2 - Hyponatremia or Hypernatremia | Manual of Nephrology. Diagnosis and Therapy 6e

Editors: Schrier, Robert W.

Title: Manual of Nephrology, 6th Edition

> Table of Contents > 2 - The Patient with Hyponatremia or Hypernatremia

The Patient with Hyponatremia or Hypernatremia

Tomas Berl

Robert W. Schrier

Control of serum sodium and osmolality. Under physiologic conditions, the concentration of sodium in plasma is kept in a very narrow range, between 138 and 142 mEq per L, despite great variations in water intake. Because sodium is the predominant cation in extracellular fluid (ECF), this reflects the equally narrow range in which the tonicity (osmolality) of body fluids is regulated, between 280 and 290 mOsm per kg. Thus, calculated plasma osmolality can be expressed as follows:

Serum sodium (concentration) and plasma osmolality are maintained in these normal ranges by the function of arginine vasopressin, a very sensitive osmoreceptor that controls the secretion of the antidiuretic hormone. This hormone, in turn, is critical in determining water excretion by allowing urinary dilution in its absence and urinary concentration in its presence. Hyponatremic disorders supervene when water intake exceeds the patient's renal diluting capacity. Conversely, hypernatremia supervenes in settings associated with renal concentrating defects accompanied by inadequate water intake.

Hyponatremia. Hyponatremia, defined as a plasma sodium concentration of less than 135 mEq per L, is a frequent occurrence in the hospitalized patient. It has been suggested that approximately 10% to 15% of patients in hospitals have a low plasma sodium concentration at some time during their stay. Hyponatremia in the ambulatory outpatient is a much less frequent occurrence and is usually associated with a chronic disease state.

Interpretation of the serum sodium. Under most clinical circumstances, a decrement in serum sodium reflects a hypo-osmolar state. However, recognizing the settings in which a normal or even low sodium level does not reflect a normal osmotic or a hypo-osmotic state is important. The addition to the ECF of osmotically active solutes that do not readily penetrate into cells, such as glucose, mannitol, or glycine, causes water to move from cells to ECF, thereby leading to cellular dehydration and a decrement in serum sodium concentration. This translocational hyponatremia does not reflect changes in total body water, but rather the movement of water from the intracellular to the extracellular compartment.

In hyperglycemia, for each 100 mg per dL rise in blood glucose, a 1.6 mEq per L fall in plasma sodium concentration occurs as water moves out of cells into the ECF. For example, in an untreated diabetic patient, as blood glucose rises from 200 to 1,200 mg per dL, the plasma sodium concentration is expected to fall from 140 to 124 mEq per L (1.6 mEq/L 10 = 16 mEq) without a change in total body water and electrolytes. Conversely, treatment with insulin and lowering of the blood sugar from 1,200 to 200 mg per dL in this diabetic patient results in a comparable osmotic water movement from the ECF into cells and a return of plasma sodium concentration to 140 mEq per L without any change in total body water or electrolytes.

Hyponatremia can occur without a change in plasma osmolality, this is termed pseudohyponatremia. Pseudohyponatremia occurs when the solid phase of plasma, primarily lipids and proteins (usually 6% to 8%), is greatly increased, as in severe hypertriglyceridemia and paraproteinemic disorders.
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This falsely low reading is a consequence of the flame photometry methods that measure the concentration of Na⁺ in whole plasma and not only in the liquid phase. It is estimated that a rise in plasma lipids by 4.6 g per L or in plasma proteins of 10 g per dL lowers serum sodium concentration by 1 mEq per L. This is not a problem when undiluted serum is analyzed with an ion-specific electrode that measures the concentration of sodium in serum water.

Approach to the hypo-osmolar hyponatremic patient. In the absence of pseudohyponatremia or an excess of osmotically active solute in the ECF, the most important initial step in the diagnosis of hyponatremia is an assessment of the ECF volume status.

Sodium is the primary cation in the ECF compartment. Therefore, sodium, with its accompanying anions, dictates ECF osmolality and fluid volume. Thus, ECF volume provides the best index of total body exchangeable sodium. A careful physical examination focused on the evaluation of ECF volume status therefore allows for the classification of the hyponatremic patient into one of three categories: (a) hyponatremia in the presence of an excess of total body sodium, (b) hyponatremia in the presence of a deficit of total body sodium, and (c) hyponatremia with a near normal total body sodium. For example, the edematous patient is classified as having hyponatremia with an excess of total body sodium. The volume-depleted patient with flat neck veins, decreased skin turgor, dry mucous membranes, and orthostatic hypotension and tachycardia is classified as having hyponatremia with a deficit of total body sodium. The patient with neither edema nor evidence of ECF volume depletion is classified as having hyponatremia with near-normal total body sodium (Fig. 2-1).

Figure 2-1. Diagnostic approach to hyponatremia. ( , increased; , greatly increased; , decreased; , greatly decreased; , not increased or decreased; U_[Na] = urinary sodium concentration, in mEq per L.)

