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Diet, evolution and aging--the pathophysiologic effects of the post-agricultural inversion of the potassium-to-sodium and base-to-chloride ratios in the human diet

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Theoretically, we humans should be better adapted physiologically to the diet our ancestors were exposed to during millions of years of hominid evolution than to the diet we have been eating since the agricultural revolution a mere 10,000 years ago, and since industrialization only 200 years ago. Among the many health problems resulting from this mismatch between our genetically determined nutritional requirements and our current diet, some might be a consequence in part of the deficiency of potassium alkali salts (K-base), which are amply present in the plant foods that our ancestors ate in abundance, and the exchange of those salts for sodium chloride (NaCl), which has been incorporated copiously into the contemporary diet, which at the same time is meager in K-base-rich plant foods. Deficiency of K-base in the diet increases the net systemic acid load imposed by the diet. We know that clinically-recognized chronic metabolic acidosis has deleterious effects on the body, including growth retardation in children, decreased muscle and bone mass in adults, and kidney stone formation, and that correction of acidosis can ameliorate those conditions. Is it possible that a lifetime of eating diets that deliver evolutionarily superphysiologic loads of acid to the body contribute to the decrease in bone and muscle mass, and growth hormone secretion, which occur normally with age? That is, are contemporary humans suffering from the consequences of chronic, diet-induced low-grade systemic metabolic acidosis? Our group has shown that contemporary net acid-producing diets do indeed characteristically produce a low-grade systemic metabolic acidosis in otherwise healthy adult subjects, and that the degree of acidosis increases with age, in relation to the normally occurring age-related decline in renal functional capacity. We also found that neutralization of the diet net acid load with dietary supplements of potassium bicarbonate (KHCO3) improved calcium and phosphorus balances, reduced bone resorption rates, improved nitrogen balance, and mitigated the normally occurring age-related decline in growth hormone secretion--all without restricting dietary NaCl. Moreover, we found that co-administration of an alkalinizing salt of potassium (potassium citrate) with NaCl prevented NaCl from increasing urinary calcium excretion and bone resorption, as occurred with NaCl administration alone. Earlier studies estimated dietary acid load from the amount of animal protein in the diet, inasmuch as protein metabolism yields sulfuric acid as an end-product. In cross-cultural epidemiologic studies, Abelow found that hip fracture incidence in older women correlated with animal protein intake, and they suggested a causal relation to the acid load from protein. Those studies did not consider the effect of potential sources of base in the diet. We considered that estimating the net acid load of the diet (i. e., acid minus base) would require considering also the intake of plant foods, many of which are rich sources of K-base, or more precisely base precursors, substances like organic anions that the body metabolizes to bicarbonate. In following up the findings of Abelow et al., we found that plant food intake tended to be protective against hip fracture, and that hip fracture incidence among countries correlated inversely with the ratio of plant-to-animal food intake. These findings were confirmed in a more homogeneous population of white elderly women residents of the U.S. These findings support affirmative answers to the questions we asked above. Can we provide dietary guidelines for controlling dietary net acid loads to minimize or eliminate diet-induced and age-amplified chronic low-grade metabolic acidosis and its pathophysiological sequelae. We discuss the use of algorithms to predict the diet net acid and provide nutritionists and clinicians with relatively simple and reliable methods for determining and controlling the net acid load of the diet. A more difficult question is what level of acidosis is acceptable. We argue that any level of acidosis may be unacceptable from an evolutionarily perspective, and indeed, that a low-grade metabolic alkalosis may be the optimal acid-base state for humans.
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Eur J Nutr 40 :200 –213 (2001)
© Steinkopff Verlag 2001
Summary Theoretically,we hu-
mans should be better adapted
physiologically to the diet our an-
cestors were exposed to during mil-
lions of years of hominid evolution
than to the diet we have been eating
since the agricultural revolution a
mere 10,000 years ago,and since in-
dustrialization only 200 years ago.
Among the many health problems
resulting from this mismatch be-
tween our genetically determined
nutritional requirements and our
current diet,some might be a con-
sequence in part of the deficiency
of potassium alkali salts (K-base),
which are amply present in the
plant foods that our ancestors ate
in abundance,and the exchange of
those salts for sodium chloride
(NaCl),which has been incorpo-
rated copiously into the contempo-
rary diet,which at the same time is
meager in K-base-rich plant foods.
Deficiency of K-base in the diet
increases the net systemic acid load
imposed by the diet.We know that
clinically-recognized chronic meta-
bolic acidosis has deleterious ef-
Received: 10 May 2001
Accepted: 23 May 2001
Anthony Sebastian,M. D. ()
Box 0126
University of California
San Francisco,CA 94143, USA
Tel.: +1-4 15/4 76-11 60
Fax: +1-415/4 76-0986
E-Mail: sebastia@gcrc.ucsf.edu
fects on the body,including growth
retardation in children,decreased
muscle and bone mass in adults,
and kidney stone formation,and
that correction of acidosis can
ameliorate those conditions.Is it
possible that a lifetime of eating di-
ets that deliver evolutionarily su-
perphysiologic loads of acid to the
body contribute to the decrease in
bone and muscle mass,and growth
hormone secretion, which occur
normally with age? That is, are con-
temporary humans suffering from
the consequences of chronic,diet-
induced low-grade systemic meta-
bolic acidosis?
Our group has shown that con-
temporary net acid-producing di-
ets do indeed characteristically
produce a low-grade systemic
metabolic acidosis in otherwise
healthy adult subjects,and that the
degree of acidosis increases with
age, in relation to the normally oc-
curring age-related decline in renal
functional capacity.We also found
that neutralization of the diet net
acid load with dietary supplements
of potassium bicarbonate
(KHCO3) improved calcium and
phosphorus balances,reduced
bone resorption rates, improved
nitrogen balance, and mitigated the
normally occurring age-related de-
cline in growth hormone secretion
– all without restricting dietary
NaCl.Moreover, we found that co-
administration of an alkalinizing
salt of potassium (potassium cit-
rate) with NaCl prevented NaCl
from increasing urinary calcium
excretion and bone resorption, as
occurred with NaCl administration
alone.
Earlier studies estimated dietary
acid load from the amount of ani-
mal protein in the diet,inasmuch
as protein metabolism yields sulfu-
ric acid as an end-product. In
cross-cultural epidemiologic stud-
ies, Abelow [1] found that hip frac-
ture incidence in older women cor-
related with animal protein intake,
and they suggested a causal rela-
tion to the acid load from protein.
