The Renal Response in Man to Acute Experimental ...

The Renal Response in Man to Acute Experimental RespiratoryAlkalosis 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.

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THE RENALRESPONSEIN MANTO ACUTEEXPERIMENTALRESPIRATORYALKALOSIS ANDACIDOSIS 1

BY E. S. BARKER,2, 8 R. B. SINGER,4 J. R. ELKINTON,2 ANDJ. 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 ofPennsylvania School of Medicine, Philadelphia, Pa.)

(Submitted for publication August 7, 1956; accepted December 6, 1956)

The experimental results to be presented heredeal with the renal component of the multiple ef-fects in man of acute experimental respiratory al-kalosis (hyperventilation) and acidosis (CO2 in-halation). One aim of the experiments has beento define an integrated picture of the total bodyresponse to acute respiratory acid-base disturb-ances. A previous paper (1) contained a de-scription of the effects observed in the same ex-periments on the composition of plasma and redcells, and a quantitative estimate of the exchangesof ions and water between red cells, plasma, extra-cellular fluids and a phase or phases outside thechloride space ("intracellular"). In the presentreport consideration is given to the changes inrenal excretion and hemodynamics and an attemptis made to define more clearly certain mechanismsinvolved. Reference should be made to the previ-ous report (1) for data on the blood or plasmachanges; only a few of these data are includedhere when they are directly important to interpre-tation and renal effects. The present findings werepreviously reported in abstract (2, 3).

EXPERIMENTALPROCEDUREANDCHEMICAL

METHODS

Six normal male subjects actively hyperventilated andsix inhaled CO. as described in detail in the precedingpaper (1). Following control periods of 47 to 74 min-utes' duration, hyperventilation was carried out for ap-

1 Laboratory facilities were aided by grants from theNational Heart Institute of the United States PublicHealth Service (Grants H-405 and H-340), the Life In-surance Medical Research Fund, and the C. MahlonKline Fund for Development in the Department ofMedicine.

2Established Investigator of the American Heart As-sociation.

8 In part during tenure of Post-doctorate Fellowship ofthe National Institutes of Health, United States PublicHealth Service.

4 Present address: 501 Boylston Street, Boston, Mass.

proximately 30 minutes in 5 of the 6 experiments, andfor twice that period in the last experiment; 7.5 to 7.7per cent CO, in air or oxygen was inhaled for 21 to 30minutes. Measurements were continued in both typesof experiments during subsequent recovery periods whichended 97 to 145 minutes after onset of the stimulus (desig-nated time zero). Standard water loading was carriedout before the experiments and continued throughoutwith water given in amounts equivalent to urine ex-creted. In respiratory acidosis a neutral or slightly al-kaline control urine was considered desirable to facilitateobservation of renal effects. Accordingly, in experi-ments 1 to 5 inclusive, the subjects were given 42 gm.NaHCO, (50 mEq.) by mouth at -95 to - 150 minutes.As a control, in the sixth experiment NaCl was sub-stituted for the NaHCO8and this experiment is not in-cluded in statistical analyses. Four additional controlexperiments were done in which the NaHCO. load wasgiven, and observations were made for the usual ex-perimental time (but with no respiratory stimulus) toindicate the effect of the loading procedure alone.

Renal clearances were determined by standard tech-niques and chemical methods (4, 5), with bladder cathe-terization and appropriate anaerobic collection of urineto prevent loss of CO,. Changes in glomerular filtra-tion rate were estimated from changes in endogenouscreatinine clearance and effective renal plasma flow fromp-aminohippurate (PAH) clearance.5 Following anequilibration period of at least 45 minutes urine was col-lected for 3 periods before, 1 to 4 periods during, and 3to 4 periods after the application of the stimulus (hyper-ventilation or CO, inhalation).

Total CO, was determined in the anaerobically col-lected urine by the manometric method of Van Slyke andSendroy (6), urine pH at 370 C by means of the photo-colorimetric method of Van Slyke, Weisiger, and VanSlyke (7), sodium and potassium with a Barclay in-ternal standard flame photometer (8), chloride by the

5Excretion of anionic PAH- in itself has some effecton urinary acid-base pattern. Administration was, how-ever, at the same slow rate during both control and ex-penmental periods and there were no significant changesin PAHexcretion during either type of respiratory stim-ulus, when urinary acid-base changes were maximal.PAHcould also form a buffer pair, but because it wouldbe a strong acid buffer (pK' = 3.83) (13), such an effectmust be very small.

515

E. S. BARKER, R. B. SINGER, J. R. ELKINTON, AND J. K. CLARK

Volhard-Harvey method (9), ammonia by the methodof Folin and Bell (10) using a Klett-Summerson photom-eter, phosphate by the method of Lowry and Lopez (11),and titratable acidity by titrating to pH 7.4. The bi-carbonate concentration was calculated from the totalCO, content and pH of each urine specimen by use offactors for CO, solubility and pK' in urine as functionsof urinary total cation concentration, derived from Send-roy, Seelig, and Van Slyke (12).