In the hypervolemic (edematous) hyponatremic patient, both total body sodium and total body water are increased, water more so than sodium. These patients have cardiac failure, cirrhosis, nephrotic syndrome, or renal failure. When hyponatremia is secondary to cardiac and hepatic disease, the disease is advanced and readily evident on clinical examination. In the absence of the use of diuretics, the urinary sodium concentration in the hyponatremic edematous patient should be quite low (less than 10 mEq per L) because of avid tubular sodium reabsorption. The exception occurs in the presence of acute or chronic renal failure, in which, because of tubular dysfunction, the urinary sodium concentration is higher (greater than 20 mEq per L).
The diagnostic possibilities in the hypovolemic hyponatremic patient are entirely different. Again, a spot urinary sodium concentration is of value. If the volume-depleted hyponatremic patient has a low (less than 10 mEq per L) sodium concentration, the kidney is functioning normally by conserving sodium in response to ECF volume depletion. Conversely, if the urinary sodium concentration is greater than 20 mEq per L in a hypovolemic hyponatremic patient, the kidney is not responding appropriately to the ECF volume depletion, and renal losses of sodium and water must be considered as the likely cause of the hyponatremia.
- In a hypovolemic hyponatremic patient with a urinary sodium concentration of less than 10 mEq per L, a gastrointestinal (or third space ) source of sodium and water losses must be sought. The source may be readily apparent if the patient presents with a history of vomiting, diarrhea, or both. In the absence of an obvious history of gastrointestinal fluid losses, several other diagnostic possibilities must be considered. Substantial ECF losses may occur into the abdominal cavity with peritonitis or pancreatitis, and into the bowel lumen with ileus or pseudomembranous colitis. The surreptitious cathartic abuser may present with evidence of ECF volume depletion and no history of gastrointestinal losses. The presence of hypokalemic metabolic acidosis and phenolphthalein in the urine may be a clue to this diagnosis. Loss of haustra on barium enema and melanosis coli on endoscopy are other clues to cathartic abuse. Burns or muscle damage may also lead to a state of hypovolemia and
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  hyponatremia secondary to substantial fluid and electrolyte losses from skin or into muscle.
- In a hypovolemic hyponatremic patient with a urinary sodium level of greater than 20 mEq per L, renal losses are occurring, and several different diagnostic possibilities must be considered.
  - Excessive use of diuretics is foremost among these diagnoses. It occurs almost exclusively with thiazide diuretics, because these agents, unlike loop diuretics, alter only urinary diluting ability; urinary concentration remains unimpaired. A fall in plasma sodium concentration in a patient receiving diuretics may be the first clue that a diuretic dosage adjustment is needed. In some patients with diuretic abuse, ECF volume depletion is not readily apparent from clinical examination. An important clue, however, to the diagnosis of diuretic-induced hyponatremia is that virtually all these patients have an associated hypokalemic metabolic alkalosis if they are receiving potassium-losing diuretics. If, however, a potassium-sparing diuretic is involved (e.g., triamterene, amiloride, or spironolactone), neither hypokalemia nor metabolic alkalosis may be present. Cessation of use of the diuretic is the best means of confirming the diagnosis of diuretic-induced hyponatremia. However, it must be remembered that restoration of ECF volume also is necessary to correct the hyponatremia. In the hypokalemic patient, potassium replacement also may be necessary for complete correction of the plasma sodium concentration imbalance.
    
