Current guidelines recommend low dietary salt intake (LDS) in patients with diabetes to reduce blood pressure (BP). However, low salt intake has been associated with higher mortality rates in people with diabetes. Our aim is to examine the effect of angiotensin II receptor blocker (ARB), telmisartan, with and without dietary sodium chloride (NaCl) supplementation, on BP [mean arterial pressure (MAP)], plasma renin activity (PRA), serum aldosterone level and estimated glomerular filtration rate (eGFR) in hypertensive patients with type 2 diabetes. In a randomized, double-blind, placebo-controlled study (RCT), 28 patients with type 2 diabetes, treated with telmisartan (40 mg daily), received 2 weeks of placebo or NaCl capsules (100 mmol/24 h). Following a 6-week washout, the protocol was repeated in reverse. Twenty-four-hour urinary sodium excretion (24hUNa), ambulatory BP (ABP) monitoring and blood tests were performed before and after each study phase. The telmisartan-associated increase in PRA was blunted by approximately 50% during salt supplementation compared with placebo; median PRA was 2.3 μg/l/h with placebo compared with 1.7 μg/l/h with salt (P<0.001). A trend towards blunting of ARB induced increases in serum aldosterone was also demonstrated. Salt supplementation significantly reduced the MAP lowering effects of telmisartan (P<0.05). The present study demonstrates that salt supplementation blunts the telmisartan induced increase in PRA in patients with type 2 diabetes.

CLINICAL PERSPECTIVES

  • In the general population and in patients with type 2 diabetes, recent studies have demonstrated an association between low 24hUNa and higher risk of cardiovascular and all-cause mortality. Based on these studies, the Institute of Medicine has cautioned against reducing dietary salt intake to less than 65 mmol/day in high-risk populations. Low salt intake has been associated with increases in RAAS and sympathetic nervous system activity.

  • Although it has been noted within the general population, in patients with type 2 diabetes the present study demonstrates for the first time that short-term dietary salt supplementation significantly blunts increases in PRA and shows a trend towards blunting of serum aldosterone in the setting of ARB use.

  • Although we have demonstrated a reduction in PRA with salt supplementation over a short period in the setting of ARB use in the current study, further studies are necessary to explore the effects of prolonged LDS on RAAS activity in patients with type 2 diabetes.

INTRODUCTION

Cardiovascular and renal diseases are well-recognized complications of diabetes [1]. Hypertension is a leading modifiable risk factor [2,3]. Reducing dietary salt intake has been associated with blood pressure (BP) reduction [4]. Thus, in order to optimize BP control in patients with chronic disease, current Australian guidelines recommend reducing dietary salt (sodium/NaCl/Na) intake to <75 mmol/24 h [5].

Despite the BP-lowering effects of reduced dietary salt intake [6], in patients with diabetes, a paradoxical association between low salt intake and increased mortality has been demonstrated [79]. In patients with type 2 diabetes, an inverse association between all-cause mortality and 24-h urinary sodium excretion (24hUNa) has been observed, such that subjects with the lowest 24hUNa have the highest cumulative hazard ratio for all-cause mortality [7].

In the general population, higher dietary salt intake has been associated with decreases in plasma renin activity (PRA), aldosterone, noradrenaline and adrenaline [10]. In patients with coronary artery disease, raised PRA is an independent predictor of cardiovascular mortality [11]. Raised serum aldosterone is also associated with increased mortality in patients with heart failure [12]. In patients with diabetes, we observed a relationship between high serum aldosterone and low 24hUNa [13]. However, the hypothesis that increased renin–angiotensin–aldosterone system (RAAS) activity contributes to the adverse outcomes observed in patients with low 24hUNa and diabetes is yet to be explored.

In hypertensive patients with diabetes and habitual low salt diet, our group has previously shown that dietary salt supplementation blunts both the BP response to telmisartan [6] and the albuminuric excretion rate [14]. The current analysis aimed to assess the effects of dietary salt supplementation on telmisartan-induced increases in RAAS activity in patients with diabetes. Thus, we specifically assessed the effects of sodium chloride (100 mmol/24 h) supplementation on PRA, serum aldosterone and estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes during angiotensin II receptor blocker treatment (ARB, telmisartan, 40 mg).

MATERIALS AND METHODS

In a randomized, double-blind, cross-over, placebo-controlled study (RCT) in patients with type 2 diabetes treated with 40 mg of telmisartan, participants received 2 weeks of placebo or NaCl capsules (100 mmol/24 h). Twenty-eight patients were recruited from diabetes clinics at a tertiary referral centre, Austin Health. Inclusion criteria were type 2 diabetes, hypertension (BP > 140/90 mmHg or taking anti-hypertensive treatment) and albumin excretion rate (AER) between 10–200 μg/min (as determined by the median of three consecutively collected 24-h urine samples in 12 months).

Patients were excluded if AER > 200 μg/min, serum creatinine > 200 μM, serum potassium > 5.0 mM, haemoglobin A1C (HbA1C) > 10.0% and in cases of major systemic illness. Informed consent was obtained from all patients prior to study participation. Ethics approval was obtained from the Austin Health Human Research Ethics Committee and the study was allocated registration number ACTRN012606000128594 through the Australian Clinical Trials Registry.

