Bartter's syndrome and erythrocytosis

Bartter’s Syndrome and Erythrocytosis

D. W. ERKELENS, L. W. STATIUS

M.D.*

VAN

Curagao, Netherlands

EPS, M.D Antilles

From the Department of Internal Medicine, St. Elisabeth Hospital, Curasao, Netherlands Antilles, affiliated with the State University of Groningen. the Netherlands. Requests for reprints should be addressed to Dr. L. W. Statius van Eps, Department of Internal Medicine, St. Elisabeth Hospital, Curagao, Netherlands Antilles. Manuscript accepted June 13,1973. * Present address: Department of Internal Medicine, State University of Groningen. the Netherlands.

We describe a patient, known since 1960, with Bartter’s syndrome and erythrocytosis. The diagnosis was made on the basis of hypokalemic alkalosis, hyperplasia of the juxtaglomerular apparatus, resistance to the pressor effect of angiotensin, extremely high plasma renin activity and normal blood pressure. This patient had a normal pattern of aldosterone excretion and a decreased ability of the kidneys to preserve potassium adequately. The nephropathy was characterized by a normal glomerular filtration rate, an irreversible inability of the kidney to concentrate the urine and a reversible inability of the kidney to excrete an acid load. The kidneys were enlarged; a biopsy specimen revealed hyperplasia of the juxtaglomerular apparatus, hyperplasia of the macula densa and an extensive fibrosis of the medulla. The intracellular red cell sodium level was elevated and the potassium level decreased during potassium depletion; they returned to nearly normal levels after adequate potassium supplementation. As a feature previously unknown in this syndrome the patient had a distinct erythrocytosis. There was an elevated red cell volume and an increase in the reticulocyte count after the oral administration of iron despite a high hemoglobin level. The erythropoietic activity of the serum, measured by bioassay, was increased to 10 times normal. We presume that there is a simultaneous overproduction of renin and erythropoietin in this patient with Bartter’s syndrome. The stimulus for this overproduction cannot be defined exactly. Our findings support the view that the primary defect in Bartter’s syndrome is an impaired reabsorption of sodium in the ascending limb of Henle’s loop. The case is further evidence for the juxtaglomerular apparatus being the production site of both renin and erythropoietin.

Bartter’s syndrome consists of hyperplasia of the juxtaglomerular apparatus, elevated plasma renin and angiotensin levels, hypokalemia and normotension. Growth disturbance, secondary hyperaldosteronism, altered membrane sodium transport and hypomagnesemia are described but not in all cases. Since the original description [l], a number of cases [2-151 have been reported; Bartter discussed the features of the syndrome critically [16]. We describe a patient with the syndrome, a normal aldosterone excretion rate, an increase in renal potassium loss over a long observation period and erythrocytosis. This increase in red cell volume was accompanied by an increase in serum erythropoietic activity.

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SYNDROME

Summary

AND

of Laboratory

Plasma Sodium (meq/liter) Potassium (meq/liter) Chloride (meq/liter) Bicarbonate (meq/liter) Calcium (mg/lOO ml) Phosphate (mg/lOO ml) Creatinine (mg/lOO ml) Blood Capillary pH

Hemoglobin (g/100 ml) Hematocrit (%) Urine Specific gravity Protein Sediment

CASE

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EPS

Values

1956

1959

1960

1961

1963

1964

1965

1967

1968

1970

1971

1971

...

. . ... ...

139 1.0

140 1.8

85 30 10.4 2.8 ...

97 28.4 10.1 3.4 1.1

139 2.1 101

138 1.8 ... ... 11.2 ... ...

138 3.0 98 19 10.7 ... 1.0

150 1.5 110 32.5 11.8 2.8 1.4

142 1.2 94 24 9.9 3.3 1.1

136 2.6 99 29.5 10.7 4.4 1.0

138 1.9 97 26 10.1 2.8 1.0

138 3.2 101 32 9.6 3.8 1.0

7.40 16.4 46

7.43 18.6 58

...

