Clinical Nutrition xxx (2011) 1e6

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Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

Review

Diet-induced metabolic acidosis

Mara M. Adeva b, *, Gema Souto a
a
b

Clinical Center of the National Institutes of Health, Washington DC, USA

Hospital General Juan Cardona, c/ Pardo Bazn s/n 15406 Ferrol, La Corua, Spain

a r t i c l e i n f o

s u m m a r y

Article history:
Received 17 November 2010
Accepted 16 March 2011

The modern Western-type diet is decient in fruits and vegetables and contains excessive animal
products, generating the accumulation of non-metabolizable anions and a lifespan state of overlooked
metabolic acidosis, whose magnitude increases progressively with aging due to the physiological decline
in kidney function. In response to this state of diet-derived metabolic acidosis, the kidney implements
compensating mechanisms aimed to restore the acid-base balance, such as the removal of the nonmetabolizable anions, the conservation of citrate, and the enhancement of kidney ammoniagenesis and
urinary excretion of ammonium ions. These adaptive processes lower the urine pH and induce an
extensive change in urine composition, including hypocitraturia, hypercalciuria, and nitrogen and
phosphate wasting. Low urine pH predisposes to uric acid stone formation. Hypocitraturia and hypercalciuria are risk factors for calcium stone disease. Even a very mild degree of metabolic acidosis induces
skeletal muscle resistance to the insulin action and dietary acid load may be an important variable in
predicting the metabolic abnormalities and the cardiovascular risk of the general population, the overweight and obese persons, and other patient populations including diabetes and chronic kidney failure.
High dietary acid load is more likely to result in diabetes and systemic hypertension and may increase
the cardiovascular risk. Results of recent observational studies conrm an association between insulin
resistance and metabolic acidosis markers, including low serum bicarbonate, high serum anion gap,
hypocitraturia, and low urine pH.
2011 Elsevier B.V. and NIPR. All rights reserved.

Keywords:
Metabolic acidosis
Ammonium ions
Citrate
Insulin resistance

Contemporary human diet in industrialized countries is decient in fruits and vegetables and contains excessive animal products and sodium chloride. Fruits and vegetables are abundant in
potassium salts of metabolizable anions, including citrate and
malate, which consume hydrogen ions when metabolized, having
an alkalinizing effect. Moreover, plant proteins are usually richer
than animal proteins in glutamate, an anionic amino acid whose
metabolism also consumes hydrogen ions to become neutral.
Animal proteins and cereal grains contain sulfur-containing amino
acids (methionine, homocysteine and cysteine) whose oxidation
generates sulfate, a non-metabolizable anion that constitutes
a major determinant of the daily acid load. The content of these
amino acids is from 2- to 5-fold higher in meat and eggs than in
grains and legumes. The accompanying anions for potassium are

chiey phosphate and chloride in animal products and cereals,

making these nutrients more acidogenic than fruits and vegetables.1e5 The modern Western diet based on animal products
generates an acid load not compensated by the shortage of fruit and
vegetables causing a lifespan state of unnoticed and growing
metabolic acidosis,6,7 which has been recently associated with
increased cardiovascular risk (Fig. 2).
The net endogenous acid production (NEAP) is the diet-dependent net acid load produced by the excessive dietary content of acid
precursors relative to alkali precursors and it can be approximately
estimated from the renal net acid excretion (RNAE), dened as:
[titratable acid (TA)] [ammonium (NH4)]e[bicarbonate
(HCO3)] in 24-h urine (in mEq/day).8
RNAE (mEq/day) [TA] [NH4]  [HCO3] z Estimated NEAP
(mEq/day)

Abbreviations: DASH, dietary approaches to stop hypertension; NEAP, net

endogenous acid production; RNAE, renal net acid excretion; TA, titratable acid;
HOMA-IR, homeostasis model assessmenteinsulin resistance; NHANES, national
health and nutrition examination surveys.
* Corresponding author. Tel.: 34 664 527 257; fax: 34 981 17 81 59.
E-mail address: [email protected] (M.M. Adeva).

The kidney net acid excretion rate varies inversely with the
urinary potassium (K) excretion (an index of fruits and vegetables
consumption) and directly with the urinary urea excretion rate,
which is an indicator of dietary protein intake. The urinary net acid

0261-5614/$ e see front matter 2011 Elsevier B.V. and NIPR. All rights reserved.
doi:10.1016/j.clnu.2011.03.008

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M.M. Adeva, G. Souto / Clinical Nutrition xxx (2011) 1e6

Table 1
Kidney adaptations to acidogenic diet.
1.
2.
3.
4.
5.

