Hemolytic-Uremic Syndrome 

Updated: Oct 25, 2019
Author: Malvinder S Parmar, MBBS, MS, FRCPC, FACP, FASN; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP 

Overview

Practice Essentials

Hemolytic-uremic syndrome (HUS) is a clinical syndrome characterized by progressive renal failure that is associated with microangiopathic (nonimmune, Coombs-negative) hemolytic anemia and thrombocytopenia. HUS is the most common cause of acute kidney injury in children and is increasingly recognized in adults.[1, 2, 3, 4]

Thrombotic thrombocytopenic purpura (TTP), childhood HUS, and adult HUS have different causes and demographics but share many common features, especially in adults, which include similar pathologic changes such as microangiopathic hemolytic anemia, thrombocytopenia, and neurologic or renal abnormalities see Presentation and Workup.

Initial therapy is similar for these conditions. Plasma exchange is the initial treatment of choice in all adult patients with HUS that is not associated with Shiga-like toxin (atypical HUS). Two monoclonal antibodies, eculizumab and ravulizumab, are approved for the treatment of pediatric and adult patients with atypical HUS. (See Treatment.) 

 

Background

Gasser et al first described HUS in 1955. In 1988, Wardle described HUS and TTP as distinct entities, but in 1987, Remuzzi suggested that these two conditions are varied expressions of the same entity.

Confirmation that HUS and TTP are clearly different diseases, despite their clinical similarities, followed the discovery of the von Willebrand factor (vWF)–cleaving metalloprotease ADAMTS13 (A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13). Researchers subsequently recognized the etiologic link between TTP and congenital deficiencies of ADAMTS13 or formation of acquired antibodies to ADAMTS13.[5, 6, 7, 8]

Pathophysiology

Damage to endothelial cells is the primary event in the pathogenesis of hemolytic-uremic syndrome (HUS). The cardinal lesion is composed of arteriolar and capillary microthrombi (thrombotic microangiopathy [TMA]) and red blood cell (RBC) fragmentation.

HUS is classified into two main categories, depending on whether it is associated with Shiga-like toxin (Stx) or not.[9, 10] Shiga-like toxin is so called because it was initially identified in studies of Shigella dysenteriae, but this toxin is also elaborated by Escherichia coli.

Typical (Stx–associated) HUS

Typical HUS (Shiga-like toxin–associated HUS [Stx-HUS]) is the classic, primary or epidemic, form of HUS. Stx-HUS is largely a disease of children younger than 2-3 years and often results in diarrhea (denoted D+HUS). One fourth of patients present without diarrhea (denoted D-HUS). Acute kidney injury occurs in 55-70% of patients, but they have a favorable prognosis, and as many as 70-85% of patients recover renal function.

In North America and Western Europe, 70% of Stx-associated HUS cases are secondary to E coli serotype O157:H7. Other E coli serotypes implicated include the following[11] :

  • O111:H8
  • O103:H2
  • O121
  • O145
  • O26
  • O113
  • O104:H4

In Asia and Africa, typical HUS is often associated with Stx-producing S dysenteriae serotype 1. Regarding Stx associated with E coli, Stx-1 is almost identical to Stx associated with S dysenteriae type 1, differing by a single amino acid. Stx-1 is 50% homologous with Stx-2. Stx-2 is associated with severe disease.

After ingestion, Stx– E coli closely adheres to the epithelial cells of the gut mucosa by means of a 97-kd outer-membrane protein (intimin). The route by which Stx is transported from the intestine to the kidney is debated. Some studies have highlighted the role of polymorphonuclear neutrophils (PMNs) in the transfer of Stx in the blood, because Stx rapidly and completely binds to PMNs when incubated with human blood. However, the receptor expressed on glomerular endothelial cells has 100-fold higher affinity than of PMN receptors; in this way, they thereby transfer the Stx-ligand to glomerular endothelial cells.

The binding of Stx to target cells depends on B subunits and occurs by means of the terminal digalactose moiety of the glycolipid cell-surface receptor globotriaosylceramide Gb3. Both Stx-1 and Stx-2 bind to different epitopes on the receptor with different affinities. Stx-1 binds to and detaches easily from Gb3, whereas Stx-2 binds and dissociates slowly, causing more severe disease than that due to Stx-1.

Data from some studies have suggested that Stx favors leukocyte-dependent inflammation by altering endothelial cell-adhesion properties and metabolism, ultimately resulting in microvascular thrombosis. Findings from earlier studies suggested that fibrinolysis is augmented in Stx-HUS, but results of more recent studies revealed higher-than-normal levels of plasminogen-activator inhibitor type 1 (PAI-1), indicating that fibrinolysis is substantially inhibited.