...

15.8 50

21.4 60

21.3 62

7.37 21.5 68

7.47 20.1 63

7.45 22.0 67

7.43 20.7 62

7.38 18.3 63

7.41 19.4 60

1.008

1.009

1.008

1.009

1.006

1.006

1.008

1.007

Trace Trace 5 wbc/hpf

Trace

...

...

...

...

...

...

...

1.006 Trace ...

1.004 ... ...

1.011 ... ...

... ... ... ...

...

...

. .. ...

...

1.4

. *. 17.2 54 1.006 ... ...

...

...

REPORT

A man, born in 1937, was seen in 1956 by the neurologist because of weakness. He was an infantile black man with paresis of the trunk and proximal muscles. A tentative diagnosis of progressive muscular dystrophy was made. His weight was 43.6 kg, height 1.68 m and blood pressure 1 lo/75 mm Hg. Laboratory values are summarized in Table I. A muscle biopsy specimen obtained in 1959 showed no abnormality. In 1960 the patient was admitted for paralytic ileus of one day’s duration. The first serum potassium determination was 1.0 meq/liter. He produced from 3 to 6 liters of urine/day. The electrocardiogram showed repolarization disturbances characteristic for potassium depletion. The potassium depletion and paralytic ileus were treated with oral potassium, 117 to 156 meq/day; after a few weeks the serum potassium was within the normal range; the urinary excretion never exceeded 60 meq/24 hours. In 1961 a further analysis of kidney function was made. The serum potassium was 1.8 meq/liter; potassium excretion in the urine was 23 meq/24 hours. Endogenous creatinine clearance was 150 ml/min, inulin clearance 125 ml/min and

Figure kidneys

Intravenous pyelogram 1. and slightly dilated calices.

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shows

... 10.1 3.8 1.0

para-amino-hippurate clearance 365 ml/min. The filtration fraction was 35 per cent. The urine could be concentrated to a maximum of 321 mOsmol/kg water when the serum potassium was low, and up to 417 mOsmol/kg water when the serum potassium was normal [17]. Acid excretion after an ammonium chloride load [18] was impaired; the urinary pH did not reach values lower than 6.2. Calcium excretion was 28 to 128 mg/24 hours on a diet containing 960 mg. There was no abnormal aminoaciduria and no renal glycosuria. An intravenous pyelogram showed enlarged kidneys and slightly distended calices (Figure 1). The patient did not take the oral potassium regularly when at home, and he was admitted to the hospital several times with a very low serum potassium level. From 1969 to 1972, observations were made during a prolonged period of controlled potassium administration. Potassium excretion rose to very high values. The concentrating ability of the kidney did not improve after potassium the maximum urinary repletion, osmolality after overnight dehydration remaining at 378 mOsmol/kg water. The excretion of acid did improve with potassium repletion, the minimal urinary pH

enlarged

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Trace 5 wbc/hpf

Figure

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Renal angiogram

BARTTER’S SYNDROME

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STATIUS

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Potassium excretion

4

in meq.lL. in 1961 and 1969

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I

of bicarbonate,

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spironolactone

November

1973

and increasing

doses

of triamterene

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reaching 5.6, the maximum titratable acid excretion 54.3 peq/min and the maximum ammonium excretion 54.0 peq/min. Arterial blood gas analysis on admission yielded a pH of 7.40, carbon dioxide tension of (pCO2) 36 mm Hg, oxygen tension (~02) 94 mm Hg, bicarbonate 22 meq/liter and base excess -2 meq/liter. After repletion with potassium the values were pH 7.38, pCO2 57 mm Hg, p02 82 mm Hg, bicarbonate 34 meq/liter and base excess i-3 meq/liter. Angiography showed no arterial abnormality and no suggestion of renal cyst (Figure 2). Intracellular red blood cell sodium and potassium were measured as previously described [19]. The erythrocyte sodium concentration was 31.5 meqfkg and the potassium 70 meq/kg when serum potassium was 1.9 meq/liter (normal values: sodium 8.4 f SD 2.2 and potassium 91 f SD 4 meq/kg). Values after prolonged repletion with potassium were sodium 16 meq/kg and potassium 88 meq/kg. The family history was not contributory: the father and paternal relatives had normal serum electrolytes, and the mother had died in childbirth. There were no brothers or sisters. During the observations the patient displayed paranoid and flight reactions, catatonic attitudes and disintegration of personality. The electroencephalogram and echoencephalogram were normal. In 1970 an open kidney biopsy was performed after 4 weeks of potassium supplementation, and later several special investigations were carried out.

