HUS Seminar

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HUS Seminar

  1. 2. ARF in India <ul><li>HUS most common cause 36% </li></ul><ul><li>Severe Infections 19% </li></ul><ul><li>Indian J Med Res. 1990 Dec;92:404-8. </li></ul><ul><li>Acute renal failure in north Indian children. </li></ul><ul><li>Srivastava RN , Bagga A , Moudgil A . </li></ul>
  2. 3. Conventional Classification <ul><li>D+ </li></ul><ul><li>D- </li></ul>
  3. 4. Kidney International (2006) 70, 423–431.
  4. 5. Classification
  5. 6. Classification
  6. 7. Unclassified S. pneumoniae Complement disorders ADAMTS defect Familial, unexplained Diarrhea, VTEC infection HUS: 95% cases Kidney International (2006) 70: 423–431
  7. 8. HUS in India <ul><li>73 patients (1980-1988) </li></ul><ul><li>Diarrhea prodrome 80% </li></ul><ul><li>Mortality 60% </li></ul><ul><li>Stool culture </li></ul><ul><ul><li>Shigella 7 </li></ul></ul><ul><ul><li>E Coli 11 </li></ul></ul><ul><ul><li>Salmonella 9 </li></ul></ul>
  8. 9. How did these otherwise harmless E. coli become such killers? <ul><li>DNA from a Stx producing bacterium (Shigella dysenteriae type 1) transferred by bacteriophage to E. coli </li></ul><ul><li>This provided E. coli with genes to produce Shiga toxin (Stx), one of the most potent toxins known to man   </li></ul>
  9. 10. Pathophysiology; from diarrhea to dialysis <ul><li>Chain of events: </li></ul><ul><li>usually preceded by colitis caused by Shiga toxin–producing Escherichia coli (STEC). </li></ul><ul><ul><li>inflammation of the colon facilitates systemic absorption of the Stx and lipopolysaccharide (LPS) from the GI tract </li></ul></ul>Andreoli SP: The Pathophysiology of the hemolytic uremic syndrome , Curr Opin Nephrol Hypertens 8:459-64,1999
  10. 12. Pathophysiology; from diarrhea to dialysis contd… <ul><li>toxins bind to globotriaosylceramide (Gb3), a glycolipid receptor molecule on the surface of endothelial cells in the gut, kidney, and occasionally other organs </li></ul><ul><li>Differential expression of Gb3 on glomerular capillaries compared with other endothelial cells </li></ul>Andreoli SP: The Pathophysiology of the hemolytic uremic syndrome , Curr Opin Nephrol Hypertens 8:459-64,1999
  11. 13. <ul><li>shiga like toxin </li></ul><ul><li>EC injury monocytes or mesangial cells </li></ul><ul><li>NOS IL-8 IL-8, IL-6 </li></ul><ul><li>NO PMN </li></ul><ul><li>activation </li></ul><ul><li>O2 Fe2+ H2O2 protease </li></ul><ul><li>enzyme </li></ul><ul><li>ONOO HO HOCl </li></ul><ul><li>amplication of endothelial cell injury </li></ul><ul><li>microthombi </li></ul>Comprehensive Pediatric Nephrology by Warady & Schafer F; Ist Edition, 2008
  12. 14. Pathophysiology; from diarrhea to dialysis contd… <ul><li>Damaged endothelial cells of the glomerular capillaries release vasoactive and platelet-aggregating substances </li></ul><ul><li>localized intravascular coagulopathy </li></ul><ul><li>glomerular filtration rate is reduced, and renal insufficiency ensues </li></ul>Andreoli SP: The Pathophysiology of the hemolytic uremic syndrome , Curr Opin Nephrol Hypertens 8:459-64,1999
  13. 15. Pathophysiology; <ul><li>Erythrocytes are damaged and fragmented as they traverse the narrowed glomerular capillaries </li></ul><ul><li>Hemolysis may also be a result of lipid peroxidation. </li></ul>
  14. 16. Pathophysiology; <ul><li>Thrombocytopenia is believed to result from </li></ul><ul><li>-platelet destruction, </li></ul><ul><li>-increased consumption, </li></ul><ul><li>-sequestration in the liver and spleen, </li></ul><ul><li>-intrarenal aggregation </li></ul>
  15. 17. PATHOPHYSIOLIOGY aHUS <ul><li>PNEUMOCOCCAL-ASSOCIATED </li></ul><ul><li>Pathogenesis </li></ul><ul><ul><li>microbial neuraminidase exposes Thomsen-Friedenreich (T) antigen </li></ul></ul><ul><ul><li>cryptic T-antigen found on erythrocytes, platelets, and glomeruli </li></ul></ul>Cochran, JB, 2004, Pediatr Nephrol 19:317-321.