Methods of blood sampling and analyses were de-scribed in the previous paper (1).

CALCULATIONS

Urinary electrolytes in microequivalents per minute(i&Eq. per min.) are presented as excretion rates (UV)rather than clearances, thus permitting immediate com-parison of cation-anion equivalents. The cations deter-mined were sodium, potassium, and ammonium; theanions were chloride, bicarbonate, and (in part) phos-phate.

Magnitude of acid-base disturbances (A HCO,-e). Un-der conditions termed a "steady state" the rate at whichcarbon dioxide from cellular metabolism is added to theextracellular fluid equals the rate at which it is lost fromthe body, and there is no resulting acid-base effect on theextracellular fluid. When the pulmonary component isdisturbed, as by hyperventilation or CO2 inhalation, a netquantity of CO, is removed from or added to the extra-cellular fluid. An acid-base effect is exerted by shiftingthe following relationship toward either the left or right:

CO2+ H20 = H2CO3 . W+ HCOI' (1)

This disturbance may be expressed in terms of equivalentsas a change in HCO-, and this change is proposed forthe purposes of this paper as an indication of the magni-tude of the acid-base disturbance. A HCOa- is definedas the change in total amount of bicarbonate in the extra-cellular fluid (plasma plus interstitial fluid) and in thered cells. It is desirable to include the red cells since theyare intimately related by the chloride shift to the acid-base changes of respiratory disturbances. The method ofdetermination, together with observed A HCO4-er in theindividual experiments, was given for a different pur-pose in the portion of the work previously published (1).

From Equation 1 it is evident that a change in Heequivalent to that in HCO; must initially occur. How-ever, at pH ranges compatible with life, free hydrogenion concentration is always insignificant compared to theother ions. Accordingly, "buffering" mechanisms mustaccept the hydrogen ion in one type of disturbances orfurnish it in the other.6

6 The role of such mechanisms was estimated quanti-tatively, and it was noted that participation of some phaseof body fluid outside the blood and typical interstitialfluid appears in these particular experiments to accountfor about two-thirds of the buffering of the hydrogen iondisturbance that would otherwise be present in the ex-tracellular fluid (M).

Changes in rate of urinary hydrogen ion excretion(A UVH+). For the purpose of this paper a quantitativeindex of rate of H+ excretion is defined as the sum ofthree components: NH4+ output plus titratable acid minusthe HCO,- output. In the case of an alkaline urine therate is a negative quantity dependent chiefly on the bi-carbonate output while for urine of neutral or slightlyacid pH values, all three terms are significant fractionsof the total. Excretion of bicarbonate is equivalent inacid-base effect to the addition of hydrogen ion to thebody and this method of calculating UVH+eliminates thenecessity of treating HCO; output as a separate factor.It is frequently not possible to distinguish, in the case oftwo separate body fluids, transfer of H+ in one directionfrom transfer of HCO, in the opposite direction.

In order to assess the rate of renal acid-base compen-sation to the respiratory disturbance it is desirable toconsider the difference between UVH+ observed and theUVH+which would have been present at the control rate.The change in urinary hydrogen ion excretion is there-fore determined, thus,

A V = A UVNH4t+ + A UVTA A UVHOC8- (2)

This consideration of A UVH+ rather than UVH+ in ab-solute terms also avoids arbitrary decisions on what con-stitutes a "neutral" urine as related to an extracellularfluid pH about 7.4 and a usual dietary intake and metabo-lism which, uncompensated, would produce a metabolicacidosis.

It should be noted that under these experimental con-ditions, once hyperventilation or CO. inhalation ceases theacid-base disturbance is rapidly corrected by respiratoryadjustments. Therefore the most meaningful indicationsof urinary adjustments appear to be the peak AUVH+achieved and the cumulative change to the time therespiratory stimulus was discontinued.

RESULTS

The results are presented in Tables I A, I B, IIand III and in Figures 1 through 4 and wereevaluated by standard statistical methods. Theaverage control data are included in the figuresand the average changes, variability (standarderror) and probability of chance occurrence areshown below the graphic part of each figure.Changes in urinary excretion rates during respira-tory alkalosis or acidosis as mentioned hereafterare the mean change (from control rates) observedin the last urine collection period during hyper-ventilation or CO2 inhalation.

Respiratory alkalosisThe magnitude of the acid-base disturbance was

indicated by an average A HCO37er of - 135 mEq.observed at the end of the period of hyperventila-

516

RENAL RESPONSETO RESPIRATORYALKALOSIS AND ACIDOSIS

Hyperventilation

+1.00

opH

mean&S.p.

+ 1.63 -0.16*0.098 *0.251

'.001 ).5

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6.78

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+010

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.01 >.5

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mean$.S.p.

