Pediatric Hemolytic Uremic Syndrome

STEC-HUS is usually preceded by a colitis caused by Shiga toxin–producing Escherichia coli (STEC). Subsequent inflammation of the colon facilitates systemic absorption of the Stx and lipopolysaccharide from the GI tract. The major toxins that cause hemolytic-uremic syndrome, Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2), are similar in structure to the classic Stx. These toxins bind to globotriaosylceramide (Gb3), a glycolipid receptor molecule on the surface of endothelial cells in the gut, kidney, and, occasionally, other organs. Differential expression of Gb3 on glomerular capillaries compared with other endothelial cells may explain the predominance of renal injury. Damaged endothelial cells of the glomerular capillaries release vasoactive and platelet-aggregating substances. The endothelial cells swell, and fibrin is deposited on the injured vessel walls.

Swelling and microthrombi formation within the glomerular capillaries produce a localized intravascular coagulopathy. The glomerular filtration rate is reduced, and renal insufficiency ensues. Erythrocytes are damaged and fragmented as they traverse the narrowed glomerular capillaries. This leads to the characteristic microangiopathic hemolytic anemia. Hemolysis may also be a result of lipid peroxidation. See the image below.

Thrombocytopenia is believed to result from a combination of platelet destruction, increased consumption, sequestration in the liver and spleen, and intrarenal aggregation. Platelets are damaged as they pass through the affected glomerular capillaries. Remaining platelets circulate in a degranulated form and show impaired aggregation. Stx also binds to activated platelets.

Abnormalities of anti–platelet-aggregating agents (eg, prostaglandin I2 [PGI2]), platelet-aggregating agents (thromboxane A2 [TXA2]) and von Willebrand factor (vWF) multimers are also important factors that contribute to thrombocytopenia. A decrease in PGI2 during the early stages of hemolytic-uremic syndrome has been noted. Defective PGI2 production is believed to play a role in STEC-HUS; abnormal PGI2 synthesis is believed to play a role in aHUS.

TXA2 levels are increased during the acute stage of hemolytic-uremic syndrome, leading to increased platelet aggregation. Another possible cause for increased platelet aggregation is large vWF multimers. In vitro, these large multimers have a greater ability to aggregate platelets than the normal, smaller multimers. Normal plasma contains a vWF-cleaving metalloproteinase (ADAMTS13) that rapidly degrades large vWF multimers. Many cases of TTP are associated with deficient function of ADAMTS13.

Abnormalities of ADAMTS13 may take the form of decreased quantity or absence of the enzyme, a mutation resulting in normal quantity of a defective enzyme, or an antibody inhibitor of the enzyme. Genetic or acquired defects in this protease have also been reported in patients with aHUS, but less frequently than in patients with TTP. Alterations in ADAMTS13 are not involved in the pathogenesis of STEC-HUS. The role of ADAMTS13 in both TTP and, less commonly, aHUS, remains incompletely understood. Most current authors define a thrombotic microangiopathy with ≤10% ADAMTS13 activity as TTP and not aHUS.

White blood cell (WBC) counts are usually elevated in the blood of patients with hemolytic-uremic syndrome. Activated neutrophils are believed to damage endothelial cells by releasing elastase (a catabolic enzyme that promotes endothelial cell detachment) and by producing free radicals. Monocytes may be stimulated to release cytokines (ie, interleukin 1 and tumor necrosis factor [TNF]) that also damage endothelial cells.

aHUS frequently occurs in patients with genetic abnormalities of the alternative pathway of the complement system. Genetically mediated cases are often not preceded by diarrheal illness, often manifest a recurrent course, and are associated with a less favorable long-term prognosis. Mutations causing aHUS have been identified in the genes coding for:

• Complement factor H (CFH)
• Complement factor I (CFI)
• Complement factor B (CFB)
• Complement C3 (C3)
• CD46, also known as membrance cofactor protein (MCP)
• DGKE
• Thrombomodulin (TBHD)
• Diacylglycerol kinase (DGKE)

This is not an exclusive list, and it continues to grow as new genetic knowledge develops. Up to 50% of patients with aHUS do not have an identifiable mutation. Patients may also develop aHUS due to an acquired antibody inhibitor of factor H or other complement factors.

Pneumococcal-associated hemolytic-uremic syndrome constitutes a distinct subgroup of aHUS. This variant occurs with infections caused by S pneumoniae, usually pneumonia.[2] It is actually a distinct entity that has little relation to the aHUS associated with complement factor mutations. The bacterial toxin neuraminidase damages endothelial cells and initiates hemolytic-uremic syndrome in this setting.

As a toxin-mediated disease, pneumococcal-associated hemolytic-uremic syndrome has much in common with STEC-HUS mediated by Stx. Bacteria with neuraminidase remove N-acetylneuraminic acid from cell-surface glycoproteins and expose the normally hidden T antigen (Thomsen-Friedenreich antigen) on erythrocytes, platelets, and glomeruli. Serum contains anti-T immunoglobulin M (IgM), which can react with the antigen and cause damage to RBCs and the kidneys.

STEC-HUS

GI tract infection with Stx–producing E coli (STEC) precedes most cases of STEC-HUS. Stx1 is identical to the Stx produced by Shigella dysenteriae. Stx2 has a 55-60% amino acid homology with Stx. They injure the gut and lead to hemorrhagic colitis. Most cases worldwide are associated with STEC 0157:H7 infection. This organism is very resilient; viable bacteria have been reported in environments up to 10 months following initial contamination. Aside from Stx production, this bacteria produces virulence factors that mediate tight adherence to the host cell, facilitating transluminal transport of the toxins into the systemic circulation. Cattle are the major reservoir for human infection. The use of antimotility agents, antidiarrheal agents, and antibiotics has been reported to increase the risk of developing hemolytic-uremic syndrome. E coli O104:H4 was responsible for a large outbreak of hemolytic-uremic syndrome in Germany.

