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Received for publication: 16.1.2015; Accepted in revised form: 17.3.2015
FULL REVIEW
Nephrol Dial Transplant (2016) 31: 39–45
doi: 10.1093/ndt/gfu243
Advance Access publication 16 July 2014
Salt and nephrolithiasis
Andrea Ticinesi1,2, Antonio Nouvenne2, Naim M. Maalouf3, Loris Borghi1,2 and Tiziana Meschi1,2
1
Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy, 2Internal Medicine and Critical Subacute Care Unit,
Parma University Hospital, Parma, Italy and 3Charles and Jane Pak Center for Mineral Metabolism and Clinical Research and Department
of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
Correspondence and offprint requests to: Andrea Ticinesi; E-mail: [email protected]
A B S T R AC T
Dietary sodium chloride intake is nowadays globally known as
one of the major threats for cardiovascular health. However,
there is also important evidence that it may influence idiopathic
calcium nephrolithiasis onset and recurrence. Higher salt intake
has been associated with hypercalciuria and hypocitraturia,
which are major risk factors for calcium stone formation. Dietary
salt restriction can be an effective means for secondary prevention of nephrolithiasis as well. Thus in this paper, we review the
complex relationship between salt and nephrolithiasis, pointing
out the difference between dietary sodium and salt intake and the
best methods to assess them, highlighting the main findings of
© The Author 2014. Published by Oxford University Press
on behalf of ERA-EDTA. All rights reserved.
epidemiologic, laboratory and intervention studies and focusing
on open issues such as the role of dietary salt in secondary causes
of nephrolithiasis.
Keywords: hypercalciuria, nephrolithiasis, salt, urinary calcium, urinary sodium
INTRODUCTION
Excessive salt intake has been focused on in the last few years as
one of the main elements that influence health status. In particular, salt is linked to hypertension and cardiovascular disease, and therefore many professional organizations have
39
issued strong recommendations to reduce salt intake [1–4]. The
relationship between salt and nephrolithiasis is perhaps less
popular, but in the same way well established. The purpose of
this manuscript is, therefore, to review the current knowledge
and to address the main controversies about salt intake and kidney stones.
FULL REVIEW
D I E TA R Y I S S U E S
In the medical literature, there is some confusion between salt
and sodium intake. By dietary salt we mean the intake of sodium chloride. Dietary sodium, on the other hand, refers to
the total amount of Na+ ions contained in foods. Naturally,
salt is by far the main dietary source of sodium, but one must
consider that foods generally contain small amounts of sodium
bicarbonate and sodium citrate as well. There is some evidence
that sodium is harmful for kidney stone disease only when it is
accompanied by the ion chloride [5]. Therefore, from a nutritional point of view, it is important to consider salt intake and
not sodium intake.
In a typical Western diet, salt is mainly supplied through
processed foods (70–80% according to some estimates) [6].
About 10–15% of the whole salt intake is naturally contained
in food composition, while only a small percentage (<10%) is
discretionally added to foods [6, 7]. Therefore, an effective program to reduce global salt intake must be primarily aimed at reducing the salt content of processed foods. On the other hand,
voluntary avoidance of discretional salt affects global salt intake
in a limited way [8].
The simplest way to assess a patient’s salt intake is a dietary
diary. Recent reports have shown a sufficient degree of accuracy of both a 24-h dietary recall and a food-frequency questionnaire in estimating the real salt intake [9, 10], but these
methods actually lack objectivity and may be complex to
carry out [11]. Better accuracy may be obtained through direct measurement of renal sodium excretion. Although some
studies suggest that sodiuria underestimates actual salt intake
by 16–40% [12–14] and others show that there is a 7–30%
overestimation [15, 16], 24-h sodiuria has entered clinical
practice as the gold standard for salt intake assessment [3].
Twenty-four hour urine collection is generally considered necessary because there may be some daily variations in sodium
output; however, an estimation using a casual urine specimen
can sometimes be acceptable for monitoring or research purposes [17].
World Health Organization recommendations state that daily
salt intake should not exceed 5 g (Na+ 85 mEq) [3]. Modern diets
in industrialized countries contain an excessive amount of salt.
For example, the mean intake in an Italian cohort was 10.9 g/
day (186 mEq/day) in men and 8.5 g/day (145 mEq/day) in
women [18]; in a Spanish cohort, it was 9.8 g/day (167 mEq/
day) [19] and in large epidemiologic studies set in the USA, it
was 8.4 g/day (143 mEq/day) [20]. Actually, during the Paleolithic era, diet contained very low amounts of salt, estimated in ∼1
g/day (17 mEq/day), so kidneys, from an evolutionist’s perspective, are not used to handle so much salt as what is generally
present in modern diets [21].
