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A low nephron number is considered a significant risk factor for susceptibility to chronic kidney disease (CKD). Total nephron number is established by birth and varies between ~200,000 and 2 Million between individuals. The progressive loss of functional nephrons is a fundamental characteristic of CKD progression. Large population studies have demonstrated that functional nephron number is an important determinant of risk of hypertension and CKD later in life. However, there are currently no clinical tools to noninvasively measure functional nephron number in individuals. There is therefore a critical gap between the recognized importance of functional nephron number and its measurement in patients. Direct measurement of functional nephron number would provide a sensitive and individualized assessment of kidney functional capacity that is not reflected in current clinical metrics. Further, functional nephron number could also guide interventions, facilitate transplant allocation, and stratify patients for clinical trials of new therapies. We propose to measure functional nephron number in vivo in humans using non-contrast ultrasound imaging. Our proposal is based on our recent observation that natural physiological fluctuations in local perfusion reflect nephron function. Specifically, we have used resting state magnetic resonance imaging (rsMRI) of the kidney to detect spontaneous physiological fluctuations in the kidney. These fluctuations in perfusion occur naturally at a frequency that are detectable, as we have shown, by noninvasive magnetic resonance imaging (MRI). Because these fluctuations are specific to nephron function, we argue that their power and distribution in the cortex directly reflects functional nephron number. This led us to the breakthrough concept that they should also be detectable by ultrasound, which would make measurements of nephron number broadly clinically accessible. We propose to develop a novel resting state ultrasound (rsUS) approach to measure these natural fluctuations in cortex as a direct measurement functional nephron number. If successful, this work will provide the first noninvasive, clinically translatable measure of nephron number in individual patients.
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