prior€¦ · case 2 a. b., a 42 year old widow, came to the hospital com-plaining of vague...

METABOLICANDRENALSTUDIES IN CHRONICPOTASSIUMDEPLETION RESULTINGFROMOVERUSEOF

LAXATIVES 1, 2

BY WILLIAM B. SCHWARTZ8 ANDARNOLDS. RELMAN

(From the Department of Medicine, Tufts College Medical School and the New England CenterHospital; the Department of Medicine, Boston University School of Medicine, and the

Evans Memorial, Massachusetts Memorial Hospitals, Boston, Massachusetts)

(Submitted for publication October 13, 1952; accepted December 18, 1952)

INTRODUCTION

It is well known that diarrhea caused by a varietyof gastrointestinal disorders may lead to potassiumdepletion (1). This paper presents observationson two otherwise healthy women who, prior tothis study, had gradually developed severe potas-sium depletion and hypokaliemia as the result ofchronic diarrhea induced by overuse of laxatives.Although in each instance there had been a lossof approximately one-third of total normal bodypotassium, there were no other significant dis-turbances of water and electrolyte balance and noovert signs of malnutrition. These two subjectsthus presented an unusual opportunity to observethe clinical and physiological effects of uncompli-cated potassium depletion.

The case histories described below present theclinical observations made before and after thespontaneous restoration of potassium balance whichoccurred when laxatives were withheld and thepatients given a normal diet.

This paper reports the results of balance stud-ies carried out in both subjects for the three-weekperiod in which repair of their potassium deficitwas accomplished. In addition, various renalfunctions were measured serially. In one patientrenal function studies were begun immediatelyafter the potassium deficit had been repaired, butin the second patient measurements were madeboth before and after treatment. The electrocar-

1This investigation was supported in part by grantsfrom the National Heart Institute of the National In-stitutes of Health, U.S.P.H.S.; the Greater BostonChapter of the Massachusetts Heart Association andLakeside Laboratories Inc.

2Presented in part in abstract at the 44th Annual Meet-ing of the American Society for Clinical Investigation,May 1952.

a Markle Scholar in the Medical Sciences.

diographic findings in these patients will be dis-cussed elsewhere (2).

CASEREPORTSCase 1

R. S., a 24 year old woman, was referred for investiga-tion of her chronic complaints of vague muscle pains,malaise, and weakness. Although her appetite was usuallygood and she had not lost weight, she stated that underemotional stress she often ate little or nothing for a dayor two at a time. For more than a year she had ob-served a tendency to gain weight and to develop ankleedema whenever she ate salt. Up to the day of admis-sion she had worked regularly as an IBM machineoperator.

Physical examination revealed a somewhat thin, butotherwise healthy-appearing female. There were no ab-normal findings. Muscle strength and tendon reflexeswere normal.

Laboratory studies of the blood, stool and urine werenot remarkable except that the maximum specific gravityof the urine after 18 hours of dehydration was 1.013.X-ray examinations of the chest, long bones, skull, kid-neys, and entire gastrointestinal tract revealed no ab-normalities. Sigmoidoscopic examination was negative.A routine electrocardiogram revealed flattened or diphasicT-waves in most leads and was thought to be suggestiveof hypokaliemia. Repeated determinations of serum po-tassium concentrations gave values between 2.1 and 2.3mEq. per 1. Serum bicarbonate concentration was 30 to33.5 mEq. per 1., but analyses for the following were nor-mal: serum sodium, chloride, albumin, globulin, choles-terol, calcium, phosphorus, and blood sugar and urea ni-trogen. A standard 8 lead electroencephalographic rec-ord was within normal limits.

During the next three weeks, while on balance study,she spontaneously corrected her potassium deficit and herelectrocardiogram returned to normal. At this time shefirst admitted to the habitual ingestion of Hinkle's Cas-cara Compound" which she had taken in quantities of 15to 30 tablets per week in order to produce 2 to 3 waterybowel movements every day. At the cotnpletion of theperiod of potassium retention she was given laxatives for

4 Each tablet contained: .016 gm. cascara, .016 gm. aloin,.01 gm. podophyllum, .008 gm. extract of belladonna, .001gm. strychnine sulfate, and .004 gm. oleoresin of ginger.

258

CHRONIC POTASSIUM DEPLETION

a few days to observe the effect on potassium balance andthe electrocardiogram. During the next six months thepatient was free of diarrhea and her serum potassium con-centration and electrocardiogram remained normal.

Case 2

A. B., a 42 year old widow, came to the hospital com-plaining of vague malaise, weakness and abdominal dis-comfort. She had been accustomed for a long time totaking indeterminate but large amounts of proprietarylaxative compounds containing phenolphthalein, podophyl-lum, and aloin. These produced several watery bowelmovements each day. Her appetite and intake of foodwere usually normal, but occasionally, at times of emo-tional stress, she ate little or nothing for several days ata time. For several months she had noted that her anklesswelled intermittently. Prior to admission she was ableto work regularly at her job as a saleslady.

On physical examination the patient looked depressedand chronically ill. There were no other abnormal find-ings. Tendon reflexes were normal and her musclestrength seemed appropriate.

Routine laboratory studies of the blood, stool and urinewere not remarkable except that maximal specific gravityof the urine after 18 hours of dehydration was 1.005.X-ray examinations of the long bones, chest, stomach,small intestines, and gall bladder revealed nothing ofsignificance. A barium enema showed a moderatelyatonic, redundant colon, but sigmoidoscopic examinationdisclosed no evidence of disease.

