Rudolph's Pediatrics, 22nd Ed.

CHAPTER 525. Primary Disturbances in Water Homeostasis

Abhinash Srivatsa and Joseph A. Majzoub

Maintenance of the tonicity of extracellular fluids within a very narrow range is crucial for proper cell function. Normal blood tonicity is maintained over a 10-fold variation in water intake by a coordinated interaction among the vasopressin, thirst, and renal systems. Dysfunction in any of these systems can result in abnormal regulation of blood osmolality, which if not properly recognized and treated, may cause life-threatening hyperosmolality or hypoosmolality.¹

PHYSIOLOGY OF WATER HOMEOSTASIS

VASOPRESSIN SYNTHESIS

Plasma osmolality is regulated principally via vasopressin (also termed anti-diuretic hormone, ADH) release from the posterior pituitary, or neurohypophysis, whereas volume homeostasis is determined largely through the action of the renin-angiotensin-aldosterone system, with contributions from both vasopressin and the natriuretic peptide family. The nine amino acid peptide vasopressin is synthesized in hypothalamic paraventricular and supraoptic magnocellular neurons, whose axons travel caudally and converge at the infundibulum before terminating in the posterior pituitary, transporting the hormone to its primary site of storage and release into the systemic circulation (see Fig. 521-2).

OSMOTIC REGULATION

Water balance is regulated in two ways: vasopressin secretion stimulates water reabsorption by the kidney, thereby reducing future water losses; and thirst stimulates water ingestion, which restores past water losses. The two systems work in parallel to efficiently regulate extracellular fluid tonicity (Fig. 525-1). However, when both vasopressin secretion and thirst are compromised, life-threatening abnormalities in plasma osmolality can occur.

Normal blood osmolality ranges between 280 and 290 milliosmoles/kg H₂O (mosm/kg). An osmosensor located outside the blood-brain barrier near the anterior hypothalamus can detect as little as 1% to 2% change in blood osmolality. When osmolality increases above a threshold of 283 mosm/kg, it signals the posterior pituitary to secrete vasopressin. Hypothalamic neurons distinct from those that control vasopressin secretion stimulate thirst sensation at a threshold (∼293 mosm/kg) slightly higher than that for vasopressin release.

NONOSMOTIC REGULATION

Vasopressin is also secreted in response to a decrease in intravascular volume or pressure. Vasopressin concentration rises exponentially after a reduction in intravascular volume that exceeds 8%. When blood volume or blood pressure decreases by 25%, vasopressin levels rise to 20- to 30-fold above normal, high enough to cause vasoconstriction and vastly exceeding those required for maximal antidiuresis (∼5 pg/mL). Nausea, pain, hypoglycemia, psychologic stress, ethanol, and chlorpropamide are also clinically important triggers for vasopressin release. Vasopressin secretion is inhibited by glucocorticoids.

VASOPRESSIN METABOLISM AND ACTION

Once in the circulation, vasopressin has a half-life of only 5 to 10 minutes, due to its rapid degradation by vasopressinase. The synthetic analog of vasopressin, dDAVP (desmopressin acetate), is insensitive to this amino-terminal degradation, and thus has a much longer half-life of 8 to 24 hours.

FIGURE 525-1. Regulation of vasopressin secretion and serum osmolality. Hyperosmolality, hypovolemia, or hypotension is sensed by osmosensors, volume sensors, or barosensors, respectively. These stimulate both vasopressin (VP) secretion and thirst. VP, acting on the kidney, causes increased reabsorption of water (antidiuresis). Thirst causes increased water ingestion. The results of these dual negative feedback loops cause a reduction in hyperosmolality or hypotension/hypovolemia.

Vasopressin affects the function of several tissue types by binding to three G-protein–coupled cell surface receptors, designated V1, V2, and V3 (or V1b). The V1 receptors on vascular smooth muscle and hepatocytes mediate vasoconstriction and glycogenolysis, respectively. The V3 receptors, on corticotrophs in the anterior pituitary, mediate adrenocorticotrophic hormone (ACTH) secretion. Modulation of water balance occurs through the action of vasopressin on V2 receptors located primarily on the basolateral (blood) side of cells in the renal collecting tubule, where it induces the insertion of aggregates of the water channel aquaporin-2 into the apical (luminal) membrane. This allows water movement from the tubular lumen along its osmotic gradient into the hypertonic inner medullary interstitium and the excretion of concentrated urine (Fig. 525-2).