Other causes of hemolytic-uremic syndrome include infection by the following:

• S dysenteriae (established as an etiologic agent)

• Salmonella typhi (established as an etiologic agent)

• Campylobacter jejuni (established as an etiologic agent)

• Yersinia species

• Pseudomonas species

• Bacteroides species

• Entamoeba histolytica

• Aeromonas hydrophilia

• Organisms of the class Microtatobiotes

aHUS

Causes of aHUS include the following:

• Inherited (eg, mutations in the gene for factor H, a complement regulatory protein)

• S pneumoniae (neuraminidase-associated)

• Portillo virus

• Coxsackie virus

• Influenza virus

• Epstein-Barr virus

• Pregnancy: Hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura (TTP) are associated with pregnancy; preeclampsia and HELLP syndrome also have features in common and should be part of the differential diagnosis.

• Drugs (eg, chemotherapy, oral contraceptives, cyclosporine, tacrolimus)

• Bone marrow or hematopoietic stem cell transplantation

• Malignancy

• Idiopathic

• Systemic lupus erythematosus (SLE)

• Glomerulonephritis, especially membranoproliferative glomerulonephritis

• Malignant hypertension

United States statistics

Between 1982 and 2002, 354 E coli O157:H7–associated hemolytic-uremic syndrome cases were reported. Transmission route was highest among swimming outbreaks, followed by person-to-person, unknown, animal contact, foodborne, and drinking water–related outbreaks. Daycare centers were the most common person-to-person outbreak setting. Although contaminated ground beef was the most common cause of foodborne outbreaks, produce-associated outbreaks are also common (ie, lettuce, sprouts, cabbage, apple cider, apple juice). These have been attributed to fecal contamination of produce in the fields, from wild animals or from fertilization containing human or animal fecal matter.

Incidence is increased during the summer and early fall. Outbreaks of diarrhea followed by hemolytic-uremic syndrome have been reported in institutions, boarding schools, and daycare centers. Seasonal variation is not observed in aHUS. STEC-HUS is much more common than aHUS.

International statistics

Hemolytic-uremic syndrome occurs worldwide but has a higher incidence in South Africa, Holland, and Argentina. The largest outbreak to date occurred in Germany in 2011.

Race-, sex-, and age-related demographics

Hemolytic-uremic syndrome occurs in all races. Race is a purely social construct, based on self-identification. It has no biologic basis, and should not be used in determining diagnosis or treatment.

Males and females are affected in equal numbers.

A large majority of cases of STEC-HUS occur in children aged 7 months to 6 years. STEC-HUS is much less common in adults, although the disease may occur at any age. A large outbreak in Germany due to a novel strain of E. coli 0104:H4 forms a notable exception, in which 88% of patients were adults.[3] No age predilection is noted for aHUS. Genetically mediated forms may present as early as birth or the neonatal period.

STEC-HUS

Most patients who receive the appropriate treatment have a good recovery. Recurrence is very rare. Poor prognostic indicators include the following:

• Elevated WBC count at diagnosis

• Prolonged anuria

• Severe prodromal illness

• Severe hemorrhagic colitis with rectal prolapse or colonic gangrene

• Severe multisystemic involvement

• Persistent proteinuria

• Genetic abnormalities in complement regulatory factors

The long-term prognosis for survivors of childhood STEC-HUS remains unknown. A 5-year follow-up of a cohort of patients showed no difference in blood pressure and slightly higher rates of microalbuminuria compared with controls.[4]  The patients also had lower glomerular filtration rates (GFRs) as measured by cystatin C but not as measured by serum creatinine levels. Other studies have shown similar findings. Continued long-term follow-up studies are needed to help determine whether survivors have residual subclinical renal injury that could manifest itself later in life. At present, patients should be counseled on avoiding risk factors for renal disease (eg, tobacco use, obesity, hypertension) and the importance of continued medical follow-up.

aHUS

The prognosis is more guarded than for STEC-HUS. Patients with aHUS are at risk for relapses and a higher risk of progression to end-stage renal disease (ESRD). Ongoing treatment with eculizumab reduces this risk.

Morbidity/mortality

Mortality rates have decreased progressively from near universal fatality in 1955 to only 3-5% during the 1990s. This improvement is attributed to better management during the acute stage of the disease, with aggressive management of hypertension, fluid overload, electrolyte disturbances, and nutrition, often requiring dialysis. The mortality rate in underdeveloped countries remains as high as 72%. Patients with hereditary hemolytic-uremic syndrome may have a worse prognosis due to the risk of recurrent episodes.

Complications

Renal system complications are as follows:

• Renal insufficiency

• Renal failure

• Hypertension

CNS complications are as follows:

• Mental retardation

• Seizures

• Focal motor deficit

• Optic atrophy

• Cortical blindness

• Learning disability

Endocrine system complications are as follows:

• Diabetes mellitus

• Pancreatic exocrine insufficiency

GI system complications can include intestinal necrosis.

Cardiac system complications can include congestive heart failure.

Diet concerns are as follows:

• Low-salt diet to decrease risk of hypertension

• Diet high in iron and folic acid content to help recover from anemia

• High-energy diet to help patient regain lost weight

Social worker or psychologist consultation can help the family cope with the illness.

Patients with Shiga toxin–producing E coli hemolytic-uremic syndrome (STEC-HUS) typically experience several days of diarrhea, with or without vomiting, followed by sudden onset of symptoms such as irritability and pallor. In more than 80% of patients, the diarrhea is visibly bloody. Other symptoms include restlessness, oliguria, edema, and macroscopic hematuria. In some patients, the prodrome may improve as hemolytic-uremic syndrome symptoms begin. The clinical picture may mimic that of an acute abdomen. In patients infected with a Shiga toxin (Stx)–producing strain of E coli, hemolytic-uremic syndrome occurs in 5-15%.

