Regulation of fluids and electrolytes

Anatomy

The kidneys are retroperitoneal paired organs located on each side of the vertebral column. A normal adult kidney measures 11 to 12 cm in length, 5 to 7.5 cm in width, and 2.5 to 3 cm in thickness. In the adult male, it weighs 125 to 170 g, and in the adult female, it weighs 115 to 155 g. Beneath its fibrous capsule lies the cortex, which contains the glomeruli, the convoluted proximal tubules, the distal tubules, and the early portions of the collecting tubules. The remainder of the tissue, the medulla, contains the pars recta, the loop of Henle, and the middle and distal portions of the collecting duct. The inner medulla borders the renal pelvis, where urine is received from the collecting ducts. The ducts and loops are arranged into cone-shaped bundles called pyramids, which have tips that project into the renal pelvis and form papillae. The pelvis drains into the ureters, which in the adult human descend a distance of 28 to 34 cm to open into the fundus of the bladder. The walls of the pelvis and ureters contain smooth muscles that contract in a peristaltic manner to propel urine to the bladder.

Renal blood flow

Despite accounting for only 0.5% of body weight, the kidneys receive about 25% of the cardiac output, with a blood flow of approximately 4 mL/min per gram of kidney tissue. Renal blood flow (RBF) in women is slightly lower than it is in men, even when normalized for body surface area, averaging 592 ± 153 mL/min per 1.73 m ² and 654 ± 163 mL/min per 1.73 m ² , respectively ( ). In children between the ages of 6 months and 1 year, normalized RBF is half that of adults but increases progressively to reach adult levels at about 3 years of age ( ). After the age of 30 years, RBF decreases progressively; by the age of 90 years, it is approximately half of the value present at 20 years ( ). This generous supply provides not only for the basal metabolic needs of the kidneys but also for the high demands of ultrafiltration.

The basic arterial supply of the kidneys is a single renal artery that divides into large anterior and posterior branches and subsequently into segmental or interlobar arteries. The latter form the arcuate and interlobular arteries. These blood vessels are end-arteries and therefore predisposed to tissue infarction in the presence of emboli. The arcuate arteries are short, large-caliber vessels that supply blood to the afferent arterioles of the glomeruli at a mean pressure of 45 mm Hg, which is higher than that found in most capillary beds. This high hydraulic pressure and large endothelial pore size lead to enhanced glomerular filtration ( ).

Glomerular capillaries have many anastomoses but recombine to form the efferent arteriole. The latter subdivide into an extensive peritubular capillary network. This arrangement allows solute and water to move between the tubular lumen and the blood. These networks rejoin to form the venous channels, through which blood exits the kidneys.

Ninety percent of RBF goes to the cortex, which accounts for 75% of the renal weight, whereas the medulla and the rest of the kidneys receive 25% of the RBF. Although cortical blood flow is 5 to 6 mL/g per minute, outer medullary blood flow decreases to 1.3 to 2.3 mL/g per minute, and the flow to the papilla is as low as 0.22 to 0.42 mL/g per minute ( ). The unevenness in the distribution of RBF between the cortex and the medulla is necessary to develop and maintain the medullary gradient of osmotically active solutes that drive the countercurrent exchange/multiplier, which is essential for the elaboration of concentrated urine. Outer medullary blood flow may preferentially supply the loop of Henle, thereby accounting for the striking influence of loop diuretics in that region. Furthermore, papillary blood flow is far greater than the metabolic needs of the renal parenchyma and is well adapted to the countercurrent concentrating mechanism characteristic of this region.

RBF remains almost constant over a range of systolic blood pressures from 80 to 180 mm Hg, a phenomenon known as autoregulation. Consequently, glomerular filtration is also constant over this range of pressures as a result of adaptations in the renal vascular resistance ( ; ). Because the changes in resistance that accompany graded reductions in renal perfusion pressure occur in both denervated and isolated perfused kidneys, autoregulation appears not to depend on extrinsic neural or hormonal factors ( ). According to the “myogenic hypothesis” first proposed by , the stimulus for vascular smooth muscle contraction in response to increasing intraluminal pressure is either the transmural pressure itself or the increase in the tension of the vascular wall. An increase in perfusion pressure, which initially distends the vascular wall, is followed by a contraction of the resistance vessels and a return of blood flow to basal levels.