Those studies did not consider the
effect of potential sources of base
in the diet.We considered that esti-
mating the net acid load of the diet
(i.e., acid minus base) would re-
quire considering also the intake of
plant foods, many of which are rich
sources of K-base, or more pre-
cisely base precursors,substances
like organic anions that the body
metabolizes to bicarbonate.In fol-
lowing up the findings of Abelow et
al., we found that plant food intake
tended to be protective against hip
fracture, and that hip fracture inci-
dence among countries correlated
inversely with the ratio of plant-to-
animal food intake.These findings
were confirmed in a more homoge-
neous population of white elderly
women residents of the U.S.
These findings support affirma-
ORIGINAL CONTRIBUTION
L. Frassetto
R. C. Morris, Jr.
D. E. Sellmeyer
K. Todd
A. Sebastian
Diet, evolution and aging
The pathophysiologic effects of the post-agricultural
inversion of the potassium-to-sodium and
base-to-chloride ratios in the human diet
L. Frassetto et al. 201
Diet, evolution and aging
Introduction
The nutritional requirements of humans were estab-
lished by natural selection during millions of years of in
which humans and their hominid ancestors consumed
foods exclusively from a menu of wild animals and un-
cultivated plants [2,3].By contrast,the past 10,000 years
– less than one percent of hominid evolutionary time
has afforded natural selection insufficient time to gen-
erate adaptations and eliminate maladaptations to the
profound transformation of the human diet that oc-
curred during that period consequent to the inventions
of agriculture and animal husbandry,and more recently,
to the development ofmodern food production and dis-
tribution technologies [2–5].
In comparison to the diet habitually ingested by pre-
agricultural Homo sapiens living in the Upper Pale-
olithic period (40,000 to 10,000 years ago), also referred
to as the Late Stone Age,the diet of contemporary Homo
sapiens has an overabundance of fat, simple sugars,
sodium and chloride,and a paucity of fiber,calcium and
potassium [2]. From an evolutionary nutritional per-
spective,contemporary humans are Stone Agers habitu-
ally ingesting a diet discordant with their genetically de-
termined metabolic machinery and integrated organ
physiology [6].This article discusses some of the poten-
tial consequences of these changes.
The modern dietary excess of NaCl
and deficiency of K+and HCO3
precursors
From extensive data on the diets ofexisting hunter-gath-
erer societies,and from inferences about the nature of
the Paleolithic environment, Eaton and Konner analyti-
cally reconstructed the Paleolithic diet and estimated
the probable daily nutrient intakes of Paleolithic hu-
mans [2]. In an estimated 3000 kilocalorie diet, meat
constituted 35 percent of the diet by weight and plant
foods, 65 percent. Total protein intake was estimated as
251 grams per day, of which animal protein was 191
grams,and plant proteins, 60 grams per day.By contrast,
modern humans consume less than one-half that
amount of animal protein,and only about one-third that
amount of plant protein, per kilocalorie of diet con-
sumed [7].Sodium intake was estimated at about 29 meq
per day, and potassium intake, in excess of 280 meq per
day. By contrast, modern humans consume between
100–300 meq of sodium per day, and about 80 meq of
potassium per day.
That is,in the switch to the modern diet,the K/Na ra-
tio was reversed, from 1 to 10,to more than 3 to1. Since
food sodium is largely in the form of chloride salts, and
food potassium largely in the form of bicarbonate-gen-
erating organic acid salts, the Cl/HCO3ratio of the diet
has become correspondingly reversed. Further, the ex-
tent to which the dietary K/Na ratio is reversed increases
with age [8], and presumably therefore also does the
Cl/HCO3ratio.Yet, the biologic machinery that evolved
to process these dietary electrolytes remains largely un-
changed, genetically fixed in Paleolithic time [2]. Thus,
the electrolyte mix of the modern diet is profoundly
mismatched to its processing machinery and the extent
of the mismatch increases with age. As a consequence of
the diet-kidney mismatch, contemporary humans are
not only overloaded with Na+and Clbut also deficient
in K+and HCO3. Fig. 1 demonstrates this exchange of
monovalent ions.
Adverse effects of excessive dietary sodium chloride
Excessive dietary sodium intake is mostly known to be
associated with elevated blood pressure.Studies in indi-
tive answers to the questions we
asked above.
Can we provide dietary guide-
lines for controlling dietary net
acid loads to minimize or eliminate
diet-induced and age-amplified
chronic low-grade metabolic acido-
sis and its pathophysiological se-
quelae.We discuss the use of algo-
rithms to predict the diet net acid
and provide nutritionists and clini-
cians with relatively simple and re-
liable methods for determining and
controlling the net acid load of the
diet.A more difficult question is
what level of acidosis is acceptable.
We argue that any level of acidosis
may be unacceptable from an evo-
lutionarily perspective,and indeed,
that a low-grade metabolic alkalo-
sis may be the optimal acid-base
state for humans.
Key words Acid-base –
Nutrition and evolution – Diet net
acid load – Protein – Organic
anions
Fig. 1 Exchange of potassium intake for sodium (meq/day) in transition from pre-
agricultural to modern diets.
202 European Journal of Nutrition, Vol. 40, Number 5 (2001)
© Steinkopff Verlag 2001
viduals [9–11] as well as populations [12–15] have
demonstrated correlations between dietary sodium in-
take and both systolic and diastolic blood pressure.
Good blood pressure control has been linked with im-
provements in cardiac, cerebral and kidney function
and in reductions in morbidity and mortality from car-
diovascular and renal disease [16–19].
Dietary sodium is a less well-known determinant of
urinary calcium excretion.Urinary excretion of calcium
is well documented to vary directly with that of Na+[20].
Even a moderate reduction of dietary sodium, from 170
to 70 mmol/day, could attenuate not only hypertension
but also hypercalciuria, and thereby prevent both kid-
ney stones and osteoporosis. That the hypercalciuric ef-
fect of excessive dietary sodium may be a preventable
cause of osteoporosis would seem supported by the re-
sults of recent studies in both post-menopausal women
and adolescent girls [21, 22].A bone-demineralizing ef-
fect of NaCl-induced hypercalciuria would also be in
keeping with the many observations made by Nordin
[23, 24] and Goulding and their associates [25, 26], in
both humans and rats.
Lack of potassium in the diet
The evolutionarily recent increase in dietary sodium in-
take has been reciprocated by a decrease in dietary
potassium intake. It has been estimated that our Pale-
olithic ancestors ate a diet containing in excess of 200
meq potassium daily [2].What effects might this lack of
potassium in the diet engender?
As early as 1928, Addison reported that potassium
administration could lower elevated blood pressure in
humans [27],and some 40 years later,Dahl et al.demon-
strated that increasing the ratio of potassium to sodium
in the diet of salt-sensitive hypertensive rats lowered
blood pressure in a stepwise fashion [28].
