Hemolytic Uremic Syndrome (HUS) (1).pptx
Acute hemolytic uremic syndrome (HUS). Post-diarrheal hemolytic uremic syndrome (D+HUS) is a severe, life-threatening complication that occurs in about 10 percent of those infected with E. coli O157:H7 or other Shiga toxin-producing (Stx) E. coli (STEC). The cascade of events leading to HUS begins with ingestion of Stx-producing E. coli (e.g., E. coli O157: H7) in contaminated food, beverages, animal to person, or person-to-person transmission. The bacteria rapidly multiply in the gut, causing inflammation and diarrhea (colitis) as they tightly bind to cells that line the large intestine. This snug attachment becomes a route for the toxin to travel from the gut into the bloodstream, where it attaches to weak receptors on white blood cells (WBCs). From there, WBCs carry the toxin to the kidneys and other organs. To induce toxicity in target cells, Shiga toxins must first bind to specific receptors on their surface (Gb3 receptors). Organ injury is primarily a function of Gb3 receptor location and density. They are found on epithelial, endothelial, mesangial, and glomerular cells of the kidney, as well as microvascular endothelial cells of the brain and intestine. Because this attachment causes these organs to be susceptible to the toxicity of Shiga toxins, this distribution explains the involvement of the gut, kidney, and brain in STEC-associated hemolytic uremic syndrome (HUS). Within the target organ, Shiga toxins disrupt the cellular machinery, resulting in cell injury and/or death. Within the intestine, infectious bacterial lesions cause derangements in the intestinal lining, disrupting the structure of the villi, affecting absorption in the gut, and eventually leading to watery diarrhea. Damage to the intestinal endothelium also causes mucosal/submucosal edema and, hemorrhage, introducing blood into the diarrhea. Within the circulatory system, Shiga toxins are directly involved in platelet activation and aggregation (clot formation). The thrombotic microangiopathy that characterizes hemolytic uremic syndrome (HUS) occurs when platelet microthrombi (tiny clots) form in the walls of small blood vessels (arterioles and capillaries) causing platelet consumption. This pathologic reduction in platelets is called thrombocytopenia and is one of the hallmarks of HUS. Within the microvasculature of the kidney these clots disturb blood flow to the organ, causing acute kidney injury and kidney failure.
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Hemolytic Uremic Syndrome (HUS) (1).pptx
- 1. Hemolytic Uremic Syndrome (HUS) The Effects and Long-Term Health Implications
- 2. Table of Contents Overview of Hemolytic Uremic Syndrome (HUS) Mechanism of HUS Development The Effects of HUS on the Organ Body Kidney Structure and Function Studies and Findings on HUS Long-term Effects and Consequences of HUS
- 3. HUS is a severe, life-threatening complication that occurs in about 10% of individuals infected with certain strains of E. coli, such as E. coli O157:H7. WHAT IS HEMOLYTIC UREMIC SYNDROME (HUS)?
- 4. Mechanism of HUS Development Ingestion of Shiga toxin (Stx)- producing E. coli in contaminated food, beverages, or transmission Shiga toxin- producing E. coli rapidly multiply in the intestine, leading to colitis (diarrhea). The toxin tightly binds to cells lining the large intestine and gets absorbed into the systemic circulation. Once in the bloodstream, the toxin attaches to receptors on white blood cells (WBC) and is transported to the kidneys, where it targets avid Gb3 receptors.
