Volume-Independent Sodium Toxicity in Peritoneal Dialysis: New Insights from Bench to Bed

Abstract

Sodium overload is common in end-stage kidney disease (ESKD) and is associated with increased cardiovascular mortality that is traditionally considered a result of extracellular volume expansion. Recently, sodium storage was detected by Na23 magnetic resonance imaging in the interstitial tissue of the skin and other tissues. This amount of sodium is osmotically active, regulated by immune cells and the lymphatic system, escapes renal control, and, more importantly, is associated with salt-sensitive hypertension. In chronic kidney disease, the interstitial sodium storage increases as the glomerular filtration rate declines and is related to cardiovascular damage, regardless of the fluid overload. This sodium accumulation in the interstitial tissues becomes more significant in ESKD, especially in older and African American patients. The possible negative effects of interstitial sodium are still under study, though a higher sodium intake might induce abnormal structural and functional changes in the peritoneal wall. Interestingly, sodium stored in the interstial tissue is not unmodifiable, since it is removable by dialysis. Nevertheless, the sodium removal by peritoneal dialysis (PD) remains challenging, and new PD solutions are desirable. In this narrative review, we carried out an update on the pathophysiological mechanisms of volume-independent sodium toxicity and possible future strategies to improve sodium removal by PD.

Tissue Sodium Accumulation Induces Organ Inflammation and Injury in Chronic Kidney Disease

“…Variability in 24 h sodium excretion was observed in healthy adults, even though total salt intake was fixed, thus providing evidence of tissue sodium storage. Rhythmic fluctuations in aldosterone, cortisol, and cortisone levels were found to be involved in this process [1,2,27]. Autocoids including endothelin-1 and adrenomedullin have also been demonstrated to be involved in sodium homeostasis.…”

“…Signaling pathways involved in hypertonic conditions that are regulated by TonEBP have received considerable research attention with regard to tonicity-dependent and tonicity-independent sodium toxicity [1,5].…”

“…Many types of non-renal cells, including heart and skeletal muscle cells, reportedly express TonEBP [50][51][52]. In addition, the biological importance of the osmotic stress response related to TonEBP-dependent gene regulation in non-renal tissues is now widely recognized [1,51,53]. High salt intake reportedly drives autoimmune diseases via TonEBP activation in immune cells [54,55].…”

“…Fluid overload is reportedly observed at high rates in chronic dialysis patients and in 30% of peritoneal dialysis (PD) patients [1][2][3][4]. One of the main causes of over-hydration in these patients is high salt intake.…”