-216 + 5* 20.7 * 9.4

.001 >.5

-105 ah --

+77 +61*24.0 * 14.2

.03 .01

Lbefore 0 after before 0 of ter

FIG. 1. AcuTE RESPIRATORY ALKALOSIS AND Acmosis: MEAN CHANGESIN URINARY PH AND THE EXCREnONOF TITRATABLE ACID AND HYDROGENION

The mean for each group of changes from the individual mean control valuesis 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 ofchance occurrence are given below the curves. The mean changes that are sta-tistically significant (p = 0.05 or less) are represented by open circles. Theabscissae represent time before, during, and after the stimulus. The mean ofthe control values is given on the horizontal axis. Hydrogen ion excretion isdefined 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-ance by retaining H+ ion as compared to controlH+ output ('& UVH+by Equation 2) averaged 2181AEq. per minute for the final period during hyper-

ventilation. During the 30 minutes of the stimulusan average of 5.9 mEq. He had been retained inthis way. During hyperventilation the pH of the

urine rose (mean = + 1.63 pH units) and titrata-ble acidity fell (- 13.0 IAEq. per min.), both re-

turning to the control values during the recoveryperiod after hyperventilation. Bicarbonate ex-

cretion was markedly increased (+ 183 REq. permin.) and ammonium ion excretion decreased(- 30 JuEq. per min.); each subsequently re-

I.

a,caQ

pEq./min.meanS.*.P.

Time

517


Hyperventilation

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p. <.001 >.5

04 ; 0 =+ame'''''mean -6. -11.0.S.A

P.mean(#AM./min.) -8.6 -10.4

CO2inhalation

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164

-14

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.43

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.009

bef oe 0 after

FIG, 2. AcuTz REsPnAToRy ALKALOSIS AND AcIDosis: MEANCHANGESIN

TH- URINARY ExcRETIoN RATES OF ANIONSThe 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 andstatistical analysis omitted. The symbol HPO4=> indicates phosphate both as

HPO,- and H2PO47.

turned to control rates. Potassium excretion in-creased markedly (+ 183 pEq. per min.), whileneither sodium nor chloride excretion showed a

statistically significant change. In the recovery

period excretion rates fell significantly below con-

trol for each of these ions (mean changes in rateper min.: Ki - 71 IAEq., Nat - 155 pEq., al-- 188 pEq.).

Respiratory acidosisIt is clearly shown by comparison of the magni-

tude of the estimated acid-base disturbance(A HCO.r = 26 mEq.), or of plasma acid-basedata (1), that CO2 inhalation was a milder acid-base disturbance than hyperventilation. It is dif-

ficult to achieve a more severe acute experimentalrespiratory acidosis without undesirable side ef-fects. Changes in urinary findings were corre-

spondingly smaller during CO2 inhalation thanthose observed during hyperventilation. A UVH+averaged 77 /Eq. per minute and cumulative H+eliminated during the stimulus was 1.9 mEq. Uri-nary pH fell (- 0.41 pH units) and titratableacidity increased (+ 6.1 IAEq. per min.). Bi-carbonate excretion decreased (-62 IAEq. per

min.) in spite of a considerable increase in filteredload that resulted from the increased plasma con-

centration during CO2 inhalation. The change in

bicarbonate reabsorption (+ 310 puEq. per min.)is accordingly significant (p = 0.03). Thus a

518

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Hyperventilation

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.004 .006 .04 .07

+70 -155 +72 +55*43.6 * 39.7 * 68o *48.0

.17 .01 .35 .32

before after before 0 after

FIG. 3. AcuTE RESPIATORY ALKOSIs AND Acmosis: MEANCHANGESIN THE URINARY EXCRETION RATES OF CATIONS

The data are presented as in Figure 1.

real physiologic response in bicarbonate regula-tion is evident, although if changes in excretionalone are considered the results just fail (p =

0.06) to show "statistical significance." Excre-tion of ammonium ion increased (+ 8.5 ,uEq. permin.) and that of potassium decreased (- 70 ptEq.per min.). Neither sodium nor chloride outputshowed statistically significant change. Phosphateexcretion was increased (+ 10 pEq. per min.).

The small oral dose of sodium bicarbonate givenpreceding the respiratory acidosis experimentsestablished a "baseline" (a neutral or alkalineurine) upon which the effect of the CO2 inhalationcould be more readily determined. Effects of thebicarbonate dose are evident in differences be-tween the average control values in the respira-tory alkalosis and acidosis experiments as shownin Figures 1 to 4. Four additional experiments

PLASMA

pH

URINARYHCO3

EXCRETION

TUBULARHCOj-

rZ 0sofrP

PLASMA

pCOt

RESPIRATORY r _ACIDOSIS I I______

RESPIRATORY ~ [ I ___

METABOLIC

(Na HCO3ADMINALKALOSIS

t t T

FIG. 4. CHANGESIN NAHCO. EXCRETION, REABSORP-TION AND REL-AXvr ExtACLiULAR FLUI (PLASMA)FACTORS IN AcuTz RESPIRATORYALKALOSIS AND Acmo-SIS AND IN METABoLIc ALKALOSIS

Direction of change in response to the stimulus is in-

dicated by the arrows. For each type of disturbance theplasma HCO,- concentration changed in the same direc-tion as the PCO. The rate of filtration of HCOJ (orHCOU load) also changed in this direction.

