FUNCTION AND PAN-HYPOFUNCTION

RENALFUNCTIONIN PATIENTS WITH ADDISON'S DISEASE ANDIN PATIENTS WITH ADRENALINSUFFICIENCY SEC-

ONDARYTO PITUITARY PAN-HYPOFUNCTION'

By JOHN H. TALBOTT, LOUIS J. PECORA, ROBERTS. MELVILLE,AND WILLIAM V. CONSOLAZIO

(From the Medical Clinic, Massachusetts General Hospital and the Fatigue Laboratory,Harvard Uniiversity, Boston)

(Received for publication September 29, 1941)

Acute adrenal insufficiency is a complex phe-nomenon and at least three dysfunctions of bodyeconomy may accompany its development in hu-mans. The disturbances which are intimately as-sociated with the pathogenesis of adrenal insuf-ficiency in patients suffering from Addison's dis-ease are: (a) dissipation of water and sodium withretention of potassium, (b) impaired glycogenesisfrom protein, and (c) depression of renal activity.The existence of these disorders has been assumedfrom the clinical findings of hyponatremia andhyperproteinemia, hypoglycemia, and azotemia, re-spectively. Experimental studies concerning theprecise dependence or the interdependence of thesedisturbances are not yet conclusive. Whether ornot the several dysfunctions are interdependent,they are partially susceptible to investigation, inde-pendently. Thus it is possible to correct tempo-rarily the disturbance of electrolyte exchange,meanwhile exerting little influence upon impairedglyconeogenesis. A clinical example of such anindependence (1) is seen in patients with Addi-son's disease who die in hypoglycemic shock witha normal concentration of serum sodium.

Experimental studies recently performed sug-gest that impairment of renal function also maybe independent of alteration of glyconeogenesisas well as independent of the typical disturbancesof electrolyte equilibrium. The hypothesis hasbeen tested in humans by quantitative measure-ments of the various functions of the kidney atdifferent levels of adrenal activity. The resultswill be presented in this communication.

1This investigation was aided by the Cori IndustriesResearch Foundation. The authors wish to thank Dr.George W. Thorn of Baltimore and the Ciba Pharma-ceutical Products Company for the generous quantitiesof desoxycorticosterone acetate (Percorten) supplied inoil and in pellets.

There are few studies reported in the literature whichare pertinent to the discussion. The first reports werepublished in 1914 when three observers, independently,discussed the development of renal insufficiency in asso-ciation with acute adrenal cortical insufficiency. Sicardand Haguenau (2) dismissed the matter with the state-ment that kidney insufficiency may be observed in humansduring an adrenal crisis. Gaillard (3) made the firstquantitative measurements of renal insufficiency and noteda blood urea of 320 mgm. per 100 cc. in a patient whohad died from adrenal failure. A similar increase ofwaste products in the blood was noted by Porak andChabanier (4) in animals following bilateral adrenal-ectomy. In 1916 Marshall and Davis (5) observed adelayed excretion of phenolsulphonphthalein dye as wellas nitrogen retention in the adrenalectomized dog. Theyascribed the changes to a "functional depression of thekidneys caused by a failure of elaboration by the ad-renals of a substance necessary for maintenance of nor-mal kidney function." Renal function in chronic adrenalinsufficiency was measured by Stahl, Atchley and Loeb(6) in an adrenalectomized dog which was maintainedfor 9 months with adrenal cortical extract and salt with-out evidence of a progressive decrease in phenolsulphon-phthalein excretion or urea clearance. A diminution inrenal function was demonstrated only during an adrenalcrisis which could be induced by withdrawal of either saltor extract. It is possible that if the dog had sufferedfrom insidious chronic adrenal insufficiency for as long atime as do many patients with Addison's disease, evidenceof renal damage might have been evident at other timesthan during an adrenal crisis.

Investigation of renal function during intercritical pe-riods in a series of patients with Addison's disease waspursued first by Rowntree (7) who reported a decreasedexcretion of -phenolsulphonphthalein dye 2 hours afterinjection in ten out of twelve patients. It is regrettablethat fractional collection of urine samples was not prac-ticed since the amount of dye excreted during a 2-hourcollection period is not as accurate: an index of mildrenal insufficiency as is the per cent excreted in the first15 minutes after injection. Subsequently, Rowntree andSnell (8) noted a decreased excretion of dye in acuteadrenal insufficiency as well as hyposthenuria, albuminuriaand cylinduria in patients with Addison's disease whosesymptoms were controlled. Inability to concentrate urinewas observed by Rosenow (9) in two patients with

107

J. H. TALBOTT, L. J. PECORA, R. S. MELVILLE, AND W. V. CONSOLAZIO

Addison's disease. He concluded that ability to concen-trate urine was a function of the endocrine glands.

It is agreed that albuminuria, cylinduria and hypos-thenuria are indicative of grave insults to the kidney.Less devastating alterations might occur, but would escaperecognition because accurate measurements of small vari-ations from the normal are not possible with the phenol-sulphonphthalein and urine concentration tests. On theother hand, dependable quantitative methods for deter-mination of renal efficiency by measuring rate of clear-ance of creatinine, inulin, diodrast and glucose have beendeveloped only recently and have not been applied gen-erally to patients with Addison's disease. Particularlypertinent is the application of these tests during the inter-critical periods when symptoms are adequately or almostcompletely controlled as the result of administration ofsodium chloride and hormones.

