Hyperkalemia, hypertension and systemic acidosis without renal failure associated with a tubular defect in potassium excretion

Hyperkalemia,

Hypertension

Acidosis without

Renal

with a Tubular Potassium

and Systemic

Failure

Associated

Defect in

Excretion*

J. E. ARNOLD, M.B. and J. K.

HEALY,

M.R.A.C.P.

South Brisbane, Queensland, Australia A twenty-one year old man is described who has what appears to be a unique renal tubular defect in potassium excretion, associated with persistent hyperkalemia (up to 8.2 mEq. per L.), hypertension, systemic acidosis and slightly impaired renal excretion of acid. Renal failure was absent; glomerular filtration rate, maximal tubular secretion of p-aminohippurate, maximal urinary concentrating ability and urinary amino acid excretion pattern were all normal, as was the appearance of renal tissue at biopsy. Clearance of p-aminohippurate and phenolsulfonphthalein excretion were somewhat reduced. A balance study showed a positive potassium balance of 142 r&q. in four days, associated with low urinary potassium excretion and rising serum potassium levels; sodium balance was normal. Red cell electrolyte content was normal, as were salivary and sweat potassium concentrations. Sodium sulfate infusion combined with a carbonic anhydrase inhibitor, which markedly increased potassium excretion in control subjects, had little effect on the patient’s potassium excretion, except when accentuated by prior salt depletion and 9cr-fluorohydrocortisone administration. Adrenal insufficiency was excluded as a cause for hyperkalemia and there was no evidence of impaired tubular response to mineralocorticoids, since sodium metabolism was normal. The hypertension, associated with blood pressures up to 140 mm. Hg diastolic, responded well to treatment with sodium polystyrene sulfonate (Resonium@ A) and chlorothiazide, which also controlled the hyperkalemia. Diastolic blood pressures correlated significantly with serum potassium levels. Endocrine causes for hypertension were excluded. Pressor responses to cold, smoking, norepinephrine and angiotensin were in the range reported in patients with hypertension of other causes. Chromosome studies were normal, but absent incisor teeth in the patient and in his brother, and a family history of mental illness raised the possibility of a genetic basis for his metabolic disorder.

A

year old boy was found to have a blood pressure of 210/120 mm. Hg on routine medical examination in another state in 1961. Hyperkalemia was also discovered, but there was no evidence of renal failure. Preliminary investigations on this patient were presented in 1964 by Paver and Pauline [ 7 1, who found that his serum potassium varied from 7.0 to 8.2 mEq. per L., but that his renal function, microscopic examination and culture of his urine, and

renal biopsy were normal. Investigations for a specific cause of hypertension were negative. The patient and his brother were also noted to have only two upper incisor teeth, but it was later established that his brother was normokalemic. Since publication of this initial report in 1964 the patient had attended several hospitals in Sydney. Without treatment, hypertension and hyperkalemia have persisted. Studies at Sydney Hospital revealed no adrenal cause for

FIFTEEN

* From the LIONS Renal Research Laboratory, Princess Alexandra Hospital, South Brisbane, Queensland, Australia 4102. The work of this Laboratory is supported by grants from the LIONS Clubs of Southern Queensland and Northern NSW, from the National Heart Foundation of Australia, and from the National Health and Medical Research Council of Australia. Requests for reprints should be addressed to Dr. J. K. Healy. Manuscript received November 25, 1968. VOL.

47,

SEPTEMBER

1969

461

Renal Tubular

Defect in Potassium

the hyperkalemia, and neither the adrenal glands nor the renin-angiotensin system appeared primarily responsible for the hypertension. Several therapeutic regimens have been given since 1966. Since the patient came to Brisbane in August 1967, therapy with chlorothiazide and sodium polystyrene sulfonate (Resonium A) has c~ontrolled his blood pressure at about 140/90 11~1. Hg, and has maintained his serum potassium

within

normal

In the original

limits.

report

of this case

it was postu-

the patient had a renal defect in potassium excretion. Recent investigations at this hospital have further characterized his renal function and the hypertension. It has been established that he does in fact have a renal tubular defect in potassium excretion, which can be overcome by a combination of salt depletion, rnineralocorticoids and sodium sulfate infusion. Slight impairment of renal excretion of acid accompanied by a mild systemic acidosis was also found. The hypertension was found to bear a relation to his serum potassium levels. Although defects in potassium metabolism have not been found in the only two relatives examined, and although chromosome studies on the patient’s leukocytes revealed no abnormality, nevertheless a strong family history of mental illness, together with the congenital dental anomaly in the patient and his brother raises the possibility that his unique metabolic defect may have been genetically determined. lated,

but

not

proved,

that

CASE REPORT

The patient, a fifteen year old boy at the time, was

found to be hypertensive on routine medical examination in 1961. Until then his only complaints had been

Excretion-Arnold,

Hdy

crearinine, urinary concentration t0i, urea clearance and urinary acidification after ammonium c t~loricle ingestion, was normal, as were microscopic examination and c.ulture ol the urine, and t,enal tliopsy. Administration of a carbonic anhytlrase inllil)itor. appeared to increase urinary potassium excretion, whercsas spironolactone did not alter it. Invc’stis_ations of the cause of hypertension at that time included histamine stimulation and phrntolaminc blocking tests, urinary catecholamine estimation. Intravenous urogram, aortogram and renal angiog_ram, tlifGrentia1 renal function studies, and estimation of urinary 17ketosteroid and 17-OH corticosteroicl rxcrrtion rates, all of which were normal. Since these findings were published in 1964, investigations at Sydney Hospital have sho\\sn that his plasma aldosterone and corticosterone kvels were normal, and that his aldosterone secretion rate was slightly elevated (232 pg. per day; normal up to 150 pg. per day). There appeared to he no obvious deficiency in renal response to mineralocorticoids, since 9,-fluorohydrocortisone caused a decrease in sodium excretion and an increase in potassium excretion. At times his urinary 17-ketosteroid and 17-OH corticosteroid excretion rates were in the high normal range, hut the administration of dexamethasonc suppressed these normally, and he had a normal plasma cortisol level which showed some diurnal variation. Plasma renin activity was low normal, but responded normally to salt depletion, and showed a rise in response to the erect posture. Further studies at Sydney Hospital showed a normal true creatinine clearance (155 ml. per minute per 1.73 M2.), but some reduction in fifteen minute urinary phenolsulfonphthalein excretion to 27.6 per cent of the dose excreted (normal >32 per cent). Acid excretion after ammonium chloride ingestion in 1965 was normal, hut was at the lower limit of normal in 1967. He was found to have a normal ability to conserve sodium during salt depletion, when urinary sodium fell to lrss than 5 mEq.

