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REVIEW JNEPHROL 2013; 26 ( 01 ) : 61- 72

DOI: 10.5301/jn.5000168

The management of hyponatremia in HIV disease

Madhav C. Menon 1, Amarinder S. Garcha 2, Department of Medicine, Mount Sinai School of Medicine,
1

Apurv Khanna 2 New York, NY - USA


Department of Medicine, SUNY Upstate Medical
2

University, Syracuse, NY - USA

ingly share the burden of chronic diseases with the general


Abstract population. Dyslipidemias (2), diabetes, cardiovascular (3,
Hyponatremia is reported to be the most common 4), and renal disease (5) and their management are gaining
electrolyte abnormality encountered in clinical prac- importance in HIV management.
tice. Diagnosis and principles of management of hy- Hyponatremia is the most common electrolyte abnormality
ponatremia are everyday issues in patient care. Inter- encountered in clinical practice (6). The frequency of hy-
est has also been generated by its association with ponatremia has varied widely in studies, depending upon
adverse prognosis from studies in specific disease the definition of hyponatremia used, the health care setting
groups. Patients with human immunodeficiency virus chosen, and the patient population studied (6, 7). In the dif-
(HIV) disease are living longer and medical diseases ferent pathologic states where hyponatremia is observed,
similar to the general population are more frequently there has been considerable interest in its association with
encountered in them. Hyponatremia has been ob-
adverse clinical outcomes (8, 9). There is a paucity of pop-
served to be widely prevalent in both hospitalized and
ulation-based data on the prevalence of hyponatremia in
outpatient HIV patients, although population-based
HIV infection and AIDS. However, prior series have reported
estimates are not known. From case series, these pa-
tients appear to be at greater risk for the development
hyponatremia to be widely prevalent in the HIV population
of hyponatremia from pathomechanisms encountered ranging from 20% to 80% of hospitalized patients (Tab. I)
in the non-HIV population. In addition, certain HIV- (10). For instance, 56% of HIV cases studied prospectively
specific mechanisms from infectious etiologies, endo- and 42% analyzed retrospectively (in a series of 48 and 71
crine causes, and medications are unique to them. Us- patients respectively) had hyponatremia (Level < 133) (11).
ing an illustrative case as an example, in the following In this subgroup, hyponatremia has also been associated
review, we discuss the varied etiologies, pathogenetic with higher inpatient mortality (10, 11). It is also prevalent in
mechanisms , clinical features, diagnosis, and outline the outpatient setting in HIV (12). Table I lists published case
the management of hyponatremia in HIV patients. series of HIV and hyponatremia (13-15).

Key words: Human immunodeficiency virus (HIV) dis-


ease, Hyponatremia, Steroid resistance
Illustrative case
A 24-year-old African American man with acquired immune
deficiency syndrome (AIDS) on HAART presented with a
one month history of fever, diarrhea, weakness, weight loss,
Introduction vague abdominal pain, and dizziness. Examination revealed
hyperpigmentation over the trunk, with an otherwise unre-
According to the World Health Organization, 1.4 million markable abdomen and normal systemic findings. He was
people (prevalence 0.6%) in North America were infected noted to be orthostatic but maintained good urinary out-
with HIV in 2008 (1). With highly active antiretroviral thera- put. Initial lab examinations revealed serum sodium of 122
py (HAART), patients with human immune deficiency virus mmol/L, serum potassium 4.1 mmol/L, serum bicarbon-
(HIV) are living longer more than ever before and increas- ate 23 mmol/L, serum chloride 92 mmol/L, serum BUN 12

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Menon et al: Management of hyponatremia in HIV disease

TABLE I
Reported case series of HIV patients with hyponatremia
Hyponatremia
Study by author (ref.) Clinical setting definition (mmol/L) Patients (no.) Frequency (%)
Viting KE et al (11) Inpatients <133 119 53.7%
Cusano AJ et al (12) Inpatients/clinic <131 96 31%
patients
Tolaymat A et al (13) Inpatients/clinic <135 86 26%
patients (pediatric)
Manfro JC et al (14) Inpatients <135 99 45%-80%
Hoen B et al (15) Inpatients <130 160 28%
Tang WW et al (23) Inpatients <135 212 39%
Agarwal A et al (41) Inpatients <130 103 34.9%

