The Renal Response in Man to Acute Experimental Respiratory Alkalosis and Acidosis

E. S. Barker, … , J. R. Elkinton, J. K. Clark

J Clin Invest. 1957;36(4):515-529. https://doi.org/10.1172/JCI103449.

Research Article

Find the latest version: https://jci.me/103449/pdf THE RENAL RESPONSE IN MAN TO ACUTE EXPERIMENTAL RESPIRATORY ALKALOSIS AND ACIDOSIS 1 BY E. S. BARKER,2, 8 R. B. SINGER,4 J. R. ELKINTON,2 AND J. K. CLARK (From the Renal Section and Chemical Section of the Department of Medicine, The Department of Research Medicine, and the Department of Biochemistry, the University of Pennsylvania School of Medicine, Philadelphia, Pa.) (Submitted for publication August 7, 1956; accepted December 6, 1956)

The experimental results to be presented here proximately 30 minutes in 5 of the 6 experiments, and deal with the renal component of the multiple ef- for twice that period in the last experiment; 7.5 to 7.7 fects in man of acute experimental respiratory al- per cent CO, in air or oxygen was inhaled for 21 to 30 minutes. Measurements were continued in both types kalosis (hyperventilation) and acidosis (CO2 in- of experiments during subsequent recovery periods which halation). One aim of the experiments has been ended 97 to 145 minutes after onset of the stimulus (desig- to define an integrated picture of the total body nated time zero). Standard water loading was carried response to acute respiratory acid-base disturb- out before the experiments and continued throughout ances. A previous paper (1) contained a de- with water given in amounts equivalent to ex- creted. In a neutral or slightly al- scription of the effects observed in the same ex- kaline control urine was considered desirable to facilitate periments on the composition of plasma and red observation of renal effects. Accordingly, in experi- cells, and a quantitative estimate of the exchanges ments 1 to 5 inclusive, the subjects were given 42 gm. of ions and water between red cells, plasma, extra- NaHCO, (50 mEq.) by mouth at -95 to - 150 minutes. cellular fluids and a phase or phases outside the As a control, in the sixth experiment NaCl was sub- stituted for the NaHCO8 and this experiment is not in- chloride space ("intracellular"). In the present cluded in statistical analyses. Four additional control report consideration is given to the changes in experiments were done in which the NaHCO. load was renal excretion and hemodynamics and an attempt given, and observations were made for the usual ex- is made to define more clearly certain mechanisms perimental time (but with no respiratory stimulus) to involved. Reference should be made to the previ- indicate the effect of the loading procedure alone. Renal clearances were determined by standard tech- ous report (1) for data on the blood or plasma niques and chemical methods (4, 5), with bladder cathe- changes; only a few of these data are included terization and appropriate anaerobic collection of urine here when they are directly important to interpre- to prevent loss of CO,. Changes in glomerular filtra- tation and renal effects. The present findings were tion rate were estimated from changes in endogenous previously reported in abstract (2, 3). creatinine and effective renal plasma flow from p-aminohippurate (PAH) clearance.5 Following an equilibration period of at least 45 minutes urine was col- EXPERIMENTAL PROCEDURE AND CHEMICAL lected for 3 periods before, 1 to 4 periods during, and 3 METHODS to 4 periods after the application of the stimulus (hyper- Six normal male subjects actively hyperventilated and ventilation or CO, inhalation). six inhaled CO. as described in detail in the preceding Total CO, was determined in the anaerobically col- paper (1). Following control periods of 47 to 74 min- lected urine by the manometric method of Van Slyke and utes' duration, hyperventilation was carried out for ap- Sendroy (6), urine pH at 370 C by means of the photo- colorimetric method of Van Slyke, Weisiger, and Van 1 Laboratory facilities were aided by grants from the Slyke (7), sodium and potassium with a Barclay in- National Heart Institute of the United States Public ternal standard flame photometer (8), chloride by the Health Service (Grants H-405 and H-340), the Life In- surance Medical Research Fund, and the C. Mahlon 5Excretion of anionic PAH- in itself has some effect Kline Fund for Development in the Department of on urinary acid-base pattern. Administration was, how- Medicine. ever, at the same slow rate during both control and ex- 2Established Investigator of the American Heart As- penmental periods and there were no significant changes sociation. in PAH excretion during either type of respiratory stim- 8 In part during tenure of Post-doctorate Fellowship of ulus, when urinary acid-base changes were maximal. the National Institutes of Health, United States Public PAH could also form a buffer pair, but because it would Health Service. be a strong acid buffer (pK' = 3.83) (13), such an effect 4 Present address: 501 Boylston Street, Boston, Mass. must be very small. 515 516 E. S. BARKER, R. B. SINGER, J. R. ELKINTON, AND J. K. CLARK Volhard-Harvey method (9), ammonia by the method Changes in rate of urinary hydrogen ion excretion of Folin and Bell (10) using a Klett-Summerson photom- (A UVH+). For the purpose of this paper a quantitative eter, phosphate by the method of Lowry and Lopez (11), index of rate of H+ excretion is defined as the sum of and titratable acidity by titrating to pH 7.4. The bi- three components: NH4+ output plus titratable acid minus carbonate concentration was calculated from the total the HCO,- output. In the case of an alkaline urine the CO, content and pH of each urine specimen by use of rate is a negative quantity dependent chiefly on the bi- factors for CO, solubility and pK' in urine as functions carbonate output while for urine of neutral or slightly of urinary total cation concentration, derived from Send- acid pH values, all three terms are significant fractions roy, Seelig, and Van Slyke (12). of the total. Excretion of is equivalent in Methods of blood sampling and analyses were de- acid-base effect to the addition of hydrogen ion to the scribed in the previous paper (1). body and this method of calculating UVH+ eliminates the necessity of treating HCO; output as a separate factor. CALCULATIONS It is frequently not possible to distinguish, in the case of two separate body fluids, transfer of H+ in one direction Urinary electrolytes in microequivalents per minute from transfer of HCO, in the opposite direction. (i&Eq. per min.) are presented as excretion rates (UV) In order to assess the rate of renal acid-base compen- rather than clearances, thus permitting immediate com- sation to the respiratory disturbance it is desirable to parison of cation-anion equivalents. The cations deter- consider the difference between UVH+ observed and the mined were sodium, potassium, and ammonium; the UVH+ which would have been present at the control rate. anions were chloride, bicarbonate, and (in part) phos- The change in urinary hydrogen ion excretion is there- phate. fore determined, thus, Magnitude of acid-base disturbances (A HCO,-e). Un- der conditions termed a "steady state" the rate at which A V = A UVNH4t+ + A UVTA A UVHOC8- (2) carbon dioxide from cellular metabolism is added to the This consideration of A UVH+ rather than UVH+ in ab- equals the rate at which it is lost from solute terms also avoids arbitrary decisions on what con- the body, and there is no resulting acid-base effect on the stitutes a "neutral" urine as related to an extracellular extracellular fluid. When the pulmonary component is fluid pH about 7.4 and a usual dietary intake and metabo- disturbed, as by hyperventilation or CO2 inhalation, a net lism which, uncompensated, would produce a metabolic quantity of CO, is removed from or added to the extra- acidosis. cellular fluid. An acid-base effect is exerted by shifting It should be noted that under these experimental con- the following relationship toward either the left or right: ditions, once hyperventilation or CO. inhalation ceases the CO2 + H20 = H2CO3 . W + HCOI' (1) acid-base disturbance is rapidly corrected by respiratory adjustments. Therefore the most meaningful indications This disturbance may be expressed in terms of equivalents of urinary adjustments appear to be the peak A UVH+ as a change in HCO-, and this change is proposed for achieved and the cumulative change to the time the the purposes of this paper as an indication of the magni- respiratory stimulus was discontinued. tude of the acid-base disturbance. A HCOa- is defined as the change in total amount of bicarbonate in the extra- cellular fluid (plasma plus interstitial fluid) and in the RESULTS red cells. It is desirable to include the red cells since they The results are presented in Tables I A, I B, II are intimately related by the chloride shift to the acid- and III and in Figures 1 through 4 and were base changes of respiratory disturbances. The method of statistical methods. The determination, together with observed A HCO4-er in the evaluated by standard individual experiments, was given for a different pur- average control data are included in the figures pose in the portion of the work previously published (1). and the average changes, variability (standard From Equation 1 it is evident that a change in He error) and probability of chance occurrence are equivalent to that in HCO; must initially occur. How- shown below the graphic part of each figure. ever, at pH ranges compatible with life, free hydrogen ion concentration is always insignificant compared to the Changes in urinary excretion rates during respira- other ions. Accordingly, "buffering" mechanisms must tory alkalosis or acidosis as mentioned hereafter accept the hydrogen ion in one type of disturbances or are the mean change (from control rates) observed furnish it in the other.6 in the last urine collection period during hyper- ventilation or CO2 inhalation. 6 The role of such mechanisms was estimated quanti- tatively, and it was noted that participation of some phase of body fluid outside the blood and typical interstitial Respiratory alkalosis fluid appears in these particular experiments to account The magnitude of the acid-base disturbance was for about two-thirds of the buffering of the hydrogen ion - disturbance that would otherwise be present in the ex- indicated by an average A HCO37er of 135 mEq. tracellular fluid (M). observed at the end of the period of hyperventila- RENAL RESPONSE TO RESPIRATORY ALKALOSIS AND ACIDOSIS 517

