ultrasound </li></ul></ul><ul><ul><li>Renal biopsy </li></ul></ul><ul><li>Function </li></ul><ul><ul><li>Glomerular filtration rate </li></ul></ul><ul><ul><li>Blood and urine creatinine </li></ul></ul><ul><ul><li>Urinalysis </li></ul></ul>
  8. 8. Structure: Renal Ultrasound <ul><li>Provides information about: </li></ul><ul><ul><li>Size </li></ul></ul><ul><ul><li>Echogenicity </li></ul></ul><ul><ul><li>Stones/Scars </li></ul></ul><ul><ul><li>Obstruction </li></ul></ul><ul><li>Provides information about function </li></ul>Courtesy S. Williamson MD, U of New Mexico
  9. 9. Structure: Kidney Biopsy Normal Glomerulus Acute HUS Glomerulus Courtesy of JC Jennette, MD, UNC-Chapel Hill
  10. 10. Function: Glomerular Filtration Rate (GFR) <ul><li>The rate at which blood is filtered by the kidney </li></ul><ul><li>Normal GFR = 90–150 ml/min/1.73m2* </li></ul><ul><li>The most accurate measure of kidney function </li></ul>*GFR is usually expressed in terms of average adult body surface area: meters squared
  11. 11. Creatinine <ul><li>A by-product of normal muscle metabolism </li></ul><ul><li>Blood or 24-hour urine levels are used to estimate GFR </li></ul><ul><ul><li>Most common </li></ul></ul><ul><ul><li>Easily obtained </li></ul></ul><ul><ul><li>Overestimates actual kidney function (GFR) </li></ul></ul>
  12. 12. <ul><li>A Window Into the Kidney’s Health </li></ul>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)
  13. 13. What Goes Wrong During HUS? <ul><li>At the cell and organ level </li></ul><ul><ul><li>Pathology and Pathophysiology </li></ul></ul><ul><li>At the patient level </li></ul><ul><ul><li>Clinical findings </li></ul></ul>
  14. 14. Thrombotic Microangiopathy (TMA) <ul><li>The pathologic lesion of HUS </li></ul><ul><li>E. Coli Shigatoxin damages endothelial cells </li></ul><ul><ul><li>Endothelial swelling narrows vessel lumen </li></ul></ul><ul><ul><li>Platelet/fibrin clots form blocking blood flow </li></ul></ul><ul><li>Poor blood flow </li></ul><ul><ul><li>Low tissue oxygen (hypoxia) </li></ul></ul><ul><li>Hypoxia </li></ul><ul><ul><li>Cell dysfunction </li></ul></ul><ul><ul><li>Cell necrosis (death) </li></ul></ul>
  15. 15. 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
  16. 16. 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
  17. 17. Micrograph of TMA in Glomerulus Courtesy of JC Jennette, MD, UNC-Chapel Hill Glomerular Light Microscopy Normal Capillary TMA Capillary Lumen Subendothelial Expansion
  18. 18. 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
  19. 19. Electron Micrograph of Fibrin Clot and Red Blood Cells Fibrin Strands Red Blood Cells Courtesy of P Tarr MD, Univ of Washington
  20. 20. Tissue Damage vs Necrosis <ul><li>HUS induced hypoxia: “Cell Suffocation” </li></ul><ul><li>Tissue injury without loss of structure </li></ul><ul><ul><li>Repairable </li></ul></ul><ul><li>Tissue death (necrosis*) leads to: </li></ul><ul><ul><li>Scar formation </li></ul></ul><ul><ul><li>Permanent injury </li></ul></ul><ul><ul><li>Loss of function </li></ul></ul>* Acute Tubular Necrosis (ATN) is an exception to this
  21. 21. Clinical Findings in Acute HUS <ul><li>Serum creatinine level </li></ul><ul><li>GFR </li></ul><ul><li>Blood pressure </li></ul><ul><li>Urine protein </li></ul><ul><li>Urine output </li></ul>
  22. 22. Normal Kidney <ul><li>Serum Cr </li></ul>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
  23. 23. Acute HUS <ul><li>Abnormalities </li></ul>- 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
  24. 24. <ul><li>Oliguria (Low Urine Output) </li></ul>Clinical Findings in Acute HUS Renal Frequency (of patients) Dialysis Blood Transfusion Platelet Transfusion Hypertension Death 70% 50% 70% 30% 30% 4%
  25. 25. 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
  26. 26. Why the Kidney? Why Children? <ul><li>Children get E. coli O157 infections: </li></ul><ul><ul><li>Peak age = 1-6 years </li></ul></ul><ul><li>The cell receptor for Shigatoxin: Gb3 </li></ul><ul><ul><li>Gb3 concentrations are: </li></ul></ul><ul><ul><ul><li>Higher in the Kidney </li></ul></ul></ul><ul><ul><ul><li>Higher in Children </li></ul></ul></ul>
  27. 27. What Happens to the Kidney as HUS Resolves? <ul><li>Areas of Cell Hypoxia repair to normal </li></ul><ul><li>Areas of TMA mostly repair to normal </li></ul><ul><li>Areas of Necrosis form Scar tissue </li></ul>
  28. 28. What Happens to the Kidney as HUS Resolves? <ul><li>Kidney compensation for scar tissue: </li></ul><ul><ul><li>Normal areas work harder: Hyperfiltration </li></ul></ul><ul><li>Excessive Hyperfiltration leads to: </li></ul><ul><ul><li>Progressive Glomerular Scarring!!! </li></ul></ul>
  29. 29. 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
  30. 30. 5 Years After HUS: Possible Outcomes III. Significant Hyperfiltration I. None/Minimal Hyperfiltration II. Moderate Hyperfiltration