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TABLE II

Respiratory alkalosis and acidosis: Cakulated extracelular acid-base disturbance (A HCOW)* andrenal 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. PermE9. mix. mEg. Meg. min. mEg.

3 -141 -215 -5.0 1 +46 + 20 +0.644 -189 -226 -5.6 2 +12 +142 +4.35 -125 -212 -5.0 3 +38 + 23 +0.166 -152 -292 -6.7 4 + 2 + 97 +2.37 - 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) andof the red cells 71).

t A UVH+ indicates the change from control in urinary hydrogen ion excretion defined as the sum of ammoniumplus titratable acid minus bicarbonate output (see Equation 2 in text).

were done without any disturbance of respirationto evaluate the effect of the oral bicarbonate alone.These experiments also provided a control forthe acidosis series with respect to the effects of thediurnal "tide" and the water loading procedure.While slight apparent changes were present at thetimes that would correspond to the respiratorystimulus, none of them was statistically significant.Changes during the stimulus in the respiratoryacidosis series which are significantly differentfrom the preceding control values also differ sig-nificantly from the slight alterations at correspond-ing times in the control series. This is true for allof the variables except urinary pH and K' ex-cretion, the differences of which were not quitesignificant at the 5 per cent level. During thecomparatively longer recovery portion of the ex-periments, a tendency in the acidosis series todisappearance of the effects of the oral bicarbonateon the "baseline" would be indistinguishable frompersistence of acidification of the urine as a com-pensatory mechanism to the respiratory disturb-ance. Accordingly, discussion of changes late inrecovery is limited to respiratory alkalosis. Re-sults are not reported in detail for the controlseries.

Renal hemodynamics and urinary volumeMeasurements made of effective renal plasma

flow, glomerular filtration rate, and rates of urineflow are not reported in detail. Significant changeswere observed only with hyperventilation. Ef-

fective renal plasma flow was depressed from con-trol at the end of these experiments, a change cor-relating with the excretion rate of sodium and chlo-ride which were also significantly depressed atthis time. Glomerular filtration rate was also de-creased significantly at the end of the experi-ments, but also decreased somewhat during thehyperventilation, at a time when excretion of so-dium and chloride and effective plasma flow werenot significantly altered and if anything were alittle increased. Changes in urine flow were prob-ably more closely related to the water loading thanto the experimental procedure.

DISCUSSION

Observation of renal acid-base adjustmentThe kidney responds promptly to primary re-

spiratory alterations of acid-base equilibrium.The renal adjustment is not a simple correctionof the abnormality present, but may be consideredas eventually producing an opposing "metabolic"(as contrasted to "respiratory") disturbancewhich may be measured as a change in the rate ofhydrogen ion excretion (A UVH+). An increasein UVH+is equivalent to an increase in buffer basein the body. Singer and Hastings (14) suggestedcertain practical advantages in focussing attentionon the buffer base concentration as a quantitativeindex of the metabolic or non-respiratory factorin acid-base equilibrium and pointed out that apure respiratory disturbance (before various com-

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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