Hyperventilation C02 inholation

+1.00 pH o 6.78

mean + 1.63 -0.16 -0.41 -t21 &S. *0.098 *0.251 *0.081 *0.096 I. p. '.001 ).5 .007 .09

+010 .E Titrotoble 30 0 .... 4.4 ...... acidity a, c pEq./min. a mean -13.0 +0.6 +61 +6.9 Q S.*. * 3.10 *3.65 *070 *0.80 P. .01 >.5 .001 .001

C +100 0) -105 2 H 01- ah -- excretion -too

-200 ,aEq. / min. mean -216 + 5 +77 +61 $.S. * 20.7 * 9.4 *24.0 * 14.2 p. .001 >.5 .03 .01

L Time before 0 after before 0 of ter

FIG. 1. AcuTE RESPIRATORY ALKALOSIS AND Acmosis: MEAN CHANGES IN URINARY PH AND THE EXCREnON OF TITRATABLE ACID AND HYDROGEN ION The mean for each group of changes from the individual mean control values is plotted for the end of the period of stimulus and the end of the experiment. The values for the mean change, its standard error, and the probability of chance occurrence are given below the curves. The mean changes that are sta- tistically significant (p = 0.05 or less) are represented by open circles. The abscissae represent time before, during, and after the stimulus. The mean of the control values is given on the horizontal axis. Hydrogen ion excretion is defined as the sum of outputs of ammonium plus titratable acidity minus bi- carbonate (see Equation 2 in text). tion. The rate of renal adjustment to the disturb- urine rose (mean = + 1.63 pH units) and titrata- ance by retaining H+ ion as compared to control ble acidity fell (- 13.0 IAEq. per min.), both re- H+ output ('& UVH+ by Equation 2) averaged 218 turning to the control values during the recovery 1AEq. per minute for the final period during hyper- period after hyperventilation. Bicarbonate ex- ventilation. During the 30 minutes of the stimulus cretion was markedly increased (+ 183 REq. per an average of 5.9 mEq. He had been retained in min.) and ammonium ion excretion decreased this way. During hyperventilation the pH of the (- 30 JuEq. per min.); each subsequently re- 518 E. S. BARKER, R. B. SINGER, J. R. ELKINTON, AND J. K. CLARK Hyperventilation CO2 inhalation

H +0 0 j2010 -.-......