As part of the original study design, patients were selected and categorized into high (HDS) and low (LDS) habitual dietary salt intake groups on the basis of 24hUNa [6,14]. Mean baseline 24hUNa in the low dietary salt group was 126 mmol/24 h compared with 256 mmol/24 h in the high dietary salt group. In the current analysis, we assessed patient's response to NaCl supplementation in the low dietary salt group and the high dietary salt group together. The wide range of 24hUNa reflects the known wide range of current community dietary salt intake [15]. However, due to the small sample size within individual groups, the effects of dietary salt intake was analysed as a continuum. As the effect of salt supplementation on BP was similar during telmisartan and placebo and telmisartan and HCT supplementation [6], treatment with telmisartan and HCT was not included in this analysis.

Study protocol

The study was carried out in four phases, which have been described in detail previously [6,14]. All patients underwent a 6-week washout period prior to the start of the study. During the initial washout phase, alternative anti-hypertensive medications that do not affect the RAAS were administered to patients requiring treatment to maintain BP < 160/95 mmHg. Computer programs randomized patients into two groups in a double-blinded manner (group A and group B). At study commencement, patients received 4 weeks of 40 mg telmisartan. During the final 2 weeks, patients in group A received additional placebo capsules whereas patients in group B received NaCl capsules. This was followed by another 6-week washout, after which all subjects recommenced telmisartan 40 mg. NaCl and placebo capsules were then administered in reverse order, allowing patients to act as their own controls.

NaCl and placebo capsules containing lactose were produced by a local compounding pharmacy (Thompsons Pharmacy). Patients were administered a total of 100 mmol NaCl every 24 h. Patients were instructed to maintain their usual patterns of food intake. Specifically, no recommendations were made to alter patients’ sodium, potassium, protein and phosphate intake. Dietician review was carried out prior to study commencement to ensure patients had an understanding of food labels and sodium consumption as a part of their usual dietary intake.

Twenty-four-hour ambulatory BP (ABP) measurements were recorded with a portable system using oscillometric methods. Twenty-four-hour urine collection was performed at baseline and following each supplement phase. Urinary sodium excretion in all samples was adjusted for average creatinine excretion for each participant.

Blood samples were collected following overnight fast at baseline and following each supplement phase. As an upright position is associated with elevated PRA [16], all blood samples were collected in the morning, after participants had been seated for at least 5 min. eGFR was determined using the modification of diet in renal disease (MDRD) formula (eGFR=32788 × serum creatinine −1.154(μmol/l) × Age−0.203 × [1.212, if black] × [0.742, if female] [17]. The GammaCoat PRA RIA (Diasorin) with a co-efficient of variation (CV) of 16% at levels between 2 and 5.5 μg/l/h was used to measure PRA. Count-A-Coat RIA (Siemens) was used to measure serum aldosterone with a CV of 10% at 110 pmol/l and 13% at 1499 pmol/l.

Statistical analysis

The original study was powered to detect the difference in BP response of one S.D. with a power of 90% and an α of 5%. In previous studies carried out by our group [18] the mean ABP taken 8 weeks apart in 10 subjects was 2±5.5 mmHg, therefore, it was calculated that 15 subjects would be required to ensure adequate power for this cross-over study design. The current study recruited a total of 32 patients.

The difference between changes in PRA, serum aldosterone, BP and eGFR between baseline and telmisartan and placebo compared with baseline and telmisartan and salt was examined during each supplementation phase using the paired t test. The relationship between baseline compared with telmisartan and placebo compared with telmisartan and salt was analysed using repeated measures of one-way ANOVA. Independent t test was used to compare effects of HDS compared with LDS on PRA and aldosterone during each supplementation phase. Statistical analysis was based on intention to treat and was performed using IBM SPSS Statistics (Version 21.0, IBM Co-operation). Skewed variables (PRA and serum aldosterone) were log transformed prior to analysis.

RESULTS

Participants

Thirty-two patients were recruited for the study. Following four drop-outs, a total of 28 patients completed the study [6,14]. Four participants were unable to complete the study. Specifically three participants were unable to meet attendance requirements and one patient was unable to tolerate the sodium chloride capsules due to nausea and gastrointestinal side effects.

Baseline characteristics

Mean age was 62 years and 68% of patients were male. Mean body mass index (BMI) and HbA1c were 32.5 kg/m2 and 7.3% respectively. Mean mean arterial pressure (MAP) was 99±6 mmHg and eGFR was 71±14 ml/min/1.73 m2. Sixty-one percent of patients had eGFR ranging from 60–89 ml/min/1.73 m2 and 80% had eGFR ≤ 59 ml/min/1.73 m2. At baseline, mean 24hUNa was 195±106 mmol (Table 1). Median PRA and serum aldosterone at baseline were 1.1 μg/l/h and 267 pmol/l respectively. No significant differences in baseline log10(PRA) [P=0.89], log10(serum aldosterone) [P=0.49] or eGFR (P=0.83) were demonstrated following each 6-week washout period, indicating adequate telmisartan washout and no intervention order effect.

Table 1
Baseline compared with effect of telmisartan+placebo compared with telmisartan+NaCl on MAP, 24hUNa, 24 h urinary potassium excretion, serum sodium, serum potassium, eGFR, PRA and serum aldosterone

Results analysed using repeated one-way measures of ANOVA. All values are mean±S.D., unless otherwise specified. P-values represent the results of the repeated one-way measures of ANOVA

