Background

Complement-mediated HUS (CM-HUS) is a rare thrombotic microangiopathy (TMA) caused by congenital or acquired dysregulation in the complement pathway. There can be significant morbidity and mortality associated with this condition if not diagnosed and treated promptly. In our study, we examine the clinical parameters and genetic alterations associated with outcomes in this patient population

Materials and Methods This was a single-center, retrospective cohort study that searched electronic medical records of patients diagnosed and treated for CM-HUS at the University of Nebraska Medical Center from January 1, 2010, to December 31, 2023. We included patients over 18 years of age who had confirmed microangiopathic hemolytic anemia (MAHA) with thrombocytopenia, ADAMTS13 activity > 10 % and did not have infection-related HUS. Patients were divided into two groups: those with a gene mutation associated with CM-HUS and those without. Continuous variables were compared between both groups using the Student t-test.

Results Forty-seven (n=47) patients meeting the inclusion criteria were enrolled in the study. Most of the patients were caucasians (n=35 74.4%), while (n=9 19.14%) patients were African American, two patients were Hispanic, and one patient was Asian. Females were (n=33 70.21%) of the total patient population. The most common pre-existing comorbidities included hypertension (n=36), obesity (n=22), autoimmune disorders (n =12), diabetes mellitus (n=7) and coronary artery disease (n=5). All of our patients had acute kidney injury at presentation. The most common extra-renal manifestations included fatigue (n=30), nausea and vomiting (n=25), abdominal pain (n=12) and confusion or other CNS symptoms (n=10).

All our study patients had genetic testing sent. Pathogenic mutation or a variant of unknown significance was noted in (n=20). Lab values were compared for these two groups. The mean age at presentation was younger in the gene mutation cohort, 42.70 (+/- 16.74), as compared to 59. 18 (+/- 15.06) in the no mutation group (p value = 0.01). Baseline lab values at presentation were not statistically different between the two groups. These included haemoglobin of 6.70 mg/dL (+/-1.69) vs 6.45 mg/dL (+/- 0.83) P-value 0.65, platelet count 62 x 109 /L (+/-39.72) vs 40.0 x 109/L (+/- 27.91) P-value 0.11, creatinine of 7.63 mg/dL (+/- 4.21) vs 6.59 mg/dL (+/- 1.57) P-value 0.44 in the mutation and non-mutation group respectivly. All other lab parameters, including total bilirubin, white blood cell count, lactate dehydrogenase, haptoglobulin, and ADAMTS-13, were not statistically different between the two groups.

The most common mutation identified was in the complement factor H (CFH), with likely pathogenic mutations in (n=4/20) patients and variants of unknown significance in (n=8/20) patients. In patients with the likely pathogenic CFH mutation (n=3/4, 75%) progressed to ESRD, and deaths were also reported in (n=3/4 patients). The second most common pathogenic mutation was in the complement factor I (CFI) in two patients. Both of these progressed to ESRD, and one of them died from CM-HUS. Likely pathogenic mutation was also noted in one patient with complement factor B (CFB), CHFR1–CHFR3 homozygous mutation, complement factor C3, and the NTHBD gene. A combination of different variants of unknown significance was noted in nine patients. (n=5/9, 55.55%) of these progressed to ESRD, while (n=4/9, 44.44%) died. Overall, (n=12/20, 60%) patients with gene mutations developed ESRD, and (n=11/2055%) died secondary to CM-HUS. In comparison, (n= 19/27, 70.37 %) patients developed ESRD, and (n=7/11, 63.63%) died from CM-HUS in the non-mutation group. All patients in the study were treated with complement blocking therapy, most commonly eculizumab. The mean duration of therapy was 40.27 months (+/- 40.90) for those with gene mutations and 21.09 months (+/- 23.72) for those without gene mutations, P-value 0.17.

Conclusions Patients with CM-HUS who have an associated gene mutation were likely to present at a younger age as compared to those with no associated mutation. However, clinical characteristics, lab values, and outcomes in the form of ESRD and death were similar in CM-HUS patients with or without mutations. Patients with gene mutations were likely to receive therapy with complement-blocking drugs for longer, possibly because of a higher risk of recurrence associated with some mutations, like CFH and MCP gene mutations.

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2025
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