Soliris Effective in aHUS Patients With or Without High Blood Pressure
Study finds untreated aHUS patients have poor prognosis, worse disease
Soliris (eculizumab) shows effectiveness in treating patients with atypical hemolytic uremic syndrome (aHUS) both with and without severe and life-threatening hypertension, or high blood pressure, a large retrospective study found.
Further, the researchers noted, “the results confirm the high [worse] severity and poor prognosis of untreated aHUS,” with a greater need for kidney transplants among patients not receiving treatment for the immune system disorder.
The study highlights the importance of genetic screening and considering a differential diagnosis of aHUS to allow for proper timely treatment.
The study, “Clinical characteristics and outcomes of a patient population with atypical hemolytic uremic syndrome and malignant hypertension: analysis from the Global aHUS registry,” was published in the Journal of Nephrology.
aHUS belongs to a group of rare conditions called thrombotic microangiopathies (TMAs), which are mainly characterized by the formation of blood clots in small blood vessels that can lead to organ damage, particularly in the kidneys.
The disease results from the abnormal activity of part of the immune system known as the complement system. Most people with aHUS have mutations in genes that regulate complement function.
Malignant hypertension (MHT) — a fast increase in blood pressure causing sudden and serious injury to the brain, eyes, and kidneys — has been considered a cause of secondary TMA, mostly due to injury to small blood vessels in those organs.
Distinguishing these conditions often is difficult, as their symptoms overlap. However, finding the correct diagnosis is crucial as treatment options differ significantly. While aHUS patients are often treated with C5 complement inhibitors, people with MHT are usually prescribed blood pressure medications.
As such, delays in diagnosis and an inadequate treatment of aHUS and MHT can have a significant negative impact on patient outcomes. Additionally, it remains unknown whether Soliris, a complement C5 inhibitor, is effective in treating both conditions.
To address this, an international group of researchers analyzed data from children and adults with aHUS, with and without MHT, either treated or not with Soliris. The patients were part of the Global aHUS Registry (NCT01522183).
This registry has been collecting data since 2012 on patients with aHUS worldwide, including those who are not treated and those receiving Soliris or Ultomiris (ravulizumab).
The new study included patients who enrolled in the registry from April 2012 until October 2020. Its main goals were to assess the clinical features of these patients and their risk of reaching end-stage kidney disease (ESKD) or death. ESKD was defined as requiring a kidney transplant or chronic dialysis.
A total of 1,097 patients were included in the study. Among them, 71 had both aHUS and MHT. These patients had a median age at diagnosis of 28.1. Less than 30% (20 patients) were treated with Soliris; the other 51 were not.
The great majority of patients — 1,026 — had aHUS without MHT. The median age at diagnosis for these individuals was 30.4. Data showed 429 received Soliris treatment and 597 did not.
The non-treated group included patients who had never received Soliris, or those who were treated with it after reaching ESKD. It also included patients who received Soliris up to and including one month prior to undergoing a kidney transplant.
Patients included in the analyses had a aHUS diagnosis for at least 90 days, or about three months. MHT was defined as having a diastolic blood pressure higher than 120 millimeters of mercury (mmHg; the normal value is less than 80 mmHg).
Genetic testing was performed for at least one aHUS-causing complement mutation. Other variables analyzed in the study included the presence of autoantibodies against complement factor H (CFH), a key regulator of the complement pathway, and kidney transplant status.
Those with MHT had significantly more mutations and anti-CFH antibodies compared with those without MHT (56% vs. 37%), suggesting that “clinicians should explicitly consider genetic screening in this specific patient population,” the researchers wrote.
Non-treated patients with MHT were found to have more mutations and anti-CFH antibodies (65%) than treated patients with MHT (35%), or those without MHT irrespective of treatment status (35% treated; 39% non-treated).
Given these results, the researchers were surprised that 72% of patients with aHUS and MHT (51 people) were not treated with Soliris, which may be explained by those patients “having a recorded onset of aHUS prior to eculizumab obtaining marketing authorization in 2011,” the researchers wrote.
Results also showed that more patients with MHT had undergone a kidney transplant compared with those without MHT (47% vs. 32%). However, the study found that the number of patients requiring a kidney transplant was significantly higher in non-treated patients than in treated ones, regardless of whether they had MHT (65% vs. 0%) or not (51% vs. 5%).
Overall, these findings indicate “a potential lack of early/correct diagnosis and high severity of disease in these patients when left untreated,” the researchers wrote.
Additionally, treated patients were found to have a significantly lower risk of reaching ESKD or death compared with non-treated patients. This risk was higher in adult patients who had complement mutations and anti-CFH antibodies. However, patients who were not treated had worse outcomes than treated patients, regardless of age.
These results “reiterate the importance of establishing an early and accurate diagnosis, as treating the correct patients with C5 inhibitors has been shown to substantially reduce morbidity and mortality,” the researchers wrote.
However, fewer patients with MHT were treated with Soliris than those without malignant hypertension, despite the increased presence of complement gene mutations in this patient group. According to the researchers, “this raises the possibility that clinicians may be continuing to regard TMA as secondary to MHT and proceed with MHT-specific treatment regimens, without considering this as a potential presentation/manifestation of aHUS/CM-TMA [complement-mediated TMA],” the team wrote.
In this study, aHUS patients had a good response to Soliris in the presence of MHT, meaning that an early and correct diagnosis is key in improving patient outcomes. As such, “a differential diagnosis of aHUS/CM-TMA should be considered in patients presenting with both MHT and TMA,” the researchers wrote.
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