3 Ca 10.4 125S 5.0 109R 1.9 124

4 C 6.6 104S 6.2 108R 0.5 80

5 C 12.1 122S 5.3 87R 9.3 118

6 C 7.5 109S 7.8 86R 3.8 96

7 C 1.6 132S 5.9 108R 3.9 109

1 C 3.0 139S 17.2 151R 4.0 135

2 C 18.2 126S 16.4 127R 17.2 131

3 C 11.1 111S 10.6 114R 13.6 117

4 C 16.7 115S 14.8 117R 15.8 116

5 C 16.8 108S 13.1 107R 14.1 106

6Q C 12.1 102S 15.3 110R 14.7 106

A. Respiratory alkalosis-hyperventilation7.38 43 24.97.62 19 19.27.40 42 25.4

7.35 43 23.67.65 15 16.57.43 37 24.4

7.39 43 25.67.63 19 20.27.44 39 25.7

7.39 43 25.37.66 16 17.97.43 37 24.2

7.30 44 24.97.56 25 22.27.39 42 24.9

B. Respiratory acidosis-COs inhalation7.40 46 27.57.35 54 29.97.45 40 27.0

7.46 40 27.87.40 47 28.77.43 40 26.5

7.50 34 25.57.37 48 27.17.44 37 24.4

7.44 41 26.77.34 51 27.07.48 34 24.6

7.44 38 25.37.33 52 26.57.44 26 24.2

7.32 49 24.77.26 62 27.17.37 45 25.5

3.11 .010 3.10 24.822.09 .184 1.91 17.523.15 0 3.15 25.42

2.45 .001 2.45 23.581.78 .171 1.61 14.921.95 0 1.95 24.41

3.13 .006 3.12 25.581.76 .166 1.59 18.293.03 .005 3.03 25.67

2.76 .002 2.76 25.281.54 .248 1.29 15.002.32 0 2.32 24.20

3.29 .002 3.29 24.892.40 .117 2.28 21.132.71 0 2.71 24.89

3.82 .0614.52 .0603.64 .010

3.76 27.054.46 29.533.64 26.97

3.50 .216 3.29 26.113.64 .123 3.52 27.713.47 .125 3.35 25.57

2.83 .084 2.75 24.763.09 .070 3.02 26.492.86 .111 2.74 23.42

3.07 .124 2.95 25.633.16 .044 3.12 26.682.85 .056 2.80 24.13

2.73 .115 2.62 24.262.84 .029 2.81 26.182.57 .053 2.51 23.68

2.52 .012 2.51 24.602.98 .021 2.96 26.902.70 .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 endof the period) rather than an interpolated value for mid-period. No correction is made for serum water or Donnanfactor.

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 subtractingfer 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 ourHCO.- reabsorption to titratable acidity plus am- index indicates the net effective acid-base adjust-

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ment accomplished by the over-all process of urineformation while theirs relates to the specific processof H' secretion by the tubular cells.7

In respiratory alkalosis the characteristic re-sponse is a decrease in He output, measured prin-cipally by an increase of HCO.- with fixed cationin an alkaline urine (17-22). Associated withthis is a decrease in output of ammonia and titrata-ble acid. The resultant effect on total body fluidsis a loss of buffer base, a further reduction of thealready lowered HCO.- concentration and a re-turn of pH toward the normal range. The ac-companying predominant change in excretion of"fixed" ion in the first half hour of acute experi-ments is increased Ke loss, rather than change inNat or Cl-. The duration of the experiments wassuch that cumulative excretion while the stimuluspersisted had very little effect in changing extracel-lular or total body fluid buffer base. The renalcompensation was therefore small compared tothe rapid sharing of the effects of the stimulus bythe various "buffer" mechanisms of the body pre-viously estimated in detail (1). Calculations basedon the data of other workers (23, 24) indicatethat in more prolonged respiratory disturbancesthe major part of A HCOB-er may be compensatedby cumulative urinary changes.

Renal compensation for acute respiratory alka-losis appears to be less efficient than that for acutemetabolic alkalosis of the "electrolyte addition"type. In seven experiments in which we gaverapid intravenous infusions of hypertonic sodiumbicarbonate (25, 26) the total dose of bicarbonategiven was of the same order of magnitude as theA HCOB-er observed in respiratory alkalosis re-ported here. Yet, within the same time, cumula-tive A UVH+averaged 19.6 mEq., indicating morethan three times the comparable renal compensa-tion during respiratory alkalosis.8 The difference

7The use of the index proposed by these authors in-volves the assumption that the basic tubular process ofHe secretion is involved in the entire quantity of HCO;reabsorbed. This view is presently held by most workers,as they point out, but it has also been recently challenged(16).

8For the bicarbonate administration studies renal ad-justment was calculated by an alternative approximationrather than by A UVH+ as defined in this paper. Fromthe laws of buffer action and electroneutrality it followsthat changes in UVW+must be accompanied by an equalchange in excretion of fixed cation minus fixed anion of

may be related to the fact that this type of meta-bolic alkalosis (a simple excess of sodium and bi-carbonate) may be corrected by the renal excre-tion of the ions present in excess.

The characteristic changes in respiratory aci-dosis are the opposite of those described for re-spiratory alkalosis (15, 17, 27). There is an in-crease in excretion rates of H+, titratable acid andammonia and a decrease in excretion of bicarbo-nate with fixed cation, especially potassium. Theurine becomes more acid. Since the acid-basedisturbance of acute experimental CO2 inhalationis considerably milder than that of hyperventila-tion, the urinary changes are much smaller in ab-solute terms. Relative to the estimated acid-basedisturbance (A HCO37er), however, the renal re-sponse appears to be of the same order of magni-tude. When the experiments were planned wepostulated that it would be difficult to detect an in-crease in UVH+ if the control urine were alreadyacid. If the "basal" state of the kidney involvescompensation for the tendency of the usual dietto produce a slight metabolic acidosis, it wouldscarcely be surprising that an acute respiratoryacidosis of mild degree should fail to bring abouta further detectable increase in UVH+. We be-lieve that this is the explanation for the lack of re-sponse in urinary acid-base factors noted byLongson and Mills (28), and in urinary outputof sodium, potassium and chloride by other work-ers (29), during acute CO2 inhalation in man.Similarly, in our Experiment 6, with NaCl sub-stituted for the small pre-medication dose ofNaHCO, (and a control urine pH of 5.9) therewas no detectable change in UVH+. In spite of theacid control urines, it seems probable that a re-nal tubular response could have been found in theexperiments of Longson and Mills (28) hadchanges in filtered load and reabsorption of bi-