A routine electrocardiogram showed sagging of theST segments and prominent U-waves in most leads.Because of this suggestive evidence of hypokaliemia, se-rum potassium analyses were done. Repeated analysesgave values between 1.6 and 2.3 mEq. per 1. Serumchloride concentration was 94 mEq. per 1. but analysesfor the following were normal: serum sodium, carbondioxide content, albumin, globulin, cholesterol, calcium,phosphorus, blood sugar, and urea nitrogen. A standard8 lead electroencephalogram was within normal limits.

The patient was placed on balance study, and duringthe next three weeks her potassium deficit was correctedand the electrocardiogram returned gradually to normal.During this time she noted a gradual, definite improve-ment in vigor and appetite and in her sense of well-being.Following discharge, the concentration of serum potas-sium, determined at frequent intervals, was usually nor-mal, as were electrocardiographic records made at thesame time. On two occasions associated with emotionalstress she suffered brief episodes of anorexia and diarrhea,which she said were not provoked by laxatives. At thesetimes the serum potassium concentration was low andthe electrocardiogram showed T-wave abnormalities.

METHODS

The patients were allowed to be ambulatory on theward. Diarrhea had stopped or diminished prior to thebeginning of the balance study and after a few days allbowel movements were of normal frequency and con-

sistency. The patients were given constant weighed dietswhich contained little sodium, a low-normal amount ofpotassium and the approximate nitrogen and caloric con-tent of the usual ward diet. No food was refused duringthe period of study. Salt was added each day in fixedamount with a weighed salt shaker in order to raise thesodium intake to a normal level. Potassium chloride, 20to 40 mEq. per day, was added to the oral intake as indi-cated in Tables I and II, but at no time did the total po-tassium intake exceed the usual range of normal. No othermedications were administered.

Organic acids in the urine were determined by themethod of Van Slyke and Palmer (3) adapted for usewith the Beckman pH-meter. No creatinine correctionwas applied. Analyses for calcium in diet, urine and stoolwere carried out by dry-ashing, followed by a modificationof the Tisdall and Kramer titration (4). Total exchange-able potassium was determined5 by analysis of urinespecific activity 24 hours after the administration of anoral tracer dose of K42C1 (5). The chemical methodsused to determine electrolytes in red blood cells will bepublished elsewhere (6). The other analytical proce-dures, the methods used in the calculation of results, aswell as other details of the balance technique have beendescribed in a previous paper (7).

The measurements of inulin clearance (C1.), p-amino-hippurate clearance (CPAE), endogenous creatinine clear-ance (Cc,), and the maximal tubular secretory rate forPAH (TmPAH) were made in the standard manner (8)with the patients well-hydrated and resting in the supineposition for at least an hour before the beginning of eachstudy. On one occasion the renal arteriovenous oxygendifference (A-V 02) and the renal extraction of PAH(EPAH) were determined in patient A. B. by the use ofsimultaneous samples obtained from an inlying peripheralarterial needle and a catheter placed in the right renalvein.7 In this case, total renal blood flow was calculatedfrom CPAH, EPAH, and the peripheral venous hematocrit(Hkt). Renal oxygen consumption (R 02) was esti-mated as the product of total renal blood flow and A-V 02.

The analyses for inulin in serum and urine were doneby the method of Roe (9); PAH was determined bySmith's adaptation (10) of the Bratton and Marshalldiazo reaction (11), and endogenous creatinine wasmeasured by Hare's modification (12) of Borsook'smethod (13), which employs Lloyd's reagent for theseparation of creatinine from non-creatinine chromogens.

5 The authors are indebted to Dr. Belton A. Burrows,Evans Memorial, Massachusetts Memorial Hospitals, forcarrying out the K0 measurements.

6Dr. Hans Keitel, Senior Assistant Surgeon, U.S.P.H.S.,Children's Medical Service, Massachusetts General Hos-pital, and Department of Pediatrics, Harvard MedicalSchool, performed the red cell analyses for us, and weacknowledge this assistance gratefully.

7 The authors are indebted to Drs. Walter E. Judsonand James D. Hatcher, Evans Memorial, MassachusettsMemorial Hospitals, for their assistance with this pro-cedure.

259

WILLIAM B. SCHWARTZAND ARNOLDS. RELMAN

A. B. 9 42 Intake

Bodyweisht HsO

Day Kgi. ml.

1 44.522 44.563 45.094 45.425 45.616 45.827 46.428 46.799 46.99

10 47.1011 47.6912 47.9613 47.7314 47.7515 46.0516 45.4317 44.9718 44.3219 44.3420 44.69

1,2002,0002,0002,0002,9002,0202,0102,0202,0202,0202,0202,0202,0202,0202,0202,0202,0202,0202,020

Na K Cl N PmEg,. mEg. mEg. ims. gms.

92 44 94 8.4 .5692 44 94 8.4 .5692 44 94 8.4 .5692 44 94 8.4 .5692 64 114 8.4 .5692 84 134 8.4 .5692 64 114 8.4 .5692 84 134 8.4 .5692 84 134 8.4 .5692 84 134 8.4 .5692 84 134 8.4 .5692 84 134 8.4 .5692 84 134 8.4 .5692 84 134 8.4 .5692 84 134 8.4 .5692 84 134 8.4 .5692 84 134 8.4 .5692 84 134 8.4 .5692 84 134 8.4 .56

TABLE I-

Urine

Camgs.

100100100100100100100100100100100100100100100100100100100

Vol.ml.

981890

1,1601,3701,1101,0601,0191,1301,2101,4801,6601,7801,8053,3102,2302,4102,3201,5201,630

Na K C1 P NH4 NmEg. mEq. mEg. gms. mEg. gms.