There are only a few studies of autoregulation of RBF in developing animals. Aortic constriction in adult animals reduces renal perfusion by 30% but has minimal effects on RBF and glomerular filtration rate, compared with the significant changes observed in 4- to 5-week-old rats ( ). Furthermore, it has been demonstrated that autoregulation of RBF in young rats occurs at renal perfusion pressures between 70 and 100 mm Hg, compared with pressures of 100 to 130 mm Hg in adult rats ( ). A similar increase in the pressure set point for autoregulation has been found in dogs ( ). It appears that autoregulation of RBF occurs in the very young and is sufficient to maintain blood flow constant over a wide range of perfusion pressures that are physiologically adequate for the age. No such human studies are available.

Several substances have been proposed to participate in the autoregulation of RBF, including vasoconstrictor and vasodilator prostaglandins, kinins, adenosine, vasopressin, the renin-angiotensin-aldosterone system, endothelin, and endopeptidases ( ; ; ; ). Nitric oxide (NO), previously known as endothelium-derived relaxing factor (EDRF), has also been shown to play an important role in regulating renal vascular tone through its vasodilatory action. Bradykinin, thrombin, histamine, serotonin, and acetylcholine act on endothelial receptors to activate phospholipase C, which in turn results in the formation of inositol triphosphate and diacylglycerol, resulting in the release of intracellular calcium ( ; ). This in turn stimulates the synthesis of NO from l -arginine. Other factors that stimulate the formation of NO include hypoxia, calcium ionophores, and mechanical stimuli to the endothelium. NO increases RBF by decreasing efferent arteriolar vascular resistance, whereas glomerular filtration remains unchanged ( ).

Because in mature kidneys, autoregulation is lost at arterial pressures less than 80 mm Hg, the lower physiologic pressures prevailing in the newborn period may be expected to limit this important control mechanism. There is evidence both to support and to refute this conclusion ( ; ).

Renal physiology

The glomerulus is a specialized capillary cluster arranged in loops that functions as a filtering unit. The capillary walls may be viewed as a basement membrane lined by a single layer of cells on either side. In contact with blood are endothelial cells, which contain many fenestrations; podocytes, with their foot processes, line the other side of the basement membrane.

The route by which water and other solutes are filtered from the blood is not fully understood, but it appears that plasma ultrafiltrate traverses the large fenestrations of the glomerular capillary endothelium and penetrates the basement membrane and the slit pores located between the podocyte foot processes. Filtration of large molecules is greatly influenced by the size and charge of the specific molecule, as well as by the integrity and charge of the glomerular basement membrane. Abnormalities in various structural proteins of the slit-pore diaphragm such as nephrin, podocin, and α-actinin may be responsible for several proteinuric disorders ( ). In general, the endothelium and the lamina rara interna of the glomerular basement membrane slow the filtration of circulating polyanions such as albumin ( ). The lamina rara externa and the slit pores slow the filtration of cationic macromolecules such as lactoperoxidase ( ). Neutral polymers such as ferritin are not filtered because of their large molecular size and shape ( ). Molecules with a radius of 4.2 nm or more are excluded from the glomerular filtrate. In practical terms, red cells, white cells, platelets, and most proteins are restricted to the circulation.

Glomerular filtration

Among the main functions performed by the kidneys is the process of glomerular filtration. The glomerulus is primarily responsible for the filtration of plasma. The glomerular filtration rate (GFR) is the product of the filtration rate in a single nephron and the number of such nephrons, which range from 0.7 to 1.4 million in each kidney ( ). Clearance, which is defined as the volume of plasma cleared of a substance within a given time, provides only an estimate or approximation of GFR.

Although tubular reabsorption and tubular secretion may influence the blood level of numerous medications and endogenously produced substances such as urea, creatinine, and uric acid, the degree of elimination of such substances depends largely on GFR. Hence, in individuals with renal impairment, estimation or measurement of GFR is crucial in determining the dosage adjustment and choice of medications needed to achieve effectiveness while avoiding toxicity. GFR is also a major factor that affects electrolyte composition and volume of body fluids, as well as acid-base homeostasis.