The creatinine clearance test devised by Rehberg (10)which measures, in humans, tubular excretory functionas well as rate of glomerular filtration was applied byMargitay-Becht and Gomori (11) to three patients withAddison's disease. Values of 68, 63, and 56 cc. of plasmacleared per minute, respectively, were observed duringcrises. Following parenteral administration of adrenalcortical extract, the rates increased to 105, 109, and 144.All of these values are below normal except the last.It is stated that the depression in creatinine clearanceshowed no direct correlation with alteration of bloodpressure, serum nonprotein nitrogen, serum sodium or col-loid osmotic pressure of the serum. It is thought thatthese are the first data which show incomplete restorationof impaired tubular function and glomerular filtration inpatients with Addison's disease whose symptoms are con-trolled by administration of adrenal cortical extract.McCance (12) reported an isolated datum of 50 cc. ofglomerular filtrate formed per minute during an inulinclearance test in one patient with Addison's disease. Nostatement was made regarding symptoms, but the patientpresumably was not in a severe crisis since he concludedthat while hypotension, dehydration, diminution in plasmavolume, hyperproteinemia, and uncompensated alkalosismight contribute to the pathogenesis of renal dysfunctionin acute renal insufficiency, these factors would not ex-plain the diminution in kidney efficiency observed. Finally,Gersh and Grollman (13) investigated glomerular filtra-tion and tubular reabsorption of ferrocyanide salts in therabbit, the dog, and the cat. These functions were studiedimmediately after adrenalectomy in some animals and 3months post-operatively in others. No diminution inglomierular filtration was noted except late in an adrenalcrisis. An increase in the rate of reabsorption of waterby the tubules was apparent during severe adrenal in-sufficiency.

SUBJECTS

There are -two clinical conditions with whichmay be associated a profound depression of ad-renal cortical activity and which are sufficiently

chronic in course to permit an accurate appraisalof changes in renal function. These are Addi-son's disease and pituitary hypofunction of thetype designated as pan-hypopituitarism by Fraser,Albright and Smith (14). In this study ten pa-tients with typical Addison's disease and six pa-tients with chronic adrenal insufficiency secondaryto pituitary hypofunction were investigated. Sixpersons acted as normal controls. None of theexperimental subjects gave a history of havinghad acute or chronic nephritis. One patient,D. S., was suspected in 1935 of having renal tuber-culosis. The diagnosis was not confirmed at thattime or subsequently. A second patient, E. D.,has had a persistent hypertension during the 2years that he has been under observation. Other-wise no gross kidney disturbance was present inany subject.

The clinical methods for studying renal functionwere (a) determination of concentration of non-protein nitrogen of the serum, (b) testing abilityto concentrate solids following abstinence fromfluids for 12 hours, (c) urinary excretion ofphenolsulphonphthalein dye 15 minutes after 1.0cc. had been given intravenously, and (d) pyelog-raphy after intravenous administration of 20 cc.of diodrast. More precise measurements of kid-ney function were obtained from estimation ofrate of clearance of inulin, creatinine, diodrast,glucose, sodium, and potassium.

The theoretical considerations which underliethe various clearance procedures will not be dis-cussed. We have assumed (15, 16) that inulinclearance measures rate of glomerular filtration,that creatine clearance measures rate of glomerularfiltration plus tubular excretion, that diodrast clear-ance at low iodine plasma levels measures maxi-mumrenal plasma flow, that diodrast clearance athigh iodine plasma levels measures maximum tubu-lar capacity for excreting diodrast, and that glu-cose dcearance at high plasma levels measuresmaximum tubular capacity for reabsorbing glucose.

The patients with Addison's disease (Table I)who were studied presented the typical clinical pic-ture. They were chosen without regard to dura-tion of symptoms. None was known to be suffer-ing from any serious complication of Addison'sdisease or from an associated malady at the timethat the tests were performed. Except for W. H.,the excretion of 17-ketosteroids was less than 10

108

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mgm. per 24 hours. The normal range for excre-tion of this fraction, as determined by our labora-tory, is from 15 to 25 mgm. per 24 hours for adultmales, and from 10 to 20 mgm. per 24 hours foradult females. The low values presented in TableI are indicative of a severe depletion of adrenalcortical tissue. -The basal metabolic rate was ap-proximately 20 per cent below normal. Calcifica-tion of the adrenals was evident by x-ray in twopatients. All of the patients except J. Coc. werestudied first while they were on a high sodiumchloride intake, but before receiving treatment withdesoxycorticosterone acetate (Percorten). Thefirst test on J. Coc. was performed 2 weeks aftertreatment with active material had begun. Thetests were repeated on five patients from 2 to 6weeks after institution of desoxycorticosteroneacetate therapy. The requirements for desoxy-corticosterone acetate were determined by the as-say method described by Thorn and Firor (17).The active material was given first in oil over aperiod of 2 or more weeks. When the main-tenance dose had been determined, pellets of de-soxycorticosterone acetate were implanted. Fivepatients were re-investigated approximately a yearlater at the time that they were admitted for re-implantation of pellets. After this long intervalof time they were beginning to note the effects ofan inadequate assimilation of desoxycorticosteroneacetate, but none was suffering from acute adrenalinsufficiency. Two patients, whose electrolyte ex-change had been restored by treatment with de-soxycorticosterone acetate were studied before andafter experimental administration of adrenal corti-cal extract (Wilson's). Twenty cc. of the ex-tract were given daily intramuscularly in divideddoses for 5 days.