Per per per Per per perday day day day day day

11 9 23 .46 73 7.611 8 22 .25 51 6.717 7 23 .28 49 7.518 8 20 .34 49 6.922 9 26 .34 43 6.727 9 34 .25 36 5.827 10 32 .25 31 5.537 12 44 .34 34 5.845 16 56 .37 39 5.773 23 89 .37 38 6.180 24 90 .37 30 7.5

128 36 143 .34 27 6.8152 42 165 .34 23 7.6313 73 328 .34 18 7.0168 56 191 .53 15 5.1194 90 224 .53 25 7.2152 84 181 .47 12 6.5

77 64 107 .53 20 6.866 81 108 .59 22 7.3

Analyses of oxygen content of whole blood were madeaccording to Van Slyke and Neill (14).

Renal concentrating ability was tested by determiningthe maximum urinary specific gravity (measured by acalibrated urinometer or by direct weighing of urine onan analytical balance) after 18 to 24 hours of dehydration.

RESULTS

I. Metabolic StudiesA. Potassium balance and serum potassiumIn the lower halves of Figures 1 and 2 are shown

the daily outputs of potassium in urine and stools

superimposed on the total daily intake of potas-sium. The upper part of each figure depicts thecumulative balance of potassium (corrected fornitrogen with an assumed K/N ratio of 2.7) andthe serum potassium concentration. Tables I andII present the complete balance data from whichthese and subsequent figures are derived.

The two figures are alike in demonstrating arapid steady rise in serum potassium concentrationand cumulative potassium balance. During thefirst week large positive balances resulted from the

TABLE II-

R. S. 9 24 Intake Urine

Na K Cl P NH4 NJwody mEg. mEg. mEg. s. mE*. gms.

weight H1O Na K Cl N P Ca Vol. per per per per per perDay Kim. m1. mEg. mEg. mEg. gms. gms. mgs. "a. day day day day day day

85 44 88 8.3127 44 130 8.3127 44 130 8.3127 44 130 8.3128 44 131 8.3127 64 150 8.3127 64 150 8.3127 64 150 8.3127 64 150 8.3127 64 150 8.3127 64 150 8.3127 73 159 8.3127 44 130 8.3127 44 130 8.3127 44 130 8.3127 44 130 8.3127 44 130 8.3127 44 130 8.3127 44 130 8.3127 44 130 8.3

.57 90

.57 90

.57 90

.57 90

.57 90

.57 90

.57 90

.57 90

.57 90

.57 90

.57 90

.57 90

.57 90

.57 90

.57 90

.57 90

.57 90

.57 90

.57 90

.57 90

1,9301,4501,4501,4201,4401,5501,4941,6751,8702,0802,5502,7433,2352,4102,2101,7001,3601,7101,3501,680

55 3 4562 3 4272 4 5463 4 4868 4 5692 6 7897 6 8592 6 85

124 8 116171 10 152249 14 213268 24 240319 34 294207 43 180192 55 160139 60 12280 51 8567 49 7762 36 7184 34 92

.71 66 7.7

.59 45 7.3

.46 40 8.4

.40 38 6.5

.53 36 5.9

.43 37 5.9

.34 34 6.3

.34 39 7.7

.34 35 5.4

.37 51 5.6

.31 42 6.9.24 30 6.0.28 24 6.6.43 13 6.3.71 11 7.1.71 14 7.1.56 19 6.9.53 23 6.5.40 24 6.8.40 25 7.2

1 43.562 43.443 43.824 44.365 44.746 45.107 45.478 45.859 46.10

10 46.0911 45.7212 44.9513 44.1014 42.7915 42.1216 41.6417 41.4118 41.7919 41.7820 41.95

2,0002,0002,2002,2002,2002,2102,1502,2102,2102,2102,2102,1832,2002,2002,2002,2002,2002,2002,2002,200

260


Anaytical data

T.A. Org. CamEg. acids mgs.

per mEq. perday per day day pH

17 53 6 6.49 38 3 6.69 38 4 6.88 35 6 6.68 35 6 6.86 34 9 6.87 34 14 6.98 35 18 6.76 31 29 6.98 30 56 6.79 29 66 6.77 33 66 6.98 31 69 6.84 27 91 6.98 38 73 6.8

12 38 49 6.913 38 58 6.915 37 61 6.015 38 36 6.5

Stool

Na K Ci N P CamEg. mEq. mEg. gms. gms. mgs.

per per per per per perday day day day day day

21 13 10 1.4 .16 22121 13 10 1.4 .16 22121 13 10 1.4 .16 22125 10 1 1.6 .25 22625 10 1 1.6 .25 22625 10 1 1.6 .25 22613 8 7 1.2 .16 15113 8 7 1.2 .16 15113 8 7 1.2 .16 15113 8 7 1.2 .16 15113 8 7 1.2 .16 15113 8 7 1.2 .16 1514 10 3 0.9 .12 1594 10 3 0.9 .12 1594 10 3 0.9 .12 1594 10 3 0.9 .12 1594 10 3 0.9 .12 1594 10 3 0.9 .12 1594 10 3 0.9 .12 159

Serum

COh Na K Ci Pmm mEg. mEq. mEg. mmper per per per

pH 1. I. I. 1. 1.

7.4 28.0 2.1 94141 2.2

7.5 30.5 139 2.2 92139 2.3

7.4 28.0 141 2.4 94 0.902.7

7.4 28.0 140 3.1 99 1.13148 2.9

7.4 27.5 145 3.2 101 1.37146 3.7

4.07.4 27.0 4.0 104 1.26

4.2 1027.4 25.5 141 4.6 102 1.52

142 4.87.4 27.5 5.1 103 1.34

5.0 104

7.4 26.0 140 4.4 105 1.45141 4.9

low renal excretion of potassium. The average in excess of nitrogen (12 mEq. per kgm. of finalurine potassium in this period was only 4 niEq. weight). At the same time serum potassium con-per day in R. S. and 9 mEq. per day in A. B., centration reached normal levels. Thereafter,despite the fact that both subjects excreted ap- urine output of potassium kept pace with intakeproximately 1 to 2 1. of urine per day containing and there was no further significant change in se-6 to 8 gms. of total nitrogen. rum potassium or external potassium balance.

