Bone buffering of acid and base in humans - 《American Journal of Physiology》美国生理学杂志干细胞之家



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发表于 2009-4-21 13:48 |只看该作者 |倒序浏览 |打印

作者：Jacob Lemann, Jr., David A. Bushinsky,  L. Lee Hamm作者单位：1 Nephrology Section, Tulane University School of Medicine, New Orleans, Louisiana 70130-5927; and Nephrology Unit, University of Rochester School of Medicine, Rochester, New York 14642
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      【摘要】) P: K' D8 j, C! e$ B
   The sources and rates of metabolic acid production in relation to renal net acid excretion and thus acid balance in humans have remained controversial. The techniques and possible errors in these measurements are reviewed, as is the relationship of charge balance to acid balance. The results demonstrate that when acid production is experimentally increased among healthy subjects, renal net acid excretion does not increase as much as acid production so that acid balances become positive. These positive imbalances are accompanied by equivalently negative charge balances that are the result of bone buffering of retained H and loss of bone Ca 2  into the urine. The data also demonstrate that when acid production is experimentally reduced during the administration of KHCO 3, renal net acid excretion does not decrease as much as the decrease in acid production so that acid balances become negative, or, in opposite terms, there are equivalently positive balances. Equivalently positive K and Ca 2  balances, and thus positive charge balances, accompany these negative acid imbalances. Similarly, positive Na balances, and thus positive charge balances, accompany these negative acid balances during the administration of NaHCO 3. These charge balances are likely the result of the adsorption of onto the crystal surfaces of bone mineral. There do not appear to be significant errors in the measurements. 3 A4 \1 |% a" ~1 ]0 C/ }# ?' F
      【关键词】 acid production acid excretion acid balance charge balance calcium balance potassium balance sodium balance organic anions sulfate ammonium4 W* _. X% g2 d2 l
   A RECENT EDITORIAL REVIEW of the balance of acid, base, and charge in health and disease ( 18 ) suggests that there is continuing controversy regarding the sources of fixed acid or base production relative to the routes and mechanisms for the buffering and excretion of acid or base and thus the maintenance of net external acid balance in health and disease. The quantitative significance of bone in buffering of acid and base has also been questioned ( 59, 60 )., Z9 }0 p. N. g" e( p
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This report reviews the development of techniques of evaluating the sources and rates of fixed acid production in relation to renal net acid excretion, thus allowing assessment of acid balance in humans. The changes from control that occur when acid production is increased or decreased will be used to clarify the responses of both acid production and excretion and of acid balances and mineral balances. We also review the possible sources of error in the measurements of acid production and renal net acid excretion and the relationship of charge balance to acid balance.( z( Q8 a8 J% [7 P+ p; ]

The results demonstrate that renal net acid excretion does not increase as much as acid production when acid production is experimentally increased among healthy subjects, so that acid balances become positive. This imbalance is accompanied by equivalently negative charge balances that are the result of bone buffering of retained H and loss of Ca 2  from bone into the urine. The data also demonstrate that when acid production is experimentally reduced renal net acid excretion does not decrease as much so that acid balances become negative, or, in opposite terms, there are equivalently positive balances. This imbalance is accompanied by equivalently positive K and Ca 2  balances, and thus positive charge balances during the administration of KHCO 3, or positive Na balances and thus positive charge balances during the administration of NaHCO 3. These charge balances are likely the result of the adsorption of KHCO 3 or of NaHCO 3 onto the crystal surfaces of bone mineral., G6 U7 \/ ]" I' t
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The evaluation of potential errors in the measurements required to quantitate acid production and net acid excretion shows that the contribution of intestinal absorption of dietary acid or base must be directly evaluated by measuring dietary and fecal composition and cannot be indirectly assessed by measurements of urinary composition. These assessments also show that there are small errors, both positive and negative, that affect the measurement of urinary organic anions as a component of acid production. There is, however, no evidence for the existence of urinary cations, other than, that contribute to net acid excretion.

EVALUATION OF ACID-BASE BALANCE IN HEALTHY HUMANS7 Q, `. r4 D4 a( h4 u8 V

The many biochemical reactions of metabolism result in the production and consumption of acids and bases. In the steady state in health, the state of titration of body buffers and thus the acidity of body fluids and tissues, as reflected by pH or H concentration ([H ]), are closely regulated and stable. Within the readily sampled extracellular fluid (ECF; blood serum or plasma) where the CO 2 /bicarbonate buffer system is quantitatively most important, the plasma concentration and P CO 2 (proportional to H 2 CO 3 ) concentrations are stable. Thus blood pH or [H ] is also stable. Because the buffering capacity and acidity of body compartments with which the plasma is in equilibrium are steady in health, normal adults must be in balance (e.g., intake-output = 0) with respect to the daily production and excretion of hydrogen ions (or actual or potential ). The rate of production of the volatile acid H 2 CO 3 from neutral fats, carbohydrates, and proteins is matched by an equivalent rate of excretion of CO 2 by the lungs. Similarly, in health there is daily production of nonvolatile or "fixed" acids. When such acids are produced, the protons (H ) liberated by the dissociation of the acid react immediately with body buffers that can be represented by plasma, resulting in the formation of H 2 CO 3 that is transported to the lungs and excreted as CO 2. Obviously, ongoing consumption of body buffers by such a mechanism could not continue for any significant time without regeneration of. Therefore, it can also be assumed that the net rate of fixed acid (e.g., noncarbonic acid) input each day must be matched by an equivalent rate of acid removal so that net external (fixed) acid balance must equal zero. Such a process is analogous to the equivalence of metabolic H 2 CO 3 (CO 2 ) production and pulmonary excretion.0 P( N( r; [! X/ I0 J1 a+ W- Y

Many studies during the first half of the 20th century led to an understanding that in health the kidneys excrete acid. These processes include the following:. X! }5 \* [( r; Q/ T6 z. \

1 ) The titration of filtered buffers, chiefly the titration of to (termed titratable acid), that are measured by titration of the urine from urinary pH to blood pH, usually pH 7.4 or estimated by calculation based on the urinary phosphate concentration, urinary pH, and the p K a2 = 6.8 for the dissociation and on the urinary concentration of creatinine (see below).; ^; X" l/ l# x9 {0 x# {  b

2 ) The production and excretion of ammonium by renal tubular cells from neutral precursors to form urinary (measured as total urinary plus the negligible amounts of NH 3 when urine pH 7.5). The protons (H ) thus added to the urine are, ultimately or in effect, derived from H 2 CO 3 and result in the simultaneous addition of equivalent quantities of to renal venous blood. The excretion of is quantitatively equal to the net generated from the metabolism of glutamine to and. Thus the excreted is equivalent to the H excreted and the new regenerated ( 2 ).

3 ) Additionally, under most conditions, nearly all of the that appears in the glomerular filtrate is reabsorbed, thus preventing urinary loss of filtered (base).7 Z8 C) a9 k. z$ ]
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Thus during the steady state in health, the daily net rate of acid excretion by the kidneys can be quantitated as urinary titratable acid plus less any filtered escaping renal tubular reabsorption and excreted into the urine. This quantity is termed renal net acid excretion. The overall excretion of net acid is now known to be accomplished by multiple transport processes along the nephron, including Na /H exchange in both the proximal and distal tubules ( 7 ) and by both an H -ATPase and an H -K -ATPase as well as by secretion in distal nephron segments ( 14, 27, 57 ).
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Because protons (H ) are always available throughout body fluids and thus cannot be directly traced, the techniques for identifying and quantifying the sources of fixed acid production are, necessarily, indirect. Measurements of metabolic products (conjugate bases, anions) that, by biochemical reasoning, must have been associated with the production or consumption of H are thus required. Early in the 20th century, several sources of fixed acid production had already been recognized; these can be detected based on urinary constituents:* w/ n* [  `. h
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1 ) The urinary excretion of organic acid anions reflecting either the ingestion and absorption of nonmetabolizable free organic acids in the diet, the formation of acids as end products of metabolism such as uric and oxalic acids; or the incomplete oxidation to CO 2 H 2 O of acids normally produced during metabolism, such as lactic and citric acids (and acetoacetic and -hydroxybutyric acids during starvation or diabetic ketoacidosis, etc.), accompanied by the production, retention and buffering of an equivalent quantity of H ( 73 ). Urinary organic anions have also been referred to as representing "loss of potential base," but this is correct only with respect to those urinary organic anions such as citrate, lactate, pyruvate, etc. that could have been metabolized to if retained within the body. Those urinary anions that reflect the formation of acid end products of metabolism such as oxalate, urate, etc. identify acid production.
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2 ) The urinary excretion of, reflecting the oxidation of sulfur contained in the neutral amino acids methionine, cysteine, or cystine of dietary protein or endogenous tissue proteins during starvation ( 28, 41, 71 ) that is also accompanied by the generation of an equivalent quantity of H  . Additionally, it was known that normal foods in the diet contain bases, as actual or potential as inorganic cationic salts (principally K-salts) of metabolizable organic anions such as citrate, acetate, etc. ( 71 ).: z5 A; n/ W; }" J
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Whether acid or base might be excreted into the feces in health had not been clarified, although large fecal losses of actual or potential with severe diarrhea as in cholera had been known for a century or more ( 70 ). However, techniques had not yet been developed that might permit, among healthy adults in the steady state, both identification of the sources of acid production as well as a quantitative comparison of the daily rate of acid production to the daily rate of renal net acid excretion.+ ?8 q/ s1 n- q3 T, F$ g  w8 Z

The original impetus for such studies arose from observations among patients with advanced chronic kidney disease who exhibited low, but stable, serum associated with low rates of renal net acid excretion related to the low rate of urinary excretion that accompanies advanced kidney diseases ( 67 ). By contrast, healthy subjects eating comparable diets had normal serum and much higher rates of and, hence, net acid excretion. These disparate observations led to consideration of two alternative explanations: 1 ) the stabilization of serum among the patients with chronic kidney diseases resulted from a reduction in the daily rate of fixed acid production equivalent to the limitation in net acid excretion caused by the kidney disease; or 2 ) normal rates of fixed acid production continued, and during acidosis additional routes for acid excretion or disposal (buffering) might become operative, serving to stabilize the low serum. A review of the acid balances and bone among patients with renal failure is presented in a subsequent section of this review.