Increased urinary elimination of sulfate, phosphate, urate, and chloride.

Increased elimination of calcium
Decreased urinary excretion of citrate
Increased urinary excretion of ammonium ions
Kidney vasodilatation and increased glomerular ltration rate

excretion falls as the ratio of urinary K/urea increases. Conversely,

as urinary urea rises and the ratio of urinary K/urea declines, the
kidney net acid excretion increases. Quantitatively, dietary protein
intake of 75 g/day produces urinary urea excretion rate of about
400 mmol/day (11 g of urea nitrogen) and net acid excretion of
50 mEq/day. The urinary net acid excretion increases by
0.10e0.15 mEq/mmol urinary urea. A ratio of urinary K/urea of
about 0.25 mmol/mmol is associated with urinary net acid excretion rates of 50 mEq/day.9
Persons consuming a diet based on animal protein have higher
kidney net acid excretion and more acidic urinary pH than persons
on a plant-based diet. The urinary excretion of sulfate, phosphate,
and uric acid is also higher in persons on the animal protein diet,
compared with the vegetarian diet.2
Dietary sodium chloride also inuences systemic acid-base
status, being an independent negative predictor of plasma bicarbonate. Excessive consumption of animal proteins and sodium
chloride with insufcient ingestion of plant-based foods increase
the body acid load and induce metabolic acidosis by accumulation of
non-metabolizable anions, predominantly sulfate and chloride.9e11
The magnitude of the lifespan diet-induced metabolic acidosis
escalates progressively with advancing age probably due to the
decline in kidney function occurring with aging. There is a gradual
increase in blood hydrogen ions concentration in healthy humans
from youth to old.7,12
In response to the metabolic acidosis imposed by the acidogenic
diet, the kidney implements adaptive processes aimed to restore
the acid-base balance, including the amplication of the urinary
excretion of non-metabolizable anions, such as chloride, phosphate
and sulfate, the conservation of metabolizable anions, such as
citrate, and the activation of the urinary excretion of ammonium
ions to expand both hydrogen ions and anions elimination (Table 1
and Table 2).
Diet-dependent accumulation of non-metabolizable (endproduct) anions triggers a widespread change in the urine ionic
composition in order to eliminate the negative charge while
maintaining urine electrically neutral, which demands simultaneous elimination of cations. In response to the diet-induced
metabolic acidosis, the urinary excretion of anions such as sulfate,
chloride, and phosphate increases and there is also urinary loss of
calcium.
The urinary excretion of sulfate correlates strongly and directly
with animal protein content, being higher in individuals consuming
animal protein-based diets than in subjects on vegetarian diets.2,7,9
Urinary sulfate excretion is inversely correlated with urine pH and
has been found signicantly greater in insulin resistant subjects
compared to persons with normal insulin sensitivity in univariate
analysis of a cross-sectional study of healthy subjects, suggesting
a link between animal dietary protein, endogenous acid production
and insulin resistance.13,14
Table 2
Clinical consequences of diet-induced metabolic acidosis.
1. Kidney stone disease.
2. Nitrogen wasting
3. Insulin resistance