In normotensive humans, Morris and colleagues re-
cently demonstrated that increases in blood pressure in-
duced by sodium loading could be progressively attenu-
ated by increasing dietary potassium intake from
30mmol/day to 120 mmol/day. In this study, potassium
was given as the bicarbonate salt. Interestingly,this de-
cline in blood pressure was significantly greater in the 24
African-American males than in the 14 Caucasian males
in the study [29], suggesting not just a dietary,but a ge-
netic component to the response of blood pressure to
potassium bicarbonate ingestion.
In this same study, supplemental KHCO3can also
override the hypercalciuric effect of dietary NaCl-load-
ing, even though such supplementation further in-
creases the urinary excretion of sodium. In a recently re-
ported metabolic study of middle-aged normal men fed
a diet marginally deficient in both K+, 30 mmol/d, and
calcium, 14mmol/d, increasing dietary NaCl from 30 to
250mmol/d induced a 50 % increase in urinary calcium
that supplemental KHCO3either reversed or abolished,
depending on whether it was supplemented to 70 or
120mmol/d, mid- and high-normal intakes,respectively
[29]. As an apparent consequence of its demonstrated
natriuretic effect, supplemental KHCO3also reversed
and abolished, respectively, NaCl-induced increases in
blood pressure in these men with such normotensive
“salt-sensitivity” (Fig. 2), a precursor of hypertension
[30,31].In women fed a normal K+diet,supplemental K-
citrate prevented not only the hypercalciuria induced by
dietary NaCl-loading, but also prevented an increase in
biochemical markers of bone resorption (Sellmeyer, D.,
et al, unpublished observations).
Specific adverse effects of excessive dietary chloride
Although much work has been done on the adverse ef-
fects of dietary sodium chloride on blood pressure,very
little has been done to explore the specific role of exces-
sive dietary chloride.And yet,the chloride content of the
modern diet is at least as high as the sodium content
[32]. Does the exchange of the bicarbonate we used to
eat for the chloride that we presently eat have any ad-
verse effects?
Morris and colleagues first demonstrated in
uninephrectomized rats given deoxycorticosterone that
while treatment with sodium as a combination of the bi-
carbonate and acetate salt raised blood pressure, treat-
ment with sodium as the chloride salt raised blood pres-
sure to a significantly higher level [33]. Luft et al.
demonstrated that sodium as the chloride salt raised
blood pressure in stroke-prone spontaneously hyper-
tensive rats [34] and sodium as the bicarbonate salt low-
ered blood pressure in mildly hypertensive humans
[35]. More recently, Morris et al. have done studies in-
vestigating the effects of KCl and KBC (potassiumbicar-
Fig. 2 Increasing dietary potassium decreases mean arterial pressure (MAP) even
on high salt diets.
L. Frassetto et al. 203
Diet, evolution and aging
bonate) on blood pressure, frequency of stroke and
severity of the renal lesions in the SHRSP [36]. Rats
treated with KCl had significantly higher PRA than rats
treated with KBC.In each group and in all combined,the
severity of hypertension was highly correlated with the
levels of PRA (log transformed). KCl loading induced
greater increases in BP than in control or KBC rats
(Fig. 3).
The incidence of strokes was significantly higher
with KCl than with KB/C (Table 1).In the KCl/KBC rates,
strokes occurred only in animals with SBP > 248mmHg
and with PRA > 26.5 ng/ml/h (logPRA=1.42).
Light microscopic examination of the kidneys re-
vealed glomerular, tubular, interstitial, and vascular le-
sions (histologically ranked in combination) similar in
quality but significantly more frequent and more severe
with KCl supplementation than either KB/C or CTL [36].
Irrespective of dietary supplements, renal lesions were
rare in rats with SBP < 200 mmHg. The overall severity
of renal lesions was highly correlated with the level of
PRA (log transformed) (R2= 0.67, p < 0.0001). Protein-
uria was significantly greater with KCl than either KB/C
or CTL (Table 1).Creatinine clearance was significantly
greater in KB/C than in KCl or CTL (Table 1).Morris and
colleagues concluded that the extent of renal damage
and likelihood of stroke are determined by the severity
of hypertension.
Diet and acid-base
In contrast to its excess chloride content, the modern
diet lacks bicarbonate and anion precursors that gene-
rate bicarbonate on metabolism. As a consequence, the
net acid load of the modern diet is higher than it would
otherwise be. The rest of this article will discuss this bi-
carbonate-deficiency-mediated dietary acid excess.
Endogenous acid production
Endogenous acid production can be considered as com-
prising three components: 1) organic acids produced
during metabolism that escape complete combustion to
Table 1 Effects of KCl vs. KB/C in SHRSP before and 15 Weeks after initiation of dietary supplements
Age 9 Weeks (baseline) Age 25 Weeks (15 weeks after assignment)
KCl KB/C CTL KCl KB/C CTL
SBP (mmHg) 173 (169/185) 176 (173/181) 178 (174/184) 248 (230/258)* 204 (197/217)** 226 (212/235)
DBP (mmHg) 124 (115/130) 124 (117/129) 125 (118/132) 179 (167/186)* 144 (140/156)** 161 (149/171)
PRA (ng/ml/hr) 17.4 (8.6/30.8)1, + 6.2 (4.7/11.2) 13.6 (6.8/26.9)
Strokes total 6/17+0/15 1/20
Renal lesions (overall rank) 37 (13)* 17 (13) 24 (13)
UV-protein (mg/d) 64 (53/70) 59 (51/66) 53 (51/62) 251 (179/301)* 108 (96/153) 147 (111/172)
Creatinine clearance 0.46 (0.13) 0.65 (0.19)** 0.48 (0.14)
(ml/min/100g BW)
UV-Na (mEq/d) 1.17 (0.54) 1.39 (0.56) 1.60 (0.55) 1.34 (0.45) 1.57 (0.22) 1.30 (0.30)
BW (g) 218 (23) 222 (22) 218 (21) 319 (24) 326 (18) 331 (13)
SBP, DBP, PRA, UV-Protein: median and (95% C. I.)
Renal lesions, creatinine clearance, UV-Na, BW: mean(±SD)
1Data not available from 2 rats who had died of stroke.
*p < 0.05; KCl vs. either KB/C or CTL, **p < 0.05; KB/C vs. either KCl or CTL, +p < 0.05; KCl vs. KB/C.
Fig. 3 Change in systolic (SBP) and diastolic blood pressure (DBP) with age in
stroke prone spontaneously hypertensive rats (SPSHR) treated with a usual rat diet
(CTL), or supplemented with KCl or potassium bicarbonate. Data are presented as
median and 95 % CI.
