INTRODUCTION

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IN ATTEMPTS TO IMPROVE short-term, high-intensity exercise performance, NaHCO₃ loading has long been used (19). There is, however, little information regarding the time course and magnitude of acute renal responses in humans who have ingested an amount of NaHCO₃ that may be considered to be of ergogenic benefit (minimum of 0.3 g/kg body mass). The chronic responses to ingested or infused bicarbonate solutions in clinical situations have been extensively documented (2, 9, 14, 23, 30, 37). Few studies, however, have examined the effects of ingested KHCO₃ (37, 38), and there do not appear to be studies that have compared the early renal responses to large, equimolar doses of NaHCO₃ (sufficient to be of ergogenic benefit in humans, see Ref. 27) and KHCO₃ in humans. The physicochemical origins of plasma fluid and ion disturbances to ingested Na⁺ and K⁺ are expected to be different due to differences in their distribution and cellular transport in the intestine, kidneys, muscles, and other tissues (27). The bulk of Na⁺ absorbed from the intestinal tract remains in the extracellular fluids (ECFs) and, if not fully excreted, will result in an increased ECF volume (ECFV); on the other hand, K⁺ rapidly enters intracellular fluid compartments (27).

Although acute effects of KHCO₃ ingestion have not been extensively studied in humans (27, 37, 38), a generalized comparison of the responses to NaHCO₃ and KHCO₃ may be obtained from various studies. Renal responses to ingested or infused NaHCO₃ or NaCl and KHCO₃ or KCl include increased excretion of the cation and water and a decreased reabsorption of HCO₃ (2, 30, 37). There are, however, some notable differences among responses, depending on the cation (Na⁺ vs. K⁺) and the accompanying anion (Cl or HCO₃). NaHCO₃ loading, compared with NaCl loading, results in increased renal excretion of K⁺ (U_K⁺V) (14) and Na⁺ (U_Na⁺V) (22), whereas NaCl loading has no effect on U_K⁺V and Cl excretion (37). KCl loading, compared with NaCl loading, results in an increased glomerular filtration rate (GFR) (29), increased plasma aldosterone (30), and increased renal U_K⁺V and Cl excretion (24, 30, 37, 38). KCl loading is also associated with decreases in plasma volume (PV) and ECFV (3, 37). KHCO₃ loading, compared with KCl loading, results in a prolonged period of urine alkalinization associated with increased HCO₃ and Cl excretion and decreased excretion of NH⁺₄ (U_NH4⁺V) and titratable acid (TA) (37).

The main purposes of this paper are to describe and interpret the acute renal contribution to the correction of the volume, acid-base, and ion disturbances resulting from NaHCO₃ and KHCO₃ loading in humans. An aim of this paper is to integrate the renal responses with the vascular and skeletal muscle responses described previously in these subjects (27). The hypothesis was tested that the kidneys play an important role in the acute correction of fluid and ion disturbances resulting from NaHCO₃ and KHCO₃ ingestion. It was also hypothesized that in the NaHCO₃ trial, compared with the KHCO₃ trial, the kidneys would excrete excess water, solute, and base equivalents at a greater rate, resulting in a more rapid correction of the fluid and ion disturbance. This study also analyzed urine composition with respect to the independent variables of acid-base control in biological fluids, namely the strong ion difference (SID) concentration ([SID]), the total concentration of weak acids and bases ([A_tot]), and the concentration of CO₂ (28, 35). These three variables determine the measured concentrations of H⁺ and HCO₃ ([H⁺] and [HCO₃], respectively), and analysis of changes in these variables provides insight as to the mechanisms of acid-base control.

	METHODS

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Five healthy men (age 29 ± 2 yr, mass 80 ± 5 kg) participated in this study. Written informed consent was obtained after the procedures and potential risks were fully described to the subjects. The study was approved by the University's human ethics committee. A sixth subject was treated for hyperkalemia (see Ref. 27); this individual's data were excluded from the experiment.

Experimental protocol. In the 24-h period before each trial, subjects abstained from caffeine and alcohol. About 2 h before their arrival at the laboratory, the subjects ate a light meal (toasted bread and juice). All experiments began at ~8:00 AM and consisted of ~1 h of preparation time and 5 h of data collection.

Measurements and analysis. Arterial and venous blood sampling and analysis have been described (27). Arterial plasma aldosterone concentration was determined by RIA (Coat-A-Count TKAL1, Diagnostics Products, Los Angeles, CA).