Potassium

250Jmeq./24h.

Figure 6. The effect of spironolactone bination with oral potassium.

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SPECIAL

INVESTIGATIONS

Pathologic anatomy of the kidney specimen (C. J. Kooiker, Department of Pathology, University of Utrecht, Netherlands): Most glomeruli showed no abnormality, but some had undergone ischemic atrophy, with hyaline connective tissue filling the capsule spaces. Hyperplasia was present in the juxtaglomerular apparatus in about 40 per cent of the glomeruli (Figure 3) and of the macula densa; next to most of the involved glomeruli, some cells showed periodic acid-Schiff-positive granules. The proximal tubule cells showed no vacuolization, but contained fine periodic acid-Schiff-positive granules and a brown pigment, probably lipofuscin. There was localized tubular atrophy with and without basement membrane thickening. The maculae densae contained many nuclei in more than one row. In some arterioles there was subendothelial hyalinization. Distinct lymphocytic infiltrates were present in the interstitium. In the medulla, the tubules were wide and grossly reduced in number; some showed vacuolization of epithelial cells. There was an impressive increase in connective tissue, the fibers running perpendicular to the tubules. There were many fibrocytes, mast cells and big vacuolized cells, probably thin-walled lymph vessels. Homogeneous hyaline material normally present in the medulla was not seen. In conclusion, it can be stated that the pathologic condition of the cortex fits the diagnosis of Bartter’s syndrome, but the picture in the medulla cannot be classified under a known diagnosis. Potassium excretion (Figure 4): During the years of observation the ability of the kidney to preserve potassium adequately was decreasing. Whereas in 1961 excretion never exceeded 60 meq/24 hours even when serum potassium was normal, in 1969 almost the entire oral potassium supplement was lost in the urine: values were frequently around 200 meq/24 hours. Effect of oral potassium, spironolactone and albumin infusion (Figures 5, 6 and 7): Spironolactone or triamterene did not restore serum potassium to normal without oral potassium supplements. Oral potassium supplements of 200 meq/day were required to bring the serum potassium level to 3.7 meq/liter. The combination of spironolactone and oral potassium produced low normal serum potassium values. Human serum albumin, 150 g given as an infusion over a period of 5 days, did not alter serum potassium. Aldosterone excretion rate (Figure 8): In 1969 the patient was studied while on a normal hospital diet when his serum potassium concentration was 1.5 meq/liter. Aldosterone excretion was 2 and 4 pg/24 hours. Measured again while he was taking potassium supplements and adhering to a normal hospital diet containing approximately 100 meq of sodium/day, it was 7 and 14 pg/24 hours. Urinary aldosterone rose to a maximum of 40 pg/24 hours with salt deprivation, and was around 10 pgjday when he was adhering to a diet containing 160 meq sodium/day. The serum potassium varied between 2.6 and 3.3 meq/liter during these studies. Angiotensin infusion tests: Angiotensin, infused at a

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“,3-/ 4 ks 140

.

.--.,”

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Body Weight

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5 Potassium 3 1-f-Y rneC$L. 15 Creatmine 5 3-mg/L Sodpm 3500

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Creatinme The aldosterone Figure 8. tion of electrolytes during load.

1500 Figure

7.

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of albumin

rate of 80 to 100 ng/kg/min

[20]

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pressure,

required

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by normal

11 ng/kg/min.