Metabolic acidosis promotes chloride (and sodium) urinary loss,

inducing negative sodium chloride balance, with secondary activation of the renin-angiotensin-aldosterone system and subsequent rise in plasma and urine aldosterone concentration.15 The
blood hydrogen ions concentration correlates positively with net
acid excretion and with the urinary excretion of chloride in crosssectional analysis of healthy subjects.11
Metabolic acidosis results in decreased renal tubular phosphate
reabsorption and negative phosphorus balance, with subsequent
increase in 1,25(OH)2 vitamin D production rate and decreased
serum concentration of intact parathyroid hormone in healthy
individuals.16 Administration of potassium bicarbonate corrects the
renal phosphate wasting associated with metabolic acidosis.17
Increased rates of endogenous acid production are also associated with reduced kidney tubule calcium reabsorption, resulting in
hypercalciuria and negative calcium balance. Quantitatively, the
urinary calcium excretion varies directly with the net acid excretion
by 0.035 mmol/mEq. The urinary excretion of calcium is enhanced
even with mild reductions of arterial pH to values still within the
normal range.3,9 The relationship between hypercalciuria and
metabolic acidosis is further conrmed by population studies, in
which urinary calcium excretion is lower when the urine is more
alkaline, whereas more acidic urine is associated with higher
urinary calcium.18
Urinary calcium excretion rate is higher in persons ingesting
an animal protein diet compared to a vegetarian diet, being
directly correlated with net acid excretion.2 As animal protein
intake increases, the urinary excretion of calcium rises and the
calcium balance becomes progressively more negative. Quantitatively, urinary calcium increases by about 0.04 mmol/g dietary
protein. On average, for every 50 g increase in dietary animal
protein, there is approximately a 1.6e2 mmol increase in 24-h
urinary calcium excretion.3,9,19 Conversely, urinary calcium
excretion falls as fruits and vegetables ingestion rises. The
consumption of plant-based foods has a calcium-retaining effect
and is a predictor of greater bone density in postmenopausal
women20 and healthy children.21 Dietary depletion of fruits and
vegetables induces hypercalciuria.22
In addition to the urinary excretion of non-metabolizable anions,
the kidney induces an avid conservation of metabolizable anions
such as citrate in response to metabolic acidosis. Citrate metabolism
permits hydrogen ions consumption having an alkalinizing effect on
this account. Furthermore, the reduction of urinary citrate facilitates
the excretion of end-product anions, assisting in the elimination of
negative charge. Kidney citrate reabsorption is primarily determined by the proximal tubule cell pH. In response to metabolic
acidosis, there is an avid increase in the kidney tubule reabsorption
of citrate with subsequent hypocitraturia. Conversely, urinary citrate
excretion increases during metabolic alkalosis. Urinary citrate
excretion is a highly sensitive indicator of whether the body is
responding to an increased acid load and even slight reductions of
arterial pH to values still within the normal range induce a reduction
in urinary citrate.23 Accordingly, the administration of potassium
citrate or potassium bicarbonate results in greater increase in
urinary citrate excretion than the administration of potassium
chloride.5,8 The urinary excretion of citrate declines as the ingestion
of animal protein increases, being higher in persons consuming
vegetarian diets compared with animal-based diets.2,9
A major homeostatic adaptation to metabolic acidosis is the
enhancement of ammonium ions (NH4) excretion by the kidney to
allow the simultaneous elimination of hydrogen ions and anions.
Urinary ammonium excretion is primarily determined by the acidbase balance. In healthy subjects under normal acid-base balance
conditions, total kidney ammonia production is approximately half
released to the kidney venous blood and half excreted by urine.

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M.M. Adeva, G. Souto / Clinical Nutrition xxx (2011) 1e6

Chronic metabolic acidosis prompts an increase in total kidney

ammonia production and urinary ammonium excretion. Glutamine
is a major precursor of kidney ammoniagenesis in normal conditions
and chronic metabolic acidosis, but other amino acids such as
glycine and ornithine may also be used to produce ammonia by the
human kidney.24,25 Urinary excretion of ammonium varies directly
with dietary animal protein content. Animal protein-based diets are
accompanied by increased acid excretion with a corresponding rise
in urinary ammonium, compared with vegetarian diets.2,10
In response to metabolic acidosis signicant functional changes
take place in the kidney, including an increase in renal plasma ow
(RPF) and glomerular ltration rate (GFR), which probably serve
to remove the excess acid load.15,26,27 Metabolic acidosis also produces kidney hypertrophy presumably due to the increase in
kidney ammoniagenesis.28 Clinical situations in which the kidney is
required to excrete a high acid load display similar renal hemodynamic changes and kidney hypertrophy. Among these conditions
are high animal protein consumption, obesity, and diabetes. High
dietary protein intake is associated with an increase in RPF and GFR.
The effect on kidney hemodynamics is different according to the
source of proteins. Unlike animal proteins, vegetable proteins do
not induce renal vasodilatation or glomerular hyperltration. In
healthy subjects, the ingestion of animal protein induce kidney
vasodilation and an increase in RPF and GFR, which is reversed by
the sequential consumption of vegetable protein by the same
individuals, who display a consistent rise in kidney vascular resistance during vegetable protein intake compared to animal protein
ingestion.2,29,30 After a meat load, healthy persons maintain acidbase parameters in the normal range, while patients with chronic
kidney failure disclose a slight metabolic acidosis, indicating that
the acid load imposed to the kidney by the meat ingested exceeds
its excretory capacity.31
Excess body weight induces kidney functional changes similar
to those related to high animal protein intake and weight loss is
associated with an improvement of these hemodynamic alterations.32,33 Protein intake (assessed from urinary excretion of urea)
is higher in overweight than in lean subjects and the GFR is positively correlated with the urinary excretion of urea, suggesting that
the excessive animal dietary protein consumption is the initiating
event causing the functional changes in the kidney.32
Similar hemodynamic adaptations than those associated with
animal protein ingestion and excess body weight are observed in
type 1 and type 2 diabetes. Elevated RPF, GFR, and kidney size are
noted in diabetic patients early in the course of the disease
compared with nondiabetic individuals.34,35 Both the consumption
of vegetable proteins and the careful metabolic control of the