Calculations. Urine [TAHCO₃] was calculated after Hills (20)

(1)

where EPBTV is the end-point base titration volume (liters), or the volume of base added to reach the desired pH end point; N_b and N_a are the normality of NaOH and HNO₃; V_u is the volume of urine titrated (liters); and V_a is the volume of HNO₃ added (liters) to remove the HCO₃. Net acid excretion was calculated as U_Na⁺4V + TAHCO₃ excretion (U_TAHCO3V).

(2)

(3)

7

11

11

14

7

Statistics. All values are means ± SE. Two-way ANOVA with repeated measures was used to analyze data with respect to time and treatment. When a significant F ratio was obtained, the Student-Newman-Keuls method was used to compare means. Statistical significance was accepted at P  0.05.

	RESULTS

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Plasma acid-base state, ions, and aldosterone. In the NaHCO₃ trial, plasma [H⁺] decreased by 7.8 ± 3 neq/l by 60 min, compared with a 5.9 ± 1.6 neq/l decrease in the KHCO₃ trial (Table 1). In both trials, plasma [H⁺] remained significantly lower than initial levels until the end of the experiment. Within 30 min of the beginning of NaHCO₃ ingestion, arterial plasma [HCO₃] increased and remained elevated until the end of the experiment. In the KHCO₃ trial, arterial plasma [HCO₃] increased above initial levels by 80 min and returned toward initial values by 120 min. Detailed responses and interpretation for both arterial and venous plasma have been published (27).

View larger version (34K): [in this window] [in a new window]   Fig. 1.   Plasma K+ concentration ([K+], solid symbols) and aldosterone concentration ([aldosterone], open symbols) before (up to 0 min), during (1-60 min), and after (61-270 min) ingestion of NaHCO3 (squares) or KHCO3 (circles) at a dose of 3.57 mmol/kg body mass. Hatched bar indicates 60-min period of HCO3 ingestion. Values are means ± SE; n = 5. * [K+] and aldosterone concentration significantly increased (P  0.05) compared with preingestion (20 and 0 min).  [K+] and [aldosterone] significantly greater in KHCO3 trial compared with NaHCO3 trial.

Water balance, GFR, and UFR. In the NaHCO₃ trial, there was no change in plasma volume during the ingestion period, and then plasma volume progressively increased, peaking at 7.5 ± 2.0% above initial levels at 210 min (Table 1). In contrast, in the KHCO₃ trial, ingestion of the solution resulted in an immediate and pronounced decrease in plasma volume that reached a nadir of 14.9 ± 1.7% below initial levels at 120 min; this was followed by a slow, significant partial recovery. Water balance summaries (Table 2) are based on estimates of complete intestinal absorption of the solutions by 270 min (see Ref. 27). The net increase in total body water in the NaHCO₃ trial was 555 ± 119 ml, compared with complete restoration of fluid balance (25 ± 83 ml) in the KHCO₃ trial. In the NaHCO₃ trial, the ECF compartment was in positive fluid balance, consistent with the retention of Na⁺ in the ECF compartment (27). In contrast, in the KHCO₃ trial, ECFV was estimated to be in negative balance by about 800 ml, consistent with a net movement of water into cells (27).

View larger version (36K): [in this window] [in a new window]   Fig. 2.   Glomerular filtration rate (GFR, A) and urine flow rate (B) before (up to 0 min), during (1-60 min), and after (61-270 min) ingestion of NaHCO3 () or KHCO3 () at a dose of 3.57 mmol/kg body mass. Urine flow rate in the KHCO3 trial was significantly (P  0.05) greater than in the NaHCO3 trial between 60 and 180 min. GFR in the KHCO3 trial was significantly (P  0.05) greater than in the NaHCO3 trial between 60 and 120 min. Hatched bars indicate the 60-min period of HCO3 ingestion. Values are means ± SE; n = 5. * Significantly different (P  0.05) from preingestion (20 and 0 min).  Significant difference between treatments.

Sodium. In the NaHCO₃ trial, 270 min after ingestion of 280 meq of Na⁺ was begun, 10% of ingested Na⁺ remained in the plasma compartment, 46% remained in the interstitial fluid compartment, and renal U_Na⁺V accounted for 30% of ingested Na⁺ (Table 3).

