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. 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.