Three Addison's patients have died since thedata were collected. A. H. died from adenocarci-noma of the ovary with metastases. A post-mortem examination showed caseous adrenals aswell as carcinoma. A second patient, J. Cob., wasa bartender and renegade. He was most unco-operative, and according to friends, died at homeafter an alcoholic bout. No autopsy was per-formed. A third patient, H. M., died suddenly inApril 1941. Two months previously she had beenadmitted to the hospital for a new supply of de-soxycorticosterone acetate pellets. This admissionwas uneventful. One month before death she

was observed to be in good physical condition, herserum electrolytes were normal and the blood pres-sure was 128/82. She lived only 18 hours afterthe sudden onset of weakness and hyperpyrexia.On the last admission, the serum sodium concen-tration was 126 m.eq. per liter; nevertheless, sub-cutaneous edema was obvious. The concentrationof blood sugar was 88 mgm. per 100 cc. A con-tinuous slow infusion of dextrose solution wasgiven during the 18 hours preceding death. Noautopsy was performed. The other patients withAddison's disease are alive and in a satisfactorystate of compensation.

The patients suffering from pan-hypopituitarism(Table II) had symptoms of myxedema andchronic adrenal insufficiency. By pan-hypopitui-tarism we mean a type of Simmond's disease inwhich the most conspicuous feature is hypothy-roidism (18) rather than cachexia. All of the pa-tients with this malady were moderately incapaci-tated in contrast to those with Addison's disease.Each patient was admitted to the hospital becauseof distressing symptoms and all had metabolic ratesbelow minus 20 per cent. Previous to admissionfour patients had had at least one crisis, the symp-toms of which had been attributed to myxedema,but in retrospect are believed to have been thoseof adrenal insufficiency. All were ambulatorywithout requiring specific treatment at the time therenal function tests were done.

A diagnosis of chronic adrenal insufficiency inthese patients was based upon the following evi-dence: (a) the syndrome of pan-hypopituitarismis known to be associated with atrophy of theadrenals; (b) excretion of 17-ketosteroids in theurine was similar to patients with Addison's dis-ease; (c) symptomatic improvement followed ahigh sodium chloride intake; (d) only smallamounts of thyroid extract were tolerated. Theblood pressure was normal in all except E. D.This patient was the only one who showed evi-dence of renal damage by routine clinical tests.Four of the patients are alive and their symptomsare moderately well controlled on a high salt dietsupplemented by parenteral administration of maleor female sex hormones. Patient C. 0. died fromdiabetes mellitus and hemochromatosis, symptomsof' which appeared after renal function studies hadbeen performed. Patient E. B. died followingsurgical removal of a suprasellar cyst. Atrophy

110

RENAL FUNCTION IN ADRENALINSUFFICIENCY

TABLE II

Summary of clinical observations on six patients with pan-hypoptuitarism

Serum Urine

0~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.

ffi~~~~~~. BooaSt SilIigiBU00 ~~~~~~~~~0

December 15 1939 100/65 80 -

D.A....29Q Jnury30 190 007013.5 30 11 102 O~ Neatv 2.42

co E :3 co 0.0 o 0 01 0N

M. M. mgm. mgm. mgm.years ~~~MM. eq. eq. per per per per peryears, Hg per per 100 100 centS4 cent

liter liter cc. CC. hoursN... . . .

' 10 November 13,1939 110/60 138.7 4.1 20 96 1.020 0 Negative 0.0 -40December 15, 1939 100/65 80 -40

C.0O....53 a" 2 December 20, 1939 122/88 21 286 1.022 0 Rare white 2.0 -39blood cell

D.A....29 9 S January 30, 1940 100/70 138.5 30 111 1.022 0 Negative 2.4 -23E.D ....70 d' 13 May 11, 1940 170/85 132.3 4.3 29 74 1.025 0 Negative 13 3.0 Normal -19

November 25, 1940 190/120 80 1.012 S.P.T. Rare cast 12 3.3 Normal -34E.B ....27 d" 1 July 19, 1941 110/70 138.4 4.0 20 82 1.017 0 Negative 34 1.8 Normal -26B.L ....18 cid' I1 August 4, 1941 104/72 1140.51 4.4 118 56 11.022 0 Negative 28 13.2 1Normal 1-35

of the adrenals was apparent at postmortem ex-amination in both patients.

Although the term adrenal insufficiency is usedfrequently throughout this communication, none ofthe observations was made during an adrenalcrisis. The study was planned in order to gatherrenal function data on ambulatory patients whoseclinical symptoms were satisfactorily controlled.When the words adrenal insufficiency are used,therefore, it implies nothing more than an ana-tomical deficiency of' adrenal cortical tissue. Bythis definition all patients with typical Addison'sdisease or pan-hypopituitarism, irrespective of ap-parent adequacy of treatment, are suffering fromadrenal insufficiency. This statement is not in-tended to imply that the current drugs used in thetreatment of Addison's disease are unsatisfactory.On the contrary, they have altered the clinicalcourse of Addison's disease tremendously.Nevertheless, we believe that in most patientseven this treatment does not provide for completerestoration.