occasional headaches, and enuresis which commenced at the age of eight years when he was deserted by his parents. There were no other urinary or cardiovascular symptoms. Physical examination revealed a blood pressure of 18Oj120 mm. Hg and the absence of two upper incisor teeth. He appeared below average intelligence, since he was three years older than other children in his school grade. About 1963 he began to have attacks of muscular weakness, one to two hours in duration, usually following exertion and tending to affect the muscles most in use. However, other similar attacks were un-

per day. He remained untreated, and between 1964 and 1966 his blood pressure varied from 180 to 210 mm. Hg systolic and from 120 to 140 mm. Hg diastolic. In January 1966 treatment with a-methyldopa, 500 mg. four times each day, was commenced. In July 1967 his treatment was changed to sodium polystyrene sulfonate (Resonium A) 15 gm. twice daily, spironolactone (Aldactone (* A) 100 mg. per day, and chlorothiazide 500 mg. per day. This controlled the hypertension more successfully and also kept his serum potassium levels within the normal range, whereas the attacks of muscular weakness diminished

related to exercise. Initial investigations by Paver and Pauline [7] showed persistent hyperkalemia (serum potassium 7.0 to 8.2 mEq. per L.). Total exchangeable body potassium (43.5 mEq. per kg. of body weight) was considered to he at the upper limit of normal. Renal function, as measured hy blood urea level, serum

in severity and frequency. The patient was asymptomatic on arrival in Brisbane in August 1967. Aldactone A therapy was ceased, hut control of the hypertension and hyperkalemia with Resonium A and chlorothiazide remained satisfactory. He was admitted for investigation; to Princess Alexandra Hospital in January 1968,

Renal Tubular Defect in Potassium Excretion-Arnold, at which time he was well and his blood pressure was 140/90 mm. Hg. A soft, functional, apical systolic murmur was present. There were no other abnormal physical findings. His past history revealed tonsillectomy, appendectomy and a fractured forearm, all in early childhood, and unassociated with any complications. His family history was of interest. The patient had one younger brother who also had only two upper incisor teeth, but who was found to be normotensive and normokalemic when examined in 1967. His mother is fifty-five years old and has had mild hypertension for twenty years. She is normokalemic and has no history of renal disease. His mother had four brothers and one sister, none of whom had a history of renal disease or hypertension, but all four brothers were dead. In one schizophrenia developed when he was twenty years old and he died of tuberculosis at the age of thirty-one. In another brother schizophrenia developed when he was twenty-five years old; he committed suicide at forty-three years of age. The other two brothers suffered from depression, and both committed suicide at the age of thirty-three years. One of these also had epilepsy (?petit mal). The mother’s sister is alive and well. The patient’s father was an alcoholic and died suddenly of myocardial infarction at sixty-seven years of age. The father had two brothers and one sister, none of whom were known to have renal disease or hypertension. METHODS

The renal clearances of inulin and creatinine, and of p-aminohippurate (C&n), and the maximal tubular secretion of p-aminohippurate (Tm,,,) were measured by standard procedures; details of the technic employed in this laboratory were described previously [Z]. The modified fifteen minute urinary phenolsulfonphthalein test was carried out as previously described [3]. For the electrolyte balance study, a constant diet was given each day. A duplicate diet was ashed for estimation of sodium and potassium. Feces were collected between carmine markers. After digestion in concentrated nitric acid for seven days, aliquots of each stool were evaporated in electrolyte-free glassware, and sodium and potassium content was estimated following the addition of glass-distilled water. Results obtained by this procedure were the same as those obtained after ashing an aliquot of feces. Twenty-four hour urinary electrolyte excretion was also measured during the study. To estimate red cell sodium and potassium, inulin was first added to whole blood samples, which were then centrifuged, the supernatant plasma was removed and electrolyte measurements were made on both the packed cells after lysis and on the plasma. Results were expressed as milliequivalents of electrolyte per liter of cell water, after correction for the amount contained in plasma trapped between the cells; the latter was determined from the inulin space VOL.

47,

SEPTEMBER

1969

Healy

463

of the centrifuged sample. Cell water was calculated, after similar correction for trapped plasma, from the change in weight when the packed cells were dried in a vacuum oven overnight at 70”~. The results in the patient were compared with the results obtained from nine red cell studies in four normal subjects. All red cell studies were performed in duplicate. To stress the patient’s capacity to excrete potassium, an intravenous infusion of sodium sulfate was given in two experimental protocols: (1) After establishment of a water diuresis, potassium excretion was measured in two control periods. This was followed by an intravenous infusion of 4.2 per cent sodium sulfate, 1 L. in two and a half to three hours, during which five more urine collection periods were obtained. At the beginning of the fourth of these periods, an intravenous injection of acetazolamide, 5 mg. per kg. of body weight, was given. (2) In further studies, a similar protocol was used, but the patient was salt depleted by the oral administration of 50 mg. of ethacrynic acid three days prior to the study, followed by a low sodium diet (30 mEq. per day) for that period. Weight loss without an increase in plasma sodium was taken as evidence of salt depletion. On the morning of the test day, 9cY-fluorohydrocortisone, 1 mg. at 6 A.M. and 1 mg. at 9 A.M., was given orally prior to commencement at 10 A.M. of urine collection periods. Urine collection periods in both experiments 1 and 2 were of thirty to forty minutes in duration, and both protocols were carried out twice with the patient, and with two normal control subjects. Acid load studies were carried out by the method of Wrong and Davies [4]. Arterial pH studies were performed anaerobically with a Radiometer type 27 pH meter. The Harvard constant infusion syringe pump used for inulin and p-aminohippurate infusions was also used to study the effect of pressor agents. To study salivary electrolyte concentrations, whole saliva was collected while the patient chewed a paraffin block. Sweat was obtained by pilocarpine iontophoresis [5]. Sodium and potassium levels were measured by internal standard flame photometry. Inulin was estimated by the method of Walser, Davidson and Orloff [6], and p-aminohippurate by the method of Smith [7]. Plasma true creatinine was measured by elution from Lloyd’s reagent with alkaline picrate, as described by Owen et al. [8]; urinary creatinine was measured by the method of Bonsnes and Taussky 191. The autoanalyzer was used to estimate calcium levels in plasma and urine [ 701, urinary ammonium [77], blood urea and glucose levels, and plasma levels of chloride, bicarbonate, inorganic phosphate and uric acid [ 721. The method of Pisano, Crout and Abraham [ 731 was used to measure 3-methoxy-4-hydroxy mandelic acid (VMA) in urine. Urinary citrate was estimated by the method of Ettinger et al. [74], and urinary amino acids were measured by paper chromatography and quantitated by reference to creatinine con-