FIGURE 525-2. Vasopressin (VP) action in the kidney. [1] VP binds to the V2 receptor (V2R), causing [2] dissociation of the trimeric G protein (α, β, γ) G_s, allowing G_sα to [3] activate adenylate cyclase (AC), resulting in an increase in cyclic adenosine monophosphate (cAMP) and [4] activation of protein kinase A (PKA). The catalytic subunit of PKA phosphorylates the aquaporin-2 (AQP2) water channel, causing it to [5] aggregate as a homotetramer in the collecting duct luminal membrane, resulting in [6 and 7] an increase in water flow down its osmotic gradient from the urine into the hypertonic renal medullary interstitium containing NaCl and urea. Demeclocycline, lithium, high calcium, and low potassium interfere with these processes.

EVALUATION OF POLYURIA, POLYDIPSIA, AND HYPERNATREMIA

In children, one must first determine if pathologic polyuria or polydipsia (> 2 L/m²/d^*) is present, by asking the following questions: (1) Can either polyuria or polydipsia be quantitated? (2) Have either interfered with normal activities and do they occur even at night? (3) Do the history, growth data or physical examination suggest another endocrinopathy or an intracranial neoplasm? (4) Is there a psychosocial reason for either polyuria or polydipsia?

If pathologic polyuria or polydipsia is present, the following laboratory tests should be obtained: serum osmolality, sodium, potassium, glucose, calcium, and blood urea nitrogen (BUN); and simultaneous measurement of urine for urine osmolality, specific gravity, glucose concentration, and urinalysis. A serum osmolality > 300 mosm/kg, with urine osmolality < 300 mosm/kg, establishes the diagnosis of diabetes insipidus (DI). If serum osmolality is < 270 mosm/kg, or urine osmolality is > 600 mosm/kg, the diagnosis of DI is unlikely. If the serum osmolality is < 300 mosm/kg, but if there is significant polyuria and polydipsia that cannot be attributed to primary polydipsia (ie, the serum osmolality > 270 mosm/kg), the patient should undergo a water deprivation test to establish a diagnosis of DI and to differentiate central from nephrogenic causes.

After a maximally tolerated overnight fast, the child is deprived of water at an outpatient testing center under close observation by personnel experienced with this procedure. Physical signs (weight, pulse, blood pressure) and laboratory data (serum sodium, osmolality, hematocrit, urine volume, osmolality, specific gravity) are monitored during the test. If at any time during the test, the urine osmolality exceeds 1000 mosm/kg or 600 mosm/kg that is stable over 1 hour, the patient does not have DI. If at any time the serum osmolality exceeds 300 mosm/kg and the urine osmolality is < 600 mosm/kg, the patient has DI. If the serum osmolality is < 300 mosm/kg and the urine osmolality is < 600 mosm/kg, the test should be continued unless vital signs disclose hypovolemia. A common error is to stop a test too soon (especially in patients with primary polydipsia who are volume overloaded), based on the amount of body weight lost. If the diagnosis of DI is made, aqueous vasopressin (Pitressin), 1 mU/m², should be given subcutaneously. If the urine volume falls and the osmolality doubles during the next hour, the patient has central diabetes insipidus (CDI). If not, the patient probably has nephrogenic diabetes insipidus (NDI). dDAVP (desmopressin acetate) should not be used for this test because it has been associated with water intoxication in small children in this setting.

Magnetic resonance imaging (MRI) is not very helpful in distinguishing CDI from NDI. Normally, the posterior pituitary is seen as an area of enhanced brightness in T1-weighted images following administration of gadolinium. The posterior pituitary “bright spot” is diminished or absent in both forms of DI, normal in primary polydipsia, and decreased in syndrome of inappropriate antidiuretic hormone secretion (SIADH).

CENTRAL DIABETES INSIPIDUS

CAUSES OF CENTRAL DIABETES INSIPIDUS

Table 525-1 shows the common causes of central diabetes insipidus (CDI). The most common is the neurosurgical destruction of vasopressin neurons following pituitary-hypothalamic surgery. Serum osmolality will be high in acute post-surgical CDI, whereas low or normal in cases of polyuria due to the normal diuresis of intraoperative fluids. The intraoperative fluid record should also help distinguish between these two possibilities. Surgical interruption of the vasopressin axons can result in retrograde degeneration of hypothalamic neurons. Not infrequently, a “triple-phase” response is seen following surgery. An initial phase of transient diabetes insipidus (DI) is observed, lasting 12 to 48 hours following surgery, possibly due to local edema interfering with normal vasopressin secretion. This is often followed by a second phase of syndrome of inappropriate antidiuretic hormone secretion (SIADH), which may last up to 10 days and is due to the unregulated release of vasopressin by dying neurons. A third phase of permanent DI may follow if more than 90% of vasopressin cells are destroyed. In patients with coexisting vasopressin and cortisol deficits, symptoms of DI may be masked because cortisol deficiency impairs renal free water clearance. In such cases, glucocorticoid therapy may precipitate polyuria, leading to the diagnosis of DI.

