The document summarizes the pathophysiology, clinical presentation, diagnosis, and management of hemolytic uremic syndrome (HUS). It notes that HUS is most commonly caused by Shiga toxin-producing E. coli infection, with diarrhea as a common prodrome. The Shiga toxin damages endothelial cells leading to thrombocytopenia, hemolytic anemia, and renal impairment. Treatment involves supportive care, dialysis, and plasma exchange or infusion depending on the subtype.

2. ARF in India HUS most common cause 36% Severe Infections 19% Indian J Med Res. 1990 Dec;92:404-8. Acute renal failure in north Indian children. Srivastava RN , Bagga A , Moudgil A .

3. Conventional Classification D+ D-

4. Kidney International (2006) 70, 423–431.

5. Classification

6. Classification

7. Unclassified S. pneumoniae Complement disorders ADAMTS defect Familial, unexplained Diarrhea, VTEC infection HUS: 95% cases Kidney International (2006) 70: 423–431

8. HUS in India 73 patients (1980-1988) Diarrhea prodrome 80% Mortality 60% Stool culture Shigella 7 E Coli 11 Salmonella 9

9. How did these otherwise harmless E. coli become such killers? DNA from a Stx producing bacterium (Shigella dysenteriae type 1) transferred by bacteriophage to E. coli This provided E. coli with genes to produce Shiga toxin (Stx), one of the most potent toxins known to man

10. Pathophysiology; from diarrhea to dialysis Chain of events: usually preceded by colitis caused by Shiga toxin–producing Escherichia coli (STEC). inflammation of the colon facilitates systemic absorption of the Stx and lipopolysaccharide (LPS) from the GI tract Andreoli SP: The Pathophysiology of the hemolytic uremic syndrome , Curr Opin Nephrol Hypertens 8:459-64,1999

12. Pathophysiology; from diarrhea to dialysis contd… toxins bind to globotriaosylceramide (Gb3), a glycolipid receptor molecule on the surface of endothelial cells in the gut, kidney, and occasionally other organs Differential expression of Gb3 on glomerular capillaries compared with other endothelial cells Andreoli SP: The Pathophysiology of the hemolytic uremic syndrome , Curr Opin Nephrol Hypertens 8:459-64,1999

13. shiga like toxin EC injury monocytes or mesangial cells NOS IL-8 IL-8, IL-6 NO PMN activation O2 Fe2+ H2O2 protease enzyme ONOO HO HOCl amplication of endothelial cell injury microthombi Comprehensive Pediatric Nephrology by Warady & Schafer F; Ist Edition, 2008

14. Pathophysiology; from diarrhea to dialysis contd… Damaged endothelial cells of the glomerular capillaries release vasoactive and platelet-aggregating substances localized intravascular coagulopathy glomerular filtration rate is reduced, and renal insufficiency ensues Andreoli SP: The Pathophysiology of the hemolytic uremic syndrome , Curr Opin Nephrol Hypertens 8:459-64,1999

15. Pathophysiology; Erythrocytes are damaged and fragmented as they traverse the narrowed glomerular capillaries Hemolysis may also be a result of lipid peroxidation.

16. Pathophysiology; Thrombocytopenia is believed to result from -platelet destruction, -increased consumption, -sequestration in the liver and spleen, -intrarenal aggregation

17. PATHOPHYSIOLIOGY aHUS PNEUMOCOCCAL-ASSOCIATED Pathogenesis microbial neuraminidase exposes Thomsen-Friedenreich (T) antigen cryptic T-antigen found on erythrocytes, platelets, and glomeruli Cochran, JB, 2004, Pediatr Nephrol 19:317-321.

19. Clinical History GI prodrome - 4-6 days following exposure to Stx producing E coli and mimic ulcerative colitis, various enteric infections, or appendicitis. Diarrhea become hemorrhagic in majority (70%) within 1-2 days of onset of diarrhea. Comprehensive Pediatric Nephrology by Warady & Schafer F; Ist Edition, 2008

20. Clinical History contd... Vomiting 30-60% Oliguria or Anuria Neurologic symptoms 33% irritability, seizures, or altered mental status.

21. Clinical Physical inciting prodromal illness the end organ in which thrombogenesis is occurring. Fever 30% GI bleeding GI involvement May lead to symptoms of an acute abdomen, with occasional peritonitis.

