REVIEW

BENJAMIN J. FREDA, DO MICHAEL B. DAVIDSON, DO PHILLIP M. HALL, MD Department of Nephrology and Hypertension, Department of Internal Medicine, The Cleveland Staff Consultant, Department of Nephrology and The Cleveland Clinic Foundation Clinic Foundation Hypertension, The Cleveland Clinic Foundation

Evaluation of : A little physiology goes a long way

■ ABSTRACT YPONATREMIA (a low plasma sodium con- H centration) is among the most common Hyponatremia is common in hospitalized patients. By laboratory abnormalities that physicians taking a careful and logical approach, one can promptly encounter, yet its causes are among the more recognize the causative factor or factors in nearly all complex in medicine. cases. Most cases of hyponatremia are due to impaired In a study of more than 2,800 hospitalized renal water excretion, and recognizing the cause and patients, 15% had plasma sodium concentra- pathophysiologic process makes it possible to provide tions below the lower end of the reference focused individualized care and avoid mistreatment. range of 134 mmol/L.1 Almost 5% had levels less than 125 mmol/L. ■ KEY POINTS In some instances, hyponatremia repre- sents a true medical emergency, requiring In evaluating hyponatremia, the clinician should immediate intervention to prevent cerebral determine the chronicity or acuity of the hyponatremia, edema. More commonly, hyponatremia may confirm that the patient has true plasma hypo-osmolality, reflect the severity of a causative underlying determine the volume status, assess illness and be a marker of morbidity and mor- laboratory tests and sodium values, and assess any tality. For example, the plasma sodium con- centration is a powerful predictor of severity of exogenous free water intake. heart failure2 and mortality in hepatic cirrho- sis.3 In heart failure and hepatic cirrhosis, effective circulating This paper reviews the volume is low, triggering release of antidiuretic and diagnostic evaluation of hyponatremia. hormone and water retention regardless of plasma Armed with a sound understanding of body osmolality. fluid physiology, clinicians should be profi- cient in treating this common disorder and If hyponatremia is severe (plasma sodium < 120 mmol/L), avoid the potentially lethal complications of quickly examine the patient for signs or symptoms of mistreatment. acute neurologic changes (seizures, altered mental status, ■ or focal neurologic signs) that may signal the need for A LITTLE PHYSIOLOGY immediate therapy with hypertonic intravenous saline The plasma sodium concentration is the main and furosemide. determinant of plasma osmolality and there- fore of the total water balance among the Plasma glucose should be measured in all cases of body’s . Perturbations of hyponatremia, and the plasma sodium concentration plasma sodium concentration reflect an under- should be corrected for . lying disorder involving water homeostasis. The challenge for the physician is to understand the disorder that is causing the hyponatremia. The mechanism, etiology, man-

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Most body water is within cells lthough the water content of humans one third of the extracellular volume is intravas- A depends on several factors such as age, gen- cular (plasma volume) and two thirds is intersti- der, and amount of adipose tissue, total body water tial. Of the total plasma volume (approximately can be estimated as 60% of body weight in men 4.6 L in a 70-kg man), 85% is in the venous circu- and 50% of body weight in women. Older persons lation and 15% is in the arterial circulation. and those with more adipose tissue have less lean Thus, a 70-kg person has an arterial volume of muscle mass and therefore less overall body water roughly 700 cc.4 As we will discuss, this seemingly than determined from the above estimate. small volume is perhaps the most critical determi- The total body water is divided between the nant of the “fullness” of the body’s circulation that intracellular space (40% of body weight) and is critical to the regulation of the body’s sodium extracellular space (20% of body weight). Roughly and fluid levels.