In A. B. (Figure 1), urinary excretion rose The course of events in R. S. was quite similarrapidly after the eleventh day, resulting in an to that in A. B. except that retention of potassiumabrupt termination of the potassium-retention continued until serum potassium had reached ab-phase. Potassium uptake was complete after 13 normally high levels. Serum drawn a few hoursdays when A. B. had retained a total of 536 mEq. after the evening meal on the twelfth day had a

Analytical data

T.A. Org. CamEg. acids mgs.

per mEg. perday per day day pH

17 32 56 6.512 34 30 6.6

9 31 35 6.89 32 34 6.7

11 33 33 6.710 36 46 6.88 34 57 6.62 37 35 7.24 30 54 6.9

none 37 71 7.7none 39 78 7.7none 35 70 7.6

4 36 76 7.311 34 33 6.713 33 51 6.616 32 51 6.520 35 46 5.721 34 72 5.717 35 41 5.719 34 60 5.3

Stool

Na K Cl N P CamEg. mEg. mEg. gms. gms. mgs.

per per per Per per perday day day day day day

4 6 2 1.2 .37 1704 6 2 1.2 .37 1704 6 2 1.2 .37 1704 6 2 1.2 .37 1704 6 2 1.2 .37 1704 6 2 1.2 .37 1704 6 2 1.2 .37 1704 6 2 1.2 .37 170

13 6 7 0.8 .12 8313 6 7 0.8 .12 83

1 2 1 0.2 .06 351 2 1 0.2 .06 351 2 1 0.2 .06 351 2 1 0.2 .06 351 2 1 0.2 .06 351 2 1 0.2 .06 351 2 1 0.2 .06 351 2 1 0.2 .06 351 2 1 0.2 .06 351 2 1 0.2 .06 35

CO,mMper

pH 1.

7.43 30.0

7.47 33.5

7.46 32.57.47 32.0

7.43 28.0

7.45 29.0

7.45

7.45

7.44

28.0

27.5

25.0

7.42 26.026.0

Serum

Na KmEg. mEg.

per per1. 1.

147 2.72.22.83.3

146 3.2144 3.3147 3.5145 3.2147 4.0147 4.0

146 5.0145 5.6145 5.6146 6.1144 5.6

5.2

Ci

mEg.per

100.5

101.0

102.0102.0

107.0108.0107.0

105.0108.0105.0105.0107.0107.0

143 4.3 108.0107.0

pmMper

5.1.42

0.97

1.26

1.291.351.311.32

1.321.411.361.34

1.52

1.52

261


SERUMPOTASSIUM

m.Eq./ L.

12 13 14 15 16 17 18 19 110111121131I4lI5DAY

FIG. 1. SERUMPOTASSIUM, CUMULATIVEPOTASSIUM BALANCE, AND DAILYEXTERNALBALANCEOF POTASSIUM, PATIENT A. B.

potassium concentration of 7.5 mEq. per 1. Atthis time, electrocardiographic tracings showedevidences of hyperkaliemia and it was deemed ad-visable to reduce the patient's oral intake of po-

tassium from 73 to 44 mEq. per day in order toavoid further intoxication. On the fifteenth toeighteenth days of the study urinary excretionexceeded intake and the cumulative retention of

R.S.? 24

B500 _

CUMULATIVEBALANCEOF 400POTASSIUMIN EXCESS 300

OF NITROGEN

m.Eq. 200

100 SER0

100 _

DAILY so IPOTASSIUM 80T

BALANCE

m. Eq. 60

potassium in excess of nitrogen gradually declinedto a final level of roughly 445 mEq. (10.8 mEq. per

kgm. of final weight), while the serum concentra-tions returned to normal.

B. Total exchangeable potassiumIn A. B. total exchangeable potassium was de-

termined at the beginning and end of the balance

SERUMPOTASSIUMm.Eq./L.

jljr. Q< ". Qs .

DAY

FIG. 2. SERUMPOTASSIUM, CUMULATIVEPOTASSIUM BALANCE, ANDDAILYEXTERNALBALANCEOF POTASSrUM, PATIENT R. S.

CUMULATIVEBALANCEOFPOTASSIUMIN EXCESS

OF NITROGENm.Eq.

DAILYPOTASSIUMBALANCE

m.Eq.

262


TABLE III

Correlation of potassium balance and exchangeablepotassium, patient A. B.

Change inExchange- exchange- Change in

Time able K able K K balancemEq. mEq. mEg.

Day 0 1,120Day 19 1,659 +539 +548

period. These values are compared in Table IIIwith the observed change in potassium balance.It will be seen that, at the beginning of the study,this patient's total exchangeable potassium wasonly 1120 mEq., or 25.2 mEq. per kgm. (Meannormal for women by this technique is 41 mEq.per kgm. [15].) At the end of the balance thisfigure was 1659 mEq., or 37.3 mEq. per kgm. Thisincrease of 539 mEq. is almost identical with the

SERUMmEq/L

Cl105_

100_

95 -

90 _

t44

144.

observed total cumulative retention of 548 mEq.over the same period.

In R. S. the first determination of exchangeablepotassium was made on the sixth day of study.Correcting the observed figure of 1425 mEq. forthe over-all retention of potassium prior to, andsubsequent to, this determination, one derives anestimate for initial exchangeable potassium of 27.0mEq. per kgm. and a final figure of 40.4 mEq. perkgm. Several weeks after this study was com-pleted, total exchangeable potassium, determinedon two occasions, averaged 39.4 mEq. per kgm.