* meean +183 A -62 -52 O .se. * 20.0 *8.5 t 24.3 * 17.8 p. <.001 >.5 .06 .04 £ 0 4oh._ U 04 ; 0 =+ame''''' mean -6. -11.0 +10.2 +16.4 0 .S.A *2.6 * 4.0 to% P. .02 .02 mean C (#AM./min.) -8.6 -10.4 +10.2 +12.8 .-

c Cl 164 0' c -14 0 Q mean +31 -188 +52 +14 S.P. A35.9 * 45.3 * 50.2 i 44.p 0 p. .43 .009 .36 >.5

Ti me: befoe 0 after before 0 ofter

FIG, 2. AcuTz REsPnAToRy ALKALOSIS AND AcIDosis: MEAN CHANGES IN TH-URINARY ExcRETIoN RATES OF ANIONS The data are presented as in Figure 1. Since phosphate was measured in only two of the hyperventilation experiments, it is shown with a dotted line and statistical analysis omitted. The symbol HPO4=> indicates phosphate both as HPO,- and H2PO47.

turned to control rates. Potassium excretion in- ficult to achieve a more severe acute experimental creased markedly (+ 183 pEq. per min.), while respiratory acidosis without undesirable side ef- neither sodium nor chloride excretion showed a fects. Changes in urinary findings were corre- statistically significant change. In the recovery spondingly smaller during CO2 inhalation than period excretion rates fell significantly below con- those observed during hyperventilation. A UVH+ trol for each of these ions (mean changes in rate averaged 77 /Eq. per minute and cumulative H+ per min.: Ki - 71 IAEq., Nat - 155 pEq., al- eliminated during the stimulus was 1.9 mEq. Uri- - 188 pEq.). nary pH fell (- 0.41 pH units) and titratable acidity increased (+ 6.1 IAEq. per min.). Bi- Respiratory acidosis carbonate excretion decreased (-62 IAEq. per It is clearly shown by comparison of the magni- min.) in spite of a considerable increase in filtered tude of the estimated acid-base disturbance load that resulted from the increased plasma con- (A HCO.r = 26 mEq.), or of plasma acid-base centration during CO2 inhalation. The change in data (1), that CO2 inhalation was a milder acid- bicarbonate reabsorption (+ 310 puEq. per min.) base disturbance than hyperventilation. It is dif- is accordingly significant (p = 0.03). Thus a RENAL RESPONSE TO RESPIRATORY ALKALOSIS AND ACIDOSIS 519 Hyperventilation Coe i holation

c + +201 .-.-12.2 IL--A _ NH4 oi -.. . 2 -201 mean -301. -2.2 +8. +2.1 M. S.. * 3.2 *5.3 *1.6 *1.7 P. ¢.X1 >.5 .006 .2S 04,

K + a. c ._0 -100 mean +183 -71 -70 -69 .S.. * 30. * 15.7 *22.3 *28. P- .004 .006 .04 .07 0''C C11 No

CP 0 40 mean +70 -155 +72 +55 S.*. *43.6 * 39.7 * 68o *48.0 p- .17 .01 .35 .32

Time: before after before 0 after FIG. 3. AcuTE RESPIATORY ALKOSIs AND Acmosis: MEAN CHANGES IN THE URINARY EXCRETION RATES OF CATIONS The data are presented as in Figure 1. real physiologic response in bicarbonate regula- PLASMA URINARY TUBULAR PLASMA tion is evident, although if changes in excretion HCO3 HCOj- pH pCOt EXCRETION rZ 0sofrP alone are considered the results just fail (p = 0.06) to show "statistical significance." Excre- RESPIRATORY r _ ACIDOSIS I I______tion of ammonium ion increased (+ 8.5 ,uEq. per min.) and that of potassium decreased (- 70 ptEq. per min.). Neither sodium nor chloride output RESPIRATORY ~ [ I ___ showed statistically significant change. Phosphate METABOLIC excretion was per (Na HCO3 ADMIN increased (+ 10 pEq. min.). ALKALOSIS t t T The small oral dose of sodium bicarbonate given preceding the respiratory acidosis experiments FIG. 4. CHANGES IN NAHCO. EXCRETION, REABSORP- established a "baseline" (a neutral or alkaline TION AND REL-AXvr ExtACLiULAR FLUI (PLASMA) urine) upon which the effect of the CO2 inhalation FACTORS IN AcuTz RESPIRATORY ALKALOSIS AND Acmo- SIS AND IN could be more readily determined. Effects of the bicarbonate dose are evident in differences be- Direction of change in response to the stimulus is in- dicated by the arrows. For each type of disturbance the tween the average control values in the respira- plasma HCO,- concentration changed in the same direc- tory alkalosis and acidosis experiments as shown tion as the PCO. The rate of of HCOJ (or in Figures 1 to 4. Four additional experiments HCOU load) also changed in this direction. 520 E. S. BARKER, R. B. SINGER, J. R. ELKINTON, AND J. K. CLARK