agement, and complications of hyponatremia excreted, this ultrafiltrate must be delivered to are more easily understood if one considers the the diluting segment of the . This physiology of water regulation by the kidney requires an adequate glomerular filtration rate and neuroendocrine axis. and an intact thick ascending limb of the loop of Henle. In the loop of Henle, salt is reab- Hyponatremia is most commonly due sorbed from the ultrafiltrate back into the to decreased renal clearance of water plasma without water. What remains is a rela- Hyponatremia can occur when there is either tively dilute (hypotonic) fluid that proceeds sodium loss or, more commonly, water reten- into the distal nephron. tion. This dilute fluid, made up mostly of water, Movement of water from cells to the will be excreted in the urine if it is not reab- Total body blood can also result in hyponatremia by sorbed in the collecting ducts. The reabsorp- water = 60% of increasing the amount of plasma water rela- tion of water depends on the presence and tive to plasma sodium (see Most body water is activity of ADH. body weight within cells, on this page). (men) or 50% Total body water can increase as a result of ADH secretion is directly tied to osmolality increased intake or decreased renal clearance. In a healthy patient, the ADH level is sensi- (women) Hyponatremia due to increased water intake tive to both the plasma osmolality (deter- happens rarely in patients with normal renal mined primarily by the plasma sodium con- function because one would have to drink centration) and the volume status. more than 20 L/day to overcome the kidneys’ As the volume of plasma water increases, capacity to excrete free water. the sodium concentration decreases, and thus Thus, in almost all cases of hyponatremia, so does the plasma osmolality. This decrease is the problem lies in an impaired ability of the sensed by osmoreceptors in the hypothalamus kidneys to excrete free water due to the action that regulate ADH secretion. These cells are of antidiuretic hormone (ADH, ). sensitive to changes in plasma osmolality of as ADH plays a central role in most cases of little as 1% above or below normal values, and renal-mediated water retention. ADH activity they respond to decreased osmolality by sig- may be increased appropriately (eg, in hypo- nalling the pituitary to inhibit ADH release. volemia) or inappropriately (eg, in cancer or a In the absence of ADH, normally func- drug effect). tioning kidneys excrete more -free water, restoring plasma osmolality and the How the kidneys regulate water balance plasma sodium concentration to normal lev- The fluid that is filtered from the glomerulus els. At a plasma osmolality of less than 275 5 has the same concentration of as mOsm/kg H2O, ADH secretion ceases. the plasma. For electrolyte-free water to be Conversely, as osmolality increases, ADH

640 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 8 AUGUST 2004 How heart failure and cirrhosis cause hyponatremia

Advanced cirrhosis Heart failure Arterial vasodilation Decreased cardiac output Reduced effective circulating blood volume (decreased tissue perfusion) Physiologic responses

Brain Kidney Increased antidiuretic hormone Decreased glomerular filtration release Increased proximal tubular sodium reabsorption Continued water intake Increased proximal tubular water reabsorption Clinical consequences Resultant secondary Increased plasma free water hyperaldosteronism and hyponatremia Sodium avidity and low urine sodium Increased extracellular fluid volume (edema) Inability to excrete free water

FIGURE 1 secretion increases. In a normal kidney, this cular tone, which is sensed by carotid and results in the reabsorption of free water and afferent arteriolar baroreceptors. In an Hyponatremia the reduction of osmolality. attempt to restore perfusion pressure to the is usually due tissues of the body, these baroreceptors signal Decreased effective circulating volume: the posterior pituitary to release ADH, result- to impaired Why patients retain water ing in free water reabsorption and hypona- clearance of in heart failure and hepatic cirrhosis tremia, even if the plasma is already dilute.6 In some diseases, the normal mechanisms of The volume of extracellular fluid needed to water water homeostasis go awry, leading the kidney maintain perfusion pressure and avoid stimu- to reabsorb water even though the patient lation of ADH release has been called the appears fluid-overloaded. As a result of water effective circulating blood volume.6 retention, the plasma osmolality decreases, Other mechanisms resulting in water and and hyponatremia ensues. sodium retention in patients with edematous Patients with heart failure or hepatic cir- states are outlined in FIGURE 1. rhosis may continue to retain sodium and Thus, the presence of hyponatremia may water, even though they may have a clinically indicate that underlying heart failure or cir- apparent excess of extracellular fluid volume rhosis is severe enough to limit tissue perfu- (ie, edema or ascites). sion as sensed by the kidney and carotid Diminished cardiac output (in heart fail- baroreceptors. ure) and peripheral vasodilation (in hepatic cirrhosis) cause baroreceptors in the renal ADH secretion afferent arterioles and the carotid sinus to can be independent of osmolality sense decreased pressure and therefore Although the prime regulator of ADH secre- decreased “circulatory fullness.” Circulatory tion is osmolality, there are also “osmolality- fullness is a combination of cardiac output, independent” stimulants of ADH secretion. intravascular blood volume, and arterial vas- These include:

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TABLE 1 cross from one fluid compartment to another, thereby limiting its ability to incite movement Initial evaluation of hyponatremia of water. Examine the patient for signs of acute neurologic changes Sodium, which resides primarily in the Confirm that the blood draw was accurate (verify result) extracellular fluid due to the action of the sodium-potassium ATPase pump, is an effec- Clinically determine his or her extracellular fluid volume status tive osmole—it tends to hold water in the Rule out hyperglycemia extracellular fluid. Similarly, potassium acts as Determine rate of development of hyponatremia (hours to weeks) the major intracellular effective osmole, act- Review all recent and current intravenous fluid orders ing to hold water within the cell. In contrast, urea is an ineffective osmole Review all intravenous medications for free water content (eg, antibiotics mixed with dextrose and water) because it readily crosses cell membranes and has similar concentrations in the intracellular Review all medications (especially use of diuretics) and extracellular fluid. Thus, although it con- Confirm true hypo-osmolality (see text and TABLE 3) tributes to measured plasma osmolality as a Review and order appropriate laboratory tests (see TABLE 2) measured solute, it does not generate an osmotic force to move water between fluid compartments.

• Hypovolemia (as described above). Hyperglycemia can cause hyponatremia Hypovolemia decreases the osmotic Glucose acts as an effective osmole in hyper- threshold at which ADH is secreted: dur- glycemic states by inducing water movement ing hypovolemia, ADH secretion will per- from the intracellular to the extracellular fluid sist even if plasma osmolality is less than space. Plasma water is increased and hypona- 275 mOsm/kg H2O. tremia develops as a result of dilution of plasma • Postoperative nausea, pain, and stress sodium. Plasma osmolality is actually increased may also stimulate ADH secretion. in severe cases of hyperglycemia, owing to Sodium and • Many neoplasms and pulmonary and cen- large amounts of glucose in the plasma. glucose act as tral nervous system disease processes can Therefore, the patient is generally not at risk be powerful stimulants of ADH secretion for the morbidity (eg, cerebral edema) associ- effective or even produce ectopic ADH. ated with truly hypo-osmolar hyponatremia. osmoles; urea • Drugs that stimulate ADH secretion Although the effect of hyperglycemia on include but are not limited to selective plasma sodium levels is dependent on addi- does not serotonin reuptake inhibitors, haloperidol, tional factors (eg, water loss via a glucose- vincristine, cyclophosphamide, and carba- mediated osmotic diuresis), normalization of mazepine. Nonsteroidal anti-inflammatory glucose levels generally leads to resolution of drugs can also contribute to hyponatremia hyponatremia. by reducing renal prostaglandins, which normally act to antagonize the free-water Hypokalemia can contribute reabsorption mediated by ADH.5 to hyponatremia Large losses of total body potassium, as in pro- Water can also move in and out of cells longed vomiting or diarrhea, resulting in severe In addition to changes in total body water and hypokalemia, will cause potassium to migrate sodium, we need to consider movement of water from the cells to the plasma. This can affect the and electrolytes between fluid compartments. plasma sodium concentration because sodium Key to understanding this movement is the con- will then move into cells to maintain elec- cept of effective and ineffective osmoles. troneutrality. In this way, hypokalemia can in Water moves between body fluid compart- itself cause a relative hyponatremia as sodium ments primarily as a result of osmotic forces. A concentration in the plasma decreases while solute that induces movement of water the concentration in the cells increases. between fluid compartments is an “effective” Thus, one must consider the effect of cor- osmole. An “ineffective” osmole can readily recting any concomitant hypokalemia on the

642 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 8 AUGUST 2004 TABLE 2 Laboratory assessment of hyponatremia

TEST DEFINITION AND NORMAL VALUE COMMENTS

Serum osmolality Measured value: amount of Low value (< 275 mOsm/kg H2O) solute in serum water confirms true hypo-osmolality (275–290 mOsm/kg H2O) Osmolal gap < 10 rules out pseudo- Calculated value: hyponatremia or unmeasured solutes (2 × serum sodium concentration) such as mannitol, glycine, or sorbitol + (serum glucose concentration / 18) Measured serum osmolality is not + (blood urea concentration / 2.8) affected by increased protein or lipids Amount of solute in urine Appropriate response to hyponatremia No “normal” value; depends on fluid is production of maximally dilute and solute intake, kidney function, urine (< 100 mOsm/kg H2O) and water balance Urine osmolality has limited value Range is 50–1,200 mOsm/kg H2O, but because nearly all patients with is more narrow in older patients and hyponatremia do not make maximally renal impairment dilute urine except in psychogenic Estimate = 35 × last two digits of urine polydipsia or reset osmostat specific gravity Urine sodium Spot value from fresh urine See TABLE 5 for caveats in Usually < 20 (mEq/L) in low effective interpreting urine sodium circulating blood volume states Usually > 20–40 in euvolemic patients without decreased effective circulating blood volume Plasma glucose Serum sodium will decrease Mandatory to measure plasma 1.6–2.4 mmol/L for every 100 mg/dL glucose in all cases of hyponatremia As plasma increase in glucose over 100 mg/dL Tests of thyroid Thyroid-stimulating hormone (TSH), Useful: osmolality and adrenal function Free thyroxine (T4) • When there is a clinical suspicion decreases, so adrenocorticotropic hormone (ACTH), of thyroid or adrenal hypofunction ACTH stimulation test • To establish a diagnosis of SIADH* does ADH (document normal thyroid and secretion, and adrenal function) • When careful evaluation the kidneys does not provide clear etiology should excrete Serum uric acid Usual values: refer to individual Helpful in differentiating euvolemic more water and blood urea laboratory SIADH from hypovolemic nitrogen (BUN) levels causes of hyponatremia Low uric acid and BUN levels are more compatible with euvolemia and SIADH