Assessment of the Sources of Acid Production and Acid Balances Among Healthy Adults Using Liquid-Formula Diets# i" K2 `* N( U3 d  h

The original technique of quantitating acid production compared with net acid excretion among healthy adults utilized a liquid-formula diet ( 65 ). That diet contained glucose, cornstarch hydrolysate (dextrin), corn oil, and a purified soy protein. Na was provided as NaCl. K was provided as KCl. The soy protein was prepared at its isoelectric point and contained essentially no Na  , K  , Ca 2 , Mg 2 , or Cl -. However, the protein did contain PO 4 (17 mmol/100 g), presumably mostly as esters of the hydroxylated amino acids serine and threonine. For some of the original studies ( 65 ), the metabolism of this esterified PO 4, effectively to H 3 PO 4, was considered to quantitatively represent acid production when H 3 PO 4 was subsequently present as and in blood in a ratio of 4:1 at pH = 7.4, at which pH the valence of PO 4 = 1.8. For a few of the original studies ( 65 ) and all subsequent studies using soy protein formulas, 0.45 mmol = 0.9 meq of Ca(OH) 2 and 0.45 mmol = 0.9 meq Mg(OH) 2 /mmol PO 4 in the protein were added to the formula, thus neutralizing to pH 7.4 the potential acid from the PO 4 in the protein. Because the other mineral salts in these diets were neutral (NaCl, KCl), the estimated unmeasured anion of these soy formulas was approximately zero, both by calculation and based on analyses of the diets {e.g, (Na    K    Ca 2 Mg 2  ), meq/day - [(Cl - ) (1.8 · PO 4 ), meq/day] = 0}. Moreover, because the formulas did not contain any fiber, the subjects defecated on average only every 2.5 days, and average fecal weight was only 45 g/day. Consequently, for those studies possible excretion of acid or base into the feces was considered minimal and was neglected.
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Utilizing these formula diets, we observed that among healthy subjects, studied when their serum  was normal and stable, mean daily net fixed acid production, estimated as urinary urinary organic acids, was, on average, identical to the mean daily rate of net acid excretion. Thus the net external fixed acid balance was zero, the subjects being in balance with respect to fixed acid production and excretion ( 65 ). Additional studies using formula diets were also carried out to assess the effects of experimental alterations in acid production on acid balance achieved by either increasing net fixed acid production among healthy subjects by the administration of NH 4 Cl or reducing net fixed acid production by the administration of NaHCO 3 ( 36 ). Those studies showed that NH 4 Cl administration caused systemic acidosis but that the consequent increase in net acid excretion was less than the increase in acid production (= organic acids the NH 4 Cl load) so that acid balances became positive ( 36 ). Moreover, NaHCO 3 administration reduced fixed acid production, but the decrease in renal net acid excretion was not as large so that acid balance became negative (i.e., there was positive base balance) ( 36 ). Serum was steady during these studies of NH 4 Cl or of NaHCO 3 loading.+ L8 @5 ^6 s0 b: P8 Z7 p5 X

In summary, studies using neutral liquid-formula diets demonstrated that fixed acid production was identified by the urinary excretion of organic anions, the sum of these two matching the simultaneous rate of renal net acid excretion so that healthy adults with normal and stable serum were in acid balance. Furthermore, the failure of net acid excretion to increase as much as did acid production during NH 4 Cl loading or to decrease as much as did acid production during NaHCO 3 loading implied the retention of acid or base (HCO 3 ), respectively, at sites outside the ECF or the apparent space of distribution for HCO 3.! a& _0 s4 E; \8 q  o

Assessment of the Sources of Acid Production and Acid Balances Among Healthy Adults Using Normal Whole-Food Diets

During the original development of the methods to assess the components of acid production and excretion ( 41, 65 ), it again became evident that normal whole-food diets contain base as actual or potential as inorganic cationic salts (principally K-salts) of metabolizable organic anions such as citrate, acetate, etc. The precise identity and quantity of such base(s) ingested each day in the diet could not be directly measured. However, that quantity could be indirectly estimated as the difference between the dietary content of inorganic cations ( Na    K    Ca 2 Mg 2 , meq) and of inorganic anions Cl - (1.8 · PO 4 ), meq] ( 43 ). It was also observed that the feces similarly contain actual or potential base, known to be principally acetate, propionate, and butyrate ( 43 ). Once again, the precise identity and quantity of such fecal base(s) could not be directly measured. However, the daily fecal excretion of such base could similarly be estimated using the same calculation applied to the analyses of the diet ( 43 ). The difference between the dietary intake of unmeasured anion and the fecal excretion of unmeasured anion thus represented the net intestinal absorption of unmeasured anion, generally a positive number, reflecting addition of actual or potential to the body. During the original studies of this type ( 43 ), it was observed that for a group of 16 healthy adults fed various diets that fixed acid production measured in this manner averaged 59 ± 30 (SD) meq/day and net acid excretion averaged 60 ± 21 meq/day. Accordingly, mean acid balance for this group was not different from zero ( P 0.7), averaging -1 ± 12 meq/day ( 43 ). The individual data for net acid excretion in relation to fixed acid production are compared among these subjects in Fig. 1 ( 43 ).% f) ?8 t6 Y  H& n2 b3 A
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Fig. 1. Daily urinary net acid excretion (titratable acid ) in relation to daily net fixed acid production, urinary ( organic anions) - diet { } - fecal {( ) - } among 16 healthy adults eating constant whole-food diets ( ), soy protein-formula diets ( ), or diets containing egg yolk ( ); y = 21.659 0.67075 x; r 2 = 0.888; P P 0.8. Redrawn from the original data in Ref. 43.- a- P, v; D* z$ L: b' _6 ^: z2 ~4 {& \
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Effects of Base or Acid Administration to Healthy Human Subjects: Results of Paired Studies During Control Periods and During Acid or Base Administration Periods in the Same Subjects- O4 r5 H- f# z# {

Obviously, multiple analyses of diets, feces, and urine are required for the measurement of acid balance, and multiple analytic errors might significantly bias the results. However, when groups of subjects are studied while eating individually constant diets during both control conditions and during the continuous administration of additional acid or base, the analytic variations should be minimized. Therefore, the changes from control ( ) in the components of the acid balance should clarify the processes involved in the consequent increases or decreases in acid production, the accompanying increases or decreases in renal net acid excretion, the directional changes in acid balance, and the distribution (buffering) of retained base or acid. Moreover, the resulting changes from control in the balances of other minerals and of charge balance can also be evaluated.

Effects of increasing acid production using NH 4 Cl. Fourteen healthy adults were studied while eating individually constant diets during control conditions and during the administration of NH 4 Cl in varying but individually constant doses ranging from 138 to 384 meq · day -1 · subject -1 and averaging for the group 231 ± 69 (SD) meq/day (3.23 ± 0.61 meq · kg body wt -1 · day -1 ) ( 1, 37, 74 ). The control observations were obtained during a 6-day period after 10 days of adaptation to each subject's constant whole-food diet. The observations during NH 4 Cl administration were also obtained during a 6-day period that began 12 days or longer after NH 4 Cl was begun. As shown in Table 1, fecal Cl - excretion did not change from control rates during the administration of NH 4 Cl, indicating that all of the administered Cl - was absorbed. Fecal excretion of unmeasured anion also did not change. Thus on average for the group, the decrease in net intestinal absorption of base (unmeasured anion) was equivalent to the quantity of NH 4 Cl administered. The consequent alteration in systemic acid-base balance and renal net acid excretion during NH 4 Cl (see below) had no effect on the fecal excretion of actual or potential base (as unmeasured anion). Because the sum of urinary excretion of and organic anion was nearly unchanged during the administration of NH 4 Cl, net fixed acid production increased by a quantity equivalent to the increased intestinal absorption of the NH 4 Cl administered (in effect reflecting the metabolism of the administered NH 4 Cl to urea HCl). However, renal net acid excretion did not increase to an equivalent degree. Thus the average acid balance for the group became significantly more positive by  24 ± 22 meq/day; P = 0.001. As shown in Fig. 2, these 14 subjects were, on average, in a steady state with respect to body weight, serum, and net acid excretion during control and with respect to serum and net acid excretion during NH 4 Cl acidosis. However, during induced acidosis these subjects exhibited a decline in body weight, averaging for the group -0.046 kg/day. Accompanying the retention of acid, Ca 2  balances ( Table 1 ) became negative by an average of -16 ± 12 meq/day, P 2  into the urine without any detectable change in net intestinal absorption of dietary Ca 2 . Additionally, K balances also were slightly, but significantly, more negative by -4 ± 6 meq/day; P = 0.033, and Mg 2  balances were marginally more negative by -4 ± 8 meq/day; P = 0.052. PO 4 balances were more negative by -6 ± 3 mmol/day; P of Ca 2  lost during the 6-day balance period averaged 96 meq, an amount that could only have been derived from bone, the sole significant body store of Ca 2 . In view of the loss in weight accompanying the retention of H during stable NH 4 Cl acidosis, it seems reasonable to assume that the K and Mg 2  losses and some of the PO 4 losses derived from cells, likely muscle cells but possibly including bone, as a result of the adverse effects of acidosis on protein metabolism (reviewed in Ref. 54 ), whereas most of the Ca 2  was lost from bone mineral together with ( 8, 11 - 13 ). Urinary hydroxyproline excretion also increases during NH 4 Cl acidosis, providing further evidence for increased bone resorption ( 33 ). The effects of metabolic acidosis on bone and bone cells in vitro are well known and reviewed elsewhere ( 10, 24 ).

