Pediatric Hemolytic Uremic Syndrome Treatment & Management

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. Supportive care measures apply to both diarrhea-associated hemolytic-uremic syndrome (D⁺ HUS) and non–diarrhea-associated hemolytic-uremic syndrome (D^- HUS). Additional special considerations for D^- hemolytic-uremic syndrome are listed at the end of this section.

• Fluid therapy

  • 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).^[2] 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.
• Management of acute renal failure

  • Approximately 50% of patients with D⁺ hemolytic-uremic syndrome 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.^{[3, 4]} 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 to maintain a platelet count near 20,000/mcL. 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 are very effective but should be used with caution in individuals with a decreased glomerular filtration rate (GFR) or with 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 due to amino acid removal by CRRT.^[5] 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

  • D⁺ hemolytic-uremic syndrome 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.
  • Acetaminophen may be used.
  • Avoid nonsteroidal anti-inflammatory drugs (NSAIDs) because of their nephrotoxicity, which is particularly risky in an acutely injured kidney.
  • 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.^{[6, 7]}
    • 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 side effects, most commonly neuro-excitation.
    • Methadone has metabolites that are excreted primarily through stool. Methadone is a good analgesic in renal impairment, but due 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 side 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.
  • 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.
• Special considerations for D^- hemolytic-uremic syndrome

  • Management of D^- hemolytic-uremic syndrome is very difficult and remains poorly understood. Clinicians caring for patients with D^- hemolytic-uremic syndrome should search recent literature and confer with physicians with expertise in this disorder.^[8]
  • Discontinue offending agent if a drug-associated cause is identified.
  • Treat bacterial infections (eg, S pneumoniae) promptly and aggressively.
  • The role of plasma therapy in pneumococcal hemolytic-uremic syndrome (P-HUS) or neuraminidase-mediated hemolytic-uremic syndrome remains controversial. 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.
  • Plasma therapies form the mainstay of treatment for most forms of D^- hemolytic-uremic syndrome. These therapies use donor plasma products to replace the deficient or abnormal von Willebrand factor (vWF) metalloproteinase or complement factors.
  • No treatment has been found to be more effective than therapeutic plasma exchange (TPE), which is also called plasmapheresis.^[9]
    • TPE is the most effective therapy for D^- hemolytic-uremic syndrome. 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 P-hemolytic-uremic syndrome or neuraminidase mediated hemolytic-uremic syndrome (see above).
    • This can be done using cell a 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.^[10]
    • 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.
  • 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.
    • The sole advantage of plasma infusion 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 have found superior outcomes with TPE.^[11]
    • Infusions typically consist of 20-30 mL of FFP or cryoprecipitate-reduced plasma per kg. One case report found 40-45 mL/kg infusions necessary.^[12]
    • 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 chronic plasma infusion.
    • In theory, one can use exclusively cryoprecipitate-reduced plasma for plasma infusion because the patient's own coagulation factors are not removed.
• Eculizumab: Eculizumab (Soliris) is the first treatment approved by the US Food and Drug Administration (FDA) (September, 2011) for adults and children with atypical hemolytic uremic syndrome (aHUS). Approval was based on data from adults and children who were resistant or intolerant to, or receiving, long-term plasma exchange/infusion. Data also included children (aged 2 mo to 17 y) who received eculizumab with or without prior plasma exchange/infusion. Eculizumab demonstrated significant improvement in platelet count from baseline (P = .0001). Thrombotic microangiopathy events were reduced, and maintained or improved kidney function was also reported.^{[13, 14, 15]}
• Management of end-stage renal disease (ESRD)

  • Patients who develop permanent renal failure due to D⁺ hemolytic-uremic syndrome 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 D- hemolytic-uremic syndrome is more difficult because of the high risk of recurrence and allograft loss, with success rates of only 18-33% reported.^{[16, 17]}
  • The risk of recurrence varies with the complement mutation identified; such testing is essential is planning and counseling patients about transplant options:
    • 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 transplant has been reported in patients with high-risk mutations such as factor H.^{[18, 19, 20, 21]} Liver transplant alone is an option for patients without renal failure.^[18]

• 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.

• 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 D^- hemolytic-uremic syndrome 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 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 due to pain, CRRT, and a generally ill state. Physical therapy can help patients maintain strength, reduce muscle wasting, and prevent deep venous thromboses.

• 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.

• Encourage activity as tolerated.
• Even minor activity such as moving out of bed to a chair is beneficial.
• Consider physical therapy to help patients maintain strength and activity.