*SIADH = syndrome of inappropriate antidiuretic hormone secretion overall rate of correction of hyponatremia. In ■ INITIAL EVALUATION: practical terms, this means that giving normal IS IT REAL? IS IT SERIOUS? saline with added potassium to a patient with hyponatremia and hypokalemia will have a TABLE 1 lists the clinical information necessary greater effect on increasing the plasma sodium to initially evaluate a patient with hypona- level than giving normal saline by itself. tremia.

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T ABLE 3 How to calculate plasma osmolality and the osmolal gap 1 Measure osmolality directly by laboratory assessment 2 Calculate plasma osmolality: (2 × plasma sodium concentration) + (plasma glucose concentration / 18) + ( concentration / 2.8) 3 Calculate osmolal gap: Measured value – calculated value*

* An osmolal gap > 10 mOsm/kg H2O suggests a nonsodium effective osmole (mannitol, glycine, or sorbitol) or pseudohyponatremia (severe hyperlipidemia or hyperproteinemia); it may also be seen with ineffective osmoles (eg, ethanol, methanol, ethylene glycol). However, these latter substances do not cause water shifts or hyponatremia.

Is it real? With any laboratory abnormal- Drugs). All recent and current intravenous ity, the clinician must be careful to exclude fluid orders should also be reviewed, and intra- errors in collecting the blood sample. This is venous medications (eg, antibiotics, cardio- especially relevant when an extremely low vascular drips) should be scrutinized for their sodium level is reported in a patient who is free water content, as many antibiotics are clinically well. In such cases the sodium level reconstituted in dextrose and free water. should be rechecked and verified to be col- Are additional laboratory tests needed? lected from a vein that is not being simultane- TABLE 2 lists laboratory tests that are useful dur- ously infused with a hypotonic intravenous ing the evaluation of hyponatremia. As dis- fluid. In patients with signs or symptoms con- cussed below, the clinician should be able to sistent with hyponatremia, the laboratory explain the hyponatremia on the basis of the Thiazide value should be taken as accurate until proven clinical history, medications, extracellular diuretics are otherwise. fluid volume status, and directed investiga- How quickly did the hyponatremia tions into the presence of comorbid disease or more likely to develop? This information is important, as it diseases that predispose to hyponatremia. induce will dictate the risk for neurologic morbidity Specific laboratory tests are useful in cases (cerebral edema) and how quickly the plasma in which the etiology is still unclear after care- hyponatremia sodium concentration must be corrected. As ful, logical, clinical evaluation. Also, addi- than are loop will be discussed in a subsequent paper in this tional laboratory tests may be necessary when diuretics journal dealing with the treatment of hypona- it is difficult to clinically assess extracellular tremia, overly rapid correction may lead to fluid volume. neuronal damage and central pontine myeli- nolysis. Rule out hyperglycemia Are there neurologic signs or symptoms? An important early step is to rule out hyper- Patients with severe hyponatremia (< 120 glycemia, and every patient with hyponatrem- mmol/L) should be examined expeditiously for ia should have his or her plasma glucose mea- signs of acute neurologic changes (seizures, sured. For every 100 mg/dL increase in plasma altered mental status, focal neurologic signs) glucose, the plasma sodium concentration will that may signal the need for immediate thera- decrease by roughly 1.6 mEq/L, although a py with hypertonic intravenous saline and recent report7 suggests that the correction fac- furosemide. tor should be closer to 2.4. What medications is the patient receiv- ing? All medications should be reviewed, with Calculate the osmolal gap careful attention to diuretics (especially thi- to confirm true plasma hypo-osmolality azide-type) or medications associated with In a few uncommon situations, hyponatremia inappropriate ADH release (see above; does not reflect true underlying plasma hypo-