204 European Journal of Nutrition, Vol. 40, Number 5 (2001)
© Steinkopff Verlag 2001
carbon dioxide and water; 2) sulfuric acid (H2SO4) pro-
duced from the catabolism of methionine and cystine,
the sulfur-containing amino acids in dietary proteins;
and 3) potassium bicarbonate (KHCO3) produced from
the metabolism of the potassium salts of organic anions
in the vegetable foods of the diet, for example potassium
citrate and potassium malate. The potassium bicarbon-
ate so produced titrates sulfuric and organic acid and
thereby downregulates net endogenous acid production
(NEAP).
NEAP then is computed as the sum of organic acid
production and sulfuric acid production minus the in-
testinally absorbed potassium salts of organic anions
that are metabolized to potassium bicarbonate.
All foods contain sulfur-containing amino acids, al-
though fruits in general contain very little;animal prod-
ucts and cereal grains contain very little or no potential
base – this comes mainly from fruits and other non-
grain plant foods. Organic acid production is driven in
part by the quantity of base-precursors in the diet, so in-
creasing dietary base precursors does not yield equiva-
lent reductions in NEAP.The greater the quantity of or-
ganic and sulfuric acids produced from metabolism,and
the lower the amounts of potassium salts metabolizable
to bicarbonate,the greater the NEAP.
Estimating the diet net acid load
It is possible to quantify NEAP in normal subjects in-
gesting whole food diets by measurements of the quan-
tity of the inorganic constituents of diet,urine and stool,
and of the total organic anion content of the urine [37].
However, such studies are extremely time-consuming
and labor-intensive. Kurtz et al. utilized renal net acid
excretion (RNAE) as a quantitative index of NEAP, since
under steady-state conditions there is a predictable rela-
tion between these two variables [37, 38], and since net
acid excretion is more readily measured.Nearly 90% of
the variance in net acid excretion among the subjects
was accounted for by differences in net endogenous acid
production (Fig. 4).
Measuring RNAE to estimate NEAP of whole food di-
ets was first used about 90 years ago [39].Volunteers ate
large amounts of one particular food item for approxi-
mately one week, while doing sequential 24-hour urine
collections, which were then analyzed for ammonia,
titratable acids and total carbon dioxide – the con-
stituents ofRNAE.This approach has a number of draw-
backs; not only is it tedious and time-consuming,but as
Blatherwick wrote in his article discussing the effects of
a boiled cauliflower diet, “It became very distasteful af-
ter the third day, so that the experiment was discontin-
ued.
Methods of estimating diet net acid load solely from
dietary intake have also been developed. Remer and
Manz developed an algorithm for calculating net acid
excretion using a formula that estimated net intestinal
absorption of cations and anions, organic acids and sul-
fate. In this study, RNAE as determined by the formula
(Cl+ P1.8– + SO4+ OA – Na+– K+– Ca2+ – Mg2+) cor-
related reasonably well with the measured NAE [40]. Us-
ing a similar formula, Remer and Manz also calculated
the potential acid load for individual food items [41].
Frassetto et al. developed a somewhat less involved
but nearly as precise method,using an algorithm to pre-
dict diet acid load from only two diet constituents: diet
protein and potassium content [42]. Data from healthy
subjects at steady-state, eating one of 20 whole food di-
ets as part of metabolic balance studies that measured
RNAE were analyzed; both dietary protein and dietary
potassium intake were demonstrated to be independent
predictors of RNAE, when evaluated by multiple regres-
sion analysis. Because protein and potassium were not
correlated to each other, the ratio of dietary protein to
potassium was evaluated. This ratio correlated signifi-
cantly with the difference between the sulfur (i.e., po-
tential acid) and potential base contents of the diets
(Fig. 5 A & B), and accounted for 70–75% of the varia-
tion in RNAE of the diets studied.
Acid-base balance in normal humans
Three factors have been found to be independent pre-
dictors of the set point for blood hydrogen ion and bi-
carbonate concentration; the partial pressure of carbon
dioxide, NEAP and age. Madias et al. [43] were the first
to propose that the interindividual differences in plasma
acidity in normal subjects can be accounted for in part
by corresponding differences in the level at which
plasma PCO2is regulated by the respiratory system in
Fig. 4 Close correspondence of endogenous acid production to renal net acid ex-
cretion in normal subjects (r=0.94, p < 0.01).
L. Frassetto et al. 205
Diet, evolution and aging
response to factors other than those entrained by
changes in plasma acidity itself.In normal subjects they
observed a positive correlation between plasma [H+]
and plasma PCO2 among subjects.
Kurtz et al. [44] were the first consider whether
“metabolic” factors might also play a role in determin-
ing the interindividual differences in plasma acidity and
plasma [HCO3] in normal subjects. At steady-state,
there was a significant direct relationship between
plasma acidity and RNAE,and a significant inverse rela-
tionship between plasma [HCO3] and RNAE, after ad-
justing for the effects of interindividual difference in the
respiratory set-point for PCO2. Subsequently, Frassetto
et al. [45] extended these findings to a larger number of
subjects and a wider variety of diets. Adding bicarbon-
ate to the diet sufficient to reduce RNAE to nearly zero
significantly reduced blood [H+] and increased plasma
[HCO3] [46].
Frassetto et al.subsequently carried out a systematic
analysis of measurements of blood [H+] and PCO2,
plasma [HCO3], RNAE and glomerular filtration rate
(GFR, estimated as 24-hour creatinine clearance) in 64
healthy adult men and women over a wide range ofages,
at steady-state on a controlled diet while residing in a
clinical research center [45].Those studies identified age
as a significant determinant of the blood acid-base com-
position in adult humans. From young adulthood to old
age (17–74 years), otherwise healthy men and women
develop a progressive increase in blood acidity and de-
crease in plasma [HCO3], indicative of an increasingly
worsening low-grade metabolic acidosis (Fig. 6 A & B).
The age effect was significant even when the effects of
differences among subjects in diet net acid load were ad-
justed for.Indeed,age and diet net acid load (reflected in
steady-state RNAE) were independent co-determinants
of the degree of metabolic acidosis. In comparing the
relative impact of age and diet net acid load, over their
respective ranges (17–74 years, 15–150 meq/day), age
had ~1.6 times greater effect on blood [H+] and plasma
[HCO3] than diet net acid load.Increasing age therefore
substantially amplifies the chronic low-grade metabolic
acidosis induced by diet.