464

Renal

SERU?dP@CASSm

Tubular

Defect

in Potassium

4.5 mE@. per L.

SFXIN POTASSIUM 7.3

n@.

per L.

FIG. 1. Electrocardiograms obtained when the patient was normokalemic and hyperkalemic. Elevation of T waves can be sren with hyperkalemia.

centration measured (Advanced

in the sample. Urinary osmolality was by a freezing-point depression technic Instruments). RESULTS

Potassium Metabolism. When treatment with Resonium A and chlorothiazide was stopped, the patient’s urinary potassium excretion remained low and his serum potassium exceeded 7.0 mEq. per L. within four to six days. An electrocardiogram then showed evidence of hyperkalemia with marked peaking of the T waves (Fig. 1). Because of the possible danger of such high levels of serum potassium, treatment was not suspended for longer periods than this. Investigations during this study were thus carried out largely in the numerous intervals in which therapy was interrupted. Two days after all drug therapy was ceased, a four day balance study was performed (Fig. 2). This showed a positive potassium balance of 142 associated with an increase in serum mEq., potassium from 5.0 to 7.4 mEq. per L.; the urinary potassium excretion rate remained low, reaching onlp 32 mEq. per day on the last day of the study, despite a constant dietary intake of 76 mEq. of potassium per day. These results demonstratcd impaired renal excretion of potassium.

Escretion-Arnold,

Heah

Feces relevant to the balance period NUC passed on the third, fourth and sixth days of the study: the total potassium content of these was 82.4 mEq., which gave an average of 20.6 rnEq. of potassium excreted per day in the fee-c,s, which is at the upper limit of the normal rallr:? (3 to 31 mEq. per day [ 751). Technical error interfered with sndiultl estimation in this study, but in a rcprat balance study in which a similar positive potassium balance (113 mEq. in four days) was observed, sodium balance remained normal (positive balance of only 5 mEq. after four days), and urinary and fecal sodium excretion rates were in the normal range. The capacity of the patient’s kiclnr)-s to excrete potassium was tested under the stress of a sodium sulfate load, as outlined under “Methods.” When protocol 1 was used, sodium sulfate caused a very slight increase in the potassium excretion rate. On two occasions potassium excretion rose from 12.6 to 14.3 PEq. per minute and from 16.4 to 34.0 PEq. per minute. The addition of acetazolalnide increased this only to 40 and 65 ~Ecl. per minute, respectively, on the two occasions (Fig. 3). These results contrasted with the lnarkecl increase in the potassium excretion rate induced by sodium sulfate, and the furt1lt.r increase following the addition of acetazolalnidr, in two normal control subjects given the salnr test. They excreted 147 and 120 PEq. per tuinute of potassium during the sodium sulfate infusion, and 319 and 312 PEq. per rninutc. when the acetazolamide was added (Fig. 3).

DlEiARV

POT&W

._

_

1 SEmm FOTASSWM mbdl.

EAV 1

wf

5.0

-

?

DAV 1

DAY 4

DAV 5

5.6

6.6

7.4

FIG. 2. Potassium balance study. \\:hile on a constant diet containing 76 mEq. of potassium and 102 mEq. of sodium per day a total positive potassium balance of 142 mEq. developed in four days, accompanied by an increase in serum potassium from 5.0 to 7.4 mEq. per L.

Renal

Tubular

Defect

in Potassium

However, when an even greater stimulus to potassium excretion was given by accentuation of the effect of sodium sulfate and acetazolamide with prior salt depletion and 9a-fluorohydrocortisone administration (protocol 2, under “Methods”), the patient’s capacity to excrete potassium was similar to that of the normal control subjects (Fig. 4). The patient’s potassium excretion rate rose to 249 and 335 PEq. per minute on two occasions with sodium sulfate infusion alone under these conditions; the addition of acetazolamide produced a further increase in potassium excretion to 335 and 513 PEq. per minute, respectively. In the control subjects, this protocol produced potassium excretion rates of 318 and 420 &q. per minute, and 432 and 544 PEq. per minute with the addition of acetazolamide (Fig. 4). The effect of sodium citrate on potassium excretion was examined. An intravenous infusion of 160 ml. of 3.8 per cent sodium citrate over an hour increased the potassium excretion rate from 41 to 53 PEq. per minute, but although the citrate infusion was continued, excretion fell to 46 PEq. per minute. The oral administration of sodium citrate, in a dose of 2 gm. three times daily, did not prevent the usual increase in serum potassium when the administration of Resonium A and chlorothiazide was stopped. The patient’s red cell electrolyte content was normal and showed no correlation with serum potassium levels. His mean red cell potassium from six measurements (* standard deviation) was 149.3 f 6.2 mEq. per L. of cell water, which was not significantly different from the mean in normal subjects (148.6 f 5.1 mEq. per L. of cell water). Corresponding results for red cell

-PATIENT

1234567

’

URINE

COLLECTION

PERIODS

FIG. 3. The effect of intravenous sodium sulfate and acetazolamide on urinary potassium excretion rate examined on two occasions in the patient and in two normal control subjects. VOL.

