aHUS symptoms differ in children, adults with same C3 variant
Dutch study found children had milder kidney injury but more blood changes
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Children and adults in the Netherlands with atypical hemolytic uremic syndrome (aHUS) experience differences in clinical presentation and outcomes despite carrying the same disease-linked genetic variant, according to a new study.
Children with this variant presented with more profound blood cell abnormalities but milder kidney impairment than adult patients. Despite frequent relapses, long-term outcomes appeared favorable, particularly for those with childhood-onset disease.
Study examines Dutch aHUS patients
The study, “Atypical hemolytic uremic syndrome in children and adults with the hot spot C3 gene variant p.Arg161Trp,” was published in Kidney International Reports.
aHUS is caused by abnormal overactivation of the complement system, a component of the immune system, with most cases involving mutations in proteins that normally regulate the complement system. Even so, not everyone who carries one of these mutations will develop the disease, which may be influenced by environmental triggers such as infection and other genetic risk factors.
In a large study involving more than 3,000 aHUS patients from Europe and the U.S., a rare mutation in the complement gene C3 — p.Arg161Trp — was the most frequent rare mutation identified. In subsequent studies, this mutation was reported in about 25% of patients in the Netherlands, compared with 0.2% to 4% in other European and non-European groups.
Scientists in the Netherlands conducted an in-depth analysis of the clinical features associated with this mutation among Dutch aHUS patients.
Of the 37 individuals with aHUS (11 children and 26 adults) included in this study, 21 presented before the approved aHUS therapy Soliris (eculizumab) became available in the Netherlands in 2012. A history of cardiovascular and/or kidney disease was reported in half of adults, but in none of the children.
All patients had disease onset in their native kidneys. Among those with available laboratory data at onset, all but two had acute kidney injury and thrombotic microangiopathy, the hallmark of aHUS that involves the formation of tiny blood clots in small blood vessels. A well-defined aHUS trigger was identified in approximately one-fourth (24%) of patients, most commonly an infection and pregnancy. Among those with available data, more than half (55%) had severe high blood pressure at onset.
Children had milder kidney injury
Children and adults presented quite differently. Among those with symptom data, red-colored urine (90% vs. 24%) and jaundice (50% vs. 10%), yellowing of the skin and the whites of the eyes, occurred significantly more often in children than adults.
Children also showed more severe blood abnormalities, including elevated markers of red blood cell breakdown (hemolysis) and lower counts of platelets, the cell fragments that help blood clot. Conversely, kidney impairment was less severe in children, who required fewer acute dialysis procedures than adults (9% vs. 62%).
All 11 children recovered kidney function after their first presentation. Ten achieved full recovery, and one achieved partial recovery. Nine of the ten children who recovered fully were treated only supportively, without plasma exchange or Soliris, and recovered spontaneously within a few days.
In adults, kidney function recovered after the first presentation in most patients (58%), with partial recovery in 10 and full recovery in five. Recovery was observed more often among adults treated with Soliris, with seven of eight recovering kidney function (88%), compared with recovery in fewer than half (44%) of those who did not receive Soliris.
Adults who achieved full kidney recovery after onset tended to be younger, had no prior history of cardiovascular or kidney disease, had better kidney function at onset, and did not need temporary dialysis. They also had lower platelet counts and more severe red blood cell breakdown, resembling the presentation seen in children, the team noted.
Among the children, nearly all (82%) experienced a relapse, with a median of 5.3 years between disease onset and the first relapse. Relapses in children again featured severe blood abnormalities but relatively mild kidney impairment. Seven of the nine children who relapsed recovered fully.
Of the 14 adults at risk for relapse, most (86%) had a suspected or definite relapse. Seven adults were treated with Soliris at relapse, and six of them (86%) recovered to their pre-relapse kidney function. Of the five adults not treated with Soliris at relapse, two (40%) recovered fully.
Relapses were common in both groups
There was also a notable difference in relapse timing depending on whether Soliris had been used at the onset. Among adults who had received Soliris at onset and then stopped, the median time from treatment discontinuation to a first relapse was about six months. For adults who experienced a relapse after not receiving Soliris at onset, the median time from their initial disease onset to that first relapse was 3.4 years.
At 10 years after the first presentation, kidney failure-free survival was 88% in children and 86% in adults treated with Soliris, and 31% in adults not treated with Soliris.
Over the entire follow-up period of a median of 19 years for children, two progressed to kidney failure, both as a result of disease relapse, while the remaining nine had well-preserved kidney function. Seven of those nine children had experienced a total of 15 relapses, nine of which were treated with Soliris.
The 10 adults who did not progress to kidney failure experienced a combined 19 relapses, almost all treated with Soliris. In all but one of these patients, relapses did not cause further loss of kidney function. No deaths directly attributed to aHUS were recorded.
“This study shows significant differences in the presentation and outcomes of children and adults with [aHUS],” the scientists wrote. “Children presented with milder [kidney injury], yet had more profound hemolysis.”
