HYPOKALEMIA WITH NEPHROCALCINOSIS: A VARIANT OF BARTTER’S SYNDROME

C. W. WANG
Medical Registrar, Department of Medicine, Auckiand Hospital, Atickiand, NLI

1. J. SIMPSON
Senior Lecturer in Medicine, Departmenf of Medicine, AucKiand Hospital, Atickiand, NZ

Abstract:
A 28-year-old male presented with profound hypokalemia and was found to have a variant of
Bartter’s syndrome with nephrocalcinosis, hypercalciuria, normal distal fractional reabsorption
of chloride and normal sodium delivery to the distal tubule. (Aust NZ J Med 1989; 19: 58-60.)
Key words: Bartter’s syndrome, hypokalemia, nephrocalcinosis, juxtaglomerular apparatus hyperplasia,
hypercalciuria, prostaglandin synthetase inhibitor.

INTRODUCTION no relevant family history. His growth was normal and puberty
Bartter’s syndrome, first described in 1962’ is included had not been delayed.
in the differential diagnosis of renal potassium loss with He was slim, of average stature, well-nourished weighing 69
hyperchloruria. Characteristic findings of this syndrome kg and normally mobile. The blood pressure was 120170 mmHg
and there was no postural hypotension, muscle tenderness or
include hypokalemic alkalosis, hyperreninemia,
iveakness demonstrable. The serum potassium was 1.2 mmolil
normotension and juxtaglomerular apparatus hyper- and serum magnesium 0.6 mmol/l. Chloride and phosphate levels
plasia. The pathogenesis of this syndrome is uncertain were also reduced and there was mild impairment of his renal
but relates to renal transport defects in either the proximal function with a urea of 8.7 nimol/l, creatinine 0.10 mmol/l and
or distal tubule, or both. Its treatment is difficult but creatinine clearance of 0.89 nil/s. The urine calcium excretion
improvement in serum potassium levels may be achieved ranged from 11 to 40 mmoV24 h. The very high excretion rates
with prostaglandin synthetase inhibitors, angiotensin occurred during IV replacement therapy but were persistently
converting-enzyme inhibitors and potassium-sparing elevated at other times. Serum calcium and parathyroid hormone
diuretics. levels were normal. The serum bicarbonate level was high normal
(range 3 1 to 38 mmol/l). An arterial blood gas sample was also
We report a variant of Bartter’s syndrome with normal (PO, 14 kPa, PCO, 4.6 kPa). The ECG reflected his
profound h ypokalemia, hypercalciuria and nephrocalci- hypokalemia with generalised T wave flattening, downward
nosis. These findings are similar to those in the children sloping ST segments and the presence of ‘u’ waves.
described by McCredie et al.* Clearance studies after an Urinary potassium losses were high, up to 1200 mmo1/24 h,
oral water load did not demonstrate a defect in either as were chloride losses of up to 900 mmo1/24 h (during IV
proximal or distal tubular sodium reabsorption. therapy). Screening of urine for diuretics’ gave consistently
negative results over his four weeks in hospital. The resting
plasma renin level was markedly elevated at 12.9 ng/ml/h (n
CASE REPORT I . 1 f0.53) although plasma and urinary aldosterone levels were
A 28-year-old Caucasian male, born in Australia, was admitted normal. Renal ultrasound (Fig. 1) and intravenous urography
to Auckland hospital with an eight year history of vague musculo- showed widespread bilateral medullary nephrocalcinosis, the
skeletal and abdominal pains, polydipsia, a one month history kidneys being otherwise normal in size and architecture. A
of depressive symptoms and three days of lethargy and weakness. percutaneous renal biopsy demonstrated juxtaglomerular
His general practitioner had found a serum potassium o f apparatus hyperplasia and no specific tubular changes (Fig. 2).
1.9 mmol/l. He denied diuretic or laxative use but had taken An oral water load test“ after two weeks potassium repletion
several body building remedies including ‘Body Bulk‘, ‘Natural (Table 1) showed that maximum free water clearance and
Balance’, ginseng and multivitamins. None of these contained maximum urinary dilution tended to be low but were not signifi-
components known to cause hypokalemia. He gabe a long history cantly below that of published normal controls. Defective
of polyuria and regularly consumed in cxcess of two litres of fractional distal chloride reabsorption (“H20/(‘H20 + CCI)), or
water daily. There was no history of vomiting or diarrhoea and increased sodium delivery to the distal tubule ((:H,O +(”a)

