Case published: December 2025
Case submitted by: Morgan Beebe
Pediatric Nephrology Faculty Reviewer: John Mahan
Diagnosis: Atypical hemolytic uremic syndrome (aHUS)
Case Summary: Well done on a tricky case! Let’s go through it to highlight the clues to the diagnosis. Our patient is only 4 weeks old, and being so premature, is already critically-ill and at high risk for further complications. He has signs of kidney injury – including elevated creatinine, edema, and hyperkalemia. He also has numerous risk factors for acute kidney injury (AKI): extreme prematurity, necrotizing enterocolitis, large patent ductus arteriosus, and need for pressor support. He is not old enough to meet criteria for chronic kidney disease (CKD), though it is unclear where his kidney function might stabilize.
Below is our mnemonic for kidney diseases that often present with low serum complement levels (THe CHAMPS):
In young patients like ours who present with suspected TMA without bloody diarrhea, the differential includes:
- Complement-mediated TMA
- Metabolism-mediated TMA
- Coagulation-mediated TMA
- Drug-induced TMA
- Hereditary or immune TTP
The presence of blood diarrhea would make Shiga-toxin hemolytic uremic syndrome more likely. Though a kidney biopsy would confirm the diagnosis of renal TMA, biopsies often are not performed in critically ill neonates due to their size and bleeding risk (e.g. thrombocytopenia). To review kidney pathology findings in TMA, check out this Renal Fellow Network post.
Atypical HUS in this age range is most likely due to a genetic mutation leading to alterations of the alternative complement pathway (Figure below) such as 1) genetic mutations that upregulate the activity of activator enzymes or downregulate the activity of inhibitor enzymes; or 2) auto-antibodies that affect complement regulation. Either mechanism leads to increased activity of the alternative pathway, resulting in increased consumption of complement and cofactors. In neonates, genetic complement system abnormalities are much more likely than development of auto-antibodies.
Figure: Overview of complement pathway (Anigoi A et al. Kidney International 2016)
Our patients testing revealed a genetic mutation of unknown clinical significant in CF1 (Complement factor 1), and also functional abnormalities that likely led to alternative complement pathway over activation.
Finally, how do you treat over activation of the alternative complement pathway? Try to block it! Our patient was treated with eculizumab, a monoclonal antibody that binds to the C5 protein involved in the terminal portion of the complement cascade.
For more on this topic, take a look below:
- Angioi A, Fervenza FC, Sethi S, et al. Diagnosis of complement alternative pathway disorders. Kidney Int. 2016;89(2):278-288. https://doi.org/10.1016/j.kint.2015.12.003
- Genest DS, Patriquin CJ, Licht C, John R, Reich HN. Renal Thrombotic Microangiopathy: A Review. Am J Kidney Dis. 2023;81(5):591-605. https://doi.org/10.1053/j.ajkd.2022.10.014
- Kottke-Marchant K. Diagnostic approach to microangiopathic hemolytic disorders. Int J Lab Hematol. 2017;39 Suppl 1:69-75. https://doi.org/10.1111/ijlh.12671
- Vieira-Martins P, El Sissy C, Bordereau P, Gruber A, Rosain J, Fremeaux-Bacchi V. Defining the genetics of thrombotic microangiopathies. Transfus Apher Sci. 2016;54(2):212-219. https://doi.org/10.1016/j.transci.2016.04.011
Case 57 Index
Case 57 Introduction
Case 57 Physical Exam & Diagnostic Testing
Case 57 Additional Diagnostic Testing
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