Hemolytic Uremic Syndrome

David G. Renter • Charles C. Dodd

Hemolytic uremic syndrome (HUS) is a thrombotic micro­angiopathy (TM) disorder of multiple etiologies. Although primarily a disease of humans, there are reports of HUS in multiple species including horses and cattle.

The typical form of HUS in humans is associated with consumption of food or water contaminated with Shiga toxin­producing bacteria, whereas atypical HUS is associated with inherited mutations of complement-regulatory proteins and diverse causes of endothelial injury including antiphospholipid antibodies, complications of pregnancy and contraceptives, vascular renal diseases like systemic sclerosis and malignant hypertension, use of chemotherapeutic and immunosuppressive drugs, and radiation.^1,4,5 Typical HUS is a major cause of ARF in young children and infants, and the majority of the cases occur after intestinal infection with Shiga toxin-producing enterohemorrhagic E. coli (EHEC).^1,6 E. coli O157:H7 is the most commonly reported serotype of EHEC in human cases of HUS, but many other EHEC serotypes have caused the syndrome.⁶ Infection with neuraminidase-producing Streptococ­cus pneumoniae has also been reported to cause typical HUS in humans.^7,8 Although literature on HUS in large animals is limited, case reports on four horses^3,9,10 and two cows^11,12 have demonstrated clinical syndromes and pathologic lesions consistent with HUS in humans.

Clinical Findings

Horses with clinical signs indicative of HUS exhibited fever, lethargy, diarrhea, hematuria, hemoglobinuria, azotemia, oliguria, and ventral edema.^3,9,10 Hematologic findings in three cases included leukocytosis, anemia, and evidence of hemolysis.^9,10 The blood smear of one of the four equine cases of apparent HUS revealed the presence of poikilocytes and schistocytes.^3,9,10 All four horses with evidence suggestive of HUS were euthana­tized following unsuccessful treatment with fluid therapy and diuretics.^3,9,10

In a postparturient mare ultimately diagnosed with HUS, there was initial clinical and laboratory evidence of endotoxemia and endometritis.³ However, after clinical signs of endotoxemia subsided, stranguria, hematuria, hemoglobinuria, tubular casts, thrombocytopenia, hyperfibrinogenemia, azotemia, and a left shift in the leukogram were noted.³ Her foal was apparently healthy at birth but subsequently developed progressive CNS signs culminating in refractory seizures.³ Although a direct causal relationship was not established, E. coli O103:H2 was recovered from the GI contents of both the mare and foal, as well as from the mare's uterus. In humans, serotype O103:H2 is one of the more common non-O157 EHECs.⁶

A reported fatal postparturient HUS case in a heifer was characterized by severe, progressive, anuric renal failure, acute hemolytic anemia, and consumptive thrombocytopenia.¹² A 6-year-old cow that had evidence of metritis 1 month after parturition was a suspected HUS case based on clinical and laboratory findings including anemia, hemolysis, thrombocy­topenia, azotemia, and hemorrhagic diathesis.¹¹

In humans, HUS can present suddenly as generalized hemorrhagic diathesis (especially hematemesis and melena), pallor, severe oligoanuria, hematuria, edema, microangiopathic hemolytic anemia, and, on occasion, seizures or other prominent neurologic changes.^1,12 In prodromal human cases, HUS develops an average of 1 week after the onset of diarrhea.¹² The classic clinical presentation of typical HUS in people includes the triad of ARF, thrombocytopenia, and hemolytic anemia.¹ Treatment in this acute phase of HUS primarily involves supportive care; there is limited evidence for more specific therapies, and some treatments may be detrimental.^4,13-15 At this writing, conflicting data exist in the published literature regarding the efficacy or potential for harm imparted by certain antimicrobials used to treat HUS.

Pathophysiology and Necropsy Findings

Two processes appear to dominate the pathogenesis of TM and ultimately cause vascular obstruction and vasoconstriction resulting in organ ischemia: (1) endothelial injury and activation, leading to intravascular thrombosis, and (2) platelet aggregation.¹ In humans, endothelial injury appears to be the primary cause of HUS, and HUS is the most common life-threatening complication of hemorrhagic colitis from EHEC infection.^1,6 EHEC produces exotoxins Shiga toxin 1 and Shiga toxin 2, also referred to as verotoxin 1 and verotoxin 2. Shiga toxins are considered a necessary but insufficient cause of typical HUS because other bacterial and host factors are important for disease progression.^6,16 Many serotypes of E. coli (as well as Shigella and other Enterobacteriaceae) can carry Shiga toxin genes and are capable of causing disease, yet certain EHEC serotypes (e.g., O157:H7) are more common human pathogens.⁶ EHECs are considered noninvasive but attach to the intestinal mucosa and produce characteristic attaching and effacing lesions seen histologically.^1,6,16 Microvascular endothelium is the major target of Shiga toxins, which are released from the bacteria in the intestine and absorbed across the gut epithelium, where they access the systemic circulation and are transported to small vessel endothelial cells.^6,16 The toxins bind to specific glycolipid receptors on the surface of vascular endothelial cells, are internalized by endocytosis, and may injure the cell through inhibition of protein synthesis, stimulation of prothrombotic messages, or induction of apoptosis.^6,16 Exposure of subendo­thelial collagen followed by activation of the coagulation cascade may result in thrombosis of small vessels in the kidney and other organs.

Cattle feces are considered to be a major source of EHEC, but these bacteria have been isolated from the feces of many other species including other livestock and humans.^16,17 Although EHECs do not generally cause illness in cattle, they do colonize the large intestine.¹⁷ It is generally believed that the lack of specific glycolipid receptors for Shiga toxins is the reason cattle typically do not develop severe colitis or HUS, despite the common presence of EHEC in their gastrointestinal tracts.¹⁷ Humans are generally infected with EHEC via consumption of food and water contaminated by feces. However, the small infectious dose makes direct contact with EHEC-positive animals (e.g., at petting zoos) and person-to-person transmission also a concern.^16,17

In four of the large animal cases reported with HUS, the inciting cause was unknown and isolation of EHEC or other Shiga toxin-producing organisms was not attempted.⁹,¹⁰,¹² One heifer had a necrotizing endometritis, but during postmortem examination of three horses, no focus of infection was identi­fied.^9,10,12 Renomegaly, renal infarcts, and scattered petechial and ecchymotic hemorrhages within the renal parenchyma were apparent on gross necropsy. Acute tubular necrosis and fibrin thrombi within the glomerular capillaries were evident on histologic examination.^9,10,12

In another equine case report, an EHEC serotype O103:H2 carrying a Shiga toxin gene was recovered from both the mare and foal, but direct Shiga toxin assays were not performed.⁶ While the causal significance of this finding is unclear, the unusual and concurrent disease progression in both animals may suggest a common etiology. Except for lack of evidence of microangiopathic hemolysis on a blood smear, the mare had clinical and postmortem signs consistent with HUS.⁶ Significant renal pathology included evidence for plasma protein and hemoglobin in both cortical and medullary tubules, with occasional epithelial necrosis.

Although the etiology is often undetermined in large animal cases of apparent HUS, the clinical signs and pathologic lesions reported are compatible with a diagnosis of HUS. It may be notable that three of six reported cases occurred postpartum. On the basis of HUS reports in large animals, it appears there may be features comparable with the disease syndrome in humans.