Table 1. Changes in body weight and in acid, mineral, and charge balances during NH 4 Cl administration among 14 healthy adults eating otherwise constant diets ( 1, 37, 74 )/ B$ D0 [# Y  {% F% g& E

Fig. 2. Mean body weight ( A ), serum HCO 3 concentration [(HCO 3 ]; B ), and daily urinary net acid excretion ( C ) among 14 healthy adults studied during control conditions ( ) and then during the administration of NH 4 Cl ( ). Adapted from data in Refs. 1, 37, 74.# F1 S: S( Y' n

Effects of decreasing acid production using KHCO 3. The effects of KHCO 3 administration are presented in Table 2 ( 34 ). Ten healthy adults were observed during a control 6-day balance period that began after they had eaten their constant diet for 10 days. They were then observed while continuing to eat the same diet during a 6-day experimental balance period that began 6 days after the ongoing administration of KHCO 3, 61 ± 1 mmol/day (0.90 ± 0.11 meq · kg body wt -1 · day -1 ) was begun. As shown in Table 2, fecal K excretion did not change from control rates during the administration of KHCO 3, and the fecal excretion of unmeasured anion also did not change. Thus on average for the group, all of the administered KHCO 3 was absorbed, and the increase in net intestinal absorption of base (unmeasured anion) was equivalent to the quantity of KHCO 3 administered. The consequent alteration in systemic acid-base balance and renal net acid excretion had no effect on the fecal excretion of actual or potential base (as unmeasured anion). Because the sum of urinary excretion of and organic anion was nearly unchanged during the administration of KHCO 3, net fixed acid production decreased by a quantity equivalent to the increased intestinal absorption of the administered as KHCO 3. However, renal net acid excretion did not decrease to an equivalent degree. Thus the average acid balance for the group became significantly more negative by -13 ± 11 (SD) meq/day; P = 0.005. Equivalently, but in opposite terms, balance became more positive by  13 ± 11 meq/day during KHCO 3 administration. Accompanying the retention of HCO 3, K balances became almost equivalently more positive by  11 ± 10 mmol/day; P = 0.006. Additionally, Ca 2  balances became slightly, but significantly, more positive by 1.8 ± 1.6 meq/day; P = 0.009. The changes in K    Ca 2  balances during KHCO 3 administration were matched by an equivalently more positive charge balance or, in other words, a more negative acid balance (equivalent to retention). Thus it seems reasonable to conclude that KHCO 3 was retained. As shown in Fig. 3, these subjects were, on average, in a steady state with respect to body weight, morning fasting serum, and daily renal net acid excretion during both control conditions and during KHCO 3 administration. Moreover, average body weight for the group did not differ during KHCO 3 administration compared with control. Mean fasting serum was slightly, but not significantly, higher during KHCO 3 administration in these studies, although during other studies, when 90 mmol of KHCO 3 were administered each day, serum was observed to increase significantly when measured 90 min after the ingestion of one-third of the daily KHCO 3 dose (30 mmol) ( 39 ). Serum K concentrations did not increase (not shown). Body weight was measured to the nearest 0.01 kg daily in each subject and was stable. That observation indicates that intracellular water was not retained in osmotic proportion to the cumulative retention of 66 mmol K over the 6-day balance period because retention of such a quantity of K within cells (with an anion) would have been expected to obligate retention of water, resulting in an increase body weight averaging 0.5 kg, an amount that should have been detectable. Thus it seems reasonable to propose that the KHCO 3 was retained in an osmotically inactive form. Speculatively, KHCO 3 was retained as a solid phase adsorbed or secreted onto the vast surfaces of apatite in bone ( 11, 15 ).

Table 2. Changes in body weight and in acid, mineral, and charge balances during KHCO 3 administration among 10 healthy adults eating otherwise constant diets ( 34 )2 n; Z/ U; Z, U% {) a4 \# k

Fig. 3. Mean body weight ( A ), serum [HCO3] ( B ), and daily urinary net acid excretion ( C ) among 10 healthy men studied during control conditions ( ) and then during the administration of KHCO 3 ( ) and NaHCO 3 ( ). Adapted from data in Ref. 34.
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Effects of decreasing acid production using NaHCO 3. The same 10 healthy adults were also studied, using the same control period and the same individually constant diets, during a 6-day period that began 6 days after the continuous administration of NaHCO 3 (60 ± 1 meq/day, 0.88 ± 0.11 meq·kg body wt -1 ·day -1 ) was begun ( 34 ). As shown in Table 3 and Fig. 3, the effects of NaHCO 3 were, for the most part, similar to those of KHCO 3 administration in that urinary net acid excretion did not decrease as much as did acid production so that acid balances became more negative by -12 ± 11 meq/day; P = 0.011. Accompanying this retention of, Na balances became almost equivalently more positive by  11 ± 14 mmol/day; P = 0.033 without any change in body weight, suggesting the retention of NaHCO 3 in an osmotically inactive form as a solid phase adsorbed or secreted onto the surfaces of apatite in bone ( 11 ). Unlike the effect of KHCO 3 administration, the administration of NaHCO 3 was not accompanied by a reduction in urinary Ca 2  excretion or more positive Ca 2  balances. The failure of NaHCO 3 to cause Ca 2  retention is the result of the additional Na load, causing extracellular volume expansion and increased urinary Ca 2  excretion when the diet also contains NaCl. Increasing dietary NaCl intake is known to increase urinary Ca 2  excretion ( 5, 39, 53, 56 ). Additionally, the ongoing administration of mineralocorticoid when the dietary intakes of NaCl and Ca 2  are constant is accompanied by NaCl retention, weight gain, and increased urinary Ca 2  excretion ( 44 ). Other studies have also shown that the administration of NaHCO 3 when the diet also contains NaCl does not result in a sustained reduction in urinary Ca 2  excretion ( 34, 39 ). However, when dietary Na intake is kept constant by substituting NaHCO 3 for part of the NaCl in the diet, urinary Ca 2  excretion does decline ( 50 ).

Table 3. Changes in body weight and in acid, mineral, and charge balances during NaHCO 3 administration among 10 healthy adults eating otherwise constant diets ( 34 )
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During growth, daily rates of renal net acid excretion among infants have been observed to exceed rates of fixed acid production, so that daily acid balances are negative ( 30 ) as during the administration of KHCO 3 or NaHCO 3 to adults. That effect necessarily must accompany the deposition of alkaline mineral into the growing skeleton, largely as Ca 10 (PO 4 ) 6 (OH) 2 /Ca 10 (PO 4 ) 6 CO 3, a process that may, in opposite terms, be thought of as an additional source of acid production.' ?. {' o! Z# m( H- e% D7 Z

Overview of acid production and excretion. Figure 4 summarizes the relationship between the changes from control in daily urinary net acid excretion and the changes in net endogenous fixed acid production for the individual subjects given NH 4 Cl ( 1, 37, 74; summarized in Table 1 ), the subjects given KHCO 3 ( 34; summarized in Table 2 ), and among 4 additional subjects in which acid production was increased by increasing dietary protein intake as egg white ( 1 ). The relationship is net acid excretion, meq/day = 3.81 ±[(SE)2.77] 0.90667 ±(SE)[0.0161] · acid production, meq/day. The slope for this relationship is significantly net acid excretion did not increase as much as acid production when acid production was increased using NH 4 Cl or egg white, the data points for those studies lie below the identity line. By contrast, the data points for the subjects given KHCO 3, with one exception, lie above the identity line because net acid excretion did not decrease as much as did acid production. In other words, the data viewed in this manner also indicate that acid balances become positive when acid production is increased and become negative, reflecting retention, when acid production is reduced.5 u) a( b+ b/ j

Fig. 4. Changes ( ) from control in daily urinary net acid excretion in relation to the changes from control in daily endogenous fixed acid production among healthy adults given NH 4 Cl ( ), egg white ( ), or KHCO 3 ( ); y = 3.81 (±2.77) 0.90667 (±0.0161) x; r 2 = 0.992; P 1, 34, 37, 74." m# b' N# [  k

To summarize, net fixed acid production among healthy adults eating normal diets can be estimated by the sum of urinary organic anions less the difference between the sum of inorganic cations and anions in the diet and their sum in the feces. This quantity matches urinary net acid excretion so that healthy adults with normal and stable serum are in acid balance. When acid production is experimentally increased, acid balances become positive and Ca 2  balances become negative, reflecting buffering by bone. When acid production is experimentally reduced, acid balances become negative, reflecting equivalent retention together with K and Ca 2  retention during the administration of KHCO 3 and of Na retention when dietary Na intake is kept constant during the administration of NaHCO 3, either also reflecting buffering of base by bone.! _9 h; f" Q6 S( m

A CONSIDERATION OF POSSIBLE ERRORS IN THE ESTIMATES OF FIXED ACID PRODUCTION AND RENAL NET ACID EXCRETION

Components of Fixed Acid Production, i& ~- {3 H' }7 _  D0 m* F

Urinary sulfate. Oxidation of organic sulfur to sulfate, as reflected by the daily urinary excretion rates of, is the first major component of fixed acid production. The measurements of urinary using either gravimetric ( 63 ) or turbidometric ( 4 ) methods appear to be adequately specific and precise and therefore not a significant source of error. The possibility exists that after its production significant quantities of might be excreted via other routes, thereby escaping detection and leading to an underestimation of fixed acid production. However, even during methionine loading, when production and urinary excretion rates were markedly increased, fecal excretion was negligible ( 41 ). Losses of sulfate via the skin would also appear to be negligible even with moderate visible sweating.: T! L; S7 n4 T! K% e0 d# F

