Comprehensive, Real-Time Monitoring of the Accumulation and Clearance of Small Molecules in Kidney Disease

Summary. Current methods for monitoring kidney function and the effectiveness of renal replacement therapy, which rely on infrequent, blood-draw measurements of plasma creatinine and urea, are simply inadequate. In response, here the team that invented electrochemical aptamer-based (EAB) sensors, the first high-frequency, real-time molecular measurement platform able to work in situ in the body, have combined forces with world- class experts in both aptamer selection and nephrology to advance the measurement of renal function and uremic solute clearance. To realize this vision, we are pursuing three specific aims. First, our aim-1 goal is the development of minimally-invasive, subcutaneous EAB sensors as a clinical tool supporting the measurement of plasma urea and creatinine concentrations, thus adding renal clearance to the list of vital signs that, like pulse and blood oxygenation, can be monitored unobtrusively and in real time. By providing accurate, real-time information regarding the rate of change of plasma creatinine, such an advance would accelerate the diagnosis and treatment of acute kidney injury and enable the immediate assessment of treatment efficacy. By providing real-time information regarding plasma urea, the proposed technology would likewise enable the high-precision personalization of renal replacement therapies, which has the potential to improve outcomes, lower costs, and enhance patient quality of life. In parallel, under aims 2 and 3 we will advance the EAB platform as a research tool to improve our understanding of uremic toxin clearance. Specifically, in aim 2 we will use the platform to characterize the clearance of uremic solutes from the blood, brain, and muscles in animal models of uremia. By improving our understanding of the extent to which the clearance of urea and creatinine from the plasma reflects their clearance from the solid tissues that are the major sites of uremic toxicity, success in these efforts will increase the clinical value of both traditional blood-draw/benchtop tests and our proposed real-time monitoring technology. And in aim 3 we will expand the platform to the measurement of a range of physicochemically and physiologically diverse uremic toxins, with our goal being to identify markers that, either alone or in conjunction with urea and creatinine, provide a more complete, more clinically meaningful descriptions of renal function, uremia, and the efficacy of renal replacement. The successful outcome of this work will be decisive demon- stration of a powerful new clinical tool for monitoring renal function, kidney failure, and renal replacement, and two powerful new research tools aimed at improving understanding of the clearance of the toxins underlying uremia. Together, these advances will significantly enhance the detection, study, monitoring, and treatment all stages of kidney disease.