Germinomas and pinealomas, which typically arise near the base of the hypothalamus where vasopressin axons converge, are among the most common primary brain tumors associated with CDI. Germinomas causing the disease can be very small and undetectable by MRI for several years following the onset of polyuria. For this reason, quantitative measurement of the beta subunit of human chorionic gonadotropin, often secreted by germinomas and pine-alomas, and serial MRI scans should be performed in children with idiopathic or unexplained DI.

Table 525-1. Causes of Central Diabetes Insipidus

DIDMOAD, diabetes insipidus, diabetes mellitus, optic atrophy, deafness.

Vasopressin secretion is initially normal in familial, autosomal-dominant CDI, but gradually declines until DI of variable severity ensues before 5 years of age. Patients respond well to vasopressin replacement therapy.

CDI is idiopathic in nearly half of the affected children. In one study, circulating antibodies to vasopressin-secreting cells were not only identified in one third of the idiopathic cases, but also in one sixth of individuals with CDI from a known cause.²

Children with primary enuresis may have a blunting or absence of the normal nocturnal rise in plasma vasopressin. The use of the V2 agonist, dDAVP (desmopressin acetate), is highly effective in abolishing bed wetting episodes, although relapse is high once therapy is stopped. Fluid intake must be limited while a child is exposed to the antidiuretic action of dDAVP to guard against water intoxication.

TREATMENT

With complete central diabetes insipidus (CDI), a urine output of ∼5 L/m² is required to excrete an average daily solute load. With an intact thirst mechanism and free access to oral fluids, a person with complete diabetes insipidus (DI) can maintain plasma osmolality and sodium in the high normal range by matching intake with urine output, although at great inconvenience. A synthetic analog of vasopressin, dDAVP (desmopressin acetate) with twice the antidiuretic potency and 100 times the duration of action of vasopressin, and no pressor activity, is routinely used to treat patients with CDI.

Vasopressin therapy coupled with excessive fluid intake (usually > 1 L/m²/d) can result in unwanted hyponatremia. Because neonates and young infants receive their nutrition in liquid form, the obligatory high oral fluid requirements for this age (3 L/m²/d), combined with vasopressin treatment, are likely to lead to this dangerous complication. Neonates may be better managed with fluid therapy alone until they start eating solid foods, when obligate fluid intake falls and dDAVP therapy can be started. However, infants with CDI have been successfully treated with subcutaneous injections of dDAVP (initial dose 0.002 ug/kg once daily, titrated upward as needed) with far fewer episodes of hyponatremia and hypernatremia than with either intranasal or oral dDAVP.³ Alternatively, the use of breast milk or Similac 60/40 formula reduces the renal solute load and the urine volume by 20% to 30%. The amount of free water supplementation needed in infants with both forms of DI is reduced even further with the addition of chlorothiazide (oral dose 5 mg/kg twice daily), a diuretic that increases the urine osmolality and decreases the urine volume through mechanisms that are unclear.⁴

In the acute postoperative management of CDI occurring after neurosurgery, vasopressin therapy may be successfully employed, but extreme caution must be exerted with its use. Vasopressin is infused intravenously (1 mU/kg/hour), titrating the dose to maintain urine output < 2 mL/kg/hour while the serum sodium level, fluid balance, urine, and serum osmolality are closely monitored in the intensive care unit. Low solute fluids or diet should also be employed to minimize fluid requirements. Intravenous dDAVP should not be used in the acute management of postoperative CDI as its long half-life is a distinct disadvantage because it may increase the chance of causing water intoxication.

In the outpatient setting, treatment of CDI in children beyond infancy should begin with oral dDAVP tablets. Young children may respond to 25 or 50 μg at bedtime. If the duration of action is short, the dose should be increased or a morning dose should be added. Patients should escape from the antidiuretic effect for at least 1 hour before the next dose to ensure that any excessive water is excreted, thus avoiding water intoxication. dDAVP is also available for intranasal administration via a rhinal tube (10 μg/0.1 mL) or as a nasal spray (10 μg/spray). The initial dose is 0.025 mL (2.5 μg) given by the rhinal tube at bedtime. (Dose equivalence of dDAVP administered through various routes: subcutaneous:intranasal:oral is ∼1:10:100–200.)