In each instance, therefore, initial body potas-sium content was far below normal limits, but wasrestored to normal at the end of the balance. Thepotassium deficit was approximately one-third ofthe normal total exchangeable potassium content.

WEIGHTKg4

+

Ngms.

g 108

DAYS

FIG. 3. CUMULATIVEELECTROLYTEAND NITROGEN BALANCE, WEIGHTCHANGES,ANDSERUMELECTROLYTES, PATENTA. B.

263


SERUMmEq/L

144

_ 2~00 -

300 _

P 200 1g. s. I14 2.0- 0

5.01-.K 0 r 05.02.0

- 00

200

C,) ~~300-400'C

FIG. 4. CUMULATIvE ELECTROLYTECHANGES,ANDSERUMEL

C. Serum electrolytes and pHThe upper sections of Figures 3 and 4 show the

values for serum electrolyte concentrations. Bothsubjects initially had a marked hypokaliemia whichimproved gradually as described in Section A.Sodium concentrations were normal in both sub-jects and did not change significantly. Serumchloride concentration was a little low in A. B., butonly in R. S. (Figure 4). was there a slight increasein initial serum bicarbonate. As potassium bal-ance was restored in this patient, serum bi-carbonate concentration returned to normal. InA. B. (Figure 3), although serum bicarbonate fellonly 2 mEq. per 1., chloride concentration rose 10mEq. per 1. This suggests the disappearance fromthe serum of some unmeasured anion, possibly anorganic acid, which had been present during thepotassium-depleted state. Serum pH (Tables I

To

Ngms.

)rr. Co)wt.

No~

DAYS

AND NITROGEN BALANCE, WEIGHTCTROLYTES PATENTR. S.

and II) was always within normal limits and didnot vary significantly as potassium was accumu-lated.

D. Electrolyte balances and weight changesIn the lower halves of Figures 3 and 4 are plotted

cumulative changes in body weight and in externalbalance of electrolytes and nitrogen. The scale forthe cumulative weight change is so chosen that onekilogram on the weight scale is equivalent on theelectrolyte scale to 140 mEq. (This latter valuewas the approximate mean sodium concentrationin extracellular fluid.) When changes in weightare due solely to changes in extracellular fluid vol-ume the lines indicating sodium balance and weightshould be parallel, provided that extracellular so-dium concentration remains the same. Unmeas-ured skin losses would cause deviation of theweight and the sodium curves. Little or no sweat-

264


ing occurred during these experiments so that un-measured losses of sodium through the skin wereprobably only 5 to 10 mEq. per day (16).

During the initial phase of potassium repletionthere was a striking retention of sodium and chlo-ride which was followed by rapid diuresis of theseions just as potassium retention was approachingcompletion. In R. S. retention of sodium occurredjust prior to and during menstruation, but A. B.,who was not menstruating, showed similar re-tention of sodium.

The cumulative weight curve in each subjectwas closely related to the change in extracellularfluid volume predicted from sodium balance, andthe close adherence of the two curves would sug-gest that expansion and contraction of extracel-lular fluid volume was responsible for the changesin weight. The curve of chloride balance paral-leled that of sodium, but chloride retention alwaysgreatly exceeded sodium retention. On the thir-teenth day in R. S. (Figure 4) and on the fifteenthday in A. B. (Figure 3), when the cumulativechanges in weight and sodium balance were ap-proximately zero, it should be noted that there werepositive balances of potassium and chloride of ap-proximately 500 mEq. each. This retention oc-curred without significant change in body fluidtonicity as measured by the sum of the concentra-tions of extracellular sodium and potassium.

E. Calcium, phosphorus and nitrogen balanceThe scales for nitrogen and phosphorus balances

in Figures 3 and 4 are related to each other and tothe scale for electrolytes so that 1 gm. of phos-phorus equals 14.7 gms. of nitrogen or 39.7 (14.7X 2.7) mEq. of potassium. These are the ap-proximate relations of these substances in proto-plasm (17) and parallel curves for nitrogen, phos-phorus, and potassium are therefore presumed toindicate that changes in the balance of these sub-stances are due to gain or loss of tissue.

It is immediately obvious from a considerationof the figures that nitrogen retention was smalland the retention of potassium was far in excess ofthe retention of nitrogen.

Using a Ca/P ratio for bone of 2.23 (17), thephosphorus balances plotted in Figures 3 and 4have been corrected for calcium balances (Tables Iand II). The small negative balances of calciumprobably were the result of the relatively low cal-

TABLE IV

Inernaw balances

Intracelular IntracellularSubject sodium potassium

mEq. mE*.

A. B. -483 +505Days 1-15

R. S. -454 +462Days 1-14

cium intake ( 18). The cumulated corrected phos-phorus retention for A. B. (Figure 3) exceeds theretention predicted from nitrogen balance by +.54 gm. This is within the limits of error inanalysis and balance technique (17). In R. S.(Figure 4) the corrected phosphorus balance was2.6 gms. less than that predicted from the nitrogenbalance. This may indicate a small loss of phos-phorus from cells. In any event, it is quite clearfrom these figures that potassium retention oc-curred with little or no change in the cell balanceof phosphorus.

F. Cell balances of sodium and potassiumShifts of sodium and potassium to and from

intracellular fluid at the end of the two-week period

FIG. S. RENAL EXCRETION OF AMMONIUM,TITRATABLEACMAND POTASSIUM, AND URINE PH, PATIENT A. B.