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subjects effect

produced

to produce of a 30

infusion.

a 20 mm

the upper this

minute

rise

limit being

infusion

of

angiotensin at a rate of 72 ng/kg/min is shown in Figure 9. There was sodium, potassium, calcium and water retention. Glomerular filtration rate and renal plasma flow decreased strikingly during the infusion, returning promptly to control values after the infusion was stopped. Potassium excretion returned to control

values

immediately

dogenous returned

after

creatinine to control

excretion r,?te and excresalt deprwat/on and salt

the

end

clearance values

amino hippurate clearance. Plasma renin activity:

more This

dioimmunoassay of angiotensin the Blood Transfusion Service

of the and

quickly was

Netherlands). Plasma renin on a high sodium intake was

ml/3

in a sample

November 1973

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after

The American Journal of Medicine

did para-

measured

I (Central of the Dutch

En-

clearance

than

Amsterdam, the patient hours

infuston.

inulin

by

ra-

Laboratory, Red Cross, activity with 2,400 ng/lO

he had rested

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6 March 24 ,---.--‘..-.........‘,““‘,....

1 Aprd

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RetuJlocytes

Figure 10. tion of iron.

Reticulocyte

count

after

oral

administra-

hours in the recumbent position, and 5,000 ng/lO ml/3 hours after he had walked around for 4 hours. Normal values are 44.2 (range 11 to 106 ng/lO ml/3 hours) in the recumbent position and 75.7 (range 15 to 150 ng/lO ml/3 hours) after walking. A patient with renovascular hypertension had values of 340 and 600 ng/lO ml/3 hours [21] in the recumbent and upright positions, respectively. Erythrocytosis: The patient’s hemoglobin value was 15.6 to 22.0 g/100 ml, his hematocrit level 46 to 68 per cent. Hemoglobin electrophoresis yielded hemoglobin AA. The reticulocyte count was constantly above 1.5 per cent, rising after iron administration (Figure 10). Blood volume (RISA) was 125 ml/kg (normal 60 to 91 ml/kg); plasma volume was 56 ml/kg (normal 30 to 54 ml/kg); red cell volume was 68 ml/kg (upper limit of normal 35 ml/kg). The spleen was not enlarged; bone marrow smear, leukocyte and thrombocyte counts, liver functions and skull roentgenograms were all within normal limits. The arterial oxygen saturation was never below 98 per cent (always measured at sea level). Erythropoietic activity was measured by bioassay (Department for Chemical Pathology, Erasmus University, Rotterdam, Netherlands) [22]. It was 30 IU/liter (normal by this method around 3 Ill/liter). COMMENTS

Figure 9. The effect of high rate angiotensin infusion on electrolyte and water excretion. Simultaneous measurement of glomerular filtration rate and renal plasma f/o w.

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The diagnosis of Bartter’s syndrome seems well established in this patient. The hyperplasia of the juxtaglomerular apparatus, the hypokalemic alkalosis, the resistance to the pressor effect of angiotensin, the extremely high plasma renin activity and the normal blood pressure are all in accordance with the diagnosis. High aldosterone excretion is not an obligatory feature of the disease [9]. It has been shown that bilateral adrenalectomy does not stop the renal potassium wasting [lo]. In Volume 55

BARTTER’S

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our patient, aldosterone excretion was subnormal without added dietary potassium, normal during intake of over 200 meq of potassium/day and slightly above normal after sodium deprivation. (Serum potassium, however, was subnormal during the study of sodium deprivation.) Sodium retention during rapid infusion of angiotensin is probably a direct vascular effect, and not aldosterone-mediated. This is supported by the fall in inulin and in para-amino hippurate clearance, with the rise of the filtration fraction [23]. (This is a normal response to angiotensin, but the rate of angiotensin infusion was much higher than that necessary to produce a similar effect in normal man [24].) Also, the effect was too prompt (i.e., within 30 minutes) to depend upon aldosterone, which does not produce sodium retention in less than 60 minutes [25]. The suggestion that renal potassium loss in patients with Bartter’s syndrome might not be entirely dependent upon aldosterone [9,10] is supported by our findings. Notwithstanding a normal or low aldosterone excretion rate and a low serum potassium, there was considerable potassium loss. Thus, there seems to be a decrease in the ability of the kidney to preserve potassium adequately. This decrease is not a feature phropathy per se and might, ture of Bartter’s syndrome.