    Surreptitious diuretic abuse occurs among premenopausal women who use diuretics for weight loss or other cosmetic reasons (e.g., thick ankles or calves, puffy face). These patients may be difficult to distinguish from patients with surreptitious vomiting, because both may present with evidence of ECF volume depletion and hypokalemic metabolic alkalosis. The presence or absence of hyponatremia depends on the patient's water intake. The pivotal diagnostic test to distinguish between the hypovolemic hyponatremic patient with metabolic alkalosis who is a diuretic abuser and the patient who is a surreptitious vomiter is the urinary chloride concentration. Surreptitious vomiters have low (less than 10 mEq per L) concentrations and surreptitious diuretic abusers high (greater than 20 mEq per L) concentrations.
  - Salt-losing nephritis. Patients with medullary cystic disease, chronic interstitial nephritis, polycystic kidney disease, analgesic nephropathy, partial urinary tract obstruction, and, rarely, chronic glomerulonephritis may present with hypovolemic hyponatremia secondary to salt-losing nephritis. These patients generally have moderately advanced renal impairment with serum creatinine levels greater than 3 to 4 mg per dL. This diagnosis should virtually never be considered in patients with renal disease that is not associated with elevated serum creatinine. Patients with salt-losing nephritis may need supplemental sodium chloride (NaCl) intake to avoid ECF volume depletion, or they may become very susceptible to ECF volume depletion in association with either decreased intake or extrarenal (e.g., gastrointestinal) sodium and water losses. Because these patients may be pigmented secondary to uremic dermatitis and exhibit hyponatremia and volume depletion, their disease was initially described as mimicking Addison's disease.
  - Mineralocorticoid deficiency. The patient with Addison's disease (i.e., primary adrenal insufficiency) generally has associated hyperkalemia; prerenal azotemia generally does not increase serum creatinine to concentrations greater than 3 mg per dL. In patients with mineralocorticoid deficiency, ECF volume repletion may correct both the hyponatremia and the hyperkalemia. During periods of stress, the plasma cortisol level may fall within the normal range. Thus, if adrenal
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    insufficiency is suspected, a 2-hour cosyntropin (Cortrosyn) stimulation test should be performed. In addition to a urinary sodium concentration of greater than 20 mEq per L, a urinary potassium concentration of less than 20 mEq per L may be another clue to mineralocorticoid deficiency. If fluid intake has been restricted, the patient with Addison's disease may not present with hyponatremia, and hyperkalemia may not be present if the ECF volume depletion is not severe. Thus, a high index of suspicion is necessary to make the diagnosis of adrenal insufficiency. These patients may present with nonspecific symptoms such as weight loss, anorexia, abdominal pain, nausea, vomiting, diarrhea, and fever.
  - Osmotic diuresis obligating anion and cation excretion is another major diagnostic consideration in the hypovolemic hyponatremic patient with a urinary sodium concentration greater than 20 mEq per L.
    - Glucose, urea, or mannitol diuresis. The uncontrolled diabetic patient may have substantial glucosuria, causing water and electrolyte losses and, thus, ECF volume depletion. The urea diuresis after the relief of a urinary tract obstruction is another example of an osmotic diuresis that can cause ECF volume depletion. A chronic mannitol infusion without electrolyte replacement can produce a similar situation.
    - Bicarbonaturia. Increased anion excretion also can obligate renal water and electrolyte losses. The most frequently encountered example of this is metabolic alkalosis with bicarbonaturia. The bicarbonate anion in the urine is accompanied by cations, including sodium and potassium, which maintain electrical neutrality. Bicarbonaturia may accompany the early development of metabolic alkalosis accompanying postoperative nasogastric suction or vomiting. Proximal renal tubular acidosis (e.g., in Fanconi's syndrome) is another condition in which bicarbonaturia causes renal electrolyte loss. In the absence of a urinary tract infection with urease-producing organisms, a urinary pH (measured by a pH meter) greater than 6.1 indicates the presence of bicarbonate in the urine.
    - Ketonuria. Ketoacid anions also can obligate renal electrolyte losses in spite of ECF volume depletion; this may contribute to urinary electrolyte losses in diabetic or alcoholic ketoacidosis or starvation.
Euvolemic hyponatremia is a commonly encountered form of hyponatremia in hospitalized patients. The urinary sodium concentration in euvolemic hyponatremia is generally greater than 20 mEq per L. However, if the patient is on a sodium-restricted diet or is volume depleted, the urinary sodium concentration may be less than 10 mEq per L. Refeeding with a normal salt intake or expansion of ECF volume with saline increases urinary sodium concentration to more than 20 mEq per L, but hyponatremia will persist in the patient with euvolemic hyponatremia. These patients show no signs of either an increase or decrease in total body sodium. Although the water retention leads to an excess in total body water, no edema is detected because two-thirds of the water is inside the cell. A limited number of diagnostic possibilities are available with hyponatremic patients who exhibit neither edema nor ECF volume depletion (i.e., euvolemic hyponatremic patients) (Fig. 2-1). Two endocrine disorders must be considered: hypothyroidism and secondary adrenal insufficiency associated with pituitary or hypothalamic disease.
- The occurrence of hyponatremia with hypothyroidism generally suggests severe disease, including myxedema coma. In some patients, particularly the elderly, the diagnosis may not be readily apparent. Thus, thyroid function must be assessed in the euvolemic hyponatremic patient.
- Glucocorticoid deficiency. An intact renin-angiotensin-aldosterone system avoids ECF volume depletion in patients with secondary adrenal insufficiency, but it is clear that glucocorticoid deficiency alone can impair water excretion and cause hyponatremia. Although skull films and computed tomographic (CT) scans should always be obtained in the euvolemic hyponatremic patient when the cause of the hyponatremia is not obvious, normal skull films or CT scans do not exclude secondary adrenal insufficiency. A low plasma cortisol level associated with a low adrenocorticotropic hormone level supports the diagnosis of secondary adrenal insufficiency. In this setting, both secondary adrenal insufficiency and secondary hypothyroidism may contribute to the hyponatremia accompanying pituitary insufficiency.
- Emotional or physical stress must be considered in the euvolemic hyponatremic patient before invoking the diagnosis of the syndrome of inappropriate antidiuretic hormone (SIADH). Acute pain or severe emotional stress (e.g., decompensated psychosis associated with continued water ingestion) may lead to acute and severe hyponatremia. It is likely that a combination of emotional shock and physical pain accounts for the frequently encountered secretion of vasopressin in the postoperative state, which in turn leads to hyponatremia in the face of hypotonic fluid administration.
- A number of pharmacologic agents either stimulate the release of vasopressin or enhance its action. These include:
  - Nicotine
  - Chlorpropamide
  - Tolbutamide
  - Clofibrate
  - Cyclophosphamide
  - Morphine
  - Barbiturates
  - Vincristine
  - Carbamazepine (Tegretol)
  - Acetaminophen
  - Nonsteroidal anti-inflammatory drugs (NSAIDs)
  - Antipsychotics
  - Antidepressants
    
    Thus, determining whether the euvolemic hyponatremic patient is receiving such drugs is an important diagnostic step.
- SIADH should be considered after exclusion of other diagnoses in the euvolemic hyponatremic patient. In general, the causes of SIADH include:
  - Carcinomas, most frequently but not exclusively of the
    - Lung
    - Duodenum
    - Pancreas
  - Pulmonary disorders, including but not limited to
    - Viral pneumonia
    - Bacterial pneumonia
    - Pulmonary abscess
    - Tuberculosis
    - Aspergillosis
  - Central nervous system (CNS) disorders:
    - Encephalitis (viral or bacterial)
    - Meningitis (viral, bacterial, or tubercular)
    - Acute psychosis
    - Stroke (cerebral thrombosis or hemorrhage)
    - Acute intermittent porphyria
    - Brain tumor
    - Brain abscess
    - Subdural or subarachnoid hematoma or hemorrhage
    - Guillain-Barr syndrome
    - Head trauma
  - Acquired immunodeficiency syndrome
    
    Thus, SIADH occurs primarily in association with infections and with vascular and neoplastic processes in the CNS or lung.

