NEPHROLOGY • CONTINUED FROM PREVIOUS PAGE
An hour later, Lucy was in a helicopter rushing to
Children’s Hospital Colorado, while her parents
drove down behind.
“She had rip-roaring high blood pressure,” says
Chief of Pediatric Nephrology Jens Goebel, MD,
who managed her care. “It took astronomical
amounts of blood pressure medications to get it
under control.”
Excessive protein in her urine prompted an initial
diagnosis of congenital nephrotic syndrome, but a
genetic test came back unrevealing. Her enlarged
kidneys and high blood pressure, for a while, led
to speculation she might have polycystic kidney
disease. But that genetic test, too, came back
negative.
“They went through four or five diagnoses,”
says Brad.
though they still didn’t know exactly what. But
once she was stable, they sent her home.
And for more than a year, she did alright — well
enough for her team to gradually reduce her
meds. Cynthia and Brad settled into the routine of
bringing her in for blood work once a month.
“She started to become anemic, and that anemia
became more progressive,” says pediatric
nephrologist Brad Dixon, MD. “That’s not unusual
for chronic kidney disease. But her kidney function
was about 70 percent of normal, and the anemia
was way out of proportion to that.”
Then, in April of last year, a routine blood test
showed Lucy’s platelet count rapidly dropping.
That was the clue that pulled it altogether.
It’s like a Ferrari someone cut the brakes on. As long as it sits in the
garage, it’s alright. But if you take that out at 150 mph and you don’t
have brakes, bad things are going to happen.”
B R A D D I XO N , M D
Pediatric Nephrologist
“And God knows how many genetic tests,” Cynthia
adds. “They just didn’t know what the cause was.”
It was a frightening ordeal, particularly for Cynthia,
who, as a teen, had suffered a meningococcal
infection that came on suddenly, shut down her
major organs and put her in a coma that lasted
weeks. It left her with skin grafts all over her body.
Doctors were forced to amputate her legs.
“My mom flew out from Australia when Lucy was
in the hospital,” Cynthia recalls. “She was saying,
‘it’s just like déjà vu.’”
Lucy’s condition stayed distressingly touch-and-
go for three months. Her team assigned her the
umbrella diagnosis of chronic kidney disease,
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A sudden spiral
Drs. Goebel and Dixon agreed: The most likely
culprit was in fact a blood disease, thrombotic
microangiopathy, or TMA. It results when platelets
clump and plug up networks of capillaries — such
as those of the kidneys — deforming red blood
cells as they squeeze through. Hence the high
blood pressure. Hence the anemia. Hence the low
platelet count.
TMA has many causes, from E. coli to cancer. In
Lucy’s case, Drs. Dixon and Goebel suspected it
was atypical hemolytic uremic syndrome, or aHUS,
the result of a genetic defect in a component of the
immune system known as complement.
“Certain molecules on the surface of bacteria
don’t occur on human cells,” says Dr. Dixon. “These
innate parts of the immune system can recognize
danger patterns and go after a pathogen without
ever being exposed to it.”
Complement destroys the bacterium
meningococcus by punching a hole in its cell wall.
Its power is immediate and immense. And once it’s
triggered, it requires a strong regulatory response.
In aHUS, that doesn’t happen.
“Complement is a protein cascade,” says University
of Colorado School of Medicine immunologist
Ashley Frazer-Abel, PhD, one of the nation’s
foremost experts on complement proteins.
“These proteins exist in circulation, and in an
activating event like an infection, it’s a cycle of
self-perpetuation. It’s very good locally to fight
infection, but when it’s systemic or uncontrolled,
it’s doing direct damage to the body or recruiting
other immune cells to perpetuate that damage.”
“It’s like a Ferrari someone cut the brakes on,”
says Dr. Dixon. “As long as it sits in the garage, it’s
alright. But if you take that out at 150 mph and you
don’t have brakes, bad things are going to happen.”
That’s what was happening to Lucy, and its sudden
spiral led to another 7 weeks in the hospital. Still,
with a diagnosis also came the brake Lucy needed:
powerful complement-blocking agents that hobble
proteins in the chain.
That would save her life, but it would also leave
her complement system powerless against
meningococcal disease — the same infection that
had taken Cynthia’s legs.
“That was a difficult conversation to have,” says
Dr. Dixon. He speculated it was possible that the
same underlying defect had caused Cynthia’s
infection. Perhaps a defective complement system
depleted by its own autoimmune attack had left
her vulnerable to the infection in the first place.
The other downside was that complement-
blockers required infusion — a long day for the
Washburns, who would have to drive a nearly
Lucy still needs regular infusions of eculizumab and will for the
forseeable future. But with her complement system under control,
she can live the relatively ordinary life of an energetic little girl.
150-mile round trip. Drs. Goebel and Dixon already
had a patient enrolled in a clinical trial for an
experimental, extended release complement-
blocking drug, which would only require Lucy to
come in monthly. Her condition was so rare that,
once she entered the trial, Children’s Colorado
became one of just two sites in the world with
more than one patient enrolled.
Initially it worked. Lucy’s platelet count went up
and her blood pressure stabilized. But by the next
week, a lab check between infusions caught her
platelet count dropping and anemia setting in.
Drs. Dixon and Goebel, who number among the
world’s foremost experts in treating TMA in
children, considered the possibility that they’d
misdiagnosed. Still, they had experience enough
to feel confident they’d got it right.
They also knew that dosing regimens in clinical
trials like the one Lucy was in extrapolate
dosing regimens from adults. But young children
metabolize some drugs much faster than adults
and older children. The half-life is shorter. Their
team had studied that phenomenon and published
their results. Maybe the experimental drug had
just worn off.
The real question, they surmised, was whether the
complement system was blocked.
NEW CONSTELLATIONS
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