Broadview Pl

ENHANCED RENAL DIALYSIS MEMBRANE PERFORMANCE USING LIPOCALIN MODIFIED SUBSTRATES - PROJECT SUMMARY: IT IS ESTIMATED THAT MORE THAN 30 MILLION AMERICAN ADULTS HAVE CHRONIC KIDNEY DISEASE (CKD), WITH NEARLY 800,000 LIVING WITH END-STAGE RENAL DISEASE (ESRD). PEOPLE WITH CHRONIC DISEASES SUCH AS DIABETES, HIGH BLOOD PRESSURE, AND HEART DISEASE ARE AT A HIGHER RISK FOR CKD. BECAUSE THEIR KIDNEYS NO LONGER FUNCTION, INDIVIDUALS WITH ESRD OFTEN RELY ON HEMODIALYSIS TO REMOVE WASTE FROM THEIR BLOOD. ALTHOUGH THE WIDESPREAD USE OF HIGH-FLUX POLYSULFONE DIALYZERS HAS DRAMATICALLY IMPROVED THE CLEARANCE OF SMALL WATER-SOLUBLE UREMIC TOXINS, THERE HAVE BEEN NO SIGNIFICANT ADVANCES IN REMOVING HYDROPHOBIC PROTEIN-BOUND UREMIC TOXINS (PBUTS) DUE TO THEIR HIGH BINDING AFFINITIES TOWARDS ALBUMIN. WHILE INITIALLY THOUGHT TO BE BENIGN, AN INCREASING BODY OF DATA HAS LINKED ELEVATED PBUT LEVELS TO DIABETES, REDUCED NEUTROPHIL FUNCTION AND INNATE IMMUNITY, PERIPHERAL VASCULAR DISEASE, DEPRESSION AND THE GENERATION OF ACCELERATED RATES OF MYOCARDIAL FIBROSIS AND CARDIAC ARRHYTHMIAS ASSOCIATED WITH SUDDEN DEATH. RECOGNIZING THE NEED FOR IMPROVED DIALYSIS TECHNOLOGIES, HIBAR MICROSCIENCES DEVELOPED A PROCESS FOR ENHANCING THE CLEARANCE OF PBUTS FROM HUMAN BLOOD BY TAKING ADVANTAGE OF THE INTERACTIONS BETWEEN PBUTS AND MEMBERS OF THE LIPOCALIN FAMILY OF PROTEINS. HIBAR MICROSCIENCES HAS SHOWN THAT LIPOCALIN-MODIFIED MEMBRANES INCREASED EXTRACTION RATES OF PBUTS FROM FETAL BOVINE SERUM, DEMONSTRATING THAT THESE MEMBRANES CAN POTENTIALLY SERVE AS A NOVEL MATRIX FOR CLEARING PBUTS FROM THE BLOOD OF HEMODIALYSIS PATIENTS. DURING THE FUNDING PERIOD OF THIS PHASE I SBIR PROPOSAL, HIBAR MICROSCIENCES WILL DEVELOP A PROTOTYPE FOR CLEAR, A NOVEL HEMODIALYSIS CARTRIDGE FOR IMPROVED PBUT CLEARANCE. IN AIM 1, A METHOD FOR IMMOBILIZING LIPOCALINS TO VARIOUS MATRICES WILL BE DEVELOPED. DURING AIM 2, CLEAR PROTOTYPES WILL BE CREATED AND TESTED FOR EFFICACY (REMOVAL OF PBUTS) AND SAFETY (RETENTION OF HUMAN VITAMINS). IN AIM 3, PBUT LEVELS IN THE SERUM OF HEMODIALYSIS PATIENTS WILL BE DETERMINED, AND PBUT LEVELS WILL BE CORRELATED TO CARDIAC EVENTS. FURTHER, THE DENSITY OF LIPOCALIN THAT NEEDS TO BE ATTACHED TO THE MEMBRANE TO PROVIDE CLINICALLY RELEVANT REMOVAL OF PBUTS WILL BE DETERMINED. THE COMPLETION OF THE PROPOSED WORK WILL EXTEND TO PHASE II STUDIES WHEREIN CLEAR WILL BE FURTHER DEVELOPED AND TESTED IN AN ANIMAL MODEL OF CKD/ESRD.