of hypokalemic netherefore, be a feaSpironolactone was

effective in restoring serum potassium to normal levels only when it was given at a high dosage, and even then the serum potassium level remained in the lower regions of normal. It may be that, after a long time, the lesion responsible for renal potassium wasting becomes irreversible; the patient is now 36 years old. Whether the basic lesion in Bartter’s syndrome is an inability of some proximal part of the nephron to reabsorb sodium adequately, so that a large, possibly increasing amount of sodium is offered to the sodium-potassium and sodium-hydrogen ion exchange sites in the distal tubule is still a matter of controversy. Our present observations of an acidification defect, reversible after correction of the potassium depletion,.and the development of metabolic alkalosis with potassium treatment, could explain the increasing potassium loss as a consequence of decreasing ability to exchange sodium for hydrogen ion because of potassium depletion. White’s observation [13] that the rapid intravenous infusion of saline solution in patients who may have had the syndrome could restore the angiotensin sensitivity and the plasma renin activity to normal suggests a secondary stimulation of the reninangiotensin system by a decreased extracellular volume. No evidence of proximal tubular dysfunction was observed. On the contrary, bicarbonate November

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reabsorption was increased suggesting increased sodium reabsorption in the proximal tubule. A low urinary calcium excretion in our patient while on a normal calcium intake and without signs of osteomalacia would be in accordance with an increased sodium reabsorption in the proximal tubule, as sodium and calcium reabsorption are linked at this part of the nephron ]26]. The metabolic alkalosis and massive renal potassium wasting in Bartter’s syndrome signify an increased sodium reabsorption in exchange for potassium and hydrogen ion in the distal nephron. This leaves the site of inadequate sodium reabsorption, as the basic defect in Bartter’s syndrome, localized in either the ascending limb of Henle’s loop and/or in the proximal part of the distal nephron. The severe disturbance in renal concentrating ability observed in our patient, with no improvement following potassium repletion, indicates an almost complete loss of countercurrent multiplication compatible with impaired sodium reabsorption in the ascending limb of Henle’s loop. This is supported by the observation of a grossly abnormal renal medulla in this patient, with a reduction in the number of tubules and an increase in connective tissue. These abnormalities could not be classified under a known diagnosis, but in the literature on Bartter’s syndrome not much attention has been paid to the pathology of the renal medulla. Impaired sodium reabsorption in the ascending limb of Henle’s loop means an increased sodium concentration in the tubular fluid delivered at the macula densa. Thurau and Schnermann [27] have postulated that renin release varies directly with sodium concentration in the reabsorbate at the macula densa. Together with the contracted extracellular fluid compartment as a result of inadequate sodium conservation, which stimulates the juxtaglomerular apparatus directly, a chronic extra stimulus might be delivered to the macula densa-juxtaglomerular complex by this mechanism, leading to the observed hyperfunction and hyperplasia. Notwithstanding the hyperreninism and hyperaldosteronism, White’s patients with Bartter’s syndrome responded inappropriately to loading with saline solution in showing excessive sodium excretion. This exaggerated natriuresis has been observed in essential hypertension. Evidence has been presented [28] that a depressed sodium reabsorption in the ascending limb of the loop of Henle contributes to this phenomenon. The exaggerated natriuresis in Bartter’s syndrome could depend in .part on this same mechanism. Certainly, the erythrocytosis is the most striking feature of our patient. In one case of juxtaglomerular apparatus hyperplasia erythrocytosis, hemoglobin values from 15 to 17 g/l 00 ml and an elevated 1973