View larger version (42K): [in this window] [in a new window]   Fig. 3.   Renal ion excretions (UNa+V, A; UK+V, C; and UClV, E) and fractional excretions of Na+ (B), K+ (D), and Cl (F) before (0 min), during (1-60 min), and after (61-270 min) ingestion of NaHCO3 () or KHCO3 () at a dose of 3.57 mmol/kg body mass. Hatched bars indicate the 60-min period of HCO3 ingestion. Values are means ± SE; n = 5. * Significantly different (P 0.05) from preingestion (20 and 0 min).  Significant difference between treatments.

Potassium. In the NaHCO₃ trial, urine [K⁺] remained unchanged at ~104 ± 16 meq/l (not shown); excretion and the fractional excretion of K⁺ also did not change (Fig. 3, C and D). In contrast, in the KHCO₃ trial, urine [K⁺] increased rapidly from 77 ± 19 meq/l at 120 min to 241 ± 37 meq/l at 270 min. This increase was accompanied by a sixfold increase in U_K⁺V between 120 and 180 min (Fig. 3C) and an elevated K⁺ fractional excretion to 71 ± 12% of the filtered load in the last 30 min of the experiment (Fig. 3D). In the KHCO₃ trial, of the 281 meq of K⁺ ingested, the increase in ECF K⁺ content only accounted for 3%, whereas net K⁺ flux into tissues accounted for 37% (Table 3). Over the 270 min of the experiment, increased (above basal) U_K⁺V accounted for 26 ± 5% of the ingested K⁺ or 76% of the total cumulative U_K⁺V of 93 ± 16 meq (Table 3).

Chloride. In the NaHCO₃ trial, urine [Cl] decreased from 186 ± 16 meq/l at 0 min to 40 ± 7 meq/l at 120 min, with no change in Cl excretion or fractional excretion (Fig. 3, E and F). In contrast, in the KHCO₃ trial, urine [Cl] decreased by only ~80 meq/l, from 197 ± 29 meq/l at 0 min to 119 ± 12 meq/l at 80 min, returning to 173 ± 15 meq/l at 270 min. Despite the decrease in urine [Cl], the marked increases in UFR and GFR resulted in a significantly increased renal Cl excretion between 60 and 120 min (Fig. 3E). Cl fractional excretion did not change significantly in either trial, although Cl fractional excretion was greater in the KHCO₃ trial than in the NaHCO₃ trial between 80 and 270 min (Fig. 3F).

Calcium, P_i, and lactate. In both trials, urine [Ca²⁺] decreased two- to threefold from 3.6 ± 0.6 meq/l at 0 min to between 1 and 2 meq/l from 80 and 270 min, with no difference between trials. Renal Ca²⁺ excretion and Ca²⁺ fractional excretion did not change from initial values (3 ± 1 µeq/min and 1.7 ± 0.7%, respectively) in either trial, with no difference between treatments.

[SID], pH, and [H⁺]. In the NaHCO₃ trial, urine [SID] increased rapidly until 80 min and then increased slowly until the end of the experiment (Fig. 4A). In the KHCO₃ trial, urine [SID] increased gradually and was greater than initially between 180 and 270 min, but it remained 125-175 meq/l lower than in the NaHCO₃ trial.

View larger version (31K): [in this window] [in a new window]   Fig. 4.   Urine strong ion difference concentration ([SID]) (A), urine pH (B), and urine [H+] (C) before (0 min), during (1-60 min), and after (61-270 min) ingestion of NaHCO3 () or KHCO3 () at a dose of 3.57 mmol/kg body mass. Dashed line in C represents relationship between [H+] and [SID] in the absence of CO2 in the solution (37). Urine [SID] (A) in NaHCO3 trial was significantly (P 0.05) greater than in KHCO3 trial from 80 to 270 min. Monoexponential relationship between urine [SID] and urine [H+] is described by the equation [H+] = 59.168 ± 4.223exp([SID] × 0.0122 ± 0.00154) (r2 = 0.670; P < 0.001; n = 54). Hatched bars indicate the 60-min period of HCO3 ingestion. Values are means ± SE; n = 5. * Significantly different (P  0.05) from preingestion (20 and 0 min).  Significant difference between treatments.