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TABLE II Respiratory alkalosis and acidosis: Cakulated extracelular acid-base disturbance (A HCOW )* and renal compensation (A UVH+)t at end of respiratory stimulus

A. Respiratory alkalosis B. Respiratory acidosis (hyperventilation) (COs inhalation) A UVH+ A UVn+ Expt. A HCOS,, Rate Cumulative Expt. A HCO,-., Rate Cumulative

AP4. %W &E. Per mE9. mix. mEg. Meg. min. mEg. 3 -141 -215 -5.0 1 +46 + 20 +0.64 4 -189 -226 -5.6 2 +12 +142 +4.3 5 -125 -212 -5.0 3 +38 + 23 +0.16 6 -152 -292 -6.7 4 + 2 + 97 +2.3 7 - 67 -146 -7.0 5 +31 +105 +2.2 Mean -135 -218 -5.9 Mean +26 + 77 +1.9 * A HCOs- indicates the total change in bicarbonate of the extracellular fluid (plasma plus interstitial fluid) and of the red cells 71). t A UVH+ indicates the change from control in urinary hydrogen ion excretion defined as the sum of ammonium plus titratable acid minus bicarbonate output (see Equation 2 in text). were done without any disturbance of respiration fective renal plasma flow was depressed from con- to evaluate the effect of the oral bicarbonate alone. trol at the end of these experiments, a change cor- These experiments also provided a control for relating with the excretion rate of sodium and chlo- the acidosis series with respect to the effects of the ride which were also significantly depressed at diurnal "tide" and the water loading procedure. this time. Glomerular filtration rate was also de- While slight apparent changes were present at the creased significantly at the end of the experi- times that would correspond to the respiratory ments, but also decreased somewhat during the stimulus, none of them was statistically significant. hyperventilation, at a time when excretion of so- Changes during the stimulus in the respiratory dium and chloride and effective plasma flow were acidosis series which are significantly different not significantly altered and if anything were a from the preceding control values also differ sig- little increased. Changes in urine flow were prob- nificantly from the slight alterations at correspond- ably more closely related to the water loading than ing times in the control series. This is true for all to the experimental procedure. of the variables except urinary pH and K' ex- cretion, the differences of which were not quite DISCUSSION significant at the 5 per cent level. During the Observation of renal acid-base adjustment of the ex- comparatively longer recovery portion re- periments, a tendency in the acidosis series to The responds promptly to primary disappearance of the effects of the oral bicarbonate spiratory alterations of acid-base equilibrium. on the "baseline" would be indistinguishable from The renal adjustment is not a simple correction persistence of acidification of the urine as a com- of the abnormality present, but may be considered pensatory mechanism to the respiratory disturb- as eventually producing an opposing "metabolic" ance. Accordingly, discussion of changes late in (as contrasted to "respiratory") disturbance recovery is limited to respiratory alkalosis. Re- which may be measured as a change in the rate of sults are not reported in detail for the control hydrogen ion excretion (A UVH+). An increase series. in UVH+ is equivalent to an increase in buffer base in the body. Singer and Hastings (14) suggested Renal hemodynamics and urinary volume certain practical advantages in focussing attention Measurements made of effective renal plasma on the buffer base concentration as a quantitative flow, glomerular filtration rate, and rates of urine index of the metabolic or non-respiratory factor flow are not reported in detail. Significant changes in acid-base equilibrium and pointed out that a were observed only with hyperventilation. Ef- pure respiratory disturbance (before various com- RENAL RESPONSE TO RESPIRATORY ALKALOSIS AND ACIDOSIS 523

TABLE III Respiratory alkalosis and acidosis: Renal fitration, reabsorption and excretion of bicarbonate