644 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 8 AUGUST 2004 osmolality. These cases of hyponatremia are TABLE 4 usually related to the presence of effective osmoles other than sodium in the plasma or Causes of hyponatremia based on extreme states of hyperproteinemia or hyper- extracellular fluid volume status lipidemia. Hypovolemic Therefore, it is necessary to calculate the Gastrointestinal solute loss (diarrhea, emesis) osmolal gap by subtracting the calculated plas- Third-spacing (ileus, pancreatitis) ma osmolality from the measured laboratory Diuretic use value (TABLE 3). If the osmolal gap is more than Addison disease 10 mOsm/kg H2O, the clinician should sus- Salt-wasting nephritis pect that other effective osmoles are present Euvolemic in the plasma (see below). Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Sodium-free irrigation fluids such as Diuretic use glycine or mannitol, used during transurethral Glucocorticoid deficiency resection of the prostate or hysteroscopic Hypothyroidism endometrial surgery, can be systemically Beer-drinker’s , psychogenic polydipsia absorbed in large amounts, leading to severe Reset osmostat hyponatremia.8 In these cases the measured Hypervolemic with decreased effective plasma osmolality is normal but the osmolal circulating blood volume gap is large, reflecting the mannitol or glycine Decompensated heart failure in the blood. Advanced liver cirrhosis Although the exact mechanism is not Renal failure with or without nephrosis completely understood, mannitol and glycine are thought to have an osmotic effect, draw- ing water from the cells into the extracellular fluid (plasma). There is also a dilutional com- differential diagnosis of hyponatremia. ponent later in the postoperative course as Almost all cases of hyponatremia are asso- glycine shifts into the cells, leaving sodium- ciated with an improperly concentrated urine It is mandatory free water behind in the extracellular fluid. (> 100 mOsm/kg H2O). Less common causes to measure Very high protein or lipid levels (usually of hyponatremia that are associated with with lactescent serum) can cause appropriately dilute urine (urine osmolality < plasma glucose the plasma sodium concentration to appear 100 mOsm/kg) include psychogenic polydip- in all cases of falsely low if it is measured by older flow pho- sia, in which patients drink excessive amounts tometry methods. These methods measure the of water, and a reset osmostat. hyponatremia concentration of sodium in the whole plasma Although it is necessary to demonstrate (including both solid and liquid phases), in that the urine is inappropriately concentrated which the amount of sodium in the sample of to diagnose the syndrome of inappropriate whole plasma is diluted by the elevated levels antidiuretic hormone secretion (SIADH; see of protein and lipid. In this situation, called below), there is no “diagnostic” correlation pseudohyponatremia, serum osmolality is normal between the osmolality of the urine and serum as measured using direct ion-specific electrodes. in this disorder. The calculated plasma osmolality will be low, and there will be an elevated osmolal gap.9 ■ NEXT, EVALUATE THE VOLUME STATUS Newer methods measure the concentra- tion of sodium in serum water independent of Once hyponatremia is verified and true hypo- the solid phase of plasma, using ion-specific osmolality is confirmed, the critical next step electrodes,10 and the problem of pseudohy- is to determine the patient’s extracellular fluid ponatremia is much rarer now. volume status. True hypo-osmolar hypona- tremia can be associated with euvolemia, Urine osmolality offers little diagnostic aid hypervolemia, or hypovolemia. Even though the urine osmolality is routinely While the exact cause of the hyponatrem- evaluated, it offers very little in narrowing the ia may not be immediately apparent (see TABLE 4

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T ABLE 5 Caveats in interpreting spot urinary sodium levels