opposite algebraic sign. Under many circumstances, in-cluding our own experimental conditions, a fairly satis-factory approximation of A UVH+ can be derived fromchanges in excretion rates of the major fixed ions ofurine, as Nae + K+ - CG. Expression of the urinary ad-justment in these alternative terms directs attention tothe effect on body fluid content of the major fixed ions,which may be convenient in consideration of acid-basechanges there. Use of this approximation during hyper-ventilation indicates an average change of + 222 /AEq. permin., surprisingly close to the A UVH+of -218 &Eq. permin. by the other method.

524


carbonate been determined rather than in excre-tion alone. Data of Denton, Maxwell, McDonald,Munro, and Williams (30) during CO, inhala-tion in sheep indicate a marked rise in HCO8-reabsorption, although, like Longson and Mills,they observed no change in rate of urinary excre-tion of HCO8-. In contrast to these negativeurinary results other workers have found charac-teristic changes in urinary acid-base factors inacute respiratory acidosis in dogs (15, 17, 31).9Where given, control urinary pH values in theseexperiments were close to 7.0 or above. Weob-served significant urinary changes in the five sub-jects who were given the preceding oral dose ofNaHCO3, and in whom the control urine pH wasalso approximately neutral.

Other factors influence the characteristic renalresponse observed during respiratory acid-basedisturbances. For example, the typical urinaryresponse to respiratory alkalosis is lacking in sub-jects who are in a state of NaCl depletion (18,20). It is to be expected that pre-existing disturb-ances of the circulation or fluid and electrolytebalance, endocrine factors, and kidney disease mayalter the characteristic changes that have beendefined.

In more prolonged respiratory disturbances(for example of four or five days' duration) theability of the kidney to compensate appears in-creased over that seen initially (32). Ammoniumexcretion is likely to constitute a larger fractionof the renal response to more prolonged acidosis.Although NH4, output begins to rise within a fewminutes of onset of acidosis, it does not approachmaximal rates for some hours or days (33).

The urinary findings in different phases of re-

spiratory acid-base disturbancesIt must be emphasized that the characteristic

combination of urinary changes described aboveis typical only of the "displacement" phase of therespiratory disturbance. While changes in uri-

9 A change is evident in the urinary data of Fuller andMacLeod (15), although their calculation of "total Hesecretion" did not change significantly because of a fallin glomerular filtration rate and therefore in bicarbonatereabsorption. Their method of calculation showed that90 to 98 per cent of "total H+ secretion" was accountedfor by bicarbonate reabsorption in respiratory disturb-ances.

nary rates of H' excretion persist they result in aprogressive increase in the degree of metabolicacidosis or alkalosis which compensates in partfor the respiratory disturbance. If the abnormallevel of PCO2 persists for periods much longerthan the duration of the present experiments,eventually a point will be reached where the sec-ondary change in extracellular buffer base andother chemical changes have restored the pH toa level of stability in or closer to the normalrange. In the ensuing "steady state" phase of thedisturbance renal compensation ceases, in thesense that no further progressive change is pro-duced in buffer base of body fluids. Output of H+then reflects the dietary intake and other physio-logical processes, as it does in a state of normalrespiration and PCO2. Finally, during the "re-covery" phase of a chronic respiratory acid-basedisturbance, when PCO2is returning toward nor-mal, renal compensation serves to restore the ex-tracellular buffer base to normal. Changes aretherefore the precise opposite of those describedfor the displacement phase: increase in UVH+ inchronic respiratory alkalosis, and decrease inchronic respiratory acidosis. Thus in chronicrespiratory disturbances a temporary increase inthe respiratory difficulty (equivalent to an addi-tional "displacement" phase) will be accompaniedby reappearance of characteristic urinary changes;a temporary decrease in the respiratory difficulty(equivalent to a partial "recovery" phase) willcause the opposite type of urinary changes. Sucha sequence of events is quite otherwise to the situ-ation found in metabolic acid-base disturbances.In a complete study of the displacement, stabiliza-tion, and recovery phases of ammonium chlorideacidosis, Sartorius, Roemmelt, and Pitts (33)have shown that the fundamental urinary re-sponse is one of increased UVH+ in all of thesephases, despite serial differences in individualconstituents that are also of importance. Thesame holds true for the opposite changes in meta-bolic alkalosis produced by electrolyte addition(25, 26). In acute respiratory experiments ofbrief duration, such as those reported here, thereis no stabilization, and recovery is marked simplyby a return of the urinary acid-base output towardcontrol levels.10 Superimposed on this return,

10Fuller and MacLeod (15) reported that urinary ef-fects of respiratory acidosis were rapidly reversible,

525


however, are the effects of other factors, such asdiurnal fluctuations (34), the wearing off of theslight metabolic alkalosis previously induced inthe subjects exposed to CO2 inhalation, persist-ence of slight differences in respiration, and lateeffects of the imposed diuresis.