Atypical (non–Stx-associated) HUS

Non–Stx-HUS, or atypical HUS, is less common than Stx-HUS and accounts for 5-10% of all cases. As the name implies, non–Stx-HUS does not result from infection by Stx-producing bacteria. In addition, the syndrome may occur year-round without a gastrointestinal prodrome (D-HUS). The term atypical HUS  complement-mediated thrombotic microangiopathy 

It may occur at all ages, but non–Stx-HUS is most frequent in adults and occurs without prodromal diarrhea (D-HUS). Patients have an unfavorable prognosis. Non–Stx-HUS can occur in sporadic cases or in families. The familial form is associated with genetic abnormalities of the complement regulatory proteins.

Overall, patients with non–Stx-HUS have a poor outcome, and as many as 50% may progress to end-stage renal disease (ESRD) or irreversible brain damage. Up to 25% of patients die during the acute phase.

Sporadic non–Stx-associated HUS

Various triggers for sporadic non-Stx–HUS have been identified, including the following:

  • Nonenteric infections
  • Viruses
  • Drugs
  • Malignancies
  • Transplantation
  • Pregnancy [12]
  • In rare cases, other underlying medical conditions (eg, antiphospholipid syndrome [APL], systemic lupus erythematosus [SLE])

Streptococcus pneumoniae infection accounts for 40% of all causes of non-Stx–HUS and 4.7% of all causes of HUS in children in the United States. Bacterial neuraminidase removes sialic acids and thus lyses cell-surface glycoproteins and exposes Thomsen-Friedenreich antigen to preformed circulating immunoglobulin (Ig) M antibodies. These bind to the neoantigen on platelets and endothelial cells and cause polyagglutination and damage to endothelial cells. On clinical examination, the disease is usually severe and causes respiratory distress, neurologic involvement, and coma, with a mortality rate of up to 50%.

Familial non–Stx-associated HUS

Familial non–Stx-HUS accounts for less than 3% of all cases of HUS. Both autosomal dominant and autosomal recessive forms of inheritance are observed. Autosomal recessive HUS often occurs early in childhood. The prognosis is poor, recurrences are frequent, and the mortality rate is 60-70%. Autosomal dominant HUS often occurs in adults, who have a poor prognosis. The risk of death or ESRD is 50-90%.

Some data suggest that familial non–Stx-HUS results from genetic abnormalities in the complement regulatory proteins, including C3, factor H, factor B, factor I, and CD46 (membrane cofactor protein, MCP). Factor H appears to be particularly important.[13, 14, 15, 16]

Factor H (HF1) consists of 20 homologous units called short consensus repeats (CSRs) and plays an important role in the regulation of the alternative pathway of complement. HF1 also serves as a cofactor for the C3b-cleaving enzyme factor I in the degradation of newly formed C3b molecules. It controls the decay, formation, and stability of C3b convertase (C3bBb), and it protects glomerular endothelial cells and the basement membrane against complement attack by binding to the polyanionic proteoglycans on the surface of endothelial cells and in the subendothelial matrix.

Fifty HF1 mutations have been described in 80 patients who had familial (36 patients) and sporadic (44 patients) forms of non–Stx-HUS. The mutation frequency is 40% in the familial form and 13-17% in the sporadic form. One patient with Stx-HUS who did not recover renal function was noted to have a mutation in exon 23 of the factor H gene.[15]

Patients with HF1 mutations have partial HF1 deficiency that causes a predisposition to the disease rather than the disease itself. Mutant HF1 has normal cofactor activity in the fluid phase, but its binding to proteoglycans is reduced, because the mutation affects the polyanion interaction at the C-terminus of HF1. Suboptimal HF1 activity is often enough to protect the patient from complement activation in physiologic conditions. However, activation of complement pathways results in higher-than-normal concentration of C3b, and its deposition on vascular endothelial cells cannot be prevented because of the inability of mutant HF1 to bind to polyanion proteoglycans.

Etiology

Hemolytic-uremic syndrome (HUS) predominantly occurs in infants and children after prodromal diarrhea. In summer epidemics, the disease may be related to infectious causes.