  16. 19. Clinical <ul><li>History </li></ul><ul><li>GI prodrome - 4-6 days following exposure to Stx producing E coli and mimic ulcerative colitis, various enteric infections, or appendicitis. </li></ul><ul><li>Diarrhea become hemorrhagic in majority (70%) </li></ul><ul><ul><li>within 1-2 days of onset of diarrhea. </li></ul></ul>Comprehensive Pediatric Nephrology by Warady & Schafer F; Ist Edition, 2008
  17. 20. Clinical <ul><li>History contd... </li></ul><ul><li>Vomiting 30-60% </li></ul><ul><li>Oliguria or Anuria </li></ul><ul><li>Neurologic symptoms 33% </li></ul><ul><ul><li>irritability, seizures, or altered mental status. </li></ul></ul>
  18. 21. Clinical <ul><li>Physical </li></ul><ul><li>inciting prodromal illness </li></ul><ul><li>the end organ in which thrombogenesis is occurring. </li></ul><ul><li>Fever 30% </li></ul><ul><li>GI bleeding </li></ul><ul><li>GI involvement </li></ul><ul><ul><li>May lead to symptoms of an acute abdomen, with occasional peritonitis. </li></ul></ul>
  19. 22. Clinical <ul><li>Physical </li></ul><ul><li>CHF and arrhythmias. </li></ul><ul><li>Microinfarcts in the pancreas </li></ul><ul><ul><li>pancreatitis or rarely, insulin-dependent diabetes mellitus. </li></ul></ul><ul><li>Retinal or vitreous hemorrhages. </li></ul><ul><li>Hypertension and oliguria </li></ul>
  20. 23. Laboratory Studies <ul><li>Hematology </li></ul><ul><li>Anemia and thrombocytopenia, with fragmented RBCs (eg, schistocytes, helmet cells, burr cells). </li></ul><ul><li>WBC differential: </li></ul><ul><ul><li>left shift (ie, immature WBCs, including bands, myelocytes, metamyelocytes </li></ul></ul><ul><li>Coombs test results: negative, except with S pneumoniae –associated hemolytic-uremic syndrome </li></ul>
  21. 24. Peripheral blood smear showing many schistocytes and RBC fragments due to hemolysis, and thrombocytopenia.