HCOs- Plasma Reabsorbed Urine Filt. Excr. flow GFR pH PCO2 HCOSt maq. maq. maq. mat. mew. per per per per L. Expt. Time* ml. per min. mm. Hg per L. mix. mix. turX jitL A. Respiratory alkalosis-hyperventilation 3 Ca 10.4 125 7.38 43 24.9 3.11 .010 3.10 24.82 S 5.0 109 7.62 19 19.2 2.09 .184 1.91 17.52 R 1.9 124 7.40 42 25.4 3.15 0 3.15 25.42 4 C 6.6 104 7.35 43 23.6 2.45 .001 2.45 23.58 S 6.2 108 7.65 15 16.5 1.78 .171 1.61 14.92 R 0.5 80 7.43 37 24.4 1.95 0 1.95 24.41 5 C 12.1 122 7.39 43 25.6 3.13 .006 3.12 25.58 S 5.3 87 7.63 19 20.2 1.76 .166 1.59 18.29 R 9.3 118 7.44 39 25.7 3.03 .005 3.03 25.67 6 C 7.5 109 7.39 43 25.3 2.76 .002 2.76 25.28 S 7.8 86 7.66 16 17.9 1.54 .248 1.29 15.00 R 3.8 96 7.43 37 24.2 2.32 0 2.32 24.20 7 C 1.6 132 7.30 44 24.9 3.29 .002 3.29 24.89 S 5.9 108 7.56 25 22.2 2.40 .117 2.28 21.13 R 3.9 109 7.39 42 24.9 2.71 0 2.71 24.89 B. Respiratory acidosis-COs inhalation 1 C 3.0 139 7.40 46 27.5 3.82 .061 3.76 27.05 S 17.2 151 7.35 54 29.9 4.52 .060 4.46 29.53 R 4.0 135 7.45 40 27.0 3.64 .010 3.64 26.97 2 C 18.2 126 7.46 40 27.8 3.50 .216 3.29 26.11 S 16.4 127 7.40 47 28.7 3.64 .123 3.52 27.71 R 17.2 131 7.43 40 26.5 3.47 .125 3.35 25.57 3 C 11.1 111 7.50 34 25.5 2.83 .084 2.75 24.76 S 10.6 114 7.37 48 27.1 3.09 .070 3.02 26.49 R 13.6 117 7.44 37 24.4 2.86 .111 2.74 23.42 4 C 16.7 115 7.44 41 26.7 3.07 .124 2.95 25.63 S 14.8 117 7.34 51 27.0 3.16 .044 3.12 26.68 R 15.8 116 7.48 34 24.6 2.85 .056 2.80 24.13 5 C 16.8 108 7.44 38 25.3 2.73 .115 2.62 24.26 S 13.1 107 7.33 52 26.5 2.84 .029 2.81 26.18 R 14.1 106 7.44 26 24.2 2.57 .053 2.51 23.68 6Q C 12.1 102 7.32 49 24.7 2.52 .012 2.51 24.60 S 15.3 110 7.26 62 27.1 2.98 .021 2.96 26.90 R 14.7 106 7.37 45 25.5 2.70 .013 2.69 25.38 * Time of individual periods and respiratory stimuli is given in Table I A and I B. C denotes average of the control periods. S denotes the last period during the respiratory stimulus. R denotes the last period for which complete data were available during recovery from the effects of the stimulus. t The plasma concentration of HCOs- given and used to calculate HCO,- filtered is that observed (often at the end of the period) rather than an interpolated value for mid-period. No correction is made for serum water or Donnan factor. t Experiment 6 during CO2 inhalation was done as a control, the urine being initially acid as explained in the text. pensations) causes no change in whole blood buf- monium excretion rather than by subtracting fer base. Fuller and MacLeod (15) have calcu- HCO - excretion as we do in calculating UVH+. lated the rate of "total Hi secretion" by adding The resulting index is quite different since our HCO.- reabsorption to titratable acidity plus am- index indicates the net effective acid-base adjust- 524 E. S. BARKER, R. B. SINGER, J. R. ELKINTON, AND J. K. CLARK ment accomplished by the over-all process of urine may be related to the fact that this type of meta- formation while theirs relates to the specific process bolic alkalosis (a simple excess of sodium and bi- of H' secretion by the tubular cells.7 carbonate) may be corrected by the renal excre- In respiratory alkalosis the characteristic re- tion of the ions present in excess. sponse is a decrease in He output, measured prin- The characteristic changes in respiratory aci- cipally by an increase of HCO.- with fixed cation dosis are the opposite of those described for re- in an alkaline urine (17-22). Associated with spiratory alkalosis (15, 17, 27). There is an in- this is a decrease in output of ammonia and titrata- crease in excretion rates of H+, titratable acid and ble acid. The resultant effect on total body fluids ammonia and a decrease in excretion of bicarbo- is a loss of buffer base, a further reduction of the nate with fixed cation, especially potassium. The already lowered HCO.- concentration and a re- urine becomes more acid. Since the acid-base turn of pH toward the normal range. The ac- disturbance of acute experimental CO2 inhalation companying predominant change in excretion of is considerably milder than that of hyperventila- "fixed" ion in the first half hour of acute experi- tion, the urinary changes are much smaller in ab- ments is increased Ke loss, rather than change in solute terms. Relative to the estimated acid-base Nat or Cl-. The duration of the experiments was disturbance (A HCO37er), however, the renal re- such that cumulative excretion while the stimulus sponse appears to be of the same order of magni- persisted had very little effect in changing extracel- tude. When the experiments were planned we lular or total body fluid buffer base. The renal postulated that it would be difficult to detect an in- compensation was therefore small compared to crease in UVH+ if the control urine were already the rapid sharing of the effects of the stimulus by acid. If the "basal" state of the kidney involves the various "buffer" mechanisms of the body pre- compensation for the tendency of the usual diet viously estimated in detail (1). Calculations based to produce a slight , it would on the data of other workers (23, 24) indicate scarcely be surprising that an acute respiratory that in more prolonged respiratory disturbances acidosis of mild degree should fail to bring about the major part of A HCOB-er may be compensated a further detectable increase in UVH+. We be- by cumulative urinary changes. lieve that this is the explanation for the lack of re- Renal compensation for acute respiratory alka- sponse in urinary acid-base factors noted by losis appears to be less efficient than that for acute Longson and Mills (28), and in urinary output metabolic alkalosis of the "electrolyte addition" of sodium, potassium and chloride by other work- type. In seven experiments in which we gave ers (29), during acute CO2 inhalation in man. rapid intravenous infusions of hypertonic sodium Similarly, in our Experiment 6, with NaCl sub- bicarbonate (25, 26) the total dose of bicarbonate stituted for the small pre-medication dose of given was of the same order of magnitude as the NaHCO, (and a control urine pH of 5.9) there A HCOB-er observed in respiratory alkalosis re- was no detectable change in UVH+. In spite of the ported here. Yet, within the same time, cumula- acid control , it seems probable that a re- tive A UVH+ averaged 19.6 mEq., indicating more nal tubular response could have