Glomerular filtration is driven by hydrostatic pressure, which forces water and small solutes across the filtration barrier. In healthy individuals, changes in hydrostatic pressure rarely affect single-nephron GFR because autoregulatory mechanisms sustain or maintain a constant glomerular capillary pressure over a large range of systemic blood pressure ( ). Hydrostatic pressure is opposed by the oncotic pressure produced by plasma proteins and the hydrostatic pressure within Bowman’s capsule. Mathematically, this relation can be expressed by the equation:

SNGFR is the single-nephron glomerular filtration rate; K _f is the glomerular ultrafiltration coefficient; P and p are the average hydraulic and osmotic pressure differences, respectively; and P _uf is the net ultrafiltration pressure. As plasma water is filtered, the proteins within the capillaries become more concentrated, so oncotic pressure increases at the distal end of the glomerular capillary loop, and the rate of filtration ceases at the efferent capillary ( ). Under normal conditions, about 20% of the plasma water that enters the glomerular capillary bed is filtered; this quantity is referred to as the filtration fraction.

RBF has the greatest influence on GFR. Renal parenchymal disorders interfere with autoregulation of RBF, such that GFR may decrease, even with low-normal mean arterial blood pressure (MABP). Still more pronounced changes in GFR may occur with hypotension or hypertension, which may accelerate ischemic or hypertensive injury. Clearance of a molecule may serve as an indicator of GFR only if the assayed molecule is biologically inert and freely permeable across the glomerular capillary, if it remains unchanged after filtration, and if it is neither reabsorbed nor secreted by the tubule. The exogenous-filtration marker inulin (a fructose polymer) has all of these attributes and is the ideal standard for measuring GFR. However, inulin-clearance measurement is rarely used clinically because it is an expensive and cumbersome method. Instead, measurement of an endogenous small molecule such as serum creatinine (molecular weight, 0.113 kDa), which is derived from muscle metabolism at a relatively constant rate and is freely filtered at the glomerulus, is a practical, rapid, and inexpensive means for estimating GFR, thereby aiding clinical decisions. Thus in the steady state, creatinine production and urinary creatinine excretion are equal even when GFR is reduced.

Serum-creatinine concentrations vary by age and gender. In 1-year-old girls, values are 0.35 ± 0.05 mg/dL (mean ± SD) and rise gradually to 0.7 ± 0.02 mg/dL (mean ± SD) by 17 years of age; boys have corresponding mean values that are 0.05 mg/dL higher until 15 years of age and 0.1 mg/dL higher subsequently ( ). Expected creatinine-excretion rates in 24-hour urine collections are often used to validate such collections. Values range from 8 to 14 mg/kg per day in neonates and in infants younger than 1 year of age, with an increase to about 22 ± 7 mg/kg per day (mean ± SD) in preadolescent children of either gender ( ). Subsequently, creatinine excretion in boys is 27 ± 3.4 mg/kg per day.

In healthy children with proportional height and weight, GFR can be estimated by creatinine clearance (CrCl) as calculated by updated Schwartz’s “bedside” formula, which does not rely on measurement of urinary creatinine or timed urine collections:

Height is in centimeters, S _cr is the serum-creatinine concentration in mg/dL, and k is a constant proportion to muscle mass (0.41). Normal CrCl ranges from 90 to 143 mL/min per 1.73 m ² , with a mean of 120 mL/min per 1.73 m ² ( ).

Although more cumbersome, calculation of CrCl based on values obtained in 12- or 24-hour urine collections provides a better estimate of GFR. Once the completeness of such collections is validated based on expected creatinine excretion, CrCl is calculated using the formula:

where U is the urinary concentration of creatinine in mg/dL, V is the total urine volume in mL, min is the time of collection in minutes, and P _cr is the serum concentration of creatinine in mg/dL. To standardize the clearance of children of different sizes, the calculated result is multiplied by 1.73 m ² (surface area of a standard man in meters squared) and divided by the body surface area of the child in meters squared.