mg/dL, and serum creatinine 0.6 mmol/L. Cytomegalovirus discusses the important causes, pathophysiology, and outli-
(CMV) antigenemia was weakly positive in buffy coat stain- nes the management of hyponatremia with specific relevan-
ing. Stool studies, sigmodioscopy with biopsy, and imaging ce to HIV disease.
studies were all negative.
Diarrhea and fever improved with Gancyclovir therapy. Pathogenesis of hyponatremia
Orthostatic hypotension persisted and hyponatremia wors-
ened (Serum sodium of 120-125) despite intravascular In the homeostatic state, plasma osmolality (Posm) is de-
volume expansion with normal saline (14 liters in three days fined largely by the plasma Na-concentration ([Na]). In nor-
without diarrhea). The patient remained polyuric with per- moglycemic patients without renal failure, glucose and BUN
sistently high urine sodium (Na) excretion (~592 meq/day). would each contribute around 5 mosm/kg to Posm. Since
Random cortisol level was 19.8 mcg/dL (normal range 6.2- urea is able to freely cross cell membranes, it is also “inef-
19.4 mcg/dL) and responded to cosyntropin stimulation. fective” as an osmole in plasma and ECF) (16).
Plasma adrenocorticotrophic hormone (ACTH) levels and
renin activity (supine) were normal. He was treated with glu- Posm ~ 2xPlasma Na
cocorticoid-hydrocortisone 50 mg IV four times a day and
mineralocorticoid-fludrocortisones 0.1 mg twice daily with Hypo-osmolality is therefore almost always encountered
resolution of orthostatic hypotension. Serum Na improved with low Plasma [Na]. Posm and plasma Na are inverse-
to 137 mmol/L and urine Na excretion decreased to 34 meq/ ly related to the extracellular fluid (ECF) water. Thus, for
day on a similar diet. example, if body water is expanded 5% (about 2 L in a
In this patient, natriuresis with orthostasis despite saline hy- typical 70-kg patient), serum sodium decreases by about
dration and adequate urine output were in favor of hypoad- 7 mEq/L (7 mmol/L) and osmolality by approximately 14
renalism or cerebral salt wasting (SW). He had no apparent mosm/kg. Daily water gain occurs through diet and wa-
clinical risk factors for SW. His clinical syndrome suggested ter comes from oxidation (from carbohydrate metabolism).
adrenal insufficiency; high baseline cortisol levels and appro- Water is lost through urine, feces, skin, and the respira-
priate response to cosyntropin stimulation pointed against tory tract. During homeostasis, Posm is tightly regulated
it. However, his serum Na levels and natriuresis corrected by closely matching water intake to output (16). Osmo-
with supraphysiologic steroid doses. In all, this reflected a receptors in the hypothalamus respond to hyperosmolal-
state of glucocorticoid resistance in this patient with AIDS. ity by thirst and cause vasopressin (antidiuretic hormone,
This case illustrates one of the many mechanisms of hypo- ADH) release from supraoptic and paraventricular neurons
natremia associated with HIV disease. The following review whose axons project into the posterior pituitary gland (17).