Urinary organic anions. Urinary organic anion excretion in humans reflects the second major component of fixed acid production. Presently, various precise methods do not appear to be available that allow individual identification and quantitation of all these organic anions. Thus their estimation remains dependent on an estimate derived from the titration of urine from pH 2.7 to urinary pH, after removal of urinary PO 4 by incubation of the urine with solid Ca(OH) 2 and reacidification of the filtrate to pH 2.7, a method devised early in the last century ( 73 )./ h& Y& R2 H* N: E  v8 L
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Studies in rats have shown that the urinary excretion of organic acids falls with acid loading and rises with alkali loading ( 6, 17, 61 ). However, as shown in Fig. 5, using the individual data for the subjects whose studies are summarized in Tables 1, 2, 3, the daily urinary excretion of total organic acids, as titrated between pH 2.7 and 7.4, did not change significantly as urinary pH or daily net acid excretion varied during the administration of NH 4 Cl, KHCO 3, or NaHCO 3. Thus unlike rats, in which urinary excretion rates of organic anions decrease markedly during acid loading and increase markedly during the administration of loads ( 6, 17, 61 ), humans do not exhibit either an evident decrease in total organic acid excretion in response to acid administration or an increase in response to the administration of base.
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Fig. 5. A : changes from control in the daily urinary excretion of total organic acids in relation to the changes from control in urinary pH among healthy adults given NH 4 Cl ( ), egg white ( ), or KHCO 3 ( ); y = 1.7 0.045 x; r 2 = 0.00, not significant. B : changes from control in the daily urinary excretion of total organic acids in relation to the changes from control in daily urinary net acid excretion for healthy adults given NH 4 Cl ( ), KHCO 3 ( ), or NaHCO 3 ( ); y = 1.6 0.002 x; r 2 = 0.00, not significant. Adapted from data in Refs. 1, 34, 37, 74.7 U1 }+ A) L+ Q7 J% |6 L
8 I. o7 j' u" P% g2 x
By contrast, as shown in Fig. 6 ( 1, 33, 34, 37, 41, 65, 74 ), the percentage of urinary organic acid anions that are titrated between pH 2.7 and urinary pH and that constitute a component of net fixed acid production increases, in a manner resembling the upper segment of a sigmoid titration curve, from 70 to 80% of total urinary organic acids (titrated from pH 2.7 to 7.4) at a urinary pH of 5 to nearly 100% above a urinary pH of 7. By contrast, the percentage of total urinary organic acids that are excreted as free acids (titrated between urinary pH and 7.4) necessarily decreases from 20 to 30% of the total at pH 5 to only a few percentage points or zero at a urinary pH above 7. These free organic acids do not contribute to fixed acid production. Thus, as shown in Fig. 7, which uses the individual studies that are summarized in Tables 1, 2, 3 ( 1, 34, 37, 74 ), the daily urinary excretion rates of organic acid anions decrease as urinary pH falls and tend to increase as urinary pH rise, whereas their excretion rates fall as net acid excretion increases and increase as net acid excretion decreases.7 V. k6 K( V* j6 [/ e) B

Fig. 6. Percentage of daily total urinary organic acids excreted as organic acid anions ( ) and as free acids ( ) in 24-h urine collected from adults eating various constant diets. Adapted from data in Refs. 1, 33, 34, 37, 41, 65, 74.

Fig. 7. A : changes from control in the daily urinary excretion of organic acid anions in relation to the changes from control in urinary pH for healthy adults given NH 4 Cl ( ), KHCO 3 ( ), or NaHCO 3 ( ); y = -2.3943 7.6893 x; r 2 = 0.535; P B : changes from control in the daily urinary excretion of organic acid anions in relation to the changes from control in daily urinary net acid excretion for healthy adults given NH 4 Cl ( ), KHCO 3 ( ), or NaHCO 3 ( ); y = 1.0795 - 0.037856 x; r 2 = 0.543; P 1, 34, 37, 74.

The p K a2 for the dissociation of is 1.7. Accordingly, it has been suggested that the titration of organic anions between pH 2.7 and urinary pH will overestimate organic anions because of the titration of some, theoretically resulting in the titration of about 10% of urinary. A reevaluation of measured mean daily organic anion excretion rates for five subjects observed during control, methionine loading, and recovery ( 41 ) demonstrates that organic anion excretion rates do increase slightly above control rates as excretion rates increase during the administration of methionine and on the first recovery day when urinary SO 4 excretion rates remain above control. This relationship is shown in Fig. 8. On average, organic anion increases by 3.5 meq · day -1 · 100 meq. Extrapolation of that relationship to the wide normal range of daily rates of urinary excretion, which may range from 15 meq/day during the ingestion of a low-protein diet to 75 meq/day during the ingestion of a high-protein diet, would indicate that the titration could overestimate urinary excretion rates of organic anions by 1-3 meq/day.5 N: E* b8 H% `

Fig. 8. Group mean changes from control in daily urinary organic acid anion excretion (as titrated from pH = 2.7 to urinary pH and corrected for the titration of creatinine) compared with the group mean changes from control in urinary = excretion for 5 subjects during each of 5 days of methionine loading ( ) and 5 recovery days ( ); y = 1.067 0.03471 x; r 2 = 0.427; P = 0.029. Adapted from data in Ref. 41.

Urinary citrate is one of the components of urinary organic anions. Citrate excretion in humans is well known to fall with acid loading and rise with alkali loading. Some data illustrating these effects are presented in Fig. 9 ( 33, 34, 39 ). As shown in Fig. 9 A, daily urinary citrate excretion falls exponentially as net acid excretion rises. Among subjects being given KHCO 3 or NaHCO 3, citrate excretion averaged 15.3 meq/day when net acid averaged -1 meq/day. Among subjects eating only control diets, citrate excretion averaged 11.2 meq/day when net acid averaged 57 meq/day. Among subjects being given NH 4 Cl, citrate excretion averaged only 0.4 meq/day when net acid averaged 264 meq/day. As shown in Fig. 9 B, evaluation of the changes from control in urinary citrate excretion in relation to the changes from control in net acid excretion among subjects given KHCO 3, NaHCO 3, or NH 4 Cl demonstrates that urinary citrate excretion falls linearly as net acid excretion rises.

Fig. 9. A : urinary citrate excretion (meq/day) in relation to urinary net acid excretion (meq/day) among subjects eating constant diets alone ( ) or also taking KHCO 3 ( ), NaHCO 3 ( ), or NH 4 Cl ( ); y = 18.2 · 10 (0.00623 x ); r 2 = 0.822. B : changes from control of urinary citrate excretion (meq/day) in relation to the changes from control of net acid excretion among subjects given KHCO 3 ( ), NaHCO 3 ( ), or NH 4 Cl ( ); y = 1.52 - 0.0522 x; r 2 = 0.749; P 33, 34, 39.
- P1 q- @$ @% u2 |
It has also been suggested that the treatment of urine with excess solid Ca(OH) 2 to precipitate before organic acid titration may cause the loss of citrate, possibly by the precipitation of calcium citrate. To asses this issue, we measured the citrate concentrations in urine specimens from seven healthy subjects before and after that treatment. We found that citrate concentration decreased from 5.02 ± 3.07 to 0.87 ± 0.87 meq/l or by an average of -83%. This methodological error indicates the loss of citrate due to Ca(OH) 2 before organic acid titration would result in the underestimation of urinary anion excretion. When acid production exceeds 100 meq/day, urinary citrate falls progressively below 5 meq/day ( Fig. 9 A ) so that in such circumstances the loss of citrate as a consequence of the Ca(OH) 2 treatment before the determination of organic anions would cause an underestimation of the later value by 1-4 meq. Urinary citrate excretion rises when acid production decreases ( Fig. 9 A ). Urinary citrate excretion was measured before and during the administration of KHCO 3 and NaHCO 3 in 9 of the 10 subjects given those salts (Tables 2 and 3; Ref. 34 ) and rose on average 4.8 ± 2.2 meq/day ( P administration of KHCO 3 and rose 3.0 ± 3.0 meq/day ( P 3 (Lemann J, unpublished observations). If 80% of those increments were lost as a consequence of the Ca(OH) 2 treatment before determination of organic anions, the resulting decrease in the organic anion estimate would have been only 2-4 meq/day.0 X; F5 r; A3 f3 e* q+ j: \5 V
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Collectively, the overestimation of organic anions resulting from the titration of and the underestimation of organic anions resulting from the loss of citrate are thus small and nearly quantitatively equal, leading to the conclusion that there are no major or significant errors in evaluating by titration the contribution of urinary organic anions to acid production.

Net Intestinal Absorption of Actual or Potential Base or Acid Ingested in the Diet

Net intestinal absorption of dietary actual or potential is estimated by calculating the difference between measured dietary [(Na K Ca Mg) - (Cl 1.8 · PO 4 )] and measured fecal dietary [(Na K Ca Mg) - (Cl 1.8 · PO 4 )]. Some of the dietary anions are ingested as free unionized acids and would not be identified by this calculation but could be a source of acid production. However, if such acids were completely metabolized to CO 2 H 2 O, they would not contribute to fixed acid production. Furthermore, if they were absorbed and buffered and not metabolized and excreted into the urine, they would be identified as a source of acid production by their inclusion in the measurement of urinary organic anions and would equivalently increase the urinary excretion of net acid. These effects as well as the effects of other possible substances on the estimation of fixed acid production and net acid excretion are summarized in Table 4.
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Table 4. Sources, identification, and fate of organic acids and effects on acid production and net acid excretion
* V% h7 ?" T; F- [  x
To avoid the need to analyze diets and to analyze feces collected over periods of sufficient duration to ensure that the fecal collections are accurately timed, it has been proposed that the measurement of urinary [(Na    K    Ca 2 Mg) - (Cl - 1.8 · PO 4 )] would provide a more convenient estimate of the net intestinal absorption of actual or potential base or acid ingested in the diet ( 58 ). Figure 10 A compares the changes from control in urinary [(Na    K    Ca 2 Mg 2  ) - (Cl - 1.8 · PO 4 )] to the changes from control in the directly measured net intestinal absorption of unmeasured {diet - fecal [(Na    K    Ca 2 Mg 2  ) - (Cl - 1.8 · PO 4 )]} for the individual subjects summarized in Tables 1, 2, 3 ( 1, 34, 37, 74 ). The slope for the relationship shown in Fig. 10 A is 0.903 ± 0.013, a value that is significantly on urine overestimates the changes from control of measured absorption during the administration of NH 4 Cl and underestimates the changes from control of measured absorption during KHCO 3 and NaHCO 3 administration. During NH 4 Cl administration, the mean of the changes from control dietary unmeasured anion absorption based on urine overestimates the directly measured mean of the changes from control absorption by an average of 16 ± 15 meq/day ( P = 0.008), because the measurement based on urine does not take into account the ongoing negative Ca 2  balances ( Table 1 ). During KHCO 3 administration, the mean of the changes from control of dietary unmeasured anion absorption based on urine underestimates the mean of the changes from control of directly measured absorption by an average of -10 ± 10 meq/day ( P = 0.011), because the urine measurement does not take into account the ongoing positive K and Ca 2  balances ( Table 2 ). Similarly, during NaHCO 3 administration, the mean of the changes from control absorption based on urine underestimates directly measured mean of the changes from control absorption by an average of -11 ± 12 meq/day ( P = 0.015), because the urine measurement does not take into account the ongoing positive Na balances ( Table 3 ). Alternatively, the changes from control in charge balances become positive as the changes from control in acid balance become negative during the administration of KHCO 3 or NaHCO 3, whereas the changes from control in charge balances become negative as the changes from control become positive during the administration of NH 4 Cl (see below).