22. Clinical Physical CHF and arrhythmias. Microinfarcts in the pancreas pancreatitis or rarely, insulin-dependent diabetes mellitus. Retinal or vitreous hemorrhages. Hypertension and oliguria

23. Laboratory Studies Hematology Anemia and thrombocytopenia, with fragmented RBCs (eg, schistocytes, helmet cells, burr cells). WBC differential: left shift (ie, immature WBCs, including bands, myelocytes, metamyelocytes Coombs test results: negative, except with S pneumoniae –associated hemolytic-uremic syndrome

24. Peripheral blood smear showing many schistocytes and RBC fragments due to hemolysis, and thrombocytopenia.

26. Laboratory Studies contd... Reticulocyte count elevated. Serum haptoglobin decreased. Bilirubin; aminotransferase levels- elevated. LDH elevated. PT; aPTT normal. Fibrin degradation products increased. Fibrinogen levels are increased or normal Remuzzi G, Ruggeneti P. The hemolytic uremic syndrome. Kidney Int 1995; 47: 2-19

27. Laboratory Studies contd... Serum chemistry testing -BUN and creatinine levels elevated - Hyponatremia, hyperkalemia, hyperphosphatemia, hypocalcemia, and acidosis. -Uric acid level may be increased Remuzzi G, Ruggeneti P. The hemolytic uremic syndrome. Kidney Int 1995; 47: 2-19

28. Laboratory Studies contd... Urinalysis Protein Heme Bilirubin RBCs (dysmorphic) WBCs Casts - Cellular, granular, pigmented, hyaline

29. Laboratory Studies contd... Stool testing Culture: -culture yield is low after 7 days of diarrhea -standard method -sorbitol MacConkey (SMAC) agar plates, characteristic sorbitol nonfermenting colonies of STEC O157:H7. -Stx - specific antibody testing, gene studies, and enzyme-linked immunosorbent assay (ELISA).

30. Laboratory Studies contd... I maging Studies -CXR- pulmonary congestion or edema, if indicated -Abd USG or CT scan – if suspicion of intestinal obstruction or perforation. -NCCT or MRI head - CNS symptoms or acute mental status changes. -Avoid iodinated contrast or gadolinium in patients with decreased renal function

31. Laboratory Studies contd... Other Tests Hyperkalemia- EKG monitoring. Renal biopsy not usually necessary (may be C/I due to thrombocytopenia ) C3 decreased in Factor H mutation

32. Glomerular TMA FIBRIN deposits in subendothelial space and in capillaries

33. Arterial TMA

34. Cortical Necrosis Focal / Diffuse

35. Hospital course and Treatment Fluid therapy Early and ample hydration with intravenous isotonic saline Fluid Monitor hydration status closely and frequently Monitor electrolytes Supportive fluid therapy for ARF Siegler R, Oakes R: Hemolytic uremic syndrome pathogenesis, treatment and outcome, Curr Opin Pediatr 17:200-04,2005

36. Even D+ HUS is not benign! Management of acute renal failure 2/3 of D + HUS require dialysis Dialysis does not alter the course of the disease only supports the patient while awaiting resolution of the illness. Patients who require dialysis usually need 5-7 days of therapy Dialysis duration>14 days- bad prognostic feature Siegler R, Oakes R: Hemolytic uremic syndrome pathogenesis, treatment and outcome, Curr Opin Pediatr 17:200-04,2005

37. Hospital course and Treatment contd… Management of hematologic abnormalities Require packed RBC (PRBC) transfusions PRBCs for symptomatic anemia (eg, tachycardia, orthostatic changes in blood pressure or heart rate, congestive heart failure) or if the hematocrit falls rapidly. Transfuse platelets if the patient has active bleeding Commonly used threshold near 20,000/mcL . Comprehensive Pediatric Nephrology by Warady & Schafer F; Ist Edition, 2008

38. Hospital course and Treatment contd… Management of hypertension Calcium channel blockers such as amlodipine ACE inhibitors are very effective Caution in individuals with a decreased glomerular filtration rate (GFR) or with hyperkalemia .

39. Hospital course and Treatment contd… Nutritional support Providing adequate protein and energy intake enterally or parenterally is important to prevent catabolism and promote healing Intravenous hyperalimentation due to prolonged diarrhea, colitis, abdominal pain, intestinal ileus, or anorexia Lipid infusion may be limited if hyper-triglyceridemia present

40. Hospital course and Treatment contd… Pain management D + hemolytic-uremic syndrome causes an intense colitis-mimic that of an acute abdomen-Evaluate as a surgical emergency Acetaminophen may be used. Avoid NSAIDs because of nephrotoxicity May require opioid medication .

41. Hospital course and Treatment contd… Special considerations for D - HUS Management-controversial Discontinue offending agent if a drug-associated cause is identified. Treat bacterial infections (eg, S pneumoniae ) promptly and aggressively.

42. Hospital course and Treatment contd… Plasma Exchange most effective therapy for D - HUS. Removes the patient's plasma and replaces it with fresh frozen plasma (FFP) or a similar product. Replaces deficient vWF or complements Removes IgG vWF/ factor H Better than plasma infusions as avoids fluid overload Different patients different thresholds Initial plasma exchanges 1.5-2.0 volume Daily, replace with plasma Later to alternate day or twice weekly regimens Role of plasma therapy in neuraminidase-mediated HUS contraindicated. Licht et al. Am J Kidney Dis 2005;45:415-16

