Water metabolism

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CHAPTER 24

Water metabolism

1. What is the water composition of the human body?

2. Where is water located within the body?

TBW comprises water located inside the cells (intracellular fluid [ICF]) and outside the cells (extracellular fluid [ECF]). TBW is 60% of body weight—40% ICF (⅔) and 20% ECF (⅓). Of the ECF, approximately ¾ is interstitial fluid (ISF) and ¼ is intravascular fluid (IVF). IVF is a major component of the total blood volume necessary to maintain effective vascular pressure. ISF is 15% of body weight, and IVF is 5% of body weight. In a 70-kg man, TBW = 42 L, ICF water = 28 L, and ECF water = 14 L. ISF is 10.5 L and IVF (plasma) is 3.5 L. Tight regulation of the relatively small volume of IVF maintains blood pressure and avoids symptomatic hypovolemia and congestive heart failure. Normal plasma is 93% water and 7% proteins and lipids. The arterial volume is only 15% of IVF. Although arterial volume is small, its integrity is most important for maintaining the effective circulation and preventing abnormalities of water balance (Fig. 24-1).

3. What is transcellular water (TCW)?

4. Explain the significance of TCW.

5. What controls distribution of body water?

With few exceptions (e.g., ascending loop of Henle [LOH] and distal nephron), water moves freely across cell membranes, depending on tonicity. Because tonicity depends on impermeable solutes, such as sodium (Na), disorders of water metabolism are reflected by changes in solute concentrations. In addition to changes in water distribution, changes in TBW, blood volume, and ECV affect overall water balance. A thorough understanding of disorders of water metabolism requires a clear understanding of changes in plasma Na concentration (PNa), plasma osmolality (Posm), and ECV.

6. What is effective circulating volume (ECV)?

7. How do baroreceptors affect ECV?

Baroreceptors are the major sensors of changes in ECV (Fig. 24-2). However, their main role is to maintain normal pressure (not volume) at the level of the baroreceptor sensors located primarily in the carotid sinus, aortic arch, atria, pulmonary veins, and afferent renal arterioles. These anatomic locations are important because perfusion to these areas affects the three main effectors of circulatory homeostasis and ECV: brain, heart, and kidneys.

8. How does vascular pressure, as sensed by the baroreceptors, relate to ECV and hyponatremia?

Baroreceptors normally maintain tonic inhibition of vasoconstrictor nerves and natriuretic hormone release but tonic stimulation of vagal cardiac nerves. A drop in ECV decreases effective vascular pressure (EVP), baroreceptor tone, tonic inhibition, and tonic stimulation. This causes vasoconstriction; increases heart rate; and increases renin, aldosterone, angiotensin II, and ADH secretion. It decreases atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) from brain and ventricles, and urodilatin (kidney). These alterations enhance renal Na and water retention. If the patient receives unlimited water, these changes may lead to hyponatremia. Hyponatremia cannot develop unless the patient retains more water than is excreted. Decreased ECV/EVP predisposes to water retention, but the patient must receive free water for hyponatremia to develop. The venous system, through atrial stretch receptors, has similar effects but responds to changes in ECV earlier than the arterial system.

9. Define osmolality and tonicity, and outline their effects on water movement.

Osmolality is the concentration of a substance in 1 L of water divided by its molecular weight. Tonicity is effective osmolality—the osmotic pressure caused by dissolved particles restricted to one side of the cell membrane. Because Na and glucose are partially restricted to the ECF, they are effective osmols and account for normal tonicity. Mannitol, sorbitol, glycerol, and glycine are also effective osmols. Urea freely crosses cell membranes and distributes evenly in TBW, and therefore it changes osmolality but not tonicity. Thus, except during early and rapid solute and water changes, urea is an ineffective osmol. Ethanol and methanol are other ineffective osmols. Water always moves across cell membranes from lower osmolality to higher osmolality until osmolality on the two sides is equal. At equilibrium, the following is always true:

image

10. What formulas are useful in evaluating osmolality and tonicity?

11. How does PNa relate to TBW, osmolality, and tonicity?

12. How does PK relate to PNa and TBW?

13. Describe the input and output of water.

14. What are the normal limits of urine output?

Water intake and osmotic products of metabolism determine the usual daily output of urine. On a normal diet, a normal adult must excrete 800 to 1000 mOsm of solute per day. The range of normal renal concentrating function is 50 to 1200 mOsm/kg. On this basis, the obligate water excretion varies from 0.8 to 20 L/day. The calculations are as follows:

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Note that higher solute loads (e.g., dietary) require more water excretion. For example, body builders consuming high-protein and high-carbohydrate diets with 1400 mOsm solute/day require a urine output of (1400/1200) to (1400/50) or 1.2 to 28 L/day. Alternatively, a low solute intake (starvation) with high water intake predisposes to water retention and water intoxication. This combination exists in binge beer drinkers, in whom the solute load may be only 300 mOsm/day. Low solute intake may also occur in starvation and in an elderly person on a “tea and toast diet.” The range of urine output would drop to (300/1200) – (300/50) or 0.25 to 6 L/day in such patients.

