Hemolytic Uremic Syndrome

Loose Bowels 2
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Diagnosis and reasoning

This young boy has presented with bloody diarrhea; this is uncommon in children, and potentially a sign of serious underlying disease. Key possibilities include bacterial and amebic dysentery, inflammatory bowel disease (although uncommon at this age), Henoch-Schonlein Purpura (HSP), hemolytic uremic syndrome (HUS), and thrombocytopenic thrombotic purpura (TTP). Note also the marked reduction in urine output; this is particularly ominous, given that he is not clinically dehydrated; acute kidney injury (AKI) is a very real concern. When the above finding is taken into account, HUS immediately rises into prominence; TTP is also a possibility, although one would expect to find more florid neurological symptoms. HSP is clinically less likely, given the absence of palpable purpura or features of arthritis; furthermore, bacterial or amebic dysentery alone is unlikely to account for these symptoms. Essential basic investigations include a urinalysis and renal function assay, along with a complete blood count (CBC) and blood smear; the former shows both creatinine and urea to be elevated, confirming the presence of AKI; the microscopic hematuria seen here is compatible with HUS. Of equal importance, the CBC demonstrates anemia and thrombocytopenia, while the blood film reveals the presence of schistocytes; this is highly suggestive of a microangiopathic hemolytic anemia (MAHA), which again is a cardinal feature of HUS. That said, it is highly advisable to exclude disseminated intravascular coagulation (DIC) in all patients with MAHA; the normal coagulation profile seen here makes this unlikely. Thus, HUS does appear to be the probable diagnosis; given the history of preceding bloody diarrhea, this is very likely 'typical' HUS. This is confirmed by the positive stool Shiga toxin test. Supportive therapy (including appropriate intravenous fluid therapy) is key in the management of these patients. Note that both plasma exchange and Eculizumab have not been shown to be of use in typical HUS (although they are effective in atypical HUS). Antibiotics are also best avoided, as this may lead to an increase in Shiga toxin production or release, thus worsening the disease.


