Pathways Case Records: A Case of Hemolytic Uremic Syndrome

An 84-year-old man with diabetes and coronary artery disease presented to another hospital after two days of hematemesis (vomiting of blood), diarrhea and lethargy. As a restaurant owner and butcher, he habitually tested raw meat samples for freshness.

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Initial tests found low platelet count (thrombocytopenia), acute kidney injury, high LDH levels and undetectable haptoglobin with fragmented red blood cells on peripheral smear. He experienced a seizure with a subsequent aspiration event resulting in intubation to protect the airway. He was transferred to Massachusetts General Hospital for further management.

The Mass General team confirmed thrombocytopenia and rapidly rising creatinine levels. The metalloprotease ADAMTS13 demonstrated reduced activity, confirming a diagnosis of hemolytic uremic syndrome (HUS). The patient's treatment course included dialysis oliguric renal failure as well as eculizumab. Over the course of 2 weeks, his thrombocytopenia resolved. However, he was found to have persistently-poor mental status and therefore was palliatively extubated as requested by his family.

The Pathways Consult Service in the Department of Medicine was consulted and focused on the mechanism of HUS, which was driven by two questions:

1. What are the etiologies of HUS?
2. What are the clinical differences between Shiga toxin- and complement-mediated HUS?

Investigation and Diagnosis

HUS is clinically described by the classic triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. Capillary and arteriole endothelial damage leads to microvascular thrombosis and subsequent end-organ damage.

Recently, HUS has been classified into hereditary (e.g., complement gene mutation) or acquired (e.g., infection, complement autoantibodies, drug toxicity, malignancy) etiologies (Lancet; Clin Kidney J). The most common subtypes of HUS are Shiga toxin (ST)-HUS and complement-mediated (CM)-HUS. ST-HUS mediated injury stems from direct damage to endothelial cells by Shiga-like toxin 1 (Stx1) and/or Stx2 (J Clin Microbiol). These toxins contain subunits that recognize globotriaosylceramide (Gb3) membrane receptor, which is abundant on renal tubular endothelial cells. Internalization of these toxins into Gb3 receptor-expressing cells triggers a series of events resulting in cell death via incompletely understood mechanisms. ST has also been suggested to contribute to platelet dysfunction and destruction through increased adhesion of platelets and inhibition of ADAMTS13.

Some patients with CM-HUS have genetic variations resulting in a gain-of-function in pro-complement proteins or loss-of-function in regulatory proteins leading to complement cascade disinhibition. This dysfunction results in severe systemic illness mediated by the overactivation of complement. These hereditary cases occur primarily in children (Clin J Am Soc Nephrol). Exacerbation of HUS by exogenous triggers in patients with genetic variants had not been fully examined.

Overall, our patient's presentation—antecedent diarrheal illness, raw meat exposure, advanced age at presentation—fits better with ST-HUS, although a presentation of atypical CM-HUS may also be possible.

Unfortunately, we were unable to confirm which HUS subtype was responsible for disease in our patient. ST-HUS presentation may be confirmed through stool ST assay, a highly sensitive test that has the greatest diagnostic yield during bouts of active diarrhea.

Following transfer to Mass General, the feasibility of this assay in our patient was reduced due to low stool burden and exposure to antibiotics. Interestingly, the impact of antibiotics in HUS patients has been controversial (Antimicrob Agents Chemother; BMJ). However, a strong correlation between antibiotic administration and the development of HUS has yet to be established, and there is no clear evidence of the effect of antibiotics on a patient's clinical course when initiated after a diagnosis of HUS.

While essential to clearing pathogens, antibiotics can disrupt the normal microbial community in the gut. The gut microbiota may play a role in the inhibition of Stx2 effects. Bacteroides thetaiotaomicron in the microbiome inhibits Stx2 synthesis. It is possible that antibiotic administration hindered this microbe, resulting in worsened ST-HUS (Infect Immun). Therefore, we wonder if a fecal transplant or probiotics in these patients may reduce symptoms in ST-HUS patients.

Exactly how HUS causes altered mental state remains poorly understood. Previous studies demonstrated neurons expressing high levels of Gb3 as well as ST-mediated changes to the blood-brain barrier may contribute to changes in cognition. While this symptom is thought to be multifactorial, it remains undetermined if changes in mental state are caused by toxic metabolic effects, thrombotic disease, direct toxin effects or some combination of these effects. Further examination of cerebrospinal fluid using unbiased methods such as proteomics or metabolomics from ST-HUS patients with altered cognition may shed further light on the underlying pathophysiology in our patient. Our patient's history of diabetes and coronary disease might further contribute to these changes. Indeed, one small study in children suggested a link between hypertension and the development of neurological symptoms of HUS. Is it possible that diabetes and coronary disease contributed to our patient's disease progression?

Understanding uncharacterized causes and risk factors for HUS may enable improved treatment options. It is possible that genetic variations in an unidentified pathway (not directly connected to complement) may predispose some individuals to the development of HUS. Furthermore, multiple hits (e.g., genetic variation combined with malignancies or toxins) may exacerbate the presentation of symptoms.

Thus, the Pathways Service hypothesized that our patient was likely under the ST-HUS subtype due to multifactorial causes. Further studies are warranted to better understand the specific etiology.

Summary and Future Steps

Here, we describe a case of hemolytic uremic syndrome with clinical history and funding most suggestive—although not completely characteristic—of ST-HUS. Numerous avenues could be investigated to understand the cause of HUS including (1) whole exome sequencing of HUS patients to identify novel pathways and rare variants associated with HUS, (2) murine modeling to understand the contribution of the microbiome, and (3) molecular diagnostics of stool samples from our patient to identify pathogens that might cause novel forms of toxin-mediated HUS.

Further review of case reports and additional experiments are warranted to provide insight into the mechanism of action leading to ST- and CM-HUS. These investigations would provide novel avenues of diagnosis and treatment of HUS.

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