Signs and symptoms. The level of hyponatremia that may cause signs and symptoms varies with the rate of decline in the plasma sodium concentration and the age of the patient. In general, the young-adult patient appears to tolerate a specific level of hyponatremia better than does the older patient. However, the acute (i.e., within a few hours) development of hyponatremia in a previously asymptomatic young patient may cause severe CNS signs and symptoms, such as depressed sensorium, seizures, and even death, when the plasma sodium concentration has reached only a level between 125 and 130 mEq per L. This is because the capacity of brain cells to extrude osmotically active particles, and thus relieve the brain swelling that accompanies hyponatremia, requires a longer time to be invoked at the beginning of the condition. Conversely, this protective mechanism against brain swelling becomes very effective with the chronic development of hyponatremia over days or weeks, so that an elderly person may present without overt signs or symptoms even with a plasma sodium concentration below 110 mEq per L.

Gastrointestinal symptoms, including anorexia and nausea, may occur early with hyponatremia. The more severe later signs and symptoms relate to the CNS, because the cell swelling that occurs with hyponatremia is tolerated worst within the rigid encasement of the skull. Severe hyponatremia of rapid onset may lead to brain edema and herniation and thus requires rapid treatment. Cheyne-Stokes respiration may be a hallmark of severe acute hyponatremia. In addition to exposure, uremia, and hypothyroidism, hyponatremia also should be considered in the differential diagnosis of the hypothermic patient.

In summary, symptoms that may be associated with hyponatremia include:
- Lethargy, apathy
- Disorientation
- Muscle cramps
- Anorexia, nausea
- Agitation
  
  Signs that may be associated with hyponatremia include:
- Abnormal sensorium
- Depressed deep tendon reflexes
- Cheyne-Stokes respiration
- Hypothermia
- Pathologic reflexes
- Pseudobulbar palsy
- Seizures
Therapy
- Factors affecting the approach to treatment. The presence or absence of symptoms and the duration of the hyponatremia are the primary guides to treatment strategy. Different time-dependent processes are involved in the adaptation to changes in tonicity, and the presence of cerebral symptoms reflects a failure of the adaptive response. In this regard, hyponatremia developing within 48 hours carries a greater risk of permanent neurologic sequelae from cerebral edema if the plasma sodium concentration is not corrected expeditiously. Conversely, patients with chronic hyponatremia are at risk of osmotic demyelination if the correction is excessive or too rapid.
- Cerebral adaptation to hypotonicity. Decreases in extracellular osmolality cause the movement of water into cells, increasing intracellular volume and causing tissue edema. Edema within the cranium raises intracranial pressure, leading to neurologic syndromes. To prevent this complication, a volume-regulatory adaptation occurs. Early in the course of hyponatremia,
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  within 1 to 3 hours, cerebral ECF volume decreases through the movement of fluid into the cerebrospinal fluid (CSF), which is then shunted into the systemic circulation. Thereafter, the brain adapts by losing cellular potassium and organic solutes, which tend to lower the intracellular osmolality without substantial gain of water. If hyponatremia persists, other organic osmolytes, such as phosphocreatine, myoinositol, and amino acids (e.g., glutamine and taurine) are lost. The loss of these solutes greatly decreases cerebral swelling. Patients in whom this adaptive response fails are prone to severe cerebral edema when they develop hyponatremia. Postoperative menstruant females; elderly women on a thiazide; directic, psychiatric polydipsic patients; and hypoxemic patients are particularly prone to hyponatremia-related encephalopathy. Conversely, as noted earlier, patients who have had the adaptive response are at risk of osmotic demyelination syndrome if the hyponatremia is excessively or too rapidly corrected. For example, a rapid increase in plasma osmolality may cause excessive cerebral water loss in previously adapted brains. Alcoholic subjects, burn victims, and severely hypokalemic patients are at risk for this complication.
- Acute symptomatic hyponatremia, developing in less than 48 hours, is almost inevitable in hospital patients receiving hypotonic fluids. Treatment should be prompt, because the risk of acute cerebral edema exceeds the risk of osmotic demyelination. The aim should be to raise the serum Na⁺ by 2 mmol per L per hour until symptoms resolve. Complete correction is unnecessary, although it is not unsafe. Hypertonic saline (3% NaCl) is infused at the rate of 1 to 2 mL per kg per hour, and a loop diuretic, such as furosemide, enhances solute-free water excretion and hastens the return to a normal serum Na⁺. If severe neurologic symptoms (seizures, obtundation, or coma) are present, 3% NaCl may be infused at 4 to 6 mL per kg per hour. Even 29.2% NaCl (50 mL) has been used safely. Serum electrolytes should be carefully monitored.
- Chronic symptomatic hyponatremia. If hyponatremia has been present for more than 48 hours or the duration is unknown, correction must be handled carefully. Whether it is the rate of correction of hyponatremia or the magnitude that predisposes to osmotic demyelination is unknown, but in practice dissociating the two is difficult, because a rapid correction rate usually means a greater correction over a given period of time.
  