Reprinf requests to: Dr I . J . Simpson, Department of Medicine, Auckland Hospital, Private Hag, Auckland.
58 Aust NZ J Med 1989; 19 WANG AND SIMPSON
 Figure I: liltrasound of left kidney with dense echogenic
renal pyramids as shown by arrows.
fiigurc 2: Hyperplastic juxtaglomerular apparatus.
Magnification x 750. Bar - 30 M.

could not be demonstrated. Formal testing for an acidification in the English literature,’ the majority presenting in
defect was not completed because the patient vomited the childhood and sometimes involving several family
ammonium chloride. Intravenous and then oral repletion of members.
potassium was commenced together with phosphate and
Although hyperaldosteronism induced by increased
magnesium supplements. There was little improvement in the
patient’s hypokalemia until amiloride, indomethacin and later levels of angiotensin 11 was described in Bartter’s original
enalapril were added. The serum potassium eventually stabilised cases, it is not primarily responsible for the renal
in the range 2.3 to 2.7 mmol/l. potassium loss. As with the patient under discussion,
some may have normal or even reduced aldosterone
DISCUSSION secretion in spite of high levels of plasma renin activity.’
This patient demonstrates an interesting variant of Hypokalemia itself may inhibit aldosterone release by a
Bartter’s syndrome. With no evidence for skin or gastro- direct effect on the adrenal gland. However, since chronic
intestinal electrolyte losses, the syndromes associated with renal potassium loss tends to have an indirect stimulatory
renal potassium wasting are most logically classified in effect on aldosterone secretion, it has been suggested that
terms of the prevailing blood pressure. Our patient was a balance may exist in Bartter’s syndrome resulting in
normotensive, and the consistently high serum bicar- normal aldosterone levels despite marked hypokalemia
bonate in the absence of respiratory acidosis effectively and hyperreninernia.6
excluded renal tubular acidosis. Bartter’s syndrome is associated with the over-
In 1962, Bartter and colleagues’ described two patients production of prostaglandins and it has been controversial
with hypokalemic alkalosis, normal blood pressure or a as to whether this is a primary phenomenon or is
tendency to hypotension, urinary potassium loss, high secondary to the hypokalemia. A reduction in urinary
plasma renin activity and hyperplasia of the renin- excretion of prostaglandin El and prostacyclin F, alpha
producing juxtaglomerular apparatus. By 1980 there had has been achieved with improvement of serum potassium
been more than 100 cases of Bartter’s syndrome reported levels though others have recorded normal prostacyclin

TABLE 1
Clearance Studies After an Oral Water Load* *

v max
(mlimin)
u OSM
(mosmikg) ” c1
MnLmum
(mmolil)
S osm
(mosmikg)
PC’
(mmolil)
CH20
(mlivin)
CNa
(mlimir)
LC1
(mlimln)
‘H20 CNa+
c ~~0
LCr
(mlisec)