The risk of progression to hemolytic-uremic syndrome is increased in very young or elderly persons, in patients who have been treated with antimotility drugs or antibiotics, and in patients with a fever or a high leukocyte count.

The history should include inquiry about possible recent exposure to E coli, such as consuming undercooked meat, encounters with livestock or petting zoos, contacts with other persons with diarrhea, and attendance at daycare or school. However, most cases of STEC-HUS are sporadic, with no clearly identifiable source of infection, even when stool culture yields a toxigenic organism. Outbreaks involving multiple persons more commonly lead to a source.

Atypical hemolytic-uremic syndrome (aHUS) may follow a respiratory illness, especially when caused by S pneumoniae.

Features of all forms of hemolytic-uremic syndrome include the following:

• Hematology: Hemolysis occurs in all patients with hemolytic-uremic syndrome. It can proceed rapidly, resulting in a rapid fall of the hematocrit. Platelet counts usually fall below 40,000/µL. However, the degree of thrombocytopenia does not correlate with the severity of hemolytic-uremic syndrome, and some children can maintain relatively normal kidney function despite severe hematologic abnormalities. Many patients have petechiae, purpura, and oozing from venipuncture sites. Overt bleeding is less common.

• CNS: Patients often present with sudden onset of lethargy and irritability. Other findings may include ataxia, coma, seizures, cerebral swelling, hemiparesis, and other focal neurologic signs. CNS changes may be caused by cerebral ischemia from microthrombi, effects of hypertension, hyponatremia, or uremia. aHUS tends to be associated with a greater number of neurologic symptoms than STEC-HUS.

• Renal system: Acute renal insufficiency usually begins with the onset of hemolysis. Although patients have decreased urine output, frequent diffuse watery stools may mask this sign. If renal insufficiency is not recognized and treated, hyponatremia, hyperkalemia, severe acidosis, ascites, edema, pulmonary edema, and hypertension ensue.

• GI tract: STEC-HUS is usually preceded by 3-12 days of watery or bloody diarrhea. Vomiting and crampy abdominal pain are also common. Note that diarrhea may improve as the other hemolytic-uremic syndrome symptoms begin (eg, thrombocytopenia, renal insufficiency). Life-threatening complications include intestinal perforation or necrosis. Even without these complications, the colitis of hemolytic-uremic syndrome may cause severe abdominal pain, which may persist for several days into the illness.

• Infectious signs: Fever is present in 5-20% of patients. The presence of fever, leukocytosis, or both is a prognostic indicator of the risk of developing more severe hemolytic-uremic syndrome.

• Pancreas: Mild pancreatic involvement is common but can be severe on occasion, with necrosis, pseudocysts, or both, which can leave the patient with type 1 diabetes and, on rare occasion, exocrine dysfunction.

• Cardiovascular: Congestive heart failure may occur.

Blood pressure may be elevated unless the patient is volume depleted (eg, from diarrhea). The child appears ill and pale. Abdominal pain and tenderness may be present, possibly severe. Peripheral edema may be present. Petechiae, purpura, or oozing from venipuncture sites may be present.

Hematology

Classic findings in hemolytic-uremic syndrome (HUS) include anemia and thrombocytopenia, with fragmented RBCs (eg, schistocytes, helmet cells, burr cells), as shown in the image below.

 

WBC differential may reveal a left shift (ie, immature WBCs, including bands, myelocytes, metamyelocytes). Patients with Shiga toxin–producing E coli hemolytic-uremic syndrome (STEC-HUS) may have extremely high WBC counts, in the range of 50,000-60,000/µL.

Coombs test results are negative, except with S pneumoniae –associated hemolytic-uremic syndrome.

Reticulocyte count is elevated.

Levels of serum haptoglobin, which binds hemoglobin, are decreased.

Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are normal.

Fibrin degradation products are increased.

Fibrinogen levels are increased or within reference range.

Serum chemistry testing

BUN and creatinine levels are elevated.

Various electrolyte and ion derangements may be present because of vomiting, diarrhea, dehydration, and renal failure; these may include hyponatremia, hyperkalemia, hyperphosphatemia, hypocalcemia, and acidosis. Phosphorus concentration is elevated.

Uric acid level may be increased because of acute renal failure, dehydration, and cell breakdown.

Protein (see Serum Protein Electrophoresis) and albumin levels may be mildly decreased.

Bilirubin and aminotransferase (see Alanine Aminotransferase and Aspartate Aminotransferase) levels are typically elevated.

Lactate dehydrogenase (LDH) level is elevated. Serial measurements of LDH help track the approximate level of hemolytic activity.

Urinalysis

Urinalysis should be performed to assess the following:

• Protein

• Heme

• Bilirubin

• RBCs (dysmorphic)

• WBCs

• Casts - Cellular, granular, pigmented, hyaline

Stool testing

Usually, culture yield is low after 7 days of diarrhea. The standard method used to detect and isolate STEC involves sorbitol MacConkey (SMAC) agar plates that enable identification of characteristic sorbitol nonfermenting colonies of STEC O157:H7. E coli 0157:H7 does not grow on agar plates used for routine stool cultures. Notify the laboratory and request specific testing for this organism when hemolytic-uremic syndrome is suspected. Even patients with documented bloody diarrhea and other classic features of STEC-HUS often do not yield a causative organism on stool culture. This reflects the limited sensitivity of stool culture, not the absence of disease. Prior treatment with antibiotic may also lead to a false-negative stool culture.  The diagnosis of hemolytic-uremic syndrome is a clinical one and is not excluded by a negative stool culture.  Stool specimens with negative cultures should also be tested by PCR for molecular detection of Shiga toxin.