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Reduced ECF volume is also a potent stimulus for ADH abnormalities is critical to understanding the pathogenesis
release (8, 17, 18). ADH acts through V2 receptors on the of this disorder.
principal cells of the collecting tubules and inserts aquapo- In HIV, the genesis of hyponatremia is similar to the non-HIV
rins (water channels) (19) into their apical surfaces, mediat- population. HIV-specific mechanisms are discussed under
ing water resorption (20). the respective etiologies.
Essentially, water retention in excess of solute needs to oc-
cur for the development of hypo-osmolal hyponatremia. Causes of hyponatremia
This can best be understood in two stages: (a) the mecha-
nism behind the initial development of hyponatremia (b) the Table II outlines common causes of hyponatremia from a
mechanism behind the maintenance of this hyponatremic mechanistic perspective and correlates these with usual
state. volume states observed clinically. Table III lists various eti-
ologies reported in HIV patients. The following discussion
The development of hyponatremia elaborates on some of these causes relevant to the HIV-AIDS
population.
The usual modalities of solute loss from the body such as
with diarrhea and vomiting are characterized by water loss Hypovolemia and hyponatremia in hiv
proportionate to the solute loss, that is, loss of isotonic fluid.
Therefore, this loss by itself is not sufficient to produce a Hypovolemia from renal and non-renal causes, acting via the
hyponatremic state. Such losses are, however, frequently baroreceptors, stimulates ADH release. If the GFR falls with
accompanied by excessive ADH action from hypovolemia hypovolemia, diminished fluid delivery to the distal parts of
and/or replacement by either free water or hypotonic fluids, the nephron further limits the ability to excrete free water,
thereby generating hyponatremia. even in the absence of ADH. The HIV population shares simi-
lar risk factors for hypovolemia with the general population.
The maintenance of hyponatremia In a series of 96 HIV patients with hyponatremia, hypovo-
lemia was identified as most commonly associated (12). In
The normal kidney has an enormous capacity to excrete their series, Tang et al, observed hypovolemia to exist in 43%
free water. This capacity is dependent on (a) the generation of hyponatremic cases that developed after admission (23).
of dilute urine by preferential sodium and chloride (NaCl)
resorption in the ascending loop of Henle and the distal Renal losses
tubule and (b) the impermeability of the collecting tubules
to this water (in the absence of ADH). Under normal cir- Thiazide diuretics have been reported to be the most
cumstances this ability would lead to restoration of normal common cause of hospital-associated, moderate-to-severe
plasma sodium concentration and osmolarity. Therefore, hyponatremia (serum sodium level of <125 mEq/L) among
with normal kidneys, reduced free water excretion and medical patients (24). In a study of 950 outpatients pre-
hyponatremia develop only with excesses of ADH. These scribed thiazides for any indication, hyponatremia (<135
excesses may be appropriate (as in response to effective mEq/L) occurred in 14% of patients (25). There are no stud-
volume depletion) or inappropriate (Syndrome of inappro- ies of diuretic use and hyponatremia in the HIV population.
priate ADH secretion or SIADH) (16, 17). Since ADH merely Thiazides cause Na loss from ECF and hypovolemia triggers
retards the excretion of water already consumed, free wa- ADH release. Oddly, most patients with thiazide-induced
ter intake must continue even in the presence of excesses hyponatremia are euvolemic (7, 16). Ongoing inhibition of
of ADH for hyponatremia to develop. It is also important DCT NaCl resorption and ADH action sets the stage for im-
to remember that most fluid ingestion occurs out of habit paired free water excretion and hyponatremia. In addition, hy-
and not thirst. This propagates hyponatremia from most pokalemia observed with thiazides promotes K+ efflux from
causes (16). Polydipsia can overwhelm the limits of the cells. Low intracellular K+ causes a direct shift of Na into
normal kidney’s capacity to excrete free water and cause cells to maintain electroneutrality. Chloride ions and, subse-
hyponatremia (16). Abnormalities of ADH secretion and wa- quently, water follow K+ to the ECF furthering ECF dilution
ter excretion have also often been observed in polydipsic and hyponatremia. Fichman et al, demonstrated correction
patients (21). Conversely, renal failure impairs the kidney’s of hyponatremia and hypokalemia in patients on thiazides,
capacity for urinary dilution and can cause hyponatremia by replacing K+ in diet alone while continuing to restrict
with lower levels of water intake (22). Understanding these Na (26).

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Menon et al: Management of hyponatremia in HIV disease

Table II
Hyponatremia – causes by mechanism
DIsorders in which renal water excretion is impaired Usual volume status
a.  Effective circulating volume depletion
1. GI losses: vomiting, diarrhea, tube drainage, intestinal obstruction, bleeding hypovolemic
2. Renal losses: diuretics, hypoaldosteronism, salt-wasting nephropathy
3. Skin losses: ultramarathon runners, burns, cystic fibrosis
4.  Edematous states: heart failure, cirrhosis, nephrotic syndrome hypervolemic

b. Renal failure hypervolemic or hypovolemic


c. Euvolemia with ADH excess euvolemic
1. SIADH: cancers, CNS disorders, drugs, pulmonary diseases, miscellaneous causes
2. Hypocortisolism and Cortisol-resistance
3. Hypothyroidism
d.  Decreased solute intake: beer potomania, tea-and-toast diet euvolemic
e.  Cerebral salt wasting euvolemic or hypovolemic
f.  Thiazides: potassium depletion, thirst-stimulation and impaired urinary dilution
Disorders in which renal water excretion is normal
a. Primary polydipsia and excessive water intake: tap water enemas, hypotonic iv
solutions euvolemic
b.  Reset osmostat: pregnancy, psychosis, quadriplegia, malnutrition

TABLE III
Hyponatremia etiologies in HIV
SIADH in HIV
Infections
  – Cerebral (Toxoplasmosis, Bacterial Meningeoencephalitis, Cryptococcus, Tuberculous meningitis, CMV)
  –  Pulmonary (Bacterial pneumonia, PCP, Fungi, CMV)
  –  Neoplasms (CNS Lymphoma)
Drugs: Pyrazinamide/ Ethambutol, Carbamezepine, anti-depressant
Cerebral Salt Wasting
Drugs – Trimethoprim, Amphotericin-B, Pentamidine, Lopinavir (with Ritonavir), Diuretics
Diarrheal diseases and GI losses:
  – Bacterial diarrhea, Cryptosporidium parvum, Isospora Belli, Microsporidiosis, Mycobacterial enterocolitis (MAI,TB),
CMV Colitis
Hypoadrenalism:
  – Mycobacterial adrenalitis (TB, MAI), CMV adrenalitis
  –  Neoplastic infiltration
Glucocorticoid resistance
Pseudohyponatremia:
  –  Polyclonal hypergammaglobulinemia