  22. 26. Laboratory Studies contd... <ul><ul><li>Reticulocyte count elevated. </li></ul></ul><ul><ul><li>Serum haptoglobin decreased. </li></ul></ul><ul><ul><li>Bilirubin; aminotransferase levels- elevated. </li></ul></ul><ul><ul><li>LDH elevated. </li></ul></ul><ul><ul><li>PT; aPTT normal. </li></ul></ul><ul><ul><li>Fibrin degradation products increased. </li></ul></ul><ul><ul><li>Fibrinogen levels are increased or normal </li></ul></ul>Remuzzi G, Ruggeneti P. The hemolytic uremic syndrome. Kidney Int 1995; 47: 2-19
  23. 27. Laboratory Studies contd... <ul><li>Serum chemistry testing </li></ul><ul><li>-BUN and creatinine levels elevated </li></ul><ul><li>- Hyponatremia, hyperkalemia, hyperphosphatemia, hypocalcemia, and acidosis.  </li></ul><ul><li>-Uric acid level may be increased </li></ul>Remuzzi G, Ruggeneti P. The hemolytic uremic syndrome. Kidney Int 1995; 47: 2-19
  24. 28. Laboratory Studies contd... <ul><li>Urinalysis </li></ul><ul><ul><li>Protein </li></ul></ul><ul><ul><li>Heme </li></ul></ul><ul><ul><li>Bilirubin </li></ul></ul><ul><ul><li>RBCs (dysmorphic) </li></ul></ul><ul><ul><li>WBCs </li></ul></ul><ul><ul><li>Casts - Cellular, granular, pigmented, hyaline </li></ul></ul>
  25. 29. Laboratory Studies contd... <ul><li>Stool testing </li></ul><ul><li>Culture: </li></ul><ul><li>-culture yield is low after 7 days of diarrhea </li></ul><ul><li>-standard method -sorbitol MacConkey (SMAC) agar plates, characteristic sorbitol nonfermenting colonies of STEC O157:H7. </li></ul><ul><li>-Stx - specific antibody testing, gene studies, and enzyme-linked immunosorbent assay (ELISA). </li></ul>
  26. 30. Laboratory Studies contd... <ul><li>I maging Studies </li></ul><ul><li>-CXR- pulmonary congestion or edema, if indicated </li></ul><ul><li>-Abd USG or CT scan – if suspicion of intestinal obstruction or perforation. </li></ul><ul><li>-NCCT or MRI head - CNS symptoms or acute mental status changes. </li></ul><ul><li>-Avoid iodinated contrast or gadolinium in patients with decreased renal function </li></ul>
  27. 31. Laboratory Studies contd... <ul><li>Other Tests </li></ul><ul><ul><li>Hyperkalemia- EKG monitoring. </li></ul></ul><ul><ul><li>Renal biopsy not usually necessary </li></ul></ul><ul><ul><li>(may be C/I due to thrombocytopenia ) </li></ul></ul><ul><ul><li>C3 decreased in Factor H mutation </li></ul></ul>
  28. 32. Glomerular TMA FIBRIN deposits in subendothelial space and in capillaries
  29. 33. Arterial TMA
  30. 34. Cortical Necrosis <ul><li>Focal / Diffuse </li></ul>
  31. 35. Hospital course and Treatment <ul><li>Fluid therapy </li></ul><ul><li>Early and ample hydration with intravenous isotonic saline Fluid </li></ul><ul><li>Monitor hydration status closely and frequently </li></ul><ul><li>Monitor electrolytes </li></ul><ul><li>Supportive fluid therapy for ARF </li></ul>Siegler R, Oakes R: Hemolytic uremic syndrome pathogenesis, treatment and outcome, Curr Opin Pediatr 17:200-04,2005
  32. 36. Even D+ HUS is not benign! <ul><li>Management of acute renal failure </li></ul><ul><li>2/3 of D +  HUS require dialysis </li></ul><ul><li>Dialysis does not alter the course of the disease </li></ul><ul><ul><li>only supports the patient while awaiting resolution of the illness. </li></ul></ul><ul><li>Patients who require dialysis usually need 5-7 days of therapy </li></ul><ul><li>Dialysis duration>14 days- bad prognostic feature </li></ul>Siegler R, Oakes R: Hemolytic uremic syndrome pathogenesis, treatment and outcome, Curr Opin Pediatr 17:200-04,2005