Bacterial infections may include the following:

  • S dysenteriae

  • E coli

  • Salmonella typhi

  • Campylobacter jejuni

  • Yersinia pseudotuberculosis

  • Neisseria meningitidis

  • S pneumoniae

  • Legionella pneumophila

  • Mycoplasma species

Rickettsial infections may include Rocky Mountain spotted fever and microtatobiotes

Viral infections may include the following:

  • Human immunodeficiency virus (HIV)

  • Coxsackievirus

  • Echovirus

  • Influenza virus

  • Epstein-Barr virus

  • Herpes simplex virus

Fungal infections can include Aspergillus fumigatus.

Vaccinations may include the following:

  • Influenza triple-antigen vaccine

  • Typhoid-paratyphoid A and B (TAB) vaccine

  • Polio vaccine

Causes of the secondary or sporadic form may include the following:

  • Pregnancy and puerperium

  • Cancers (chiefly mucin-producing adenocarcinomas)

  • Drugs

  • Malignant hypertension

  • Collagen-vascular disorder (eg, SLE, antiphospholipid antibody syndrome) - It is possible to have both true HUS and a lupus anticoagulant, but in most patients, the thrombocytopenia, microangiopathic hemolytic, and renal disease are due to antiphospholipid antibodies rather than true HUS

  • Primary glomerulopathies

  • Transplantation (eg, of kidney, bone marrow): This can be de novo or recurrent. It occurs in 5-15% of renal transplant patients who receive cyclosporine and in about 1% of patients who receive tacrolimus.

  • Allogenic hematopoietic cell transplantation (HCT)

Pregnancy-associated HUS occasionally develops as a complication of preeclampsia. Patients may progress to full-blown hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Postpartum HUS usually occurs within 3 months of delivery. The prognosis is poor, with a 50-60% mortality rate, and residual renal dysfunction and hypertension occur in most patients.

Drugs implicated in causing non–Stx-HUS are as follows:

  • Quinine - Most common cause of drug-induced TTP-HUS and has been confirmed to cause recurrent disease with recurrent exposure; chronic kidney disease appears to be common following quinine-induced HUS[17]

  • Anticancer agents: These include mitomycin, cisplatin, bleomycin, and gemcitabine. The risk for HUS after mitomycin therapy is 2-10%, and onset may be delayed, occurring almost 1 year after the patient starts treatment. The prognosis is poor, with a 75% mortality rate at 4 months.

  • Immunotherapeutic agents: Examples are cyclosporine, tacrolimus, OKT3, and interferon.

  • Antiplatelet agents: Examples are ticlopidine and clopidogrel.

  • Oral contraceptives

Posttransplantation HUS is reported with increasing frequency and may be primary (de novo) or recurrent. It is often a consequence of the use of calcineurin inhibitors or of humoral (C4b positive) rejection. This condition occurs in 5-15% of renal transplant patients treated with cyclosporine and in about 1% of patients treated with tacrolimus.

An immunodeficiency-related cause includes thymic dysplasia.

Familial causes account for 3% of all cases of HUS, and both autosomal dominant and autosomal recessive forms of inheritance have been reported. Autosomal recessive HUS occurs in childhood, and patients have a poor prognosis with frequent recurrences and a mortality rate of 60-70%. Autosomal dominant HUS occurs mostly in adults, who have a poor prognosis; the cumulative incidence of death or ESRD is 50-90%.

No cause is identified in about 50% of all cases of sporadic non–Stx HUS.

Epidemiology

United States

Stx-HUS occurs with a frequency of 0.5-2.1 cases per 100,000 population per year, with a peak incidence in children younger than 5 years, in whom the incidence is 6.1 cases per 100,000 population per year. In 2012, 274 cases of postdiarrheal HUS were reported in the United States, the majority in children 1-4 years of age.[18]

Non–Stx-HUS accounts for 5-10% of all cases of hemolytic-uremic syndrome (HUS), and the incidence in children is about one-tenth of that of Stx-HUS. This rate corresponds to about 2 cases per 100,000 population per year.

International

In children younger than 15 years, typical hemolytic-uremic syndrome (HUS) occurs at a rate of 0.91 cases per 100,000 population in Great Britain, 1.25 cases per 100,000 population in Scotland, and 1.44 cases per 100,000 population in Canada.

Seasonal variation occurs, with hemolytic-uremic syndrome (HUS) peaking in the summer and fall.

Race-, Sex-, and Age-related Demographics

Hemolytic-uremic syndrome (HUS) occurs infrequently in blacks. Both sexes are affected equally with HUS.

HUS occurs mainly in young children; however, adolescents and adults are not exempt. In young children, spontaneous recovery is common. In adults, the probability of recovery is low when HUS is associated with severe hypertension.