47,

SEPTEMBER

1969

Excretion-Arnold,

465

Healy

CWTKXS -

URINE

COLLECTloN

P*TIENT

FERI’XS

FIG. 4. The effect of intravenous sodium sulfate and acetazolamide on urinary potassium excretion rate after prior salt depletion and 9cr-fluorohydrocortisone administration. Two studies in the patient and results from two normal control subjects shown.

sodium content for the patient and control subjects were also not significantly different atient 7.3 f 1.2, controls, 9.4 f 2.9 mEq. per ? .O f cell water). The potassium content of the patient’s saliva was 16.2 mEq. per L. at a flow rate of 1.3 ml. per minute, which was in the normal range [16], as was the sweat potassium content of 6.6 mEq. per L. [17]. Renal Function. Glomerular filtration rate as measured by inulin clearance was persistently normal. The mean of eight separate measurements was 116 ml. per minute per 1.73 M2. (range 101 to 125 ml. per minute per 1.73 M2.) ; individual readings were unrelated to serum potassium level. True creatinine clearance was also normal, the mean of measurements on four occasions being 146 ml. per minute per 1.73 M2. (range 124 to 173 ml. per minute per 1.73 M2.). Plasma true creatinine (0.96 to 1.04 mg. per cent), serum uric acid levels (5.7 to 6.7 mg. per cent) and blood urea levels (18 to 44 mg. per cent) always remained within normal limits. After the patient had been normokalemic for some months on treatment, his CPAn was normal at 622 ml. per minute per 1.73 M2. After two months of investigation there was a marked decrease in this value; it was then 350 and 353 ml. per minute per 1.73 M2. on two separate occasions when serum potassium was 5.0 and 6.3 mEq. per L., respectively. During that time his serum potassium level had frequently been high, and his blood pressure was also generally higher than when continuous treatment was

166

Renal

Tubular

Defect

in Potassium

Excretion-_

lrdd.

Hra!l

given. Several months after continuous treatlnent was reinstated, his CPAH was 450 ntl. per minute per 1.73 M’. ‘TmpA ki was 63.0 and 86.4 mg. per minute per 1.73 M”. on two occasions, values within normal limits even though the latter result was obtained when CP.~H was reduced. The fifteen minute exrrction urinar) of phenolsulfonphthalein showed some reduction, a range of 21.3 to 25.4 per cent of the dose being recovered from the urine in that time in six estimations (normal for males >32 per cent [3]). Small fluctuations in phcnolsulfonphthalein excretion were unrelated

r ?$a&,.

-

FEB. 16. 1968.

.- FEB. #JG. 23.1968. 3. 868. FIG. 6. Changes in serum potassium, plasma chloride and plasma bicarbonate levels produced by wssation and recommrnc~mcnt of therapy.

PH

12345678

,uE&nin

&

TIME IN HOURS FIG. 5. Urine pH changes, titratable acid excretion and ammonium excretion (obtained on the third test only) after an ammonium chloride acid load on three occasions. The shaded areas indicate the range of normal rcsults for this test reported by Wrong and Davies [ I].

to the serum potassium level. hlaximum urinary concentration after the intramuscular injection of 5 units of Pitressin” tannate in oil was normal at 900 mOsm. per kg. A\cid load tests were performed on three occasions and suggested slight impairment of acid excretion. Figure 5 shows that on each occasion there was some delay in the fall in urine pH, whirh was also reflected in a delayed increase in the excretion of titratablc acid. On two of the three occasions the Ininimum urine pH (5.33 and 5.45) remained slightly above the normal range given by Wrong and Davies 141. Technical error interfered with amnionium estilnation in the first two studies, but the third study suggested slightly impaired ammonium excretion, even though in this study the lowest urine pH (4.95) was recorded (Fig. 5). It was noted that before the ammonium chloride load was given on each occasion the plasma bicarbonate level was reduced, which suggested a tendency to metabolic acidosis. This was confirmed by arterial pH studies. When all treatment was stopped arterial pH fell in four days frown 7.295 to 7.260 and standard bicarbonate fell from 21.2 to 18.0 mEq. per L., whereas the plasma chloride level rose from 107 to 111 mEq. per L. A decrease in plasma bicarbonate and an increase in plasma chloride wcrr also regularly noted whenever treatment was stopped, in association with the development of hyperkalemia (Fig. 6). This pre-existing acidosis tended to increase the significance of the slightly

467

FIG. 7. Diastolic blood pressure and serum potassium levels over a thirty-four day period. The general relationship between these parameters can be seen, as well as the effect on them of variations in therapy.

impaired acid excretion observed after ammonium chloride load. Other aspects of renal function that were measured were normal. These included the pattern of diurnal variation for sodium and potassium excretion and urine volume; the twenty-four hour urinary calcium excretion (230 to 300 mg. per day while intake was 900 mg. per day); twenty-four hour urinary citrate excretion (348 mg. ; normal range 300 to 900 mg. per day); serum calcium and inorganic phosphate levels; and the pattern and quantity of urinary amino acids on paper chromatography. Blood Pressure. The patient’s blood pressure had been in the range of 180 to 210 mm. Hg systolic and 120 to 140 mm. Hg diastolic before treatment. At that time he was persistently hyperkalemic. After treatment with Resonium A and chlorothiazide began in 1967, his blood pressure ranged from 130 to 150 mm. Hg systolic and from 80 to 100 mm. Hg diastolic, and he remained normokalemic. However, during the four months of this investigation, early in 1968, his blood pressure rose again to 145 to 220 mm. Hg systolic and 85 to 140 mm. Hg diastolic. During this period treatment was intermittent, and his serum potassium level was frequently elevated, even above 7.0 mEq. per L. When the serum potassium level was compared on many occasions during this period of investigation with the diastolic blood pressure, a general direct relationship was found (Fig. 7). Although this relationship was by no means close, nevertheless a regression line derived from these vol_.

47,

SEPTEMBER

1969

data (diastolic blood pressure = 3.53 X serum potassium + 86.7 f 8.8 (SD.) mm. Hg, Fig. 8) had a significant correlation coefficient (r = 0.335, p < 0.025) and was significantly sloped (p < 0.050). Following the completion of investigations the patient left the hospital and was treated again with Resonium A 15 gm. twice daily and chlorothiazide, 500 mg. daily. It was then found that his blood pressure did not quite fall to the prethe investigation levels; over three months, mean of seven readings was 159/101 mm. Hg (range 150 to 170/85 to 110 mm. Hg). Chloro-

. .

