Traditional physiologic paradigms focus on 2 fluid compartments, intracellular volume (ICV) and extracellular volume (ECV), in addition to renal sodium (Na) handling to explain Na and water homeostasis. A potential 3rd compartment, where Na is stored without an osmotic effect on ICV or ECV, has recently been popularized. However, this candidate 3rd compartment does not invalidate traditional physiology; it remains true that Na loading will predictably influence ICV/ECV and the kidney will excrete the overwhelming majority of loaded Na. Since only a small fraction of the variance in Na handling can be attributable to the candidate 3rd compartment, measurement error (or measurement omission) of traditional physiologic parameters can be of similar or greater magnitude to the 3rd compartment signal. Likely as a result, essentially the same salt loading rodent experiment has been published multiple times often with different results/conclusions. Notwithstanding the difficulty in studying this question, if a 3rd compartment does meaningfully contribute to Na/water homeostasis, revolutionary biologic and therapeutic insights could be gained by understanding it. However, before we can understand a 3rd compartment, we first need to definitively prove it exists. We propose a comprehensive set of porcine and human studies that will definitively answer 3 primary questions 1) Can a stoichiometrically relevant amount of NaCl be acutely stored or released without water? 2) Is this storage location primarily intracellular or extracellular? 3) Does this physiology apply to humans? Specifically, Aim 1 will establish if significant acutely mobilizable non-ECV sodium storage occurs. We will administer large amounts of NaCl (without significant water) to nephrectomized otherwise normal pigs and measure the change in total ECV osms compared to equal osmolar mannitol, which is known to distribute into ECV and not a 3rd compartment. We will also remove large amounts of Na (without significant water) via peritoneal dialysis with a sodium-free dialysate solution and determine the change in ECV sodium as well. Aim 2 will determine if the non-ECV sodium storage location is primarily intracellular or extracellular. In the above porcine models, we will measure 22Na storage in the skin (primarily acellular) and erythrocytes/skeletal muscle cells (primarily cellular) between the NaCl group and a mannitol control. Aim 3 will determine if significant mobilizable non-ECV sodium storage occurs in humans. We will conduct an ultra- rigorous inpatient balance study with randomized crossover design of 10 patients treated with 5 days of sodium free 5% dextrose (titrated to remove ~150 mmol/day Na without water) added to their standard PD prescription versus a blinded control 1.5% dextrose commercially available PD solution (both minimal Na and water removal). We hypothesize that 5 days of ~150 mmol/day Na removal will result in a large negative sodium balance without significant change...