  33. 37. Hospital course and Treatment contd… <ul><li>Management of hematologic abnormalities </li></ul><ul><li>Require packed RBC (PRBC) transfusions </li></ul><ul><li>PRBCs for symptomatic anemia (eg, tachycardia, orthostatic changes in blood pressure or heart rate, congestive heart failure) or if the hematocrit falls rapidly. </li></ul><ul><li>Transfuse platelets if the patient has active bleeding </li></ul><ul><li>Commonly used threshold near 20,000/mcL . </li></ul>Comprehensive Pediatric Nephrology by Warady & Schafer F; Ist Edition, 2008
  34. 38. Hospital course and Treatment contd… <ul><li>Management of hypertension   </li></ul><ul><ul><li>Calcium channel blockers such as amlodipine </li></ul></ul><ul><ul><li>ACE inhibitors are very effective </li></ul></ul><ul><ul><ul><li>Caution in individuals with a decreased glomerular filtration rate (GFR) or with hyperkalemia . </li></ul></ul></ul>
  35. 39. Hospital course and Treatment contd… <ul><li>Nutritional support </li></ul><ul><li>Providing adequate protein and energy intake enterally or parenterally is important to prevent catabolism and promote healing </li></ul><ul><li>Intravenous hyperalimentation due to prolonged diarrhea, colitis, abdominal pain, intestinal ileus, or anorexia </li></ul><ul><li>Lipid infusion may be limited if hyper-triglyceridemia present </li></ul>
  36. 40. Hospital course and Treatment contd… <ul><li>Pain management </li></ul><ul><li>D + hemolytic-uremic syndrome causes an intense colitis-mimic that of an acute abdomen-Evaluate as a surgical emergency </li></ul><ul><li>Acetaminophen may be used. </li></ul><ul><li>Avoid NSAIDs because of nephrotoxicity </li></ul><ul><li>May require opioid medication . </li></ul>
  37. 41. Hospital course and Treatment contd… <ul><li>Special considerations for D - HUS </li></ul><ul><li>Management-controversial </li></ul><ul><li>Discontinue offending agent if a drug-associated cause is identified. </li></ul><ul><li>Treat bacterial infections (eg, S pneumoniae ) promptly and aggressively. </li></ul>
  38. 42. Hospital course and Treatment contd… <ul><li>Plasma Exchange </li></ul><ul><ul><li>most effective therapy for D - HUS.  </li></ul></ul><ul><ul><li>Removes the patient's plasma and replaces it with fresh frozen plasma (FFP) or a similar product. </li></ul></ul><ul><ul><li>Replaces deficient vWF or complements </li></ul></ul><ul><ul><li>Removes IgG vWF/ factor H </li></ul></ul><ul><ul><li>Better than plasma infusions as avoids fluid overload </li></ul></ul><ul><ul><li>Different patients different thresholds </li></ul></ul><ul><ul><li>Initial plasma exchanges </li></ul></ul><ul><ul><ul><li>1.5-2.0 volume </li></ul></ul></ul><ul><ul><ul><li>Daily, replace with plasma </li></ul></ul></ul><ul><ul><ul><li>Later to alternate day or twice weekly regimens </li></ul></ul></ul><ul><li>Role of plasma therapy in neuraminidase-mediated HUS contraindicated. </li></ul><ul><li>  </li></ul>Licht et al. Am J Kidney Dis 2005;45:415-16
  39. 43. Hospital course and Treatment contd… <ul><li>Management of ESRD </li></ul><ul><li>--Supportive therapy; renal replacement therapy </li></ul><ul><li>--TRANSPLANTATION </li></ul><ul><li>D + HUS  </li></ul><ul><ul><li>recurrence rate post KTP-0-1% </li></ul></ul><ul><ul><li>Graft loss due to recurrence-0-1% </li></ul></ul><ul><li>D- HUS </li></ul><ul><ul><li>Recurrence rate- 20-80% </li></ul></ul><ul><ul><li>Graft loss due to recurrence-10-83% </li></ul></ul><ul><ul><li>Liver-Kidney transplantation (replenishes Factor H) </li></ul></ul><ul><li>Cochat P et al . Pediatr Nephrol (2009) 24:2097-2108 </li></ul>