Age and GFR were highly correlated,and were not in-
dependent predictors of blood acidity or plasma bicar-
bonate. One explanation may be that renal acid-base
regulatory function tends to decline with increasing age
[47,48].Thus,as we age, renal acid-base regulatory func-
tion declines and the degree of diet-induced metabolic
acidosis increases.
Pathophysiologic consequences of
severe metabolic acidosis in humans
Before discussing the possible effects of the mild meta-
bolic acidosis produced by age and diet,let us briefly re-
view some of the effects on the body of more severe
metabolic acidosis, such as that associated with ad-
vanced renal failure or in experimental loading studies
with ammonium chloride. It is well recognized that se-
vere metabolic acidosis can cause pathophysiologic con-
sequences in humans.Long term increases in acid loads
have been shown to affect multiple systems.
Fig. 5 Comparison of the predictive ability of dietary
sulfur minus potential base and the ratio of protein to
potassium on steady-state renal net acid excretion
(RNAE) for the 16 of 20 diets studied for which sulfur
and potential base contents were known. Protein is
expressed as g/day/2500 kcal; RNAE, sulfur, potential
base and potassium are expressed as meq/day/2500
kcal.
206 European Journal of Nutrition, Vol. 40, Number 5 (2001)
© Steinkopff Verlag 2001
Chronic acidosis and bone
Loss of bone substance is a well-known pathophysio-
logic consequence of severe metabolic acidosis [49, 50].
Bone is a large reservoir of base in the form of alkaline
salts of calcium (phosphates, carbonates), and those
salts are mobilized and released into the systemic circu-
lation in response to increased loads of acid [51–54].The
liberated base mitigates the severity of the attendant
systemic acidosis, contributing to systemic acid-base
homeostasis.The liberated calcium and phosphorus are
lost in the urine, without compensatory increase in gas-
trointestinal absorption, and reduce bone mineral con-
tent [51, 53, 55, 56]. Reduction of bone mineral content
occurs as an unavoidable disadvantage of the participa-
tion of bone in the body’s normal acid-base homeosta-
tic response to the acid load.
The response of bone to acute acidosis has been stud-
ied most extensively by Bushinsky and coworkers using
a variety of in vitro models. Acute metabolic acidosis
promptly results in buffering of hydrogen by bone car-
bonate,with attendant release ofsodium, potassium and
calcium [57–59].
When acid loading continues over days to weeks,
bone continues to participate in systemic acid-base
homeostasis, slowing the acidward shift in systemic
acid-base equilibrium,to its own detriment [51–53].Net
external acid balance remains positive, indicating con-
tinuing internal buffering of the net acid load. Mobiliza-
tion of bone base persists, and the bone minerals (cal-
cium and phosphorus) accompanying that base
continue to be wasted in the urine, without compen-
satory increases in intestinal absorption [60]. With
chronicity of the acidosis, bone mineral content and
bone mass progressively decline [61,62] and osteoporo-
sis develops[61, 63,64].
The destructive process is not only a passive physi-
cochemical dissolution of bone mineral by acidic extra-
cellular fluid, but also an active process involving cell-
mediated bone resorption and formation signaled by
increased extracellular fluid [H+] and decreased
[HCO3]1[65–67]. Extracellular acidification increases
the activity of osteoclasts, the cells that mediate bone re-
sorption [65–67], and suppresses the activity of os-
teoblasts, the cells that mediate bone formation [65].
Not only the mineral phase, but also the organic
phase of bone,is lost during chronic acidosis.Release of
bone mineral by osteoclasts is accompanied by osteo-
clastic degradation of bone matrix [50, 61, 63, 64]. In
chronic acid loading studies in humans, urinary hy-
droxyproline excretion increases[46,51], and serum os-
teocalcin levels decrease[46], suggesting that matrix re-
sorption increased and formation decreased.
Chronic acidosis and calcium excretion
Even mild reductions of plasma [HCO3] and arterial pH
to values still within their normal range also induce an
increase in urinary calcium, negative calcium balance
[46] and a reduction in urinary citrate [68]. It has been
suggested that a reduced urinary excretion of citrate
may be useful in identifying such low-grade metabolic
Fig. 6 Steady-state blood hydrogen ion content in-
creases and plasma bicarbonate concentration de-
creases independently with increasing age and renal
net acid excretion.
1 Chronic respiratory acidosis,in which acidemia but not hypobicar-
bonatemia occurs,is not accompanied by increased urinary excre-
tion of calcium and phosphorus [100].
L. Frassetto et al. 207
Diet, evolution and aging
acidosis (vide infra). In fact, supplemental KHCO3in
amounts that can be predicted to induce only a modest
increase in the plasma bicarbonate concentration, but
one still attenuating of low-grade metabolic acidosis
(vide infra) [46],can both induce a positive calcium bal-
ance, by reducing the urinary excretion of calcium, and
reduce the formation of kidney stones, apparently by
also correcting hypocitraturia [69]. Supplemental K-cit-
rate and KHCO3are effective in reducing the urinary ex-
cretion of calcium and in increasing the urinary excre-
tion of citrate presumably because both alkaline salts
induce equal increases in plasma bicarbonate [68].
In patients with classic RTA,bicarbonate therapy that
sustains correction of frank metabolic acidosis not only
reduces the formation of calcium-containing kidney
stones, but also induces a positive calcium balance [70,
71] and can induce healing of osteomalacia [72].
Furthermore, with bicarbonate therapy in children
with classic RTA, can correct hypercalciuria and im-
prove somatic growth,even when severe stunting has al-
ready occurred [73, 74]. Bicarbonate therapy has been
found to induce these effects only when provided in suf-
ficient amounts to maintain the plasma bicarbonate at
concentrations well within the normal range. These
amounts must be great enough both to offset the renal
bicarbonate wasting that characterizes classic RTA in
rapidly growing children, and to titrate their endoge-
nously produced non-volatile acid [73].
Chronic acidosis and skeletal muscle nitrogen
metabolism and renal nitrogen excretion
In disorders that cause chronic metabolic acidosis,
protein degradation in skeletal muscle is accelerated
[75–77], which increases the production of nitrogen
end-products that are eliminated in the urine, thereby
inducing negative nitrogen balance [77]. This disturb-
ance of nitrogen metabolism apparently results directly
from the acidosis,not its cause,nor from other sequelae
of the underlying acidosis-producing disorder, because
it occurs with widely differing acidosis-producing con-
ditions [77–79] and because it is reversible by adminis-
tration of alkali [80–82],which corrects the acidosis but
not its cause.
Acidosis-induced proteolysis appears to be an acid-
base homeostatic mechanism. By releasing increased
amounts of amino acids, including glutamine and
amino acids that the liver can convert to glutamine,
which is the major nitrogen source used by the kidney
for synthesis of ammonia, the kidney can increase the
excretion of acid (as ammonium ion) in the urine,
thereby mitigating the severity of the acidosis [76, 77,
83].
