Physiological Sensitivity to Salt and Uninephrectomy

Abstract

Salt sensitivity, with or without concomitant hypertension, is associated with increased mortality. Reduced functional renal mass plays an important role in causing salt sensitive hypertension for many individuals but the mechanisms are unclear. Moreover, different derangements in human physiology can result in the same phenotype. Methodologies that could discover patterns in sensitivity to dietary change or interventions would be a revolutionary tool in personalizing medicine. We used HumMod, an integrative mathematical model of human physiology, to simulate population responses to changes in salt intake with or without reduced kidney mass (uninephrectomy). A heterogeneous population of 1000 virtual patients was created by randomly varying important physiological parameters. We examined potential physiological mechanisms responsible for the chronic blood pressure (BP) response to salt (8‐fold change in salt intake for 3 weeks) with full kidney mass and again with a single kidney in the same group of virtual patients. We also used topological data analysis (TDA), a new clustering algorithm tool, to separate patient subpopulations. In the entire population, BP increased with increased salt intake (14 ± 3 mmHg). This was associated with small changes in glomerular filtration rate (GFR) but significant increases in renal blood flow, total peripheral resistance, and distal tubular sodium reabsorption. Interestingly, TDA distinguished 5 unique clusters of salt sensitive individuals (> 15 mmHg change in BP with increased salt). While these clusters had similar BP responses to salt, they were significantly different in the mechanisms of salt sensitivity (e.g. greater reductions in GFR or impairments in the renin angiotensin system.) After kidney removal in these same individuals, the three most salt sensitive clusters were associated with a blunted increase in renal blood flow (RBF), exaggerated increases in loop and distal sodium reabsorption, and greater sodium and volume retention as compared to the salt resistant population. These data suggest that the suppression of sodium reabsorption and renin angiotensin system is key for salt resistance, while RBF in addition to GFR may be an important factor when considering criteria for potential kidney donors.Support or Funding InformationSupported by NSF EPS‐0903787, P20 GM104357, and NIH PO1 HL51971.