TRANSPLANT PROGRAMS
TRANSPLANT PROGRAMS
DOING OUR BEST
PATHWAYS TO
THE CURE
REPURPOSING AN ADULT CHOLESTEROL DRUG TO FIGHT
KIDNEY DISEASE IN KIDS
It begins before birth, with small
dilations in the developing renal
tubules, a glitch in the coding of
the gene that helps build them.
The dilations fill with fluid and
seal themselves off into cysts.
The process repeats until the adult
kidney — normally the shape of
a bean and the size of a fist —
becomes so calcified and riddled
with cysts it looks like a geode,
bloats to the size of a football, and
eventually shuts down.
MELISSA
CADNAPAPHORNCHAI, M.D.
About 50 percent of babies
born with Autosomal Dominant
Polycystic Kidney Disease (ADPKD)
will develop kidney failure by age
60. Affecting about one in 500 to
1,000 people, it’s a leading cause
of kidney transplant in the U.S.
That recently changed with
the discovery, first observed at
neighboring University of Colorado
Hospital, of an interesting side
effect of an adult cholesterol drug.
The drug, pravastatin, works by
blocking cholesterol-producing
enzymes, enzymes that also seem
to aid the growth of cysts.
At least in theory: the physiology
isn’t completely understood. But
the fact, shown in trials led by Dr.
Cadnapaphornchai at Children’s
Colorado, is that using pravastatin
to treat ADPKD slows cyst growth
considerably. Slowed cyst growth
ostensibly means less tissue damage
and hormone problems, and longer
kidney life. It’s the first drug to treat
the root problem of ADPKD.
“We are the only group doing large-scale
drug trials for this disease in children,” says
Dr. Cadnapaphornchai.
Normal adult kidneys are about
the size of fists
Kidneys with ADPKD can reach
the size of footballs
48
It does plenty of damage along
the way. Cysts injure kidney tissue
as they expand, triggering it to
release hormones that raise the
blood pressure, stiffen the arteries,
and cause the body to retain water
and salt.
“For many years, all we could offer
kids with ADPKD was medications
to treat the symptoms,” says
Children’s Hospital Colorado
pediatric nephrologist Melissa
Cadnapaphornchai, M.D. “It was
like, well, we’ll do our best.”
This is great for kids, but it’s also
great for public health. A drug — or
some eventual combination of drugs
— that slows down or even stops cyst
growth can certainly help a 40-yearold, but how much more good could
it do if that patient had started at 8
years old, or even 2?
A drug treatment’s best effects
may be revealed over the course
of many years. “We’re looking at
younger and younger kids,” says Dr.
Cadnapaphornchai. “The pravastatin
study gave us a great database of
kids to follow long-term.”
THE IMMUNE SYSTEM’S B CELLS MAY BE KEY
TO UNDERSTANDING BILIARY ATRESIA
It’s not known what triggers the
devastating immune malfunction of
biliary atresia. The leading theory
links it to a perinatal virus infection,
which may initiate the progressive,
autoimmune attack on the bile duct
cells of the liver — an attack against
which no defense currently exists.
“Biliary atresia accounts for
50 percent of pediatric liver
transplants in the United States,”
says Cara Mack, M.D., a pediatric
hepatologist at Children’s Hospital
Colorado. It’s far and away the
number-one indication.
“For the past 15 years, we’ve been
teasing apart the features of the
various immune pathways that
contribute to bile duct injury,” says
Dr. Mack. The root of the problem in
biliary atresia is not only the immune
system’s destruction of bile duct
cells; it’s also the massive scarring
that results, and the accompanying
blockage of bile flow. Untreated, it
would effectively destroy an infant’s
liver by 2 years old.
Dr. Mack’s team has made
significant inroads into
understanding those pathways,
specifically the role of T cells, the
immune cells that typically identify
and destroy infectious agents.
And recently, working with Roberta
Pelanda, Ph.D., an immunologist
at the neighboring University of
Colorado School of Medicine, they
discovered another important
player in the biliary atresia immune
response: the B cell. Working in the
lab with genetically engineered mice,
Dr. Mack’s team showed that mice
without B cells are protected from
biliary atresia. “This tells us that B
cells are essential to the onset and
progression of bile duct injury in
biliary atresia,” says Dr. Mack.
“This new finding —
that B cells may be the
key to subsequent T cell
activation — will open
the door to creating
new therapeutics.”
The upshot: you can’t genetically
engineer babies not to have B cells,
but it’s possible that an immune
system-modulating compound that
targets B cell function may produce
a drug that can stop or slow down
the progression of biliary atresia.
For now, a liver transplant works
well for patients with biliary atresia.
But transplantation comes with
its own set of challenges — the
risk of complications, a lifetime
of immun osuppressive drugs,
the abbreviated life of the organ
itself — aside from the potentially
lengthy wait on the transplant list.
“If we can figure out how to treat
this disease,” says Dr. Mack, “we
can delay or even negate the need
for a liver transplant.”
CARA MACK, M.D.
49