Metabolic acidosis induces nitrogen wasting in part
by directly increasing the rate of protein degradation in
skeletal muscle, without commensurately increasing the
rate of protein synthesis [75,76].
Chronic acidosis and growth hormone
More severe forms of metabolic acidosis from renal
tubular acidosis and chronic renal failure in children are
associated with low levels of growth hormone, and their
height and weight are often below the 5th percentile for
age.In 6 pediatric subjects with chronic renal failure and
6 subjects with renal tubular acidosis, Caldas and col-
leagues demonstrated that treatment with enough bi-
carbonate to correct the pH and plasma bicarbonate
levels to normal causes both 24-hour mean growth
hormone and IGF-1,a growth-related hormone,to dou-
ble, from 2.7±0.2 to 4.8±0.2 and 156±17 to 271±19 re-
spectively (p < 0.001) [84].As mentioned above, treating
children with RTA with potassium citrate,who are short
and have weak bones, causes them to start growing at a
normal rate and to attain normal stature [73].Brunnger
et al. [85] report that experimentally induced, chronic
metabolic acidosis in humans results in hepatocellular
resistance to growth hormone and consequent reduc-
tion in serum IGF-1 levels, and Mahlbacher subse-
quently showed that driving IGF-1 production with
exogenous growth hormone could correct acidosis-in-
duced nitrogen wasting [86].
Pathophysiologic consequences of diet-induced,
age-amplified chronic low-grade metabolic
acidosis in humans
It is understandably difficult to think “metabolic acido-
sis” when the values for plasma acid-base composition
are in the range traditionally considered normal,though
clinicians are accustomed to considering metabolic aci-
dosis under those circumstances in the context of diag-
nosing “mixed” acid-base disorders. The term “meta-
bolic acidosis” implies pathophysiologic sequelae. If
such sequelae were not present with normal diet net acid
loads, one might remain skeptical about the appropri-
ateness of the term.But,as discussed in this next section,
such acidosis-induced pathophysiological conditions as
negative calcium and phosphorus balance, accelerated
bone resorption, and renal nitrogen wasting appear to
be consequences of the normal diet acid load,as they are
significantly improved by “normalizing” blood acid-
base composition by neutralizing the diet net acid load
with small amounts of exogenous base [46,87, 88].
Although the degree of diet-induced, age-amplified
metabolic acidosis may be mild as judged by the degree
of perturbation of blood acid-base equilibrium from
currently accepted norms, its pathophysiologic signifi-
cance cannot be judged exclusively from the degree of
208 European Journal of Nutrition, Vol. 40, Number 5 (2001)
© Steinkopff Verlag 2001
that perturbation. Adaptations of the skeleton, skeletal
muscle,kidney and endocrine systems that serve to mit-
igate the degree ofthat perturbation impose a cost in cu-
mulative organ damage that the body pays out over
decades of adult life [89,90].
Evidence that diet-induced metabolic
acidosis mobilizes skeletal base
In the studies referred to in the previous section,the ef-
fects of metabolic acidosis were studied in response to
large exogenous acid loads. What is the evidence that
bone contributes to acid-base homeostasis in subjects
with the chronic low-grade metabolic acidosis that re-
sults from eating a normal,net acid-producing diet?
For any level of acid loading, if bone is contributing
to acid-base homeostasis, even though blood acid-base
equilibrium appears to be stable, not all of the daily net
acid load should be recoverable in the urine [51,52], i.e.,
acid should appear to be accumulating in the body on a
daily basis. As discussed earlier, continued acid reten-
tion in normal subjects has been demonstrated at diet
net acid loads within the normal range. The stability of
the blood acid-base equilibrium is de facto evidence of
the existence of an internal reservoir of base that con-
tinually delivers base to the systemic circulation in an
amount equal to the fraction ofthe net acid load that the
kidneys fail to excrete. Bone is the major such internal
reservoir of base known to exist.
Another way to test whether persisting bone loss oc-
curs in response to chronic low-level diet-induced meta-
bolic acidosis is to examine the effect of neutralizing the
diet net acid load by addition of exogenous base. Such
studies have been carried out in postmenopausal
women [46].Potassium bicarbonate, when administered
in doses that nearly completely neutralize the diet net
acid load,reduces urinary wasting of calcium and phos-
phorus, improves preexisting negative balances of cal-
cium and phosphorus, and as indicated by biochemical
markers,reduces the rate of bone resorption and stimu-
lates the rate of bone formation [46]. Lemann [91] like-
wise demonstrated significant improvement in calcium
and phosphorus balances when the diet net acid load
was neutralized during potassium bicarbonate adminis-
tration in humans.
Thus,two lines of evidence indicate that chronic low-
level diet-induced acidosis imposes a chronic drain on
bone: a) stability of blood acid-base equilibrium in the
face of continuing retention of acid, and,b) amelioration
of negative calcium and phosphorus balances,reduction
of bone resorption and stimulation of bone formation
attendant to neutralization of the dietary acid load.
Evidence that diet-induced metabolic acidosis
is a factor in the pathogenesis of clinical osteoporosis
If chronic low-level diet-induced metabolic acidosis im-
poses a chronic, clinically significant drain on bone
mass, it might be possible to account in part for diffe-
rences in bone mass among individuals by differences in
the net acid load from their habitual diets. Unfortu-
nately, the measurements of net acid production or ex-
cretion rates needed to test that possibility directly are
not currently available.It is possible, however,to obtain
indirect but still realistic estimates of the differences in
diet net acid load among select groups of individuals,
and to relate those to differences in rate of bone mass
among those groups.
Specifically, it is possible to estimate the differences
in diet net acid load among the residents of different
countries.That can be accomplished using international
food consumption data compiled by the United Nation’s
Food and Agricultural Organization (FAO).For each of
some 130 countries, FAO tables report consumption of
vegetable and animal foods in units of daily per capita
vegetable and animal protein consumed.Many vegetable
foods are rich in potassium salts of organic anions [92]
that can be metabolized to the base, bicarbonate, which
in turn reduces the net rate of endogenous acid produc-
tion for a given rate of acid production from animal
foods [39, 93, 94]. Animal foods have a relatively lower
content of potassium and organic anions. Per unit pro-
tein, the potassium content of many vegetable foods ex-
ceeds that of animal foods by more than an order of
magnitude. Because organic anion content of foods par-
allels that of potassium, the content of base precursors
also is substantially greater in those vegetable foods
than in animal foods. For a given total protein intake,
therefore, the ratio of vegetable-to-animal protein con-
sumed can provide a rough index for comparison of the
base-to-acid-generating potential of the diet among the
differing countries.