I

* 4.0 SERUM

5.0 FOTASSIUM

7.0

&II m&/t.

FIG. 8. Relation between diastolic blood pressure and fifty consecutive serum potassium levels over a sixty-one day period. Regression line f standard deviation is shown.

36X

Kenal

Tubular

Defect

in Potassium

thiazidc therap). was stopped, and control of the blood pressure was found to be almost as effective with Kesonium A alone (average of eight readings over two weeks, 166/106 mm. Hg, range 141) to 185190 to 115 mm. Hg). His blood pressure showed some instability-; with emotional stress, sudden elevations to 32Oi140 mm. Hq were noted, even when the patient was on ireatment. A cold pressor test produced a rise of 35 mm. Hg in both systolic and diastolic pressures from a base-line of 155: 100 111111. Hg. Smoking one cigarette in hen minutes caused a rise of 15 mm. Hg in both systolic and diastolic pressures from an initial pressure of 150/‘105 mm. Hg. An intravenous infusion of norepinephrine at 0.5 pg. per kg. per minute produced a 20 mm. rise in both pressures lronl an initial pressure of 160/100 mm. Hg. Intravenous angiotensin infusions of 2.5 and 6.0 snug. per kg. per minute were found necessary to cause a 20 mn. Hg rise in diastolic pressure from an initial level of 100 mm. Hg in each case. During all these studies of pressor stimuli the patient’s serum potassium was between 5.8 and 6.0 InEq. per L. Angiotensin infusion at 2.5 mpg. per kg. per minute also caused a decrease in the urinary sodium excretion rate from 82 to 56 PEq. per Ininute, without detectable changes in glomerular filtration rate, urine flow rate or urinary potassium excretion rate. Three estimations of the daily urinary VMA excretion rate were made, the results (3.7, 3.7 and 4.8 mg. per day) lying well within the normal range (1.8 to 7.1 mg. per day [12]). Serum potassium was normal on each occasion (3.8, 4.7 and 4.3 mEq. per L.) and diastolic blood pressures were 95, 90 and 115 mm. Hg, respectively. Othu Investigations. As indicated in the introduction, renal biopsy had shown no significant abnormality when performed previously in 1962. This was repeated in 1968, and again glomeruli and tubules showed no abnormality. Full blood count, platelet count, screening tests for coagulation disorders and hernolysis were all normal. A glucose tolerance test, serum electrophoretic pattern, tests for antinuclear factor and the twenty-four hour urinary porphyrin excretion rate showed no abnormality. Electrolnyography was normal on two occasions when the serum potassium was 4.5 and 5.8 mEq. per L. Chromosome analysis of peripheral leukocytes showed a normal 46-XY complement.

E;xc-retiotl-- ~.-lr~~dd,Iirt~h

Thtk lrlain features of this cast’ ar(’ pcrsistclll hypcrkalemia without renal failure, a t~~ltfe~lc~\~ to metabolic acidosis, slightl!. ilnpalrc~cl rcllal cscrcLion of acid and hypertension. So silrlilal case has been found in the litcratury. 7‘11~ lllost comnlon cause of hyperkalelnia is ad\~anced renal failure, but this was excluded ill the prcsent case by the demonstration that o;lolllc.rular filtration rate, maximum urinar). concc.litrating ability, T~nl,_%~and renal biopsy \tcrc all norlrlal. Because of the patient’s low urinar!, potassiultl excretion rate when treatment was stopped. a unique renal tubular defect in potassiulll cxcrt‘tion was suspected. This was confirn~ed by the balance study, which showed low renal potassium excretion despite a marked positive potassium balance and hyperkalemia (Fit. 2). and b) the poor response of the patient’s urinary potassium excretion rate to the stilllulus provided by the intravenous administration of sodiuln sulfate and acctazolamide, when colltparcd with control subjects gi\ren the sanlc trratIllent (Fig. 3). No other cause for hyperkalcmia, such as leukocyte or platelet abnormalit)[ Itu 211, or hemolysis, was found. Unlike the findings in patients with muscle disorders, such as adynatnia episodic-a hereditaria, in which only rpisodic increases in serum potassium from norlnal may occur [22,2,3], hyperkalemia in this cast was persistent when treatment was withheld. l-iypcrkalemia associated with attacks of muscle weakness has also been rcportcd in adrenal insufficiency [Z], and in one case of isolated aldosterone insufficiency [Z:?]. In both these conditions there was a deficient\. of aldosterone and an inability to conserve sodiulll. features absent in the present case. Because of recent developments in the field, a summary of the current concept of the Irlfzchanism of potassium excretion and the factors which influence it is needed for discussion of the possible defects in the present case. Most of the potassium in the glomerular filtrate is reabsorbed before the early distal tubule is reached [I&~.%I]. I II the distal tubule and collecting duct, potassiurll is thought to be secreted in exchange for sodiunl and in competition with hydrogen ions [.?7,.3/]. Because of the high hydrogen ion gradients that can be established between the plasma alld the tubular lumen, it is thought that active secretion of hydrogen ions must occur [27]. However, the electrochemical potential gradient produced by sodiutn reabsorption is sufficient to account for