43. Hospital course and Treatment contd… Management of ESRD --Supportive therapy; renal replacement therapy --TRANSPLANTATION D + HUS recurrence rate post KTP-0-1% Graft loss due to recurrence-0-1% D- HUS Recurrence rate- 20-80% Graft loss due to recurrence-10-83% Liver-Kidney transplantation (replenishes Factor H) Cochat P et al . Pediatr Nephrol (2009) 24:2097-2108

44. Transplantation in Atypical HUS Living related Kidney transplant contraindicated Strategies: Liver Kidney transplantation Pre transplant plasma exchange with kidney transplant

45. Transplant Decisions CFH or CFI Mutation* Wait for new Rx FH concentrate Complement inhibitors Renal Tx * Plasma exchange before and chronically after Combined Liver-Kidney Tx Pre-operative Plasma exchange Loirat, C et al. Pediatric Transplantation 2008, Saland,et al. JASN 2009

46. Hospital course and Treatment contd… Surgical Care Severe abdominal pain or other abdominal findings, which may be similar to an acute abdomen. For placement of a dialysis catheter.

47. Follow-up Regular follow-up until their symptoms resolved renal function and hematology normalises D - HUS persistent and relapsing course most require frequent and lifelong follow-up Spizzirri FD et al. Pediatr Nephrol 11:156-60,1997

48. Deterrence/Prevention General preventive measures Avoid ingestion of raw or undercooked meat. Unpasteurized milk and cheese. Antidiarrheal or antimotility agents for diarrhea. Antibiotics for diarrhea unless under the management of a physician. Seek medical care immediately for bloody diarrhea . Practice good hand-washing technique, especially during outbreaks of diarrhea. Siegler R, Oakes R: Hemolytic uremic syndrome pathogenesis, treatment and outcome, Curr Opin Pediatr 17:200-04,2005

49. Deterrence/Prevention Early and ample rehydration with isotonic saline is associated with lower risk of developing oligoanuric renal failure Monitor fluid status, intake and output closely as renal function may change rapidly, requiring adjustments to fluid therapy. Use potassium supplementation with great caution. Siegler R, Oakes R: Hemolytic uremic syndrome pathogenesis, treatment and outcome, Curr Opin Pediatr 17:200-04,2005

50. Complications Renal system Renal insufficiency Renal failure Hypertension CNS Mental retardation Seizures Focal motor deficit Optic atrophy Gagnadoux MF et al. Long term outcome of childhood hemolytic uremic syndrome, Clin Nephrol 46:39-49,1996

51. Complications CNS -Cortical blindness -Learning disability Endocrine system Diabetes mellitus Pancreatic exocrine insufficiency GI system - Intestinal necrosis (> D - HUS) Cardiac system - Congestive heart Failure Gagnadoux MF et al. Long term outcome of childhood hemolytic uremic syndrome, Clin Nephrol 46:39-49,1996

52. Outcome Typical HUS Severe condition: Acutely 2.5% mortality, significant morbidity Long term results (10-20 years after HUS*) 63%-Complete recovery 12%-Recovery with proteinuria 6%- Recovery with proteinuria and HTN 16%- Recovery with low GFR ± proteinuria or HTN 3%- ESRD Spizzirri et al. Pediatric Nephrology 1996

53. Outcome Atypical HUS Clinically very severe 15% died 25% ESRD 60% major sequelae 15% renal insufficiency 1/3 recover without significant renal disease most (75%) of these had a single episode few (25%) of these had recurrent aHUS Taylor et al ; Ped Neph 2004

54. Prognosis D + HUS- Poor prognostic indicators - Elevated WBC count at diagnosis -Prolonged anuria > 14 days - Dialysis dependence> 14 days -Severe prodromal illness -Severe hemorrhagic colitis with rectal prolapse or colonic gangrene -Severe neurological involvement -Persistent proteinuria Garg AX, Suri RS, Barrowman et al. Long term renal prognosis of diarrhoea asso HUS, JAMA 290:1360-70,2003

55. Prognosis D - HUS- - prognosis guarded -frequent relapses -higher risk of progression ESRD

56. Prevention- Can Antibiotics help? VTEC diarrhea- No association between diarrhea & HUS Shigella dysent. Type 1 Very severe Complications and Bacteremia common Unless early use of antibiotics

57. Patient Education Diet Low-salt diet Adequate diet Social worker or psychologist consultation

58. What is new in D+HUS Synsorb Pk-Diatomaceous silicon diamide linked to oligosacchride chain- avidly bind and neutralize shiga toxin Starfish- pentamer- bind 1000 times more efficiently Monoclonal antibodies specific for A subunit of ST-2 Comprehensive Pediatric Nephrology by Warady & Schafer F; Ist Edition, 2008

59. What is new in D-HUS ECULIZUMAB- monoclonal antibody against C5 Loirat C. Complement and the atypical hemolytic uremic syndrome in children. Pediatr Nephrol (2008) 23: 1957-1972 Nurnberger et al. eculizumab for atypical HUS NEJM 2009; 360: 542-4

60. What is new in D-HUS Complement factor H concentrate Immunosuppression in antibody mediated Rituximab (anti CD 20) IVIG Steroids