disease contribute to ameliorate these functional kidney modications, presumably via improvement of the acidotic state associated with high animal protein dietary intake and uncontrolled
diabetes.36,37 The differing effect of vegetable and animal proteins
on kidney hemodynamics observed in healthy subjects is also
apparent in diabetic patients, which show lower GFR and RPF
during the consumption of vegetable protein diets compared to
animal protein diets.37 Additionally, vegetarian diets reduce the
urinary albumin excretion rate in healthy individuals, patients with
chronic kidney disease, and diabetic patients compared with
animal protein diets.30e32,37,38
The adaptive mechanisms imposed by the diet-derived metabolic acidosis elicit tradeoff deleterious consequences, including
predisposition to kidney stone disease, nitrogen wasting, and
resistance to the insulin action on skeletal muscle (Fig. 1).
Diet-induced metabolic acidosis promotes low urine pH,
hypercalciuria, and hypocitraturia, predisposing to uric acid and
calcium kidney stone formation. Low urine pH is a major risk factor
for uric acid stone formation whereas hypocitraturia and hypercalciuria are predisposing factors for calcium nephrolithiasis.
Calcium associates with citrate in the urine to form water soluble
complexes, so low amounts of citrate in urine allow calcium to form
less soluble complexes. Prospective and epidemiological studies
reveal a robust association between dietary components and
nephrolithiasis. Plant-based food rich in dietary magnesium and
potassium strongly decrease the risk of nephrolithiasis, while
animal protein ingestion is associated with increased frequency of
kidney stones.2,39,40 Urinary potassium correlates with potassium
intake from fruits and vegetables and the occurrence of kidney
stones is highly correlated to the urinary Na/K ratio.21
The activation of kidney ammoniagenesis and intensication of
urinary excretion of ammonium ions imposed by metabolic acidosis
requires amino acids catabolism and promotes loss of skeletal
muscle and negative nitrogen balance.8,41 Quantitatively, one Kg of
lean body mass is equivalent to 32 gr nitrogen. Correction of the
acidosis with potassium bicarbonate reduces urinary ammonia and
urea nitrogen and reverses the muscle protein breakdown in postmenopausal women.42 Urinary potassium excretion is positively
correlated with the percentage of lean body mass in healthy elderly
persons.43 Maintaining muscle mass while aging is important to
prevent falls and fractures and the diet-dependent and age-amplifying chronic metabolic acidosis contributes to the decline in skeletal muscle mass occurring with aging.42,43
In healthy individuals even a slight degree of metabolic acidosis
results in decreased sensitivity to insulin and subsequent impairment of glucose tolerance.44 Other situations leading to metabolic

ACIDOGENIC DIET
(Insufficient intake of fruits and vegetables to compensate the acidifying effect of meat and
other dietary components)

LOW URINE pH
HYPOCITRATURIA, HYPERCALCIURIA

KIDNEY
STONE DISEASE

Fig. 1. Acidogenic diet and kidney stone disease.

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M.M. Adeva, G. Souto / Clinical Nutrition xxx (2011) 1e6

ACIDOGENIC
DIET

CHRONIC
METABOLIC ACIDOSIS

RESISTANCE TO THE
INSULIN ACTION

METABOLIC
SYNDROME

CARDIOVASCULAR
RISK
Fig. 2. Acidogenic diet and cardiovascular risk.