BaselineTelmisartan+PlaceboTelmisartan+NaClP-value
MAP (mmHg) 99±6 92±10 96±8 0.001 
Systolic BP (mmHg) 139±13 131±16 133±11 0.005 
Diastolic BP (mmHg) 77±8 72±9 74±8 0.005 
24hUNa (mmol/24 h) 195±106 193±98 251±98 <0.001 
24 h urinary potassium excretion (mmol/24 h) 87±35 81±33 82±29 0.438 
Serum sodium (mmol/l) 138±2 138±2 139±2 0.253 
Serum potassium (mmol/l) 4±0.3 5±0.4 4±0.3 0.002 
eGFR (ml/min/1.73 m271±14 73±14 76±14 0.031 
PRA (μg/l/h) median+IQR (interquartile range) 1.1 (0.6 − 2.5) 2.3 (1.5 − 7.0) 1.7 (1.0 − 3.4) < 0.001 
Serum aldosterone (pmol/l) median+IQR 267 (172 − 449) 181 (127 − 268) 150 (73 − 286) < 0.001 
BaselineTelmisartan+PlaceboTelmisartan+NaClP-value
MAP (mmHg) 99±6 92±10 96±8 0.001 
Systolic BP (mmHg) 139±13 131±16 133±11 0.005 
Diastolic BP (mmHg) 77±8 72±9 74±8 0.005 
24hUNa (mmol/24 h) 195±106 193±98 251±98 <0.001 
24 h urinary potassium excretion (mmol/24 h) 87±35 81±33 82±29 0.438 
Serum sodium (mmol/l) 138±2 138±2 139±2 0.253 
Serum potassium (mmol/l) 4±0.3 5±0.4 4±0.3 0.002 
eGFR (ml/min/1.73 m271±14 73±14 76±14 0.031 
PRA (μg/l/h) median+IQR (interquartile range) 1.1 (0.6 − 2.5) 2.3 (1.5 − 7.0) 1.7 (1.0 − 3.4) < 0.001 
Serum aldosterone (pmol/l) median+IQR 267 (172 − 449) 181 (127 − 268) 150 (73 − 286) < 0.001 

PRA and serum aldosterone

Salt supplementation led to a halving of the ARB-associated increase in PRA (Figure 1A). In absolute terms, there was a 26% reduction in median PRA following salt supplementation (2.3 μg/l/h compared with 1.7 μg/l/h) (Table 1). The mean difference in Δlog10(PRA) during telmisartan and placebo compared with telmisartan and salt was 0.23 μg/l/h [95% confidence interval (CI): 0.08–0.38, P<0.001]. PRA level was higher in patients with habitual LDS compared with those with HDS (Figure 2A). At baseline, this difference was found to be statistically significant (P=0.040); however, following telmisartan and placebo and telmisartan and salt this difference was no longer significant (Figure 2A).

Effects of salt compared with placebo supplementation on PRA, serum aldosterone, MAP and eGFR in the setting of ARB

Figure 1
Effects of salt compared with placebo supplementation on PRA, serum aldosterone, MAP and eGFR in the setting of ARB

Change in (A) log10(PRA) P<0.001, (B) log10(serum aldosterone) P=0.05, (C) MAP P<0.05, (D) eGFR. P=0.05 from baseline during telmisartan and placebo (white) compared with telmisartan+salt supplementation (grey). *P<0.05 (values are mean±95% CI unless otherwise indicated). Results analysed using paired t test.

Figure 1
Effects of salt compared with placebo supplementation on PRA, serum aldosterone, MAP and eGFR in the setting of ARB

Change in (A) log10(PRA) P<0.001, (B) log10(serum aldosterone) P=0.05, (C) MAP P<0.05, (D) eGFR. P=0.05 from baseline during telmisartan and placebo (white) compared with telmisartan+salt supplementation (grey). *P<0.05 (values are mean±95% CI unless otherwise indicated). Results analysed using paired t test.

Effects of habitual LDS compared with habitual HDS on serum aldosterone and PRA during telmisartan+placebo and telmisartan+salt supplementation

Figure 2
Effects of habitual LDS compared with habitual HDS on serum aldosterone and PRA during telmisartan+placebo and telmisartan+salt supplementation

(A) Mean log10(PRA) and (B) mean log10(aldosterone). *P<0.05 (values represent mean±95% CI). Results analysed using independent t test.

Figure 2
Effects of habitual LDS compared with habitual HDS on serum aldosterone and PRA during telmisartan+placebo and telmisartan+salt supplementation

(A) Mean log10(PRA) and (B) mean log10(aldosterone). *P<0.05 (values represent mean±95% CI). Results analysed using independent t test.

Compared with PRA, salt supplementation had a smaller effect on serum aldosterone. A 28% reduction in the ARB induced increase in serum aldosterone levels (P=0.05) was demonstrated with salt supplementation (Figure 1B). Median reduction in serum aldosterone following telmisartan and salt supplementation compared with telmisartan and placebo was 31 pmol/l (Table 1). Mean log10(aldosterone) was generally lower in the HDS cohort, compared with LDS (Figure 2B).

Blood pressure

Salt supplementation reduced the telmisartan-induced decrease in MAP by approximately 50% (Figure 1C) [6]. Mean change in MAP was 4 mmHg (95% CI: 0.5–6 mmHg, P<0.05), Table 1.

eGFR

Mean eGFR with telmisartan and placebo was 73ml/min/1.73 m2 compared with 76 ml/min/1.73 m2 with telmisartan and salt (Table 1). However, ARB with telmisartan and placebo did not lead to any significant changes in eGFR.

DISCUSSION

The key finding of the present study is that short-term salt supplementation is associated with a small, but significant reduction in the ARB-associated increase in PRA and a trend towards blunting of the ARB-associated increase in serum aldosterone in hypertensive patients with type 2 diabetes. Salt supplementation also led to reductions in ARB-induced decreases in MAP; however, there were no reductions in eGFR. This is consistent with our understanding of the effects of salt supplementation reducing RAAS activity in the general population. The current study confirms these effects in patients with diabetes.

