Hemolytic Uremic Syndrome

Etiology

Shiga toxin causing typical HUS can be divided into 2 main subtypes—Stx1 and Stx2. Stx2 is associated with more severe disease and a greater need for renal replacement therapy.[3] Traditionally, Escherichia coli 0157:H7 (E coli 0157:H7) has been linked to typical HUS; however, in recent years, non-0157 serotypes have become dominant. The most common cause of typical HUS in North America and Europe is E coli 026:H11. Shiga toxin from Shigella dysenteriae produces a similar disease pattern to STEC, except symptoms are much more severe, and the fatality of HUS with Shigella dysenteriae is estimated at 36%.[11] Rarely, Salmonella spp are also associated with HUS caused by STEC.(doi: 10.1007/978-3-662-52972-0_26)

The cause of aHUS is the abnormal activation of the alternative complement pathway. The complement system is part of the innate immune system and is composed of 3 pathways of activation: classical, alternative, and lectin-binding. The initial steps of each separate pathway converge at the step of forming C3 convertase, leading to the formation of the membrane-attack complex (MAC), which then lyses target cells.

In aHUS, the complement pathway becomes uncontrolled, most often due to mutations in genes for alternative path initiators, regulatory proteins, or autoantibodies-to-regulatory proteins. The most common identifiable mutation in aHUS is a pathogenic variant of the CFH gene, which encodes Factor H—the main regulatory protein of the alternative complement pathway at the C3b level.[6][7] Because of incomplete penetrance, a second inciting agent, such as infection, is often required for aHUS to develop, even if genetic abnormalities are present.[8]

Epidemiology

HUS and aHUS are most often associated with children younger than 10, with most cases in those younger than 5.[4] Globally, STEC causes 43 acute illnesses per 100,000 person-years and 3890 cases of HUS.[12] STEC-HUS is one of the most common causes of pediatric renal replacement therapy. A large retrospective study showed that 15% of children (younger than 18) who presented to the emergency department with bloody diarrhea developed STEC-HUS.[13]

STEC-HUS incidence is estimated at 0.57 cases per 100,000 children, and in the highest risk group—children aged 6 months to 2 years—the incidence is as high as 3 per 100,000 children.[3] Incidence directly coordinates with environmental exposure and agricultural practices, such as cattle raising, and most patients are diagnosed between April and September when cattle show higher colonization of STEC.[3]

In contrast to HUS, aHUS is notably less frequent; nevertheless, aHUS exhibits substantially elevated morbidity and mortality rates. Like typical HUS, atypical HUS affects young children, predominantly those younger than 5, and prevalence is estimated at 2 to 9 cases per million people aged 20 years or younger.[6] Cases due to S Pneumonia usually occur in the winter during cold season. (doi: 10.1007/978-3-662-52972-0_26)

Pathophysiology

HUS is typically associated with bacterial infection resulting from the consumption of undercooked beef, unpasteurized milk, or other food or drink contaminated by cattle manure; cattle are asymptomatic carriers of STEC.[3] Once ingested, STEC penetrates the mucous layer of the intestine and secretes Shiga toxin, which binds to the receptor Gb3. The Shiga toxin/Gb3 complex binds to cell ribosomes, inhibiting protein synthesis and causing apoptosis; inflammatory cytokines are also produced.[3] 

In addition to cytotoxic effects, Shiga toxin is capable of activating the complement system by inhibiting complement factor H. Upon entering the bloodstream, Shiga toxin persists in binding to cells via the Gb3 receptor, with the highest prevalence found in the glomerular microvasculature. Endothelial damage is caused by 1) direct cytotoxicity of Shiga toxin, 2) disturbance of the hemostatic pathway, 3) increased cytokine release, and 4) alternative pathway activation.[3] This endothelial damage then initiates the pathology associated with TMA. 

In aHUS, the alternative complement pathway is activated as described above, with particular emphasis on regulatory Factor H that stabilizes C3 and inactivates C3b.[3] aHUS is usually associated with a genetic abnormality affecting the regulation in the alternative complement system coupled with an inciting stress such as infection. Secondary HUS generally follows the same pathophysiology pattern as aHUS.