Fig. 10. A : changes from control in urine unmeasured anions or cations, estimated as [(Na    K    Ca 2 Mg 2  ) - (Cl - 1.8 · PO 4 )], compared with the changes from control in the measurements of intestinal absorption of unmeasured cations or anions, estimated as dietary - fecal [(Na    K    Ca 2 Mg 2  ) - (Cl - 1.8 · PO 4 )], during the administration of NH 4 Cl ( ), KHCO 3 ( ), or NaHCO 3 ( ); y = 5.1 (± 2.1 SE) 0.9033 (±0.0132 SE) x; r 2 = 0.993; P B : estimation of net intestinal absorption of cations or anions based on the analyses of urine [(Na    K    Ca 2 Mg 2  ) - (Cl 1.8 · PO 4 )] in relation to the direct measurements of intestinal absorption of unmeasured cations or anions, estimated as dietary minus fecal [(Na    K    Ca 2 Mg 2  ) - (Cl -  1.8 · PO 4 )], during control ( ) and the administration of NH 4 Cl ( ), KHCO 3 ( ), or NaHCO 3 ( ); y = - 3.1 (±3.2 SE) 0.987 (±0.0293 SE) x; r 2 = 0.95; P 1, 34, 37, 74.
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When Oh ( 58 ) suggested that the measurement of net intestinal absorption of potential base or acid could be indirectly assessed by measurement of urine [(Na    K    Ca 2 Mg 2  ) - (Cl - 1.8 · PO 4 )], that view was based on a reanalysis of earlier data ( 36, 39, 43, 45, 65 ) that are inadequate for such an evaluation. Except for the data for five subjects given NH 4 Cl ( 39 ), the other data were for studies utilizing liquid-formula diets ( 36, 43, 63 ) during which Mg 2  was not measured. Moreover, during the latter studies the duration of fecal collections was too short to adequately evaluate daily excretion rates of fecal Na  , K  , Ca 2 , Cl -, and PO 4 as well as Mg, had it been measured. Figure 10 B shows urinary [(Na    K    Ca 2 Mg 2  ) - (Cl - 1.8 · PO 4 )] in relation to directly measured net intestinal absorption of unmeasured anions {diet - fecal [(Na    K    Ca 2 Mg 2  ) - (Cl - 1.8 * PO 4 )]} using the absolute measurements during control and during either the administration of NH 4 Cl, KHCO 3, or NaHCO 3 for the studies summarized in Tables 1, 2, 3, as proposed by Oh ( 58 ). When the data are viewed in this manner, the slope for the relationship is 0.987 ± 0.029, a value that is not different from one. Thus the changes from control ( Fig. 10 A ) become undetectable, and the urinary and directly measured estimates of intestinal absorption of cations or anions do not differ. Consequently, during the administration of NH 4 Cl, that estimation of intestinal absorption of unmeasured anions based on urinary composition does not, in the absence of Ca 2  balance data, reveal that the increase in net acid excretion is less than the amount of potential acid fed, indicating H retention, nor that the increase in urinary Ca 2  is derived from body stores (bone), not enhanced intestinal Ca 2  absorption (see below). Similarly, the use of the measurement of urinary composition [(Na    K    Ca 2 Mg 2  ) - (Cl - 1.8 · PO 4 )] to estimate intestinal absorption of unmeasured anions during the administration of KHCO 3 or NaHCO 3 does not, in the absence of K or Na balance data, reveal that the decrease in net acid excretion is less than the amount of base ( ) administered nor the retention of K  , Ca 2 , or Na  , as previously described. Thus, unfortunately, urinary measurements and analyses alone do not adequately reflect important changes in acid-base and electrolyte balance with changes in dietary acid-base content.9 g2 y3 \# e9 K) g0 {$ Z

In summary, the components of fixed acid production appear to be adequately measurable without significant errors as the sum of urinary organic anions less the difference between the sum of inorganic cations and anions in the diet and their sum in the feces.

Components of Urinary Net Acid Excretion
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Ammonium. The measurements of urinary ammonium, whether by microdiffusion and titration ( 19 ) or an automated method ( 49 ), appear to be specific and sufficiently precise and thus not subject to significant error.
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The possibility has been suggested that urine may contain other cationic buffer(s) capable of carrying secreted H into the urine in addition to, perhaps histidine or a similar substance ( 60 ). On theoretical grounds, histidine is unlikely to serve in this manner. Whereas p K a for the dissociation of the iminazole group of histidine is 6.0, so that one-half of the histidine present at an average urine pH of 6.0 would buffer a proton, the average urinary excretion of histidine among adults is in the range of 0.5 to 1.0 mmol/day, so that histidine would carry only a very small amount of H secreted along the nephron into the final urine. Further evidence for the absence of significant quantities of unmeasured cation as well as unmeasured anion is summarized in Fig. 11. The mean sum of the directly measured urinary anions for a large number of studies ( 1, 34, 36, 37, 40, 42, 51; Lemann J, unpublished observations), estimated as Cl -       organic anions, averaged 298 meq/day. That value was not significantly different from the simultaneously measured sum of the urinary cations, estimated as Na    K    Ca 2 Mg 2    creatinine  , that averaged 303 meq/day. Furthermore, when the relationship between the sum of the anions for each subject was evaluated in relation to the sum of the cations for each subject, the slope of the relationship was not different from unity and the intercept was not different from zero. Additionally, 76 of these studies were carried out while the subjects ate control diets (mean urinary pH = 6.05 ± 0.44; mean urinary net acid excretio n = 49 ± 28 meq/day), 26 studies while the subjects received NH 4 Cl (mean urinary pH = 5.40 ± 0.13; mean urine net acid excretion = 272 ± 61 meq/day), and 20 studies while the subjects received KHCO 3 or Na HCO 3 (mean urinary pH = 6.67 ± 0.18; mean urinary net acid excretion = 6 ± 13 meq/day). Regardless of variations in fixed acid production and both net acid excretion rate and urinary pH, the data points are similarly distributed above and below the identity line. Thus experimental variation of acid-base balance does not reveal the urinary excretion of presently unrecognized or unidentified urinary cations or anions.
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Fig. 11. Comparison of the sums of the mean daily urinary excretion rates of anions, estimated as (meq/day) to the sums of the cations, estimated as (meq/day) during control ( ) and during the administration of NH 4 Cl ( ) or KHCO 3 or NaHCO 3 ( ). Mean sum of cations = 303 meq/day. Mean sum of anions = 298 meq/day. Mean = 5 ± 14 meq/day; y = -7.8 (±4.2) 1.009 (±013); r 2 = 0.980; P 1, 34, 36, 37, 40, 42, 51, Lemann J, unpublished observations.) \' f/ d5 N/ W
! S4 q8 m; [% F/ t  g
Titratable acid. Historically, titratable acid has most often been directly determined by titration of urine from urinary pH to blood pH, usually pH = 7.40. The titration measures the contribution of the major urinary buffers, phosphate and creatinine, to urinary proton excretion and, in addition, the contribution of urinary organic anions that are, effectively, not ionized at urinary pH. The latter fraction of urinary organic acids, that are titrated between urinary pH and blood pH, does not represent acid excretion because they are excreted as free acids, just as they were produced. Moreover, these free urinary organic acids are not a component of net acid excretion as they do not identify regeneration. Furthermore, it has been known for almost a century ( 21 ), and subsequently confirmed ( 35 ), that when urine contains increasingly large concentrations of ammonium, titratable acid, as measured by direct titration, is increasingly overestimated because of the titration of. Additionally, when urine contains increasingly large concentrations of Ca 2  together with, there is precipitation of CaHPO 4 /Ca 3 (PO 4 ) 2 (OH) 2 /Ca 10 (PO 4 ) 6 CO 3 from solution when the titration reaches a pH of 7.0, resulting in the simultaneous release of H that also causes overestimation of titratable acid. Accordingly, it would appear preferable to estimate titratable acidity by calculation using urinary pH, the urinary contents of PO 4, and a p K a2 = 6.8 for the reaction, and the urinary content of creatinine and a p K a = 4.97 for the reaction creatinine creatinine H ( 35 ).
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. The measurement of urinary excretion requires the collection of urine under a layer of mineral oil or toluene to minimize the loss of dissolved CO 2. The concentration of is then calculated from measurements of urinary pH and total CO 2 concentration, as employed in the studies reviewed in this report, or of urinary pH and P CO 2. Figure 12 illustrates the exponential relationships between urinary and urinary pH and between daily urinary excretion rates and pH for a large number of 24-h urinary measurements ( 34, 39, 40, Lemann J, unpublished observations). When urinary pH is in the range of 6.0-6.4 or less, are mostly 5 mmol/l, but daily urinary excretion rates may reach 10-15 mmol/day, quantities that significantly reduce renal net acid excretion. When urinary pH rises to levels above pH 6.4, urinary and excretion rates increase progressively. The urinary loss of becomes negligible when urine pH is 6.0.. I( H% T* g+ j$ y

Fig. 12. A : urinary (meq/l) calculated from manometric measurements of total CO 2 concentration and pH in relation to urinary pH; y = 6.5418 e - 8 · 10 (1.2215 x ); r 2 = 0.910. B : daily urinary excretion rates calculated from urinary and urinary volumes in relation to urinary pH. y = 1.7899 e - 7 · 10 (1.979 x ); r 2 = 0.804. Data are for 631 24-h urine collections from 42 adults studied in Refs. 34, 39, 40, and Lemann J, unpublished observations.
7 n2 |% ]" b/ U
To summarize, renal net acid excretion appears to be accurately measured, without significant errors, by the sum of urinary plus titratable acid as calculated from the urinary content of PO 4 and creatinine together with urinary pH minus urinary HCO 3.