Several neurohormonal mechanisms regulate the balance between salt intake, renal plasma flow and measured GFR. As characterized by the exponential relationship between salt intake, PRA and serum aldosterone [19,20], the RAAS is key in maintaining cardiovascular health in the salt depleted state [21]. Increases in RAAS activity are most pronounced when 24hUNa is less than 120 mmol [19,22]. Angiotensin converting enzyme inhibitor (ACE-i) use in healthy subjects is associated with 5-fold and 2-fold increases in PRA and serum aldosterone respectively [23]. Despite recognized benefits of RAAS blockade in patients with diabetes, reduced dietary salt intake is associated with an increased risk of developing ‘aldosterone breakthrough’ [24], which may be associated with increased cardiovascular [25] and renal morbidity [26].

To date, the largest study of dietary salt intake involving 69000 subjects estimated worldwide mean 24hUNa to be 159 mmol/24 h (95% CI: 114–210 mmol/24 h) [27]. Baseline 24hUNa in our study was in keeping with these estimates. The consistency of sodium intake is hypothesized to arise from a physiological need to maintain a minimum level of salt intake to prevent adverse consequences such as hypotension, reduced GFR and hypokalaemia due to increased aldosterone secretion [28]. Whereas there may have been scope to further maximize dietary salt loading, the dose of 100 mmol/24 h was specifically chosen based on observed dietary salt intake habits and to prevent excessive dietary salt intake in patients already categorized as HDS.

Increased RAAS activity in the setting of LDS, therefore provides a possible mechanism for the observation of increased overall mortality in patients with diabetes and low 24hUNa [7,29]. A Cochrane review concluded that reducing dietary salt intake by 125–150 mmol/24 h led to significant increases in PRA, serum aldosterone, adrenaline and noradrenaline in the general population [10]. In patients with known cardiovascular disease, sodium depletion induces further PRA increases, which are associated with increased mortality risk [28]. However, there was no associated increase in BP, thus increased mortality risk cannot be attributed to BP increases alone [28]. Sealey et al. [28] suggested that careful liberalization of salt intake sufficient to reduce reactive hyper-reninaemia without inducing unacceptable increases in BP may benefit patients with PRA elevations. In the present study, 100 mmol of NaCl blunted the ARB-induced decrease in MAP by 4 mmHg. However, both extremes of LDS and extremes of HDS may be associated with increased overall mortality risk. A meta-analysis by Graudal et al. [30] demonstrated a U-shaped relationship between cardiovascular and mortality risk, concluding that daily salt intake within the range of ‘normal’ estimates (115–215 mmol/day) was associated with the lowest mortality risk [30]. These findings are supported by the recent PURE study, where a J-shaped relationship between dietary salt intake, cardiovascular and overall mortality was observed. Optimal daily dietary sodium was estimated to range from 130 to 260 mmol/day [31].

In our study, salt supplementation reduced telmisartan related increases in PRA (P<0.001) with a similar trend for increases in serum aldosterone (P=0.05). It is well recognized that NaCl supplementation blunts both the BP and the albuminuric responses to ACE-i and ARB. In patients with non-diabetic causes of proteinuric nephropathy, increase in 24hUNa of 100 mmol/day has been shown to be associated with blunting of systolic BP and proteinuric responses to ACE-i and ARB in the order of 10% and 25% respectively [32,33]. In patients with diabetic nephropathy the anti-hypertensive effects of ARB have been halved following salt supplementation [6] and the albuminuric response was reduced by 75% [14]. However, a cross-sectional study in patients with diabetes, demonstrated an association between low 24hUNa and increased serum aldosterone levels (P<0.001), both in the presence and in the absence of RAAS modifying agents [13].

PRA indirectly measures renin activity by measuring the constant production of angiotensin I from angiotensinogen. Measured PRA therefore incorporates both angiotensinogen and renin concentration [34]. As ARBs block RAAS activity at sites distal to the enzymatic release of angiotensin I, ARB use may overestimate effective PRA by up to 90% [35]. Plasma renin concentration (PRC) is an alternative method of measuring PRA, which is not influenced by plasma angiotensin [34]. PRC measurements complement measured PRA and may provide additional insight into the effects RAAS activity. Angiotensin II is another surrogate marker for RAAS activity that may be measured. However, measurement of angiotensin II is associated with several technical challenges due to its short plasma half-life, rapid degradation to inactive peptides and low plasma concentration [36]. We recognize the lack of PRC and angiotensin II measurements as a limitation of the current study. Potential interference from other components of the RAAS system in response to salt supplementation such as angiotensin (1–7) also needs to be considered. Angiotensin (1–7) is a bioactive component of the RAAS that has been observed to oppose angiotensin II activity leading to vasodilation and increased renal blood flow [37]. Low salt diet has been observed to attenuate its effects [38]. However, at present we are unable to accurately quantify the vasodilatory effects or fully define the effect dietary salt supplementation has on angiotensin (1–7)'s in vivo actions.

The relationship between dietary salt intake, the RAAS and end-stage renal disease (ESRD) is poorly understood. Short-term reduction in daily sodium intake by 100 mmol/24 h was associated with significant reductions in BP and proteinuria in patients (n=20) with stage three and four chronic kidney disease (P<0.001) [39]. However, increases in PRA and serum aldosterone in response to reduced dietary salt intake were also demonstrated [39]. Although altered renal haemodynamics are a prominent feature of diabetes, in the ONTARGET study cohort, which consisted of high risk patients with diabetes, there was no observed association between longitudinal dietary salt intake and risk of developing ESRD at 5.5 years of follow-up after adjustments were made for confounding factors [40].

