Diagnostic Process Using Genetic, Clinical Data May Aid in Identifying aHUS

Aisha I Abdullah PhD avatar

by Aisha I Abdullah PhD |

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A diagnostic process combining genetic, clinical, and patient inquiry data may help in the identification and categorization of patients with suspected atypical hemolytic uremic syndrome (aHUS), a study suggests.

The new scheme already has aided in identifying a new, likely disease-contributing gene variant for aHUS.

The study, “Clinical characterization and identification of rare genetic variants in atypical hemolytic uremic syndrome: a Swedish retrospective observational study,” was published in the journal Therapeutic Apheresis and Dialysis

aHUS is characterized by the formation of blood clots in the small blood vessels of the kidneys, which can lead to hemolytic anemia, or the destruction of red blood cells, as well as low blood platelet counts, and kidney failure. Complement-mediated aHUS results from impairments in the regulation of the body’s complement system, part of the immune system.

The severity and degree of kidney damage in patients with aHUS depend on multiple factors, including conditions that also impact the complement pathway. These factors include autoimmune diseases or infections, genetic risk factors, and the presence of antibodies against factor H, a protein that regulates the complement pathway.

Due to similarities to other more common diseases, misdiagnosis and delayed diagnoses are frequent among individuals with aHUS.

Now, researchers in Sweden used a diagnostic process — based on the American College of Medical Genetics and Genomics guidelines — to assess the prevalence of complement-mediated aHUS in a group of patients suspected of having the disease.

These Swedish patients had been described in a previous study as showing signs of hemolytic anemia, low blood platelet counts, and kidney impairment.

The diagnostic process consisted of gathering information from different sources, including patient inquiries, medical evaluations such as lab and genetic tests, and medical records, to arrive at a final conclusion.

From the 134 patients who participated in the previous study, a total of 20 were included in this analysis. Among them, 16 had potential aHUS triggers, while four had no known disease triggers.

Based on genetic and clinical data, a total of 10 patients (50%) were classified as having non-complement-mediated aHUS, six (30%) as having definite or highly suspected complement-mediated aHUS, and four (20%) as having an aHUS-like condition. Of the six patients with complement-mediated aHUS, two (33%) had not received a proper diagnosis before entering the study. 

A total of 20 unique genetic variants were detected in 14 patients. These included one disease-contributing variant and four likely disease-causing variants, all detected in the group of six complement-mediated aHUS patients. Among these gene variants was a newly identified, likely disease-contributing variant — called c.3450A>G,p.I1150M — in the CFH gene, which encodes factor H.

A larger proportion of patients with complement-mediated aHUS underwent dialysis as compared with those with non-complement-mediated aHUS (67% vs. 50%). These patients also were more likely to require kidney transplants after dialysis (75% vs. 40%). These results suggested that complement-mediated aHUS patients had worse kidney outcomes than those with non-complement-mediated aHUS.

The research team noted that although the study was limited to its small sample size and low aHUS prevalence, it “managed to identify and systematically categorize cases of suspected aHUS by applying the diagnostic scheme” to a group of patients with suspected disease.

“The study illustrates the risk of misdiagnosis in the management of patients with complement-mediated aHUS and the importance of a comprehensive assessment … to reach a diagnosis,” the investigators concluded.