During the period that these studies were inprogress, seven additional patients with Addison'sdisease were admitted to the hospital in an acuteadrenal crisis. Not one of these patients wasthought to be a suitable subject for clearance testssince we were interested in renal function inchronic adrenal insufficiency. Microscopic exam-ination of the kidneys from three of these pa-tients is discussed under Pathological Observations.

METHODS

Most of the data were collected while the patients werein the research ward of the Massachusetts General Hos-pital. Approximately 25 grams of inulin were given in-travenously for the determination of inulin clearance.For the determination of renal blood flow, the concentra-tion of diodrast iodine in the serum was maintained atapproximately 1 mgm. per 100 cc. Maximum tubularexcretory capacity was determined with diodrast iodinelevels in the serum, decreasing each 10-minute periodfrom approximately 50 mgm. per 100 cc. to 25 mgm. per100 cc. Maximum tubular reabsorption capacity wasdetermined with rising serum glucose levels above 400mgm. per 100 cc. The inulin, creatinine, sodium andpotassium clearance and diodrast clearance at low plasmalevels represent an average of 3 or more 10-minute col-lection periods. The data for diodrast and glucose clear-ance at high plasma levels are the average for 3 periodsor less. All of the clearance tests are corrected to abody surface area of 1.73 sq.m. (16).

The tests were begun while the subjects were in abasal state except as regards consumption of water. Oneliter of fluid was allowed 12 hours and 2 hours, respec-tively, before each test. All urine specimens were col-lected by a urethral catheter. A sample of blood wastaken at the halfway time in most periods. When thiswas not done, the concentration of constituents of serumwas interpolated from data collected during periods im-mediately before and after. Venous blood was taken forall determinations except glucose. When concentrationof this constituent was desired, arterial blood was takenfrom the brachial artery. Timing was done by meansof a stop watch. Iodine was determined according to themethod described by Smith and associates (16). Themethods used for determination of the other constituentsin blood and urine have been described (19).

ill


RESULTS

Addison's disease

In the summary given in Table I of the clinicalobservations on patients with Addison's disease, itis apparent that at the time most of the tests wereperformed, clinical evidence of acute adrenal in-sufficiency was lacking. At the time of the thirdtest on H. M., at the time of the first test on E. H.,and at the single test on J. Cob., symptoms of mildadrenal insufficiency were evident. The serumsodium concentrations during these tests tendedto be less than 135 m.eq. per liter. In all deter-minations except the first on D. S., the serum po-tassium was within the range for normals. Labo-ratory and clinical evidence of hypoglycemia wasabsent in each patient. Previous to our studies,treatment in all patients except J. Coc. consistedonly of a high salt intake and other conservativemeasures.

Examination of kidney function by routineclinical procedures showed no striking or constantvariation from the normal. A total of 91 separatedeterminations, which include maximum specificgravity, phenolsulphonphthalein excretion, con-centration of nonprotein nitrogen in the serum,albumin in the urine, urinary sediment and intra-venous pyelography, are reported in Table I. Ofthese only 16, or less than 18 per cent, were out-side the average range for normals. Albuminwas noted at 2 examinations, blood cells or castsat 4 examinations. Eight of the ten patients wereable to concentrate urine to 1.020 during at leastone examination. The nonprotein nitrogen wasabove 35 mgm. per 100 cc. in only two instances.The intravenous pyelogram was normal in all ex-cept two patients. All except one subject was ableto excrete more than 25 per cent phenolsulphonph-thalein dye during the first 15 minutes afterinjection.

In contrast to these data, the rate of formationof glomerular filtrate as determined by inulinclearance was below normal at the first observationin each patient (Table III). Thus, W. H. onDecember 9, 1939, had an inulin clearance of only82 cc. per minute; yet he was able to concentrateurine to 1.024 and excreted 30 per cent of phenol-sulphonphthalein dye during the first 15 minutesafter intravenous injection. The values in nine

patients ranged between 56 cc. and 97 cc. Theaverage was 77 cc. In our investigations of inulinclearance we have chosen arbitrarily 100 cc. ofplasma per minute as the lower limit for a normalperson and 120 cc. as an average normal value.These data are similar to those reported by Gold-ring and associates (20).

Following the first series of renal function stud-ies, desoxycorticosterone acetate in oil was admin-istered and, later, pellets of this substance wereimplanted. Subsequently, an increase in rate offormation of glomerular filtrate was apparent inthe five patients on whom this function was stud-ied. The increases averaged 32 per cent, a signifi-cant gain. Simultaneous clinical improvement wasmore subtle than obvious since the patients werein a relatively satisfactory clinical condition at thetime of the initial tests. Following implantationof pellets for one year or longer, the improvementin renal function noted shortly after institution ofdesoxycorticosterone acetate therapy had regressedin all except E. H. Three of the five patients onwhom these tests were repeated showed an inulinclearance below that observed at the time of thefirst admission to the hospital. This result is notsurprising since the life of the pellets used in thisstudy is approximately 12 months and the amountof drug available from this source decreases rap-idly after one year. It shou,ld be stressed, how-ever, that except for H. M. no clinical symptomsof acute adrenal insufficiency were apparent andthe patients were readmitted because we had ad-vised it. Each patient believed that clinical im-provement which developed month by month fol-lowing desoxycorticosterone acetate therapy hadbeen maintained in a large part.