  The following guidelines are fundamental to successful therapy:
  - Because cerebral water is increased only by approximately 10% in severe chronic hyponatremia, promptly increase the serum Na⁺ level by 10%, or by approximately 10 mEq per L.
  - After the initial correction, do not exceed a correction rate of 1.0 to 1.5 mEq per L per hour.
  - Do not increase the serum Na⁺ by more than 12 mEq per L per 24 hours.
    
    It is important to take into account the rate of infusion and the electrolyte content of infused fluids and the rate of production and electrolyte content of the urine.
    
    Once the desired increment in serum Na⁺ concentration is obtained, the treatment should consist of water restriction.
- The approach to the chronic asymptomatic patient with hyponatremia is different. Initial bedside evaluation includes searching for an underlying disorder. Hypothyroidism and adrenal insufficiency should be sought as possible etiologies, and hormones must be replaced if these deficiencies are found. A careful analysis of the patient's medications should be made and necessary adjustments undertaken.
  
  For patients with SIADH, if the etiology is not identifiable or cannot be treated, the approach should be conservative, because rapid changes in serum tonicity lead to a greater degree of cerebral water loss and possible demyelination. Various approaches can be considered.
  - Fluid restriction is an easy and usually successful option, if the patient complies. A calculation must be made of the fluid restriction that will
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    maintain a specific serum Na⁺. The daily osmolar load ingested divided by the minimal urinary osmolality (a function of the severity of the diluting disorder) determines a patient's maximal urine volume. On a normal North American diet, the daily osmolar load is about 10 mOsm per kilogram of body weight; in a healthy person, the minimum urinary osmolality (given no circulating vasopressin) can be as low as 50 mOsm per kg. Thus, the daily urine volume in a 70-kg man can be as high as 14 L (700 mOsm per 50 mOsm per L). If the patient has SIADH, and the urinary osmolality cannot be lowered below 500 mOsm per kg, the same osmolar load of 700 mOsm per day allows for only 1.4 L of urine. Thus, if the patient drinks more than 1.4 L per day, the serum Na⁺ will fall. A measurement of urinary sodium (U_Na) and potassium concentration (U_K) can guide the degree of water restriction that is required. If U_Na + U_K is greater than the serum sodium concentration, water restriction alone may not be sufficient to increase serum sodium concentration.
  - Pharmacologic agents. Lithium was the first drug used to antagonize the action of vasopressin in hyponatremic disorders. Lithium may be neurotoxic, and its effects are unpredictable. Therefore, demeclocycline has become the agent of choice. This drug inhibits the formation and action of cyclic adenosine monophosphate in the renal collecting duct. The onset of action is 3 to 6 days after treatment is started. The dose must be decreased to the lowest level that keeps the serum sodium concentration within the desired range with unrestricted water intake; this dose is usually 300 to 900 mg daily. The drug should be given 1 to 2 hours after meals, and calcium-, aluminum-, and magnesium-containing antacids should be avoided. However, polyuria tends to make patients noncompliant. Skin photosensitivity may occur; in children, tooth or bone abnormalities may result. Nephrotoxicity also limits the drug's use, especially in patients with underlying liver disease or congestive heart failure, in whom the hepatic metabolism of demeclocycline may be impaired.
  - Vasopressin antagonists. Specific antagonists of vasopressin action on the collecting duct may soon supplement these pharmacologic agents. Orally active, nonpeptide vasopressin type 2 (V₂) receptor antagonists that have shown encouraging results in animal models and humans with hyponatremia are undergoing clinical studies, but these aquaretic agents have not yet been approved by the U.S. Food and Drug Administration (FDA).
  - Increase in solute excretion. Because urine flow can be significantly increased by obligating the excretion of solutes and thereby allowing a greater intake of water, measures to increase solute excretion have been used. A loop diuretic, when combined with high sodium intake (2 to 3 g additional NaCl), is effective. A single diuretic dose (40 mg furosemide) is usually sufficient. The dose should be doubled if the diuresis induced in the first 8 hours is less than 60% of the total daily urine output. Administration of urea to increase the solute load increases urine flow by causing an osmotic diuresis. This permits a more liberal water intake without worsening the hyponatremia and without altering urinary concentration. The dose is usually 30 to 60 g of urea daily. The major limitations are gastrointestinal distress and unpalatability.
- Hypovolemic and hypervolemic hyponatremia. Symptoms directly related to hyponatremia are unusual in hypovolemic hyponatremia, because loss of both sodium and water limits osmotic shifts in the brain. Restoration of ECF volume with crystalloids or colloids interrupts the nonosmotic release of vasopressin. In patients with hypovolemic hyponatremia from diuretics, the drug must be discontinued and potassium repletion ensured. The treatment of hyponatremia in hypervolemic states is more difficult, because it requires attention to the underlying disorder of heart failure or chronic liver disease. In congestive heart failure, both sodium and water restriction are critical. Refractory patients may be treated with a combination of an
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  angiotensin-converting enzyme (ACE) inhibitor and a diuretic. The resultant increase in cardiac output with ACE inhibitors may increase solute-free water excretion and correct hyponatremia. Loop diuretics diminish the action of vasopressin on the collecting tubules, thereby increasing solute-free water excretion. Thiazide diuretics impair urinary dilution and may worsen hyponatremia. Water and salt restriction are also the mainstay of therapy in cirrhotic patients. For both disorders, V_2- receptor antagonists are under investigation, and these aquaretics may be clinically available to treat hyponatremia in the near future.