40
E P I D E M I O LO G I C A L C O N N E C T I O N B E T W E E N
S A LT A N D N E P H R O L I T H I A S I S
The most convincing epidemiologic proof that salt intake is
linked to nephrolithiasis comes from a large American prospective study conducted on >90 000 healthy middle-aged
women, showing a clear increasing trend in the relative risk
of developing stones as the quintiles of salt intake rise [maximum RR 1.30 for a salt intake >10.3 g/day (176 mEq/day)]
[22]. However, other large prospective studies failed to demonstrate such a correlation, especially in younger women and men
[23–25]. These studies, however, evaluated dietary habits at
baseline and kidney stone prevalence was detected after many
years of follow-up, so that salt intake might have changed at
the time of stone formation. Moreover, they were based on
food-frequency questionnaires, which may not always be sufficiently precise in estimating the actual salt intake [26], thus
introducing a possible bias. In any case, the existence of
age- and gender-related differences in the epidemiological
connection between salt intake and nephrolithiasis cannot be
excluded, also because of difficulties in estimating the actual sodium intake.
Some studies focusing on dietary habits of idiopathic calcium stone formers have clearly demonstrated that these individuals have a significantly higher daily intake of salt and a
more frequent consumption of salty foods, such as sausages
and ham, than healthy controls, especially among younger females [27, 28]. Salt intake in subjects with idiopathic hypercalciuria is, furthermore, higher than in stone formers with a
normal calcium excretion [29]. Calcium stone formers also
showed significantly different intakes of other nutrients, thus
the specific contribution of salt and salty foods in stone formation is not known.
The uncertainties in this field are, however, counterbalanced
by a large number of studies showing that high salt intake does
affect other urinary parameters of lithogenic risk and that a lowsalt diet may be effective in kidney stone prevention.
E F F E C T S O F S A LT O N U R I N A R Y
PARAMETERS OF LITHOGENIC RISK
In 1964, Kleeman et al. first reported an association between
salt intake and calcium excretion, documenting a dramatic
rise in calciuria (+82%) after the shift from a very-low-sodium
diet [1.1 g/day (19 mEq/day)] to a very-high-sodium diet [24.5
g/day (419 mEq/day)] [30]. Since then, a large number of interventional studies have reported a linear association between salt
intake and calcium excretion in healthy subjects, even for more
modest levels of salt intake [31]. It has been suggested that a dietary increase of 6 g/day (103 mEq/day) in salt intake may result in
a 40 mg/day (1 mmol/day) increase in urinary calcium [32].
Moreover, a 3.5 g (60 mEq/day) increase in salt intake leads to
a 1.63-fold increase in the relative risk for hypercalciuria, while
healthy subjects with a daily salt intake >10 g (171 mEq) have
a 21.8% prevalence in hypercalciuria, compared with a 3.9%
prevalence in those with a lower intake [33].
A. Ticinesi et al.
Salt and nephrolithiasis
F I G U R E 1 : Correlation of calciuria–sodiuria in a case series of 1192
males from Parma Kidney Stone Clinic, 1986–2011.
F I G U R E 2 : Correlation of calciuria–sodiuria in a case series of 760
females from Parma Kidney Stone Clinic, 1986–2011.
However, little is known on how salt intake influences the actual
lithogenic risk in postmenopausal women.
Salt is not the only nutrient with a calciuric effect. Animal
protein intake is in fact related to calcium excretion and kidney
stone risk [23, 49, 50]. There is some evidence in the literature
that high-salt and high-protein diets influence urinary calcium
excretion in an additive way. For example, when a subject on
usual diet [8 g/day (137 mEq/day) of salt intake and 1 g/kg/
day of protein intake] shifts to a high-salt diet [12 g/day (205
mEq/day)], urinary calcium increases by 50 mg/day (1.25
mmol/day), but if protein intake rises to 2 g/kg/day too, urinary
calcium increases by 100 mg/day (2.5 mmol/day) [51].
