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.

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

6. Normal
Kidney
Structure and
Function

7. Renal Artery
• Takes blood into kidney
Renal Vein
• Takes blood from
kidney
Ureter
• Takes urine to the
bladder

8. Renal
Cortext
• Where
blood is
filtered
into urine

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)

15. Function: Urinalysis

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

22. Micrograph of
TMA in
Glomerulus

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

29. Clinical
Findings
in Acute HUS
Renal

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?

44. Rarity of
Disease

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.