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Cerebral (renal) salt wasting or acidosis could cause insensible water loss (33). These
free water losses may thus offset the negative free water
Cerebral salt wasting (SW) has been reported in HIV in losses incurred through ADH action and thirst and could
both early and newer reports. It often occurs in the same normalize serum sodium. Thus, the presence of hypo-
clinical scenarios as SIADH, and may co-exist. They are volemia, patient’s age, access to fluids, type of replace-
differentiated based on the presence of ECF volume de- ment fluid, and associated insensible losses will all decide
pletion and a negative Na balance in SW (27). Brain-type changes in plasma Na in diarrhea (34). Prior to the wide-
natriuretic peptide (BNP) release may play a role in the spread use of HAART, diarrhea was highly prevalent in the
natriuresis. Proximal tubular dysfunction has been impli- HIV population. In a series of hospitalized patients from
cated in its pathogenesis. Both conditions are associated North America, diarrhea was documented in 55% to 66%
with hypouricemia (<4) and an increased fractional excre- of admissions for all causes (35, 36). Recent series have
tion (FE) of uric acid. The mechanism of hypouricemia is also demonstrated high prevalence of acute and chronic
not entirely clear in SIADH and may represent an effect of diarrhea in adults and children with HIV, although the exact
plasma dilution and enhanced renal clearance because of prevalence of hyponatremia in this specific situation has
volume expansion (10, 27). In SW, hypouricemia has been not been reported (37, 38).
linked to abnormal uric acid transport as part of the more
generalized disorder in solute transport in the PCT (27). Euvolemic hyponatremia in hiv
Persistence of an increased FE Uric acid after correction
of hyponatremia, and an elevated FE phosphate may be
pointers to SW over SIADH. Elevated ADH levels can oc- Syndrome of inappropriate ADH release (SIADH)
cur in SW from volume depletion; conversely, BNP levels in HIV
may elevate in SIADH from volume expansion and atrial
stretch (27, 28). SIADH is characterized by evidence of excessive ADH ac-
Cusano et al, studied 10 patients with AIDS with saline-re- tion in the absence of an appropriate (volume or osmo-
sponsive postural hypotension. All the patients had central lar) stimulus for ADH release. The prevalence of SIADH in
venous pressure of 0 cm water, increased renin and aldoste- hospitalized patients has been reported to be as high as
rone, hyponatremia, hypouricemia, elevated FEurate, and 35%. ADH levels are practically difficult to obtain quickly
UNa >40 mmol/L, which collectively support the diagnosis (39). Therefore, an elevated urine osmolality in the presence
of SW (29). A report described a 30-year-old man with AIDS of low serum osmolality in a euvolemic patient, suggests
and tuberculous meningitis who developed acute hypona- SIADH. Since ADH is released in response to a variety of
tremia following the insertion of a ventricular drain for hydro- stimuli, SIADH has been encountered in diverse clinical
cephalus. Assessment revealed natriuresis with clinical fea- scenarios (Tab. II). A high urine Na, low blood urea, and se-
tures of hypovolemia, which reversed with isotonic volume rum uric acid are often encountered (7, 16, 40). Significant
resuscitation, consistent with SW (30). Another report docu- liver disease, heart failure, renal failure, adrenal insufficiency,
mented a patient with disseminated toxoplasmosis who and hypothyroidism should be ruled out. A fall in serum Na
developed natriuresis and diuresis with acute hyponatremia with isotonic saline infusion strongly favors euvolemia and
three days after a diagnostic brain biopsy. The patient’s SIADH (7, 16, 39).
hyponatremia similarly responded to saline replacement In HIV, the reported etiologies of SIADH are listed in
suggesting SW (31). Table III (10). In the prospective analysis of 212 HIV patients
during 259 inpatient admissions (Tab. I), 68% of hypona-
Gi losses tremic episodes developed after admission with clinical
euvolemia. In these episodes a syndrome consistent with
Secretory diarrhea is generally iso-osmotic to plasma and SIADH was identifiable (23). Similarly, 34% of hyponatremic
therefore should not cause hyponatremia (16, 32). On the episodes in 103 HIV patients analyzed revealed elevated
other hand, in osmotic diarrhea, the unabsorbed osmoles Uosm with euvolemia and increased ADH levels (41). In
tend to osmotically drive water secretion into the lumen another series of 119 HIV patients (Tab. I), only 16 hypo-
and could result in hypernatremia. In either case, hypovo- natremic patients had Posm, Uosm, and vasopressin levels
lemia would lead to ADH release. Drinking only water, or measured. In 15 patients, low Posm with high Uosm and
electrolyte-free fluid replacement in this setting will also elevated ADH levels were observed. Interestingly, 5/16 pa-
contribute to hyponatremia. However, any associated fever tients who died had the highest ADH levels (11).