Small increases in eGFR following short-term dietary salt supplementation were noted in our study. This differs from expected reductions in eGFR following ARB and cannot be assumed to have a direct relationship with the long-term eGFR trajectory. In the early stages of diabetic nephropathy, LDS is postulated to increase renal plasma flow and GFR contributing to hyperfiltration [20]. In contrast, several studies have demonstrated increased renal plasma flow without changes to measured GFR in diabetic patients treated with ACE-i and ARB [41,42]. The lack of effective renal plasma flow measurements following salt supplementation is a limitation of the current study.

Study strengths include the randomized, double-blinded, placebo-controlled design and the use of 24hUNa to determine daily dietary salt intake. As 90% of dietary salt is excreted via the kidney, 24hUNa remains the most accurate estimate of dietary salt intake [43]. A further strength was the correction of 24hUNa by adjusting for average creatinine excretion over six samples collected during the study duration from each patient. Although oral supplementation of NaCl was 100 mmol/24 h, the mean increase in urinary 24hUNa was 56 mmol in the current study. These findings are consistent with earlier studies which similarly found mean increases in 24UNa to be approximately 75%–80% of additional dietary NaCl [44] or slow release NaCl capsule supplementation [45] after accounting for insensible losses. Despite slow release NaCl supplementation of 200 mmol/24 h in a previous study, 24hUNa increased by 150 mmol/24 h with NaCl supplementation, giving an average discrepancy between total dietary supplementation and 24hUNa of 50 mmol [45]. A similar phenomenon was demonstrated in GenSalt study [46] where a discrepancy of 60 mmol/24 h between dietary salt intake (307 mmol/24 h) and mean 24hUNa excretion (248 mmol/24 h) in 487 subjects placed on a high salt diet was noted. Dispensed NaCl and placebo capsules were regularly counted throughout the duration of the current study to assess compliance. Overall rate of compliance was found to be high. It has been hypothesized that increased salt satiety following dietary salt supplementation [43], may lead to inadvertent reductions in the intake of salt in food and therefore explain reduced sodium excretion during NaCl supplementation. A limitation of the current study was the small number of study participants.

The present study demonstrates a blunting of ARB-associated increases in RAAS activity following salt supplementation with no decreases in eGFR observed in the short-term. This phenomenon is consistent with observations in the general population and confirms, for the first time, its presence in patients with diabetes. It is difficult to determine whether these short-term effects will persist. Although reduced dietary salt intake is associated with BP reductions [4], increased RAAS activity in the setting of LDS, if carried into the long-term, may provide some explanation for findings of increased overall and cardiovascular mortality associated with reduced dietary salt intake in diabetic patients. In keeping with recent recommendations from the Institute of Medicine, which no longer supports reducing dietary salt intake to ≤65 mmol/24 h [47] and in observational studies examining salt intake over time in people with diabetes [48] and the general population [31], our findings emphasize the need to strike a balance in salt intake that mitigates both the risks posed by excessive increases in BP as well as the potential risks of increased RAAS activity. Furthermore, at present, we cannot exclude the possibility that salt appetite and cardiovascular risk are linked to a common unidentified aetiological factor, which may be specific for patients with diabetes. These findings call for further research into the effects of long-term low salt intake on the RAAS, endothelial function and sympathetic nervous system activity in people with diabetes.

AUTHOR CONTRIBUTION

Elif Ekinci, George Jerums and Richard MacIsaac designed the research. Angela Chen, Sara Baqar, Elisabeth Lambert, Georgina Thomas, Goji Somarajah, Christopher O’Callaghan and Elif Ekinci performed the data collection. Angela Chen, Elif Ekinci and George Jerums drafted the paper. All authors approved the final version of the paper.

FUNDING

This work was supported by the National Health and Medical Research Council (NHMRC) postgraduate scholarship [grant number APP466611 (to E.I.E.)]; the NHMRC early career fellowship [grant number APP1054312] and the Heart Foundation scholarship [grant number 100287 (to S.B.)].

Abbreviations

     
  • 24hUNa

    24 h urinary sodium excretion

  •  
  • ABP

    ambulatory blood pressure

  •  
  • ACE-I

    angiotensin converting enzyme inhibitor

  •  
  • AER

    albumin excretion rate

  •  
  • ARB

    angiotensin II receptor blocker

  •  
  • BP

    blood pressure

  •  
  • CV

    co-efficient of variation

  •  
  • eGFR

    estimated glomerular filtration rate

  •  
  • ESRD

    end-stage renal disease

  •  
  • HbA1C

    haemoglobin A1C

  •  
  • HDS

    high dietary salt intake

  •  
  • LDS

    low dietary salt intake

  •  
  • MAP

    mean arterial pressure

  •  
  • PRA

    plasma renin activity

  •  
  • PRC

    plasma renin concentration

  •  
  • RAAS

    renin–angiotensin–aldosterone system

  •  
  • RCT

    randomized, double-blind, placebo-controlled study

References

References
1
Haffner
 
S.M.
Lehto
 
S.
Rönnemaa
 
T.
Pyörälä
 
K.
Laakso
 
M.
 
Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction
N. Engl. J. Med.
1998
, vol. 
339
 (pg. 
229
-
234
)
[PubMed]
2
Sowers
 
J.R.
Epstein
 
M.
Frohlich
 
E.D.
 
Diabetes, hypertension and cardiovascular disease: an update
Hypertension
2001
, vol. 
37
 (pg. 
1053
-
1059
)
[PubMed]
3
Harvey
 
J.N.
 