Renal

Tubular

Defect

in Potassium

potassium secretion on a passive basis; it is not known if active secretion also occurs [28,29]. Recent micropuncture experiments by Malnic, Klose and Giebisch [32] have demonstrated that in the rat there is also constant active reabsorption of potassium from the distal tubular lumen. The degree of permeability of the luminal cell boundary to passive diffusion of potassium may also be a factor determining the rate of potassium excretion [32], as may the intracellular potassium concentration [33]. Mineralocorticoids cause increased distal sodium reabsorption, which results in increased secretion of potassium and hydrogen ions due to an increase in the electrochemical potential gradient across the tubule cell. Sodium sulfate infusion also increases potassium and hydrogen ion secretion because the reabsorption of sodium greatly exceeds that of sulfate, to which the tubules are relatively impermeable [34]. Sodium sulfate in fact increases the distal tubule electrochemical potential gradient, an effect which can be enhanced by prior salt depletion [35]. As well as increasing potassium secretion, an increase in this gradient would increase hydrogen ion excretion because of a reduction in passive backdiffusion of this ion [36]. Carbonic anhydrase inhibitors reduce hydrogen ion secretion and increase the electrochemical potential gradient is inP81; as a result, potassium excretion creased. With regard to the defect in this patient, it should first be noted that the renal handling of sodium was normal; sodium balance persisted, sodium excretion was reduced to low levels when salt intake was restricted, and there was a normal reduction in sodium excretion following the administration of mineralocorticoids. Thus the defect in potassium excretion appears to be primary, rather than secondarily dependent on some defect in sodium excretion. In the light of what is known about potassium excretion three possible explanations emerge for the patient’s anomaly: (1) active distal potassium reabsorption might be increased, if this process occurs in man as it does in the rat [32]; (2) permeability of the tubule cells to diffusion of potassium into the lumen could be reduced; and (3) intracellular potassium concentration in the patient’s distal tubules and collecting ducts could be reduced, which might reduce potassium secretion [33]. However, since the potassium content of his red cells was not reduced, his body cells are at least not generally affected in this way. Either (1) or (2) appears the most likely VOL.

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explanation of the defect in this patient. Whatever its nature, the defect is of course not complete, in that his capacity to excrete potassium must have matched dietary intake when his serum potassium reached about 8 mEq. per L., at which level it stabilized when he was untreated. Also the very powerful stimulus of the combination of salt depletion, which increases endogenous mineralocorticoid production, and of 9cz-fluorohydrocortisone plus sodium sulfate infusion resulted in a response in the patient’s potassium excretion rate nearly equal to that of the control subjects; a further increment was also possible when acetazolamide was added (Fig. 4). Although the renal defect in secretion of hydrogen ion was not marked, it was persistent, and could have accounted partly for the development of systemic acidosis when the patient was untreated. However, the degree of systemic acidosis was more than might have been expected from the degree of impairment of acid excretion, and hyperkalemia itself may have contributed by causing a shift of hydrogen ion out of body cells in exchange for potassium. There is only limited experimental evidence that such a shift can occur [37,38], but data on this subject are not extensive. Against this view must also be weighed the apparently unaltered red cell potassium content in the patient, even when his serum potassium was 6 mEq. per L. However, the conclusion that potassium must have entered body cells of some type is inescapable in view of a positive potassium balance of 142 mEq. in four days of the balance study associated with an increase in serum potassium of only 2.4 mEq. per L. (Fig. 2). The patient, in fact, represents evidence in favor of the hypothesis that hyperkalemia can cause an extracellular acidosis. The reverse, that is a tendency for acidosis to increase serum potassium concentration independently of changes in total body potassium, presumably by a shift of hydrogen ion into and potassium out of cells, has been demonstrated in man [39]. However, the increase in serum potassium in the present case was far greater than could be accounted for on this basis. The observed impairment of renal excretion of hydrogen ion could be a second tubular defect, independent of impaired potassium excretion. However, if the hypothesis that hyperkalemia can induce hydrogen to move out of cells in exchange for potassium is correct, then as a corollary an intracellular alkalosis would develop; if this occurred in distal tubules

470

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Tubular

11efect

in Potassium

and collecting ducts it could have accounted for the impairment in acid excretion observed. In support of this theory, it has been shown that the administration of potassium salts can result in an alkaline urine [J&41] and reduced renal tubular reabsorption of bicarbonate [38]. In contrast to the present case, patients with impaired renal excretion of hydrogen ion (i.e., renal tubular acidosis) generally have increased llrinary potassium losses [&?I. Evidently some such reciprocal relation still existed between potassium and hydrogen ion excretion in the present case, since potassium excretion was augmented when hydrogen ion excretion was inhibited by acetazolamide. It has been suggested that citrate might provide energy for cation transport in distal tubules [43], but it did not significantly affect the patient’s potassium excretion rate. Another avenue of investigation followed was examination of sweat and salivary potassium excretion in case the metabolic defect was widespread; this was evidently not so. The reason that phenolsulfonphthalein excretion was impaired, even when renal plasma flow (C,,,) was normal, is not clear. Phenoland p-aminohippurate are sulfonphthalein thought to be transported by similar mechanisms in renal tubules [44], and yet TmrAH was normal. The patient’s syndrome thus appears to embrace defective tubular secretion of potassimn, hydrogen ion and phenolsulfonphthalein. Slightly impaired ammonium excretion might simply reflect the pattern of diminished hydrogen ion excretion, but might also represent an incipient tubular defect. We have concluded that the patient’s hypertension is related to his metabolic disorder. The tendency for his blood pressure to rise during four months of investigation when treatment was and the significant correlation intermittent, between his blood pressure and the serum potassium level (Fig. 8) support this view. However, hyperkalemia is apparently not the sole cause of the hypertension, for at present, although normokalemia is maintained with therapy, his mean diastolic blood pressure remains slightly above 100 mm. Hg. Intracellular and extracellular concentrations of potassium and other cations have important effects on vascular tone and blood pressure [&‘,&I. However, acute experiments in animals have shown a slight decrease in vascular tone [45,47] and no significant change in blood pressure [48] with elevation in serum potassium