TA, NH⁺₄, and net acid excretion. In both trials, there were large and rapid decreases in urine [TAHCO₃], U_TAHCO3V, and net acid excretion (Fig. 5). Urine [TAHCO₃] was significantly decreased from initial values by 80 min in both trials, with similar magnitudes and time course of change (Fig. 5A). The associated large and rapid decrease in U_TAHCO3V (Fig. 5B) represented a pronounced net excretion of titratable base between 80 and 180 min; there was no difference between trials.

View larger version (48K): [in this window] [in a new window]   Fig. 5.   Urine titratable acid minus HCO3 concentration ([TA  HCO3], A), renal TA  HCO3 excretion (UTAHCO3V; B), [NH+4] (C), NH+4 excretion (UNH+4 V; D), net acid concentration ([net acid], E), and net acid excretion (UNetAcidV; F) before (0 min), during (1-60 min), and after (61-270 min) ingestion of NaHCO3 () or KHCO3 () at a dose of 3.57 mmol/kg body mass. Negative values represent net base excretion. Hatched bars indicate 60-min period of HCO3 ingestion. Values are means ± SE; n = 5. * Significantly different (P  0.05) from preingestion (20 and 0 min).  Significant difference between treatments.

	DISCUSSION

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This appears to be the first study to compare the acute renal responses to large, equimolar doses (3.57 mmol/kg body mass) of ingested NaHCO₃ and KHCO₃ in humans and in mammals in general. The dose of NaHCO₃ used is sufficient to be of ergogenic benefit (19), but this dose of KHCO₃ was three to four times greater than that used in previous studies. Earlier studies focused on longer term responses and therefore missed the rapidity with which the kidneys respond to large fluid and electrolyte loads. Furthermore, the ingested Na⁺ and K⁺ resulted in marked differences in renal fluid and ion excretion, consistent with differences in intestinal Na⁺ and K⁺ absorption and differences in the distribution of these cations within body fluid compartments. It is noteworthy that, despite such differences, there was little difference in the renal excretion of base between the two treatments.

Urine acid-base status. Stewart (35) has mathematically described the physicochemical relationships among independent variables contributing to [H⁺] and [HCO₃] in physiological solutions. The independent determinants of [H⁺] and [HCO₃] in urine are the concentrations of strong (fully dissociated) ions represented by the [SID], the total concentration of weak acids and base represented by [A_tot], and PCO₂ (28, 35). In healthy, resting humans, the main determinants of [SID] are [Na⁺], [K⁺], [Cl], and [Ca²⁺]. The ions NH⁺₄ (pK 9.26), Mg²⁺, lactate (pK = 3.8), and SO²₄ play minor roles and largely cancel each other with respect to charge. In urine, the sum of the charges of strong ions, the [SID], thus provides an index of total acid excretion (8). The main determinants of [A_tot] are weak organic anions [the most abundant of which are citrate and some amino acids (8)] and P_i. [A_tot] is equivalent to the TA minus bicarbonate term of classical renal physiology. TA refers to the amount of secreted acid titrated by nonvolatile buffers, i.e., weak acids, in the tubular lumen and subsequently excreted as fixed acid. P_i with an apparent pK' = 6.8 accounts for most of the TA content of the urine (20, 35). In classical renal physiology, acid is excreted in the urine as NH⁺₄ and TA, so that net acid excretion equals NH⁺₄ + TA  HCO₃ excretion.

Water balance. Ingestion of NaHCO₃ resulted in a prolonged retention of fluid with total cumulative urine volume accounting for only 44% of ingested volume. An estimated 56% of ingested Na⁺ remained in the ECF compartment at the end of the experiment (Table 3) consistent with the nearly 1-liter expansion of ECFV (27). Increases in the delivery of Na⁺, K⁺, and base, i.e., increased osmolal clearance, to the distal tubules, without concomitant change in GFR, suggest that decreased tubular fluid reabsorption occurred in association with increased distal tubule Na⁺ delivery. The increase in UFR, however, was largely normalized 2 h after ingestion of the solution, indicating that there was a decreased sensitivity of the volume regulatory system or some feed-forward mechanism to prevent overadjustment in terms of water excretion and U_Na⁺V.

