تشخیص

Hemolytic-Uremic Syndrome

§    Hemolytic microangiopathic anemia:           

§    Thrombocytopenia

§    Uremia: acute renal failure

§    Further symptoms / complications:

n    Central nervous system (seizures, hemorrhages)

n    Hypertension and heart failure

n    Liver / Pancreas (with diabetes mellitus)

n    Eye: retinal bleedings

n   

HUS: D+ and D-

 n  D+ = Diarrhea-positive

  n  Verotoxin (or Shigatoxin)-producing E. Coli

  n  Other bacteria, e.g. Shigella....

  n  Hemorrhagic colitis: mild – severe, intussusception

 n  D- = Diarrhea-negative

  n  Pneumococcal infections

  n  Inherited and/or recurrent forms: e.g. complement (factor I/H) or vWF-cleavage  protease deficiency

  n  Others: Pregnancy, drugs …

  n  „ Many“ cases of unknown cause

n      
  What is Post-Diarrheal  Hemolytic Uremic Syndrome (D+HUS) and where did it come from ?

 n  The syndrome includes:

 n  Acute kidney failure

 n  Hemolytic anemia

 n   Thrombocytopenia (low platelet count)

        n  Most common cause of acute renal (kidney) failure in young children; also occurs in older children and adults

  Major Causes of TTP-HUS

  n  Idiopathic: 37%

  n  Drug-Associated: 13%

   n  Cyclosporine

   n  Tacrolimus

   n  Mitomycin C

   n  Bleomycin and cisplatin

   n  Quinine

  n  Autoimmune Disease: 13%

   n  Scleroderma

   n  SLE

 §  Familial(AR-AD)

  n  Infection: 9%

   n  Viral(HIV,EBV,…)

   n  Streptococcus pneumoniae

  n  Bloody Diarrhea Prodrome: 6%

   n  Shiga toxin production (ex: E. coli 0157:H7)

   n  Shigella dysenteriae type 1

  n  Pregnancy/Postpartum: 7%

  n  Hematopoietic cell transplantation: 4%

  Classic Symptoms of  TTP-HUS

 n  Microangiopathic hemolytic anemia (MAHA)

 n  Thrombocytopenia

 n  Acute renal insufficiency (more common in HUS)

 n  Neurologic abnormalities (more common in TTP)

 n  Fever

    Signs and Symptoms

  n  Diarrhea (usually bloody) with severe pain;  Dehydration

  n  Pallor

  n  Bruises,petechiae

  n  Seizures and/or coma (occasionally)

  n  Little (oliguria) or no (anuria) urine

  n  High blood pressure ,edema

  n  Pancreatic damage (diabetes)

  n  Hepatosplenomegaly

  n  Irritability,weakness,lethargy

    Pathogenic Cascade; from diarrhea to dialysis

 n Chain of events:

  n   ingestion of Stx producing E. coli

 n  multiplication in bowel

 n  absorption of Stx into circulation

  pathogenic cascade, cont.

 n Chain of events, cont.:

 n attachment of Stx to receptors in kidney, and occasionally other organs

 n  movement of toxin into cells

 n cell injury or death

     pathogenic cascade, cont. the end result is:

 n  hemorrhagic colitis (bloody diarrhea)

 n  kidney injury, causing acute renal failure

 n damage of red blood cells causing anemia

 n trapping and destruction of platelets causing bleeding

 n occasional damage to other organs (brain, pancreas, heart, lungs, eyes)

        Labs to Look For

 n  Schistocytes,helmet cells,burr cells,fragmented RBC on peripheral smear

 n  Elevated LDH,Retic count and leukocytosis

 n  Decreased Haptoglobin

 n  Increased Creatinine

 n  Thrombocytopenia

 n   Hb level(5-9g/dl)

 n  Coombs test (neg.),PT and PTT(normal)

 n  Urinalysis (microscopic hematuria and proteinuria)

 n  Differential Diagnosis of Thrombotic Microangiopathy:

  n  Typical HUS (Shiga/vero toxin-related or rarely Strep. pneumoniae)

  n  TTP (ADAMTS13 primary deficiency or inhibitor)

  n  Atypical HUS (mostly complement-mediated)

  n  Others: defective inborn errors of cobalamine metabolism, quinine-induced,    other drugs, HIV, malignancy, pregnancy/pre-eclampsia, SLE, scleroderma crisis    and antiphospholipid antibody syndrome.

           T.S. Jokiranta et al. Molecular Immunology 44 (2007). 3889-3900.