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Drugs in HIV and hyponatremia these cases (50, 51). Furthermore, in addisonian subjects,
mineralocorticoid replacement alone did not reverse the
Table III lists some of the important drugs reported to be defect in renal water handling (52). That the hyponatremia
associated with HIV-related hyponatremia. Trimethoprim in is because of hypocortisolism, is further evidenced by the
Bactrim, frequently prescribed in HIV infection, is an organic syndrome of isolated ACTH deficiency with preserved al-
cation (42). It is used in HIV regimens for prophylaxis and dosterone secretion wherein it is also encountered (53). In
treatment of Pneumocystis Jirovecii pneumonia and pro- adrenelectomized rats, impaired water excretion has been
tozoal infections (43). During animal and human studies, associated with elevated ADH levels and significantly im-
amiloride-like (another cation) effects have been demonstrat- proves with physiologic glucocorticoid replacement (54). A
ed at high doses. Fonseca et al showed that trimethoprim vasopressin deficient rat model continued to show persis-
competes with amiloride for the binding site on Na channels tent defects in renal water excretion after adrenalectomy
on sweat glands in frog skin (44). In a study of 30 hypona- suggesting that there may be vasopressin-independent
tremic HIV patients on trimethoprim, inhibition of the apical mechanisms (55). A detailed review of the multiple causes
Na channels with reduced voltage dependent K+ excretion of involvement of the adrenal cortex in the case of HIV in-
and natriuresis were observed (45). In intravenous prepara- fection is beyond the scope of this article. In short, bilateral
tions of Co-trimoxazole, the excess volume of free water in adrenal infiltration by opportunistic infections and malignan-
the diluents used is also involved (42). Pyrimethamine, a di- cies, pituitary infiltration, and drug-related adrenal dysfunc-
hydrofolate reductase inhibitor used as an alternative to tri- tion are all well reported. Advancing HIV infection is more
methoprim in combination with sulfonamides has also been often associated with hypoadrenalism (46, 56, 57).
reported to cause hyponatremia in HIV (10). Antitubercular Vitting et al studied 16 of their 119 HIV patients intensively.
agents have been associated with SIADH in HIV (Tab. III). Adrenal axis testing revealed overt cortisol deficiency with
Rifampicin induces cortisol metabolism and can precipitate inappropriate response to ACTH in four patients. Only 2/16
adrenal insufficiency and hyponatremia thereof (46). had basal cortisol levels above their cut off (>1100 nmol/L).
Among anti-retrovirals, a single report cited the develop- Of the total cohort of 119 patients, eight underwent autopsy.
ment of hyponatremia with euvolemia and elevated urine All eight had adrenal abnormalities – six had necrosis, hem-
osmolality, consistent with SIADH in a 45-year-old African orrhage, and opportunistic infection (MAC, CMV) and two
patient with AIDS dementia treated with Lopinavir-Ritonavir had e/o lipid depletion (including one of the patients with
combination. The hyponatremia reversed and did not recur inappropriate response to ACTH) (11).
after lopinavir was substituted with Atazanavir (47). Another In the series of 212 patients by Tang et al, two had serum
report from Romania documented reversible hyponatremia cortisol < 100 nmol/L. One of these patients had CMV ad-
in 1 out of 100 children (9-14 years) treated with this com- renalitis on autopsy (23). Functional adrenal insufficiency in
bination (48). However, a post-marketing surveillance study critically ill HIV patients, defined by a morning random corti-
did not find hyponatremia as an adverse event (49). sol < 25 mcg/dL, was encountered in 21 out of 113 patients
(19%). In these patients, hyponatremia tended to occur more
Glucocorticoid deficiency often, although this difference was not statistically significant
on multivariate analysis (OR 3.67; CI – 0.99-13.53) (58).
Whereas aldosterone deficiency and consequent hypovole-
mia with natriuresis is a well-recognized cause of hypovole- Glucocorticoid resistance in HIV
mic hyponatremia, isolated glucocorticoid deficiency is also
associated with hyponatremia (7, 16). Several lines of evi- Aside from the multiple causes of adrenal insufficiency,
dence have suggested that neurohypophysial vasopressin both adult and pediatric studies have frequently observed
secretion is under the influence of glucocorticoid negative elevated levels of cortisol in patients with both AIDS and
feedback (20). Altered free water excretion accompanies hy- HIV infection (59-61). Christeff et al had also observed low
poadrenalism. Studies in clinical and experimental adrenal levels of urinary 17-hydroxy steroid, the end products of
insufficiency have implied that this impaired water excretion glucocorticoid metabolism in 60 AIDS patients, suggesting
may be because of elevated vasopressin levels. Interesting- decreased catabolism (62). Norbiato et al reported a series
ly, the elevated vasopressin levels in some of these studies of nine IV drug-abusers with AIDS who had clinical features
were not suppressed by saline or volume replacement (with- suggestive of hypoadrenalism with hyponatremia, hypoten-
out concomitant glucocorticoid replacement). This implied a sion, weakness, and intense muco-cutaneous melanosis.
volume-independent mechanism for vasopressin release in Biochemical testing, however, revealed an elevated cor-