Hypernatremia. Hypernatremia, defined as a plasma sodium concentration greater than 150 mEq per L, is less common than hyponatremia, probably not because of a more frequent occurrence of disorders of urinary dilution than of urinary concentration, but rather because of drinking behavior. Specifically, if an inability to dilute the urine is present, water intake of 1 to 2 L per day may cause hyponatremia. This amount of fluid intake may be ingested as routine behavior in spite of a hypo-osmolar stimulus to suppress thirst, which may explain the frequency of hyponatremia. Conversely, urinary-concentrating defects that cause renal water losses generally do not cause hypernatremia unless a disturbance in thirst is also present or the patient cannot drink or obtain adequate fluid to drink. The very young, the very old, and the very sick are, therefore, those populations that develop hypernatremia most frequently. In the absence of an inability to drink (e.g., with coma, nausea, and vomiting) or to obtain water (e.g., in infants or severely ill adults), the thirst mechanism is very effective in preventing hypernatremia. Although, as noted, hyponatremia does not always reflect a hypotonic state (i.e., pseudo- or translocation hyponatremia), hypernatremia always denotes a hypertonic state.

Approach to the hypernatremic patient. As is the case with hyponatremia, hypernatremic patients may have low, high, or normal total body sodium (Fig. 2-2). Such a classification allows the clinician to focus on the most likely diagnosis in each category.

Figure 2-2. Diagnostic approach to hypernatremia. ( , increased; , greatly increased; , decreased; , greatly decreased; , not increased or decreased; U_[Na] = urinary sodium concentration, in mEq per L.)

Hypovolemic hypernatremic patient. The hypernatremic patient may have evidence of ECF volume depletion that has occurred secondary to either renal or extrarenal losses. These patients have sustained water losses that are greater than the sodium losses.
- Extrarenal losses. If the losses have been from an extrarenal site (e.g., in diarrhea), then sodium and water conservation by the kidney should be readily apparent. In such patients, the urine sodium concentration is less than 10 mEq per L, and the urine is hypertonic. In fact, hypotonic diarrhea losses are among the most common causes of hypernatremia in both children and adults, especially in those who are on lactulose for underlying liver disease.
- Renal losses. In contrast, hypotonic electrolyte losses may occur in the urine during osmotic diuresis or use of loop diuretics. In these patients, evidence of renal sodium and water conservation is, of course, not present, because the urine is the source of the losses. Thus, the urine is not hypertonic, and urine sodium concentration is generally greater than 20 mEq per L. In the hyperglycemic diabetic patient with good renal function and profound glucosuria, hypernatremia may be a presenting feature, because hypotonic renal losses may obscure any effect of hyperglycemia to shift water osmotically from cells to ECF. This is particularly true if the patient does not have access to water or is incapable of ingesting fluids (e.g., a comatose, ketoacidotic diabetic patient). In the setting of high-protein tube feedings, the high rate of urea excretion leads to significant renal water losses.
Hypervolemic hypernatremic patient. Patients with hypernatremia also may have evidence of ECF volume expansion. Generally, these patients have received excessive amounts of hypertonic NaCl or sodium bicarbonate. In such an acute setting, the incidence of ECF volume expansion is most likely to be associated with pulmonary congestion, elevated neck veins, or both, rather than with peripheral edema. This variety of hypervolemic
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hypernatremia is rather infrequent, but may occur with cardiac resuscitation or NaCl tablets taken during exercise in a high temperature, high humidity environment.

Euvolemic hypernatremia. Most patients with hypernatremia secondary to water loss appear euvolemic with normal total body sodium, because loss of water without sodium does not lead to overt volume contraction. Water loss in and of itself need not culminate in hypernatremia unless it is unaccompanied by water intake. Because such hypodipsia is uncommon, hypernatremia usually supervenes only in those who have no access to water or who have a neurologic deficit that does not allow them to seek it. Extrarenal water loss occurs from the skin and respiratory tract in febrile or other hypermetabolic states. Urine osmolality is very high, reflecting an intact osmoreceptor-vasopressin-renal response. Thus, the defense against hyperosmolality requires both stimulation of thirst and the ability to respond by drinking water. The urine sodium concentration varies with sodium intake. The renal losses of water that lead to euvolemic hypernatremia are a consequence of a defect in vasopressin production or release (central diabetes insipidus), a failure of the collecting duct to respond to the hormone (nephrogenic), or excessive rapid degradation of vasopressin (gestational).