The effect of administration of adrenal corticalextract (Wilson's) upon kidney function was in-vestigated in two patients. Each was given 20 cc.of the material daily in divided doses intramuscu-larly for 5 days. The extract was given to ascer-tain whether it would have any demonstrable ef-fect upon inulin clearance. No striking improve-ment in clinical state was anticipated because thiswas satisfactory before administration of this ma-terial. The experiment was negative in both sub-jects. It was concluded that adrenal cortical ex-tract in the doses given is unable to restore im-paired renal function in patients with Addison's

112


disease beyond that achieved by desoxycorticos-terone acetate.

Creatinine clearance was determined simultane-ously with inulin clearance in most instances. Anormal person excretes approximately 25 per centof the total creatinine by means of tubular excre-

tory activity and the remainder by glomerularfiltration. The patients with Addison's disease inour series excreted slightly more than 30 per centof the total by the tubules and proportionately lessby glomerular activity. This is indirect evidencethat glomerular filtration in Addison's disease isdepressed to a greater extent than is renal bloodflow; the latter supplying creatinine-containingblood for tubular excretion.

Further evidence to support the assumption thatin Addison's disease glomerular filtration suffersmore than does renal blood flow was deduced frommeasurements of diodrast clearance at low plasma

levels (Table III). Effective renal blood flowmay be calculated from diodrast clearance at lowplasma levels and cell volume. This functionwas not determined in many patients, but the col-lected observations show proportionately less de-pression below normal than do inulin clearances.Renal plasma flow averaged 465 cc. per minute in10 tests on the Addisonian patients. The average

for the normal subjects was 690 cc. per minute.Administration of adrenal cortical extract did notaffect this function.

The ratio of glomerular filtration to renalplasma flow has been designated filtration fractionby Smith. In five normal subjects this averaged21.5 per cent. In the Addison's patients it aver-

aged 15.7 per cent. A diminution in filtrationfraction may be accomplished by a decrease inblood pressure or a diminution of tone of efferentarterioles of the nephron. Since the blood pres-

TABLE III

Renal function observations on ten patients with Addison's disease

Cc. of plasma cleared per minute.ager Average of 3 or more periods. Effec- Dio- Glu- Filtra-Bodyurine - _____ - _____ ~~~tive drast

Patient Date sBo°fdaye uflrOmae renal drat- Tm. tionsurface flow

Do lo iodineTx frac-during eInulinCeati- Sodi- Potas- drast- flow Tm. tion

test nin um slum iodine

CC.c. mgm. mgm.,pesq. M. per fer r ter extminute msnute msnxu msnuteH.M. November 8, 1939 1.40 6.6 97 152 6.8 27.2

November 28, 1939 1.41 7.3 102 145 6.5 35.3February 15, 1941 1.34 0.6 55 0.9 442 692 36 12.5

W.H. December 9, 1939 1.63 5.7 82 118 0.9 8.9December 23, 1939 1.64 11.5 100 159 2.9 10.1March 3, 1941 1.68 3.9 57 0.7 7.8 592 924 42 9.7

A.H. January 12, 1940 1.42 1.9 70 122 1.7 9.4January 31, 1940 1.44 2.5 106 125 4.0 12.8

A.O. February 13, 1940 1.48 1.3 82 115 0.6 7.7February 28, 1940 1.52 1.1 91 139 1.4 9.2

D.S. March 19, 1940 1.42 4.0 56 69 2.8 6.7June 5, 1940 1.46 2.0 95 132 0.5 14.4April 17, 1941 1.49 2.8 78 358 560 186 21.8April 21, 1941 1.49 1.8 72 376 586 188 19.2

J.Coc. May 3, 1940 1.65 1.5 92 132 1.1 7.8April 4, 1941 1.67 2.7 70 0.3 416 614 16.8April 9, 1941 1.68 3.2 68 0.9 366 538 23 18.9

J.Cob. June 23, 1940 1.61 2.4 82 103 1.8 10.8

E.H. July 19, 1940 1.85 3.1 68 116 1.2 12.1 388 682 .29 153 17.5July 17, 1941 1.84 1.0 80 1.0 6.0 504 840 36 15.9

J.Col. March 13, 1941 1.86 1.0 81 0.5 690 1110 11.8

J.L. July 28, 1941 1.64 1.8 74 2.6 520 850 35| 14.2

113


sures were essentially normal, it is assumed thatthe decreased fraction was produced by efferentarteriolar relaxation.

The observations on maximum tubular capacityfor excretion of diodrast (diodrast Tm.) andmaximum tubular capacity for reabsorption of glu-cose (glucose Tm.) are too few for one to drawconclusions. It may be stated, however, that tubu-lar excretory capacity appears to be maintainedremarkably well, while capacitv for reabsorbingglucose is impaired seriously. Reabsorption ofwater by the tubules was calculated for five pa-tients before and after treatment with desoxycorti-costerone acetate. The percentile reabsorptionwas unchanged in three patients, increased in oneand decreased in one. No significant change wasnoted in the two patients who received adrenalcortical extract. Our data, therefore, do not con-firm the conclusions of Gersh and Grollman (13)and Silvette and Britton (21) that tubular re-absorption of water is increased in animals inadrenal insufficiency. Increased tubular reabsorp-tion of water would be a rather unexpected find-ing since glomerular filtration is depressed. Fur-thermore, in acute adrenal insufficiency increasedurinary output accompanies development ofsymptoms.