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JNEPHROL 2013; 26 ( 01 ) : 61- 72

tisol level with blunted circadian changes in this group of temporally and quantitatively correlated with hyponatremia
patients. Contemporaneously drawn ACTH levels were also in these patients (67). Aquaporin-2 trafficking is increased in
normal to elevated. This group was compared with 12 HIV the experimental cirrhosis model. Most interestingly, ADH-
patients without the clinical syndrome (controls) who were deficient (Brattleboro) rats do not develop hyponatremia
then shown to have normal cortisol and ACTH levels (63). In when cirrhotic (68).
our illustrative case, treatment with supraphysiologic doses Viral hepatitides, HCV and HBV, share similar risk factors and
of glucocorticoids led to complete resolution of symptoms are widely prevalent in HIV infection. A nationwide French
and normalization of urinary and serum Na levels. study revealed an increased liver disease-related proportion-
In toto, these may represent a state of glucocorticoid re- al mortality rate in HIV infected patients from 1.5% (1995) to
sistance in a proportion of AIDS patients (64). In the same 14.3% (2003) (70). Similar data has emerged from a study in
study, Norbiato et al cultured mononuclear leukocytes from Veterans in the USA (71). It is likely that cirrhosis as a cause of
peripheral blood of cases and controls. Using radiolabeled hyponatremia is more often encountered in the HIV popula-
dexamethasone [H3], they elegantly demonstrated elevated tion, although no study has addressed this issue specifically.
steroid receptor concentrations and reduced receptor affin-
ity for dexamethasone in cases compared to controls. In- Pseudohyponatremia in hiv
corporation of radiolabeled thymidine [H3] (a marker of ste-
roid receptor activation) was also decreased among cases It is an apparently low measurement of plasma Na that oc-
for equimolar concentrations of dexamethasone in the cul- curs in patients with elevated plasma proteins or lipids (72).
ture. This suggested a decreased effect of given amounts of Tonicity, which is a function of the osmotic effects of non-
dexamethasone on these leukocytes. In the Cusano series, permeable plasma solutes alone, is characteristically normal
hypovolemic hyponatremia was associated with inappropri- in these patients. True hyponatremia on the other hand, is
ately high urinary Na levels. This again could suggest either associated with plasma hypotonicity (16, 72). Normal plas-
glucocorticoid deficiency or resistance in them (12). ma is constituted by an aqueous phase (approximately 93%)
and a non-aqueous phase. Pseudohyponatremia occurs
Hypervolemic hyponatremia in hiv with any significant increase in the non-aqueous or solid
phase of plasma (proteins and lipids). Associated decreases
The common factor in these hypervolemic states (Tab. II) is in plasma water ensue. Any measurement of Na assum-
effective circulating volume depletion in spite of hypervol- ing its distribution in 93% of plasma and/or correction by
emia. Baroreceptor-mediated afferents trigger ADH release a similar factor will result in erroneous estimation in these
with consequent hyponatremia. Inability to restrict fluid be- situations (73). Direct ion-sensitive electrode (DSE) potenti-
cause of thirst and non-compliance is a further issue in most ometry-based estimation obviates this error (74). In addition,
of these patients. applying a correction factor after estimation of actual plasma
water may also minimize this error (74). It is important to be
Hyponatremia in cirrhosis mindful of this condition as it has resulted in inappropriate
management and adverse outcomes.
Hyponatremia frequently accompanies cirrhosis. Depend- In HIV, polyclonal hyper-gammaglobulinemia is well docu-
ing on the cirrhotic population studied and the defining level mented (75). Garibaldi et al reported a 52-year-old man with
of Na used, it has ranged from 35% (Level<130) to 57% AIDS and Hepatitis C Cirrhosis with hyponatremia (119 meq/L)
(hospitalized patients; level <135) (65). For a detailed review on initial testing. He had elevated total proteins (11.7 g%)
of the pathogenesis of hyponatremia in cirrhosis, the reader with serum osmolality of 290 mosm/kg. His serum electro-
is referred to excellent reviews on this topic (43, 66). Cir- phoresis revealed polyclonal hypergammaglobulinemia. On
rhosis is understood to be a state of effective arterial hy- retesting with the DSE method, the Na had corrected signifi-
povolemia. Decreased systemic vascular resistance, relative cantly (128 meq/L) (76). Grateau et al reported a 29-year-old
systemic hypotension, renal hypoperfusion, and activation man AIDS patient with pseudohyponatremia in the hyperpro-
of the renin-angiotensin system lead to avid renal sodium teinemia phase (11.2 g%) (77). Given the high prevalence of
retention. Hyponatremia occurs because of increased non- HCV co-infection in HIV, both of which can cause hyperglob-
osmotic ADH secretion and impaired free water excretion. ulinemia (78), it is surprising that this phenomenon has not
That ADH is singularly important to the genesis of hypona- been reported more often. It is a matter of conjecture whether
tremia in cirrhosis is evidenced by both experimental and some of the hyponatremia reported in older series of HIV pa-
human studies (67-69). ADH levels have been shown to be tients may have been attributable to pseudohyponatremia.