been found in the than three times the comparable renal compensa- experiments of Longson and Mills (28) had tion during respiratory alkalosis.8 The difference changes in filtered load and reabsorption of bi- 7The use of the index proposed by these authors in- opposite algebraic sign. Under many circumstances, in- volves the assumption that the basic tubular process of cluding our own experimental conditions, a fairly satis- He secretion is involved in the entire quantity of HCO; factory approximation of A UVH+ can be derived from reabsorbed. This view is presently held by most workers, changes in excretion rates of the major fixed ions of as they point out, but it has also been recently challenged urine, as Nae + K+ -CG. Expression of the urinary ad- (16). justment in these alternative terms directs attention to 8For the bicarbonate administration studies renal ad- the effect on body fluid content of the major fixed ions, justment was calculated by an alternative approximation which may be convenient in consideration of acid-base rather than by A UVH+ as defined in this paper. From changes there. Use of this approximation during hyper- the laws of buffer action and electroneutrality it follows ventilation indicates an average change of + 222 /AEq. per that changes in UVW+ must be accompanied by an equal min., surprisingly close to the A UVH+ of -218 &Eq. per change in excretion of fixed cation minus fixed anion of min. by the other method. RENAL RESPONSE TO RESPIRATORY ALKALOSIS AND ACIDOSIS 525 carbonate been determined rather than in excre- nary rates of H' excretion persist they result in a tion alone. Data of Denton, Maxwell, McDonald, progressive increase in the degree of metabolic Munro, and Williams (30) during CO, inhala- acidosis or alkalosis which compensates in part tion in sheep indicate a marked rise in HCO8- for the respiratory disturbance. If the abnormal reabsorption, although, like Longson and Mills, level of PCO2 persists for periods much longer they observed no change in rate of urinary excre- than the duration of the present experiments, tion of HCO8-. In contrast to these negative eventually a point will be reached where the sec- urinary results other workers have found charac- ondary change in extracellular buffer base and teristic changes in urinary acid-base factors in other chemical changes have restored the pH to acute respiratory acidosis in dogs (15, 17, 31).9 a level of stability in or closer to the normal Where given, control urinary pH values in these range. In the ensuing "steady state" phase of the experiments were close to 7.0 or above. We ob- disturbance renal compensation ceases, in the served significant urinary changes in the five sub- sense that no further progressive change is pro- jects who were given the preceding oral dose of duced in buffer base of body fluids. Output of H+ NaHCO3, and in whom the control urine pH was then reflects the dietary intake and other physio- also approximately neutral. logical processes, as it does in a state of normal Other factors influence the characteristic renal respiration and PCO2. Finally, during the "re- response observed during respiratory acid-base covery" phase of a chronic respiratory acid-base disturbances. For example, the typical urinary disturbance, when PCO2 is returning toward nor- response to respiratory alkalosis is lacking in sub- mal, renal compensation serves to restore the ex- jects who are in a state of NaCl depletion (18, tracellular buffer base to normal. Changes are 20). It is to be expected that pre-existing disturb- therefore the precise opposite of those described ances of the circulation or fluid and electrolyte for the displacement phase: increase in UVH+ in balance, endocrine factors, and kidney disease may chronic respiratory alkalosis, and decrease in alter the characteristic changes that have been chronic respiratory acidosis. Thus in chronic defined. respiratory disturbances a temporary increase in In more prolonged respiratory disturbances the respiratory difficulty (equivalent to an addi- (for example of four or five days' duration) the tional "displacement" phase) will be accompanied ability of the kidney to compensate appears in- by reappearance of characteristic urinary changes; creased over that seen initially (32). Ammonium a temporary decrease in the respiratory difficulty excretion is likely to constitute a larger fraction (equivalent to a partial "recovery" phase) will of the renal response to more prolonged acidosis. cause the opposite type of urinary changes. Such Although NH4, output begins to rise within a few a sequence of events is quite otherwise to the situ- minutes of onset of acidosis, it does not approach ation found in metabolic acid-base disturbances. maximal rates for some hours or days (33). In a complete study of the displacement, stabiliza- tion, and recovery phases of ammonium chloride The urinary findings in different phases of re- acidosis, Sartorius, Roemmelt, and Pitts (33) spiratory acid-base disturbances have shown that the fundamental urinary re- sponse is It must be emphasized that the characteristic one of increased UVH+ in all of these combination of phases, despite serial differences in individual urinary changes described above constituents are is typical of the that also of importance. The only "displacement" phase of the same holds true for the opposite changes in meta- respiratory disturbance. While changes in uri- bolic alkalosis produced by electrolyte addition 9 A change is evident in the urinary data of Fuller and (25, 26). In acute respiratory experiments of MacLeod (15), although their calculation of "total He brief duration, such as those reported here, there secretion" did not change significantly because of a fall is no stabilization, and recovery is marked simply in glomerular filtration rate and therefore in bicarbonate by a return of the urinary acid-base output toward reabsorption. Their method of calculation showed that control levels.10 Superimposed on this return, 90 to 98 per cent of "total H+ secretion" was accounted for by bicarbonate reabsorption in respiratory disturb- 10Fuller and MacLeod (15) reported that urinary ef- ances. fects of respiratory acidosis were rapidly reversible, 526 E. S. BARKER, R. B. SINGER, J. R. ELKINTON, AND J. K. CLARK however, are the effects of other