Mortality/Morbidity

For Stx-HUS, acute renal failure occurs in 55-70% of patients; up to 70-85% recover renal function.

For non–Stx-HUS, patients have poor outcomes, with up to 50% progressing to ESRD or irreversible brain damage. As many as 25% die during the acute phase.

Complications of HUS may include the following:

  • Renal failure
  • Stroke
  • Coma
  • Seizures
  • Bleeding

Schuppner et al reported that in an outbreak of Stx-associated HUS resulting from E coli O104:H4 infections in Germany in 2011, neurological complications occurred in 48-100% of adults in different patient groups. On follow-up conducted 19 months after disease onset in 31 patients, 22 still suffered from symptoms such as fatigue, headache, and attention deficits. On neuropsychological assessment, 61% of patients scored borderline pathological or lower. Secondary decline of cognitive function was found in about one-quarter of the patients.[19]

Prognosis

Stx-HUS prognosis is as follows:

  • Acute renal failure occurs in 55-70% of patients, but 85% recover renal function with supportive therapy.

  • Approximately 15-20% of children may develop hypertension 3-5 years after the onset of disease.

  • Recurrence with renal allografting is 10% or lower.

Ardissino et al developed an early prognostic index for Stx-HUS outcome that uses the combination of hemoglobin (Hb) and serum creatinine (sCr) concentrations at onset of illness. The formula is as follows:

                       Hb (in g/dL) + (sCr [in mg/dL] × 2)

On testing of the index in a cohort of of 197 Stx-HUS patients, 8% of those with a score > 13 died or entered a permanent vegetative state, compared with 0% of those with a score of ≤ 13.[20]

Alconcher et al reported that the best independent predictors of mortality in children with Stx-HUS were central nervous system (CNS) involvement, hyponatremia (serum sodium ≤ 128 meq/L) and elevated hemoglobin concentration (≥ 10.8 g/dL).[21]

Non–Stx-HUS prognosis is as follows:

  • Patients collectively have a poor prognosis, and as many as 50-60% progress to ESRD (50% in those with the sporadic forms and 60% in those with the familial forms) or develop irreversible brain damage. About 25% die during the acute phase.

  • The recurrence rate in patients receiving renal transplants is as high as 50%, with graft loss occurring in more than 90% who have recurrence. Recurrence rates are higher in patients with HF1 mutation.

Factors predictive of poor prognosis are as follows:

  • Non–Stx-HUS

  • Prolonged oliguria or anuria

  • Severe hypertension (especially delayed onset of hypertension)

  • Involvement of medium-sized arteries

  • Severity of CNS symptoms

  • Persistent consumption of clotting factors

  • Extensive glomerular involvement (>80%)

  • Age older than 5 years

In a retrospective study of 323 adult kidney transplant recipients with HUS and 121,311 transplant recipients with other renal diseases, Santos and colleagues found that while mortality did not significantly differ between groups in the 5 years following transplantation, death-censored graft loss occurred twice as often (hazard ratio 2.05) in patients whose native kidney disease was HUS than in other transplant recipients. HUS patients with post-transplant recurrence had a 5-year graft loss rate significantly higher than that of patients without recurrence (graft survival 14.7% vs.77.4%, P< 0.001).[22]

Patient Education

Advise patients to avoid eating raw or partially cooked meat. Improperly cooked or contaminated meat is a potential source of E coli O157:H7. Educate patients on the proper treatment of drinking water. Communities must make adequate efforts to ensure proper treatment and monitoring of drinking water. Educate patients about proper hygienic measures, especially in cattle fields and farms.

For patient education information, see Anemia, Blood in the Urine, and Acute Kidney Injury.

 

Presentation

History

History findings may include the following:

  • Prodromal gastroenteritis (83%) - Fever (56%), bloody diarrhea (50%) for 2-7 days before the onset of renal failure
  • Irritability, lethargy
  • Seizures (20%)
  • Acute renal failure (97%)
  • Anuria (55%)

Physical Examination

Physical findings may include the following:

  • Hypertension (47%)
  • Edema, fluid overload (69%)
  • Pallor, often severe
 

DDx

Diagnostic Considerations

Other problems to consider include the following:

  • Decreased platelet count

  • Decreased plasma levels of clotting factors V and factor VIII

  • Increased activated partial thromboplastin time (aPTT) and prothrombin time (PT)

  • Increased D-dimer and fibrinogen-degradation products (FDP)

  • Scleroderma renal crisis

  • Thrombotic microangiopathy in patients with cancer

  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency[23]