Na⁺ excretion. In the NaHCO₃ trial, the rapid and large increases in urine [Na⁺], U_Na⁺V, and fractional excretion accounted for 24% of ingested Na⁺, with the bulk of the Na⁺ remaining in the ECF compartment (27). The increase in U_Na⁺V can be attributed to the modest increases in GFR and increased Na⁺ delivery with decreased proximal tubule Na⁺ reabsorption. The primary mechanism for reduced proximal tubule Na⁺ reabsorption is through inhibition of proximal tubular Na⁺-K⁺-ATPase (2, 22), resulting in increased Na⁺ (and water) delivery to the distal tubules. There is also evidence that acute, transient elevations in dietary Na⁺ induce a natriuresis by a dopamine-mediated decrease in proximal tubule Na⁺-K⁺-ATPase activity (1).

K⁺ excretion. NaHCO₃ ingestion resulted in a small, although not statistically significant, increase in U_K⁺V, a tendency (Fig. 4) that was associated with a modest hypokalemia. A tendency (P < 0.1) toward increased U_K⁺V is consistent with increased delivery and net reabsorption of Na⁺, but not Cl, at the distal tubules; this tendency establishes a negative electrochemical gradient that favors modest increases in U_K⁺V (16, 39). Alkalosis has also been reported to stimulate Na⁺-K⁺-ATPase-mediated uptake of K⁺ into principal cells, resulting in enhanced K⁺ secretion (34). An increased delivery of HCO₃ to the distal nephron, in the presence of increased aldosterone, may also stimulate U_K⁺V during alkalosis (34).

Cl excretion. In the NaHCO₃ trial, as may be expected with increased HCO₃ delivery to the tubules, there occurred a 146 meq/l decrease in urine [Cl] and a modest increase (not statistically significant but appearing to be of physiological importance) in tubular Cl reabsorption (Fig. 3F). This response is similar to that seen occurring after acute lactate loading caused by high-intensity exercise (28); there appears to be a preferential reabsorption of Cl over HCO₃ and lactate. Overall, though, the NaHCO₃ load had only a small effect on renal Cl transport, similar to the absence of effect of NaCl loading on renal Cl excretion (17, 37).

Renal Ca²⁺ and P_i regulation. The ingestion of NaHCO₃ and KHCO₃ did not significantly affect renal Ca²⁺ and P_i excretion. In both trials, the decreases in urine [Ca²⁺] and [P_i] were due solely to the accompanying diuresis, consistent with the absence of significant change in plasma Ca²⁺ content (27).

Implications for exercise performance. NaHCO₃ loading is widely practiced in human and equine athletic competition as a means of reducing the severity of extra- and intracellular acidosis resulting from the performance of high-intensity exercise (19). Indeed, the dose of NaHCO₃ administered in the present study consistently results in performance-enhancing effects in humans (19). It is also noteworthy that NaHCO₃ loading resulted in an ~1-liter expansion of plasma volume that persisted in excess of 3 h after ingestion of the solution. This result indicates that the gastrointestinal tract may be used as a reservoir of readily available water and Na⁺ for maintaining extracellular volume during prolonged exercise. On the negative side, there was a twofold increase in UFR during the first 2 h after ingestion that may compromise exercise performance.

Conclusions. Renal responses to ingested NaHCO₃ and KHCO₃ solutions are more rapid and of greater magnitude than previously appreciated. In both trials, excreted Na⁺ and K⁺ accounted for 25-40% of the ingested ion and, in the KHCO₃ trial, cumulative urine volume over 270 min equaled the ingested volume load. In both trials, the GFR and UFR responses were transient and largely normalized by 210 min postingestion. The neural and cellular mechanisms for the rapid up- and downregulation of GFR and UFR in the NaHCO₃ trial are not well understood. The rapidity of the downregulation suggests either that, after some time, the regulatory systems become tolerant of the remaining fluid imbalance or that there may be feed-forward mechanisms for preventing overadjustment of fluid and Na⁺ balance. In the KHCO₃ compared with the NaHCO₃ trial, renal ion excretions occurred with greater rapidity, were of greater magnitude, and resulted in an increased osmotic clearance. In both trials, increases in base excretion were sustained until the end of the experimental period. It is also noteworthy that, although the plasma acid-base disturbances had markedly different physicochemical origins (27), the renal acid-base responses were similar with respect to excretion of base. The rapidity and magnitude with which the kidneys responded to the NaHCO₃ and KHCO₃ loading demonstrate their capacity, and physiological importance, for restoring body fluid homeostasis in the face of large, acute disturbances in water, ion, and acid-base balance.