In children with impaired renal function, GFR estimates based on creatinine methods may grossly overestimate the true GFR, because tubular and gastrointestinal secretion of creatinine increases disproportionately. Hence, serum creatinine concentrations are less reflective of filtration at the glomerulus. For example, Schwartz’s formulas overestimate GFR by 10% ± 3% when GFR is greater than 50 mL/min per 1.73 m ² but by 90% ± 15% when GFR is less than 50 mL/min per 1.73 m ² . Other limitations of creatinine-based GFR determinations stem from variations of analytical assays, reference values ranging from 0.1 to 0.6 mg/dL in children younger than 9 years of age, diurnal variation in serum creatinine levels resulting from high intake of cooked meat or intense exercise, influence of body mass index, and inaccurate urine collections—all of which make comparisons of GFR difficult over time, especially in growing children ( ). Using cimetidine to block tubular secretion of creatinine before measuring CrCl in urine collections may improve such measurements ( ).

Measurement of cystatin-C, a 13-kDa serine proteinase produced at a constant rate by all nucleated cells, is purported to be a superior endogenous marker of filtration, because cystatin-C is less susceptible to variation than is plasma creatinine. A meta-analysis compared the correlation between GFR measured by inulin clearance, radiolabeled methods, nonlabeled iothalamate or iohexol, and either plasma creatinine or cystatin-C concentrations measured nephelometrically ( ). The correlation between GFR and cystatin-C was significantly higher compared with plasma creatinine (0.846 versus 0.742, P < 0.001). Thus cystatin-C measurements are becoming increasingly popular in clinical practice, and reference ranges have been generated in children up to 16 years of age ( Table 6.1 ) ( ; ; ; ).

Studies in renal transplant donors and in individuals with various renal disorders have shown that plasma-creatinine concentration changes minimally as GFR falls to about 50 mL/min per 1.73 m ² ( Fig. 6.1 ) ( ). This compensation is largely the result of hypertrophy and hyperfiltration of the remaining nephrons. When more than 50% of the nephrons cease to function and “renal reserve” is outstripped, serum creatinine may rise rapidly in a parabolic fashion (see Fig. 6.1 ). Thus when a more accurate clinical assessment of GFR is desirable for research purposes, radiolabeled methods with an identity exceeding 97% give a better approximation of GFR relative to inulin clearance and may be more useful in aiding clinical decisions. In multicenter investigations conducted in the United States using a uniform method for GFR measurement, ¹²⁵ I-iothalamate is often used because this isotope has low radiation exposure and long isotope half-life and can be assayed at a central laboratory ( ). Otherwise, ^99m Tc-diethylenetriaminepenta-acetic acid (Tc-DTPA) is commonly used to estimate GFR for routine clinical purposes. In other countries, ⁵¹ Cr-ethylenediaminetetra-acetic acid (Cr-EDTA), which delivers a greater radiation dosage, is also popular, as are nonlabeled iothalamate and iohexol methods.

Although GFR may fluctuate, the kidneys retain the ability to regulate the rate of solute and water excretion according to changes in intake. This regulation is achieved by changes in tubular reabsorption rates—a phenomenon known as glomerular-tubular balance ( ). The result is preservation of ECF volume and chemical composition. Glomerular-tubular balance can be disturbed by several factors, including volume expansion, loop diuretics, and inappropriate secretion of antidiuretic hormone (ADH).

Overview of tubular function

The proximal tubule is the site of reabsorption of large quantities of solute and filtered fluid ( Fig. 6.2 ). Many transporters subserving tubular electrolyte transport have been characterized at the genetic level, and various pathologic disorders have been elucidated ( ). Under physiologic conditions, the proximal convoluted tubule isotonically reabsorbs 50% to 60% of the glomerular filtrate ( ). The initial portion of the proximal convoluted tubule reabsorbs most of the filtered glucose, amino acids, and bicarbonate. Glucose and amino acids are absorbed actively, whereby they are transported against their electrochemical gradient, coupled to sodium (Na ⁺ ). Active Na ⁺ transport at the peritubular membrane provides the driving force that ultimately is responsible for other transport processes. The system is driven by Na ⁺ , K ⁺ , (activated) adenosine triphosphatase (Na ⁺ /K ⁺ -ATPase), or the Na ⁺ “pump,” which requires the presence of K ⁺ in the peritubular fluid and is inhibited by ouabain. Micropuncture studies show that around 50% to 70% of the filtered Na ⁺ is reabsorbed in this segment, mostly by a process of active cotransport.