Trends in the prevalence of diabetic nephropathy in type 1 and type 2 diabetes
Curr. Opin. Nephrol. Hypertens.
2003
, vol. 
12
 (pg. 
317
-
22
)
[PubMed]
4
He
 
F.J.
Li
 
J.
Macgregor
 
G.A.
 
Effect of longer-term modest salt reduction on blood pressure: Cochrane systematic review and meta-analysis of randomised trials
BMJ
2013
, vol. 
346
 pg. 
f1325
 
[PubMed]
5
National Health and Medical Research Council
Australian Dietary Guidelines
2013
Canberra
National Health and Medical Research Council
[PubMed]
6
Ekinci
 
E.I.
Thomas
 
G.
MacIssac
 
R.J.
Johnson
 
C.
Houlihan
 
C.
Panagiotopoulous
 
S.
Premaratne
 
E.
Hao
 
H.
Finch
 
H.
O’Callaghan
 
C.
Jerums
 
G.
 
Salt supplementation blunts the blood pressure response to telmisartan with or without hydrochlorothiazide in hypertensive patients with type 2 diabetes
Diabetologia
2010
, vol. 
53
 (pg. 
1295
-
1303
)
[PubMed]
7
Ekinci
 
E.I.
Clarke
 
S.
Thomas
 
M.C.
Moran
 
J.L.
Cheong
 
K.
MacIssac
 
R.J.
Jerums
 
G.
 
Dietary salt intake and mortality in patients with type 2 diabetes
Diabetes Care
2011
, vol. 
34
 (pg. 
703
-
709
)
[PubMed]
8
Thomas
 
M.C.
Moran
 
J.
Forsblom
 
C.
Harjutsalo
 
V.
Thorn
 
L.
Ahola
 
A.
Waden
 
J.
Tolonen
 
N.
Saraheimo
 
M.
Groop
 
P.
 
The association between dietary sodium intake, ESRD and all-cause mortality in patients with type 1 diabetes
Diabetes Care
2011
, vol. 
34
 (pg. 
861
-
866
)
[PubMed]
9
O’Donnell
 
M.J.
Yusuf
 
S.
Mente
 
A.
Gao
 
P.
Mann
 
J.F.
Teo
 
K.
McQueen
 
M.
Sleight
 
P.
Sharma
 
A.M.
Dans
 
A.
Probstfield
 
J.
Schmieder
 
R.E.
 
Urinary sodium and potassium excretion and risk of cardiovascular events
JAMA
2011
, vol. 
306
 (pg. 
2229
-
2238
)
[PubMed]
10
Graudal
 
N.A.
Hubeck-Graudal
 
T.
Jurgens
 
G.
 
Effects of low-sodium diet vs high-sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol and triglycerides (Cochrane review)
Am. J. Hypertens.
2012
, vol. 
25
 (pg. 
1
-
15
)
[PubMed]
11
Volpe
 
M.
Battistoni
 
A.
Chin
 
D.
Tocci
 
G.
 
Renin as a biomarker of cardiovascular disease in clinical practice
Nutr. Metab. Cardiovasc. Dis.
2011
, vol. 
22
 (pg. 
312
-
317
)
12
Tomaschitz
 
A.
Pilz
 
S.
Ritz
 
E.
Meinitzer
 
A.
Boehm
 
B.O.
Marz
 
W.
 
Plasma aldosterone levels are associated with increased cardiovascular mortality: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study
Eur. Heart. J.
2010
, vol. 
31
 (pg. 
1237
-
1247
)
[PubMed]
13
Libianto
 
R.
Jerums
 
G.
Lam
 
Q.
Chen
 
A.
Baqar
 
S.
Pyrlis
 
F.
MacIssac
 
R.J.
Moran
 
J.
Ekinci
 
E.I.
 
Relationship between urinary sodium excretion and serum aldosterone in patients with diabetes in the presence and absence of modifiers of the renin-angiotensin-aldosterone system
Clin. Sci.
2014
, vol. 
126
 (pg. 
147
-
154
)
[PubMed]
14
Ekinci
 
E.I.
Thomas
 
G.
Thomas
 
D.
Johnson
 
C.
MacIssac
 
R.J.
Houlihan
 
C.A.
Finch
 
S.
Panagiotopoulos
 
S.
O’Callaghan
 
C.
Jerums
 
G.
 
Effects of salt supplementation on the albuminuric response to telmisartan with or without hydrochlorothiazide therapy in hypertensive patients with type 2 diabetes are modulated by dietary salt intake
Diabetes Care
2009
, vol. 
32
 (pg. 
1398
-
403
)
[PubMed]
15
Bernstein
 
A.M.
Willett
 
W.C.
 
Trends in 24h urinary sodium excretion in the United States, 1957–2003: a systematic review
Am. J Clin. Nutr.
2010
, vol. 
11
 (pg. 
1172
-
80
)
16
Cohen
 
E.L.
Conn
 
J.W.
Rovner
 
D.R.
 
Postural augmentation of plasma renin activity and aldosterone excretion in normal people
J Clin. Invest.
1967
, vol. 
46
 (pg. 
418
-
28
)
[PubMed]
17
Levey
 
A.S.
Bosch
 
J.P.
Lewis
 
J.B.
Green
 
T.
Rogers
 
N.
Roth
 
D.
 
A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation
Ann. Intern. Med.
1999
, vol. 
130
 (pg. 
461
-
70
)
[PubMed]
18
Houlihan
 
C
Allen
 
T.J.
Baxter
 
A.L.
Panangiotopoulos
 
S.
Casley
 
D.J.
Cooper
 
M.E.
Jerums
 
G.
 