NEPHROGENIC DIABETES INSIPIDUS

Nephrogenic diabetes insipidus (NDI) is a disorder in which the collecting tubule is unresponsive to vasopressin.^5,6

PATHOPHYSIOLOGY

The urine osmolality ranges from 50 to 1200 mosm/kg H₂O in adults and from 50 to 500 mosm/kg H₂O in neonates. The urine osmolality is dependent on the formation of a hypertonic medullary interstitium and the secretion of antidiuretic hormone (ADH; also called arginine vasopressin). ADH is secreted by the neurohypophysis in response to hyperosmolality or volume depletion and acts on the collecting tubule to increase passive water transport. ADH binds to the vasopressin 2 receptor, which triggers the insertion of water channels (designated aquaporin-2) by exocytotic insertion into the luminal membrane, which increases collecting tubule water permeability (Fig. 525-2). The hypertonic medullary interstitium is formed by the countercurrent system.

CAUSES OF NEPHROGENIC DIABETES INSIPIDUS

In most patients, congenital nephrogenic diabetes is an X-linked recessive disorder due to a mutation in the vasopressin 2 receptor. Although males with X-linked nephrogenic diabetes insipidus (NDI) have the severe disease described previously, females with one mutant allele will have variable degrees of polydipsia and polyuria based on stochastic X chromosome inactivation. NDI can also result from a mutation in the aquaporin-2 water channel. This disease presents the same as in the males with the X-linked form described previously. Although this mutation is usually inherited in an autosomal-recessive fashion, an autosomal-dominant inherited defect of this water channel has been described in a few kindreds. NDI can also be secondary to drugs, electrolyte disorders, and a number of diseases. Secondary causes of NDI are detailed in Table 525-2. These secondary causes of NDI result from an attenuated effect of vasopressin on the collecting tubule, or a disruption of the medullary concentration gradient. Primary polydipsia can result in secondary NDI because the chronic excretion of dilute urine lowers the osmolality of the hypertonic renal interstitium, thus decreasing renal concentrating ability.

CLINICAL FEATURES AND DIAGNOSIS

Congenital nephrogenic diabetes insipidus (NDI) can present in the first week of life with irritability, vomiting, and unexplained fever. The infant will have repeated episodes of hyper-natremic dehydration, which may be accompanied by seizures, until the diagnosis is made and therapy is initiated. Many infants with NDI initially present with fever, vomiting, and dehydration, often leading to an evaluation for infection. They may also have growth failure and mental retardation. Intracerebral calcification of the frontal lobes and basal ganglia is not uncommon in children with X-linked NDI.

Table 525-2. Causes of Nephrogenic Diabetes Insipidus

Repeated episodes of hypernatremia can result in intellectual impairment. Patients often fail to thrive due to their need to ingest water at the expense of food. The enormous urine volumes can result in urinary tract dilatation.

TREATMENT

Early diagnosis of congenital diabetes insipidus can prevent the uniqueness of repeated hypernatremic dehydration. The main goals of treatment of congenital nephrogenic diabetes insipidus (NDI) should be to ensure the intake of adequate calories for growth and to avoid severe dehydration. Foods with the highest ratio of caloric content to osmotic load should be ingested to minimize the urine volume required to excrete urine solute. However, even with the early institution of therapy, growth impairment and mental retardation are not uncommon. Thiazide diuretics in combination with amiloride are the most commonly used regimen because amiloride counteracts thiazide-induced hypokalemia and is well tolerated, even in infants.

SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION

The differential diagnosis and treatment of hyponatremia (serum sodium < 130 mEq/L) is discussed in Chapter 466.

DIAGNOSIS

Syndrome of inappropriate antidiuretic hormone (SIADH) exists when a primary elevation in vasopressin secretion is the cause of hyponatremia. It is characterized by hyponatremia and hypoosmolality (< 275 mosm/kg), inappropriately concentrated urine (> 100 mosm/kg), a normal or slightly elevated plasma volume, and a normal to high urine sodium (because of volume-induced suppression of aldosterone and elevation of atrial natriuretic peptide). Serum uric acid is low in patients with SIADH, whereas it is high in those with hyponatremia due to decreased intravascular volume.