factors, such as the terms in which the data are reported. Exami- diurnal fluctuations (34), the wearing off of the nation of the directional changes given in Figure 4 slight metabolic alkalosis previously induced in will disclose that actually no disagreement exists. the subjects exposed to CO2 inhalation, persist- In our consideration of the over-all effect of the re- ence of slight differences in respiration, and late nal compensation on the body we stressed output effects of the imposed diuresis. (excretion). The figure illustrates that HCO- Once the "balance" between the existing re- excretion is decreased in respiratory acidosis and spiratory disturbance and the compensatory meta- increased in both respiratory and metabolic alka- bolic acidosis or alkalosis (produced by the kid- losis. Since both plasma PCO2 and plasma HCO3- ney) has been reached, there similarly may be concentration move in the opposite directions in nothing distinctive about the urinary excretion for respiratory alkalosis and metabolic alkalosis, it is individual ions except as related to the accompany- obvious that HCO,- excretion is better correlated ing composition of plasma. For example, in one with plasma pH. The three groups of investi- of our unpublished cases of chronic CO2 retention gators mentioned above, however, were interested with a plasma PCO2 of 120 mm. Hg, urinary primarily in the renal component due to active tu- chloride excretion exceeded 40 mEq. per day, bular processes. In studying the regulation of corresponding approximately to the intake, de- these processes they therefore logically stressed spite an extremely low plasma chloride concen- bicarbonate reabsorption. Figure 4 shows that tration of 74 mEq. per liter. It is not surprising the rate of HCO.- reabsorption is decreased in that the observer may erroneously conclude that respiratory alkalosis but increased in metabolic renal compensations are unimportant in such dis- alkalosis (electrolyte addition). Obviously, then, turbances if he directs his attention to the urinary reabsorption does not correlate well with plasma composition alone. Determination of clearance pH but could be correlated (in direction of rates or reabsorptive rates for acid-base factors change) with either plasma bicarbonate concen- will, however, disclose the presence of renal re- tration or PCO2.. In experiments carefully de- sponse. signed to test this point the groups mentioned above found in dogs that PCO2 was the more Regulation of renal bicarbonate excretion closely related. If our human data are used for Change in the rate of excretion of bicarbonate calculation of correlation coefficients it is found was the principal anionic response of the kidney that reabsorptive rate does correlate somewhat to the respiratory disturbances. In a preliminary better with PCO2 than with plasma bicarbonate report of the present work (3) it was stated that concentration. Thus, it should be apparent that bicarbonate excretion rate correlated better with conclusions about changes in bicarbonate excretion plasma pH than with other plasma factors such cannot be considered as simply the opposite of as PCO2 or HCO8- concentration. About the changes in reabsorption. If the filtered load same time Brazeau and Gilman (35), Dorman, changes sufficiently, rates of reabsorption and ex- Sullivan, and Pitts (36), and Relman, Etsten, and cretion may change simultaneously in the same Schwartz (37) each reported studies showing that direction, as happened in the bicarbonate admin- the reabsorption of bicarbonate was more closely istration experiments. related to the PCO2 of the blood than to pH or Renal excretion of potassium concentration of bicarbonate. Several recent ref- erences misconstrue our data and interpretations The predominance of changes in potassium ex- as in disagreement with the above groups. This cretion rate over those of sodium is a striking re- confusion has resulted from the failure to note sult since the sodium greatly exceeds potassium in the glomerular filtrate. At the end of either while hyperventilation produced lasting depression of hyperventilation or CO2 inhalation the significance titratable acid excretion and increase in bicarbonate ex- cretion. These findings in anesthetized dog experiments of change in potassium excretion compared to con- differ from the return to control values after hyperven- 11 Several workers have advanced the suggestion that tilation noted in humans in our studies and those of Stan- this effect may be mediated through changes in pH within bury and Thomson (20). the tubule cells (38, 39). RENAL RESPONSE TO RESPIRATORY ALKALOSIS AND ACIDOSIS 527 trol rate clearly exceeded that of the correspond- physiological process must be involved. This ing changes in sodium excretion. Indeed in the might concern mechanisms of electrolyte con- hyperventilation experiments even the absolute servation, hormonal factors, or renal hemodynamic magnitude of increased excretion was much greater changes. Renal plasma flow, but not glomerular (Ki + 183 pEq. per min., Nat + 70 pEq. per filtration rate, showed a positive correlation with min.). Since potassium is the predominant intra- sodium and chloride excretion in the hyperventila- cellular cation one might suggest that the release tion studies, while neither showed statistically of potassium from body cells as a compensatory significant changes with CO2 inhalation. mechanism to hyperventilation is involved. A close relation between potassium and buffering Excretion of other ions action of intracellular fluid has been prominently Phosphate excretion changes in two ways: as considered since the work of Darrow and his as- the rate of total phosphate output (in ,pM per sociates (40, 41) on certain potassium deficiency min.) and as the proportion as HPO4 or as states. The calculated "cellular exchanges" of H2PO0-. Changes in the buffer role of phosphate potassium in our experiments (1) would affect as a transporter of H' are included in the titratable extracellular concentration in the same direction acidity, of which phosphate is an important part. as do the changes in urinary excretion of potas- This may be expressed quantitatively by the dif- sium. Thus they are in the direction opposite to ference between the excretion rate of phosphate in that which would be required to explain the