flxcretion-Arnold,

Hedy

to about 8 mEq. per L. ; abo\ c this lr\ cl, vasoconstriction develops. Although the patient‘s serunl potassium was rarely above 8 nlEq. per L., a species difference in thr degrrv of hyperkalemia needed to induce \~asoc.o!lstrictic,rl ma) exist, and it is also possible that long-tcsrrtl clcvation of serum potassium may ha1.r different effects from those seen in acute situations. The patient’s pressor responses 10 the cold pressor test, smoking, norepinephrint: and angiotensin were within the range seen in hypertension ol other causes [4%52] which suggests no unusual alteration in his vascular reactivity. Potassium infusions can cause adrenal release of catecholamines [47], but increased catccholamine production apparently did not contribute to the patient’s hypertension since catecholamine excretion rates and the response to the phentolamine blocking test were normal at tirncs when he was both hyperkalemic and hypertcnsi\,e. With regard to other aspects of the patient’s endocrine status, he clearly has no adrenal insufficiency. The slightly increased aldosteronc secretion rate may be a secondary response to which can dircctlv increase hyperkalemia, aldosterone secretion [5.?]. Rcduc& plasma renin may be a compensatory rcsponsc to the raised aldosterone secretion rate and to hypertension. There seems to be no evidence that endocrine abnormality is responsible for either hypertension or hyperkalemia in this case. Since defects in renal tubular transport arc often genetically determined, it is possible that the present case may represent an inherited disorder; this is not excluded by the finding of a norlnal chromosome pattern. The unusually strong family history of mental illness might point to genetic anomalies in the family, and the absence of two maxillary incisor teeth in the patient and in his brother may gi\re some support to this theory, although the latter defect has been recorded in 0.4 to 1.7 per c’c.nt of the ostensibly normal population I5Jl. Acknowledgment: We wish to express our thanks to Miss E. R. Graeme, technician, LIONS Renal Research Laboratory; to Dr. G. Stokes, Sydney Hospital, for records frown Sydney Hospital and for plasma renin assays; and to Miss L. Williams, Anatomy Department, University of (jueensland, for chromosome studies. Assistance was also given by the Divisions of Biochemistry, Princess Alexandra Hospital and Royal Brisbane Hospital, and by the dietitians, Princess Alexandra Hospital. Dr. J. Coghlan,

Renal Tubular

Defect in Potassium

Physiology Department, Melbourne University, and Dr. L. Lazarus, St. Vincent’s Hospital, Sydney, performed aldosterone, corticosterone and cortisol assays on the patient when he was under the care of Sydney Hospital. REFERENCES

19.

20.

21.

1. PAVER, W. K. A. and PAULINE, G. 1. Hypertension

and hyperpotassemia without renal disease in a young male. M. J. Australia, 2: 305, 1964.

2. DOUGLAS, J. B. and HEALY, J. K. Nephrotoxic effects of amphotericin B, including renal tubular acidosis. Am. J. Med., 46: 154, 1969. 3. HEALY, J. K. Clinical assessment of glomerular filtration rate by different forms of creatinine clearance and a modified urinary phenolsulfonphthalein excretion test. Am. J. Med., 44: 348, 1968. 4. WRONG, 0. and DAVIES, H. E. F. The excretion of acid in renal disease. Quart. J. Med., 28 : 259, 1959. 5. GIBSON, L. E. and COOKE, R. E. A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilising pilocarpine iontophoresis. Pediatrics, 23: 545, 1959. 6. WALSER, M., DAVIDSON,G. D. and ORLOFF, J. The renal clearance of alkali-stable inulin. J. Clin. Invest., 34: 1520, 1955. 7. SMITH, H. W. Principles of Renal Physiology, p. 212. New York, 1962. Oxford University Press. 8. OVEN, J. A., Icco, B., SCANDRETT, F. J. and STEWART, C. P. The determination of creatinine in plasma or serum, and in urine; a critical examination. Biochem. J., 58: 426, 1954. 9. BONSNES,R. W. and TAUSSKY, H. H. On the colorimetric determination of creatinine by the Jaff& reaction. J. Biol. Chem., 158: 581, 1945. 10. WEIME, R. J. and VAN RAEPENBUSCH,F. R. Automatic determination of calcium in blood and urine using Corinth Ca. Clin. chim. acta, 7: 883, 1962. 11. LOGSDON,E. E. A method for the determination of ammonia in biological materials on the autoanalyzer. Ann. New York Acad. SC., 87: 801, 1960. 12. Technicon Methods, Nla, N2a, N4a, N13a, N21a. Auto-analyzer N Methodology. Technicon Instruments Co;p. Chauncey, N. y., 1963. 13. PISANO. , J. J.., CROUT. J. R. and ABRAHAM.D. Determination of 3-methoxy-4-hydroxy mandelic acid in urine. Clin. chim. acta, 7: 285, 1962. 14. ETTINGER, R. H., GOLDBAUM, L. R. and SMITH, L. H. A simplified photometric method for the determination of citric acid in biological fluids. J. Biol. Chem., 199: 531, 1952. 15. DEMPSEY, E. F., CAROLL, E. L., ALBRIGHT, F. and HENNEMAN,P. H. A study of factors determining electrolyte excretion. Metabolism, 7: 108, 1958. 16. NIEDERMEIER,W., DREIZEN, S., STONE, R. E. and SPIES, T. D. Sodium and potassium concentrations in the saliva of normotensive and hypertensive subjects. Oral Surg., 9: 426, 1956. 17. GRAND, R. J., DI SANT’AGNESE, P. A., TALAMO, R. C. and PALLAVICINI,J. C. The effects of exogenous aldosterone on sweat electrolytes. I. Normal subjects. J. Pediat., 70: 346, 1967. 18. BRONSON,W. R., DE VITA, V. T., CARBONE, P. P. and COTLOVE, E. Pseudohyperkalemia due to reVOL.

47,

SEPTEMBER

1969

22. 23.

24.

25.

26.