The exchange of sodium, chloride and potassiumby the kidney was calculated as cc. of plasmacleared per minute and recalculated to determineper cent reabsorption by the tubules according to

the formula -( sodium clearance X 100. Ininulin clearance

employing the term clearance for electrolyte ex-change, we have assumed that it implies and em-bodies a process similar to the clearance of sub-stances such as urea, phosphate, and urate. In-herent aspects of electrolyte clearance include ap-pearance of these substances in the glomerular fil-trate in the same concentration as they exist inplasma, and reabsorption in part by tubular cellsas the glomerular filtrate passes through the tubu-lar lumina. We have assumed that electrolytesare not excreted by the tubules.

The electrolyte clearances were determined be-cause the statement has been made that the tubulecannot absorb adequate quantities of sodium in ad-renal insufficiency (22, 23). Additional data on

this subject seemed desirable. Normal persons ona sodium chloride intake of from 6 to 10 gramsper day will have a "sodium clearance" of from1 to 5 cc. of plasma per minute. All of the Addi-son's patients except H. M. had a sodium clear-ance within this range or below. During the pe-riod of the test, therefore, no dissipation of sodiumwas apparent. Similar conclusions were reachedby Schafer (24) who employed a different tech-nique for the study of renal activity of the ad-renalectomized dog and cat. Our conclusions arenot intended to imply that a dissipation of sodiumdoes not occur in adrenal insufficiency (25). Infact these clearance data may be interpreted asconfirming the assumption that, during the tests,none of the patients was suffering from acuteadrenal insufficiency. An alternate explanationfor our inability to detect any dissipation of so-dium is that these studies on renal function arenot sufficiently precise to detect subtle variationsin sodium exchange. The results obtained fromthe calculation of tubular reabsorption of chlorideare scattered and are not conclusive.

The data on potassium clearance appear to bemore definitive. Each of the first five patientsstudied showed an increased clearance of potas-sium following treatment with desoxycorticos-terone acetate. This was an expected result sincethis substance promotes elimination of potassiumas well as retention of sodium. The increasedexcretion of potassium is produced mainly by anincrease in glomerular filtration. Calculation ofthe amount reabsorbed by substituting potassiumclearance in the above-mentioned formula givesscattered results just as for sodium.

Adrenal insufficiency secondaryto pan-hypopituitarism

All of the patients with pituitary hypofunctionshowed a profound depression in inulin clearance(Table IV). The average for the group was ap-proximately one-half that for normal controls.Creatinine clearance showed a smaller percentiledecrease from normal, as was observed in patientswith Addison's disease. More than 30 per cent ofthe creatinine excreted was by means of tubularactivity. Diodrast clearance at low plasma levelswas determined on two patients. The filtrationfractions were 21.1 and .19.1 per cent, respectively.

114


TABLE IV

Renal function observations on six patients withpan-hypopituitarism

Cc. of plasa cleaed per _B minute. Average of 3 or cmore periods.

a a0~~~~~C 0

_ _ _I_cc. i1._eq. Per per perm. mn- mtn- cend

N.W. November 13, 1939 1.35 0.9 49 70 0.3 16.9December 15, 1939 1.37 1.8 40 0.6 9.0

C.O. December 20, 1939 1.71 9.6 70 118 1.0 8.5

D.A. January 30; 1940 1.87 8.0 61 89 0.6 21.3

E.D. May 11, 1940 1.70 11.4 63 91 7.4 11.8November 25, 1940 1.81 7.6 43 5.2 13.3 204 16.6 21.1

E.B. July 19, 1941 1.64 5.1 61 320 27.5 19.1

B.L. August 4,1941 1.64 9.8 77 _ 43.9

Normal controls

The effect of desoxycorticosterone acetate upon

renal activity was studied in two normal subjects,B. C. and B. D. Each subject was given daily10 mgm. of the substance in oil for 7 days. Clear-ance studies before and after administration toB. C. were similar. Before-administration studieswere not done on B. D. but after-treatment studieswere within the average range for normals.

These observations suggest that desoxycorticos-terone acetate does not influence rate of formationof glomerular filtrate in normal persons. Severalobservations of sodium and potassium clearancewere made on R. J. following a high as well as a

low potassium intake (Table V). High potas-sium clearances followed a high potassium intake.They approximated inulin clearance, which indi-cates that most of the potassium which appearedin the glomerular filtrate was excreted and was notreabsorbed. On a low potassium intake, the clear-ance of potassium was maintained within the aver-

age range for normals. Large changes in potas-sium clearance were not reflected by a similarchange in sodium clearance. It is suggested thatsodium and potassium possess independent mecha-nisms for excretion by the kidney and no recip-rocal excretion of these substances is manifest.