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erythropoietic activity of plasma have been reported [29]. Since there was no polycythemia vera or known cause for secondary polycythemia, the elevated erythropoietic activity must be caused by another, probably renal, mechanism. Whereas the site of production of erythropoietin in the kidney is not known, two possibilities have been suggested. Hirashima and Takaku [30] produced hypergranularity of the juxtaglomerular apparatus by different procedures and showed that they also increased erythropoietin production. This and other observations prompted Erslev [31] to look upon the juxtaglomerular apparatus as the major production site of erythropoietin. Gordon et al. [32], however, finding renal erythropoietic factor in the light mitochondrial fraction of both cortical and medullary cells, stated that its production must be distributed evenly throughout the kidney. The juxtaglomerular apparatus hyperplasia and the extensive fibrosis of the medulla in our patient favor the first view. The erythropoietin overproduction can be explained as another mechanism by which the kidney tries to maintain normovolemia. Bartter et al. [l] originally proposed that renin overproduction was a reaction to hypotension resulting from unresponsiveness to angiotensin of the vascular wall. In our case, however, the blood volume was increased by an elevated red blood cell volume, as confirmed by volume measurements. This probably explains why albumin infusion was ineffective in correcting the defect. The hypervolemia makes the question, “What is the stimulus for the juxtaglomerular apparatus to produce renin and possibly erythropoietin to such an extent in this syndrome?“, even more difficult to answer [33]. It might be the potassium depletion per se [34]. It might be the aforementioned high sodium concentration present at the macula densa. Primary juxtaglomerular apparatus hyperplasia as a variant of a renin-producing tumor should have caused hypertension [35]. Longstanding secondary hyperplasia, at last resulting in autonomous production of renin and erythro-

poietin when hypovolemia does not exist any more, seems a more feasible solution. We found a very high erythrocytic sodium. This might be a result of the inability of the cell membrane to sustain an adequate sodium efflux [14] representing the primary defect in Bartter’s syndrome, although in another patient [12] an elevated active sodium transport and an elevated passive sodium leak were found. This suggests inhibition of the potassium-dependent, glucoside-sensitive, sodium pump [36]. The intraerythrocytic sodium was lowered by adequate potassium supplementation in our patient. In conclusion, our observations support the view that an impaired sodium absorption in the ascending limb of Henle’s loop is the primary defect in Bartter’s syndrome. They stress the finding that the presence of hyperaldosteronism is not obligatory and that renal potassium wasting might be a sequela of increased sodium delivery to the distal tubule. This potassium. wasting increases during the course of the disease. The erythrocytosis adds a new feature to the syndrome. This is not an unexpected one, however, as an increased erythropoietin secretion had been anticipated by Bartter [37]. On one hand, it is new evidence that the juxtaglomerular apparatus is the production site of erythropoietin; on the other hand, it supports the thesis that stimuli for renin and erythropoietin production are related and might be at work simultaneously in Bartter’s syndrome. ACKNOWLEDGMENT

We wish to thank Dr. H. Schouten, Curacao, for his expert advice and laboratory work; Dr. C. J. Kooiker, University of Utrecht, for his excellent pathologic report; Dr. J. L. Touber, Amsterdam, for the plasma renin activity measurements; and Dr. W. E. Wiltink, Erasmus University, Rotterdam, for the erythropoietin assay. We are most grateful to Dr. Frederic C. Bartter, National Institutes of Health, Bethesda, Maryland, for his interest in our patient, his encouragement and his critical evaluation of the manuscript.

REFERENCES 1.

2.

3.

4.

718

Bartter FC, Pronove P, Gill Jr JR, MacCardle RC: Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis, a new syndrome. Am J Med 33: 811, 1962. Hanze S, Pierach CA, Stark G: Das Bartter Syndrome, vasale Angiotensine I I Resistenz mit juxtaglomerularer Zellhyperplasie und Hyperaldosteronismus. Dtsch Med Wochenschr 90: 2041,1965. Bryan GI, MacCardle RC, Bartter FC: Hyperaldosteronism, hyperplasia of the juxtaglomerular complex, normal blood pressure and dwarfism: report of a case. Pediatrics 37: 43, 1966. Greenberg, AJ, Arboit JM, New MI. Worthen AG: Nor-

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5.