Differential Diagnoses

 

Workup

Laboratory Studies

Laboratory studies for hemolytic-uremic syndrome (HUS) may include the following:

  • Urinalysis: Benign mild proteinuria is frequently present; red blood cells (RBCs) and RBC casts may be present

  • Measurement of blood urea nitrogen (BUN), serum creatinine, and serum electrolyte levels

  • Hematologic determination: Severe anemia may be present. Perform peripheral smear for schistocytes (count >1% or two or more schistocytes in a 100× magnification field strongly suggests microangiopathic hemolysis).[24] The degree of thrombocytopenia does not correlate with the severity or the length of illness in HUS. The platelet count usually returns to normal within 2 weeks. Determine activated partial thromboplastin time (aPTT), fibrinogen degradation product (FDP), and D-dimer values.

  • Hemolytic workup: Results may show anemia. Bilirubin levels may be elevated. Lactate dehydrogenase (LDH) levels may be elevated. Haptoglobin levels may be decreased.

  • Stool culture: Obtain a sample for stool culture. Evaluate especially for E coli 0157:H7 and Shigella bacteria.

  • ADAMTS-13 activity: ADAMTS-13 activity is often severely deficient (< 10% of normal) in patients with classic thrombotic thrombocytopenic purpura (TTP), but can be seen in patients with severe sepsis (especially in association with disseminated intravascular coagulation or multiorgan failure) and in patients with severe liver disease.

  • On complement serology  testing, a decrease in both complement factor B (CFB) and CH50 may offer important support for the diagnosis of atypical HUS.ref36} In diarrhea-associated HUS, a lowered concentration of C3 (<  0.825 g/L) at the time of initial presentation is associated with a more severe clinical course.[25]

Imaging Studies

Perform renal ultrasonography in patients with renal failure to rule out obstruction.

Procedures

Biopsy findings pathologically establish the diagnosis of hemolytic-uremic syndrome (HUS). However, kidney biopsy is not required in children. In adults, kidney biopsy is rarely required.

Histologic Findings

The characteristic pathologic findings of hemolytic-uremic syndrome (HUS) are occlusive lesions of the arterioles and small arteries and consequent tissue microinfarctions. In HUS, the lesions are usually limited to the kidneys, whereas the lesions are more widespread in thrombotic thrombocytopenic purpura (TTP). Renal lesions are primarily focal and involve both the glomerular capillaries and the afferent arterioles. The venous side of the circulation is usually spared.

A fully developed vascular lesion consists of amorphous-appearing, hyalinelike, thrombi-containing platelet aggregates and a small amount of fibrin that partially or fully occludes the involved small vessels (see images below). Despite extensive arterial changes, no perivascular cellular infiltration or evidence of associated vasculitis is present. Subendothelial deposits with overlying endothelial proliferation may be present.

Photomicrograph (hematoxylin and eosin, original m Photomicrograph (hematoxylin and eosin, original magnification ×25) shows diffuse thickening of the glomerular capillary wall with double contouring (arrow) and swelling of endothelial cells. Fibrin thrombi and packed red blood cells are visible in the lumina (arrowhead). Courtesy of Madeleine Moussa, MD, FRCPC, Department of Pathology, London Health Sciences Centre, London, Ontario, Canada.
Photomicrograph (periodic acid-Schiff, original ma Photomicrograph (periodic acid-Schiff, original magnification ×40) shows diffuse thickening of the glomerular capillary wall with double contouring (arrow) and swelling of endothelial cells. Courtesy of Madeleine Moussa, MD, FRCPC, Department of Pathology, London Health Sciences Centre, London, Ontario, Canada.

As a rule, changes in renal function and the course of renal failure are well correlated with the pathologic findings in the kidney. Obliterative arteriolar lesions are correlated with hypertension and progressive loss of renal function. Glomerular thrombotic microangiopathic lesions and cortical necrosis are the most frequent histologic findings in Stx-HUS, whereas arterial thrombotic microangiopathic lesions are the most frequent features in non – Stx-HUS.

 

Treatment

Medical Care

Specific treatments for Shiga toxin–associated hemolytic-uremia syndrome (Stx-HUS) have not proven of value. Instead, comprehensive supportive therapy is still the mainstay during the acute phase.

There is no clear consensus on the use of antibiotics. The evidence avoidance of antibiotics unless patient is septic. An in-vitro study demonstrated that although growth-inhibitory levels of antibiotics suppressed Stx production, subinhibitory levels of certain antibiotics that target DNA synthesis, including ciprofloxacin and trimethoprim-sulfamethoxazole, increased Stx production.[26] Stx production did not increase with use of antibiotics that target the cell wall, transcription, or translation. In contrast, Stx levels were significantly reduced with azithromycin, even when Escherichia coli O157:H7 viability remained high.