  Treatment

 n  Supportive care

 n  Attention to salt and water balance

 n  Dialysis for kidney failure

 n  Blood transfusions for anemia

 n  Platelet transfusions for bleeding

 n  Aggressive nutritional support [TPN]

 n  Treatment of high blood pressure

 n  Treatment of seizures

 n  Shiga toxin-binding resin ?

 n  Plasmapheresis ?

 n  FFP ?

 n Plasma Exchange

 n Initially performed daily until platelet count normalizes and hemolysis i mproved

 n Average of 7-16 daily exchanges needed

  If Plasma Exhange Does not Work  (occurs in 10-20% of patients)

 n Increase to twice daily Plasma Exchange

 n Rituximab +/- cyclophosphamide

 n Vincristine

 n Intravenous immune globulin

 n Cyclosporine (* can cause TTP *)

   HUS: Indications for dialysis modality since 1995 (1)

 n  Peritoneal dialysis: „in general“ first choice

 n  On ICU: CAPD

 n  On ward: mainly automated PD

 n  Hemodialysis if

 n  „older“ patient in „good general condition“ not requiring care in intensive  care unit

 n  D-HUS and plasma-exchange (PEX) anticipated

 n  life-threatening hyperkalemia

  HUS: Indications for dialysis  modality since 1995 (2)

 n  Continuous veno-venous hemo(dia)filtration if

 n „in bad general condition“ (+/- PEX)

 n severe colitis

 n  Plasma-exchange (PEX) or plasma infusion if

 n D-HUS and inherited type / complement deficiency suspected

            D- or D+ HUS with severe central nervous

         system symptoms, e.g. impaired consciousness, neurological deficit

   Acute PD

 n  before 1995:

  n  „stiff“ Cook-catheter or

  n  „soft“catheter, inserted with trocar or

  n  Tenckhoff

  n  since 1995:

  n  only Tenckhoff catheter

  n  surgically placed by the surgeon (and the

            nephrologist also in theatre) under general

        anasthetic; at the same time insertion of

         central venous line

        Acute and chronic PD

 n  Tenckhoff catheter:

   HUS: clinical complications (1)

  n  Hypertension: requiring medication

  n  Cardiomyopathy:

  n  Pancreatitis: Amylase ↑

  n  Hepatopathy: Transaminases ↑

    HUS: clinical complications (2)

 n  Gastrointestinal tract: n = 4 (all D+)

 n  2 intussusception

 n  1 rectum perforation

 n  1 severe colitis

 n  Severe central nervous system: n = 7

 n  4 D+:   3: remission,  

 n  3 D-:    2: sequelae (pneumococcal meningitis,

                                     massive hemorrhage), (SLE)

 n  Retinal bleeding: n = 2 (all D+)

       Prognosis of HUS

 n With HUS caused by E. Coli O157:H7:

 n Mortality occurs in up to 3-5% of patients.

 n 20% will develop CKD leading to ESRD. 

 n With HUS associated with S. dysenteriae:

 n Mortality is greater, approaching 7%.

 n 40% develop CKD.

 n With non-diarrhea associated HUS:

 n Mortality up to 25% in acute illness.

 n Up to 50% will require continued RRT.

  Outcomes

 n  Death in 3-5%, due to:

 n Brain damage (stroke and/or brain swelling)

 n Bowel necrosis and perforation

 n Heart damage

 n Lung injury

 n Multiorgan injury (seen in most fatal cases)

  outcomes, cont.

 n Those who survive may be left with:

 n  permanent kidney damage

 n brain damage

 n  hypertension

 n diabetes

     Monitoring
 

 n  Chronic kidney failure may occur decades later (due to hyperfiltration injury)

 n most common in those who had prolonged kidney failure (oligoanuria) >10 days

 n proteinurea (protein in the urine) is an early sign

     monitoring, cont.

 n  Hypertension may begin years later (in those with chronic kidney damage)

         n  Diabetes can latter occur (in those with pancreatic injury)

       Conclusions (1): HUS

 n  Incidence:

 n D+ >>> D- (over the last 35 years)

 n  80% require dialysis

 n  Outcome: D+ >> D-

 n Patient survival

 n Recovery of renal function

      Conclusions (2):  HUS – PD

  n  Surgically placed Tenckhoff-catheter:

  n  Simple technique

  n  High efficacy

  n  Low frequency of side effects / complications       

 n  PD in HUS is

 n  safe

 n  efficient

 n  convenient

 n      economic

     Summary

 n  D+ HUS is a life threatening complication of Stx producing E. coli and shigella,…

 n  It occurs primarily in infants and young children, but also affects adults

 n  Is fatal 3-5% of victims        

 n  Survivors (30-50%) are left with chronic kidney damage that can be progressive  later in life

 n  Life long monitoring is necessary