A low-sodium diet potentiates the effects of losartan in type 2 diabetes
Diabetes Care
2002
, vol. 
25
 (pg. 
663
-
671
)
[PubMed]
19
Brunner
 
H.R.
Laragh
 
J.H.
Baer
 
L.
Newton
 
M.A.
Goodwin
 
F.T.
Krakoff
 
L.R.
Bard
 
R.H.
Buler
 
F.R.
 
Essential hypertension: renin and aldosterone, heart attack and stroke
N. Engl. J. Med.
1972
, vol. 
286
 (pg. 
441
-
449
)
[PubMed]
20
Miller
 
J.A.
 
Renal responses to sodium restriction in patients with early diabetes mellitus
J. Am. Soc. Nephrol.
1997
, vol. 
8
 (pg. 
749
-
755
)
[PubMed]
21
Hall
 
J.E.
 
Control of sodium excretion by angiotensin II: intrarenal mechanisms and blood pressure regulation
Am. J. Physiol.
1986
, vol. 
250
 (pg. 
R960
-
R972
)
[PubMed]
22
Luft
 
F.C.
Rankin
 
L.I.
Bloch
 
R.
Weyman
 
A.E.
Willis
 
R.
Murray
 
R.H.
Grim
 
C.E.
Weinberger
 
M.H.
 
Cardiovascular and humoral responses to extremes of sodium intake in normal black and white men
Circulation
1979
, vol. 
60
 (pg. 
697
-
706
)
[PubMed]
23
Kocks
 
M.J.
Lely
 
A.T.
Boomsma
 
F.
de Jong
 
P.E.
Navis
 
G.
 
Sodium status and angiotensin-converting enzyme inhibition: effects on plasma angiotensin-(1- 7) in healthy man
J. Hypertens.
2005
, vol. 
23
 (pg. 
597
-
602
)
[PubMed]
24
Moranne
 
O.
Bakris
 
G.
Fafin
 
C.
Favre
 
G.
Pradier
 
C.
Esnault
 
V.L.
 
Determinants and changes associated with aldosterone breakthrough after angiotensin II receptor bloackade in patients with type 2 diabetes with overt nephropathy
Clin. J. Am. Soc. Nephrol.
2013
, vol. 
8
 (pg. 
1694
-
1701
)
[PubMed]
25
Sato
 
A.
Saruta
 
T.
 
Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy
J. Int. Med. Res.
2001
, vol. 
29
 (pg. 
13
-
21
)
[PubMed]
26
Schojedt
 
K.J.
Andersen
 
S.
Rossing
 
P.
Tarnow
 
L.
Parving
 
H.H.
 
Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate
Diabetologia
2004
, vol. 
47
 (pg. 
1936
-
1939
)
[PubMed]
27
McCarron
 
D.A.
Kazaks
 
A.G.
Geerling
 
J.C.
Stern
 
J.S.
Graudal
 
N.A.
 
Normal range of human dietary sodium intake: a perspective based on 24 hour urinary sodium excretion worldwide
Am. J. Hypertens.
2013
, vol. 
26
 (pg. 
1218
-
1223
)
[PubMed]
28
Sealey
 
J.E.
Alderman
 
M.H.
Furberg
 
C.D.
Laragh
 
J.H.
 
Renin-angiotensin system blockers may create more risk than reward for sodium-depleted cardiovascular patients with high plasma renin levels
Am. J. Hypertens.
2013
, vol. 
26
 (pg. 
727
-
738
)
[PubMed]
29
Stolarz-Skrzypek
 
K.
Kuznetsova
 
T.
Thijs
 
L.
Tikhonoff
 
V.
Seidlerova
 
J.
Richart
 
T.
Jin
 
Y.
Olszanecka
 
A.
Malyutina
 
S.
Casiglia
 
E.
, et al 
Fatal and non-fatal outcomes, incidence of hypertension and blood pressure changes in relation to urinary sodium excretion
JAMA
2011
, vol. 
305
 (pg. 
1777
-
1785
)
[PubMed]
30
Graudal
 
N.
Jurgens
 
G.
Basland
 
B.
Alderman
 
M.H.
 
Compared with usual sodium intake, low- and excessive- sodium diets are associated with increased mortality: a meta-analysis
Am. J. Hypertens.
2014
, vol. 
27
 (pg. 
1129
-
1137
)
[PubMed]
31
O’Donnell
 
M.
Mente
 
A.
Rangarajan
 
S.
McQueen
 
M.J.
Wang
 
X.
Liu
 
L.
Yan
 
H.
Lee
 
S.F.
Mony
 
P.
Devanath
 
A.
, et al 
Urinary sodium and potassium excretion, mortality and cardiovascular events
N. Engl. J. Med.
2014
, vol. 
371
 (pg. 
612
-
623
)
[PubMed]
32
Slagman
 
M. C. J.
Waanders
 
F.
Hammelder
 
M.H.
Wottiez
 
A.
Janssen
 
W. M. T.
Lambers
 
H.J.
Navis
 
G.
Laverman
 
G.D.
 
Moderate dietary sodium restriction added to angiotensin converting enzyme inhibition compared with dual blockade in lowering proteinuria and blood pressure: randomised controlled trial
BMJ
2011
, vol. 
343
 pg. 
d4366
 
[PubMed]
33
Vogt
 
L.
Waanders
 
F.
Boomsma
 
F.
de Zeeuw
 
D.
Navis
 
G.
 
