Sodium Reduction in CKD: Suggestively Hazardous or Intuitively Advantageous?

In the United States and most countries worldwide, mean dietary sodium intake is much higher than daily requirements. Although the potential consequences of high dietary sodium intake, including higher BP, fluid retention, and cardiovascular disease (CVD) risk, are much more common in individuals with CKD;¹ few trials have been done, and to our knowledge, only one is underway in CKD patients based on a search of ClinicalTrials.gov.²

In the absence of clinical trials, guidelines for dietary sodium intake in CKD are based on expert opinion, observational studies, and extrapolation from general population studies. For example, recent Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines recommend “lowering salt intake to < 90 mmol (<2 g) per day of sodium, unless contraindicated.”¹ This recommendation corresponds to 5 g of sodium chloride. The recommendation is graded “1C,” indicating that the KDIGO panel considered it important enough to serve as a candidate for making public policy decisions and as a performance measure, although simultaneously indicating that the quality of evidence was low and that the true effect may be substantially different from the estimated effect. This grade appears consistent with the widespread belief that dietary sodium reduction is probably beneficial in CKD, albeit with little evidence to support it.

In this issue of JASN, McMahon and colleagues provide new clinical trial data in this area.³ The elegant design and careful measurements in their study provide reassurance to the existing KDIGO guidelines, despite enrolling only 20 individuals. The authors report data from a randomized, double-blind, crossover trial in patients with stage 3–4 CKD. Participants were placed on a low-sodium diet for a 1-week run-in, then randomly assigned to a high-sodium arm (accomplished by the addition of a salt tablet on top of the low-sodium diet) or a low-sodium arm (low-sodium diet with the addition of a placebo tablet). Participants were treated for 2 weeks in one arm, followed by a 1-week washout period, and then crossed over to the other arm. Effects on BP, proteinuria, fluid status, body weight, plasma renin and aldosterone concentrations, and measures of arterial stiffness were examined.

Key strengths of the study include the use of slow-release sodium tablets to achieve contrast between the low- and high-sodium arms without influencing other aspects of diet. Thus, total caloric intake and potassium intake were held constant on both the high- and the low-sodium diet. This design feature allows clear insights into the effects of dietary sodium without confounding effects from changes in other dietary factors. Importantly, the sodium exposure categories (i.e., 4140–4600 mg/d and 1380–1840 mg/d in the high- and low-sodium arms, respectively) are highly relevant to public policy because few data are available on outcomes at the range of intake <2000 mg/d, as currently recommended by KDIGO.

The authors found that mean systolic BP was 9.7 mmHg lower in the low-sodium arm than in the high-sodium arm; this level of BP reduction is substantial and clinically relevant. In addition, four participants required dose reductions of antihypertensive medications because of symptomatic hypotension while in the lower-sodium arm, suggesting that effects may have been even greater if use of antihypertensive medications were held constant. Moreover, proteinuria was decreased by about 50% during the low-sodium intervention, an effect that was statistically independent of BP changes. As expected, body weight and fluid status decreased, and plasma renin and aldosterone concentrations markedly increased during the low-sodium intervention. No effect on arterial stiffness was observed.

This study is salient because few intervention studies have evaluated dietary sodium reduction in patients with CKD.⁴ The evaluation of other outcomes in addition to BP is an additional strength of the trial. Although BP is considered a valid surrogate outcome for estimating risk of CVD in the general population,⁵ there are other considerations in the context of CKD. The reported effects on proteinuria, fluid status, and body weight in addition to the marked change in BP should all be beneficial.

Large trials with hard endpoints are costly and logistically challenging. One reason is the requirement for a high level of safety monitoring. Thus, contributions from trials such as that by McMahon and colleagues³ are important additions to the field. It is also likely, therefore, that the preponderance of new evidence will continue to come from observational studies. These studies provide key insights. However, the limitations of observational studies and inaccuracies in 24-hour urine collections raise concerns about confounding and even reverse causality because the oldest, sickest, and least compliant participants will be those with the lowest apparent sodium intake if they systematically undercollect their urine. In this case, there is the possibility of paradoxical and even spurious associations of low sodium intake with risk of death and ESRD.⁶

To date, observational studies have provided inconsistent results. Studies in nondiabetic patients with CKD⁷ and in dialysis patients⁸ have reported that low sodium intake is associated with improved outcomes, as might be expected on the basis of the findings of McMahon et al.³ On the other hand, there have also been reports that lower 24-hour urine sodium excretion is associated with higher risk of death and ESRD in individuals with type 1⁹ and type 2¹⁰ diabetes with overt proteinuria. As shown again in the study by McMahon and colleagues, dietary sodium reduction is known to increase plasma renin and aldosterone concentrations, and some authors have argued that long-term exposure to high plasma renin and aldosterone may promote atherosclerosis.¹¹ Others have argued that in the setting of diabetes, low dietary sodium intake may increase renal plasma flow and GFR and may contribute to hyperfiltration in the early stages of diabetic nephropathy.^12,13 Thus, although the study by McMahon et al. shows impressive results over a short 2-week intervention, the observational studies raise questions about the long-term effects of dietary sodium reduction in patients with CKD that may be independent of BP or proteinuria per se, and they underscore the need for larger well designed studies with longer follow-up.

Whether an intensive short-term dietary sodium restricted intervention in the closely monitored setting of a clinical trial will translate into similar improvements in routine clinical practice is unknown. Further, whether such diets are sustainable over the long term, and whether effects on surrogate or hard clinical outcomes will manifest, are uncertain. We must also be mindful that dietary recommendations are complex, particularly in CKD. Outside of a clinical trial, advice to restrict dietary sodium intake may influence absorption calcium, protein, net endogenous acid production, potassium, and calories. Nonetheless, this study makes us cautiously optimistic.

We commend the authors for providing important clinical trial data in support of current clinical practice consensus guidelines through this study. Their findings underscore the need for larger studies with longer follow-up specifically designed and carried out in CKD populations to help inform recommendations to both individual patients and policymakers. Until we have such studies, we are left uncertain of whether dietary sodium reduction in CKD may be suggestively hazardous or intuitively advantageous.

Disclosure

C.A.M.A. is supported, by a grant to the University of California San Diego from the National Heart, Lung and Blood Institute (K01HL092595). J.H.I. is supported by grants from the National Heart, Lung and Blood Institute (R01HL094555) and the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK097093).