Once the "balance" between the existing re-spiratory disturbance and the compensatory meta-bolic acidosis or alkalosis (produced by the kid-ney) has been reached, there similarly may benothing distinctive about the urinary excretion forindividual ions except as related to the accompany-ing composition of plasma. For example, in oneof our unpublished cases of chronic CO2 retentionwith a plasma PCO2 of 120 mm. Hg, urinarychloride excretion exceeded 40 mEq. per day,corresponding approximately to the intake, de-spite an extremely low plasma chloride concen-tration of 74 mEq. per liter. It is not surprisingthat the observer may erroneously conclude thatrenal compensations are unimportant in such dis-turbances if he directs his attention to the urinarycomposition alone. Determination of clearancerates or reabsorptive rates for acid-base factorswill, however, disclose the presence of renal re-sponse.

Regulation of renal bicarbonate excretionChange in the rate of excretion of bicarbonate

was the principal anionic response of the kidneyto the respiratory disturbances. In a preliminaryreport of the present work (3) it was stated thatbicarbonate excretion rate correlated better withplasma pH than with other plasma factors suchas PCO2 or HCO8- concentration. About thesame time Brazeau and Gilman (35), Dorman,Sullivan, and Pitts (36), and Relman, Etsten, andSchwartz (37) each reported studies showing thatthe reabsorption of bicarbonate was more closelyrelated to the PCO2 of the blood than to pH orconcentration of bicarbonate. Several recent ref-erences misconstrue our data and interpretationsas in disagreement with the above groups. Thisconfusion has resulted from the failure to notewhile hyperventilation produced lasting depression oftitratable acid excretion and increase in bicarbonate ex-cretion. These findings in anesthetized dog experimentsdiffer from the return to control values after hyperven-tilation noted in humans in our studies and those of Stan-bury and Thomson (20).

the terms in which the data are reported. Exami-nation of the directional changes given in Figure 4will disclose that actually no disagreement exists.In our consideration of the over-all effect of the re-nal compensation on the body we stressed output(excretion). The figure illustrates that HCO-excretion is decreased in respiratory acidosis andincreased in both respiratory and metabolic alka-losis. Since both plasma PCO2and plasma HCO3-concentration move in the opposite directions inrespiratory alkalosis and metabolic alkalosis, it isobvious that HCO,- excretion is better correlatedwith plasma pH. The three groups of investi-gators mentioned above, however, were interestedprimarily in the renal component due to active tu-bular processes. In studying the regulation ofthese processes they therefore logically stressedbicarbonate reabsorption. Figure 4 shows thatthe rate of HCO.- reabsorption is decreased inrespiratory alkalosis but increased in metabolicalkalosis (electrolyte addition). Obviously, then,reabsorption does not correlate well with plasmapH but could be correlated (in direction ofchange) with either plasma bicarbonate concen-tration or PCO2.. In experiments carefully de-signed to test this point the groups mentionedabove found in dogs that PCO2 was the moreclosely related. If our human data are used forcalculation of correlation coefficients it is foundthat reabsorptive rate does correlate somewhatbetter with PCO2 than with plasma bicarbonateconcentration. Thus, it should be apparent thatconclusions about changes in bicarbonate excretioncannot be considered as simply the opposite ofchanges in reabsorption. If the filtered loadchanges sufficiently, rates of reabsorption and ex-cretion may change simultaneously in the samedirection, as happened in the bicarbonate admin-istration experiments.

Renal excretion of potassiumThe predominance of changes in potassium ex-

cretion rate over those of sodium is a striking re-sult since the sodium greatly exceeds potassiumin the glomerular filtrate. At the end of eitherhyperventilation or CO2 inhalation the significanceof change in potassium excretion compared to con-

11 Several workers have advanced the suggestion thatthis effect may be mediated through changes in pH withinthe tubule cells (38, 39).

526


trol rate clearly exceeded that of the correspond-ing changes in sodium excretion. Indeed in thehyperventilation experiments even the absolutemagnitude of increased excretion was much greater(Ki + 183 pEq. per min., Nat + 70 pEq. permin.). Since potassium is the predominant intra-cellular cation one might suggest that the releaseof potassium from body cells as a compensatorymechanism to hyperventilation is involved. Aclose relation between potassium and bufferingaction of intracellular fluid has been prominentlyconsidered since the work of Darrow and his as-sociates (40, 41) on certain potassium deficiencystates. The calculated "cellular exchanges" ofpotassium in our experiments (1) would affectextracellular concentration in the same directionas do the changes in urinary excretion of potas-sium. Thus they are in the direction opposite tothat which would be required to explain the uri-nary findings through a change in plasma potas-sium concentration and secondarily in renal load.The change in potassium excretion under thesecircumstances might result from a reciprocal re-lationship between the tubular secretions of hy-drogen ion and potassium as suggested by Ber-liner, Kennedy, and Orloff (42).