Effects of dietary sodium and hydrochlorothiazide on the antiproteinuric efficacy of losartan
J. Am. Soc. Nephrol.
2008
, vol. 
19
 (pg. 
999
-
1007
)
[PubMed]
34
Campbell
 
D.J.
Nussberger
 
J.
Stowasser
 
M.
Danser
 
A.H.
Morganti
 
A.
Frandsen
 
E.
Menard
 
J.
 
Activity assays and immunoassays for plasma renin and prorenin: information provided and precautions necessary for accurate measurement
Clin. Chem.
2009
, vol. 
55
 (pg. 
867
-
877
)
[PubMed]
35
Sealey
 
J.E.
Parra
 
D.
Rosenstein
 
R.
Laragh
 
J.H.
 
“Effective” plasma renin activity: a derived measure for assessing residual plasma activity in patients taking angiotensin converting enzymes inhibitors or angiotensin receptor blockers
Hypertension
2010
, vol. 
55
 pg. 
e16
 
[PubMed]
36
Fredline
 
V.F.
Kovacs
 
E.M.
Taylor
 
P.J.
Johnson
 
A.G.
 
Measurement of plasma renin activity with the use of HPLC-electrospray-tandem mass spectrometry
Clin. Chem.
1999
, vol. 
45
 (pg. 
654
-
664
)
37
Santos
 
R.A.
 
Angiotensin (1–7)
Hypertension
2014
, vol. 
63
 (pg. 
1138
-
1147
)
[PubMed]
38
van Twist
 
D.J.
Houben
 
A.J.
de Haan
 
M.W.
Mostard
 
G.J.
Kroon
 
A.A.
de Leeuw
 
P.J.
 
Angiotensin (1–7) induced renal vasodilation in hypertensive humans is attenuated by low sodium intake and angiotensin II co-infusion
Hypertension
2013
, vol. 
62
 (pg. 
789
-
793
)
[PubMed]
39
McMahon
 
E.J.
Bauer
 
J.D.
Hawley
 
C.M.
Isbel
 
N.M.
Sotwasser
 
M.
Johnson
 
D.W.
Campbell
 
K.L.
 
A randomised trial of dietary sodium restriction in CKD
J. Am. Soc. Nephrol.
2013
, vol. 
24
 (pg. 
2096
-
2103
)
[PubMed]
40
Dunkler
 
D.
Dehghan
 
M.
Teo
 
K.K.
Heinze
 
G.
Gao
 
P.
Kohl
 
M.
Clase
 
C.M.
Mann
 
J.F.
Yusuf
 
S.
Oberbauer
 
R.
ONTARGET investigators
 
Diet and kidney disease in high risk individuals with type 2 diabetes mellitus
JAMA
2013
, vol. 
173
 (pg. 
1682
-
1692
)
41
Hollenberg
 
N.K.
Price
 
D.A.
Fisher
 
N.D.
Langsang
 
M.C.
Perkins
 
B.
Gordon
 
M.S.
Williams
 
G.H.
Laffel
 
L.M.
 
Glomerular hemodynamics and the renin- angiotensin system in patients with type 1 diabetes mellitus
Kidney Int.
2003
, vol. 
63
 (pg. 
172
-
178
)
[PubMed]
42
Fliser
 
D.
Wagner
 
K.K.
Loos
 
A.
Tsikas
 
D.
Haller
 
H.
 
Chronic angiotensin II receptor blocake reduces (intra)renal vascular resistance in patients with type 2 diabetes
J. Am. Soc. Nephrol.
2005
, vol. 
16
 (pg. 
35
-
40
)
43
Holbrook
 
J.T.
Patterson
 
K.Y.
Bodner
 
J.E.
Douglas
 
L.W.
Veillon
 
C.
Kelsay
 
J.L.
Mertz
 
W.
Smith
 
J.C.
 
Sodium and potassium intake and balance in adults consuming self-selected diets
Am. J. Clin. Nutr.
1984
, vol. 
40
 (pg. 
786
-
793
)
[PubMed]
44
Dodson
 
P.M.
Beevers
 
M.
Hallworth
 
R.
Webberley
 
M.J.
Fletcher
 
R.F.
Taylor
 
K.G.
 
Sodium restriction and blood pressure in hypertensive type II diabetics: randomised blind controlled and crossover studies of moderate sodium restriction and sodium supplementation
BMJ
1989
, vol. 
298
 (pg. 
227
-
30
)
[PubMed]
45
He
 
F.J.
Markanandu
 
N.D.
MacGregor
 
G.A.
 
Importance of the renin system for determining blood pressure fall with acute salt restriction in hypertensive and normotensive whites
Hypertension
2001
, vol. 
38
 (pg. 
321
-
325
)
[PubMed]
46
Gu
 
D.
Zhao
 
Q.
Chen
 
J.
Chen
 
J.C.
Huang
 
J.
Bazzano
 
L.A.
Lu
 
F.
Mu
 
J.
Li
 
J.
Cao
 
J.
, et al 
Reproducibility of blood pressure responses to dietary sodium and potassium interventions: The GenSalt study
Hypertension
2013
, vol. 
62
 (pg. 
499
-
505
)
[PubMed]
47
IOM (institute of Medicine)
Sodium Intake in Populations: Assessment of Evidence
2013
Washington DC
The National Academies Press
48
Ekinci
 
E.I.
Moran
 
J.L.
Thomas
 
M.C.
Cheong
 
K.
Clarke
 
S.
Chen
 
A.
Dobson
 
M.
MacIssac
 
R.J.
Jerums
 
G.
 
Relationship between urinary sodium excretion over time and mortality in type 2 diabetes
Diabetes Care
2014
, vol. 
37
 (pg. 
e62
-
e63
)
[PubMed]