(Press-News.org) PHILADELPHIA -- 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.
INFORMATION:
The research was supported by the National Institute of Allergy and Infectious Diseases (AI068730, AI030040, AI097805) and the European Community's Seventh Framework Programme (602699).
Editor's Note: Lambris and Ricklin are the inventors of patents and/or patent applications that describe the use of complement inhibitors for therapeutic purposes. Lambris is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors for clinical applications.
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2013 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2013, Penn Medicine provided $814 million to benefit our community.
Like a smart sensor that adjusts the lighting in each room and a home's overall temperature, a protein that governs the making of other proteins in the cell also appears capable of controlling fat levels in the body.
The finding, which appeared in Cell Reports on Dec. 11, applies to the Maf1 protein in worms.
A version of the protein, which exists in humans, also regulates protein production in the cell, raising the possibility that it too may control fat storage. A protein with such a function would offer a new target for pharmaceuticals to regulate fat, said Sean ...
The Perioperative Surgical Home (PSH) model consistently and significantly improves quality of care for patients and reduces health care costs, reports a first-of-its-kind, large-scale literature review of the PSH in the United States and abroad. The review, published online this month in Milbank Quarterly, provides further evidence to support the benefits, and encourage the adoption, of the PSH model.
"There is a global push for more rigorously coordinated and integrated management of surgical patients to enhance patient satisfaction and improve quality of care and ...
Oil reservoirs are scattered deep inside the Earth like far-flung islands in the ocean, so their inhabitants might be expected to be very different, but a new study led by Dartmouth College and University of Oslo researchers shows these underground microbes are social creatures that have exchanged genes for eons.
The study, which was led by researchers at Dartmouth College and the University of Oslo, appears in the ISME Journal. A PDF is available on request.
The findings shed new light on the "deep biosphere," or the vast subterranean realm whose single-celled residents ...
BOZEMAN, Mont. - Cathy Cripps doesn't seem to worry about the grizzly bears and black bears that watch her work, but she is concerned about the ghosts and skeletons she encounters.
The ghosts are whitebark pine forests that have been devastated by mountain pine beetles and white pine blister rust, said the Montana State University scientist who studies fungi that grow in extreme environments. The skeletons are dead trees that no longer shade snow or produce pine cones. The round purple pine cones hold the seeds that feed bears, red squirrels and Clark's nutcracker birds. ...
Amsterdam, NL, December 12, 2014 - A patient who had suffered a traumatic brain injury unexpectedly recovered full consciousness after the administration of midazolam, a mild depressant drug of the GABA A agonists family. This resulted in the first recorded case of an "awakening" from a minimally-conscious state (MCS) using this therapy. Although similar awakenings have been reported using other drugs, this dramatic result was unanticipated. It is reported in Restorative Neurology and Neuroscience.
Traumatic brain injuries occur at high rates all over the world, estimated ...
New Rochelle, NY, December 11, 2014--In cases of traumatic brain injury (TBI), predicting the likelihood of a cranial lesion and determining the need for head computed tomography (CT) can be aided by measuring markers of bone injury in the blood. The results of a new study comparing the usefulness of two biomarkers released into the blood following a TBI are presented in Journal of Neurotrauma, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available free on the Journal of Neurotrauma website at http://online.liebertpub.com/doi/full/10.1089/neu.2013.3245 ...
Training older people in the use of social media improves cognitive capacity, increases a sense of self-competence and could have a beneficial overall impact on mental health and well-being, according to a landmark study carried out in the UK.
A two-year project funded by the European Union and led by the University of Exeter in partnership with Somerset Care Ltd and Torbay & Southern Devon Health and Care NHS Trust gave a group of vulnerable older adults a specially-designed computer, broadband connection and training in how to use them.
Those who received training ...
WOODS HOLE, Mass.--Since the first "catalog" of the normal bacterial makeup of the human body was published in 2012, numerous connections between illness and disturbances in the human microbiota have been found. This week, scientists report yet another: Cancerous tumors in the ascending colon (the part nearest to the small intestine) are characterized by biofilms, which are dense clumps of bacterial cells encased in a self-produced matrix.
"This is the first time that biofilms have been shown to be associated with colon cancer, to our knowledge," says co-author Jessica ...
PITTSBURGH--An interest in the gender gap between the representations of female candidates in U.S. elections compared to their male counterparts led two University of Pittsburgh professors to take the issue into the laboratory for three years of research.
Associate Professors of Political Science Kristin Kanthak and Jonathan Woon have published an article about the first phase of their research findings. "Women Don't Run? Election Aversion and Candidate Entry" was published online Dec. 2 in the American Journal of Political Science.
"Past research has shown that women ...
A group of researchers from Recep Tayyip Erdoğan University, Faculty of Fisheries in Turkey discovered a new trout species. The newly described species Salmo kottelati, belongs to the Salmonidae family, which includes salmons, trouts, chars, graylings and freshwater whitefishes.
Salmonids include over 200 species, which have a high economic value because of their taste and famed sporting qualities.
The genus Salmo is widely distributed in rivers and streams of basins of the Marmara, Black, Aegean and Mediterranean seas. The genus is represented by 12 species in ...