- 5. Recruit more doctors. Our first key focus. Measuring Kidney Structure and Function • Structure ⚬ Renal ultrasound ⚬ Renal biopsy • Function ⚬ Glomerular filtration rate ⚬ Blood and urine creatinine ⚬ Urinalysis
- 7. Renal Artery • Takes blood into kidney Renal Vein • Takes blood from kidney Ureter • Takes urine to the bladder
- 9. Normal Kidney • Each kidney contains thousands of filtering units called nephrons. • The glomerulus, located in Bowman's capsule, is the main filter responsible for waste removal from the blood into the urine. Glomerulus
- 10. Normal Kidney
- 11. • Provides information about: ⚬ Size ⚬ Echogenicity ⚬ Stones/Scars ⚬ Obstruction • Provides information about function Structure: Renal Ultrasound
- 12. Structure: Kidney Biopsy Normal Glomerulus Acute HUS Glomerulus Courtesy of JC Jennette, MD, UNC-Chapel Hill
- 13. • The rate at which the kidney filters blood • Normal GFR = 90–150 ml/min/1.73m2* • The most accurate measure of kidney function Function: Glomerular Filtration Rate (GFR)
- 14. Function: 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)
- 16. What Goes Wrong During HUS? • At the cell and organ level ⚬ Pathology and Pathophysiology • At the patient level ⚬ Clinical findings
- 17. • The pathologic lesion of HUS • E. coli Shiga-toxin 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) Thrombotic Microangiopathy (TMA)
- 18. HUS Pathogensis
- 19. • HUS primarily targets the kidneys, leading to acute kidney injury (AKI) and potentially permanent kidney damage. • The toxin produced by certain strains of E. coli leads to the formation of blood clots in the small blood vessels of the kidneys, impairing their ability to filter waste products and excess fluid from the blood. • The damaged kidney cells and reduced blood flow can result in decreased urine output, leading to anuria (no urine output) or oliguria (decreased urine output). Kidneys
- 20. The Kidney in HUS
- 21. Red Blood Cells + Platelets • The toxin can directly damage red blood cells, leading to their destruction, a condition known as hemolytic anemia. • As damaged red blood cells try to pass through partially blocked blood vessels, they may rupture, causing further destruction and exacerbating anemia. • HUS can cause damage to blood platelets, which are essential for normal blood clotting. The damaged or trapped platelets can decrease their numbers, affecting the body's ability to control bleeding. Normal Glomerular blood vessel Damaged Glomerular blood vessel
- 23. Micrograph of TMA in Renal Artery
- 24. Electron Micrograph of Fibrin Clot and Red Blood Cells
- 25. 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
- 26. Clinical Findings in Acute HUS • Serum creatinine level • GFR • Blood Pressure • Urine Protein • Urine output
- 27. Normal Kidney
- 28. Normal Kidney
- 30. • •
- 31. Other Organs Involved in Acute HUS
- 32. Why the Kidney? Why Children? • Children get E.coli O157 infections: ⚬ Peak Age = 1-6 years old • The Cell Receptor for Shigatoxin: Gb3 ⚬ Gb3 concentrations are: ￭ Higher in the Kidney ￭ Higher in Children
- 33. 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
- 34. Six months after HUS
- 35. 5 Years After HUS: Possible Outcomes
- 36. 10-30 Years After HUS
- 37. • Glomerular Filtration Rate (GFR) • Urinalysis: Proteinuria • Blood Pressure • Renal Biopsy How Do We Study the Effects (Sequelae) of HUS?
- 38. • 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 GFR after HUS
- 39. • Causes in general ⚬ Infection, renal inflammation, fever, etc. • After HUS: Proteinuria ⚬ Hyperfiltration Proteinuria After HUS
- 40. • ACE Inhibitors (ACEIs) ⚬ Blood Pressure Medications • ACEIs also decrease • Renal Hyperfiltration • ACEIs slow damage due to Hyperfiltration Proteinuria and ACE Inhibitors
- 41. 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
- 42. Renal Biopsy • To evaluate structural damage after HUS • Useful in predicting future problems • Does not provide information about the function • Rarely done in the U.S. ?(except in research)
- 43. • Rarity of Disease • Variation in ⚬ Disease Severity and E. coli virulence ⚬ Measuring Outcomes • Lack of long-term follow-up by patients Why Is It Difficult to Interpret Outcome Studies in HUS?
- 45. • 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 Evaluation of HUS Outcomes
- 46. A Word About Study Size
- 47. • Measures used most consistently • Hypertension • Proteinuria • Low GFR • ESRD (End Stage Renal Disease) What Do The Outcome Studies Show So Far?
- 48. Recruit more doctors. Our first key focus. Outcome Studies of Note • E. coli-associated patients only • Follow-up > 5 years • Study Assessed ⚬ Hypertension ⚬ Proteinuria ⚬ Renal Function ⚬ Evaluated outcome predictors
- 49. 9 Outcome Studies on E. coli-related HUS Published 1988–1998
- 50. 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.”
- 51. • Elevated WBC count at presentation • Prolonged Oliguria or Anuria (or Dialysis) • Severe tissue damage on HUS biopsy ⚬ Extensive TMA (> 50% of gloms) ⚬ Cortical necrosis • Low GFR at > 2-year follow-up Predictors of Renal Damage in HUS
- 52. • Most common: NONE • High Blood Pressure, Low GFR, Proteinuria usually cause no noticeable signs or symptoms Common Symptoms with Renal Damage after HUS
- 53. 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 years,… etc.