Stx may be detected using specific antibody testing and enzyme-linked immunosorbent assay (ELISA), but PCR testing has largely replaced these methods.

Stool leukocytes have little value in detecting E coli 0157:H7. They are absent in approximately 50% of cases.

Other tests

Testing for ADAMTS13 activity may help distinguish between atypical hemolytic-uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP). ADAMTS13 activity of less than 10% is consistent with a diagnosis of TTP. Patients with low levels of ADAMTS13 activity should also be tested for the presence of antibody to ADAMTS13. If plasma exchange is planned, specimens should be obtained before starting plasma exchange, as the donor plasma may confound the results. Use of a laboratory with rapid turnaround time is recommended, as the results may significantly impact treatment. Several laboratories now offer ADAMTS13 results in 24 hours or less.

Complement C3 may be decreased in patients with aHUS.

Genetic testing for complement factor mutations is now available from several laboratories. Due to the complexity and cost of this testing, consultation with an expert in this area is recommended. Historically, genetic testing has taken weeks or even months to perform; thus, it has not been useful in the immediate management of a patient with hemolytic-uremic syndrome. However, advances in genetic testing methods have significantly reduced the turnaround time, and at least one provider offers results in two business days. Acute treatment decisions should not be delayed while awaiting results. Results may be helpful in determining long-term prognosis (eg, the presence of factor H mutations portends a very high risk of recurrence).

Patients with suspected aHUS should be tested for an inhibitory antibody to complement factor H.

A test for serum antibodies to STEC 0157:H7 is available, but its clinical use is not well defined.

Note that HUS is a reportable condition in many jurisdictions.

Consider performing chest radiography to evaluate for pulmonary congestion or edema, if clinically indicated.

Renal ultrasound typically reveals nonspecific findings (eg, increased echogenicity) and is of limited use. Ultrasonography may be helpful if the diagnosis is uncertain or if one needs evaluation of blood flow in the large renal vessels.

Abdominal ultrasonography or CT scanning may help if clinical findings raise suspicion of intestinal obstruction or perforation.

Noncontrast CT scanning or MRI of the head is indicated in patients with CNS symptoms or acute mental status changes.[5] Avoid iodinated contrast or gadolinium in patients with decreased renal function.

Patients with hyperkalemia may require ECG monitoring.

Renal biopsy is not usually necessary for diagnosis and may be contraindicated due to thrombocytopenia. Histologic analysis of kidney specimens reveals thrombotic microangiopathy, with swollen glomerular endothelial cells and red cells and platelets in the capillaries. Accumulation of fibrinlike material in the subendothelial space creates a thickened appearance to the capillary walls. Thrombi may be observed in the glomerular capillaries and arterioles. These findings can progress to acute cortical necrosis involving both glomeruli and convoluted tubules.

Histological slides are presented below.

Tissue section of the gut shows microangiopathy, with endothelial cell injury, and thrombosis, with submucosal edema and hemorrhage.

Microthrombi may be observed in other organs, including the lungs, liver, heart, adrenal glands, brain, thyroid, pancreas, thymus, lymph nodes, and ovaries.

Successful management of hemolytic-uremic syndrome (HUS) begins with early recognition of the disease and supportive care. Management includes good control of volume status, electrolyte abnormalities, hypertension, and anemia. Correct identification of the subtype of HUS is critical to selecting appropriate treatment. This is complicated because confirmatory testing may take considerable time, and the results may be inconclusive.  For example, a negative genetic profile does not rule out a diagnosis of atypical HUS. Consultation with a physician with significant experience and expertise in managing patients with HUS is strongly recommended.

Supportive care measures apply to both Shiga toxin–producing E coli hemolytic-uremic syndrome (STEC-HUS) and atypical hemolytic uremic syndrome (aHUS). Additional special considerations for aHUS are listed at the end of this section.

Fluid and electrolyte management

Early and ample hydration with intravenous isotonic saline is associated with a lower risk of progression to oligoanuric hemolytic-uremic syndrome in patients with diarrhea (see Deterrence/Prevention).[6] Studies on fluid therapy in patients with established hemolytic-uremic syndrome are lacking; however, based on the data above, the authors recommend that patients with hemolytic-uremic syndrome continue to receive intravenous isotonic saline to maintain a euvolemic state.

Monitor hydration status closely and frequently. This includes serial and frequent measurements of body weight, fluid intake and output, heart rate, and blood pressure. Renal function may rapidly decline, so laboratory test results obtained in the morning may not reflect the patient's renal function or electrolyte status later in the day. Patients may develop fluid overload or hyperkalemia if not carefully managed.

Monitor electrolytes. Testing may need to be performed frequently in the early stages of disease or while children are on dialysis. In children in whom kidney function is stable, testing may be performed daily.

Use potassium-free fluids until renal function has stabilized. Mild hypokalemia is tolerable and much less critical than hyperkalemia. Treat severe or symptomatic hypokalemia with very cautious potassium replacement.

Once fluid deficits have been replaced, restrict fluid replacement to insensible losses plus actual output.

A study by Ardissino et al explored the benefits of volume expansion after hemolytic uremic syndrome (HUS) onset, and compared those results to historical controls. The study found that patients undergoing fluid expansion of at least 10% soon after the diagnosis, showed a mean increase in body weight of 12.5%, had significantly better short-term outcomes with a lower rate of central nervous system involvement, had less need for renal replacement therapy or intensive care unit support, and needed fewer days of hospitalization. The study also added that long-term outcomes were also significantly better in terms of renal and extrarenal sequelae, compared to the historical controls from the same instituion.[7]

Management of acute renal failure

Approximately 50% of patients with STEC-HUS require a period of dialysis. Consider early dialysis if the patient develops fluid overload, hyperkalemia, acidosis, hyponatremia, or oligoanuria that is unresponsive to diuretics.