The major fraction of filtered bicarbonate (HCO ₃ ⁻ ) is absorbed early in the proximal convoluted tubule. Hydrogen (H ⁺ ) gains access to luminal fluid via an Na ⁺ /H ⁺ electroneutral exchange mechanism and forms carbonic acid. The latter is dehydrated to H ₂ O and CO ₂ under the influence of carbonic anhydrase. CO ₂ diffuses into the cell, and HCO ₃ ⁻ is reformed and ultimately absorbed into the bloodstream. In general, the concentration of HCO ₃ ⁻ is maintained at 26 mmol/L, which is slightly below the renal threshold of approximately 28 mmol/L ( ).

The renal clearance of glucose is exceedingly low, even after complete maturation of glomerular filtration. The amount filtered increases linearly as plasma glucose increases. Initially, all filtered glucose is reabsorbed until the renal threshold has been exceeded (at around 180 mg/dL), at which point filtered glucose appears in the urine. However, maximal tubular glucose (T _mG ) reabsorption is attained at a filtrate glucose concentration of about 350 mg/mL ( ). The reabsorption of glucose in the proximal tubule occurs via a carrier-mediated, Na ⁺ /glucose cotransport process across the apical membrane, followed by passive facilitated diffusion and active Na ⁺ extrusion across the basolateral membrane.

Apart from Na ⁺ , other solutes reabsorbed in the proximal tubule include K ⁺ , Ca ²⁺ , P ²⁻ , Mg ^{2 +} , and amino acids. These are discussed in detail in other sections of this chapter.

The loop of Henle makes the formation of concentrated urine possible and contributes to the formation of dilute urine ( ). This dual function is achieved through the unique membrane properties of the loop, the postglomerular capillaries, and the hypertonicity of the interstitium. The proximity of the descending and ascending portions of the loop allows it to function as a countercurrent multiplier, whereas the capillaries serve as countercurrent exchangers (see Fig. 6.2 ). The descending loop of Henle abstracts water from tubular fluid, increasing the intraluminal concentrations of NaCl and other solutes. However, the intraluminal osmolality remains in equilibrium with the interstitium, where 50% of the osmolality results from urea. In the thin ascending limb of the loop of Henle, there is passive efflux of NaCl and urea into the interstitium. The thick ascending limb of the loop of Henle, by being impermeable to water, contributes to the formation of dilute urine.

The final creation of hypotonic or hypertonic urine depends on the distal tubules and collecting ducts and their interaction with ADH. In the distal convoluted tubule, Na ⁺ reabsorption occurs against a steep gradient, largely under the influence of aldosterone. K ⁺ is secreted by the distal tubule in association with Na ⁺ reabsorption and H ⁺ secretion. Moreover, this segment of the nephron acidifies the urine and is the only site of new bicarbonate formation. At the end of the collecting duct, about 1% of the filtered water and about 0.5% of the filtered Na ⁺ appear in the final urine.

The kidneys and antidiuretic hormone

ADH plays a pivotal role in water homeostasis by acting on the most distal portion of the nephron. ADH is a cyclic octapeptide that, along with its carrier protein, neurophysin, is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus ( ). The prohormone migrates along the nerve axons to the posterior pituitary gland, where it is stored as arginine vasopressin. It is released through exocytosis ( ).

Several variables affect ADH secretion. Physiologically, the most important factor is plasma osmolality. A very small rise in plasma osmolality is sufficient to trigger a response from the sensitive osmoreceptors located in and around the hypothalamic nuclei, leading to ADH secretion. Conversely, plasma ADH concentrations are less than 1 pg/mL at a physiologic plasma osmolality of less than 280 mOsm/kg water. The antidiuretic activity of ADH is maximal at plasma osmolality of greater than 295 mOsm/kg water, when plasma ADH exceeds 5 pg/mL ( ). Once plasma osmolality exceeds this limit—thus surpassing the capacity of the ADH system to affect maximal fluid retention—the organism depends on thirst to defend against dehydration. Intracerebral synthesis of angiotensin II largely mediates this thirst response and the oropharyngeal reflex. Atrial natriuretic peptide (ANP) opposes the release of ADH and of angiotensin II. In summary, plasma osmolality and Na ⁺ are maintained within a narrow range. The upper limit of this range is determined by the sensitivity of the thirst mechanism located in the hypothalamus, whereas its lower range is affected by ADH release.

