Hemolytic-uremic syndrome (HUS) is a clinical syndrome characterized by progressive kidney failure that is associated with microangiopathic (nonimmune, Coombs-negative) hemolytic anemia and thrombocytopenia.[1] HUS is the most common cause of acute kidney injury in children and is increasingly recognized in adults.[2, 3, 4, 5]
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 kidney 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 complement inhibitors, eculizumab and ravulizumab, are approved for the treatment of pediatric and adult patients with atypical HUS. (See Treatment.)
See also Pediatric Hemolytic Uremic Syndrome.
The Swiss pediatric hematologist Conrad von Gasser and colleagues first described hemolytic-uremic syndrome (HUS) in 1955.[6] In 1983, Karmali and colleagues reported finding a toxin produced by specific strains of Escherichia coli in the stools of children with HUS. This toxin was lethal to Vero cells (a line of kidney cells isolated from the African green monkey), and so was termed verotoxin. Also in 1983, O’Brien and colleagues purified a lethal toxin from the enteropathogenic E coli O157:H7 strain that structurally resembled that of Shigella dysenteriae type 1, and termed it Shiga-like toxin (both terms honor the Japanese bacteriologist Kiyoshi Shiga, who in 1898 discovered S dysenteriae and its toxin as the cause of dysentery).[7, 8]
The term Shiga-like toxin was replaced with the term Shiga toxin when the two were found to be identical. E coli strains produce two types of Shiga toxins. Shiga toxin type 1 (Stx1) is identical to the toxin produced by Shigella spp or differs by only one amino acid. Stx2 is structurally and functionally similar to Stx1 but immunologically distinct; it shares approximately 50% homology with Stx1 but the two are not cross-neutralized with heterologous antibodies. Stx2 is strongly associated with hemorrhagic colitis and HUS. In addition, there are 10 subtypes of Stx1 and Stx2, each of which is divided into variants, which have different pathogenicity. The capacity of certain E coli strains to produce Shiga toxins appears to have resulted from transduction of the responsible genes by bacteriophages.[7, 8]
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.[9, 10, 11, 12]
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 toxin (Stx) or not.[13, 14]
Typical HUS (Shiga 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 kidney function.
In Asia and Africa, typical HUS is often associated with Stx-producing Shigella dysenteriae serotype 1. 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[15] :
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.
Non–Stx-HUS, or atypical HUS, is less common than Stx-HUS and accounts for 5-10% of all cases. As the name indicates, non–Stx-HUS does not result from infection by Stx-producing bacteria. Unlike HUS caused by enterohemorrhagic E coli, which occurs principally in summer, atypical HUS may occur year-round without a gastrointestinal prodrome (D- HUS). Atypical HUS is a complement-mediated thrombotic microangiopathy.
Non–Stx-HUS may occur at all ages but is most frequent in adults and occurs without prodromal diarrhea (D- HUS). It 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, with as many as 50% progressing 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:
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. The pathogenesis in these cases appears to have several mechanisms. For example, S pneumoniae strains isolated from patients with pneumococcal-induced HUS have been shown to bind high levels of human plasminogen, which when activated to yield plasmin causes damage to endothelial cells, with exposure of the underlying matrix; this leads to thrombosis.[17, 18] Clinically, pneumococcal-induced HUS is usually severe, with 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 also have a poor prognosis, with a 50-90% risk of death or ESRD.
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.[19, 20, 21, 22]
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 kidney function was noted to have a mutation in exon 23 of the factor H gene.[21]
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.
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:
Viral infections may include the following:
Fungal infections can include Aspergillus fumigatus.
Vaccinations may include the following:
Causes of the secondary or sporadic form may include the following:
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 kidney dysfunction and hypertension occur in most patients.
Drugs implicated in causing non–Stx-HUS are as follows:
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 kidney 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.
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 2015, 274 cases of HUS were reported in the United States, 122 of them in children 1-4 years of age.[26]
Non–Stx-HUS accounts for 5-10% of all cases of 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.
In children younger than 15 years, typical 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 cases peaking in the summer and fall.
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.
For Stx-HUS, acute rkidney injury occurs in 55-70% of patients; up to 70-85% recover kidney 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:
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.[27]
Stx-HUS prognosis is as follows:
A study by Balestracci et al comparing 145 cases of non-severe Stx-HUS with 71 severe cases found that a shorter prodromal phase is associated with worse prognosis. Rates of severe disease were 75.8% in patients with a prodrome of 1-2 days, 29.6% in those with a prodrome of 3-7 days, and 11.4% in those with a prodrome of 8 days or longer.[28]
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.[29]
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).[30]
Non–Stx-HUS prognosis is as follows:
Factors predictive of poor prognosis are as follows:
In a retrospective study of 323 adult kidney transplant recipients with HUS and 121,311 transplant recipients with other kidney 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).[31]
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 Blood in the Urine, and Acute Kidney Failure.
The history in a patient with typical hemolytic-uremic syndrome (HUS) may include the following:
Physical findings may include the following:
Hemolytic-uremic syndrome (HUS) is primarily a clinical diagnosis, confirmed by laboratory studies showing a microangiopathic hemolytic anemia.
Biopsy findings pathologically establish the diagnosis of HUS. However, kidney biopsy is not required in children. In adults, kidney biopsy is rarely required.
Perform kidney ultrasonography in patients with acute kidney injury, to rule out obstruction.