Histopathology

Most biopsies performed on patients with HUS occurred prior to 1990 because patients with suspected HUS are not routinely biopsied due to the presence of thrombocytopenia and general instability. In biopsies that were performed, light microscopy revealed fragmented RBC in glomerular capillary loops and variable fibrin staining in glomerular capillaries and renal arterioles. Electron microscopy shows endothelial and mesangial cell deposits of fibrin and proteinaceous material pushing into the capillary lumen giving the appearance of a glomerular basement membrane with a double contour. In typical STEC-associated HUS, staining for C1q, C3, or C4 is not observed.(doi: 10.1007/978-3-662-52972-0_26)

Despite extra-renal manifestations, other organs are generally not biopsied with the exception of the gastrointestinal tract which can show extensive vascular thrombosis histologically.(doi: 10.1007/978-3-662-52972-0_26)

History and Physical

The typical patient is a child younger than 5 with painful diarrhea and abdominal cramping between 1 and 10 days (median 4 d) after exposure to STEC; fever and vomiting may also be present. HUS generally begins 5 to 13 days after the start of diarrhea (median 6.5-7 d).[3] HUS symptoms include renal symptoms, such as anuria, oliguria, and fluid overload, and symptoms related to anemia, such as syncope, fatigue, and pallor. Petechiae and easy bleeding may be notable due to thrombocytopenia.

Although less common in adults, when HUS emerges, particularly during food-related outbreaks, its clinical trajectory displays greater variability and an unfavorable prognosis. Notably, most HUS-related deaths occur in adults older than 60. In adult patients, neurological symptoms such as confusion, seizures, and coma are markedly more prevalent than in children. Older patients often also have neuropsychiatric symptoms.[12]

The initial clinical presentation of aHUS is usually nonspecific symptoms such as fatigue, pallor, or somnolence, which can progress to signs of acute kidney injury (AKI), such as oliguria, uremia, and fluid overload. If the inciting factor is S Pneumoniae, patients may have underlying pneumonia, empyema, or meningitis. Diarrhea, including bloody diarrhea, can also be prominent in atypical HUS.[3] 

Extrarenal manifestations are common with both typical and atypical HUS. Neurologic and cardiac symptoms are often responsible for much of the morbidity and mortality of HUS.[3]

Evaluation

The diagnosis of HUS requires a high index of suspicion based on symptoms, travel history, laboratory data, and dietary history.[14][15][16] Initial tests should include a complete blood count with differential and comprehensive blood metabolic panel. Elevated LDH and indirect bilirubin, as well as low haptoglobin and elevated plasma hemoglobin, are diagnostic of hemolytic anemia, as are schistocytes on peripheral smear. A Coombs test should be negative, with the exception of HUS caused by S pneumonia.

Up to 20% of patients have elevated amylase and lipase due to pancreatic damage, which may be accompanied by hyperglycemia.(doi: 10.1007/978-3-662-52972-0_26) A stool sample should be collected to test for Shiga toxin whenever diarrhea is present. The results may not be positive for the Shiga toxin if it has been cleared or is avidly bound to the endothelium. If clinically indicated, testing for the presence of S dysenteriae and S pneumonia should also be performed. 

Low complement levels are suggestive of, but not specific to aHUS, as typical HUS also causes immune system abnormalities.[5] Patients may have hyponatremia, hyperkalemia, and other electrolyte abnormalities from acute kidney injury as the disease progresses. Genetic testing can also be sent to evaluate for genetic causes of aHUS.

An ADAMTS13 level should be sent to rule out TTP. Abnormal coagulation studies, such as prolonged prothrombin time (PTT), activated partial thromboplastin time (aPTT), elevated D dimer, and elevated fibrin degradation products, are suggestive of DIC.

All of the above tests have therapeutic value, but if clinical suspicion is high, treatment should not be delayed while waiting for all testing results, as early treatment initiation is associated with improved outcomes.