15. What are the main factors controlling water metabolism?

16. What are the stimuli of thirst?

17. What hormonal mechanisms are involved in control of body water?

Although natriuretic peptides, aldosterone, angiotensin II, prostaglandins, and neurohumoral changes affect renal water retention and excretion, ADH is most important. ADH is also called arginine vasopressin (AVP). Supraoptic and paraventricular nuclei in the hypothalamus secrete ADH in response to increased osmolality and decreased volume. ADH attaches to vasopressin 2 receptors (V2-Rs) on the basolateral membrane of renal collecting tubular cells. This activates cyclic adenosine monophosphate (cAMP) and protein kinase A, causing intracellular water channels called aquaporins (AQPs) to insert into the luminal membrane. Water moves down osmotic gradients from tubular lumen through AQP channels into the cell and interstitium. At least seven AQP isoforms (AQP1-4, AQP6-8) are present in the kidney. AQP1 is constitutively expressed in the proximal tubule and descending loop of Henle and is important for isotonic fluid reabsorption and water conservation. The collecting duct has high concentrations of AQP2 that serve as the major target for ADH-mediated water reabsorption. Abnormalities of the V2-R cause most cases of nephrogenic diabetes insipidus (DI), but some are caused by abnormalities of AQP2. Increased AQP2 may cause water retention in conditions such as pregnancy and congestive heart failure. Twenty percent of ADH receptors in the collecting tubular cells are vasopressin 1 receptors (V1-Rs). ADH activates V1-Rs only at very high levels. This increases prostaglandin E2 and prostacyclin, which opposes the antidiuretic effects of excessive ADH.

18. What are the major conditions that influence ADH secretion?

ADH functions to maintain osmotic and volume homeostasis. Secretion starts at an osmotic threshold of 280 mOsm/kg and increases proportionately to further rises in tonicity. Maximum diuresis (urine dilution) occurs at ADH levels of 0.5 pmol/L, and maximum reabsorption (urine concentration) occurs at ADH levels of 3 to 4 pmol/L. A 1% to 2% increase in osmolality stimulates ADH secretion, whereas an 8% to 10% drop in vascular volume is required for the same effect. Through action on baroreceptors, increased ECV raises the osmotic threshold for ADH secretion, and decreased ECV lowers this threshold. Severe volume depletion and hypotension may completely override the hypo-osmotic inhibition of ADH secretion. This finding has been called the “law of circulating volume.” In severe volume depletion and hypotension, ADH secretion continues despite low osmolality, thereby worsening the hyponatremia. Nausea, pain, and stress (as seen postoperatively) are potent stimuli of ADH release and may cause lifethreatening hyponatremia if hypotonic fluid is given. This is particularly true if patients with these symptoms also receive hypotonic fluid and drugs that potentiate the release or action of ADH.

19. What are the major causes of ADH secretion?

Major causes of ADH secretion include hyperosmolality, hypovolemia, nausea, pain, stress, human chorionic gonadotropin as in pregnancy (reset osmostat), hypoglycemia, corticotropin-releasing hormone (CRH), central nervous system (CNS) infections, CNS tumors, vascular catastrophes (thrombosis, hemorrhage), and ectopic ADH of malignancy (carcinomas of lung [primarily small cell], duodenum, pancreas, ureter, bladder, and prostate, and lymphoma). ADH secretion may be increased by any major pulmonary disorder, including pneumonia, tuberculosis, asthma, atelectasis, cystic fibrosis, positive pressure ventilation, and adult respiratory distress syndrome. Human immunodeficiency virus (HIV) infection may have the multifactorial role of causing CNS dysfunction, pulmonary disease, and malignancy. Excessive exogenous ADH or desmopressin acetate (DDAVP) in patients with DI directly increases ADH effect. Oxytocin also has significant ADH activity in the large dosages used to induce labor. Other drugs that affect ADH secretion and action are listed in Table 24-2.

TABLE 24-2.