Any type of dialysis or related technique (eg, hemofiltration) may be used, depending on local availability and individual patient factors. Suitable techniques include peritoneal dialysis, hemodialysis, or continuous renal replacement therapies (CRRT).

Peritoneal dialysis is widely used for pediatric patients. Peritoneal dialysis is usually well tolerated and is technically easier, especially in small infants.

Hemodialysis is also suitable for children. Hemodialysis may be preferable in patients with severe abdominal pain, in whom intestinal edema and pain may reduce achievable fill volumes. The intense visceral inflammation may lead to ultrafiltration failure. Omentectomy and placement of a peritoneal catheter may worsen their pain and complicate evaluation of continued pain.

Abdominal pain is more complex to assess in patients with a new peritoneal catheter. Pain could be due to a catheter-related complication, dialysis-associated peritonitis, or critical complications of hemolytic-uremic syndrome, such as intestinal perforation.

CRRT may be preferable for hemodynamically unstable patients. CRRT allows very precise control of volume status. CRRT also circumvents the issue of abdominal pain discussed above.

A growing body of evidence from critically ill patients shows that volume overload is a major contributor to morbidity and mortality.[8, 9] Initiate dialysis promptly if patient has, or is approaching, a state of fluid overload.

Dialysis does not alter the course of the disease; it only supports the patient while awaiting resolution of the illness. Early dialysis as a preventive or therapeutic measure is not justified. Current data do not support a previous theory that peritoneal dialysis could improve outcomes by removal of plasminogen-activator inhibitor type 1 (PAI-1).  However, several studies support early use of dialysis when indicated to optimize fluid, electrolyte, or nutritional status.

Patients who require dialysis usually need 5-7 days of therapy, although this number widely varies.

Management of hematologic abnormalities

Most children with hemolytic-uremic syndrome require packed RBC (PRBC) transfusions. PRBCs may be administered for symptomatic anemia (eg, tachycardia, orthostatic changes in blood pressure or heart rate, congestive heart failure) or if the hematocrit falls rapidly. The authors try to maintain the hemoglobin at approximately 7 g/dL, or the lowest amount required to prevent symptomatic anemia. Maintaining a relatively anemic state keeps the blood less viscous, theoretically helping prevent further thrombus formation.

Transfuse platelets if the patient has active bleeding. Other indications for platelet transfusion remain controversial. Most physicians try to avoid platelet transfusion because it may promote platelet aggregation and thrombus formation, worsening the disease. A commonly used threshold is to transfuse as needed, using clinical judgment, to maintain a platelet count near 20,000/µL. Platelets may also be given just before a surgical or catheter placement procedure.

Management of hypertension

A wide range of antihypertensive medications are available, and treatment should be individualized. Calcium channel blockers such as amlodipine or isradipine are commonly used in pediatrics. ACE inhibitors, and angiotensin receptor blockers should be avoided in the acute phase of illness as they may worsen acute kidney injury and hyperkalemia.

Treatment is covered separately in Hypertension.

Nutritional support

Providing adequate protein and energy intake enterally or parenterally is important to prevent catabolism and promote healing. Initiating dialysis, if needed, to provide adequate nutrition is preferred than to withhold nutrition in the hopes of avoiding the need for dialysis.

Patients may require intravenous hyperalimentation due to prolonged diarrhea, colitis, abdominal pain, intestinal ileus, or anorexia.

Lipid infusion may have to be limited if hypertriglyceridemia is present.

Patients receiving CRRT may require additional nutrition because of amino acid removal by CRRT.[10] Patients receiving hyperalimentation while on CRRT may require 3-4 g/kg/d of protein. Consult a dietician with renal expertise for assistance.

Pain management

STEC-HUS causes an intense colitis that can be extremely painful. Abdominal pain may mimic that of an acute abdomen. Severe pain or acute changes in pain should be evaluated as a surgical emergency, just as with any other patient.

Patients should receive adequate pain control. Patients with renal disease require special care and vigilance, but renal failure is not a valid reason to withhold appropriate pain management.

Acetaminophen may be used. Avoid nonsteroidal anti-inflammatory drugs (NSAIDs) because of their nephrotoxicity, which is particularly risky in an acutely injured kidney.

Opioids

Many patients will require opioid medication. Observe special precautions when using opioids in patients with renal insufficiency or failure. Start with a low dose, titrate to effect, and observe carefully for signs of toxicity.[11, 12]

Fentanyl has no active metabolites and is an excellent choice for patients with renal dysfunction. It has a rapid onset of action but a relatively short duration.

Hydromorphone has active metabolites, but they do not consistently cause symptoms in renal impairment. Most authors consider hydromorphone to be relatively safe in renal patients, with cautious monitoring for adverse effects, most commonly neuroexcitation.

Methadone has metabolites that are excreted primarily through stool. Methadone is a good analgesic in renal impairment, but owing to its slower onset of action and long half-life, it is less suitable for acute pain.

Do not use morphine, codeine, or meperidine in patients with decreased renal function. The human body converts these drugs into numerous metabolites that have no analgesic function but cause many adverse effects. Patients with renal failure cannot excrete these metabolites; thus, they accumulate and cause nausea, vomiting, altered mental status, hallucinations, and other deleterious effects.

Little data are available on the use of most other opioid analgesics in patients with renal failure. Use other agents with caution because the drug or its metabolites may have very different effects in patients with renal failure as opposed to those with normal renal function.

Special considerations for aHUS

Management of aHUS is very difficult and remains incompletely understood. Clinicians caring for patients with aHUS should search recent literature and confer with physicians with expertise in this disorder.[13, 14]

Discontinue the offending agent if a drug-associated cause is identified.

