Doctor of Philosophy
McIntyre, Christopher W.
Chronic kidney disease (CKD), especially when requiring kidney replacement therapy (hemodialysis (HD) and peritoneal dialysis (PD)), is associated with extracellular water expansion with increased total body sodium. Sodium can also be accumulated in tissues independently of extracellular water. Sodium-23 magnetic resonance imaging (23Na MRI) can quantify the concentration of sodium nuclei in tissues. Applied to the human leg, quantification of tissue sodium concentrations mainly at the skin and muscle level is possible. We hypothesized that increased tissue sodium concentrations exert toxic effects in CKD and dialysis. We aimed to (1) compare tissue sodium concentrations in adults, children and adolescents with CKD, HD and PD against healthy individuals, (2) identify their predictors, (3) understand their connection to left ventricular structure in patients receiving HD and (4) observe their relationship with adverse cardiovascular events and mortality in patients receiving HD and PD. Tissue sodium concentrations were increased in adult patients receiving HD and PD, with respect to healthy individuals. In children and adolescents with CKD, tissue sodium concentrations varied depending on CKD etiology, suggesting kidney disorders can be associated with either sodium wasting or accumulation. Tissue sodium concentrations were associated with older age and overweight in healthy individuals; in patients with CKD and receiving dialysis, hypoalbuminemia was an important predictor of tissue sodium concentrations. In pediatric CKD, proteinuria was also positively associated with tissue sodium concentrations, suggesting a role of proteinuria in increased sodium reabsorption. In patients receiving HD, dialysate sodium concentration was strongly positively associated with skin sodium concentrations.
In patients receiving HD, tissue sodium concentrations were associated with left ventricular hypertrophy and dilatation, with tissue sodium concentrations being highest in patients with a dilated heart. Skin sodium concentration was associated with major cardiovascular adverse events and mortality in patients receiving HD or PD. These findings expand our understanding on the toxicity of sodium in CKD and point out critical issues of current dialysis treatment practices. Future studies should explore improved technical applications of 23Na MRI and experiment with new therapies and treatment strategies to reduce tissue sodium concentration in patients with CKD and those receiving dialysis.
Summary for Lay Audience
Sodium, one of the two constituents of table salt along with chloride, is the main ion contained in extracellular water. One of the main functions of the kidneys is to control extracellular water balance by excreting excess sodium and water. With sodium-23 magnetic resonance imaging (23Na MRI) sodium concentration in human leg tissues can be measured. We hypothesized that diseased kidneys, especially when kidney replacement therapy is necessary, are associated with increased tissue sodium concentration. Our goals are to (1) compare tissue sodium concentrations in adults and children with kidney disease and receiving dialysis against healthy individuals, (2) identify what factors are associated with them, (3) understand their connection to heart structure in patients receiving dialysis and (4) observe their relationship with heart disease such as myocardial infarction and death in patients receiving dialysis.
In the first project, we found that adult patients receiving dialysis had higher tissue sodium concentrations compared with healthy individuals. Tissue sodium concentrations were higher in older, overweight individuals and when serum levels of the protein albumin were lower. In the second project, we found that tissue sodium concentrations in children and adolescents with kidney disease differed depending on what kind of kidney disease they had, suggesting that some forms of kidney disease lose sodium though the urine, whereas others reabsorb too much sodium from the urine. In the third project, we found that tissue sodium concentrations in patients receiving hemodialysis were mirrored by alterations in the heart structure, such as ventricle dilatation and increased wall thickness. In the fourth project, we observed that higher tissue sodium concentrations in the skin of patients receiving dialysis was associated with more occurrences of heart disease and death. We also found out that hemodialysis using high sodium concentration in the dialysis fluid led to higher skin sodium concentration, suggesting hemodialysis itself may lead to tissue sodium accumulation.
These findings suggest that tissue sodium in kidney disease and dialysis is toxic. These results should prompt a change in dialysis prescriptions to reduce the amount of sodium accumulation, and future studies should design new treatments using tissue sodium as a target.
Salerno, Fabio R., "Noninvasive Quantification of Tissue Sodium Concentration in the Kidney Disease Spectrum using 23Na Magnetic Resonance Imaging" (2022). Electronic Thesis and Dissertation Repository. 9025.
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