Much Ado about N…atrium: modelling tissue sodium as a highly sensitive marker of subclinical and localized oedema

Abstract

Hypertonic Na+ accumulation in peripheral tissues is a recently described phenomenon: it has been associated with ageing, hypertension, diabetes, chronic kidney disease and heart failure, but its clinical meaning has yet to be determined. This concept conflicts with the classic physiological paradigm of constant balance between salt intake and excretion, and its water-independent nature is still a matter of debate.We developed a theoretical model explaining changes in the chemical composition of tissues as a function of extracellular volume fraction and excess extracellular fluid, i.e. oedema. The model suggests that the proportional increase in absolute Na+ content and concentration due to different degrees of oedema is higher than the parallel increase in water content, thus making Na+ a more sensitive index to detect this oedema.Our model would explain some of the recent findings of high tissue Na+ content in pathological conditions. More importantly, it prompts the reappraisal of tissue Na+ analysis from being a topic of niche interest to a potential diagnostic tool with broad applicability in the investigation of subclinical systemic and localized oedema.

Tissue sodium excess is not hypertonic and reflects extracellular volume expansion

“…The difference in the proportional changes of Na + and water does not reflect different amounts, as previously suggested, but different sensitivities to oedema detection ( Supplementary Fig. 2b) 22 . In fact, water paralleled Na + content with identical regression slopes across all groups ( Supplementary Fig.…”

“…Different experimental results for tissue Na + across organs fit well with a prediction model based on the intracellular/extracellular volume proportion (ECV/ICV) typical of each tissue ( Supplementary Fig. 2a) 22,26 . Lower water and Na + between control (NS) strains in skin and liver reflect differences in fat content that limit the volume of distribution (and total content, accordingly) of both ( Supplementary Fig.…”

“…We have previously suggested that tissue architecture per se can markedly impact on Na + content and concentration ( Fig. 1) 22 . Such histochemical 23,24 considerations are key to conclude on the HT nature of this Na + excess, which currently lacks demonstration in humans.…”

Chloride in Heart Failure Syndrome: Its Pathophysiologic Role and Therapeutic Implication

“…In particular, dermal interstitial space is reported to have an extensive depot of water-independent Na ? storage, a capability of local regulatory mechanisms entailing glycosaminoglycans as the putative binding site, a buffering system for tonicity-dependent modulation via the skin lymphatic system, and a property that its disruption defines the hypertensive phenotype [163][164][165][166]. The extent of the contribution of electrolyte chloride to body fluid dynamics in the dermal interstitial space, however, is not known.…”

Animal, Human, and 23Na MRI Imaging Evidence for the Negative Impact of High Dietary Salt in Children

“…Recently, 23 Na MRI became available as a non-invasive tool to estimate sodium accumulation in soft tissues such as skin and muscles in the extremities [ 63 , 64 ]. Importantly, this imaging technique does not distinguish water-bound from water-free sodium, and increased tissue sodium concentrations are mainly a function of extracellular volume expansion [ 65 ]. Skin and muscle sodium concentrations increase with age likely due to a reduction of cellular mass in favor of interstitial expansion [ 22 , 63 ].…”