Renal transplantation is safe and effective for children who progress to end-stage renal disease (ESRD). The recurrence rate in patients who undergo renal transplantation for HUS is 0-10%.

The U.S. Food and Drug Administration (FDA) has approved two monoclonal antibodies for the treatment of atypical HUS: eculizumab and ravulizumab. These monoclonal antibodies inhibit complement-mediated thrombotic microangiopathy. Both of these agents carry black box warnings regarding meningococcal infection, which include a recommendation to immunize patients with meningococcal vaccines at least 2 weeks before starting treatment.

Other treatments during the acute phase of the disease, including plasma therapy and use of intravenously infused immunoglobulin (IgG), fibrinolytic agents, antiplatelet agents, corticosteroids, and antioxidants have proved ineffective in controlled clinical trials.[27] Plasma exchange is not recommended as initial therapy in typical HUS.

Non–Styx-associated HUS

Plasma exchange is the initial treatment of choice in all adult patients with non-Stx–HUS (atypical HUS) or thrombotic thrombocytopenic purpura (TTP) and should be considered as early as possible in the disease course. The remarkable decline in mortality with the use of therapeutic plasma exchange has changed the course of this disease from fatal to mostly curable. At present, the findings of unexplained thrombocytopenia and microangiopathic hemolytic anemia are sufficient to consider thrombotic microangiopathy and initiate plasma exchange.

Plasma exchange might be more effective than infusion, as it removes potentially toxic substances from the circulation. Plasma exchange rather than infusion should be considered first-line therapy in situations that limit the amount of plasma that can be infused, such as renal impairment or heart failure.

Plasma treatment should be started within 24 hours of the patient's presentation, to decrease treatment failures. It should be continued once or twice a day for at least 2 days after complete remission.

Plasma therapy is contraindicated in Streptococcus pneumoniae–induced non–Stx-HUS; it may exacerbate the disease because adult plasma contains antibodies against the Thomsen-Friedenreich antigen. A case was recently described showing efficacy of long-term, high-dose plasma infusion (30 mL/kg) at weekly intervals over 30 months, but the long-term effects are still unknown.[16]

Eculizumab

Eculizumab (Soliris) was approved for the treatment of non–Stx-HUS by the FDA in 2011. Eculizumab is a humanized monoclonal antibody against C5 that inhibits the activation of terminal components of complement.

The safety and effectiveness of eculizumab in non–Stx-HUS were established in two single-arm trials in 37 adults and adolescents and one retrospective study in 19 pediatric and 11 adult patients. In those studies, eculizumab treatment led to improvement in kidney function, including elimination of the need for dialysis in several cases that had not responded plasma therapy. Patients treated with eculizumab also exhibited improvement in platelet counts and other blood parameters.[28]

Prospective phase II trials by Legendre and colleagues in 37 patients with non–Stx-HUS who were 12 years of age or older demonstrated that a shorter interval between the clinical manifestation of the disease and the initiation of treatment) was associated with significantly greater improvement in the estimated glomerular filtration rate. Legendre and colleagues concluded that, “the data highlight the inadequate efficacy of management with plasma exchange or infusion and confirm the clinically relevant treatment effect of eculizumab.”[29]

In a prospective phase III trial by this group in 41 patients with non–Stx-HUS who were 18 years of age or older, 30 patients had complete response of thrombotic microangiopathy, with normalization of the platelet count and lactate dehydrogenase (LDH) level and, and preservation of kidney function. Other benefits included improved quality of life, discontinuation of dialysis, and transplant protection.[30]

In the first prospective trial of eculizumab in pediatric non–Stx-HUS, Greenbaum et al reported that of  22 patients (5 months–17 years of age) 14 achieved a complete thrombotic microangiopathy response, 18 achieved hematologic normalization, and 16 had 25% or better improvement in serum creatinine. All patients were able to discontinue plasma exchange/infusion, and 9 of the 11 patients who required dialysis at baseline discontinued; none initiated new dialysis. Eculizumab was well tolerated; no deaths or meningococcal infections occurred.[31]

Ravulizumab

Ravulizumab (Ultomiris) was approved by the FDA in October 2019 for the treatment of aHUS in adult and pediatric patients aged 1 month and older. Like eculizumab, ravlizumab is a monoclonal antibody that inhibits complement-mediated thrombotic microangiopathy (TMA) 