Approximately 50% of instances of central diabetes insipidus have no detectable underlying cause and thus are classified as idiopathic. Trauma, surgical procedures in the area of the pituitary or hypothalamus, and brain neoplasms, either primary or secondary (e.g., from metastatic breast cancer), constitute the majority of the remaining causes of central diabetes insipidus. In addition, encephalitis, sarcoidosis, or eosinophilic granuloma may cause central diabetes insipidus. Central diabetes insipidus can be partial, with some preservation of vasopressin release. When the central diabetes is associated with hypothalamic lesions and hypodipsia, these patients present with hypernatremia and a concentrated urine. A congenital form of central diabetes insipidus has also been described.
Nephrogenic diabetes insipidus. This disorder can be congenital or acquired. The congenital form is inherited as an x-linked disorder. The underlying defect resides in the vasopressin receptor that is localized to the x chromosone. A rarer autosomal recessive form is related to a mutation in the vasopressin dependent water channel (AQP2). A number of acquired causes have been described, many of them also associated with decreased AQP2 production:
- Secondary to renal diseases. Medullary or interstitial renal diseases are particularly likely to be accompanied by vasopressin-resistant renal concentrating defects; the most frequent of these diseases are medullary cystic disease, chronic interstitial nephritis (e.g., analgesic nephropathy), polycystic kidney disease, and partial bilateral urinary tract obstruction. Far-advanced renal disease of any cause is uniformly associated with a renal concentrating defect. However, because of the very low glomerular filtration rate, the renal water loss (i.e., polyuria) is modest (2 to 4 L per day).
- Secondary to hypercalcemia and hypokalemia. Hypercalcemia secondary to any cause, including primary hyperparathyroidism, vitamin D intoxication, milk-alkali syndrome, hyperthyroidism, and tumor, may also cause nephrogenic diabetes insipidus. Similarly, hypokalemia secondary to any cause, including primary aldosteronism, diarrhea, and chronic diuretic use, may cause nephrogenic diabetes insipidus. However, some of the polyuria accompanying hypercalcemia or hypokalemia may be due to stimulation of thirst and the resultant increase in water intake.
- Drugs, dietary abnormalities, and other causes. Various drugs impair the end-organ response to vasopressin and thus cause a renal concentrating defect (see section I.C.2.d.3). Excess water intake and dietary
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  sodium and protein restriction also have been shown to impair urinary concentration. Other unique causes of nephrogenic diabetes insipidus include multiple myeloma, amyloidosis, Sj gren's syndrome, and sarcoidosis.
- A summary of acquired causes of nephrogenic diabetes insipidus includes:
  - Chronic renal disease
    - Polycystic kidney disease
    - Medullary cystic disease
    - Pyelonephritis
    - Urinary tract obstruction
    - Far-advanced renal failure
    - Analgesic nephropathy
  - Electrolyte disorders
    - Hypokalemia
    - Hypercalcemia
  - Drugs
    - Lithium
    - Demeclocycline
    - Acetohexamide
    - Tolazamide
    - Glyburide
    - Propoxyphene
    - Amphotericin
    - Methoxyflurane
    - Vinblastine
    - Colchicine
  - Dietary abnormalities
    - Excessive water intake
    - Decreased sodium chloride intake
    - Decreased protein intake
  - Miscellaneous
    - Multiple myeloma
    - Amyloidosis
    - Sj gren's syndrome
    - Sarcoidosis
    - Sickle cell disease
Diabetes insipidus secondary to vasopressinase. Central diabetes insipidus and nephrogenic diabetes are not the only causes of polyuria during pregnancy. Vasopressinase is an enzyme, produced in the placenta, that causes in vivo degradation of arginine vasopressin during pregnancy. Normally, an increase in vasopressin synthesis and release during pregnancy compensates for the increased degradation of the hormone. In rare cases, however, excessive vasopressinase has been incriminated in causing polyuria during pregnancy. Because vasopressinase cannot degrade deamino-8-D-arginine vasopressin, this is the treatment of choice for pregnancy-related polyuria.

Response to fluid deprivation and arginine vasopressin in the diagnosis of polyuric disorder. The various forms of diabetes insipidus must be differentiated from primary polydipsia in patients who present with polyuria. Table 2-1 summarizes the procedure and interpretation of a water deprivation test. Patients with compulsive water drinking may present with polyuria and a blunted response to the fluid deprivation test; on cessation of fluid intake, hypernatremia does not develop in these patients and their renal concentration defect is primarily due to a resistance of the kidney to vasopressin. However, because patients with central or nephrogenic diabetes insipidus may present with polyuria and polydipsia in the absence of hypernatremia, awareness of the diagnosis of compulsive (psychogenic) water drinking is quite important. Menopausal women

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with previous psychiatric problems are particularly prone to compulsive water drinking. Psychoneurosis and psychosis are also frequently associated with increased water intake. Last, the patient with nephrogenic diabetes insipidus may occasionally have vasopressin-resistant hypotonic urine (e.g., hypercalcemic or hypokalemic nephropathy); thus, the temporary absence of fluid intake because of an intercurrent illness can be associated with hypernatremia. In all hypernatremic patients who primarily have water losses without electrolyte losses, the urine sodium excretion concentration merely reflects sodium intake. During any solute-free water diuresis, the urinary sodium concentration declines so that sodium balance is maintained.

