Kidney nontumor

Vascular disease

Thrombotic microangiopathy and acute endothelial injury

Hemolytic uremia syndrome / thrombotic thrombocytopenic purpura

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Last staff update: 30 June 2022

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PubMed Search: Hemolytic uremia syndrome thrombotic thrombocytopenic purpura (HUS/TTP)

Nikhil Sangle, M.D.
Him G. Kwee, M.D.
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Cite this page: Sangle N, Kwee HG. Hemolytic uremia syndrome / thrombotic thrombocytopenic purpura. website. Accessed August 13th, 2022.
Definition / general
  • Thrombosis in capillaries and arterioles throughout the body, microangiopathic hemolytic anemia, thrombocytopenia, renal failure with platelet fibrin thrombi in interlobular renal arteries and glomeruli, necrosis and thickening of vessel walls
  • Morphologic changes resemble malignant hypertension, but usually no pre-existing hypertension
  • HUS and TTP are usually considered part of clinical spectrum, in which disease manifestations depend on distribution of microangiopathy (but see Arch Pathol Lab Med 2003;127:834)
  • HUS: fibrin / red cell rich thrombi, largely confined to kidney and often severe; usually no pancreas, adrenal gland, brain or heart involvement
  • Atypical HUS: due to excessive complement activation in microvasculature; inherited and acquired abnormalities affecting components of the alternative complement pathway are found in 60% (Hematology Am Soc Hematol Educ Program 2011;2011:15)
  • TTP: platelet rich thrombi in myocardial arteries; also pancreas, kidney, adrenal gland or brain; usually no permanent kidney damage
  • Pathophysiology: endothelial injury by toxins (certain strains of E. coli 0157:H7 producing Shiga-like toxin, Hum Pathol 1988;19:1102) or antibodies and activation cause intravascular thrombosis and platelet aggregation, which causes vascular obstruction and vasoconstriction, affects predominantly the renal vessels; TTP occurs due to enhanced platelet aggregation, e.g., metalloproteinase activity causing abnormal vWF-cleavage
Childhood HUS
  • 75% of cases occur after shiga-toxin producing E. coli O157:H7 infection (also called verocytotoxin because it damages Vero cells in culture)
  • Main cause of childhood acute renal failure
  • Usually infants and young children, may occur at any age
  • Symptoms: sudden onset of influenza, bleeding (hematemesis or melena), severe oliguria, hematuria, microangiopathic hemolytic anemia, neurologic changes in 1/3 and hypertension in 50%
  • Pathogenesis: related to Shiga-like toxin, which promotes adhesion of white blood cells to endothelium; also increases endothelin and decreases nitrous oxide production, causing vasoconstriction
  • Poor prognosis with high mortality due to CNS disease or uncontrollable bleeding; survivors develop chronic renal failure
  • Causes: typhoid fever, E. coli (enterohemorrhagic strains), viral infections, shigellosis, antiphospholipid syndrome (primary or secondary to SLE), postpartum or after placental hemorrhage, vascular renal diseases such as scleroderma or malignant hypertension, drugs (mitomycin C, cyclosporine, bleomycin, cisplatin) and various malignancies
  • Lupus patients may have more severe disease (Am J Med Sci 2009;338:343, Nephron Clin Pract 2009;112:c177)
Idiopathic HUS/TTP
  • More common in women age 40 years or less; mortality 50%
  • Symptoms: CNS involvement dominant (fever, neurologic symptoms), hemolytic anemia, thrombotic thrombocytopenic purpura and renal involvement in only 50% (thrombi in glomerular capillaries and afferent arterioles)
Atypical HUS
  • aHUS is due to uncontrolled complement activation resulting in complement mediated thrombotic microangiopathy (TMA)
  • aHUS has similar renal biopsy findings as HUS but differs from HUS by:
    1. Absence of diarrhea, present in 75% of HUS cases
    2. In typical HUS, either Shiga-like exotoxins are present in stool (identified with Vero cell assay), serum antibodies against Shiga toxin are present (detect with ELISA) or lipopolysaccharides O157, O26, O103, O111 and O145 are present (detect with ELISA) but these tests are negative in aHUS (N Engl J Med 2009;361:1676)
    3. HUS may subside when the underlying cause is removed but aHUS frequently relapses even after complete recovery and usually causes death or permanent renal or neurologic impairment
  • aHUS differs from TTP by:
    1. TTP has more protean systemic manifestations but the manifestations of aHUS are usually limited to renal impairment
    2. 80% of TTP patients have deficiency of ADAMTS13 activity not seen in aHUS (ADAMTS13 is a protease that cleaves von Willebrand factor; its activity can be measured in serum or plasma by the collagen binding assay)
  • Atypical HUS causes:
    • Genetic, acquired (sporadic) or idiopathic
    • Genetic: autosomal recessive or autosomal dominant manner with incomplete penetrance