DIFFERENTIAL DIAGNOSIS

Causes of syndrome of inappropriate anti-diuretic hormone (SIADH), which is uncommon in children, are listed in Table 525-3. In the vast majority of children with SIADH, the cause is the excessive administration of vasopressin, whether to treat central diabetes insipidus (CDI), or less commonly, bleeding disorders, or very rarely following dDAVP (desmopressin acetate) therapy for enuresis. Although SIADH has been believed to be the cause of hyponatremia associated with viral meningitis, volume depletion is more commonly the etiology.⁷ Deficiencies of cortisol and thyroid should be considered in all hyponatremic patients. Drug-induced hyponatremia should be considered in patients on potentially offending medications (Table 525-2). In children with SIADH who do not have an obvious cause, a careful search for a tumor (thymoma, glioma, bronchial carcinoid) causing the disease should be considered.

Table 525-3. Causes of Syndrome of Inappropriate Antidiuretic Hormone Secretion

TREATMENT

Syndrome of inappropriate antidiuretic hormone (SIADH) is best treated by fluid restriction to 1 L/m²/d and by addressing the underlying cause. In young children with chronic SIADH, increasing the urine output by increasing the renal solute load (by using sodium chloride alone or with a loop diuretic or by using urea) or the creation of nephrogenic diabetes insipidus (NDI) using demeclocycline may be indicated to allow sufficient fluid intake for normal growth. Acute treatment of hyponatremia due to SIADH is similar to the previously described for treatment of hyponatremia from any other cause in Chapter 466. V2 receptor antagonists may soon be available to treat SIADH and chronic disorders of decreased effective volume associated with hyponatremia.⁸

PRIMARY POLYDIPSIA AND HYPONATREMIA WITHOUT ELEVATED VASOPRESSIN SECRETION

Primary polydipsia is characterized by hyponatremia without an elevation in vasopressin secretion. It occurs in neonates, who normally cannot dilute their urine very well and can develop water intoxication at rates of ingestion > 4 L/m²/d (> 60 mL/hour). This may happen when infant formula is inappropriately diluted with excess water, either by accident or otherwise. With a normal kidney and the ability to suppress vasopressin secretion, an older child develops hyponatremia only with water intake > 10 L/m²/d. Cortisol and thyroid hormone are required for normal free water clearance. All patients with hyponatremia should be suspected of having adrenal or thyroid deficiency, and appropriate tests should be performed if indicated, given the subtle clinical findings often associated with these diseases. Some drugs (carbamazepine, oxcarbazepine) may cause hyponatremia by inhibiting renal water excretion without stimulating secretion of vasopressin, an action that could be termed nephrogenic syndrome of inappropriate antidiuretic hormone. More recently, several patients have been described with hyponatremia with autosomal-dominant mutations that constitutively activate the V2 receptor.⁹

HYPONATREMIA DUE TO SALT LOSS

Primary salt-losing disorders can cause hyponatremia. Salt can be lost from the kidney (congenital polycystic kidney disease, acute interstitial nephritis, chronic renal failure, mineralocorticoid deficiency, pseudohypoaldosteronism, diuretic use), the gastrointestinal tract (usually gastroenteritis with diarrhea and/or vomiting), or the skin (cystic fibrosis).

Hyponatremia in some patients, with central nervous system disorders, including brain tumor, head trauma, hydrocephalus, neuro-surgery, cerebral vascular accidents, and brain death, may be due to the primary hypersecretion of atrial natriuretic peptide (ANP). This syndrome, termed cerebral salt wasting (CSW), is defined by hyponatremia accompanied by hypovolemia, elevated urinary sodium excretion (often > 150 mEq/L), excessive urine output, suppressed vasopressin, and elevated ANP concentrations (> 20 pmol/L).¹⁰ Thus, it is distinguished from syndrome of inappropriate antidiuretic hormone (SIADH), in which euvolemia, normal or decreased urine output, only modestly elevated urine sodium concentration, and elevated vasopressin concentration occur. The distinction is important because the therapies of the two disorders are markedly different. When the presence or absence of hypovolemia was clearly established, CSW was determined to be the cause of hyponatremia in only 6% or less of patients following an acute neurologic injury.⁶

In general, patients with hyponatremia due to salt loss require ongoing supplementation with sodium chloride and fluids. Initially, intravenous replacement of urine volume with fluid-containing sodium chloride, 150 to 450 mEq/L (0.9–3%), depending on the degree of salt loss, may be necessary. Oral salt supplementation may be required subsequently. This treatment contrasts with that of SIADH, where water restriction without sodium supplementation is the mainstay.