265

WILLIAM B. SCHWARTZAND ARNOLD5. RELMAN

of potassium repletion are shown in Table IV.The similarity of the magnitude of the shifts atthe time of complete repair in both subjects andthe almost equal exchange of sodium for po-

tassium are striking. In R. S. it is estimated that462 mEq. of potassium entered cells in exchangefor 454 mEq. of sodium. In A. B. 483 mEq. ofsodium left cells while 505 mEq. of potassium were

taken up.

G. Red blood cell compositionInitial concentrations of sodium, potassium and

phosphorus, expressed either as "per kgm. of red

8.0 [R.S. 24

pH70 .

m.Eq. /Day

70

~~~~~K60

~~NH450 io

40

30 -

20 -

TA\r.

DAY

FIG. 6. RENAL EXCRETION oF AMMONIUM,TImATABLEACID AND POTASSIUM, AND URINE PH, PATIENT R. S.

(The ammonium excretion for the eleventh day hasbeen plotted incorrectly. It should be 42 mEq.)

blood cell solids" or "per kgm. of red blood cellwater," were both within normal limits (19).During potassium repletion there was a rise in eachpatient of approximately 13 per cent in red cell po-

tassium content, but the final values were still nor-

mal. Red cell phosphorus did not change signifi-cantdy.

H. Urine pH, excretion of ammonium, titra-table acid, and organic acids

The changes in urine pH, ammonium, and titrat-able acid, and the relation of these values to uri-nary potassium are shown in Figures 5 and 6.

TABLE V*Renal function data, patient R. S.

Before K After K therapytherapy

Patient R. S. 9 24 10/2/51 11X6/Si 11/29/S1 2/7/52

Ci. ml./min. - 103 99 116Ccr ml./min. 88 111 133Pcot mgm. % - .82 .76 .71Cpr ml./min. 379 462 507FF % 27.3 21.4 22.9Hkt % - 37.4 39.0 42.5ERBF$ml./min. 606 758 882TmpHmgm./min. 74 90 93Sp. Gr. 1.013 1.013 - 1.026

* All clearance and TmpAHvalues corrected to 1.73 sq. m.t Serum creatinine concentration.$ Effective renal blood flow, calculated from Cpm and

Hkt.

An outstanding feature of each figure is theprogressive decline in excretion of ammonium.In A. B. (Figure 5), ammonium decreased with-out significant alteration in urine pH or titratableacid. In R. S. (Figure 6), the sharp decline inurinary ammonium which began on the twelfthday was associated with a fall in urine pH and arise in titratable acidity.

Except for the period of the initial fall in am-monium excretion when the balance regime wasstarted, there was a roughly inverse relationshipbetween excretion of ammonium and potassium.

Excretion of total organic acids did not changesignificantly at any time in either patient.

TABLE VI*

Renal function data, patient A. B.

Before K After K therapy Followingtherapy diarrhea

Patient A. B. 9 42 1/16/52 2/5/52 3/21/52 7/15/52

Cl. ml./min. 43 72 103 73Cor ml./min. 56 88 125 87PC, mgm. %§ .87 .94 .70 .79CpAHml./min. 315 376 584 346FF % 14.0 19.2 17.7 21.0Hkt % 38 29 35 35ERBFt ml./min. 508 530 897 531TmpA mgm./min. 45 53 71 69EpA - .71RBFt ml./min. - 746A-V 02 vols. % - 1.33R 02 ml./min. 9.9 - -Sp. Gr. 1.005 1.015 1.025

* All clearances, TmpHand R02 corrected to 1.73 sq. m.t Effective renal blood flow, calculated from CpA and

Hkt.t True renal blood flow, calculated from ERBF and

EpAq.§ Serum creatinine concentration.

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II. Renal Function Studies

The renal function data are presented in TablesV and, VI. All clearances and Tmvalues are cor-rected to a standard surface area of 1.73 sq. m.

1. Patient R. S. (Table V):

The first observations were made approximatelya week after this patient's potassium deficit hadbeen corrected. Cl. and TmPAHwere at the lowerlimits of normal, but Ccr and CPAH were slightlybelow normal. Prior to restoration of potassiumbalance as well as immediately thereafter, dehy-dration for 18 hours had resulted in a maximumurine specific gravity of only 1.013.

During the subsequent months, the patient re-mained well and her serum potassium concentra-tion and electrocardiographic records did not showany evidence of recurrence of potassium depletion.Three weeks after the first observations CCr andCPAHwere at the lower limits of normal and TmPAHhad increased from low normal to high normalvalues. Final observations made 10 weeks later( 14 weeks after the restoration of potassiumbalance) revealed that all renal functions were un-equivocally normal. As indicated. in Table V,Ccr, Cln, and CPAHincreased slightly, but TmpAHremained at its previous high normal level. Thepatient was now able to concentrate her turine to1.026.

2. Patient A. B. (Table VI):A. B.'s renal function was first measured im-

mediately before restoration of her potassium defi-cit was begun. Cln was 43 ml. per min. and Ccrwas 56 ml. per min. TmpAHwas also greatly re-duced and CPAHwas little more than half of normal.Maximum urine specific gravity was only 1.005.

The second observation was made immediatelyafter body potassium had been completely restored.At this time all functions measured were consider-ably improved, but nevertheless they were stillfar below normal. Renal A-V 02 difference wasnormal, but renal oxygen consumption was 9.9ml. per min. (normal about 16 + 2.9 ml. per min.[20]), and EPAH was only .71. True renal bloodflow (RBF) was therefore considerably higherthan the effective blood flow (ERBF) and wasnear the lower limit of normal. Maximum specificgravity was 1.01 5.

During the next six weeks the patient remainedwell, and occasional electrocardiographic tracingsand serum potassium determinations were normal.At the end of this time, a third evaluation of renalfunction revealed that all functions measured (C1.,CCr, CPAH, TmPAH) had increased substantiallyand were now within normal limits. A concen-tration test produced a maximum urine specificgravity of 1.025:

The final study of renal function listed in TableVI was carried out at the end of a two-week pe-riod of diarrhea, when the serum potassium was3.0 mEq. per 1. and the electrocardiogram showedmarked changes in Q-T interval and T-waves con-sistent with hypokaliemia. CCr, C1,, and CPAHwere now roughly 30 per cent below their previ-ously normal levels, but TmPAHwas essentially un-changed.

DISCUSSION