  31. 31. 10-30 Years After HUS Chronic Renal Failure 4.0 NO Maybe? Probable Serum Cr 28 GFR U Prot Elevated BP High
  32. 32. How Do We Study the Effects (Sequelae) of HUS? <ul><li>Glomerular Filtration Rate (GFR) </li></ul><ul><li>Urinalysis: Proteinuria </li></ul><ul><li>Blood Pressure </li></ul><ul><li>Renal Biopsy </li></ul>
  33. 33. GFR After HUS <ul><li>The most accurate method of following actual renal function </li></ul><ul><li>Methods </li></ul><ul><ul><li>Iothalamate, Inulin, Cr Clearance, EDTA, or DPTA </li></ul></ul><ul><ul><li>Time consuming </li></ul></ul><ul><ul><li>Require either an IV line and/or long urine collection </li></ul></ul>
  34. 34. Proteinuria After HUS <ul><li>Causes in general </li></ul><ul><ul><li>Infection, renal inflammation, fever, etc. </li></ul></ul><ul><li>After HUS: Proteinuria </li></ul><ul><ul><li>Hyperfiltration </li></ul></ul>
  35. 35. Proteinuria and ACE Inhibitors <ul><li>ACE Inhibitors (ACEIs) </li></ul><ul><ul><li>Blood Pressure Medications </li></ul></ul><ul><li>ACEIs also decrease Renal Hyperfiltration </li></ul><ul><li>ACEIs slow damage due to Hyperfiltration </li></ul>
  36. 36. Blood Pressure <ul><li>New High Blood Pressure after HUS may be a sign of permanent kidney damage </li></ul><ul><li>Renal scars cause high blood pressure through </li></ul><ul><ul><li>Renin </li></ul></ul><ul><li>ACEIs block Renin action </li></ul>
  37. 37. Renal Biopsy <ul><li>To evaluate structural damage after HUS </li></ul><ul><li>Useful in predicting future problems </li></ul><ul><li>Does not provide information about function </li></ul><ul><li>Rarely done in the U.S. (except in research) </li></ul>
  38. 38. Why Is It Difficult to Interpret Outcome Studies in HUS? <ul><li>Rarity of Disease </li></ul><ul><li>Variation in </li></ul><ul><ul><li>Disease Severity and E. Coli virulence </li></ul></ul><ul><ul><li>Measuring Outcomes </li></ul></ul><ul><li>Lack of long term follow-up by patients </li></ul>
  39. 39. Rarity of Disease <ul><li>Incidence </li></ul><ul><li>(cases/100,000 children/yr) </li></ul>HUS ALL (Leukemia) Congenital Heart Disease Urinary Tract Infection 2 13 100 225
  40. 40. Evaluation of HUS Outcomes <ul><li>Renal Function </li></ul><ul><ul><li>GFR by serum Cr, urine CrCl, Iothalamate, EDTA, etc. </li></ul></ul><ul><ul><li>Renal Plasma Flow </li></ul></ul><ul><ul><li>Renal Concentrating Ability </li></ul></ul><ul><li>Proteinuria </li></ul><ul><ul><li>Dipstick </li></ul></ul><ul><ul><li>U Prot / Cr ratio </li></ul></ul><ul><ul><li>24 hr urine protein </li></ul></ul><ul><li>Renal Biopsy </li></ul>
  41. 41. A Word About Study Size <ul><li>Number Followed </li></ul>Number Abnormal Percentage Abnormal 1 1 10 100 1000 1 10% 1% 0.1%
  42. 42. What Do The Outcome Studies Show So Far? <ul><li>Measures used most consistently </li></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Proteinuria </li></ul></ul><ul><ul><li>Low GFR </li></ul></ul><ul><ul><li>ESRD (End Stage Renal Disease) </li></ul></ul>
  43. 43. Outcome Studies of Note <ul><li>E. coli associated patients only </li></ul><ul><li>Follow-up > 5 years </li></ul><ul><li>Study Assessed </li></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Proteinuria </li></ul></ul><ul><ul><li>Renal Function </li></ul></ul><ul><ul><li>Evaluated outcome predictors </li></ul></ul>
  44. 44. 9 Outcome Studies on E. coli- related HUS Published 1988–1998 <ul><li># Patients Followed </li></ul>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 %
  45. 45. Renal Sequelae May Develop After a Period of Normal Renal Tests <ul><li>Siegler, Utah, 1991 </li></ul>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.”
  46. 46. Predictors of Renal Damage in HUS <ul><li>1) Elevated WBC count at presentation </li></ul><ul><li>2) Prolonged Oliguria or Anuria (or Dialysis) </li></ul><ul><li>3) Severe tissue damage on HUS biopsy </li></ul><ul><ul><li>Extensive TMA (> 50% of gloms) </li></ul></ul><ul><ul><li>Cortical necrosis </li></ul></ul><ul><li>4) Low GFR at > 2 year follow-up </li></ul>
  47. 47. Common Symptoms with Renal Damage after HUS <ul><li>Most common: NONE </li></ul><ul><li>High Blood Pressure, Low GFR, Proteinuria usually cause no noticeable signs or symptoms </li></ul>
  48. 48. How Will You Know If Your Child Is at Risk of Future Kidney Damage? <ul><li>Yearly follow-up with a Pediatric Nephrologist </li></ul><ul><li>Yearly blood pressure and urinalysis </li></ul><ul><li>GFR and creatinine every few years </li></ul><ul><ul><li>1, 3, 5, 10, 15 yrs, …etc. </li></ul></ul>
  49. 49. For More Information See Links Below <ul><li>Hemolytic Uremic Syndrome </li></ul><ul><li>Food Poisoning Law </li></ul><ul><li>Food Poison News and Updates </li></ul>

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