Treatment / Management

The management of typical HUS caused by STEC is generally supportive. Patients are often volume depleted, and less volume resuscitation has been linked to an increased need for renal replacement therapy, which half of all patients require.[3][13] Blood transfusions are provided as clinically needed, and platelet transfusions should be given sparingly to avoid thrombotic complications. (B3)

Antimotility agents and antibiotics are avoided in typical HUS caused by STEC, as they correlate with poorer outcomes, likely due to heightened Shiga toxin exposure. On the other hand, if S dysenteriae or S pneumonia is present, early antibiotics are associated with improved outcomes.(doi: 10.1007/978-3-662-52972-0_26)

For aHUS, early treatment is crucial to avoid end-stage renal disease (ESRD) and mortality. The cornerstones of treatment for aHUS are first-line treatment with eculizumab and second-line with plasma exchange.[17] Eculizumab is a recombinant monoclonal antibody that targets the C5 component of complement activation by preventing its cleavage; early eculizumab administration improves its effectiveness.[7][17] The advent of eculizumab treatment has decreased progression to ESRD or death in children from 30% to 50% down to 9% and in adults from 60% down to 6% to 15%.[5] (B2)

Ravulizumab is a new C5 inhibitor approved for use in the USA in 2019 and the EU in 2020. Ravulizumab also binds to C5, preventing cleavage, and it has similar efficacy to eculizumab but with 4 times as long of a half-life.[8] Prior to eculizumab, plasma exchange was the standard of care for HUS and is still used if eculizumab is not available or in addition if clinically indicated.(B3)

One ongoing question is how to treat patients who develop ESRD due to aHUS because patients with aHUS often develop renal failure necessitating kidney transplant, and there is a high recurrence rate of aHUS in the transplanted kidney. Studies suggest that prophylactic administration of eculizumab in patients with a high risk of aHUS recurrence prolongs graft survival and may also be cost-effective in the high-risk groups despite the drug's high cost.[7][17] Adverse effects of eculizumab are infection by encapsulated organisms such as S pneumoniae and Haemophilus influenzae, and all patients should be given appropriate vaccines and monitored.[7] (B2)

The treatment for secondary HUS is largely dependent on the treatment of the underlying condition. Small studies have shown eculizumab to have some efficacy in treating pregnancy-related secondary HUS; however, many of these patients are shown to have an underlying genetic component predisposing them to aHUS as well.[10][18] In another small study, patients with secondary HUS who had worsening renal function despite treatment of underlying disease were administered eculizumab with improvement in symptoms within the kidneys and extrarenal symptoms.[18]

Differential Diagnosis

Initially HUS may present similarly to other TMAs such as TTP, DIC, HELLP, and systemic vasculitis. Often clinical presentations and laboratory testing will rule out other causes. 

Thrombotic Thrombocytopenic Purpura (TTP)

TTP is thrombotic microangiopathy characterized by a pentad of hemolytic anemia, thrombocytopenia, renal dysfunction, fever, and neurological dysfunction. TTP is due to a deficiency or mutation in "a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13" (ADAMTS13) and usually has adult-onset symptoms.

Disseminated Intravascular Coagulation (DIC)

DIC is the systemic activation of the coagulation cascade and is characterized by abnormal coagulation studies, including prolonged prothrombin time and activated partial thromboplastin time, elevated D dimer, and elevated fibrin degradation products, which are usually normal in HUS. Patients with DIC usually have serious underlying illnesses such as septic shock, trauma, or malignancy.

HELLP Syndrome

HELLP syndrome is observed in women pregnant in the third trimester or immediately postpartum, and it is characterized by hemolysis of red blood cells, elevated liver enzymes, and a low platelet count usually occurring with preeclampsia.

Systemic Vasculitis

Patients with systemic vasculitis typically present with inflammatory signs like fever, rash, and arthralgia, and lack prodromal diarrhea. Patients generally have a markedly elevated erythrocyte sedimentation rate.

Prognosis

The prognosis of typical HUS is generally good with mortality estimated at 5% overall.[19][20][21] However, up to 25% of patients with HUS develop long-term renal insufficiency with a glomerular filtration rate <80 mL/min/1.73 m², hypertension, or proteinuria, which could predispose patients to increased renal insufficiency as they get older. The most significant prognostic indicator of ongoing renal dysfunction is the length of time on dialysis, with long-term complications evident after 2 to 3 weeks of dialysis dependency.[3] One exception to the low mortality rate of typical HUS is in adults older than 60 who comprise most fatalities.[12]

The course of aHUS has traditionally been much less benign than typical HUS; however, the advent of eculizumab treatment has decreased progression to ESRD or death in children from 30% to 50% down to 9% and in adults from 60% to 6% down to 15%.[5]