Nephrol Dial Transplant (2008) 23: 393–395

doi:10.1093/ndt/gfm372
Advance Access publication 19 October 2007

Nephroquiz
(Section Editor: M. G. Zeier)
See http://www.oxfordjournals.org/our_journals/ndtplus/

Hyponatraemic syndrome in a patient with tuberculosis—always

the adrenals?

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Keywords: hyponatraemic; tuberculosis; meningitis
Table 1. Patient characteristics

Quiz Characteristics Range Follow-up

At Under
A 42-year-old African man was admitted to our baseline treatment
Nephrology Department for the management of a
severe hyponatraemia (117 mmol/l).
Serum parameters
The patient had been hospitalized 1 month earlier Serum sodium (mmol/l) 136–142 118 138
for generalized weakness, weight loss (30 kg in the Serum osmolarity (mOsm/l) 285–295 260 292
past 3 months), abdominal pain, cough, dyspnoea, Serum creatinine (mmol/l) 70–100 35 40
haemoptysis and confusion. His clinical examination Serum urea (mmol/l) 2.5–5 8 4
Serum uric acid (mmol/l) 240–350 100
was unremarkable except for severe malnutrition. His Serum ADH (pg/ml) <14 20 NA
Glasgow coma scale was 15, with no focal neurological Serum BNP (pg/ml) <100 330 NA
signs. Blood pressure was 100/70 mmHg with ortho- Serum ANP (pmol/l) <14 12.6 NA
static hypotension and tachycardia (120 pulse/min). Serum renin (pg/ml) 3.5–19 10.5 NA
Routine blood tests revealed hyponatraemia at Serum aldosterone (pg/ml) 12–125 <12 NA
Synacten test
117 mmol/l, plasma osmolarity of 250 mOsm/l, serum Serum cortisol (before) (ng/ml) 60–249 292 NA
glucose level 5.5 mmol/l and normal serum potassium Serum cortisol (after) (ng/ml) 195–400 402 NA
level (4.5 mmol/l). Chest X-ray showed an excavated Urinary parameters
shadow of the right superior lobe. Head CT scan was Urinary sodium (mmol/l) 143 120
Urinary osmolarity (mOsm/l) 650 300
normal. CSF examination revealed a lymphocytic
reaction (130 cells/cm) with a protein of 1.9 g/l and NA, not available.
glucose of 2.3 mmol/l. Meanwhile, the patient was
found to be HIV-1 positive with disseminated tuber- serum sodium decreased to 118 mmol/l. Urine output
culosis (i.e. pulmonary and meningitis). Based on the increased (5 l in 24 h). Biochemistrical parameters
clinical and biological findings, the patient was treated are summarized in Table 1.
for adrenal insufficiency with gluco- and mineralocor-
ticoid substitution and normal saline perfusion with
an improvement in plasma sodium level (from 117 to Question
123 mmol/l). However, since Synacthen test remained
normal, steroid substitution was stopped and the What is your diagnosis?

Correspondence and offprint requests to: Dr Hassane Izzedine,

Department of Nephrology, La Pitié-Salpêtrière Hospital,
47-83 Boulevard de l’Hôpital, Assistance Publique-Hopitaux
de Paris, Pierre et Marie Curie University, 75013 Paris-France.
Email: hassan.izzedine@psl.aphp.fr