Moreover, a high intake of salt has been linked to a lower
urinary excretion of citrate, which is one of the main inhibitors
of lithogenesis. A rise in salt intake from 2.9 to 14.5 g/day (50–
248 mEq/day) resulted in a significant decrease in urinary citrate from 593 mg/day (3.14 mmol) to 476 mg/day (2.52 mmol)
in a small cohort of healthy volunteers [42]. A concomitant rise
in protein intake may result in a further decrease in citrate excretion, strengthening the hypothesis that salt and protein intake concur in determining a rise in lithogenic risk [51]. A
diet with a high salt or protein content impairs citrate excretion
by inducing a subclinical intracellular and extracellular acidosis
[52]. This condition promotes the conversion of trivalent citrate3− to bivalent citrate2− in the lumen of the renal proximal
tubule, with the latter form more efficiently reabsorbed by
41
FULL REVIEW
The same relationship has also been demonstrated in idiopathic calcium stone formers, regardless of the levels of calcium
intake [30, 34–37]. The levels of calcium excretion are generally
higher in stone formers than in healthy subjects with the same
sodium intake, so that a 6 g/day (103 mEq/day) rise in salt intake may result in a 80 mg/day (2 mmol/day) increase in urinary calcium in stone formers [38] versus 40 mg/day in nonstone formers.
At the Kidney Stone Clinic of Parma University Hospital,
Parma, Italy, we analyzed 24-h urinary excretion of calcium
and sodium of all patients who underwent a full urinary profile
of lithogenic risk from 1986 to 2011 (1952 subjects: 1192 males
and 760 females). We actually found that calciuria (in mg/day)
is dependent on sodiuria (in mEq/day) in a linear regression
model, both in males (y = 0.7721x + 131.68, R 2 = 0.15, r = 0.4,
P < 0.001) and females (y = 0.9482x + 80.524, R 2 = 0.22, r = 0.47,
P < 0.001), as shown in Figures 1 and 2. The relationship persisted after categorization of patients for hypertensive or hypercalciuric status. Moreover, from the analysis of a subset of 743
male and 429 female normotensive calcium stone formers compared with 179 male and 292 female healthy controls from the
Parma area, we also found that stone formers of both genders
have higher levels of calcium excretion for each category of salt
intake, as shown in Figure 3.
This relationship may be explained on the basis of renal
physiology. In the renal proximal tubule, calcium handling is
strongly dependent on sodium. A high dietary salt intake induces a high-sodium load to the kidney and a status of relative
hypervolemia. According to the mechanisms of glomerulotubular balance, this condition diminishes the efficacy of sodium
and water reabsorption in proximal tubule [39, 40]. At the
same time, the reabsorption of calcium, whose handling is passively coupled with sodium and water, is less effective. Since in
the distal sections of nephron calcium reabsorption is unrelated
to volume status, this condition leads to higher urinary calcium
excretion [41]. On the other hand, a low dietary salt intake induces relative hypovolemia, thus promoting directly sodium
and indirectly calcium reabsorption in the proximal tubule,
and subsequently lower calciuria.
A high level of urinary calcium is notoriously one of the main
risk factors for developing kidney stones. The salt-induced rise in
calciuria actually results in higher levels of urinary supersaturation
indexes for calcium phosphate and uric acid, but probably not for
calcium oxalate, which is by far the most common component of
stones [42]. Recent hypotheses have, however, assigned a primary
role to calcium phosphate supersaturation in the early phases of
calcium oxalate lithogenesis [43, 44]. Moreover, excessive salt intake is associated with lower levels of the upper limit of metastability for calcium oxalate, which means that salt affects lithogenesis
through different and more complex mechanisms than a simple
calciuric effect [42, 45].
It should also be considered that the relationship between
sodium intake and calcium excretion is influenced by hormonal
factors. In fact, there are some reports demonstrating that calcium excretion is higher in postmenopausal women than in
pre-menopausal women at any level of salt intake [46, 47]. Hormonal replacement therapy surprisingly seems to enhance, rather than mitigate, the calciuric effect of salt intake [48].