That excessive use of laxatives was the solecause of the potassium depletion in these twowomen is not proven conclusively by these data,but the clear-cut history of diarrhea related to thechronic use of laxatives and the lack of evidencefor any other mechanism make this conclusionhighly probable. Furthermore, when R. S. wasallowed to use laxatives again, balance study dem-onstrated loss of potassium in the diarrheal stoolsand a negative daily potassium balance (21). Theconcentration of potassium in stool water duringthis laxative-induced diarrhea was 50 to 55 mEq.per l., and the stools contained 2 to 4 per cent ofsolids.

The extraordinarily severe potassium deficits inthese two women apparently developed graduallyover a period of months or years without producingany striking symptoms or signs. This suggeststhat the rate at which potassium depletion developsis of importance in determining symptomatology.Although rapid loss of potassium from isolatedprirused muscle will reduce contractility (22), ithas been shown that the gradual production ofpotassium depletion in rats does not impair themuscular response to a tetanic stimulus (23) orreduce the animals' swimming ability (24). Fur-ther evidence that tissue may become acclimatizedto potassium deficiency is provided by the "po-tassium paradox" of Libbrecht (25).

The important contribution of renal "leakage"

267


of potassium to the development of potassium de-pletion in man has been emphasized (26, 27).Although there are no observations on the effi-ciency of renal conservation of potassium early inthe development of the potassium deficit in the twocases reported here, the data in R. S. demonstrateunequivocally that, with prolonged depletion, renalexcretion of potassium may sometimes be reducedto extremely low levels despite normal urine vol-umes. In this patient the renal excretion of potas-sium during repair remained so low that her bodyfluids became temporarily surfeited with this ionand signs of potassium intoxication appeared in theelectrocardiogram. This temporary failure in re-nal regulation may have been due in part to im-pairment of renal function.

The very close correlation letween total ex-changeable potassium and the potassium balancein patient A. B. is notewvorthy. This observationimplies that exchangeable potassium measured themetabolically active pool of potassium in the body,irrespective of whether it measured total body po-tassium.

The apparent discrepancy between the net bal-ance of water and cations (Section D, above)could have resulted from excessive unmeasuredskin losses of electrolytes or froml other systematicerrors in balance technique. However, in the ab-sence of any evidence for such an explanation, itwould appear likely that uptake of potassium wasassociated with a reduction in' the osmotic- activityof some intracellular constituent (28, 29). Totalintracellular cation concentration (calculated onthe assumptions that [a] "chloride space" isequivalent to extracellula'r space, and [bl intra-cellular calcium and magnesium did not change[29] ) increased approximately 40 mEq. per l. inR. S., and 25 mEq. per 1. in A. B. If the final tis-sue composition was normal, this would indicate alow intracellula'r cation concentration prior totreatment. Similar changes are regularly foundin the muscles of potassium-deficient rats (29).

Restoration of tissue potassium was also ac-companied. by a large but transient retention ofsodium, an observation similar to that made byElkinton, Squires, and Crosley (30). Sodium re-tention may have been related to the reversibledisturbances in renal function observed in the pres-ent patients. No explanation can be offered atpresent for the sustained retention of chloride

(Figures 3 and 4) and expansion of the "chlo-ride space."

The absence of significant alkalosis in thesepatients despite a prolonged period of severe po-tassium depletion requires consideration. It hasbeen suggested that the alkalosis usually presentin potassium deficiency may be due, at least in part,to exchange of intracellular potassiumi for extra-cellular hydrogen ions (31, 32). The approximateequivalence of the sodium and potassium shiftslisted in Table IV would suggest that no largetransfers of hydrogen occurred in either of the pres-ent cases. However, the methodological errorsinherent in these calculations (31) preclude closeinterpretation of the data. Further evidenceagainst a shift of hydrogen ions from the cells canbe deduced from the fact that the excretion ofammonium plus titratable acid decreased duringthe uptake of potassium. This is in contrast to thefindings of Cooke and associates (32), who ob-served an increased excretion of ammonium andtitratable acid during treatment of potassium-defi-cient, alkalotic rats. Interpretation of the presentdata is complicated by the possibility that previousloss of bicarbonate in the diarrheal stools mayhave affected the acid-base balance.

The observations of urinary excretion of am-monium and potassium depicted in Figures 5 and 6show that, contrary to prevailing hypotheses (33),changes in aimimonium excretion were independentof changes in urine pH. The rapid decline in uri-nary ammonium coincided with an increase in theexcretion of potassium and sodium in both sub-jects. Such an inverse relationship between theurinary excretion of potassium and ammoniummight be expected if renal ammonium productioninvolves secretion of hydrogen ions (33) and' ifthere is a competition between tubular secretion ofhydrogen and potassium (34). However, thehypothesis of hydrogen-potassium competitionwould still fail to explain the apparent indifferenceof urine pH and titratable acidity to the largechanges in potassium excretion.

An alternative explanation is that ammoniummay, under certain conditions, passively serve thedemands of electroneutralit- in the urine by actingas "available cation." According to this hypothesisthe presence of increasing amounts of potassiumions in the tubular fluid would, if all other rele-vant factors were kept constant, reduce the stimu-

268


lus for release of ammonia by reducing the po-tential excess of urinary anions over cations.However, in view of the evidence presented herethat potassium depletion impairs certain tubularfunctions, any interpretation of these data mustbe considered for the present as only tentative.