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Menon et al: Management of hyponatremia in HIV disease

tion of chronic hyponatremia is 10-12 mmol/L in 24 hours and


Clinical features < 18 mmol/L in 48 hours (85). Patients with severe malnutri-
tion, alcoholism or advanced liver disease are more prone to
Most clinical and experimental studies suggest that the develop osmotic demyelination (86). In patients with severe
symptoms of hyponatremia are dependent on the rate of symptoms attributable to hyponatremia, especially those
development and magnitude of fall in serum Na (usually having seizures, a small quick increase in serum sodium
< 125 meq/L) (7, 79). The Na level at which symptoms ap- (~ 2-4 mmol/L) has been found to be effective in decreasing
pear have varied in different series suggesting heteroge- the intracerebral pressure (85). This is usually accomplished
neous susceptibility among patients to the effects of hypo- with hypertonic (3%) saline. Conversely, correction by <3-4
natremia (80). In general, symptoms appear to be related to mmol/L in 24 hours may be associated with worse outcomes
cerebral swelling from plasma hypo-osmolality (81). Elegant in patients with acute hyponatremia (87). The correction of
studies have demonstrated the reduction in brain osmolytes hyponatremia involves the use of formulae to estimate so-
in patients with chronic hyponatremia as a protective mech- dium deficit and anticipated rate of correction of sodium with
anism (82, 83). This adaptation, however, also puts the indi- intravenous fluids (Tab. IV). Both formulae do not take into ac-
vidual at risk for osmotic demyelination during correction of count ongoing sodium and free water losses (although these
hyponatremia. Deficient ECF-Na, required for routine neuro- effects are often minor). Formula 2 attempts to incorporate
muscular processes such as synaptic transmission and ac- the obligatory volume of free water given with any infusate.
tion potential generation may also be responsible for some An assessment of the patient’s volume status is essential to
clinical effects (7). Although some population-groups, such manage hyponatremia. Obvious offending agents contrib-
as menstruating women, appear to be particularly prone to uting to impair free water excretion or ADH excess should
the effects of hyponatremia, no such sensitivity has been be identified and discontinued. Adrenocortical and thyroid
reported in the HIV population (84). insufficiency should be suspected in euvolemic patients.
Headache, lethargy, restlessness, nausea and vomiting, and When an identifiable non-osmotic stimulus for AVP secre-
muscle cramps have been reported as early symptoms. tion is removed, patients with hyponatremia should tend to
Severe acute hyponatremia has been associated with dis- excrete maximally dilute urine (88). In hypovolemic hypona-
orientation, hyporeflexia, and can result in coma, seizures, tremia, treatment is directed at volume expansion with iso-
and fatal brainstem herniation (7, 79). Interestingly, in many tonic saline to abolish the volume stimulus for ADH release.
clinical studies, although hyponatremia is an indicator of Restricting free water intake is the mainstay of treatment
an adverse prognosis, deaths occurred when the serum in most patients with chronic asymptomatic hyponatremia
Na had been corrected suggesting hyponatremia is itself (39). Acute symptomatic hyponatremia secondary to SIADH
seldom the cause (81). is treated with hypertonic saline since isotonic saline clas-
sically worsens this condition. This phenomenon, desalina-
Management tion, is because of the retention of electrolyte-free water that
occurs when the infusate osmolality is lower than the patient’s
The treatment of hyponatremia is based on the pathophysiol- urinary osmolality. The rapid correction of hyponatremia
ogy, severity, presumed duration, and clinical features. Spe- is generally discontinued if either the symptoms resolve
cial care must be taken to prevent rapid correction in chronic and/or a safe serum sodium level is accomplished (usually
hyponatremia (hyponatremia of > 48 hours) to minimize the greater than 120 mmol/L) (7, 39). Hypervolemic hyponatre-
risk of osmotic demyelination. The acceptable rate of correc- mia requires fluid restriction to amounts less than insensible