FULL REVIEW
F I G U R E 3 : Comparison of calcium excretion in male and female stone formers versus male and female healthy controls, split into categories of
salt intake. Subjects (743 male and 429 female stone formers and 179 male and 292 female healthy controls) came from the Parma area, Italy, and
were evaluated at the Kidney Stone Clinic of Parma University Hospital. Dietary salt intake was categorized as 3 g/day when sodiuria was 0–51
mEq/day, 6 g/day when sodiuria was 51–102 mEq/day, 9 g/day when sodiuria was 103–153 mEq/day, 12 g/day when sodiuria was 154–204 mEq/
day and >12 g/day when urinary sodium excretion exceeded 204 mEq/day. Numbers in brackets at the bottom of each column represent the
numbers of subjects that have been classified in each category. Numbers at the top of each column represent average calcium excretion with
standard deviation (in mg/day).
sodium-dependent dicarboxylate transporter (NaDC-1) that
cotransports 3Na+–1citrate2−. Moreover, acidosis promotes
the institution of a luminal-cellular electrochemical gradient
for citrate reabsorption because it is transformed into bicarbonate in the mitochondria of epithelial cells [53]. This mechanism
is sodium chloride-specific, because some reports state that sodium bicarbonate can actually promote citrate excretion [54,
55]. This is probably one of the reasons why a recent epidemiologic study demonstrated that there is a positive correlation between sodium and citrate excretion, contradicting classical
physiologic findings [56].
Salt intake can influence nephrolithiasis also indirectly,
by inducing and maintaining hypertension. Salt-sensitive
42
hypertension is the most frequent type of primary arterial
hypertension, consisting in an exaggerated increment in
blood pressure driven by a salt load [57]. The pathophysiology
of this condition, not yet fully understood, depends on renal
mechanisms, such as water retention due to the high-sodium
load, and extra-renal pathways, such as a salt-induced increase
in sympathetic nerve activity that underlies a complex neurohormonal interplay [58]. Both males and females with stable
primary hypertension have higher levels of urinary calcium
and oxalate excretion than normotensive controls without kidney stones, resulting in a 5-fold increased risk for incident nephrolithiasis after 5 years of follow-up [59]. Moreover, large
epidemiological studies have demonstrated that a past history
A. Ticinesi et al.
INTERVENTIONAL STUDIES REDUCING
S A LT I N TA K E
The first interventional study assessing the effects of dietary salt
reduction on nephrolithiasis, set in 1959 by Hills et al. [67],
showed that a 3.8 g/day (65 mEq/day) decrease in two healthy
subjects resulted, after 4 days, in a 23 mg/day (0.58 mmol/day)
reduction in calcium excretion. These findings are surprisingly
very similar to those by Lin et al. [68], who, 40 years later, tested
the effects of a salt intake reduction and of a Dietary Approaches to Stop Hypertension (DASH) diet approach on a larger cohort of healthy volunteers for a longer period of time (one
month), although in this case it was difficult to discern the consequences of salt reduction and of fruit and vegetable increase.
Salt reduction can also prevent the calciuric effect of dietary potassium depletion in a cohort of healthy volunteers [69].
A salt-reduction strategy has proven to be effective in lowering
calcium excretion also in postmenopausal women [46] and in
idiopathic calcium stone formers [37, 70]. The size of calciuria
reduction was particularly impressive in calcium stone formers.
For example, in one study, a 11.3 g/day (193 mEq/day) salt
intake reduction resulted in an average of 343 mg/day
(8.5 mmol/day) reduction in calciuria [70]. In another larger
study, a 7.7 g/day (132 mEq/day) reduction in salt intake diminished calcium excretion by 109 mg/day (2.7 mmol/day) after
only 3 days [37].
Another study from our research group randomized a cohort of male idiopathic stone formers prospectively followed
up for 5 years to receive a low-salt low animal protein diet versus
Salt and nephrolithiasis
a low-calcium diet (with unrestricted salt intake), confirming
that the reduction in salt intake lowers calciuria and demonstrating that the low-salt low animal protein diet is associated
with a significantly lower rate of stone recurrence rate (unadjusted RR 0.49) [71]. Thus, salt reduction does not only
lead to decreased calciuria, but also to an improvement in the
disease course. These findings have been more recently indirectly supported by Taylor et al. [72], who found that a
DASH-style diet (i.e. with low intake of sodium and high intake
of fruits and vegetables) is associated with lower rates of kidney
stone onset and recurrence.
However, in these studies, the effects of low salt intake are not
fully discernible from the effects of other nutritional elements,
such as proteins, fruits and vegetables. However, some recent research clearly demonstrates that a mere reduction in salt intake of
∼8 g/day (137 mEq/day) is able to correct hypercalciuria in a
hypertensive individual cohort of both genders prospectively followed up for 3 months [73]. Therefore, salt reduction alone may
actually be effective in preventing kidney stone recurrence.