Sodium and chloride excretion.In extracellular fluid, changes in buffer base

are approximately equal to changes in Na - Cl-.Yet during the first half hour of respiratory acid-base disturbances those changes that did occurin sodium and chloride excretion tended to be inthe same direction. Therefore urinary Na - Cl-excretion showed little variation and change infixed ions accompanying A UVH+ was associatedpredominantly with K". The alterations in so-dium and chloride excretion were not directly cor-related with the continuation and withdrawal ofthe experimental stimuli, and were not necessarilyopposite in direction in the acidosis from the alka-losis experiments. Our data therefore do notsupport the suggestion of Stanbury and Thomson(20) that a fall in chloride output following acutehyperventilation may represent a separate acid-base mechanism favoring conservation of "fixedacid" (Cl-). Since these parallel changes of so-dium and chloride excretion are not concernedwith preserving acid-base homeostasis, some other

physiological process must be involved. Thismight concern mechanisms of electrolyte con-servation, hormonal factors, or renal hemodynamicchanges. Renal plasma flow, but not glomerularfiltration rate, showed a positive correlation withsodium and chloride excretion in the hyperventila-tion studies, while neither showed statisticallysignificant changes with CO2 inhalation.

Excretion of other ionsPhosphate excretion changes in two ways: as

the rate of total phosphate output (in ,pM permin.) and as the proportion as HPO4 or asH2PO0-. Changes in the buffer role of phosphateas a transporter of H' are included in the titratableacidity, of which phosphate is an important part.This may be expressed quantitatively by the dif-ference between the excretion rate of phosphate inpEq. per min. at the observed pH and the calcu-lated rate in IAEq. per min. that would occur if thesame number of FMwere excreted at a pH of 7.4.An increase in !LM per min. phosphate excretionis regularly observed in respiratory acidosis (17,30, Table I B) and a decrease in respiratory alka-losis (17, 19, 20, Table I A), but these changesare small relative to the other changes. Calcu-lated undetermined anion excretion showed onlyvery small changes in both types of experiments.It is therefore unlikely that changes in excretionof sulfate, lactate or organic acids are quantita-tively important compared to the other changesreported.

SUMMARY

Acute respiratory alkalosis by voluntary hy-perventilation for approximately thirty minutes,or acidosis by CO2 inhalation for a similar period,were induced in normal human subjects. Theurinary excretion of water and electrolytes andthe acid-base pattern of the urine were observedin multiple clearance periods before, during andafter the respiratory stimuli.

In respiratory alkalosis the kidney respondedpromptly by retaining hydrogen ion compared tocontrol excretion, measured principally as an in-crease in output of bicarbonate with potassium.Urinary pH rose and titratable acidity, ammoniumion, and phosphate excretion fell. The potassiumeffect appeared to be due to renal regulation ratherthan secondary to systemic intracellular adjust-

527


ments. Chloride excretion tended to vary withthat of sodium, increasing slightly during hyper-ventilation and then falling far below the controllevel.

Changes observed during respiratory acidosiswere, for most variables, opposite in direction tothose noted during hyperventilation. They weresmaller in magnitude since the experimental acuterespiratory acidosis by CO2 inhalation was amilder acid-base disturbance than hyperventilationas indicated by degree of plasma changes andestimation of total extracellular acid-base disturb-ance. Changes in excretion of sodium and chlo-ride were not as definite as those in other factorsand were not always opposite in direction in thetwo types of experiment. At least part of thischange (when sodium and chloride change in thesame direction) appears not immediately con-cerned with acid-base homeostasis. If the urine isalready acid the typical urinary changes may notbe evident during acute CO2 inhalation.

Renal mechanisms account for only a smallpart of the adjustments observed in experimentsof short duration, but become more important withprolonged stimuli. The rate of renal acid-basecompensation is considerably greater in acute ex-tracellular alkalosis of similar magnitude inducedby sodium bicarbonate administration. The uri-nary patterns described are typical of the "displace-ment" phase of respiratory disturbances. Withchronic respiratory disturbances a stabilized situ-ation may be reached in which changes are notevident in rates of urinary output of hydrogenion except as compared to abnormalities of theacid-base composition of plasma; if "recovery"then occurs the direction of hydrogen ion ex-cretion typical of the "displacement" phase isreversed.

The data are compatible with the finding ofothers that the tubular reabsorption of HCO.- isbetter correlated with plasma PCO2 than withother extracellular acid-base factors. Changes inexcretion of HCO,-, however, which determine theeffect on the body, correlate with plasma pH andnot with plasma PCO2, if one considers bothrespiratory and metabolic disturbances.

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