CHARGE BALANCE IN RELATION TO ACID BALANCE. p3 s1 `9 B# ~1 w
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A fundamental inviolate law of physics and chemistry requires that compounds are electrically neutral. In other terms, the positive charges must always equal the negative charges so that the charges balance. With respect to human biology, charge balance must exist throughout the body, in the foods that are eaten and in the excreta, particularly the urine and the feces as well as in customarily unmeasured losses of sweat and of desquamated skin, hair, and nails. Furthermore, charge balance must prevail whether net external acid, mineral, and nitrogen balances are positive, especially during growth, or negative, either subtly during senescence or slowly advancing chronic diseases, more severely during acute illnesses, or during experimentally induced increases or decreases in acid production. The positive and negative charges must, necessarily, always balance.8 f9 u$ K+ M9 l% S

Figure 13 A summarizes the changes from control of charge balances in relation to the changes from control of acid balances for the subjects given NH 4 Cl ( Table 1 ), KHCO 3 ( Table 2 ), or NaHCO 3 ( Table 3 ). As shown in Fig. 13 B, negative Ca 2  balances primarily account for the negative charge balances during the administration of NH 4 Cl, whereas positive K    Ca 2  or positive Na balances primarily account for the positive charge balances during the administration of KHCO 3 or NaHCO 3, respectively. Accordingly, as shown in Fig. 13 C, charge balances become negative during the administration of acid, as Ca 2  balances become negative via urinary Ca 2  losses as acid balance become positive in relation to bone buffering of H  . Charge balances become positive during the administration of base as acid balances become more negative due to retention with K    Ca 2  during the administration of KHCO 3 or with Na during the administration of NaHCO 3.: W$ K+ Y: ^7 P( d! i7 }

Fig. 13. A : changes from control of charge balances in relation to the changes from control of acid balances among the subjects given NH 4 Cl (, Table 1 ); KHCO 3 (, Table 2 ); and NaHCO 3 (, Table 2 ); y = 1.0277 - 0.70891 x; r 2 = 0.716; P B : changes from control of Ca 2  balances among the subjects given NH 4 Cl (, Table 1 ); K    Ca 2  balances among the subjects given KHCO 3 (, Table 2 ); and Na balances among the subjects given NaHCO 3 (, Table 3 ) in relation to the changes from control in charge balances; y = 3.02 0.63048 x; r 2 = 0.662; P C : changes from control of Ca 2  balances among the subjects given NH 4 Cl (, Table 1 ), K    Ca 2  balance among the subjects given KHCO 3 (, Table 2 ); and Na balances among the subjects given NaHCO 3 (, Table 3 ) in relation to the changes from control of acid balances; y = 3.69 - 0.48378 x; r 2 = 0.554; P 1, 34, 37, 74.7 X$ C  x- r/ Z( j5 c! V+ P

RELATIONSHIP OF CA BALANCES TO ACID BALANCES IN HEALTHY HUMAN SUBJECTS
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Figure 14 shows the relationships between the changes from control of Ca 2  balances, net intestinal Ca 2  absorption, and urinary Ca 2  excretion, each in relation to the changes in acid balances for the individual subjects given NH 4 Cl (summarized in Table 1; 1, 37, 74 ); the subjects given KHCO 3 (summarized in Table 2; 34 ); and among the four additional subjects in whom acid production was increased by increasing dietary protein intake as egg white ( 1 ). As depicted in Fig. 14 A, the changes from control of Ca 2  balances became progressively more negative as the changes from control of acid balances became more positive. By contrast, the changes from control of Ca 2  balances became positive when the changes from control of acid balances became negative, although in this circumstance the increase was not progressive; rather, the changes of Ca 2  balances appear to have reached a modestly positive but stable level. No significant changes from control in net intestinal Ca 2  absorption were detected as the changes from control of acid balances varied, as shown in Fig. 14 B. As a consequence, the more negative Ca 2  balances that appeared as acid balances became more positive were only the result of the increases from control in urinary Ca 2  excretion, as shown in Fig. 14 C. When the changes from control in acid balances were negative during KHCO 3 administration, urinary Ca 2  excretion decreased but did not fall progressively.

Fig. 14. Individual changes from control of Ca 2  balances ( A ), net intestinal Ca 2  absorption ( B ), and urinary Ca 2  excretion ( C ) in relation to the changes from control of acid balances among 14 subjects given NH 4 Cl, summarized in Table 1 ( ), 10 subjects given KHCO 3, summarized in Table 2 ( ), together with additional data for 4 subjects given egg white ( ). Adapted from data in Refs. 1, 34, 37, 74.4 c/ X" g1 p2 f+ w

Among healthy adults eating a wide range of diets of different composition, the type and quantity of dietary protein are determinants of acid production related to the dietary content of sulfur-containing amino acids and their oxidation to sulfate. Some data illustrating these effects are summarized in Fig. 15. As shown in Fig. 15 A, daily urinary SO 4 excretion rates increase as dietary protein intake increases. Additionally, the magnitude of the increase in SO 4 excretion varies with the type of dietary protein. The increase in SO 4 excretion is greatest when dietary protein is provided as egg white, which contains large amounts of sulfur-containing amino acids; is less when a mixture of normal foods including meat, milk, and cereal are the dietary protein sources; and is least when a soy protein, which is deficient in methionine, is used ( 1, 20, 36, 37, 41, 45, 52, 65, 74, unpublished observations). As illustrated in Fig. 15 B, when acid production is increased by the administration of wheat gluten and lactalbumin ( 66 ), egg white ( 1 ) or methionine ( 41 ), the resulting increases from control in urinary net acid excretion are less than the increases in acid production, as estimated by the increases in urinary SO 4 excretion, the slope of the regression line being significantly excretion, in response to acid loads derived from protein is incomplete as it is for NH 4 Cl loads.! j: ^" s- ?# H& ]; [4 h$ d$ n

Fig. 15. A : relationships between urinary and dietary intake of protein among subjects fed diets providing protein as egg white ( y = 8.7 0.744 x; r 2 = 0.788); as mixed proteins contained in meat, milk, and cereals of normal whole-food diets ( y = -3.7 0.45 x; r 2 = 0.839); and as soy protein ( y = 21.9 0.12 x; r 2 = 0.238). Adapted from data in Refs. 1, 20, 36, 37, 41, 45, 52, 65, 74, and unpublished observations. B : relationship between the changes from control in urinary net acid excretion rate and the changes from control in urinary excretion rate when dietary sulfur-containing amino acid intake is increased by methionine ( ), egg white ( ), or wheat gluten and lactalbumin ( ); y = 11.95(±5.62 SE) 0.6932(±0.0.0661 SE) x; r 2 = 0.859; P 1, 41, 66.: s( b; Z# v, H' x! U
0 i0 F" x% G6 S& `. T7 N
The other dietary factor affecting acid production is the intake in fruits and vegetables of actual KHCO 3 or potential KHCO 3, as K-salts of organic acids (citrate, lactate, etc.), that are metabolized to. That process, by contributing base, reduces acid production. There apparently are no studies presently available that evaluate the separate effects of increased intakes of individual fruits or vegetables on K and net acid excretion. However, the effects of adding or removing KHCO 3 from the diet have been assessed. The results of such studies ( 34, 39, 40 ) are shown in Fig. 16. When KHCO 3 is added to the diets of subjects fed otherwise constant diets, the changes from control in daily urinary net acid excretion falls in inverse proportion to the increments from control of urinary K excretion. The opposite sequence occurs when KHCO 3 is removed from the diet. Additionally, the administration of KHCO 3 to postmenopausal women is accompanied by significantly less negative Ca 2  balances, a decrease in urinary hydroxyproline excretion, and an increase in serum osteocalcin concentrations, all reflecting a decrease in bone resorption ( 69 ). The interaction of the dietary intakes of protein and of K to determine net acid excretion is reviewed in detail elsewhere ( 23, 31, 55, 68 ).- c6 f1 W, e# ^
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Fig. 16. Changes from control in urinary net acid excretion rates in relation to the changes from control in urinary K excretion rate among healthy adults when KHCO 3 is added to ( ) or removed from ( ) the diet; y = -3.36 0.8806 x; r 2 = 0.941. Adapted from data in Refs. 34, 39, 40.

Measurements of urinary net acid excretion are more readily made and are more precise than are measurements of rates of acid production rates as well as acid balances. Moreover, net acid excretion rates vary directly with acid production, and urinary Ca 2  excretion rates vary inversely with acid balances and directly with net acid excretion rates.) e% J! R) k) [. j* g7 ?
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Thus it is informative to evaluate the changes from control of urinary Ca 2  excretion in relation to the changes in net acid excretion from control. Figure 17 illustrates such data for urinary Ca 2  excretion among healthy adults subjected to several differing alterations in diet composition that change net acid excretion ( 1, 33, 34, 36, 37, 39 - 42, 74 ). The changes from control of urinary Ca 2  excretion vary exponentially with the changes from control of net acid excretion. As the changes 0, the changes from control of urinary Ca 2  excretion increase progressively, reflectin
      【参考文献】
Adams ND, Gray RW, and Lemann J Jr. The calciuria of increased fixed acid production in humans: evidence against a role for parathyroid hormone and 1, 25-(OH) 2 -vitamin D. Calcif Tissue Int 27: 233-239, 1979.

3 g( X+ N7 m9 |2 o: p! ?
+ b( _& R  B  O7 ~) F5 \
Alpern RJ, Star R, and Seldin DW. Hepatic renal interrelations in acid-base regulation. Am J Physiol Renal Fluid Electrolyte Physiol 255: F807-F809, 1988.

Arnaud CD. Hyperparathyroidism and renal failure. Kidney Int 4: 89-95, 1973.) V3 X. F  Z3 C0 y1 u
3 y. l  j' z% l: `: `
! ~8 H+ W9 u& ^+ i0 V/ z7 D

Berglund F and Sorbo B. Turbidimetric analysis of inorganic sulfate in plasma and urine. Scand J Clin Lab Invest 12: 147-153, 1960.* g9 W, y0 x/ e% }) Y4 c* x) t
7 x$ G2 F0 a0 z# V7 _6 R& K" Y" K

" l# o# l2 ?! S- h
Breslau NE, McGuire JL, Zerwekh JE, and Pak CYC. The role of dietary sodium on renal excretion and intestinal absorption of calcium and on vitamin D metabolism. J Clin Endocrinol Metab 55: 369-373, 1982.