Treat bacterial infections (eg, S pneumoniae) promptly and aggressively.

Complement inhibitors

The complement inhibitors eculizumab and ravulizumab have revolutionized the treatment of aHUS, and they are now first-line treatment for aHUS.  Their use is discussed in detail in the Medication section.

Plasma therapies

Prior to the development of eculizumab, plasma therapies formed the mainstay of treatment for most forms of aHUS. These therapies theoretically use donor plasma products to replace the deficient or abnormal von Willebrand factor (vWF) metalloproteinase or complement factors. Their efficacy was never confirmed in controlled clinical trials.[15]  Complement inhibitors have supplanted plasma therapies in the treatment of aHUS. Plasma therapies may be considered in resource-limited regions where complement inhibitors are not available.

Therapeutic plasma exchange

Therapeutic plasma exchange (TPE), which is also called plasmapheresis, was previously the preferred plasma therapy for aHUS.

TPE removes the patient's plasma and replaces it with fresh frozen plasma (FFP) or a similar product. Albumin should not be used for replacement because it does not contain the vWF metalloproteinase or complement factors, except in the case of pneumococcal-associated hemolytic-uremic syndrome or neuraminidase mediated hemolytic-uremic syndrome (see above).

TPE can be performed using a cell-separator device or a special plasma filter used on a CRRT machine, both of which require specially trained staff to operate. Both methods work well, and local availability is the main selection factor. TPE requires a central venous catheter for vascular access.

No consensus or evidence-based guidelines guide therapy dose or schedule. Most clinicians use a tapering schedule, with several daily sessions followed by alternate-day treatments. Intervals between treatments are extended based on patient response. Individual regimens widely vary. Some authors advocate twice-daily TPE for refractory cases, but note that the benefit of this approach cannot be confirmed.[16]

TPE can lower the serum creatinine because it removes the patient's serum and replaces it with serum from donors with a normal creatinine value. This does not necessarily mean the patient's renal function is improving. Platelet count is a more reliable marker of response.

In theory, FFP may contain some large vWF multimers. Some authors advocate using cryoprecipitate-reduced plasma. However, multiple TPE sessions with cryoprecipitate-reduced plasma alone may deplete other coagulation factors and put the patient at risk for bleeding. Consider using FFP for at least some exchanges.

The role of plasma therapy in pneumococcal-associated hemolytic-uremic syndrome is controversial. Donor plasma may contain antibodies to the T antigen, which, in theory, could worsen the hemolytic process. Alternately, plasma exchange may remove neuraminidase and decrease the amount of circulating anti–T antibody. Some authors advocate plasma exchange using albumin replacement, since albumin does not contain antibodies.

Plasma infusion

Plasma infusion consists of simply infusing donor plasma, such as FFP or cryoprecipitate-reduced plasma. In theory, this delivers the absent or abnormal vWF metalloproteinase or complement factors. Plasma infusion does not remove the abnormal factors, as TPE does.

The sole advantage of plasma infusion over TPE is its simplicity, because it can be performed in almost any medical facility and does not require specialized equipment, central venous access, or specially trained staff. Studies comparing TPE to plasma infusion have found superior outcomes with TPE.[17]

Infusions typically consist of 20-30 mL of FFP or cryoprecipitate-reduced plasma per kilogram. One case report found 40-45 mL/kg infusions necessary.[18]

Volume overload may complicate plasma infusion, especially in patients with reduced renal function. For example, a 50-kg child receiving 40 mL/kg of plasma would require a 2000 mL infusion, approximately equal to the entire daily fluid requirement for a patient with normal renal function. The risk of volume overload may limit the volume administered, reducing the effectiveness of the therapy.

Hyperproteinemia, as shown by elevated serum total protein, has been reported in a patient receiving long-term plasma infusions.

In theory, one can use exclusively cryoprecipitate-reduced plasma for plasma infusion because the patient's own coagulation factors are not removed.

Special considerations for pneumococcal-associated HUS

Complement inhibitors should not be used in patients with pneumococcal-associated HUS, since complement-mediated cytotoxicity is of great importance in the immune response to encapsulated organisms such as Streptococcus pneumoniae. Supportive care and treatment of the underlying infection are the mainstays of treatment of this type of HUS.

Management of end-stage renal disease

Patients who develop permanent renal failure due to STEC-HUS have a low risk of recurrence and can proceed to renal transplantation similar to patients with most other renal diseases.

Renal transplantation in patients with aHUS is more difficult because of the high risk of recurrence and allograft loss. The risk of recurrence varies with the complement mutation identified; such testing is essential, as is planning and counseling patients about transplantation options. Note the following mutations and recurrence rates (these data were obtained prior to the availability of eculizumab therapy, which may prevent recurrence of aHUS):

• Factor H mutation: 80-100% recurrence

• Factor I mutation: 80% recurrence

• Membrane cofactor protein mutation: 10-20% recurrence

• No (known) mutation identified: 30% recurrence

Combined liver-kidney transplantation has been reported in patients with high-risk mutations, such as factor H.[19, 20, 21, 22] Liver transplantation alone is an option for patients without renal failure.[19] The principle behind liver transplantation is that the DNA in the donor liver does not have the patient's complement mutation, so it produces normal complement factors.

Prior to the development of eculizumab, kidney transplantation success rates of only 18-33% were reported for patients with high-risk mutations.[23, 24]

Many newer reports describe patients with high-risk mutations who have had successful kidney transplantation, without liver transplants, using eculizumab to prevent recurrence of aHUS.[25, 26, 27]

Supportive medical care is the mainstay of treatment of hemolytic-uremic syndrome.

Obtain surgical consultation if the patient has severe abdominal pain or other abdominal findings, which may be similar to an acute abdomen.

Surgery may also be required for placement of a dialysis catheter.