SETTING EFFECT ON COMMENTS URINE SODIUM

Diuretics Increase Urine sodium may be falsely elevated by diuretic action, but may still be low if there is severe concomitant hypovolemia Osmotic diuresis Increase Solute diuresis (eg, glucosuria) obligates sodium and water loss even in the setting of hypovolemia Chronic kidney disease, Increase Sodium handling is altered due to renal disease, tubulointerstitial disease and urine sodium may be elevated even in the presence of hypovolemia Bicarbonaturia Increase loss obligates sodium loss to balance negative charge in urine (eg, proximal renal tubular acidosis and emesis-induced metabolic alkalosis)

for major causes), assessing the extracellular and increased extracellular fluid volume have fluid volume is critical in determining the prop- either decompensated heart failure or er initial treatment (ie, fluid restriction vs resus- advanced hepatic cirrhosis. citation with isotonic saline). Although edema or ascites always indicate Careful evaluation of the history (diar- elevated total body sodium, and therefore ele- rhea, vomiting, thirst, and polyuria), nursing vated extracellular fluid volume, total body records (daily weights, intake and output), water is elevated to an even greater degree in In true and physical examination (orthostasis, neck these patients due to reduced effective circu- hyponatremia, veins, peripheral edema, and ascites) should lating volume. be adequate to determine the patient’s extra- In the absence of diuretic use or other determine if cellular fluid volume status. variables affecting renal handling of sodium fluid volume Peripheral edema or ascites indicates ele- (TABLE 5), patients with hyponatremia, expand- vated total body sodium and therefore elevat- ed extracellular fluid volume, and reduced is high, normal, ed extracellular fluid volume. On the other effective circulating blood volume are pro- or low hand, patients with circulatory compromise foundly “sodium-avid” (their kidneys will (orthostatic changes or supine hypotension retain sodium). This will be manifested by a and tachycardia) and no edema have low low urine sodium level (< 10–20 mEq/L). extracellular fluid volume. Other patients may A urine sodium level greater than 20 have hypovolemia not detectable by initial mEq/L in a patient with expanded extracellu- examination or may be truly euvolemic. lar fluid volume and no recent diuretic use is Although it is usually easy to determine if consistent with adequate effective circulating a patient is hypervolemic, it may be harder to volume. differentiate euvolemia from subtle hypo- TABLE 5 reviews important caveats that may volemic states.11 Other data such as urine affect interpretation of urinary sodium values sodium, serum uric acid, and blood urea nitro- in patients with hyponatremia. gen (BUN) levels and response to isotonic Severe renal impairment. The hallmark intravenous saline may be helpful in these of renal impairment is reduced functional cases (see If the extracellular fluid volume is nephron mass and impaired glomerular filtra- normal, below). tion. Smaller volumes of fluid are filtered, and if water intake exceeds the amount that can be If the extracellular fluid volume is elevated filtered, water will be retained and hypona- Most hospitalized patients with hyponatremia tremia will develop. An acute worsening of

646 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 8 AUGUST 2004 renal function may also impair free water dysfunctional in patients with chronic kidney excretion independent of changes in water disease or tubulointerstitial disease. In these intake. circumstances the kidney may not be able to Patients with nephrotic syndrome may avidly retain sodium even in hypovolemic develop hyponatremia regardless of the pres- states. ence or degree of renal impairment. Loss of If urine sodium is high or normal in plasma oncotic pressure due to hypoalbumin- patients with clinically suspected extracellular emia favors a shift of fluid from the plasma fluid , then the patient is into the interstitial compartment. This either taking diuretics or the kidney is wasting reduces the effective circulating blood volume sodium. and triggers ADH release. However, this Diuretic use is the most common cause of mechanism may not apply in all patients with hypovolemic hyponatremia, which in most nephrotic syndrome who develop hypona- cases occurs within the first 2 weeks of thera- tremia.12 py.13 A combination of hypokalemia, con- tracted extracellular fluid volume, and If the extracellular fluid volume is low impaired urinary dilution contribute to its Nonedematous patients with hyponatremia occurrence. Clinicians must be careful to and signs of extracellular fluid volume con- interpret the urine sodium excretion in the traction are losing sodium and water and context of the timing of the last diuretic dose. replacing it with hypotonic fluids. Solute loss Patients with hyponatremia who are tak- and resulting extracellular fluid volume con- ing diuretics can also present with hyper- traction stimulate ADH release. volemia or euvolemia, depending on sodium The sodium loss is nearly always hypoton- intake and other underlying diseases (eg, ic or isotonic to plasma; therefore, the devel- heart failure). opment of hyponatremia is usually caused by Thiazide diuretics are more likely to replacement of the fluid losses with intra- induce hyponatremia than are loop diuretics venous or oral free water. because they impair both diluting and con- centrating mechanisms in the kidney. As a Edema or Measure urine sodium result of tubular sodium loss from the distal ascites to determine the source of sodium loss nephron, thiazide diuretics preserve the The evaluation of patients with hyponatrem- medullary osmotic gradient; therefore, free indicates ia and decreased extracellular fluid volume water can still be reabsorbed in the presence elevated total begins by determining the source of sodium of ADH. loss. Acting at a more proximal location, loop body sodium Sodium loss usually occurs via the gas- diuretics decrease the medullary osmotic gra- trointestinal tract or kidney. Common causes dient and therefore impair free water reab- include diarrhea and emesis. Third-spacing of sorption (urinary concentration) and urinary fluid and sodium, seen in pancreatitis, burns, dilution. rhabdomyolysis, or ileus, may also lead to sodi- Other causes. Salt-wasting nephritis is um loss and contracted extracellular fluid vol- associated with several uncommon renal dis- ume. orders, including renal cystic diseases, anal- The cause of sodium loss may not always gesic nephropathy, obstructive uropathy, and be clinically obvious, however. In these cases, chronic pyelonephritis.14 it is critical to measure urine sodium in a spot These states are associated with the sample to evaluate the renal response (or con- inability to conserve sodium even in the pres- tribution) to extracellular fluid volume con- ence of hypovolemia, most often when renal traction. impairment is severe (glomerular filtration If urine sodium is low. Urine sodium rate < 10–15 mL/minute). In patients with should be low (< 20 mEq/L) if extrarenal fac- adrenal insufficiency due to Addison disease tors (ie, gastrointestinal losses or third-spac- (mineralocorticoid and glucocorticoid defi- ing) account for solute loss. However, as out- ciency), there is sodium wasting due to aldos- lined in TABLE 5, renal sodium handling may be terone deficiency.