Table 2-1. Procedure and Interpretation of a Water Deprivation Test


Cause of polyuria	Urinary osmolality with water deprivation (mOsm/kg of water)	Plasma arginine vasopressin (AVP) after dehydration	Increase in urinary osmolality with exogenous AVP

Normal	>800	>2 pg/mL	Little or no increase
Complete central diabetes insipidus	<300	Undetectable	Substantially increased
Partial central diabetes insipidus	300 800	<1.5 pg/mL	Increase of more than 10% after water deprivation
Nephrogenic diabetes insipidus	<300 500	>5 pg/mL	Little or no increase
Primary polydipsia	>500	<5 pg/mL	Little or no increase

Note: Water intake is restricted until the patient loses 3% to 5% of his or her body weight or until three consecutive hourly determinations of urinary osmolality are within 10% of each other. (Caution must be exercised to ensure that the patient does not become excessively dehydrated.) Aqueous AVP (5 units subcutaneously) is given, and urinary osmolality is measured after 60 minutes. The expected responses are given above.
From Lanese D, Teitelbaum I. Hypernatremia. In: Jacobson HR, Striker GE, Klahr S, eds. The principles and practice of nephrology, 2nd ed. St. Louis: Mosby, 1995:893 898. Reprinted with permission.

Signs and symptoms. Polyuria and polydipsia may be prominent symptoms in the patient who subsequently develops hypernatremia in association with inadequate water intake.
- CNS dysfunction. Neurologic abnormalities constitute the most prominent manifestations of hypernatremic states. These neurologic manifestations appear to be due primarily to the cellular dehydration and shrinkage of brain cells that are associated with tearing of cerebral vessels. Capillary and venous congestion, subcortical and subarachnoid bleeding, and venous sinus thrombosis all have been described with hypernatremia.
- Prognosis of acute versus chronic hypernatremia. The signs and symptoms of hypernatremia are more severe in acute than in chronic hypernatremia. Indeed, 75% mortality has been reported in association with acute hypernatremia in adults with acute elevations of plasma sodium concentration above 160 mEq per L. These adults, however, frequently have severe primary diseases associated with their hypernatremia, and these primary diseases may largely account for the high mortality. A 45% mortality has been reported in children with acute hypernatremia, and as many as two-thirds of the surviving children may have neurologic sequelae.
- Idiogenic osmoles with chronic hypernatremia. The more benign course of chronic hypernatremia appears to be related to cellular mechanisms that protect against severe brain dehydration. The brain, however, requires some
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  period of time, perhaps days, to adapt. In chronic hypernatremia, brain cells generate idiogenic osmoles, some of which appear to be amino acids; these idiogenic osmoles are osmotically active and restore brain water to near-control levels in spite of persistent hypernatremia. The presence of these idiogenic anions with chronic hypernatremia, although protective against brain dehydration and shrinkage, may predispose to brain edema if the hypernatremia is corrected too rapidly.
- Correlation of CNS dysfunction with degree of hyperosmolality. The earliest manifestations of hypernatremia are restlessness, increased irritability, and lethargy. These symptoms may be followed by muscular twitching, hyperflexia, tremulousness, and ataxia. The level of hyperosmolality at which these signs and symptoms occur depends not only on the rapidity of the change in the plasma sodium concentration but also on the age of the patient; the very young and the very old exhibit the most severe manifestations. In general, however, these signs and symptoms may occur progressively with plasma osmolality in the range of 325 to 375 mOsm per kg of water. At plasma osmolalities above this level, tonic muscular spasticity, focal and grand mal seizures, and death may occur. The elderly patient with dementia or severe cerebrovascular disease may demonstrate these life-threatening signs and symptoms at a lower level of plasma hyperosmolality.
Therapy. Hypernatremia is frequently a preventable electrolyte disorder if water losses are recognized and appropriately replaced. In most cases, hypernatremia can be treated by the judicious administration of water to patients with water-losing disorders who cannot obtain water. The treatment of hypernatremia depends on two important factors: ECF volume status and the rate of development of the hypernatremia.
- Correction of ECF volume depletion. When hypernatremia is associated with ECF volume depletion, the primary therapeutic goal is to administer isotonic saline until restoration of ECF volume is achieved, as assessed by normal neck veins and absence of orthostatic hypotension and tachycardia. Hypotonic (0.45%) NaCl or 5% glucose solutions can then be used to correct plasma osmolality.
- Correction of ECF volume expansion. In contrast, if hypernatremia is associated with ECF volume expansion, diuretics (e.g., furosemide) can be used to treat the hypernatremia. In the presence of advanced renal failure, the patient with hypernatremia and fluid overload may need to be dialyzed to treat the hypernatremia.
- Water-replacement method of calculation. Last, the patient with euvolemic hypernatremia can be treated primarily with water replacement either orally or parenterally with 5% glucose in water. The method of calculation of the necessary water replacement for a 75-kg man with a plasma sodium of 154 mEq per L is as follows:
  
  Then,
  
  Therefore, the repletion of 4.5 L (49.5 L 45 L) positive water balance will correct the plasma sodium concentration. Ongoing water losses should not be overlooked.
- Rate of correction. The recommended rate of correction of hypernatremia depends on the rate of development of the hypernatremia and the symptoms. More neurologic signs and symptoms are associated with acute
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  hypernatremia; therefore, this biochemical abnormality should be corrected rapidly, over a few hours.
  
  Conversely idiogenic osmoles appear to accumulate in brain cells during periods of chronic hypernatremia, a mechanism that protects against brain shrinkage. Thus, the rapid correction of chronic hypernatremia can create an osmotic gradient between the ECF and intracellular compartments, with osmotic water movement into cells and subsequent brain edema. In general, therefore, chronic hypernatremia is best corrected gradually, at a rate not to exceed 2 mOsm per hour. One-half of the correction can be achieved in 24 hours and the other half in the next 24 hours or longer.