27. 28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

Excretion--Arnold,

Healy

471

lease of potassium from white blood cells during clotting. h’ew England J. Med., 274: 369, 1966. REED, C. and HUGHES, J. D. “Dangerous” hyperkalemia in hemorrhagic thrombasthenia. M. J. Australia, 1: 79, 1964. F~HITFIELD,J. B. Spurious hyperkalemia and hyponatremia in a patient with thrombocythcmia. J. Clin. Path., 19: 496, 1966. WILLS, M. R. and FRASER, I. D. Spurious hyperkalaemia. J. Clin. Path., 17: 649, 1964. Lead article. Inherited disorders of potassium metabolism. Brit. M. J., 2: 266, 1964. HERMAN, R. H. and MCDOWELL, M. K. Hyperkalemic paralysis (adynamia episodica hereditaria). Report of four cases and clinical studies. Am. J. Med., 35: 749, 1963. BELL, H., HAYES, W. L. and VOSBURG,J. V. Hyperkalemic paralysis due to adrenal insufficiency. Arch. Int. Med., 115: 418, 1965. POSNER, J. B. and JACOBS, D. R. Isolated analdosteronism. 1. Clinical entity, with manifestations of persistent hyperkalemia, periodic paralysis, saltlosing tendency, and acidosis. Metabolism, 13: 513, 1964. BENNETT,C. M., CLAPP, J. R. and BERLINER,R. W. Micropuncture study of the proximal and distal tubule in the dog. Am. J. Physiol., 213: 1254, 1967. BERLINER,R. W. Renal mechanisms for potassium excretion. Harvey Lect., 55: 141, 1961. MALNIC, G., KLOSE, R. M. and GIEBISCH,G. Micropuncture study of renal potassium excretion in the rat. Am. J. Plpsiol., 206: 674, 1964. MALNIC, G., KLOSE, R. M. and GIEBISCH,G. Micropuncture study of distal tubular potassium and sodium transport in rat nephron. Am. J. Pf@ol., 211: 529, 1966. WATSON, J. F., CLAPP, J. R. and BERLINER,R. W. Micropuncture study of potassium concentration in proximal tubule of dog, rat, and Necturus. J. Chin. Inutxt., 43: 595, 1964. BERLINER,R. W., KENNEDY, T. J. and ORLOFF, J. Relationship between acidification of the urine and potassium metabolism. Am. J. Med., 11: 274, 1951. MALNIC, G., KLOSE, R. M. and GIEBISCH,G. Microperfusion study of distal tubular potassium and sodium transfer in rat kidney. Am. J. Physiol., 211: 548, 1966. MUDGE, G. H., FOULKES,J. and GILMAN, A. Renal secretion of potassium in the dog during cellular dehydration. Am. J. Physiol., 161: 159, 1950. SCHWARTZ,W. B., JENSON,R. L., and RELMAN, A. S. Acidification of the urine and increased ammonium excretion without change in acid-baseequilibrium: sodium reabsorption as a stimulus to the acidifying process. J. ?lin. Invest., 34: 673, 1955. CLAPP, J. R.. RECTOR. F. C. and SELDIN, D. W. Effect of unreabsorbkd anions on proxidal and distal transtubular potentials in rats. Am. J. P&iol., 202: 781, 1962. RECTOR, F. C. and SELDIN, D. W. Inlluence of unreabsorbed anions on renal threshold and Tm for bicarbonate. Am. J. Physiol., 202: 313, 1962. ANDERSON,H. M. and MUDGE, G. H. The effect of potassium on intra-cellular bicarbonate in slices of kidney cortex. J. Clin. Invest., 34: 1691, 1955.

472

Renal

‘Tubular

Defect

in Potassiulrl

38. FULLER, G. Ii., MACLEOD, M. B. and Prrrs, K. E. Influence of administration of potassium salt. on the: renal tubular reabsorption of bicarbonate. .4m. J. Phpiol., 182: 111, 1955. 3’). BURNELL, J. M., VILLAMIL, M. F., UYENO, B. 7’. and SCRIBNER, B. H. The effect in humans of extracellular pH change on the relationship between serum potassium concentration and intracellular potassium. J. Clirz. Invest., 35: 935, 1956. 40. BERLINER, R. W., KENNEDY, T. J. and HILTON. J. G. Renal mechanisms for excretion of potassium. Anz. J. Ptysiol., 162: 348, 1950. 41. LOEB, R. F., .\TCIILEY, D. W., RICHARDS, D. Cv., BENEDICT, E. M. and DRISCOLL, M. E. On the mechanism of nephrotic edema. J. C&r. Znoest., 11: 621, 1932. 42. MILNE, M. D. Renal tubular dysfunction. In: Diseases of the Kidney, p. 828. Edited by Strauss, M. B. and Welt, L. G. Boston, 1963. Little, Brown & Co. 43. GY&Y, A. Z. and EDWARDS, K. D. G. Renal tubular acidosis. Am. J. Med., 45: 43, 1968. 44. TAGGART, J. V. Mechanisms of renal tubular transport. Am. J. .Wed., 24: 774, 1958. 45. FRIEDMAN, S. M. and FRIEDMAN, C. L. Effects of ions on vascular smooth muscle. In: Handbook of Physiology; Circulation, 1135. vol. 2, p. Washington, D. C., 1963. American Physiological Society. 46. LAB, W. Transmembrane cationic gradient and

47.

48.

40.

50.

51.

52.

53.

54.

F;xcretion~-- rlrnold. Eim/\ blood pressure rc~q~~la~ion.iirr~. ./. (,hr~/~~~,l.. 4 752. 1959. S~OT.I., J., EMANLXL, 11. and I IADD\,. I‘. IXflxt 01 potassium on renal vascular resistance, alld urinr. llow ratr. Am. J. P/yin/., 197: 305, 1959. M.XXWELL, G. M. Effects of hyprrkalcrma upon thv ~encral and coronary haemodynamics of thl. dog. .lurtralian J. @er. Hinl. Lg M. .\; . . 43 057, 1065. HINES, E. I\. The significance of vascular hypes-reaction as measured by thr cold prc’ssor test. .Ir//. Hmrt .J., 19: 408, 1940. KOTI~, G. M. and SCHICK, K. M. EkTcct of smoking on thr cardiovascular system of mall Circrrlatinr~, 17: 443, 1958. GOLDENBERG, M., PINES, K. L., BALUWIN, E.. GREENE, D. G. and ROH, C. E. ‘rhr hrmodynamic response of man to norepincphrinc and epinephrine and its relation to the problrm of hypcrtension. Am. J. Med., 5: 792, 1948. KAPLAN, N. M. and SILAH, .I. G. Thr angiotensin infusion test. .\ new approach to the* differential diagnosis of renovasrular hypcrtrnsiorr. :v?w I&gland J. Med., 271 : 536, 1964. DAVIS, .I. O., URQLJHAR~, J. and lllccr~s, .I. T. The effects of alterations of plasma sodium and potassium concentration on aldostrronc srcretion. ./. Clin. Znrvst., 42: 597, 1963. GORLIN, K. J. and PINDBORG, J. J. Sylldromes of the Head and Neck, p. 546. New York, 1964. McGrawHill Book Co.

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