Case Study 2: aHUS in a 20-month-old Infant
Complement-Mediated Kidney Disorders: A Case SeriesLearning Goals:
- Describe the presentation and differential diagnosis of aHUS
- Identify the genetic causes of aHUS
- Review the management of aHUS
Case Presentation
Chief Complaint: Sudden onset of lethargy and pallor in a previously healthy 20-month-old girl.
Case Presentation: AA is a previously healthy child who has been growing and developing normally. About a week before admission, she developed a low-grade fever of 38°C, rhinorrhea, and low-grade cough. The fever was controlled with acetaminophen. Over the last 24 hours, she has become increasingly listless, much less playful, and noticeably pale.
Past Medical History: AA was the 2.95 Kg product born to a 30-year-old G1P1 mother. The pregnancy was complicated by pre-eclampsia at 37 weeks gestation. She was delivered by C-section and had normal Apgar scores. She was observed for 24 hours in the neonatal intensive care unit, and was discharged home with her mother.
Past Surgical History: No prior surgery.
Medications: No medications.
Family History: There is a history of unexplained infant deaths in two children born to two maternal aunts. There are no family members with known kidney disease.
Social History: The father is a high school math teacher and the mother is a social worker. They live in a single family home.
Physical Examination: Temperature 37.7°C (rectal). Blood pressure: 118/76 mm Hg. Heartrate: 134 beats per minute. Respiration: 28 breaths per minute. Weight: 10 kg (50th percentile). Height: 85 cm (75th percentile).
General: The child is lying still on the exam table. She is in no obvious pain but is only marginally responsive. Her complexion is pale and slightly jaundiced. She has a grade 2/6 flow murmur along the left sternal border. Her abdomen is soft and non-tender, and the liver edge is palpable 1 cm below the costal margin. There is no evidence of edema, petechiae, or purpura.
Laboratory Studies: Hemoglobulin: 6.0 g/dL. Hemacrit:19%. Platelet count: 26,000. Sodium: 129 mmol/L. Potassium: 5.8 mmol/L. Blood urea nitrogen (BUN): 54 mg/dl. Creatinine 1.9 mg/dl. A peripheral smear of the blood revealed fragmented erythrocytes and Burr cells.
Preventative Health History: All of her immunizations are up to date, and she is on an age-appropriate diet.
Additional Important Information: The child has not had any recent immunizations, and the family has not travelled in the last 3 months. Subsequent genetic testing revealed a nonsense mutation in the Factor H gene. She was treated with eculizumab with a prompt normalization of the thrombocytopenia and anemia.
Learner Reflection Questions Click each to view answers
What are the key considerations in a child with sudden onset of kidney failure and severe thrombocytopenia?
Correct Answer Rationale and Clinical Commentary
There are very few clinical conditions in pediatrics that cause this combination of findings. [1-3] The most urgent diagnosis is sepsis, bacterial or viral. It is unlikely in this child who is afebrile and has a modestly elevated blood pressure. Hemolytic uremic syndrome (HUS) is the next most likely explanation and can be caused by infection with Shiga toxin-producing strains of E. coli (STEC). The vast majority of cases of STEC-related HUS occur in the summer months and develop shortly after an episode of gastroenteritis plus bloody diarrhea. The presence of an upper respiratory tract infection as the triggering event makes it more likely that this child does not have STEC-HUS but atypical HUS (aHUS) instead. Patients with thrombotic thrombocytopenia (TTP) can present at a young age with severe TTP but they rarely have significant kidney dysfunction.
What are the different types of HUS, and how are they distinguished from one another?
Correct Answer Rationale and Clinical Commentary
All forms of HUS are characterized by microangiopathic anemia, thrombocytopenia, and kidney injury. [1-3] The microangiopathic anemia is confirmed by the detection of burr cells and schistocytes on a peripheral smear. All forms of HUS are systemic disorders that affect virtually every body organ. The most common form of HUS represents a sequela of gastrointestinal infection with STEC. The Shiga toxin binds to the globotriaosylceramide (Gb3) molecule in the apical membrane of endothelial cells. It is internalized and transported retrograde to the ribosome where it inhibits protein synthesis and triggers cell death. [4] There is the binding of platelets to the injured endothelium, formation of platelet-fibrin thrombi, and hypoperfusion of organs including the kidney and brain, with the most severe consequences arising from central nervous system involvement. The listless condition of the child in this case likely reflects this complication. CNS involvement is the most severe and is highly associated with mortality. Alternatively, aHUS is the result of genetic or acquired defects leading to dysregulation and activation of the alternative pathway of complement and direct injury to the endothelial cells.