Brown JC, Packer RK, and Knepper MA. Role of organic anions in renal response to dietary acid and base loads. Am J Physiol Renal Fluid Electrolyte Physiol 257: F170-F176, 1989.
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9 e) T# m' f1 y; r
; `* {" c3 W4 D
Burckhardt G, Di Sole F, and Helmle-Kolb C. The Na /H exchanger gene family. J Nephrol 15, Suppl 5: S3-S21, 2002./ H; x; `! N. y6 N/ t4 z

8 {7 l6 g0 f( J3 c% v; z  ]

Bushinsky DA. Net calcium efflux from live bone during chronic metabolic, but not respiratory, acidosis. Am J Physiol Renal Fluid Electrolyte Physiol 256: F836-F842, 1989.
% N% o% h0 N. O# @# z7 D$ u( j  X

Bushinsky DA. Net proton influx into bone during metabolic, but not respiratory, acidosis. Am J Physiol Renal Fluid Electrolyte Physiol 254: F306-F310, 1988.

. V" J# l% V, \. M4 V6 T9 n1 n# m! q
Bushinsky DA and Frick KK. Effects of acid on bone. Curr Opin Nephrol Hypertens 9: 369-379, 2000.

0 x7 K( y) ?; {- }, s$ n
. k; m, H& r9 F6 y# O
Bushinsky DA, Gavrilov K, Chabala JM, Featherstone JD, and Levi-Setti R. Effect of metabolic acidosis on the potassium content of bone. J Bone Miner Res 12: 1664-1671, 1997.
; H; z5 C9 y# j1 O' d
5 B0 x& A/ m- h$ z- @

Bushinsky DA and Lechleider RJ. Mechanism of proton-induced bone calcium release: calcium carbonate dissolution. Am J Physiol Renal Fluid Electrolyte Physiol 252: F998-F1005, 1987.9 M$ z$ m- z" \. y8 S
4 j4 _8 a& f* Z4 k
% O3 ?; b- H0 D/ b/ Q

Bushinsky DA and Sessler NE. Critical role of bicarbonate in calcium release from bone. Am J Physiol Renal Fluid Electrolyte Physiol 263: F510-F515, 1992.
. b6 z7 z; L) w0 J! o  k2 [
( c7 |/ J1 `9 R8 ~+ U8 c

Caviston TL, Campbell WG, Wingo CS, and Cain BD. Molecular identification of the renal H  , K -ATPases. Semin Nephrol 19: 431-437, 1999.
" y) K/ H( I% S8 D7 ^" e7 C" a
; q( i! Y( i6 i% Q( x/ F6 E$ d) `

Chabala JM, Levi-Setti R, and Bushinsky DA. Alteration in surface ion composition of cultured bone during metabolic, but not respiratory, acidosis. Am J Physiol Renal Fluid Electrolyte Physiol 261: F76-F84, 1991.
) W0 ^9 N% d/ c7 V

Chan JCM. Acid-base, calcium, potassium and aldosterone metabolism in renal tubular acidosis. Nephron 21: 152-158, 1979." S; F2 \' g, i1 e/ V
* d5 }8 _7 S% L0 G, Q% w/ S

- G9 {" m( ]6 o0 Y" S% w
Cheema-Dhadli S, Lin SH, and Halperin ML. Mechanisms used to dispose of progressively increasing alkali loads in rats. Am J Physiol Renal Physiol 282: F1049-F1055, 2002.
6 J; D; Z% J4 r8 T
. m+ M9 P: ~* I. n1 G% z- s
: p# k7 a0 m  O# f. a
Cohen RM, Feldman GM, and Fernandez PC. The balance of acid, base and charge in health and disease. Kidney Int 52: 287-293, 1997., t$ x' I. K. J2 ]! P+ x/ B: E4 W
& s' P# Q8 G6 Q) s
; ~: d- B6 I* a, U+ w& H
3 w1 Q, W+ Y3 d, z* \0 o5 s% Q
Conway EJ. Microdifusion Analysis and Volumetric Error (rev. ed.). London: Lockwood, 1947.0 z9 p  x: g# q1 u2 x" f1 B4 ]
$ F7 j4 `- J6 h4 o& A1 y, Y

Dominguez JH, Gray RW, and Lemann J Jr. Dietary phosphate deprivation in women and men: effects on mineral and acid balances, parathyroid hormone and the metabolism of 25-OH-vitamin D. J Clin Endocrinol Metab 43: 1056-1068, 1976.6 I  L7 X$ |* }" v! Z2 R& m6 `
, v4 _% e. ^1 A5 _) @7 h9 G8 O

Folin O. The acidity of urine. Am J Physiol 9: 265-278, 1903.
! `" z0 f7 G, }! u

Fraser RM, Harrison M, and Ibbertson K. The rate of calcium turnover in bone. Measurement by a tracer test using stable strontium. Quart J Med 28: 85-111, 1960.0 B/ x* ~/ _/ `

1 J2 @: d0 y# _6 a2 }
/ a( y1 w8 V% ~% \& L4 F" d
Frasetto LA, Todd KM, Morris CM Jr, and Sebastian A. Estimation of net endogenous noncarbonic acid production in humans from diet potassium and protein contents. Am J Clin Nutr 68: 576-583, 1998.: B# L3 T! W3 l, v; w

Frick KK and Bushinsky DA. Metabolic acidosis stimulates RANKL RNA expression in bone through a cyclo-oxygenase-dependent mechanism. J Bone Miner Res 18: 1317-1325, 2003.( x4 H' r  S2 b0 w/ K
% X) n/ [7 v6 ?( f8 B( l. F
  u: s) D5 `$ o" s

Gauthier P, Simon EE, and Lemann J Jr Acidosis of chronic renal failure. In : Acid-Base and Electrolyte Disorders, edited by DuBose TD Jr. and Hamm LL. Philadelphia, PA: Saunders, 2002, p. 207-216." t1 J2 q; H+ O
0 t! X6 }* x; v/ H: n
+ g* G& b( L2 @1 y6 I/ A6 C
5 H6 a5 r6 [5 J( Z
Goodman AD, Lemann J Jr, Lennon EJ, and Relman AS. Production, excretion and net balance of fixed acid in patients with renal acidosis. J Clin Invest 44: 495-506, 1965.0 F, p  _3 R# |" ]* H& ]

% K3 L- C% a3 W3 f( ~
$ c, r! G+ X$ f( E8 h0 a; [8 u2 S) D
Hamm LL and Hering-Smith KS. Acid-base transport in the collecting duct. Semin Nephrol 13: 246-255, 1993.

9 a1 p0 `# O0 S6 e
Hunt JN. The influence of dietary sulfur on the urinary output of acid in man. Clin Sci (Colch) 15: 119-134, 1956.

$ v0 J2 ^: ^. ~- l7 f, f
Kaye M. Hypocalcemia after an acute phosphate load is secondary to reduced calcium efflux from bone: studies in patients with minimal renal function and varying parathyroid activity. J Am Soc Nephrol 6: 273-280, 1995.3 F5 {* R; Q9 R" Y1 _, U, E2 U

) q) c( Z1 Z+ B  f
Kildeberg P, Engel K, and Winters RW. Balance of acid in growing infants. Acta Paediatr Scand 58: 321-329, 1969.5 O; Y% P0 D7 X) H( A) g6 V& q
/ s' W# D- }+ g& l6 E2 L) i4 H
& z* F% y  v! k3 `) E( }7 f7 Z+ V

Lemann J Jr. The relationship between urinary calcium and net acid excretion as determined by dietary protein and potassium: a review. Nephron 81, Suppl 1: 18-25, 1999.: J9 k) K1 c" W& N
5 F& z! m. i8 V0 j+ j
4 v6 l; n# D( H/ R* j; l. T

Lemann J Jr, Adams ND, Wilz DR, and Brenes L. Acid and mineral balances and bone in hereditary proximal renal tubular acidosis. Kidney Int 58: 1267-1277, 2000.

# T1 e8 n. F& t& Z! S

Lemann J Jr, Gray RW, Maierhofer WJ, and Cheung HS. The importance of renal net acid excretion as a determinant of fasting urinary calcium excretion. Kidney Int 29: 743-746, 1986.
" g' ^2 g/ P0 I5 a0 ~, E

Lemann J Jr, Gray RW, and Pleuss JA. Potassium bicarbonate but not sodium bicarbonate reduces urinary calcium excretion and improves calcium balances in healthy men. Kidney Int 35: 688-695, 1989.
+ W* P8 M3 d! N2 j/ B( X
% H2 T9 F& v- T) k: |. L
- B8 u9 ~) Z' |6 |' z% D2 z. t) ^
Lemann J Jr and Lennon EJ. A potential error in the measurement of urinary titratable acid. J Lab Clin Med 67: 906-913, 1966.

$ g- ^9 A. D" Y( T
. ~* q) K! y& j  |
Lemann J Jr, Lennon EJ, Goodman AD, Litzow JR, and Relman AS. The net balance of acid in subjects given large loads of acid or alkali. J Clin Invest 44: 507-517, 1965.; c# T& p" h, ^; I9 {
. w$ T, }1 U8 _. U3 \: e

Lemann J Jr, Litzow JR, and Lennon EJ. The effects of chronic acid loads in normal man: further evidence for the participation of bone mineral in the defense against chronic metabolic acidosis. J Clin Invest 45: 1608-1614, 1966.; h# ?" L& w0 P9 T4 f' t

( ~; l% D5 J+ I" W% i( F! q; k
Lemann J Jr, Litzow JR, and Lennon EJ. Studies of the mechanism by which chronic metabolic acidosis augments urinary calcium excretion in man. J Clin Invest 47: 1318-1328, 1967.2 S) Y5 o/ H; D( d' K

$ \& L' R% H& I

Lemann J Jr, Pleuss JA, Gray RW, and Hoffman RG. Potassium administration reduces and potassium deprivation increases urinary calcium excretion in healthy adults. Kidney Int 39: 971-983, 1991 [Corrigenda. Kidney Int 40: August 1991, p. 388].