It is also possible to approximate differences in bone
mass among countries,based on published reports ofthe
incidence of hip fractures in women over the age of 50
years. Hip fracture incidence is a good index of bone
mass because bone mass is a major determinant of the in-
cidence of fractures of bone in older individuals. So, if
chronic low-level diet-induced metabolic acidosis im-
poses a chronic,clinically significant drain on bone mass,
it might be possible to account in part for differences in
hip fracture incidence among countries by differences in
the ratio of vegetable-to-animal protein consumed.
Fig. 7 depicts the results of such an analyses for the 33
countries in which both hip fracture incidence and per
capita food consumption data were available as of 1999
[95]. Note that there is a strong nonlinear relation be-
tween fracture incidence and ratio of vegetable-to-ani-
mal protein consumed. Over two-thirds (r2=0.70) of the
L. Frassetto et al. 209
Diet, evolution and aging
total variability in hip fracture incidence among coun-
tries can be accounted for by its correlation with the ra-
tio of base-generating (vegetable) to acid-generating
(animal) foods consumed.Countries with the lowest ra-
tio of vegetable-to-animal protein intake have the high-
est incidence of hip fracture,and vice versa.This finding
provides evidence that dietary base deficiency relative to
acid load is a factor in the pathogenesis of the decline in
bone mass that occurs with age. Given that low-grade
metabolic acidosis of severity proportionate to the diet
net acid load is to be expected,this finding supports the
hypothesis that diet-induced chronic low-grade meta-
bolic acidosis is a factor in the pathogenesis of clinical
osteoporosis.
Recently Sellmeyer et al. have reexamined the rela-
tionship between the ratio of vegetable-to-animal food
intake and hip fracture rates in a more homogeneous
population (white elderly women residents of the U.S),
and found a similar result [96]. In addition, they found,
with repeated measures of hip bone mineral density,
that the rate of bone loss in the subjects was greatest in
those with the lowest vegetable-to-animal food intake
ratio. Those studies are significant because they elimi-
nate the confounding effects of racial and cultural fac-
tors on hip fracture risk unavoidable in the cross-cul-
tural study [95],and support the hypothesis that chronic
low-grade diet-induced metabolic acidosis accelerates
bone loss rates in humans.
Using a less indirect index of diet net acid load,
namely the ratio of dietary protein-to-potassium [42],
New and associates recently reported their observations
on bone health in elderly Scottish women to include es-
timates of dietary net acid load [97].The values for lum-
bar spine mass were lower and the values of urinary ex-
cretion of bone resorption markers were higher in those
women in the highest quartile of net acid load, com-
pared to those in the lowest quartile. Further, the net
acid load was significantly higher in the group of sub-
jects who had sustained fractures during the observa-
tion period, compared to those who had not.
Evidence that diet-induced metabolic acidosis effects
renal nitrogen excretion in humans
Frassetto and coworkers also explored the possibility
that nitrogen wasting might occur even with the low-
grade “tonic” background metabolic acidosis that ac-
companies eating a typical net acid-producing diet [87].
In postmenopausal women, correcting their diet-in-
duced low grade metabolic with potassium bicarbonate
in amounts that just neutralized their daily diet net acid
load, reduced in urinary ammonium excretion, which
returned to control when the acidosis was allowed to re-
cur by discontinuing the KHCO3supplement (Fig. 8).
But, in addition to the reduction in ammonia nitrogen
excretion during KHCO3administration,a sustained re-
duction in urea nitrogen excretion also occurred, sug-
gesting that the higher pre-treatment urea nitrogen ex-
cretion rates were contributing to the acidosis-induced
nitrogen wasting (Fig. 8). The reductions in urea and
ammonia excretion contributed about equally to the ni-
trogen sparing effect.
The most straightforward interpretation of these
findings is that KHCO3administration reduced NEAP
and corrected the pre-existing low-grade metabolic aci-
dosis, reducing the total rate of renal ammonia produc-
tion and, by raising urine pH, reducing intraluminal
trapping of ammonium ion. As a consequence, both the
excretion of ammonia in the urine and the delivery of
ammonia to the systemic circulation via the renal vein
decreased.The reduction in urine ammonia contributed
directly to improvement in nitrogen balance.The reduc-
tion in ammonia delivery to the systemic circulation via
the renal vein contributed indirectly to improvement in
nitrogen balance by limiting substrate (viz., ammonia)
availability for hepatic urea production [98],thereby re-
ducing external loss of nitrogen as urinary urea.And by
correcting the pre-existing low-grade metabolic acido-
sis, KHCO3decreased the pre-treatment rate of muscle
proteolysis,further contributing to the improvement in
nitrogen balance.The magnitude of the KHCO3-induced
nitrogen sparing effect was potentially sufficient to both
prevent continuing loss of muscle mass and to restore
previously accrued deficits.
Fig. 7 Age-adjusted hip fracture incidence in women in 33 countries decreases as
the ratio of vegetable to animal foods in the diet increases (p < 0.001).
210 European Journal of Nutrition, Vol. 40, Number 5 (2001)
© Steinkopff Verlag 2001
Evidence that diet-induced metabolic acidosis effects
growth hormone excretion in humans
Frassetto and coworkers also explored the possibility
that growth hormone excretion might be affected by this
same low-grade “tonic” background metabolic acidosis
[87]. In postmenopausal women, correcting their diet-
induced low grade metabolic with potassium bicarbon-
ate in amounts that just neutralized their daily diet net
acid load, was accompanied by an increase in 24-hour
mean growth hormone secretion. The average total
serum GH secretion, calculated as the 24-hour inte-
grated serum GH concentration, increased from
826±548 pg/ml before KHCO3to 915±631 pg/ml after
KHCO3supplementation (p < 0.05), approximately an
11% increase over baseline.Was this physiologically sig-
nificant? Consistent with the effect of growth hormone
on bone metabolism, osteocalcin levels also rose in
nearly every subject after KHCO3supplementation, and
were higher at nearly all time points. The 24-hour mean
osteocalcin level rose from 7.0±0.9 to 8.3±1.2 ng/ml af-
ter KHCO3treatment (p < 0.005).
Stone age diets for the 21st century?
Increasingly, nutritionists are directing attention to the
potential detrimental health effects of the major trans-
formation of the human diet that occurred relatively re-
cently in evolutionary time [99],viewing them as the ef-
fects of a conflict of the encounter of old genes with new
fuels [3].Our group is emphasizing the potential conflict
between our old genes and new levels of K-base and
NaCl in our diet, an insufficiency ofthe former and over-
sufficiency of the latter. In this effort, much remains to
be understood, and many interesting questions can be
formulated. The subtitle above is one such question.
