Continuing Education Activity

Hemolytic uremic syndrome (HUS) is a rare but potentially serious condition, often due to infection and less commonly to genetic predisposition or other underlying conditions. Prompt recognition of HUS's varied etiologies and manifestations is essential for timely diagnosis and intervention, optimizing patient outcomes. This activity describes the evaluation of hemolytic uremic syndrome and how to differentiate HUS from other forms of thrombotic microangiopathies. The differing etiologies of HUS, varying clinical presentations, and cellular pathways are reviewed. The roles of the interprofessional healthcare team and regulatory bodies in implementing best practices for treating and preventing this disease to improve patient outcomes are presented.

Objectives:

• Differentiate between typical and atypical hemolytic uremic syndrome etiologies based on clinical presentations, genetics, and complement pathway involvement.

• Implement evidence-based diagnostic protocols and treatment strategies tailored to different hemolytic uremic syndrome subtypes.

• Apply knowledge of atypical hemolytic uremic syndrome's genetic basis, complement system dysregulation, and treatment options to optimize patient care.

• Coordinate multidisciplinary care, especially in complex cases, to ensure optimal patient outcomes and long-term management of hemolytic uremic syndrome.

Introduction

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. HUS is most commonly caused by Shiga toxin (typical HUS) or, less commonly, infections or genetic abnormalities activating the alternative complement pathway (atypical HUS). Additional causes can be secondary to malignancy, autoimmune disorders, genetic mutations, and medication use.[1] Extrarenal manifestations are common in HUS, particularly neurological symptoms.[1] Prompt recognition of HUS's varied etiologies and manifestations is essential for timely diagnosis and intervention, optimizing patient outcomes.

Thrombotic microangiopathy encompasses various systemic diseases in which endothelial damage causes thrombosis in the microvasculature, including capillaries, arterioles, and venules, resulting in consumptive platelet aggregations. This leads to mechanical shearing of the red blood cells (RBCs), Coombs-negative hemolytic anemia, and end-organ damage. The triad of thrombocytopenia, hemolytic anemia, and ischemic end-organ damage defines thrombotic microangiopathy.[2][3] Some of the more common TMAs from which HUS must be differentiated are thrombotic thrombocytopenic purpura (TTP); syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP); and disseminated intravascular coagulation (DIC). Despite similar pathogeneses, the treatments of these entities differ significantly.[2][4]

Prior classifications of HUS often depended on the presence or absence of bloody diarrhea, with its presence used to diagnose typical HUS associated with Shiga toxin. However, atypical HUS can also present with bloody diarrhea in up to 30% of cases, so an etiology-based classification system is preferred.[3]

Typical HUS

Shiga toxin–producing Escherichia coli (STEC), called typical HUS, is the most common cause of HUS. Typical HUS comprises 90% to 95% of HUS cases and commonly arises from consuming contaminated food or drink and through person-to-person contact. The incidence of HUS among individuals infected with STEC ranges from 5% to 15%, predominantly affecting children younger than 5.[3] Typically, a presentation of bloody diarrhea occurs around day 2 or 3 following exposure, with HUS onset developing 3 to 10 days after the start of diarrhea.[3] Other common symptoms are vomiting (67%), fever (37%), and abdominal pain (29%).[4][5]

Atypical HUS

Atypical HUS (aHUS) constitutes 5% to 10% of HUS cases and is linked to genetic mutations affecting the alternative complement pathway. Under physiological conditions, the alternative complement system is continuously active at low levels. However, inflammatory conditions such as infections can induce endothelial damage, triggering the activation of the coagulation cascade and causing a TMA presentation.[6][7] 

The initial clinical manifestation of aHUS typically involves nonspecific symptoms like fatigue, pallor, or somnolence. These symptoms can progress to signs of acute kidney injury (AKI), including oliguria, uremia, and fluid overload. The risk of progression to stage 3 or 4 chronic kidney disease (CKD) and end-stage renal disease (ESRD) in aHUS is high. In contrast to typical HUS, patients with aHUS often fail to regain kidney function without treatment. Untreated, approximately 50% of aHUS cases progress to dialysis dependency, with a mortality rate of 25%.[7][6][8]

Similar to typical HUS, aHUS may exhibit extrarenal manifestations, notably cardiac and neurological, including heart failure, pulmonary hypertension, seizures, coma, and blindness. These manifestations significantly contribute to the morbidity and mortality associated with aHUS.[6][8] In contrast to typical HUS, patients with aHUS commonly relapse; patients must be monitored closely for relapse after treatment is discontinued.[7][8]

Secondary HUS 

The last category of HUS involves patients with HUS secondary to underlying conditions or infections, commonly presenting as aHUS with abnormal complement system activation. The most significant component of this category is HUS caused by Streptococcus pneumoniae, accounting for 5% to 15% of all cases of HUS in children.[5] S pneumoniae releases neuraminidase, exposing cellular antigens and activating the alternative complement system. This is the only cause of Coombs-positive HUS, and early antibiotic administration is indicated.[8] 

Other causes of secondary aHUS are as follows:

• inherited vitamin B12 (cobalamin) metabolism disorders;
• diacydiacylglycerol kinase ε (DGKE) mutations;
• HIV;
• influenza virus;
• autoimmune disease, eg, systemic lupus erythematosus, antiphospholipid antibody syndrome;
• drugs, eg, quinine, calcineurin inhibitors, chemotherapeutic agents; and
• malignant hypertension.[7] 

Recent studies have shown that COVID-19 can trigger aHUS in adults and children.[8] Pregnancy triggers aHUS activation, leading to increased pregnancy complications in women with established aHUS compared to those without the condition.[9][10]

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. 

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] 

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.

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] 

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]

Enhancing Healthcare Team Outcomes

Although HUS has less than 5% mortality, it can lead to long-term renal complications, especially in children. Timely diagnosis and appropriate management are crucial. A high index of suspicion in children presenting with symptoms related to HUS and appropriate investigations can lead to better patient outcomes. Clinicians must monitor for reduced hemoglobin and platelet counts and signs related to anemia and thrombocytopenia.

Including a nephrologist in the care team is crucial for patients who develop acute renal failure and need dialysis. Thus, proper coordination among interprofessional team members, consisting of physicians, advanced practice practitioners, nurses, pharmacists, and nephrologists, is optimal. Prompt recognition of HUS's varied etiologies and manifestations is essential for timely diagnosis and intervention, optimizing patient outcomes.