CON TROV E R S IA L ISS UE S
It is plausible, as seen in clinical practice, that dietary salt restriction
may not be effective in reducing calcium excretion in all patients,
because some subjects may be unresponsive or less responsive to
dietary intervention. The concepts of salt-sensitivity and -resistance are actually well established in the hypertension field. The existence of these concepts also in idiopathic calcium stone formers
has not been investigated properly so far. However, there are some
reports indicating that salt-sensitive hypertensive subjects exhibit
higher levels of calcium excretion after a standard sodium chloride
load than salt-resistant hypertensive subjects [74–76]. More recent
studies carried out on animal models (Dahl rats) of salt-sensitivity
and -resistance showed that the calciuric response to salt is influenced by the status of salt-sensitivity only in females [77, 78], suggesting that there may be gender-related factors influencing how
the kidneys handle calcium excretion after a salt load. Actually,
some human genetic markers of salt-sensitive hypertension
may affect renal calcium handling [79], thus establishing a possible connection between salt-sensitivity, -resistance, hypertension and kidney stone risk.
Very few studies investigated the role of salt intake in patients with a well-established cause of hypercalciuria. In primary hyperparathyroidism, calcium excretion is generally
thought to be independent from diet, because abnormally
high levels of parathyroid hormone and subsequent hypercalcemia are sufficient to explain hypercalciuria. However, there are
some data suggesting that salt intake is very important to
modulate the calciuric response to high parathyroid hormone
levels. For example, the comparison between a low salt intake
[4.6 g/day (79 mEq/day)] and a high salt intake [11.7 g/day
(200 mEq/day)] in a small cohort of subjects with primary
hyperparathyroidism showed significantly lower levels of calciuria in the low-salt group [304 versus 424 mg/day (7.6 versus
10.6 mmol/day)] [80]. These findings are partially contradicted
by some unpublished data from our research group, showing
that a median 5 g/day (85 mEq/day) reduction in salt intake
43
FULL REVIEW
of nephrolithiasis without hypertension is a risk factor for
hypertension development [60, 61], thus suggesting that a
renal damage caused by stones or by urinary stone risk factors
may play an important role in hypertension development.
Hypertensive kidney stone formers generally have higher calciuria [62] and urinary acid excretion [63] than normotensive
stone formers, while hypertension has also been proved to be a
major determinant of recurrence for stone formers [64].
As shown above, the majority of scientific evidence highlights a harmful role for salt intake in kidney stone onset. However, there are also some reports showing that in selected
populations, a higher salt intake is linked to a decrease in calcium oxalate supersaturation [65] and that dietary salt supplementation may benefit calcium stone formers in some cases, by
leading to a higher voluntary fluid intake [54]. It should also be
noted that high salt intake, by increasing the number of molecules dissolved in urine, produce an increase in ionic strength,
thus resulting in a decrease of activity of the ionic species
involved in saturation [66]. This means that, at any level of calcium concentration in urine, the crystallization and precipitation of lithogenic salts is less likely when there is a high
concentration of sodium chloride, which may in this way
exert a protective action against nephrolithiasis. However, the
precise clinical significance of these mechanisms is still
uncertain and current state of art does actually support the
need for a reduction of salt intake for idiopathic kidney stone
prevention.
(from an average of 10–5 g/day) in a cohort of 23 female patients with primary hyperparathyroidism awaiting for elective
parathyroidectomy did not result in significant changes in calcium excretion after a median 8-week follow-up (438 ± 115 versus 413 ± 120 mg/day). Further research is, however, needed to
confirm if there are behavioral factors, such as dietary salt intake, that can modulate calcium excretion in primary
hyperparathyroidism.
CONCLUSION
Most scientific evidence suggest that excessive salt intake is associated with a higher risk for hypercalciuria and thus for idiopathic nephrolithiasis onset or recurrence. Limiting salt intake
may be an effective preventive measure. However, the complex
interplay between salt intake and other dietary manipulations is
far from being fully understood. Moreover, few data are available on the role of salt restriction in secondary types of hypercalciuria and on the determinants of salt-sensitivity and
-resistance. Further research is needed to address these issues
and to raise awareness of the harmful effects of salt also in
this setting of human pathology.
FULL REVIEW
FUNDING
The authors have no direct or indirect commercial financial incentive associated with publishing this paper, nor any extra-institutional funding.
C O N F L I C T O F I N T E R E S T S TAT E M E N T
The authors have no conflict of interest to declare. They have
no involvements that might raise the question of bias in the
work reported or in the conclusions, implications or opinions
stated. The results presented in this paper have not been
published previously in whole or part, not even in abstract
format.
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