  40. 44. Transplantation in Atypical HUS <ul><li>Living related Kidney transplant contraindicated </li></ul><ul><li>Strategies: </li></ul><ul><ul><li>Liver Kidney transplantation </li></ul></ul><ul><ul><li>Pre transplant plasma exchange with kidney transplant </li></ul></ul>
  41. 45. Transplant Decisions CFH or CFI Mutation* <ul><li>Wait for new Rx </li></ul><ul><li>FH concentrate </li></ul><ul><li>Complement inhibitors </li></ul>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
  42. 46. Hospital course and Treatment contd… <ul><li>Surgical Care </li></ul><ul><li>Severe abdominal pain or other abdominal findings, which may be similar to an acute abdomen.  </li></ul><ul><li>For placement of a dialysis catheter. </li></ul>
  43. 47. Follow-up <ul><li>Regular follow-up </li></ul><ul><ul><li>until their symptoms resolved </li></ul></ul><ul><ul><li>renal function and hematology normalises </li></ul></ul><ul><li>D - HUS  </li></ul><ul><ul><li>persistent and relapsing course </li></ul></ul><ul><ul><li>most require frequent and lifelong follow-up </li></ul></ul>Spizzirri FD et al. Pediatr Nephrol 11:156-60,1997
  44. 48. Deterrence/Prevention <ul><li>General preventive measures </li></ul><ul><li>Avoid </li></ul><ul><li>ingestion of raw or undercooked meat. </li></ul><ul><li>Unpasteurized milk and cheese. </li></ul><ul><li>Antidiarrheal or antimotility agents for diarrhea.  </li></ul><ul><li>Antibiotics for diarrhea unless under the management of a physician. </li></ul><ul><li>Seek medical care immediately for bloody diarrhea . </li></ul><ul><li>Practice good hand-washing technique, especially during outbreaks of diarrhea. </li></ul>Siegler R, Oakes R: Hemolytic uremic syndrome pathogenesis, treatment and outcome, Curr Opin Pediatr 17:200-04,2005
  45. 49. Deterrence/Prevention <ul><ul><li>Early and ample rehydration with isotonic saline is associated with lower risk of developing oligoanuric renal failure </li></ul></ul><ul><ul><li>Monitor fluid status, intake and output closely </li></ul></ul><ul><ul><ul><li>as renal function may change rapidly, requiring adjustments to fluid therapy.  </li></ul></ul></ul><ul><ul><li>Use potassium supplementation with great caution. </li></ul></ul>Siegler R, Oakes R: Hemolytic uremic syndrome pathogenesis, treatment and outcome, Curr Opin Pediatr 17:200-04,2005
  46. 50. Complications <ul><li>Renal system </li></ul><ul><ul><li>Renal insufficiency </li></ul></ul><ul><ul><li>Renal failure </li></ul></ul><ul><ul><li>Hypertension </li></ul></ul><ul><li>CNS </li></ul><ul><ul><li>Mental retardation </li></ul></ul><ul><ul><li>Seizures </li></ul></ul><ul><ul><li>Focal motor deficit </li></ul></ul><ul><ul><li>Optic atrophy </li></ul></ul>Gagnadoux MF et al. Long term outcome of childhood hemolytic uremic syndrome, Clin Nephrol 46:39-49,1996
  47. 51. Complications <ul><ul><li>CNS </li></ul></ul><ul><ul><li>-Cortical blindness </li></ul></ul><ul><li>-Learning disability </li></ul><ul><li>Endocrine system </li></ul><ul><ul><li>Diabetes mellitus </li></ul></ul><ul><ul><li>Pancreatic exocrine insufficiency </li></ul></ul><ul><li>GI system - Intestinal necrosis (> D - HUS) </li></ul><ul><li>Cardiac system - Congestive heart Failure </li></ul>Gagnadoux MF et al. Long term outcome of childhood hemolytic uremic syndrome, Clin Nephrol 46:39-49,1996