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394
Answer to the quiz on the preceding page
Diagnosis
Acute hyponatraemia due to cerebral salt-wasting
syndrome (CSWS) during tuberculosis meningitis
(TBM) in an HIV-1-infected patient.
Clinical follow-up
Hyponatraemia associating TBM has three main
differential diagnoses: Adrenal insufficiency, inapprop-
riate secretion of antidiuretic hormone syndrome
(SIADH) and CSWS.
Absence of hyperkalaemia and negative Synacten
test suffice to eliminate adrenal insufficiency.
Diminished extracellular volume associated with natri-
uretic hyponatraemia excludes SIADH. We therefore,
considered the diagnosis to be CSWS, the following are
supporting arguments:
Severe volume depletion (postural hypotension with
tachycardia), high urinary sodium concentration
and excretion, and correction of hyponatraemia and
volume status with saline and fludrocortisone therapy,
features atypical on SIADH and favouring CSWS.
Furthermore, demonstration of elevated BNP levels in
our patient with TBM would support this diagnosis.
Hypertonic saline given at the dose of 12 g the first
day and then 6–10 g/day for the following seven days,
associated with 2 l of normal saline/day along with
increasing doses of fludrocortisone (up to 0.5 mg/day)
stabilized the serum sodium concentration at the level
of 130 mmol/l. However, normalization of higher brain
functions was not obtained until CSF TBM subsided
(decreased cellularity 100–50 lymphocyte/ml, negative
ADA level). Two months later, plasma sodium level
remained stable at 138 mmol/l.
Discussion
CSWS is defined as renal loss of sodium during
intracranial diseases, leading to hyponatraemia, exces-
sive natriuresis, volume depletion and clinical response
to volume and salt replacement. It was first described
by Peters et al. [1] in 1950, 7 years before the
identification of SIADH [2]. As early as 1951,
Rapoport et al. [3] described a salt-losing state as a
possible cause for hyponatraemia in TBM. Up to 1993,
however, hyponatraemia in TBM was thought to be
caused by SIADH.
A variety of processes have been linked with CSWS,
including central nervous system injury, subarachnoid
haemorrhage, encephalitis, tuberculous meningitis,
craniotomy, poliomyelitis, and pituitary adenoma,
among others [4]. It can occur between 6 months and
65 years of age, and the exact underlying pathophys-
iology is unclear. The main pathophysiological
mechanisms involved in CSWS are a decrease in the
L. Camous et al.
Table 2. Differential criteria of CSWS and SIADH
Variable CSWS SIADH
Weight # "
Postural hypotension þþ –
Serum osmolarity # #
Serum uric acid Normal or " #
Plasma urea Normal or " #
Urine sodium "" "
Urine volume "" #
CSW, cerebral salt wasting syndrome; SIADH, syndrome of
inappropriate antidiuretic hormone secretion.
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sympathetic nervous system outflow during intracra-
nial disease leading to decrease sodium reabsorption
in the proximal tubules, inhibition of the RAS, and
also the release of some natriuretic factors such as
brain natriuretic factor (BNP), ANP and some other
natriuretic proteins [5,6]. The net effect of all these
changes is the induction of natriuresis, which in turn
causes polyuria and a decrease in the effective
circulating volume, thus leading on to hypotension
and hyponatraemia. Our patient presented suppressed
RAS, inappropriately normal ANF and elevated BNP
levels as reported in the literature. Indeed, Narotam
et al. [7] described a state of inappropriate ANP
secretion with suppressed or inappropriately normal
RAS and ADH levels as the cause of hyponatraemia
in 65% of patients with TBM. Berendes et al. [8] have
provided evidence that BNP might be the more likely
candidate to mediate CSWS.
The main differential diagnosis is SIADH.
A thorough clinical and laboratory examination is
essential to distinguish between the two and attention
to extracellular volume status is critical. Despite
apparent similarities, the pathophysiology, biochemis-
try and treatment of these two conditions are quite
different (Table 2). The major difference between
CSWS and SIADH is that CSWS involves renal salt
loss, resulting in hyponatraemia and extracellular fluid
volume decrease, whereas SIADH involves physio-
logically inappropriate secretion of ADH or increased
renal sensitivity to ADH, leading to renal conserva-
tion of water and euvolaemic or hypervolaemic
hyponatraemia. Conversely, an elevated serum ADH
does not exclude a diagnosis of CSWS as it may be
raised physiologically in response to hypovolaemia [9].
Misdiagnosis of CSWS as SIADH can be fatal,
as water restriction is detrimental to patients
with CSWS.
Other causes of hyponatraemia, such as drug
therapy and adrenal insufficiency, must also be
excluded. The possibility that our patient had some
degree of hypothalamus pituitary–adrenal axis sup-
pression is a confounding factor in the diagnosis
of CSWS. Both AIDS and tuberculosis can cause
suppression of the hypothalamus pituitary–adrenal
axis and destruction of the adrenal gland [10,11] and
may have accounted for the mild hyponatraemia seen
Hyponatraemic syndrome during tuberculosis
on admission. This may lead to adrenal insufficiency
and subsequent hyponatraemia. However, the high
urinary potassium levels, as well as the absence of
hyperkalaemia and normal adrenal stimulation test,
make this diagnosis less likely. Patients with AIDS or
AIDS-related complex can also develop acute
hyponatraemia from diarrhoea and vomiting as well
as renal insufficiency [12]. Our patient had normal
renal function and had no evidence or gastrointestinal
losses.
Therapy of SIADH and CSWS is diagonally
opposed, i.e. volume restriction in SIADH vs volume
and salt replacement in CSWS. Volume restriction in
CSWS would be potentially disastrous, in causing a
further decrease in the cerebral perfusion pressure.
The volume replacement achieved with 0.9% (or 3%
sodium chloride if necessary) is the cornerstone of
treatment of CSWS. The rapidity of salt replacement
depends on the rate at which the hyponatraemia
developed. Treatment of hyponatraemia developing
at a rate of
0.5 mmol/l/h should be aggressive, as it
is a life-threatening complication and may cause
death from severe cerebral oedema and cerebral
herniation [13]. Unlike chronic hyponatraemia, rapid
correction of serum sodium level is associated with
marked neurological improvement, with less danger of
developing central pontine myelinolysis [14]. As ANP
can inhibit mineralocorticoid secretion in patients with
CSWS, administration of an agent with mineralocorti-
coid activity, such as fludrocortisone, has also been
shown to be effective in returning serum sodium levels
to normal [15], by acting directly on the renal distal
tubules to enhance sodium reabsorption [16]. Ishikawa
et al. [16] reported a resolution of CSWS with
fludrocortisone acetate at a dose of 0.2–0.4 mg/day.
Adverse effects of fludrocortisone including hyperten-
sion, hypokalaemia and pulmonary oedema should be
monitored.
In our patient, sodium deficit was replaced within
3 weeks (plasma sodium level, 138 mmol/l) by intrave-
nous hypertonic (although within the recommended
limit of 0.5 mmol/l/h for the first days), then normal
saline perfusion and mineralocorticoid substitution
(fludrocortisone 0.5 mg daily dose).
This case shows the difference between CSWS and
SIADH, and the importance of correct diagnosis and
treatment. Mineralocorticoid supplementation seems
to be a safe and effective treatment for CSWS, whereas
normal saline and hypertonic saline could be a
temporary measure. However, serum sodium level
normalization was obtained only with TBM disease
control.
Conflict of interest statement. None declared.
395
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Laurent Camous1
Nadia Valin2
Jose´ Luis Lopez Zaragoza2
Edward Bourry1
Eric Caumes2
Gilbert Deray1
Hassane Izzedine1
1
Department of Nephrology
2
Department of Infectious Diseases, Pitie Salpetriere
Hospital, Paris, France
Received for publication: 1.1.07
Accepted in revised form: 16.5.07