PATHOLOGICALOBSERVATIONS

One of our interests in pursuing this investiga-tion of renal function in adrenal insufficiency was

the reported absence of structural damage in thekidney of patients dying from Addison's disease(2, 26, 27, 28, 29). One might assume, there-fore, that the changes in the kidney were "func-tional" and reversible if the adrenal insufficiencycould be controlled. A comprehensive study of

TABLE V

Renal function observations on six control subjects

co. of plasma clearedper minute. Average

Jfa3 or more periods

Remarks

CC. ~ ~ ~ 0 .

years~ ~ s. erper periears m. mm- ,n~~~~~~~~~in-centust uSe

R.J. 40 ci' January 4, 1939 1.63 112 153 2.0 25.4 Normal rgmnJanuary 3, 1940 1.68 16.6 103 131 5.4 75.1 7 grams ofptassiumn chloride during 3 hours before test.January 6, 1940 1.68 17.2 104 145 3.1 78.4January 16, 1940 1.67 16.8 95 142 3.2 11.4 Low potassium diet for 8 days.January 19, 1940 1.68 7.5 98 142 5.1 12.3 Low potassum diet for 11 days. 30 grams sodium chloride during 48 hours

before test.

B.C. 19 d" November 14,1940 1.74 8.5 183 254 4.9 16.1 730 66.4 25.0 Normal regimen.December 10 1940 1.74 2.0 190 269 1.7 20.2 710 65.4 26.7 10 mgm desoxycorticosterone acetate intramuscularly esch day for 7 days.

D.D. 54 6' November 22, 1940 1.99 3.4 116 164 3.4 8.8 530 43.8 21.9 10 mgm. desoxycorticosterone acetate intramuscularly each for day 7 days.

L.C. 32 9 December 4, 1940 1.64 8.8 122 179 2.8 27.4 676 54.5 18.1 Normal regimeLR1. 18 di July 27, 1940 1.77 3.5 185 210 3.1 870 44.0 21.3 Normal regime.F.M. 23 9 August 7, 1940 1.61 9.2 139 190 1.1 675 48.0 20.6 Normal regimen.

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postmortem material was reported by Guttman(30) in 1929. In a statistical study of 566 autop-sied cases of Addison's disease collected from theliterature, less than 10 per cent showed morpho-logic changes in the kidneys sufficient to justifyan anatomic diagnosis of renal disease. Approxi-mately one-half of this number showed tubercu-losis of the kidney; the remainder showed amongother conditions acute and chronic nephritis andpyelonephritis.

Somewhat different findings were reported byBarker (31) in thirty-one autopsied cases. Tenof this number showed tubular atrophy whichconsisted of "flattening of the epithelial cells anddiminution in the amount of cytoplasm. Thetubular lumina usually appeared diminished indiameter with intertubular edema. Occasionally,fat was evident in the tubular cells." Barker in-terpreted these changes as the analogue of a toxicnephrosis which had been produced by hypotensionand anoxemia. Similar pathological findings havebeen observed in adrenalectomized animals. Fatdeposits in the epithelium of the collecting tubuleshave been noted in the cat (5, 32) and generalswelling of the tubular cells in the dog (33).It is of interest that Simpson and Korenchevsky(34) prevented the development of degenerativechanges in the tubules of rats following adrenal-ectomy by the use of adrenal cortical extract. Nomention was made of time allowed for the devel-opment of degenerative changes or the amount ofextract necessary for prevention of changes.

In our series of patients none of them gave ahistory of having had any renal disturbance anda diagnosis of acute or chronic nephritis, nephro-sis, or pyelonephritis was not presumed in any.D. S. had changes by intravenous pyelogram whichsuggested unilateral tuberculosis of the kidney.He has been followed over a period of more than4 years and the diagnosis has never been confirmedeither by medical or urological consultants. In-jection of a sample of urine into a guinea pigdid not lead to tuberculosis in the animal.

Finally, we are able to report on postmortemmaterial from three patients studied in this seriesas well as three other patients who died fromAddison's disease. The microscopic examinationswere made by Dr. B. M. Castleman. The kidneysof A. H. at autopsy showed minimal structural

changes consistent with pyelitis and pyelonephri-tis. It is significant that our studies which weredone 5 months before death from carcinomashowed a low normal inulin clearance followingimplantation of pellets. If the pyelonephritiswere playing a large role in depression of glom-erular filtration, it is assumed that desoxycorti-costerone acetate could not have restored thisfunction to normal. It is concluded that glomeru-lar filtration on entry was not depressed becauseof pyelonephritis, but was an integral part of theadrenal disturbance. C. 0. had normal kidneysexcept for small deposits of hemosiderin. It isnot believed that the hemosiderin deposits hadinterfered seriously with renal function duringlife. The kidneys of E. B., as well as those ofthree other patients who died from Addison's dis-ease during the past 2 years, but who were notsuitable patients for clearance studies, appearednormal.

DISCUSSION

The capacity of the kidney has been investi-gated in patients with Addison's disease and inpatients with adrenal cortical atrophy secondaryto pituitary hypofunction. Both groups of pa-tients were studied at a time when clinical symp-toms of acute adrenal insufficiency were absent.The data reported, therefore, are to be inter-preted as an integral part of controlled adrenalinsufficiency rather than severe adrenal depletion.Renal function was studied by the clinical testsusually applied and by more quantitative meas-urements of specific renal activity. Routine clini-cal tests in the majority of instances were normal.On the other hand, precise measurement of renalfunction by the clearance tests recently describedby Smith and associates showed considerableimpairment.