  48. 52. Outcome <ul><li>Typical HUS </li></ul><ul><li>Severe condition: </li></ul><ul><li>Acutely 2.5% mortality, significant morbidity </li></ul><ul><li>Long term results (10-20 years after HUS*) </li></ul><ul><li>63%-Complete recovery </li></ul><ul><li>12%-Recovery with proteinuria </li></ul><ul><li>6%- Recovery with proteinuria and HTN </li></ul><ul><li>16%- Recovery with low GFR ± proteinuria or HTN </li></ul><ul><li>3%- ESRD </li></ul><ul><li>Spizzirri et al. Pediatric Nephrology 1996 </li></ul>
  49. 53. Outcome <ul><li>Atypical HUS </li></ul><ul><li>Clinically very severe </li></ul><ul><li>15% died </li></ul><ul><li>25% ESRD 60% major sequelae </li></ul><ul><li>15% renal insufficiency </li></ul><ul><li>1/3 recover without significant renal disease </li></ul><ul><li>most (75%) of these had a single episode </li></ul><ul><li>few (25%) of these had recurrent aHUS </li></ul><ul><li>Taylor et al ; Ped Neph 2004 </li></ul>
  50. 54. Prognosis <ul><ul><li>D + HUS- </li></ul></ul><ul><ul><li>Poor prognostic indicators </li></ul></ul><ul><ul><ul><li>- Elevated WBC count at diagnosis </li></ul></ul></ul><ul><ul><ul><li>-Prolonged anuria > 14 days </li></ul></ul></ul><ul><ul><ul><li>- Dialysis dependence> 14 days </li></ul></ul></ul><ul><ul><ul><li>-Severe prodromal illness </li></ul></ul></ul><ul><ul><ul><li>-Severe hemorrhagic colitis with rectal prolapse or colonic gangrene </li></ul></ul></ul><ul><ul><ul><li>-Severe neurological involvement </li></ul></ul></ul><ul><ul><ul><li>-Persistent proteinuria </li></ul></ul></ul>Garg AX, Suri RS, Barrowman et al. Long term renal prognosis of diarrhoea asso HUS, JAMA 290:1360-70,2003
  51. 55. Prognosis <ul><li>D - HUS- </li></ul><ul><li>- prognosis guarded </li></ul><ul><li>-frequent relapses   </li></ul><ul><li>-higher risk of progression ESRD </li></ul>
  52. 56. Prevention- Can Antibiotics help? <ul><li>VTEC diarrhea- No association between diarrhea & HUS </li></ul><ul><li>Shigella dysent. Type 1 </li></ul><ul><ul><li>Very severe </li></ul></ul><ul><ul><li>Complications and Bacteremia common </li></ul></ul><ul><ul><li>Unless early use of antibiotics </li></ul></ul>
  53. 57. Patient Education <ul><li>Diet </li></ul><ul><ul><li>Low-salt diet </li></ul></ul><ul><ul><li>Adequate diet </li></ul></ul><ul><li>Social worker or psychologist consultation </li></ul>
  54. 58. What is new in D+HUS <ul><li>Synsorb Pk-Diatomaceous silicon diamide linked to oligosacchride chain- avidly bind and neutralize shiga toxin </li></ul><ul><li>Starfish- pentamer- bind 1000 times more efficiently </li></ul><ul><li>Monoclonal antibodies specific for A subunit of ST-2 </li></ul><ul><li>Comprehensive Pediatric Nephrology by Warady & Schafer F; Ist </li></ul><ul><li>Edition, 2008 </li></ul>
  55. 59. What is new in D-HUS <ul><li>ECULIZUMAB- monoclonal antibody against C5 </li></ul><ul><ul><li>Loirat C. Complement and the atypical hemolytic </li></ul></ul><ul><ul><li>uremic syndrome in children. Pediatr Nephrol (2008) </li></ul></ul><ul><ul><li>23: 1957-1972 </li></ul></ul><ul><ul><li>Nurnberger et al. eculizumab for atypical HUS NEJM 2009; 360: 542-4 </li></ul></ul>
  56. 60. What is new in D-HUS <ul><li>Complement factor H concentrate </li></ul><ul><li>Immunosuppression in antibody mediated </li></ul><ul><ul><li>Rituximab (anti CD 20) </li></ul></ul><ul><ul><li>IVIG </li></ul></ul><ul><ul><li>Steroids </li></ul></ul>

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