The unexpected discovery of fixed urine specificgravity in patient R. S. while she was potassium-depleted suggested that more detailed study of herrenal function might be of interest. It was notuntil after balance studies had been completedand potassium balance restored that the clearancesreported in Table V could be carried out. Thechanges in renal function in this patient were smallbut they suggested that glomerular and tubularfunction may have been impaired during the pe-riod of potassium depletion.

The more complete observations in patient A. B.who also initially exhibited isosthenuria indicatedthat there was marked impairment of glomerularand tubular function during potassium depletionwhich slowly returned to normal after treatmentwith potassium. Immediately after a second epi-sode of diarrhea and potassium depletion renalfunction was found once more to be distinctlyimpaired.

Both patients had habitually ingested laxativemixtures containing aloin. Although this an-thraquinone compound is said to cause renal dam-age in rabbits when administered subcutaneouslyin total doses of 0.2 to 2.25 gms. over a periodof 1 to 4Q days (35), the quantities of aloin in-gested by these patients over a comparable periodwere far below this toxic level. Furthermore, hu-mans are resistant to the nephrotoxic action ofaloin because they excrete practically none of -thissubstance in the urine when the drug is taken bymouth (36).

Disorders of fluid and electrolyte metabolismknown to impair renal function, such as dehydra-tion, sodium depletion, and alkalosis, were notpresent in these patients. The absence of any con-comitant weight gain or retention of nitrogen sug-gests that the improvements in renal function can-not be ascribed to improved nutrition. Recent se-rial studies of another patient with severe chronicpotassium depletion have also revealed reduc-tions in glomerular and tubular function whichwere restored within six weeks by treatmentwith potassium (21). Although this patient's po-

tassium depletion was complicated by steatorrheaand malnutrition, there was no clinical change inthese factors during the period of observation, andthere were no other known disorders of water orelectrolyte balance. The present data wouldtherefore strongly suggest that potassium depletionmay depress renal function.

Tubular dysfunction in these patients may berelated to the observations of altered renal tubu-lar morphology in potassium-deficient rats (37)and in patients dying with clinical evidences of po-tassium depletion (38, 39). The apparent changesin renal plasma flow could have been due in partto reductions in the tubular extraction of PAHsuch as occurred in patient A. B. (See Table VI.)In addition, plasma flow, as well as glomerularfiltration, may have been affected by the expan-sion of the "chloride space" which occurred dur-ing uptake of potassium (Figures 3 and 4).

Renal dysfunction of the type reported here couldaccount for certain phenomena associated with se-vere potassium depletion. Sodium retention (30,40, 41), elevated blood nitrogen concentration(40), and reduced urea clearance (41) may be inpart due to the reduction in glomerular filtration.Renal tubular damage could explain the isosthen-uria in these and other cases of potassium deple-tion (38, 39, 42) as well as the polyuria in potas-sium-deficient dogs (43) and rats (44). Thefailure of the kidney in potassium depletion toadjust extracellular bicarbonate concentration (32)may also be related to the functional disorders re-ported here. Another interesting implication ofthese data is that potassium depletion may be re-sponsible at least in part for the renal dysfunctionfound in many cases of alkalosis (30, 45).

SUMMARYAND CONCLUSIONS

Balance studies were carried out on two womenwho had gradually developed severe potassium de-pletion and hypokaliemia as the result of chronicdiarrhea induced by overuse of laxatives. Neitherof the patients had any overt neuromuscular symp-toms or signs, and it was only through the dis-covery of T-wave changes in routine electrocardio-grams that hypokaliemia was discovered. Therewere no other disturbances of serum electrol-tesexcept for slight elevation of plasma bicarbonatein one patient. Red cell sodium, potassium and

269


phosphorus concentrations were normal. Renalexcretion of potassium was very low.

When laxatives were withdrawn and the pa-tients given normal oral intakes of potassium, eachretained an amount of potassium roughly equiva-lent to one-half her total initial body potassiumcontent (as estimated by K42 dilution), withoutsignificant retention of nitrogen or phosphorus.Changes in total exchangeable potassium were ap-proximately equal to the actual potassium retention.In both instances potassium retention was accom-panied by a large but transient retention of sodium.Internal balance calculations indicated that cellu-lar uptake of potassium was approximately equalto the estimated loss of intracellular sodium andthat total initial intracellular cation concentrationwas markedly reduced. Excretion of ammoniumwas relatively high initially and during correctionof the potassium deficit ammonium diminishedrapidly without significant change in urine pH ortitratable acidity.

Ability to concentrate the urine was impairedin both patients prior to treatment, but was re-stored to normal after correction of the potassiumdeficit. Clearance studies begun immediately af-ter treatment in the first patient revealed slightreductions in glomerular and tubular function.In the second patient glomerular and tubular func-tions were found to be markedly depressed priorto therapy. After correction of the potassium defi-cit there was a gradual return to normal of allfunctions in both patients. It is suggested thatrenal dysfunction may account for certain disturb-ances in water and electrolyte metabolism observedin potassium deficiency.

ACKNOWLEDGMENTS

The authors are grateful to Dr. Lamont E. Danzig forhis assistance in carrying out the studies of renal function.Miss Jacquelyn Allen, Miss Helen Connors, Mr. JosephGreaney, Mrs. Elizabeth Hughes, Mrs. Mary Kimball,and Miss Arlene Roy gave invaluable technical aid.

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prior€¦ · case 2 a. b., a 42 year old widow, came to the hospital com-plaining of vague...

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