Approved was based on data from 2 ongoing single-arm open-label studies that evaluated the efficacy of ravulizumab in pediatric (n=13) and adult (n=56) patients with aHUS. The studies demonstrated a complete TMA response in 71% of children and 54% of adults during the initial 26-week treatment period, as evidenced by normalization of hematological parameters (platelet count and LDH level) and ≥25% improvement in serum creatinine from baseline. Additionally, ravulizumab treatment resulted in reduced thrombocytopenia in 93% of children and 84% of adults; reduced hemolysis in 86% of children and 77% of adults; and improved kidney function in 79% of children and 59% of adults.[32]

Transplantation

Renal transplantation is not an option for non–Stx-HUS because of the 50% recurrence rate and >90% rate of graft failure in patients with recurrence. Recurrence rates (30-100%) are significantly higher in patients with HF1 mutations than in those without this mutation. In patients with MCP mutation, however, outcomes are favorable, and renal transplantation may correct the local MCP dysfunction, as MCP is a membrane-bound protein that is highly expressed in the kidney.

In patients with HF1 genetic defect, liver transplantation was thought to correct the defect, because HF1 is a plasma protein of hepatic origin. However, simultaneous liver and kidney transplantation in two children was complicated by premature liver failure. At present, this procedure should not be performed unless a patient is at imminent risk for life-threatening complications.

Supportive therapy

Supportive therapy is as follows:

  • Maintain fluid and electrolyte balance

  • Adequate blood-pressure control and adequate renin-angiotensin blockade is helpful for patients who have chronic kidney disease after an episode of Stx-HUS

  • For seizure control, consider prophylactic phenytoin in patients with neurologic symptoms (20-40% of patients have seizures)

  • Control azotemia

  • Optimize nutrition

Consultations

Patients with hemolytic-uremic syndrome (HUS) may require consultation with the following specialists:

  • Nephrologist
  • Hematologist
  • Neurologist in cases of neurologic involvement
  • Intensivists for intensive care unit (ICU) management

Diet

Provide nutritional support during the acute illness. If patients have severe diarrhea, they may require parenteral nutrition. Early restriction of proteins, in addition to renin-angiotensin blockade, may have a beneficial effect on the long-term renal outcome in patients who develop chronic kidney disease after Stx-HUS.

 

Medication

Medication Summary

The U.S. Food and Drug Administration has approved two monoclonal antibodies for the treatment of hemolytic-uremic syndrome (HUS) that is not associated with Shiva-like toxin (non–Stx-HUS; atypical HUS): eculizumab and ravulizumab.

Supportive care only is used for Stx-HUS (typical HUS). Medications for supportive care may include angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs)for control of hypertension, or phenytoin for prevention of seizures.

Monoclonal Antibodies

Class Summary

Agents in this category may block the formation of membrane attack complex, which can stabilize the hemoglobin and reduce the need for RBC transfusions.

Eculizumab (Soliris)

Monoclonal blocking antibody to complement protein C5; inhibits cleavage to C5a and C5b, thus preventing terminal complement complex C5b-9, thereby preventing RBC hemolysis

Inhibits terminal complement mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS

Ravulizumab (Ravulizumab-cwvz, Ultomiris)

Ravulizumab is a monoclonal blocking antibody to complement protein C5; it inhibits cleavage to C5a and C5b, thus preventing terminal complement complex C5b-9, thereby preventing RBC hemolysis. It inhibits terminal complement-mediated intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and complement-mediated thrombotic microangiopathy in patients with aHUS.

 

Follow-up

Further Outpatient Care

Monitor renal function and blood pressure, because as many as 80% of adults with hemolytic-uremic syndrome (HUS) require long-term dialysis or renal transplantation.

Ensure adequate blood pressure control and consider renin-angiotensin blockade with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers.

Early protein restriction may be needed in patients who develop residual chronic kidney disease after the acute phase.

Further Inpatient Care

Provide nutritional support during the acute illness in patients with hemolytic-uremic syndrome (HUS). Some children with gastrointestinal involvement may require prolonged parenteral feeding. Closely monitor electrolyte levels, renal function, and platelet counts.

Transfer

The patient may need to be transferred to a tertiary care facility for specialized treatment (eg, plasma exchange, dialysis, ICU monitoring).

Deterrence/Prevention

Because typical hemolytic-uremic syndrome (HUS) commonly occurs in epidemics, consider this possibility and inform health authorities to monitor for the possibility of index cases and to prevent the spread of disease in the community.