Rate of formation of glomerular filtrate asmeasured by inulin clearance was depressed sig-nificantly in all patients before treatment. From1 to 4 weeks following treatment with desoxycor-ticosterone acetate, the patients with Addison'sdisease showed partial restoration of glomerularfiltration. One year or more following implanta-tion of pellets of desoxycorticosterone acetateand, in spite of continued clinical improvement,regression of glomerular filtration rate had takenplace. Renal plasma flow as measured by diodrast

116


clearance at low plasma levels showed a smallerpercentile depression than did inulin clearance.The ratio of inulin clearance to diodrast clear-ance, i.e., filtration fraction, was considerably be-low normal. Of all the measured functions,maximum tubular capacity for excreting diodrastat high iodine plasma levels was affected least.Maximum tubular capacity for reabsorbing glu-cose at high plasma levels was most affected.

There are several factors which might be re-sponsible for the pathogenesis of renal impair-ment in symptomatically controlled adrenal in-sufficiency. These are (1) vasomotor unrespon-siveness and hypotension, (2) increase in concen-tration of serum protein, (3) decrease in meta-bolic rate, (4) structural changes in the kidney,(5) non-specific result of a chronic disease, and(6) lack of some specific action of one or moreadrenal cortical hormones.

Diminution of blood pressure may be suspectedbecause hypotension might produce many of theobserved changes. In acute adrenal insufficiency,a significant depression in renal function un-doubtedly may be attributed to hypotension. Inour studies, however, blood pressures were normalin most instances. Furthermore, if hypotensionhad been responsible, renal plasma flow shouldhave suffered quite as much as inulin clearance,instead of the reverse. The data suggest a dim-inution in efferent arteriolar tone with less im-pairment of tubular activity than rate of forma-tion of glomerular filtrate. This is consistentwith the clinical findings of a poorly functioningvasomotor system.

Dehydration with increase in colloid osmoticpressure was not seriously implicated because theconcentrations of serum protein were within therange for normal.

A decrease in metabolic rate has not beenentirely excluded as being responsible for theobserved effects. In Addison's disease, as well asin adrenal insufficiency secondary to pituitaryhypofunction, the metabolic rate is depressed.If the averages of the two groups are compared,the patients with pituitary hypofunction had agreater depression of kidney function as well asa greater depression in metabolic rate. Since thehormone produced by the thyroid has an effectupon cellular activity generally, it is reasonable to

assume that depressed tubular activity may fol-low inadequate elaboration of it.

Structural changes in the kidney are observedinfrequently in Addison's disease and cannot beheld responsible for the functional impairment.

We cannot refute with certainty the supposi-tion that the observed changes are the effect of achronic disease per se. Signs of grave renal in-sufficiency which accompany acute adrenal insuf-ficiency argue for a more specific relationship.

Maintenance of the integrity of the kidney byhormones of the adrenal cortex was postulated byMarshall and Davis in 1914 (5). Such a postu-lation is not unreasonable and partial restorationin inulin clearance immediately following treat-ment with desoxycorticosterone acetate supportsit. The failure of kidney functioti to be main-tained a year after implantation of pellets andthe absence of improvement in renal function inAddison's disease following administration of ad-renal cortical extract negate the postulation.

In conclusion, the correct explanation of thepathogenesis of renal impairment may be multiplerather than single. A combination of all or ofmost of the hypotheses would be in keeping withthe statement made in the introduction of thepaper, i.e., adrenal insufficiency is a complexphenomenon.

SUMMARY

Studies of kidney function have been pursuedin ten patients with chronic adrenal insufficiencyassociated with Addison's disease and in six pa-tients with chronic adrenal insufficiency associatedwith pan-hypopituitarism. All of the patientsexcept two gave a negative history for acute orchronic renal disease. In most instances the pa-tients were well compensated and symptoms ofsevere adrenal insufficiency were not present im-mediately before, during or after any of the tests.The function tests included accepted clinical pro-cedures, as well as clearance of inulin, creatinine,diodrast, glucose, sodium, chloride and potassium.

The clinical tests for renal disease were normalin most patients. On the other hand, more pre-cise tests showed evidence of impairment of allmeasured aspects of renal function in all patientsat most examinations. Rate of formation ofglomerular filtrate and tubular reabsorptive ca-

17


pacity for glucose were affected most. Renalplasma flow was affected less and tubular capacityfor excreting diodrast was affected least. Thefiltration fraction was depressed below normal.Administration of desoxycorticosterone acetatecorrected partially, but temporarily, these de-ficiencies. Administration of adrenal cortical ex-tract had no demonstrable action upon the meas-ured functions. Administration of desoxycorti-costerone acetate to two normal persons waswithout demonstrable effect upon renal activity.

The pathogenesis of these aberrations is as-sumed to be "functional" in so far as no structuralchanges are consistently observed in the kidneysof patients who have died from adrenal insuffi-ciency. Vasomotor unresponsiveness, a decreasein metabolic rate, a nonspecific effect of a chronicdisease, and a lack of specific action by the adrenalcortical hormones may each contribute.

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FUNCTION AND PAN-HYPOFUNCTION