acidosis, such as elevations of basal lactate in healthy persons, the

presence of ketone bodies in diabetic subjects, and chronic kidney
disease-related metabolic acidosis are associated with the development of insulin resistance as well.45e48 Metabolic acidosis
induces skeletal muscle resistance to the insulin action to permit
protein degradation, a process required in order to provide amino
acids for ammonium generation.44 Metabolic acidosis enhances
glucocorticoid secretion and increases plasma and urine cortisol
concentrations. Excess cortisol may contribute to insulin resistance,
proteolysis and increased urinary ammonium excretion in metabolic acidosis.3,41,49 Modern acidogenic diet is associated with
cortisol excess and bicarbonate administration decreases signicantly plasma cortisol concentration and urinary excretion of free
cortisol and tetrahydrocortisol.3
Recent observational studies conrm an association between
insulin resistance and indicators of metabolic acidosis, such as low
serum bicarbonate, high serum anion gap, hypocitraturia, and low
urine pH. In participants in the 1999e2000 and 2001e2002
National Health and Nutrition Examination Surveys (NHANES).
Both lower bicarbonate and higher anion gap are independently
associated with insulin resistance.50 In nondiabetic patients with
calcium nephrolithiasis, there is a negative correlation between
insulin resistance estimated by the homeostasis model assessment
(HOMA-IR) and the urinary citrate excretion.51 A signicant inverse
relationship between urine pH and the degree of insulin resistance
has been found in several population groups, including healthy
volunteers, uric acid stone formers, and in patients with gout.14,52,53
The incidence of diabetes mellitus and glucose intolerance is much
higher in persons with a lower urinary pH than in normal volunteers.54 As mentioned before, the urinary sulfate excretion is
inversely correlated with urine pH and is greater in insulin resistant
subjects than in persons with normal insulin sensitivity.13,14
Metabolic acidosis is also linked to systemic hypertension,
which usually is a component of the metabolic syndrome associated with insulin resistance. In participants of the 1999e2000 and
2001e2002 NHANES a direct correlation between the anion gap
and systolic blood pressure has been shown and plasma bicarbonate is inversely related to blood pressure.55 A cross-sectional
direct association between the serum anion gap and blood pressure
is also present among nondiabetic patients, in whom is estimated
that every 1 mEq/L higher serum anion gap is associated with
a 0.27 mm Hg higher systolic and 0.20 mm Hg higher diastolic
arterial blood pressure.56 In healthy participants in the Nurses
Health Studies I and II and the Health Professionals Follow-up
Study, lower urinary citrate excretion is independently associated
with prevalent hypertension.57

The increase in fruits and vegetables dietary consumption

improves insulin sensitivity and blood pressure control mediating
a denite benecial effect upon the metabolic syndrome and systemic
hypertension. Plant-based diets are abundant in soluble ber and
carbohydrates with low glycemic index (legumes, whole grain products such as oats and barley, fruits and vegetables), which are characterized by a slow intestinal absorption and minimal postprandial
insulin secretion, preventing hyperinsulinemia and insulin resistance.
In healthy subjects with normal weight, it has been shown that animal
protein ingestion is associated with insulin resistance. Glucose,
insulin, and HOMA-IR values were signicantly lower in vegetarians
than in subjects on a Western-type diet. There is a signicant increase
of HOMA-IR values in non-vegetarians already in the age decade
31e40 years, whereas vegetarian subjects maintain a HOMA-IR of
approximately 1 in all age decades. The occurrence of HOMA-IR values
greater than 3.8 was found in 6% of the healthy normal weight population ingesting animal protein but in no vegetarian.58 Plant-based
diets have also shown favorable metabolic effects in other populations. In nondiabetic overweight women, a vegan diet is associated
with increased insulin sensitivity (and reduced body weight).59 Vegan
diets improve glycemic and lipid control in type 2 diabetic patients.38
Furthermore, high potassium intake has been associated with lower
risk of developing type 2 diabetes.4,60
The blood pressure lowering effect associated with potassium
ingestion and the protective role of fruits and vegetables against
systemic hypertension and stroke have been known for years.4,8
The dietary (and urinary) Na/K ratio associates positively with
blood pressure.29
The administration of potassium salts results in a large reduction in blood pressure and improves essential hypertension
control.5 Dietary potassium has been long known to have a robust
natriuretic and diuretic action and even minimal dietary potassium
deciency evokes an impaired renal capacity to excrete sodium
chloride and generates sodium retention.5,21,61
The Dietary Approaches to Stop Hypertension (DASH) consist of
a diet high in fruits and vegetables and low in animal protein but
with plant protein from legumes and nuts.20 The DASH diet
substantially reduces blood pressure and is usually recommended
for the prevention and treatment of systemic hypertension.
Adherence to the DASH diet also reduces the blood concentration of
low-density lipoproteins cholesterol and is associated with a lower
risk of coronary heart disease and stroke in prospective studies.62
Conicts of interest
There are no conicts of interest.

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M.M. Adeva, G. Souto / Clinical Nutrition xxx (2011) 1e6

Acknowledgments
MA conceived the study and drafted the manuscript. GS
participated in its design and helped to revise it. All authors read
and approved the nal manuscript.
There is no nancial support for this work.
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