Subject 10 3 107 13 278 89 64 07 15 08 70 15+006

Control’ 12 69 18 287 104 91 ’2 11 08 103 22503
P,bl sned
controls
Solomon‘ 1 2 4 + 2 3 70+‘8 14t5 281k4 98+4 92+16 - 1 8 t 0 8 08t006 - -
Stein‘ - 100 5 11 ‘3 0809 614 1623
‘Laboratory con!rol (author)
“*After a Iigh! breakfast with nc tea, coffee 0‘ salted food 1 L of waier taken over 20 miriutes Uriie was col1ec:eo by spon:aneous voiding one-half
hourly for three hours CHIO CNa CC1 are dererminen at V max
BAR1 IER’S SYNDROME A N D NEPHROCAI CINOSIS Aust NZ J Med 1989: 19 59
metabolite excretion during ingestion of both normal and nephrocalcinosis. This patient also had mild impairment
high intakes of potassium.’ of chloride reabsorption. Stein suggests that this small
Insensitivity to the pressor effect of infused angiotensin group of patients with both renal potassium and calcium
was found in the original studies and was suggested as loss may constitute a separate entity.
the primary abnormality causing high circulating renin It is interesting to note that the subject of this report
levels and potassium loss. The absence of hypertension was born in Australia and would be of a similar age to
in the syndrome results from this vascular resistance to the cases described by McCredie et aL2 Even though an
angiotensin 11. More recently, defective proximal sodium inherited defect in membrane transport is thought to be
reabsorption alone or in association with a defect in the likely cause of Bartter’s syndrome, a common
chloride reabsorption in the thick ascending limb of the environmental factor producing distal nephron injury and
loop of Henle leading to excessive potassium secretion nephrocalcinosis in this group of patients is possible.
by the distal tubule has been suggested.BHowever, the
distal abnormality has not been demonstrated in a number
Acknowledgements
of patients who otherwise seem to have Bartter’s The authors wish to thank Professors P . J. Scott and J. D. K .
~ y n d r o m e . ~Our
. ~ patient successfully achieved a North for permission to publish the details of this patient and
minimum urinary chloride within the normal range after also Nancy MacKay and Charlotte de Vry for secretarial
an oral water load. assistance. The electron photomicrograph was kindly provided
Stein9 has categorised Bartter’s syndrome according to by Dr Mary Miller, Department of Pathology, University of
three postulated functional defects of the renal tubules. Auckland School of Medicine.
The patient reported here would fit Stein’s Type 1,
comprising patients with a primary, isolated, potassium References
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collecting tubule. These patients have normal fractional of the juxtaglomerular complex with hyperaldosteronism and
distal solute reabsorption and normal sodium delivery to hypokalemic alkalosis: a new syndrome. Am J Med 1962;
the distal tubule. The patients with Stein Type I1 and 111 33: 811-28.
defects have defects in proximal or distal sodium chloride 2. McCredie DA, Rotenberg E, Williams AL. Hypercalciuria
transport which were not proven in this patient. in potassium-losing nephropathy: A variant of Bartter’s
syndrome. Aust Pediatr J 1973; 10: 286-95.
The association of Bartter’s syndrome with nephrocal- 3. Simpson IJ, Black P, Couch R. Surreptitious diuretic
cinosis has been infrequently reported but it has been ingestion mimicking Bartter’s syndrome. NZ Med J 1986;
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is used to examine the kidneys of infants with Bartter’s 4. Solomon LR, Bobinski H, Astley P , Goldby FS, Mallick
syndrome.lO The patient reported here showed a dramatic N P . Bartter’s syndrome-observations o n the
echogenicity of the renal pyramids which appears to be pathophysiology. Q J Med 1982; 51: 251-70.
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films and urography showed widespread calcification in 6. Costello J , Bourke E. Bartter’s syndrome - the case for
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Four children with Bartter’s syndrome were reported 7. Watson ML, Gill JR, Branch RA, Oates JA, Brash AR.
by McCredie ef all with hypercalciuria and nephrocal- Systemic prostaglandin 1 synthesis is normal in patients with
cinosis. They postulated that a defect in proximal sodium Bartter’s syndrome. Lancet 1983; 2: 368-70.
and calcium reabsorption accounted for the findings and 8. Gill JR Jr, Bartter FC. Evidence for a prostaglandin-
that hypercalciuria was an important component of this independent defect in chloride reabsorption in the loop of
syndrome. Our patient also had elevated urinary calcium Henle as a proximal cause of Bartter’s syndrome. Am J Med
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,~ findings of hypercalciuria in some 10. Cumming WA, Ohlsson A. Nephrocalcinosis in Bartter’s
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activity.” Fanconit2 reported two children with failure 11. Meyer WJ, Middler SA, Delea CS, Bartter FC. Hypercal-
to thrive and hypercalciuria who developed hypokalemia, ciuria and increased plasma renin activity. In: Assaykeen
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In their studies on the pathophysiology of Bartter’s hyperrenin-hyperaldosteronism(‘Ranter’s syndrome’), and
syndrome, Solomon ef found one patient with hypercalciuria. Helv Ped Acta 1971; 26: 144-63.

60 Aust NZ J Med 1989; 19 WANG AND SIMPSON