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When sodium intake cannot keep up with Monitor response to isotonic saline. In sodium loss (eg, during diarrhea), hypo- cases in which it is still unclear if the patient volemia develops in the face of elevated con- is euvolemic or hypovolemic (equivocal tinuing renal sodium loss (ie, Addisonian cri- examination and urine sodium), the clinician sis). Renal salt loss and hypovolemia-induced can monitor the renal response to isotonic stimulation of ADH cause the hyponatremia.4 intravenous fluids (1–2 L of 0.9% saline over 24–48 hours). If the extracellular fluid volume is normal If the patient is truly hypovolemic, the The causes of hyponatremia associated with plasma sodium level should increase as fluid clinical euvolemia include the syndrome of resuscitation corrects the hypovolemia and inappropriate antidiuretic hormone secretion decreases nonosmotic ADH release, resulting (SIADH), hypocortisolism, diuretic use, beer- in excretion of free water. drinker’s potomania, psychogenic polydipsia, On the other hand, euvolemic patients and hypothyroidism. Diuretic use and SIADH would be expected to excrete relatively more contribute the majority of cases. In making of the sodium load from the intravenous saline the diagnosis of SIADH, euvolemia must be than patients with hypovolemia. An increase demonstrated (see below). in the fractional excretion of sodium of more In patients with hyponatremia who than 0.5% after isotonic saline infusion has appear euvolemic, the challenge is to rule out been proposed to distinguish truly euvolemic hypovolemia that is not revealed by clinical patients (ie, those with SIADH) from patients examination. The clinical suspicion of euvo- with hypovolemia.15 lemia should be confirmed by appropriate Serum uric acid and BUN can also be laboratory assessment with random urine used to distinguish between euvolemic and sodium, BUN, and serum uric acid measure- hypovolemic hyponatremia. ments. Patients with normal or slightly expanded Clinical euvolemia with elevated urine extracellular fluid volume are more likely to sodium. If a spot urine sodium measurement is have low levels of serum uric acid and nonel- Confirm not low and there are no conditions that may evated BUN. The converse is true in cases of euvolemia by affect the interpretation of urine sodium val- hypovolemia in which uric acid is normal and ues (TABLE 5), the patient is likely truly eu- BUN is elevated due to decreased renal perfu- measuring volemic. sion. In euvolemic patients with SIADH, urine sodium, Clinical euvolemia with low urine sodi- serum uric acid is often low due to increased um. In patients who appear euvolemic, urine urate excretion.16 BUN, and serum sodium may be low if: uric acid • There was recent extracellular fluid vol- ■ SYNDROME OF INAPPROPRIATE ume loss that was replaced by hypotonic fluids, ANTIDIURETIC HORMONE SECRETION or • Dietary solute intake is very low but water In patients with hyponatremia, euvolemia, intake is adequate (eg, in beer-drinker’s poto- and true hypo-osmolality, the continued mania, as detailed below), or release of ADH is inappropriate. However, • It is early in the course of hypovolemia release can continue in SIADH. Most cases of when clinical signs (eg, tachycardia, orthostat- SIADH are associated with tumors, pul- ic changes) are lagging behind the onset of monary and central nervous system disease, or sodium retention by the kidney. various drugs, although the cause is not always In these situations, repeat measurement is evident when hyponatremia is detected.17 advised. While most cases of SIADH appear to be associated with abnormal and inappropriate If there is uncertainty levels of ADH (relative to plasma osmolality), about the patient’s volume status 10% to 20% of patients do not have measur- If there is uncertainty about the patient’s able levels of the hormone in their serum, extracellular fluid volume status after initial despite continued renal free water reabsorp- examination and urine sodium measurement: tion.18