Consider the following consultations:

• Nephrologist: Most patients with hemolytic-uremic syndrome require assistance, if not primary management, from a nephrologist.

• Hematologist/oncologist: Consult with a hematologist or oncologist if needed for assistance with transfusion management. Patients with aHUS have findings very similar to thrombotic thrombocytopenic purpura (TTP), which is traditionally considered a hematologic disorder, and a hematologist/oncologist may provide assistance with evaluation and management.

• Cardiologist: Consult with a cardiologist if the patient has cardiac failure or other abnormalities.

• Neurologist: Consult with a neurologist if the patient has seizures or other CNS findings.

• Endocrinologist: Consult with an endocrinologist if the patient develops diabetes due to pancreatitis.

• Surgeon: Consult with a surgeon for evaluation of abdominal pain or placement of dialysis access.

• Social worker: Consult with a social worker for patient and family support with school, financial, and coping/adjustment issues.

• Child life specialist: Consult with this specialist to help the child understand medical care and find age-appropriate strategies to facilitate treatments.

• Psychologist/psychiatrist: Consult with this specialist if the patient has depression, anxiety, or adjustment issues related to disease.

• Dietician: Consult with a dietician to help manage nutrition, especially in patients with inadequate oral intake.

• Physical therapist: Patients with hemolytic-uremic syndrome may be bedridden for a prolonged time because of pain, CRRT, and a generally ill state. Physical therapy can help patients maintain strength, reduce muscle wasting, and prevent deep venous thromboses.

Transfer may be required if the patient requires care or services not available at the patient's facility, such as pediatric specialist consultation, pediatric intensive care, or dialysis.

In the acute stage of illness, limit fluid intake to replace insensible losses and urine output.

A low-salt diet helps prevent fluid retention and elevated blood pressure.

Patients should be encouraged to eat as tolerated if there is no contraindication to doing so. Supplemental formulas orally or by nasogastric tube may be used if oral intake is poor. Consult a dietician early in the course of illness.

Many patients require intravenous hyperalimentation.

Supportive care remains the mainstay of therapy for Shiga toxin–producing E coli hemolytic-uremic syndrome (STEC-HUS) and is very important in atypical hemolytic-uremic syndrome (aHUS) as well. Medications such as antihypertensives, diuretics, anticonvulsants, and analgesics are indicated to treat specific symptoms or complications of hemolytic-uremic syndrome. These medications have not been demonstrated to alter the disease process.

Complement C5 inhibitors

The development of the complement inhibitors eculizumab and ravulizumab has changed dramatically the treatment of aHUS. Both are humanized monoclonal antibodies that bind to complement C5, preventing its cleavage to C5a and C5b. This, in turn, prevents assembly of the membrane attack complex, also referred to as C5b-9 (because it is composed of C5b, C6, C7, C8 and C9.) Eculizumab, approved by the US Food and Drug Administration (FDA) in September 2011, was the first specific, disease-modifying therapy for aHUS. Ravulizumab, approved in 2018, is technically classified as a biosimilar variant of eculizumab. The main difference is that ravulizumab has a longer duration of action, generally requiring less frequent infusions. Dosing in pediatric patients is based on weight. Individualized dosing based on disease measures, biomarkers, and individual pharmacokinetics is being studied.[28]  Both drugs specifically state on their labels that they are not indicated for STEC-HUS. In addition, they should not be used for pneumococcal-associated HUS, since they inhibit complement activation, which is of particular importance in fighting infections with encapsulated organisms such as S pneumoniae. 

Duration of complement-inhibiting therapy

Complement-inhibiting therapies are generally continued for an extended duration: months, years, or even lifelong, particularly in patients with known complement mutations or inhibitors. When to discontinue these drugs, if at all, has been a subject of much interest. The benefits of cost savings and reduced risk of infections must be balanced against the risk of recurrence of aHUS, with associated complications such as renal failure.

In a retrospective study of 38 adult and pediatric patients who discontinued eculizumab, none of the patients with normal genetic studies relapsed over a median follow-up period of 22 months. Among patients with a known genetic variant in a complement gene, 31% relapsed after discontinuing therapy.[29]  In another retrospective study of pediatric patients, eculizumab was withdrawn in 18 patients with no known complement mutations; 4 relapsed, all of whom returned to remission and recovered renal function after restarting eculizumab.[30]  A subsequent prospective study of 55 adult and pediatric patients who discontinued eculizumab showed similar results. Eleven of the 13 patients who relapsed after discontinuation had a complement mutation. Importantly, all of the relapsing patients experienced acute kidney injury; one required dialysis; and two had worsening of their preexisting chronic kidney disease, including one who progressed to end-stage renal disease. The remaining patients returned to their baseline level of renal function.[31]  The authors conclude that discontinuation of eculizumab is feasible and safe in patients with no known complement mutation. Similar studies regarding ravulizumab withdrawal have not been reported.

In summary, preliminary data suggest that withdrawal of complement inhibition may be reasonable in patients with no known gene mutations and possibly other favorable risk factors, provided that careful monitoring is in place, and therapy can be promptly resumed in the event of a relapse. However, the long-term risk of relapses and other late complications in untreated patients remains unknown. Episodes of acute kidney injury in general (not specifically due to HUS), even if the patient has fully recovered, are associated with a higher risk of chronic kidney disease. These issues should be discussed, and patients should be engaged in decisions regarding withdrawal of therapy.