As in the case above, the most common genetic cause is a mutation in factor H, a serum molecule that prevents constitutive overactivation of the alternate complement cascade. [5] Antibodies to factor H can inactivate the molecule and trigger aHUS. In genetically susceptible individuals, episodes of aHUS can be triggered by intercurrent infections like the upper respiratory illness in the case above, medications, or pregnancy. STEC-HUS is a warm weather disease with a bloody diarrhea prodrome. aHUS often has a positive family history like in this case with unexplained infant deaths, a greater likelihood of recurrence, and a substantial risk of progression to kidney failure.
There is no proven therapy for STEC-HUS, while eculizumab, a monoclonal antibody to C5a, is an approved treatment for aHUS that has substantially improved the outcomes of affected children. In cases of aHUS secondary to an autoantibody, the standard of care is plasmapheresis in combination with anti-B-cell therapy, e.g., rituximab, which can lead to successful elimination of the causative antibody. Administration of fibrinolytic agents, anti-platelet drugs or plasma infusions has not been demonstrated to improve the outcome of children with STEC-HUS or aHUS. aHUS can recur in transplanted kidneys, with varying risks depending on the underlying genetic mutation. It is highest for patients with mutations in circulating complement proteins.
What is the role of genetic testing in this case?
Correct Answer Rationale and Clinical Commentary
The alternate complement cascade is composed of several molecules that interact in a sequential manner to form C3 convertase and lead to the release of chemotactic and inflammatory subcomponents and the assembly of the terminal C5b-9 membrane attack complex. [1-3] In addition, there are several circulating and membrane-associated molecules that act to inhibit the overactivation of the alternate complement cascade, which is pivotal to the development of aHUS. Genetic testing can identify mutations in specific proteins which can be combined with functional assays to assess the activity of the alternative pathway. This information is important in defining prognosis for maintenance of kidney function, selection of the optimal therapy, and prediction of recurrent disease in a kidney transplant if a patient has progression to kidney failure. Regarding the latter, the risk of recurrence can be upwards of 70% for some pathogenic variants (e.g. CFH, CFB, C3) but lower for other variants (e.g., [membrane cofactor protein (MCP)].
Working Together as a Team
Children with aHUS are usually quite ill at presentation. [1-3] The onset of disease is usually sudden in previously healthy children. The beneficial impact of treatment is linked to the rapidity with which appropriate therapy is initiated. This can require the input and expertise of many disciplines. Pharmacy is essential to ensure access to eculizumab in a timely manner and proper dosing of the biological agent. Pediatric surgery is required to enable the creation of suitable vascular access if plasmapheresis is required to remove an autoantibody. Genetic counseling is advisable to assist in the interpretation of genetic testing and to convey the implication of the findings to the patient and family members.
Closing Commentary
aHUS is a severe condition that can present abruptly in children of all ages. It is most commonly caused by mutations in proteins involved in the activity or regulation of the alternative pathway of complement. Genetic testing is an essential component in the diagnosis of aHUS and provides vital information about prognosis and treatment. Eculizumab has converted this once nearly fatal condition into one that is manageable with long-term preservation of kidney function and maintenance of overall health.
References
- Leon J et al. Complement-driven hemolytic uremic syndrome. Am J Hematol. 2023;98 (suppl 4):S44-S56.
- Fakhouri F et al. How I diagnose and treat atypical hemolytic uremic syndrome. Blood. 2023;141:984-995.
- Lorait C et al. An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol. 2016;31: 15-39.
- Trachtman H et al. Renal and neurological involvement in typical Shiga toxin-associated HUS. Nat Rev Nephrol. 2012;8:658-659.
- Bu F et al. Genetic analysis of 400 patients refines understanding and implicates a new gene in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2018;29:2809-2819.