Discussion

Hemolytic uremic syndrome (HUS) is characterized by the triad of hemolysis, thrombocytopenia, and acute kidney injury (AKI); it is one of the most frequent etiologies of both AKI and acquired chronic kidney disease (CKD) in children. HUS is most common in children less than 5 years of age, although all age groups are affected; the overall incidence in the general population is approximately 1 to 2 per 100,000 individuals. To understand the pathophysiology and clinical manifestations of HUS, one must first appreciate that it is one of the thrombotic microangiopathies (TMAs), a group of diseases characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and the occlusion of small vessels by thrombi. The clinical manifestations of TMAs depend on the site of vascular involvement; based on clinical presentation, they have traditionally been divided into HUS and thrombotic thrombocytopenic purpura (TTP), with the former giving rise to AKI, and the latter to neurological disease. However, this simplistic classification is misleading, as HUS can give rise to neurological symptoms, while TTP can affect the kidney; note also that both diseases can affect other organ systems, including the liver, pancreas, and heart. Another important point is that HUS is not a single condition, but rather a group of diseases with a similar clinical presentation, but differing genetic or environmental etiologies. Approximately 90% of cases of HUS occur following infection with Shiga toxin-producing E. coli (STEC), most frequently of the O157 subtype; this is termed 'typical' HUS, or 'diarrhea associated HUS' (D+ HUS). It is believed that the toxins affect vascular endothelial cells, initiating a cascade of enzyme activation leading to platelet aggregation and a consumptive thrombocytopenia; the resulting microvascular obstruction causes mechanical damage to erythrocytes, resulting in MAHA. The toxins also preferentially localize to the kidneys, inhibiting protein synthesis and leading to cell necrosis and renal impairment. Most of the remaining 10% of cases are due to 'atypical' HUS, where abnormal complement activation results in endothelial damage and activation, and small-vessel thrombosis. Atypical HUS is is further divided into 'familial' disease (in which certain mutations predispose to the condition), and 'non-familial' disease, which is usually due to infectious causes such as Streptococcus pneumoniae, Mycoplasma pneumoniae, Histoplasmosis, HIV, and Coxsackie virus. Note that in familial atypical HUS, a trigger such as an acute infection, drugs, or pregnancy, is typically necessary to set off the condition. Clinically, most patients are visibly ill; intense pallor secondary to the MAHA may be noted, while edema and oliguria may signify the onset of AKI; as mentioned before, certain individuals may experience neurological symptoms such as lethargy, stupor and coma, as well as seizures and strokes. Where other organ systems are involved, features of adult respiratory distress syndrome (ARDS), myocardial dysfunction, pancreatitis, and even liver failure may be present. Note that in patients with typical HUS, a preceding history of abdominal pain and bloody diarrhea is present, although these symptoms may have ceased by the time of presentation. Conversely, atypical HUS is not preceded by a bloody diarrhea; however, gastroenteritis with diarrhea may act as a trigger. Where HUS is suspected, a panel of basic hematological studies (including a complete blood count and blood film), urinalysis and renal profile, and a clotting profile are mandatory. Typical hematological results include a low hemoglobin level and thrombocytopenia, and schistocytes in the peripheral blood film; renal function assays will demonstrate azotemia, while urinalysis may reveal hematuria and/or proteinuria. As there is no activation of the clotting cascade, PT/INR, aPTT and TT should be within normal parameters. If typical HUS is suspected, infection with STEC should be confirmed; this may be via cultures, serology, or polymerase chain reaction (PCR) based assays. Unfortunately, there is no test to definitively establish the presence of atypical HUS; this is typically diagnosed by excluding both typical HUS, and TTP (via an ADAMTS13 activity assay). In both typical and atypical HUS, close supportive care is a key aspect of the management; this includes appropriate fluid and electrolyte management and renal support where necessary. In particular, between 50% to 70% of cases will require renal replacement therapy at some point; this may be via peritoneal dialysis, hemodialysis, or continuous renal replacement therapy (CRRT). Packed red blood cell transfusions may be required in symptomatic anemia, or if the hematocrit falls rapidly; platelet transfusions should be considered if active bleeding occurs. As of writing, there does not appear to be any specific treatment which affects the course of typical HUS; note that antibiotic therapy is controversial, and probably best avoided, as there is evidence this may lead to an increase in Shiga toxin production or release. On the other hand, plasma exchange is highly efficacious in atypical HUS; this replaces functionally defective complement proteins and removes overactive proteins; in addition, treatment with the complement inhibitor Eculizumab may be even more effective than plasma therapy. In both forms of HUS, a population of patients will experience permanent deterioration of renal function, necessitating maintenance dialysis, and renal transplantation; with typical HUS, post-transplantation outcomes are good, with recurrent disease being uncommon. However, 60% of patients with atypical HUS develop recurrences following transplantation, 90% of whom will subsequently lose their graft. Strategies to reduce recurrence include aggressive therapy with eculizumab or prophylactic plasma exchange sessions before and after transplantation, or combined liver and kidney transplantation (as most complement proteins are synthesized in the liver). Overall, 75% of patients with typical HUS experience a complete recovery; upto 25% are are left with ongoing sequelae such as chronic kidney disease, hypertension, and, rarely, chronic pancreatitis and diabetes. Unfortunately, atypical HUS has a markedly worse prognosis, with a 3-year patient or kidney survival of just 50%.


Take home messages

  1. Hemolytic Uremic Syndrome (HUS) is characterized by the triad of hemolysis, thrombocytopenia, and renal insufficiency.
  2. HUS is subdivided into typical and atypical HUS; differentiation is critical for appropriate management.
  3. All patients with HUS require close supportive therapy; plasma exchange and Eculizumab are specific therapies for atypical HUS.
  4. Atypical HUS carries a significantly worse prognosis than typical HUS.

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