At present, prevention is the main approach to decreasing the morbidity and mortality associated with Stx-E coli infection.

Antibiotic treatment of children with E coli O157:H7 infection increases the risk of hemolytic-uremic syndrome (HUS) and should be avoided unless they have septicemia.[33]

 

Questions & Answers

Overview

What is hemolytic-uremic syndrome (HUS)?

When was hemolytic-uremic syndrome (HUS) first described?

What is the pathogenesis of atypical (non-Stx-associated) hemolytic-uremic syndrome (HUS)?

What is the pathogenesis of familial non-Stx-associated hemolytic-uremic syndrome (HUS)?

What is the primary event in the pathogenesis of hemolytic-uremic syndrome (HUS)?

How is hemolytic-uremic syndrome (HUS) categorized?

What is the pathogenesis of typical (Stx-associated) hemolytic-uremic syndrome (HUS)?

What are triggers for sporadic non-Stx-associated hemolytic-uremic syndrome (HUS)?

Which patient group is at highest risk for hemolytic-uremic syndrome (HUS)?

Which bacterial infections cause hemolytic-uremic syndrome (HUS)?

Which viral infections cause hemolytic-uremic syndrome (HUS)?

Which fungal infection causes hemolytic-uremic syndrome (HUS)?

Which vaccines may cause hemolytic-uremic syndrome (HUS)?

What causes secondary or sporadic hemolytic-uremic syndrome (HUS)?

How does pregnancy-associated hemolytic-uremic syndrome (HUS) develop?

Which drugs are implicated in the etiology of non-Stx-hemolytic-uremic syndrome (HUS)?

What is the prevalence of hemolytic-uremic syndrome (HUS) following transplantation?

How prevalent is hemolytic-uremic syndrome (HUS) in the US?

How prevalent is hemolytic-uremic syndrome (HUS) globally?

How prevalent is hemolytic-uremic syndrome (HUS) by race and sex?

How prevalent is hemolytic-uremic syndrome (HUS) by age?

What are possible complications of hemolytic-uremic syndrome (HUS)?

What is the prevalence of neurological complications of hemolytic-uremic syndrome (HUS)?

What is the prognosis of Stx-hemolytic-uremic syndrome (HUS)?

What is the prognosis of non Stx-hemolytic-uremic syndrome (HUS)?

Which factors predict a poor prognosis for hemolytic-uremic syndrome (HUS)?

How does kidney transplant affect the prognosis of hemolytic-uremic syndrome (HUS)?

What information should be given to patients with hemolytic-uremic syndrome (HUS)?

Presentation

What are the signs and symptoms of hemolytic-uremic syndrome (HUS)?

Which physical findings suggest hemolytic-uremic syndrome (HUS)?

DDX

Which conditions should be included in the differential diagnoses of hemolytic-uremic syndrome (HUS)?

What are the differential diagnoses for Hemolytic-Uremic Syndrome?

Workup

What is the role of lab studies in the diagnosis of hemolytic-uremic syndrome (HUS)?

What is the role of imaging studies in the diagnosis of hemolytic-uremic syndrome (HUS)?

What is the role of biopsy in the diagnosis of hemolytic-uremic syndrome (HUS)?

What are characteristic pathologic findings of hemolytic-uremic syndrome (HUS)?

Treatment

How are the treatment options for Stx-hemolytic-uremic syndrome (HUS)?

What is the role of plasma exchange in the treatment of non-Stx-hemolytic-uremic syndrome (HUS)?

What is the role of monoclonal antibodies in the treatment of hemolytic-uremic syndrome (HUS)?

What is the role of renal transplantation in the treatment of hemolytic-uremic syndrome (HUS)?

What is included in supportive therapy for hemolytic-uremic syndrome (HUS)?

Which specialists should be consulted in the treatment of hemolytic-uremic syndrome (HUS)?

What dietary restrictions are needed during treatment of hemolytic-uremic syndrome (HUS)?

Medications

Which medications are used in the treatment of hemolytic-uremic syndrome (HUS)?

Which medications in the drug class Monoclonal Antibodies are used in the treatment of Hemolytic-Uremic Syndrome?

Follow-up

How should patients be monitored following treatment of hemolytic-uremic syndrome (HUS)?

What is included in inpatient care for hemolytic-uremic syndrome (HUS)?

When is transfer to a tertiary care facility indicated for treatment of hemolytic-uremic syndrome (HUS)?

How is hemolytic-uremic syndrome (HUS) prevented?