What is the optimal NaCl intake for humans under ordi-
nary circumstances? Does adding NaCl to the diet really
make much difference if K-base intakes are optimal?
What are optimal K-base intakes? Was the Paleolithic
diet net base-producing? Is the optimal systemic acid-
base status of humans a low-grade diet-induced chronic
metabolic alkalosis without potassium deficiency?
Should we increase our protein intakes and balance the
acid effects with increased K-base?
Prospects
Based on the studies and arguments reviewed here, it
seems reasonable to expend further effort to investigate
the extent of the modulating effect of dietary NaCl and
K-base on the expression of osteoporosis, age-related
decline in muscle mass, kidney stones, and perhaps age-
related decline in renal function. Re-exchanging the
NaCl in our present diet for the K-base that our ances-
tral Homo and pre-Homo hominid species ate in abun-
dance can be shown to correct diet-induced low-grade
metabolic acidosis, and the consequent biochemical ev-
idences of decreased growth hormone secretion, in-
creased bone resorption with decreased bone formation
and increased protein catabolism. Beyond that, the sup-
plementation of the diet with K-base can override the ef-
fects of NaCl loading on blood pressure and urinary cal-
cium excretion.Thus,increasing dietary K-base to levels
approaching those of our stone-age forebears, either
with fruits and non-grain plant foods, or with supple-
mental K-base, would seem to hold particular promise
for preventing or delaying expression of these age- and
diet-related diseases and their consequences.
Acknowledgments This work was supported by the UCSF/Moffitt
General Clinical Research Center (NIH grant MO1 RR-00079) and by
NIH grants RO1-AG/AR0407 and RO1-HL64230.
Fig. 8 Decrease in urinary nitrogen excretion only during the period when the diet
in these normal postmenopausal women is supplemented with sufficient base to
lower their net acid excretion to near zero.
L. Frassetto et al. 211
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... [1][2][3] However, human diet has considerable changes in pH levels based on food constituents; making food as alkaline or acidic . [1,4] Furthermore, with the revolution in agriculture, the content of potassium (K) has been decreased as compared with sodium (N). Hence, the ratio of K/Na has been reversed, which was 10:1 previously, however, now modern diet constitutes 1:3 of K/Na . ...
... Hence, the ratio of K/Na has been reversed, which was 10:1 previously, however, now modern diet constitutes 1:3 of K/Na . [4] Moreover, an increase in chloride (Cl) as compared with bicarbonate has also been found in diet . [2,5] It has been observed that human diet lacks magnesium and potassium as well as dietary fiber, however, rich in saturated fats, sodium, chloride, simple sugars as compared with the pre-agricultural period of several years ago . ...
... [13] Regulation of pH by acid-base homeostasis pH regulation in human body is a key component for maintaining homeostasis and buffering system is of utmost importance regarding this issue . [4,7] Buffering systems in human body primarily contributed towards prevention of abnormal pH which arises from excessive proton production . [1] Moreover, bicarbonate-carbonate system acts as a main buffering system inside intra-cellular and extra-cellular body fluid. ...
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... Micronutrient deficiencies that increase with ageing become more severe due to the increased acid load and homeostatic mechanisms also start to fail, e.g. urinary excretion of calcium increases, bone mineral density decreases, urolithiasis develops and renal failure becomes more severe (98,99). Thus, the acid load in the elderly may further increase in modern times, which can be explained by comparing the current dietary fibre consumption with that in the old times. ...
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INTRODUCTION The influence of individual foods on the composition of the urine has been studied from several points of view. Many of the relations have been satisfactorily determined.It is a matter of common knowledge that the urine of herbivorous animals is alkaline to litmus, while that of the carnivora is acid in reaction. Human urine, likewise, is normally acid. The alkaline urine of herbivora has been supposed to result from the vegetable foods on which they live. Similarly, the acid reaction of the carnivorous urine was referred to the meat diet of these animals. What is present in these foods that may be held responsible for the differences in urinary acidity? The excess of base-forming elements in vegetables and of acid-forming elements in meats at once suggests an answer. It was not until Sherman and Gettler1 made more complete ash analyses of a large number of foods that
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The effects of age and acid stress on renal, serum and bone responses in 13- and 25-month-old rats, which were fed two levels of dietary calcium, 100 and 500 mg/100 g of diet, for 9 months, with and without dietary ammonium chloride (2%), were investigated. Acid-stressed animals showed significant decreases in urinary pH and significant increases in urinary total acid, calcium and phosphorus excretions, kidney weights, and phosphate-dependent glutaminase activities. Renal responses were affected by the level of calcium in the diet and the age of the animal. Acid stress tended to decrease serum calcium and phosphorus. Serum phosphorus was decreased in old animals, while serum calcium was unaffected by age. Tibia ash weights of old animals were significantly less and their fat content was significantly higher than that of young animals. However, neither acid stress nor the level of calcium in the diet significantly affected bone analysis in either age group.
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Growth was evaluated in a group of 10 infants and children with familial or idiopathic classic renal tubular acidosis in whom alkali therapy was initiated at ages ranging from 8 days to 9.5 yr and administered at dosage schedules documented to sustain correction of acidosis in at least four prolonged observation periods on the Pediatric Clinical Research Ward. When alkali therapy was begun, six patients (four infants and two children) were stunted (height <2.5 SD below mean). Of the four who were not, two infants were too young (<2 wk of age) to have become stunted, and two children had been documented earlier to be nonacidotic. At the start of alkali therapy, the heights of the patients correlated inversely with the maximal possible duration of prior acidosis. WITH SUSTAINED ALKALI THERAPY: (a) each patient attained and maintained normal stature; (b) the mean height of the 10 patients increased from the 1.4+/-4 to the 37.0+/-33 percentile (of a normal age- and sex-matched population); (c) the mean height reached the 69th percentile in the eight patients whose heights could be analyzed according to parental prediction (Tanner technique); (d) the rate of growth increased two- to threefold, and normal heights were attained within 6 mo of initiating alkali therapy in the stunted infants and within 3 yr in the stunted children; (e) the height attained correlated inversely with the maximal possible duration of acidosis (before alkali therapy) only in those patients in whom alkali therapy was started after 6 mo of age, and not in those treated earlier. The amount of alkali required to sustain correction of acidosis increased substantially during the course of treatment in each patient. The maximal alkali requirement ranged from 4.8 to 14.1 meq/kg per day, and in each patient its amount was determined principally by the magnitude of renal bicarbonate wasting.