In patients with atypical hemolytic-uremic syndrome (aHUS), Kidney Disease: Improving Global Outcomes (KDIGO) recommends genetic testing to identify an underllying hereditary abnormality.[33]
Laboratory findings in patients with hemolytic-uremic syndrome (HUS) may include the following:
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.
![]() View Image | Photomicrograph (hematoxylin and eosin, original magnification ×25) shows diffuse thickening of the glomerular capillary wall with double contouring (.... |
![]() View Image | Photomicrograph (periodic acid-Schiff, original magnification ×40) shows diffuse thickening of the glomerular capillary wall with double contouring (a.... |
As a rule, changes in kidney function and the course of kidney failure correlate well with the pathologic findings in the kidney. Obliterative arteriolar lesions are correlated with hypertension and progressive loss of kidney 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.
Specific treatments for Shiga toxin–associated hemolytic-uremic 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 suggests 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.[37] 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.
Kidney transplantation is safe and effective for children who progress to end-stage renal disease (ESRD). The recurrence rate in patients who undergo kidney transplantation for HUS is 0-10%.
The US Food and Drug Administration (FDA) has approved two complement inhibitors 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.[38] Plasma exchange is not recommended as initial therapy in typical 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 report describes 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.[22]
Eculizumab
Eculizumab (Soliris) was approved for the treatment of non–Stx-HUS (atypical 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.[39]
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.”[40]
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.[41]
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.[42]
In a prospective study of eculizumab discontinuation after a mean treatment duration of 16.5 months in 36 adults and 19 children with atypical HUS, Fakhouri et al reported an increased risk of relapse in female patients and those with a rare variant in a complement gene (mostly in MCP, CFH, and CFI). An increased sC5b-9 plasma level at eculizumab discontinuation was also associated with a higher risk of relapse However, requirement for dialysis during a previous episode of acute atypical HUS was not associated with increased relapse risk. Of the patients who experienced relapse, 11 regained their baseline kidney function after restarting eculizumab and 2 had a worsening of their preexisting chronic kidney disease, including 1 patient who progressed to end-stage kidney disease.[43]
Ravulizumab
Ravulizumab (Ultomiris) was approved by the FDA in 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.[44]
Transplantation
In the past, kidney transplantation was not an option for patients with non–Stx-HUS (atypical HUS [aHUS]) because of the 50% recurrence rate and > 90% rate of graft failure in patients with recurrence. Recurrence rates (30-100%) were significantly higher in patients with HF1 mutations than in those without this mutation. In patients with MCP mutation, however, outcomes are favorable; kidney transplantation may correct the local MCP dysfunction, as MCP is a membrane-bound protein that is highly expressed in the kidney.
The advent of eculizumab broadened the indications for kidney transplantation in aHUS. Prophylactic eculizumab therapy—initiated at transplantation, because most posttransplant recurrence of non–Stx-HUS occurs within the first year—has been used to prevent recurrence and associated graft injury. In a United Kingdom study of 118 kidney transplants in 86 recipients who had a confirmed diagnosis of aHUS, prophylactic eculizumab treatment improved allograft survival in medium and high-risk recipients, with 1-y survival of 97% versus 64% in untreated patients.[45]
In the Netherlands, where kidney transplantation in patients with aHUS has been performed without eculizumab prophylaxis since 2016, rescue treatment with eculizumab has proved effective. Some patients with recurrence have suffered irreversible loss of kidney function, likely caused by delayed diagnosis and treatment and/or overly aggressive discontinuation of eculizumab.[46]
In patients with HF1 genetic defect, liver transplantation was thought to correct the defect, because HF1 is a plasma protein of hepatic origin. Combined liver and kidney transplantation has been used in HUS patients with mutations in Factor H, most of them children. Initial attempts had a fatal outcome, but the introduction of pre-emptive plasmapheresis with plasma exchange has proved very successful in improving results, although risks remain.[47]
Supportive therapy is as follows:
Patients with hemolytic-uremic syndrome (HUS) may require consultation with the following specialists:
Provide nutritional support during the acute illness. If patients have severe diarrhea, they may require parenteral nutrition. Some children with gastrointestinal involvement may require prolonged parenteral feeding. 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.
Because typical 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 HUS and should be avoided unless they have septicemia.[48]
Although most pediatric patients with Stx-HUS recover completely, sequelae can develop years after the acute phase, so regular long-term follow-up is needed. In a European study of 138 patients with Stx-HUS, 34% later presented with a decreased glomerular filtration rate, proteinuria, hypertension, or neurologic symptoms. In most cases, onset of those sequelae occurred in the first year after Stx-HUS, but in others the onset was delayed for as long as 10 years. Late onset of sequelae occurred more commonly in patients who had experience critical illness in the acute phase, as indicated by need for kidney replacement therapy or plasma treatment.[49]
Monitor kidney function and blood pressure, because as many as 80% of adults with HUS require long-term dialysis or kidney 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.
The US Food and Drug Administration has approved complement inhibitors for the treatment of hemolytic-uremic syndrome (HUS) that is not associated with Shiva 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.
Clinical Context: 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 paroxysmal nocturnal hemoglobinuria and complement-mediated thrombotic microangiopathy (TMA) in atypical hemolytic uremia synrome (aHUS)
Clinical Context: 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.
Agents in this category may block the formation of membrane attack complex, which can stabilize the hemoglobin and reduce the need for RBC transfusions.
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 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.
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 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.