Table IV
Methods of estimating rate of Serum Na correction with hyponatremia treatment (7)
Number Formula
1 Sodium deficit = TBW X (target serum sodium [to be attained at a given time interval] – actual serum
sodium)
2 Change in serum sodium with one liter of infusate = ([infusate sodium + infusate potassium] - serum
sodium/[TBW +1])

68 © 2012 Società Italiana di Nefrologia - ISSN 1121-8428


JNEPHROL 2013; 26 ( 01 ) : 61- 72

fluid losses plus urine output (85). The widespread use of of clinical improvements compared to heart failure patients
aquaretics (ADH antagonists) in euvolemic and hypervolemic with normal serum sodium levels (91). In patients with cir-
hyponatremia is at present restricted by the high cost and rhosis, hyponatremia is an independent predictor of mortality
dearth of data showing a mortality benefit (89). and is associated with increased frequency of complications
No studies thus far have reported the need to address the of cirrhosis (65). In a series of hospitalized HIV patients, those
rate of correction differently in HIV. Hypovolemic hypona- with hyponatremia were hospitalized longer than normona-
tremia from GI losses was much more frequent in the pre- tremic patients and had a higher mortality (23). As noted pre-
HAART era (35, 36). Both intravenous and oral cotrimoxa- viously, serum Na has often already been corrected in these
zole, certain antiretrovirals, and antiprotozoal medications patients at the time of death and may not be directly impli-
have been implicated in the genesis of hyponatremia as out- cated (81).
lined (Tab. III). From linear regression analysis on pooled data To conclude, hyponatremia is widely prevalent in HIV. In as-
from case series in HIV and non-HIV patients, hyponatremia sessing such patients, the physician should keep in con-
with cotrimoxazole appears to be related to the dose and the sideration HIV-specific causes of hyponatremia in addition
presence of renal dysfunction; therefore, this often responds to general causes. Management of hyponatremia from HIV-
to dose reduction or discontinuation of the drug (90). Discon- specific causes such as drugs (including antiretrovirals),
tinuation of any medication in HIV patients should, however, endocrine syndromes, and salt wasting appears to require
be carefully weighed, taking into account the severity of hy- the same general treatment principles as in non-HIV cases.
ponatremia and efficacy of available alternative agents. Adre- If glucocorticoid resistance is suspected, supraphysiolog-
nocortical and pituitary diseases are important as causes of ic doses of steroids should be considered after carefully
hyponatremia in these patients (46, 56, 57, 85). In the occa- weighing risks and benefits. In addition, the presence of hy-
sional AIDS patient with hyponatremia with clinical features ponatremia in HIV may carry prognostic significance.
of adrenal insufficiency, natriuresis, and high normal cortisol
levels, it may be prudent to consider glucocorticoid resis- Financial support: None.
tance. Supraphysiologic doses of glucocorticoids should, at
present, be instituted, only after carefully weighing the risks
Conflict of interest statement: The authors have no conflict of
and benefits of such treatment. Finally, in HIV patients with
interest to declare.
hyperglobulinemia when using non-DSE based assays, mild
hyponatremia may be pseudohyponatremia.

Prognosis Address for correspondence:


Apurv Khanna
Recent studies have focused on the association between
343 CWB
hyponatremia and mortality in hospitalized patients. Patients 750 E Adams Street
with heart failure and hyponatremia were found to have in- Syracuse, NY, 13210 USA
creased hospitalization, re-hospitalization or mortality in spite khannaa@upstate.edu

3. Bozzette SA, Ake CF, Tam HK, Chang SW, Louis TA. Car-
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