6.

7.

motensive secondary hyperaldosteronism. J. Pediat 69: 719, 1966. Beilin LJ, Schiffman N, Crane M, Nelson DH: Hypokalemic alkalosis and hyperplasia of the juxtaglomerular complex without hypertension or oedema. Br Med J 4: 327,1967. Brackett NC Jr, Koppel M, Randall RE, Nixon WP: Hyperplasia of the juxtaglomerular complex with secondary hyperaldosteronism without hypertension (Bartter’s syndrome). Am J Med 44: 803. 1968. Cannon PJ, teeming JM, Sommers SC, Winters RW, Laragh JH: Juxtaglomerular cell hyperplasia and secondary hyperaldosteronism (Bartter’s syndrome): a

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10.

11.

12.

13. 14.

15.

16. 17.

18. 19.

20.

21.

22.

23.

reevaluation of the pathophysiology. Medicine (Baltimore) 47: 107, 1968. Klaus D, Bocskor A, Seif F: Regulation der Reninsekretron beim Bartter-Syndrom. Klin Wochenschr 22, 1201, 1968. Goodman AD, Vagnucci AH, Hartroft PM: Pathogenesis of Bartter’s syndrome N Engl J Med 281: 1435, 1969. Trygstad CW. Mangos JA, Bloodworth JMB. Lobeck CC: A sibshib with Bartter’s syndrome: failure of total adrenalectomy to correct the potassium wasting. Pediatrics 44: 234, 1969. lmai M, Yabuta K, Murata H, Takita S, Ohbe Y, Sokabe H A case of Bartter’s syndrome with abnormal renin response to salt load. J Pediat 74: 738, 1969. Gall G. Vaitukaitis J, Haddow JE, Klein R: Erythrocyte Na flux in a patient with Bartter’s syndrome. J Clin Endocr 32: 562, 1971. White MG: Bartter’s syndrome, a manifestation of renal tubular defects. Arch Intern Med 129: 41, 1972. Gardner JD, Simopoulos AP, Lapey A, Shibolet S: Altered membrane sodium transport in Bartter’s Syndrome. J Clin Invest 51: 1565, 1972. Gitelman HJ, Graham JB. Welt LG: A familial disorder characterized by hypokalemia and hypomagnesemia. Ann NY Acad SC 162: 856,1969. Bartter FC: So-called Bartter’s syndrome (Editorial). N Engl J Med 281: 1482, 1969. Statius van Eps LW. ter Haar Romeny-Wachter CC, Schouten H, Struyker Boudier AM: Renal concentration test in a tropical climate. Clin Chim Acta 14: 637, 1966. Wrong 0. Davies HEF: The excretion of acid in renal disease Quart J Med 28: 259. 1959. Statius van Eps LW, Schouten H, Slooff PAM, van Delden GJA: Sodium, potassium and calcium in erythrocytes in sickle-cell anemia. Clin Chim Acta 33: 475, 1971. Kaplan NM, Silah JG: The effect of angiotensin II on the blood pressure in humans with hypertensive disease. J Clcn Invest 43: 659, 1964. Van der Meer J: Plasma renin activity measurements by radioimmunoassay of angiotensin I. Thesis, University of Amsterdam. Drukkerij “Aemstelstad,” Amsterdam, Netherlands, 1969. Wagemaker G, van Eyk HG, Wiltink WF, Leijnse B: A sensitive bioassay for erythropoietin and its clinical application. To be published. Statius van Eps LW. Smorenberg-Schoorl ME,

SYNDROME

24.

25

26. 27.

28.

29.

30.

31.

32. 33. 34.

35.

36. 37.

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The American Journal of Medicine

Volume 55

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