TAMING THE INFLAMMATORY RESPONSE IN KIDNEY DIALYSIS
Frequent kidney
dialysis is essential for the approximately 350,000 end-stage renal disease
(ESRD) patients in the United States. But it can also cause systemic
inflammation, leading to complications such as cardiovascular disease and
anemia, and patients who rely on the therapy have a five-year survival rate of
only 35 percent. Such inflammation can be triggered when the complement
cascade, part of the body's innate immune system, is inadvertently activated by
modern polymer-based dialysis blood filters. New work by Penn researchers has
found an effective way to avoid these problems by temporarily suppressing
complement during dialysis. Their work appears online in Immunobiology ahead of print.
Over the past
several years, lead author John Lambris, PhD, the Dr. Ralph and Sallie Weaver
Professor of Research Medicine, Perelman School of Medicine at the University
of Pennsylvania, and his colleagues have developed small molecule versions of
the drug compstatin, which inhibits a component of the complement immune
response called C3. Lambris explains that this next-generation compound, called
Cp40, "is a small peptide similar to cyclosporine in many aspects, however
it uses a different mechanism of action."
Previous studies by
Lambris and his team, in which modern polymer-based hemodialysis filters were
perfused with human blood, showed significant complement activation and an
increase in inflammatory biomarkers. This response could be suppressed using
compstatin, suggesting that it might be used in dialysis to decrease the
inflammatory response side effect.
The new study took
place in non-human primates to validate Cp40's complement-inhibiting properties
in whole animals. Even after undergoing a single session of dialysis using a
pediatric hemodialysis filter with high biocompatibility, healthy animals
showed strong complement activation with 5 percent of their C3 being converted
to a form that can trigger inflammation and stimulate the immune system.
"This is a huge
amount of activation because hemodialysis patients go every two or three days,
three times a week, for treatment," says Lambris. Such repetitive
complement activation may create a cytokine boost in humans that could fuel the
chronic inflammatory response in renal disease patients. When a single dose of
the Cp40 compound was administered, the animals displayed a complete
suppression of complement, as indicated by C3 activation levels.
A major advantage of
this new approach is that it's short-term: "The treatment is only for the
time of hemodialysis," Lambris explains. "It's not a lasting
inhibition. You start hemodialysis, you give the compound, and you inhibit
during hemodialysis. After the procedure, the complement system quickly regains
its full activity." This avoids potential concerns about adverse effects
caused by long-term complement suppression. Cp40 can also be manufactured at
relatively low cost, easing the already-high financial burden of maintenance
dialysis for ESRD patients.
Study co-author
Daniel Ricklin, PhD, research assistant professor of Pathology and Laboratory
Medicine, adds, "Technical challenges make it almost impossible to perform
these studies in mice or other small animals in a clinically relevant context,
so you have to go to another animal model. I think this new monkey model that
we established is a very important step in evaluating disease mechanisms and
novel routes of inhibition for this indication."
The Cp40 treatment
can be even more cost-effective because, as Ricklin notes, "You may select
patients who would benefit most from the treatment, depending on their
underlying condition, or have to use filters with lower biocompatibility.
Physicians would then have the option of a selective add-on treatment, therefore
controlling the treatment cost overall."
Says Lambris,
"We're very excited about this, because we feel it's the first time we
have an opportunity to try a complement inhibitor in hemodialysis, and it can
be something good for so many hemodialysis patients. I feel they're a neglected
group of people."
The chances for
clinical translation of this novel therapeutic approach are promising since
AMY-101, a drug that is based on Cp40, is currently under clinical development,
notes Lambris.
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