648 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 8 AUGUST 2004 TABLE 6 Diagnostic criteria for the syndrome of inappropriate antidiuretic hormone secretion (SIADH) Essential criteria True plasma hypo-osmolality (< 275 mOsm/kg H2O) Inappropriate urinary response to hypo-osmolality (urine osmolality > 100 mOsm/kg H2O) Euvolemia; no edema, ascites, or signs of hypovolemia Elevated urine sodium(> 30 mEq/L) during normal sodium and water intake No other causes of euvolemic hyponatremia (hypothyroidism, diuretic use, hypocortisolism) Supplemental criteria Unable to excrete > 80% of a water load (20 cc/kg) in 4 hours and/or failure to achieve urine osmolality < 100 mOsm/kg H2O No significant increase in serum sodium after volume expansion, but improvement with fluid restriction MODIFIED FROM VERBALIS JG. THE SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION AND OTHER HYPO-OSMOLAR DISORDERS. IN: SCHRIER RW, EDITOR. DISEASES OF THE KIDNEY AND URINARY TRACT, 7TH ED. PHILADELPHIA; LIPPINCOTT WILLIAMS & WILKINS, 2001: 2511–2548.

Diagnosis of SIADH also make an appropriately dilute urine (< 100 SIADH is a diagnosis of exclusion. As with mOsm/kg H2O). They can appear euvolemic other cases of hyponatremia, true plasma or volume-expanded, depending on solute hypo-osmolality must be confirmed. There intake and other comorbidities. must also be failure to excrete a maximally Beer-drinker’s potomania refers to the dilute urine and documentation of euvolemia. development of hyponatremia from water As discussed previously, the latter can some- intake (in this case in the form of beer) that is times prove difficult. In these cases we recom- disproportionate to a severely reduced dietary mend measuring serum uric acid and BUN sodium intake.19 At reduced levels of solute and testing the response to isotonic saline to intake, there is a decrease in the ability of the SIADH is a rule out hypovolemia. The diagnostic criteria nephron to excrete free water. As most adults diagnosis of for SIADH are listed in TABLE 6.18 ingest approximately 1,000 mOsm of solute During the course of chronic hypona- per day and can dilute their urine to 50 exclusion tremia due to SIADH, a steady state is mOsm/kg H2O, the kidney can excrete achieved in which urinary sodium excretion around 20 L (1,000/50) of free water per day. typically matches dietary sodium intake, If dietary solute intake is severely reduced resulting in a urine sodium of around 40 to 300 mOsm/day and the resulting maximum 5 mEq/L. In this case, the persistence of capacity for renal dilution is 50 mOsm/kg H2O, hyponatremia depends on continued water any water intake from beer over 6 L will result intake, as patients will often become nor- in free water retention and hyponatremia. monatremic on proper water restriction. Hypothyroidism can also impair free However, if a patient with SIADH water excretion. Although the mechanisms becomes hypovolemic, urine sodium may fall are not fully understood, giving thyroid hor- to levels below 20 mEq/L, confusing the clin- mone can correct the low plasma sodium con- ical picture. Furthermore, in patients with centration.20 euvolemia and SIADH, serum uric acid levels Pure glucocorticoid deficiency due to and BUN are commonly reduced. adrenocorticotropic hormone deficiency or anterior hypopituitarism can cause hypona- Other causes of euvolemic hyponatremia tremia in the presence of preserved mineralo- Patients with psychogenic polydipsia ingest corticoid function. These patients are usually massive amounts of water (typically 20–30 euvolemic. Cortisol replacement suppresses L/day) and overcome the renal capacity for ADH release from the hypothalamus and pro- free water excretion. They have true plasma motes free water release at the level of the kid- hypo-osmolality, but most importantly, they ney.21

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