# Exploring water free sodium storage

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $751,928

## Abstract

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...

## Key facts

- **NIH application ID:** 10781155
- **Project number:** 1R01DK138155-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** JEFFREY M TESTANI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $751,928
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10781155

## Citation

> US National Institutes of Health, RePORTER application 10781155, Exploring water free sodium storage (1R01DK138155-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10781155. Licensed CC0.

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