/ `3 ^2 I" \. ^* m

Lemann J Jr, Pleuss JA, Hornick L, and Hoffmann RG. Dietary NaCl-restriction prevents the calciuria of KCl-deprivation and blunts the calciuria of deprivation in healthy adults. Kidney Int 47: 899-906, 1995.: E( ^/ m: R. l0 q$ M

5 h* [$ Z% K  s
Lemann J Jr and Relman AS. The relation of sulfur metabolism to acid-base balance and electrolyte excretion; the effects of dlmethionine in normal man. J Clin Invest 38: 2215-2223, 1959.: Q: a0 \+ S/ O6 ]$ m# ?
/ H* U* f. Y$ z  f
& s- z% X+ j- X9 C$ c- X

Lennon EJ and Lemann J Jr. The effect of a potassium-deficient diet on the pattern of recovery from experimental metabolic acidosis. Clin Sci (Colch) 34: 365-378, 1968.

, M8 W7 {7 ]& X+ U; n: ?
# D( h3 W; G' T1 m8 x5 h- O- X
Lennon EJ, Lemann J Jr, and Litzow JR The effects of diet and stool composition on the net external acid balance of normal subjects. J Clin Invest 45: 1601-1607, 1966.6 Y! J9 N  A1 p7 T1 Z/ P1 @
' w( b% j4 x0 a0 J
* u) p7 t/ ~2 t1 o  Z5 f5 o6 J

Lennon EJ, Lemann J Jr, Piering WF, and Larson WS. The effect of glucose on urinary cation excretion during chronic extracellular volume expansion in normal man. J Clin Invest 53: 1424-1433, 1974.
5 A1 Z# p9 U9 U3 z8 n! [$ n
3 R7 I' L2 V5 ^! p! z2 R9 u9 i

Lennon EJ, Lemann J Jr, and Relman AS. The effect of phosphoproteins on acid balance in normal subjects. J Clin Invest 41: 637-645, 1962.
: |) |) \- \2 o8 R& M
! m% I8 Z. l7 h5 q) o
' @  B0 D1 j' d
Lichtwitz A, de Séze S, Parlier R, Hioco D, and Bordier P. L'hypocalciurie glomerulaire. Bull Soc Méd Hôp Paris 76: 98-119, 1960.

Litzow JR, Lemann J Jr, and Lennon EJ. The effects of treatment of acidosis on calcium balance in patients with chronic azotemic renal disease. J Clin Invest 46: 280-286, 1967.8 q% U) q. [# R* ]
0 Y; D# u( Q9 i; y

Liu SH and Chu HI. Studies of calcium and phosphorus metabolism with special reference to pathogenesis and effect of dydydrotachysterol (A.T. 10) and iron. Medicine 22: 103-161, 1943.5 W4 n( U- o# x( c- S5 Z( h" ?. y; y

3 V* z0 H, [+ z" N7 c. Y/ D' f7 H
Logsdon EE. A method for the determination of ammonia in biological material on the autoanalyzer. Ann NY Acad Sci 87: 801-807, 1960.
+ e9 y/ l2 \3 y
4 ~( x0 o+ w+ ~

Lutz J. Calcium balance and acid-base status of women as affected by increased protein intake and sodium bicarbonate ingestion. Am J Clin Nutr 39: 281-288, 1984.  m& D* `4 n$ E: c2 k" s7 F
: B1 I$ t; m3 R- I3 y- F  _6 Y* i

Maierhofer WJ, Gray RW, Cheung HS, and Lemann J Jr. Bone resorption stimulated by elevated serum 1,25-(OH) 2 -vitamin D concentrations in healthy men. Kidney Int 24: 555-560, 1983.( F9 @" O9 h& N. Q+ ]! ^- k

! @6 `# ~# p* u% k/ Y8 M+ r: D

Maierhofer WJ, Lemann J Jr, Gray RW, and Cheung HS. Dietary calcium and serum 1,25-(OH) 2 -vitamin D concentrations as determinants of calcium balance in healthy men. Kidney Int 26: 752-759, 1984.# F) U5 K" g7 e/ q$ T% `$ \

4 ]5 A5 f1 R1 n+ W1 V" U
McCarron DA, Rankin LI, Bennett WM, Krutzik S, McClung MR, and Luft FC. Urinary calcium excretion at extremes of sodium intake in normal man. Am J Nephrol 1: 84-90, 1981.2 M0 N: I( `4 {. W

- ~  t  s; H! ?) }+ w/ s/ V4 m

Mitch WE. Insights into abnormalities of chronic renal disease attributed to malnutrition. J Am Soc Nephrol 13, Suppl 1: S22-S27, 2002.% Q% C3 v! i8 s/ o2 g9 h

5 A! \, i* ?4 ]% t/ U
Morris, CM Jr, Frasetto LA, Schmidlin O, Forman A, and Sebastian A. Expression of osteoporosis as determined by diet-disordered electrolyte and acid base metabolism. In: Nutritional Aspects of Osteoporosis, edited by Burckhardt P, Dawson-Hughes B, and Heany RB. San Diego, CA: Academic, 2001, chapt. 31, p. 357-377.& C! a! A! U8 Z; \% f7 j6 l) `
; s5 p) C6 t+ N% `: o

Muldowney FP, Freaney R, and Moloney MF. Importance of dietary sodium in the hypercalciuria syndrome. Kidney Int 22: 292-296, 1972." N' M( p' p# [& l( `/ o3 a/ d
% W1 R& @0 z. `. E
8 F3 {. P7 U; Y

Nakhoul N and Hamm LL. Vacuolar H -ATPase in the kidney. J Nephrol 15, Suppl 5: S22-S31, 2002.
) A4 W& {" X( U6 `
! b( [- @! d4 V; v) h$ a$ P8 `7 S! c

Oh MS. A new method for estimating G-I absorption of alkali. Kidney Int 36: 915-917, 1989.

3 J$ N/ U9 K( m, E' p
$ T) C. u% y* |( s
Oh MS. Irrelevance of bone buffering to acid-base homeostasis in chronic metabolic acidosis. Nephron 39: 7-10, 1991.1 A' T- n- H2 n6 l  @, A# A
7 C. a; l% L7 g0 R

Oh MS and Carroll HJ. External balances of electrolytes and acids and bases. In: The Kidney (3rd ed.), edited by Seldin DR and Geibisch G. Philadelphia, PA: Lippincott Williams & Wilkins, 2000, p. 33-59.

Packer RK, Curry CA, and Brown KM. Urinary organic anion excretion in response to dietary acid and base loading. J Am Soc Nephrol 5: 1625-1629, 1995.8 F; f+ J) S$ ]

) o9 T4 X) e& J# v( d
( W8 o$ Y9 d0 {  D; \: K0 u
Pellegrino ED and Biltz RM. The composition of human bone in uremia. Observations on the reservoir functions of bone and demonstration of a labile fraction of bone carbonate. Medicine 44: 397-418, 1965.
% ?0 }! E5 F% t4 b% H

Peters JP and Van Slyke DD. Quantitative Clinical Chemistry. Methods. Baltimore, MD: Williams & Wilkins, 1932, vol. II, p. 896.

5 k! t$ T; Z6 x7 h
6 J% Z2 E0 w( u3 O1 T+ _2 t4 ^" k
Raisz LC. Bone resorption in tissue culture: factors influencing the response to parathyroid hormone. J Clin Invest 44: 103-116, 1965." W9 v5 z. i. y) F: w  y* c

Relman AS, Lennon EJ, and Lemann J Jr. Endogenous production of fixed acid and the measurement of the net balance of acid in normal subjects. J Clin Invest 40: 1621-1630, 1961.

% Q" A9 U# P7 z1 l2 s. |
Schuette SA, Zemel MB, and Linkswiler H. Studies on the mechanism of protein-induced hypercalciuria in older men and women. J Nutrition 110: 305-315, 1980.7 }" R$ _3 @' Y. i, \

Schwartz WB, Hall PM III, Hays RM, and Relman AS. On the mechanism of acidosis in chronic renal disease. J Clin Invest 38: 39-53, 1959.

' n; t5 w% o; @  j
6 J# ^/ H  x; v2 }9 k
Sebastian A, Frasetto LA, Meriam RL, Sellmeye DE, and Morris RC Jr. An evolutional persepctive on the acid-base effects of the diet. In: Acid-Base (2nd ed.), edited by Gennari FJ, Androgue H, Galla JH, and Madias N. New York: Dekker, 2003.
0 ]5 f+ ~4 g8 A1 r# G; h, b
) e. a! a  r& M! A* }

Sebastan A, Harris ST, Ottoway JH, Todd KM, and Morris RC Jr. Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate. New Engl J Med 330: 1776-1781, 1994.& p* q# q$ ^# c* Z3 K! S
, g  n" F/ v5 k
1 ~1 x2 _4 |9 _% U: V, x1 R9 r

Sellards AM. The relationship of the renal lesions of Asiatic cholera to the ordinary nephritides with especial reference to acidosis. Am J Tropical Dis 2: 104-117, 1914.

( {- {  z" @# `: s, ?& L1 u
1 F( x( f2 {8 @4 I8 {& \
Sherman HC and Gettler AO. The balance of acid-forming, and base-forming elements in food and its relation to ammonia metabolism. J Biol Chem 11: 323-338, 1912.

Slatopolsky E, Gray RW, Adams ND, Lewis J, Hruska K, Martin K, Klahr S, DeLuca H, and Lemann J Jr. Low serum levels of 1,25-(OH) 2 -D are not responsible for secondary hyperparathyroidism in early renal failure (Abstract). Kidney Int 14: 733, 1972.

/ K1 f. ^" C1 v0 ]5 ~! L: k: D8 [

Van Slyke DD and Palmer WW. Studies of acidosis. XVI. The titration of organic acids in urine. J Biol Chem 41: 567-585, 1920.6 X6 Y% B% u; _
" m$ k& N! C) v. D

Weber HP, Gray RW, Dominguez JH, and Lemann J Jr. The lack of effect of chronic metabolic acidosis on 25-OH-vitamin D metabolism and serum parathyroid hormone in humans. J Clin Endocrinol Metab 43: 1047-1055, 1976.

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