uri- pEq. per min. at the observed pH and the calcu- nary findings through a change in plasma potas- lated rate in IAEq. per min. that would occur if the sium concentration and secondarily in renal load. same number of FM were excreted at a pH of 7.4. The change in potassium excretion under these An increase in !LM per min. phosphate excretion circumstances might result from a reciprocal re- is regularly observed in respiratory acidosis (17, lationship between the tubular secretions of hy- 30, Table I B) and a decrease in respiratory alka- drogen ion and potassium as suggested by Ber- losis (17, 19, 20, Table I A), but these changes liner, Kennedy, and Orloff (42). are small relative to the other changes. Calcu- lated undetermined anion excretion showed only Sodium and chloride excretion. very small changes in both types of experiments. In extracellular fluid, changes in buffer base It is therefore unlikely that changes in excretion are approximately equal to changes in Na - Cl-. of sulfate, lactate or organic acids are quantita- Yet during the first half hour of respiratory acid- tively important compared to the other changes base disturbances those changes that did occur reported. in sodium and chloride excretion tended to be in SUMMARY the same direction. Therefore urinary Na - Cl- excretion showed little variation and change in Acute respiratory alkalosis by voluntary hy- fixed ions accompanying A UVH+ was associated perventilation for approximately thirty minutes, predominantly with K". The alterations in so- or acidosis by CO2 inhalation for a similar period, dium and chloride excretion were not directly cor- were induced in normal human subjects. The related with the continuation and withdrawal of urinary excretion of water and electrolytes and the experimental the acid-base pattern of the urine were observed stimuli, and were not necessarily in multiple clearance periods before, during and opposite in direction in the acidosis from the alka- after the respiratory stimuli. losis experiments. Our data therefore do not In respiratory alkalosis the kidney responded support the suggestion of Stanbury and Thomson promptly by retaining hydrogen ion compared to (20) that a fall in chloride output following acute control excretion, measured principally as an in- hyperventilation may represent a separate acid- crease in output of bicarbonate with potassium. base mechanism favoring conservation of "fixed Urinary pH rose and titratable acidity, ammonium acid" (Cl-). Since these parallel changes of so- ion, and phosphate excretion fell. The potassium dium and chloride excretion are not concerned effect appeared to be due to renal regulation rather with preserving acid-base homeostasis, some other than secondary to systemic intracellular adjust- 528 E. S. BARKER, R. B. SINGER, J. R. ELKINTON, AND J. K. CLARK ments. Chloride excretion tended to vary with respiratory alkalosis and acidosis on ionic trans- that of sodium, increasing slightly during hyper- fers in the total body fluids. J. Clin. Invest., 1955, ventilation and then falling far below the control 34, 1671. 2. Singer, R. B., Clark, J. K, Barker, E. S., and Elkin- level. ton, J. R., The effects of acute respiratory alka- Changes observed during respiratory acidosis losis on electrolyte excretion and renal hemody- were, for most variables, opposite in direction to namics in man. J. Clin. Invest., 1952, 31, 663. those noted during hyperventilation. They were 3. Elkinton, J. R., Singer, R. B., Barker, E. S., and smaller in magnitude since the experimental acute Clark, 3. K, Effects of acute respiratory acidosis CO2 was a on electrolyte excretion in man. Federation Proc., respiratory acidosis by inhalation 1953, 12, 38. milder acid-base disturbance than hyperventilation 4. Smith, H. W., Finkelstein, N., Aliminosa, L., Craw- as indicated by degree of plasma changes and ford, B., and Graber, M., The renal clearances of estimation of total extracellular acid-base disturb- substituted hippuric acid derivatives and other ance. Changes in excretion of sodium and chlo- aromatic acids in dog and man. J. Clin. Invest., ride were not as definite as those in other factors 1945, 24, 388. 5. Brod, J., and Sirota, J. H., The renal clearance of and were not always opposite in direction in the endogenous "creatinine" in man. 3. Clin. In- two types of experiment. At least part of this vest, 1948, 27, 645. change (when sodium and chloride change in the 6. Van Slyke, D. D., and Sendroy, J., Jr., Carbon diox- same direction) appears not immediately con- ide factors for the manometric blood gas appara- cerned with acid-base homeostasis. If the urine is tus. J. Biol. Chem., 1927, 73, 127. already acid the typical urinary changes may not 7. Van Slyke, D. D., Weisiger, J. R., and Van Slyke, K. K, Photometric measurement of urine pH. be evident during acute CO2 inhalation. J. Biol. Chem., 1949, 179, 757. Renal mechanisms account for only a small 8. Wallace, W. M., Holliday, M., Cushman, M., and part of the adjustments observed in experiments Elkinton, J. R., The application of the internal of short duration, but become more important with standard flame photometer to the analysis of bio- prolonged stimuli. The rate of renal acid-base logic material. J. Lab. & Clin. Med., 1951, 37, 621. compensation is considerably greater in acute ex- 9. Harvey, S. C., The quantitative determination of the chlorids in the urine. Arch. Int. Med., 1910, 6, tracellular alkalosis of similar magnitude induced 12. by sodium bicarbonate administration. The uri- 10. Folin, O., and Bell, R. D., Applications of a new re- nary patterns described are typical of the "displace- agent for the separation of ammonia. I. The colori- ment" phase of respiratory disturbances. With metric determination of ammonia in urine. J. chronic respiratory disturbances a stabilized situ- Biol. Chem., 1917, 29, 329. ation may be reached in which changes are not 11. Lowry, 0. H., and Lopez, J. A., The determination of inorganic phosphate in the presence of labile evident in rates of urinary output of hydrogen phosphate esters. J. Biol. Chem., 1946, 162, 421. ion except as compared to abnormalities of the 12. Sendroy, J., Jr., Seelig, S., and Van Slyke, D. D., acid-base composition of plasma; if "recovery" Studies of acidosis. XXII. 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