    • Genetic: due to mutation in one of six genes - CFH (encoding complement factor H), CD46 (encoding membrane cofactor protein), CFI (encoding complement factor I), CFB (encoding complement factor B), C3 (encoding the third component of complement C3) or THBD (encoding thrombomodulin, Pediatr Nephrol 2010;25:2431)
    • Determine mutated gene by:
      1. Measuring serum concentrations of CFH, CFI and CFB
      2. Evaluating CD46 protein expression on peripheral blood leukocytes by flow cytometry
      3. Sequence analysis of coding regions of these genes
      4. Deletion / duplication analysis of CFH can detect the CFH/CFHR1 hybrid allele and the CFHR3/CFHR1 and CFHR1/CFHR4 deletions (Blood 2010;115:379)
    • Note: 5 - 10% have serum anti-CFH IgG autoantibodies but normal plasma CFH levels; these patients may benefit from immunosuppressive therapy (J Am Soc Nephrol 2004;15:787)
Case reports
  • Eculizumab / Soliris® was approved by U.S. Food and Drug Administration for treatment of paroxysmal nocturnal hemoglobinuria (all cases) and in September 2011 for atypical hemolytic uremic syndrome refractory to plasma exchange therapy
    • Eculizumab is a recombinant human monoclonal IgG2/4 kappa antibody against C5 (a terminal complement factor) produced by murine myeloma cell culture and given intravenously (Haematologica 2010;95:523, Blood 2009;113:6522)
    • Eculizumab costs ~$400,000 a year and is considered the world's most expensive medicine
    • Eculizumab increases the risk of meningococcal infections so recommended to vaccinate patients with a meningococcal vaccine at least 2 weeks prior to receiving the first dose and monitor patients for early signs of meningococcal infections
    • Only available through a restricted program under a risk evaluation and mitigation strategy (REMS)
    • Not currently indicated for treatment of typical (or Shiga-like toxin E.coli) HUS but there are clinical trials investigating the efficacy of eculizumab for this condition (Alexion Pharmaceuticals: Soliris Indication [Accessed 14 December 2018])
    • See also CD55, CD59, Chronic myelogenous leukemia - LAP score
  • Atypical HUS triggering agents and treatment:
    • Streptococcus pneumoniae infection; do not treat with plasma infusion / exchange therapy; use washed red blood cells or platelets (Pediatr Nephrol 2008;23:1951)
    • Drugs, including anticancer agents, immunosuppressive agents (including cyclosporine, tacrolimus, etc.), antiplatelet agents (including clopidogrel), anti-inflammatory agents, oral contraceptives
    • Cancer, especially gastric carcinoma
    • Posttransplantation (kidneys or other organs)
    • Preeclampsia or postpartum (within 3 months after delivery)
    • Underlying medical conditions, especially autoimmune diseases
    • aHUS is considered idiopathic if no trigger (genetic or environmental) can be found
  • Gross description
    • Patchy or diffuse renal cortical necrosis
    Microscopic (histologic) description
    • Fibrin deposits in capillary lumina
    • Fibrinoid necrosis of larger vessels, thrombosis and endothelial cell proliferation in small arteries and arterioles
    • Ischemic changes in glomeruli with endothelial swelling and capillary luminal narrowing
    • Expanded mesangial thrombi appear red on trichrome stain, thrombi are not essential for a pathologic diagnosis

    • Intense basophilic thickening in small arteries and arterioles which restricts lumen, aneurysmal dilatation and proliferation of arterioles at hilus of glomerulus
    • May have double contour of glomerular basement membrane
    Microscopic (histologic) images

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    HUS: kidney

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    Atypical HUS: kidney

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    TTP: kidney

    Peripheral smear images

    Case #403
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    Numerous schistocytes and nucleated RBCs with extremely low platelets on peripheral smear

    Immunofluorescence description
    • Demonstrates fibrin and fibrinogen, irregular staining for IgM, C3 and C1q, negative for IgA and IgG
    Electron microscopy description
    • Widening of subendothelial space, filled with pale, finely particulate or fibrillar material (fibrinogen) and intraluminal platelet microthrombi causing narrowing of capillary lumen
    • Swollen mesangial cells with numerous phagolysosomes
    • Later: mucinous, onion skin-type obliterating endarteritis
    Differential diagnosis
    • Antiphospholipid antibody syndrome: thrombosis in veins, arterioles, capillaries with glomerular subendothelial expansion
    • Malignant hypertension: similar vascular lesions but different clinical presentation
    • Systemic sclerosis: similar vascular lesions but different clinical presentation
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