Hemolytic-uremic syndrome

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Overview
In medicine, hemolytic-uremic syndrome (or haemolytic-uraemic syndrome, abbreviated HUS) is a disease characterized by microangiopathic hemolytic anemia, acute renal failure and a low platelet count (thrombocytopenia).

History

 * Described by Moschowitz in 1925 - disease with hyaline thrombi in many organs
 * Pentad from 1964 case series of 271 published cases:
 * Thrombocytopenia
 * Microangiopathic hemolytic anemia
 * Neurologic symptoms and signs
 * Renal function abnormalities
 * Fever
 * When first described, >90% fatal

HUS first described in 1955 in 5 children with ARF who died with renal cortical necrosis

Epidemiology
HUS has a peak incidence between 6 months and 4 years of age.

HUS and the E. coli infections which caused it have been the source of much negative publicity for the Food and Drug Administration (FDA), meat industries, and fast-food restaurants since the 1990's, especially in the Jack in the Box contaminations. It was also featured in the Robin Cook novel Toxin. In 2006, an epidemic of harmful E. coli emerged in the United States due to contaminated spinach. 183 known cases have been reported, including 29 cases of HUS.

Molecular Biology

 * Platelet-rich thrombi in affected organs (unclear etiology of tissue specificity CD36)
 * vWF (endothelially synthesized) -> ULvWf multimers -> shear stress unfolds and causes massive platelet aggregation
 * Normally, UlvWf digested by metalloprotease to “normal” size vWf multimers
 * Familial forms of TTP lack metalloprotease activity
 * Acquired forms of TTP have IgG antibody, which reduce metalloprotease activity during flares

Metalloprotease activity appears normal in HUS


 * In HUS, and in cases of TTP without decreased metalloprotease activity, other etiologies of platelet activation have been proposed:
 * Endothelial injury (esp. drug induced)
 * Toxins (i.e. Shiga toxin)
 * PAI – 1
 * Other genetic factors (Factor H, Factor I deficiencies, complement derangements)

Pathophysiology and Etiology

 * Childhood HUS
 * After enterohemorrhagic E. Coli (usually O157:H7)
 * Idiopathic
 * Adult TTP-HUS
 * Idiopathic
 * Drug toxicity
 * Mitomycin C, cyclosporine
 * Immune mediated:
 * Quinine
 * Ticlopidine
 * Clopidogrel
 * Bleomycin
 * Cisplatin
 * OCPs
 * Tacrolimus
 * Valacyclovir
 * Rifampin
 * Simvastatin
 * Penicillin
 * Quinolones
 * Risperidone
 * MDS
 * Conditioning for BMT
 * Pregnancy or postpartum
 * Autoimmune disease (APL syndrome, SLE, scleroderma)
 * HIV/AIDS
 * CMV
 * Tuberculosis
 * After enterohemorrhagic E. Coli

Diagnosis
Clinically, HUS can be very hard to distinguish from thrombotic thrombocytopenic purpura (TTP). The laboratory features are almost identical, and not every case of HUS is preceded by diarrhea. The only distinguishing feature is that in TTP, neurological symptoms occur more often, but this is not always the case.

Signs and symptoms
The classic childhood case of HUS occurs after bloody diarrhea caused by E. coli O157:H7, a strain of E. coli that expresses verotoxin (also called Shiga toxin). The toxin enters the bloodstream, attaches to renal endothelium and initiates an inflammatory reaction leading to acute renal failure (ARF) and disseminated intravascular coagulation (DIC). The fibrin mesh destroys red blood cells and captures thrombocytes, leading to a decrease of both on complete blood count. The usual age of onset is between 2 and adolescence.

HUS occurs after 2-7% of all E. coli O157:H7 infections.

Adult HUS has similar symptoms and pathology but is an uncommon outcome of the following: HIV; antiphospholipid syndrome (associated with Lupus erythematosus and generalized hypercoagulability); post partum renal failure; malignant hypertension; scleroderma; and cancer chemotherapy (mitomycin, cyclosporine, cisplatin and bleomycin).

A third category is referred to as familial HUS. It represents 5-10% of HUS cases and is largely due to mutations in the complement proteins factor H, membrane cofactor protein and factor I leading to uncontrolled complement system activation. Recurrent thromboses result in a high mortality rate.

Treatment
Treatment is generally supportive with dialysis as needed. Platelet transfusion may actually worsen outcome.

In severe cases or when there is diagnostic uncertainty between HUS and TTP, plasmapheresis is the treatment of choice.

Antibiotic treatment of O157:H7 colitis may stimulate further verotoxin production and thereby increase the risk of HUS.


 * Plasma exchange daily until LDH normal and platelets stable
 * Renal pathology may not entirely resolve (no data on continued plasma exchange after plts and markers of hemolysis have resolved)
 * Average 7-16 exchanges required to induce remission
 * Caution plasmapheresis-associated thrombocytopenia (more with certain instruments)
 * Cryopoor plasma exchange not better than regular FFP

Future or Investigational Therapies

 * ASA and dipyridamole not effective alone, ? benefit when added to plasma exchange
 * In poorly responsive or resistant disease, INCREASE PLASMA EXCHANGE
 * Then consider:
 * prednisone (1 mg/kg per day)
 * methylprednisolone (125 mg IV bid)
 * Vincristine
 * IVIG

Prognosis
With aggressive treatment > 90% survive acute phase. About 9% may develop end stage renal disease. About one-third of persons with hemolytic-uremic syndrome have abnormal kidney function many years later, and a few require long-term dialysis. Another 8% of persons with hemolytic uremic syndrome have other lifelong complications, such as high blood pressure, seizures, blindness, paralysis, and the effects of having part of their colon removed. The overall mortality rate from HUS is 5-15%. Older children and adults have a worse prognosis.