Neisseria meningitidis prophylaxis while on complement inhibition

Eculizumab and ravulizumab have been associated with life-threatening infections with the encapsulated organism Neisseria meningitidis. Ideally, patients should be vaccinated against meningococcus at least 2 weeks before starting complement inhibitors. Such a delay in therapy would be highly undesirable in acutely ill patients. Therefore, unvaccinated patients may receive initial meningococcal vaccination at the time of starting therapy, with antibiotic prophylaxis for at least 2 weeks to allow time for immunity to develop. Importantly, breakthrough meningococcal infections have been observed in fully vaccinated patients[32] ; a Centers for Disease Control and Prevention publication recommends considering continued meningococcal prophylaxis for the entire duration of treatment with complement inhibition. The Advisory Committee on Immunization Practices (ACIP) recommends that patients treated with complement inhibitors receive both serogroup B meningococcal vaccine (MenB) and quadrivalent meningococcal conjugate vaccine (MenACWY).[33]  In the United States, eculizumab and ravulizumab can be prescribed only by providers who are enrolled in a Risk Evaluation and Mitigation Strategy (REMS) program. 

Conversion from eculizumab to ravulizumab

Pediatric patients maintained on eculizumab may change to ravulizumab.[34]  Conversion is based on the previous dose of eculizumab and is detailed on the ravulizumab product label. The main advantage to conversion is reduced frequency of infusions (depending on patient weight, as often as every 8 weeks versus every 2 weeks for eculizumab). The reduced frequency may also reduce costs. A cost-minimization analysis modeling study showed lifetime cost reductions of 32.4-35.5% for ravulizumab compared with eculizumab.[35]

Other medications

Unfortunately, several other agents that in theory should ameliorate hemolytic-uremic syndrome have failed to do so in clinical trials. These include thrombolytic agents (eg, heparin, urokinase), platelet inhibitors (eg, aspirin, dipyridamole), and a Shiga toxin (Stx)–binding agent (ie, Synsorb-Pk). Current evidence does not support use of these medications.

Corticosteroids are not useful in STEC-HUS. They may be of value in aHUS if the patient has an autoimmune-produced inhibitor of ADAMTS13. 

Limited case reports describe using intravenous immune globulin (IVIG) in patients with aHUS associated with organ transplantation. IVIG does not have a role in hereditary aHUS nor in STEC-HUS.

Studies have shown that antibiotics given to patients with diarrhea due to E coli 0157:H7 increase the risk of developing hemolytic-uremic syndrome.[36] A theory proposed to explain this finding is that antibiotic therapy causes rapid large-scale bacterial lysis with massive release of Stx, overwhelming host defense mechanisms. Whether antibiotics affect the course of established hemolytic-uremic syndrome remains unknown. Patients with E coli 0157 colitis usually clear the infection spontaneously.

Most pediatric nephrologists do not routinely use antibiotics in patients with STEC-HUS, based on a theoretical concern it could exacerbate the disease process.[37] However, antibiotics should be used when indicated according to clinical judgment. Examples include patients having suspected or documented bacteremia, urinary tract infection, or sepsis.

Class Summary

Eculizumab and ravulizumab are monoclonal antibodies indicated for atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy; effectiveness is based on the effects on thrombotic microangiopathy and renal function. 

Eculizumab (Soliris)

Eculizumab 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.

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.

STEC-HUS

Patients recovering from Shiga toxin–producing E coli hemolytic-uremic syndrome (STEC-HUS) should have regular follow-up until their symptoms have resolved and their hemoglobin, platelet counts, and renal function have returned to normal.

Beyond that, no consensus is noted regarding frequency of follow-up or testing required. Preliminary data suggest many survivors may have persistent, subclinical renal injury, putting them at risk for future development of hypertension, proteinuria, and/or chronic renal disease.[38]

All patients should have their blood pressure checked at each medical encounter. Patients with persistent hypertension require antihypertensives.

The authors suggest annual follow-up with a nephrologist, with consideration of annual urinalysis, urine microalbumin, serum creatinine, and fasting glucose levels on an annual basis.

Counsel patients on the importance of a healthy lifestyle, with regular exercise, healthy diet, and avoidance of tobacco and obesity. These measures are beneficial for all patients, but especially those at higher risk for future renal disease.

Atypical HUS

Patients with pneumococcal-associated hemolytic-uremic syndrome have a lower risk of recurrence and should have follow-up as outlined for STEC-HUS above.

Patients with idiopathic or genetically mediated atypical hemolytic-uremic syndrome (aHUS) are at high risk for having a persistent and relapsing course, and most require more frequent and lifelong nephrology follow-up.

General preventive measures

Avoid ingestion of raw or undercooked meat.

Avoid unpasteurized milk and cheese.

Practice good hand hygiene, especially during outbreaks of diarrhea, after touching livestock, farm animals, or "petting zoo" animals. Supervise children to ensure good technique.

Avoid taking antidiarrheal or antimotility agents for diarrhea. Avoid taking antibiotics for diarrhea unless under the management of a physician.

Seek medical care immediately for bloody diarrhea.

Preventive measures for medical practitioners

Avoid antibiotic treatment of patients with possible GI E coli 0157:H7 infection, unless other clinical factors require antibiotic therapy.[36]

Use ample parenteral volume expansion with isotonic (normal) saline in patients with suspected E coli 0157:H7 infection (eg, those with bloody diarrhea). Early recognition is important.

A study has shown that early and ample rehydration with isotonic saline is associated with a lower risk of developing oligoanuric renal failure.[6] Many patients who received this therapy still developed hemolytic-uremic syndrome, but they had a less severe course, with shorter lengths of stay and fewer patients requiring dialysis. Ake et al recommend that patients with suspected E coli 0157:H7 infection be admitted for inpatient therapy, using intravenous isotonic saline for both maintenance and replacement fluid requirements, avoiding use of hypotonic fluids. The authors of this article concur with this advice. Trials of oral rehydration, normally an appropriate practice, should be avoided in this situation due to the risk of prolonged renal hypoperfusion.

Monitor fluid status, intake, and output closely because renal function may change rapidly, requiring adjustments to fluid therapy. Use potassium supplementation with great caution.