Dietary sodium-restriction shows great promise as a modifiable factor for reducing risk of cardiovascular disease (CVD) and chronic kidney disease (CKD) progression in CKD patients through reducing blood pressure (BP), volume overload, proteinuria, and other cardiovascular abnormalities. Numerous meta-analyses have been published showing the efficacy of sodium-restriction in non-CKD populations. However, as salt-sensitivity is thought to be at least partially dependent on kidney function, research specific to CKD is warranted.
The first aim of this thesis was to assess existing evidence for sodium-restriction in CKD, through general literature review as well as a meta-analysis of randomised controlled trials of altered dietary sodium intake in CKD. Through systematic review, six studies (192 individuals; 178 in low salt group; 174 in high salt group) were identified as being eligible for inclusion (median intervention duration: 6 weeks). In pooled-analysis, reducing salt intake by 110 mmol/day reduced BP by 9/5 mm Hg. Reductions in 24-hour proteinuria between 20-50% were demonstrated with reduced salt diet. Data on effect of salt restriction on albuminuria, renal function or fluid status were limited.
The results of this systematic and general literature review were used to inform design of three original research trials investigating efficacy and effectiveness of dietary sodium-restriction in CKD (LowSALT CKD Trial-1; LowSALT CKD Trial-2; Taste-CKD Trial).
LowSALT CKD Trial-1 (LowSALT-1) was a six week randomized-crossover trial assessing effect of two weeks of 170 mmol sodium/day compared with 75 mmol sodium/day in 20 stage III-IV non-dialysed, non-transplanted CKD patients (mean age 68 ± 11 years; eGFR 31.6 ± 10.6 ml/min/1.73m2) on outcomes including ambulatory BP, proteinuria, albuminuria, extracellular fluid (ECF) volume and arterial stiffness. Sodium-restriction resulted in clinically and statistically significant reductions in ambulatory BP (mean reduction 10/4 mm Hg), ECF volume (mean reduction 0.8 L) and proteinuria and albuminuria (median reduction 40-50%), while arterial stiffness was not significantly altered. This magnitude of change was more pronounced than that usually seen in studies of patients without CKD, suggesting that patients with CKD may be particularly salt-sensitive.
LowSALT CKD Trial-2 (LowSALT-2) was a longitudinal uncontrolled follow-up aiming to assess effectiveness of 6 months of continued dietary advice to reduce sodium intake. Outcome measurement continued as per LowSALT-1 with the addition of patient-centred outcomes such as dietary adherence and taste assessment. Dietary advice reduced mean sodium excretion to 110 ± 52 mmol/day at 6-months. Most participants agreed with perceived benefits of a sodium-restricted diet, consistent with previous research. Specific barriers to following a low sodium diet were difficulty when eating out (50%), choosing reduced-salt bread (55%) and taste (25%). Participants who achieved a change in sodium intake of more than 50 mmol/day experienced BP reductions of 14/7 mm Hg, compared to minimal changes in those with a change of <50 mmol/day (although difference in SBP change did not reach statistical significance). The groups did not have a statistically significant difference in proteinuria, albuminuria or eGFR, although clinically significant differences were evident. Taste function was not related to sodium-restriction. This subgroup analysis must be interpreted with caution due to the small sample size and limited statistical power.
The Taste-CKD study assessed taste disturbance in CKD and the relationship between sodium intake and taste perception. This was a cross-sectional study of 91 adult stage 3-5 CKD participants (78% male; aged 65.9 ± 13.5 years; eGFR 33.1 ± 12.7 ml/min/1.73m2), and 30 controls (47% male; aged 55.2 ± 7.4 years, without kidney dysfunction). The CKD group correctly identified one less tastant than controls, and this difference remained significant after adjustment for age and gender. Specific impairment was found in sour, umami and salty tastes. Participants with low sodium intake were more likely to correctly identify salty and umami tastants, and rated intensity of umami and bitter significantly higher than those with high sodium intake. These findings add to the body of evidence suggesting that taste changes occur with CKD, independent of age and gender differences. The finding that sodium intake is related to umami and bitter disturbance warrants further investigation. In LowSALT-2, change in taste function was not related to sodium restriction; therefore evidence for the relationship between sodium intake and function of other taste qualities (besides salt) remains inconclusive.
The research presented in this thesis contributes to the body of evidence for the efficacy and effectiveness of sodium-restriction in CKD. The main limitation of the interventional research was small sample size limiting statistical power and reducing generalisability of the findings, while limitations of the Taste-CKD Trial relate to potential bias from unmeasured confounders and limitations inherent in outcome measurement and study design. A long-term study of the effects of dietary sodium-restriction on ambulatory BP, other cardiovascular risk factors (specifically markers of fluid volume and central haemodynamics), risk factors for kidney function decline (proteinuria and albuminuria), as well as taste function, is warranted.