DRUGS THAT AFFECT ANTIDIURETIC HORMONE (ADH) SECRETION AND ACTION*

Increase ADH secretion Antidepressants
Amitriptyline
Protriptyline
Desipramine
Fluoxetine
Selective serotonin reuptake inhibitors
Duloxetine
Antipsychotics*
Fluphenazine
Haloperidol
Phenothiazines
Butyrophenones
Monoamine oxidase inhibitors
Ecstasy
Nicotine
Bromocriptine
Carbamazepine
Chlorpropamide
Clofibrate
Cyclophosphamide
Ifosfamide
Morphine
Nicotine
Thioridazine
Vincristine
Angiotensin-converting enzyme inhibitors
Amiodarone
Methyldopa
Increase ADH effect Acetaminophen
Carbamazepine
Chlorpropamide
Cyclophosphamide
Nonsteroidal anti-inflammatory drugs
Tolbutamide
Decrease ADH secretion EthanolPhenytoin
Decrease ADH effect Demeclocycline
Lithium
Acetohexamide
Tolazamide
Glyburide
Methoxyflurane
Propoxyphene
Colchicine
Amphotericin
Vinblastine
Prostaglandin E2
Prostacyclin

*Because psychosis itself may cause the syndrome of inappropriate secretion of ADH (SIADH), one must question the true ADH-stimulatory effect of the antipsychotic drugs. Changes in ADH secretion may be direct or indirect.

20. How does the kidney handle salt and water?

To control excess or deficient water intake, there must be an adequate glomerular filtration rate (GFR) and delivery of filtrate to the LOH and distal nephron. Solute is separated from water in the ascending limb of the LOH, distal convoluted tubule (DCT), and cortical connecting segment; normal action of ADH allows controlled reabsorption of water in the cortical and medullary collecting tubules. The proximal convoluted tubule reabsorbs 65% and the descending limb of the LOH 25% of filtered solute and water isotonically. The ascending limb is impermeable to water but removes solute, resulting in dilution of the luminal filtrate, concentration of the interstitium (important for ADH action), and delivery of 10% of the filtrate to the cortical collecting tubules with an osmolality of 100 mOsm/kg. In the absence of ADH, this fluid (image18 L/day) would be lost in the urine and cause marked dehydration. In the presence of ADH, the collecting duct becomes permeable to water and reabsorbs all but 1% of the filtrate. Thus the final urine volume is only 1.5 to 2.0 L/day. Because normal GFR is 125 mL/min, the normal kidneys filter 180 L of plasma each day and reabsorb 99%. In normal adults, 99% of all Na and H2O filtered is reabsorbed.

21. What are the causes and consequences of decreased renal water excretion?

22. How do hypothyroidism and adrenal insufficiency cause hyponatremia?

Hypothyroidism and adrenal insufficiency reduce cardiac output and thereby decrease ECV and increase ADH release. A hypothyroidism-associated decrease in ECV reduces renal blood flow, glomerular filtration, and maximal solute-free water excretion. Failure to dilute the urine maximally results from nonosmotic ADH release and increased ADH-mediated AQP2 receptors and action. The main effect of glucocorticoid deficiency is altered systemic hemodynamics, and not salt and water loss. Low cortisol impairs cardiac output and the systemic vascular responses to catecholamines, reducing both blood pressure and ECV. The resulting drop in absolute and effective vascular filling pressure reduces stretch on the arterial baroreceptors and thereby decreases tonic vagal and glossopharyngeal inhibition of ADH release. These baroreceptor changes override the hypo-osmotic inhibition of ADH release, and consequently, ADH secretion increases. The decreased ECV also lowers GFR, thereby reducing delivery of filtrate to the distal nephron and enhancing proximal tubular water reabsorption. Normally, CRH and ADH are co-secreted from the same neurons in the paraventricular nuclei of the hypothalamus, and both hormones work synergistically to release adrenocorticotropic hormone (ACTH) from the anterior pituitary—ADH via the vasopressin V1b receptor. Cortisol feeds back negatively at the hypothalamus and pituitary to inhibit the release of both CRH and ADH. Cortisol deficiency decreases this negative feedback and increases ADH release to further enhance water reabsorption.

Unlike secondary adrenal insufficiency, mineralocorticoid deficiency associated with primary adrenal insufficiency causes a hyperkalemic non–anion gap metabolic acidosis. This is due to retention of K+ and H+ that are normally excreted under aldosterone influence. The aldosterone deficiency also causes renal NaCl loss and associated volume (ECF) depletion. The resulting low ECV stimulates ADH release. There is also upregulation of collecting duct AQP2 and AQP3, which enhances ADH action. The combination of increased ADH secretion and augmented ADH responsiveness promotes the development of hyponatremia. A high-sodium diet compensates for the mineralocorticoid deficiency and improves the hyponatremia. Although hyponatremia may occur with both primary and secondary adrenal insufficiency, it occurs more commonly in primary adrenal insufficiency. This fact emphasizes the importance of aldosterone deficiency in renal salt wasting, volume depletion, and ADH secretion. All of these events combined with continued water intake synergistically contribute to hyponatremia.

23. What PNa concentrations are causes for concern?