Nonosmolar factors also influence ADH secretion and may be the key stimuli of ADH secretion in pathologic disorders, leading to hypovolemia and hypotension. These changes are mediated by low-pressure (located in the left atrium) and high-pressure (located in the carotid sinus) baroreceptors. Experimental studies suggest that this nonosmotic pathway of ADH release is less sensitive than the osmotic pathway and is triggered by a 5% to 10% fall in blood volume, whereas a 1% to 2% increase in ECF osmolality can trigger ADH release.

Euvolemic states of ADH excess can lead to hyponatremia with an elevated fractional excretion of urate (>10%), hypouricemia (serum uric acid level <4 mg/dL), increased urinary sodium excretion (urine sodium >30 mEq/L), and increased fraction excretion of sodium >0.5%) ( ; ). These conditions result in hyponatremia. Conversely, inhibitors of ADH release or primary or acquired nephropathies may result in the inability to respond to ADH or to conserve water, and these inhibitors are often accompanied by polyuria with urine osmolality (U _osm ) of less than 150 mOsm/kg, dehydration, and hypernatremia.

ADH has a major effect on the medullary thick ascending limb and thereby influences the countercurrent multiplier mechanism and urinary concentration. More directly, ADH binds to V ₂ receptors in the basolateral membrane of the collecting duct, causing the activation of adenylate cyclase and the formation of cyclic 3′,5′-adenosine monophosphate (cAMP) ( ; ). This results in the insertion of aquaporin-2 water channels in apical membranes and in the activation of apical Na ⁺ channels, which causes water conservation ( ). These effects are counterbalanced by prostaglandin E ₂ (PGE ₂ ) and the calcium-sensing receptor in cells of the medullary thick ascending limb that mediate saluresis and diuresis.

Polyuric syndromes can be separated on the basis of urine osmolality and generally consist of water diuresis, solute diuresis, or a mixed water-solute diuresis with typical U _osm of less than 150 mOsm/kg, 300 to 500 mOsm/kg and 150 to 300 mOsm/kg, respectively ( ). The etiology of polyuria may be facilitated by obtaining a urinalysis; a measurement of urine pH; and measurements of electrolytes, creatinine, osmolality, glucose, urea nitrogen, and bicarbonate, preferably in a timed urine collection together with the corresponding serum values. Such assessment may serve to prevent dehydration, acid-base disturbances, hypokalemia, or hypernatremia, which often accompany such polyuric disorders ( Table 6.2 ) ( ). Proper correction of acute hypernatremia is needed to prevent brain demyelination. Normal saline infusion may be the agent of choice in polyuric conditions associated with solute diuresis, whereas ADH and electrolyte-free fluid administration may be appropriate in cases of “pure” water diuresis. The recommended rate of correction of hypernatremia is about 10 mEq/L per 24 hours, amounting to a fall in plasma osmolality of about 20 mOsm/kg H ₂ O per day ( ).

Renin-angiotensin-aldosterone system

The renin-angiotensin-aldosterone axis plays a key role in control of vascular tone, Na ⁺ and K ⁺ homeostasis, and, ultimately, circulatory volume and cardiovascular and renal function. Renin is an enzyme with a molecular weight of 40 kDa that is synthesized and stored in the juxtaglomerular apparatus surrounding the afferent arterioles of the glomeruli ( ). The primary stimuli for renal renin release are reductions in renal-perfusion pressure, Na ⁺ restriction, and Na ⁺ loss as detected by the specialized macula densa cells located in the distal tubule. Mechanical (stretch of the afferent glomerular arterioles), neural (sympathetic nervous system), and hormonal (PGE ₂ and prostacyclin) stimuli act in an integrated fashion to regulate the rate of renin secretion ( Fig. 6.3 ).

Once released into the circulation, renin cleaves the leucine-valine bond of angiotensinogen, forming angiotensin I. Angiotensin-converting enzyme that is present in the lungs, kidneys, large caliber vessels, and other tissues cleaves the carboxyl terminal (histidine-leucine dipeptide) from angiotensin I to form the biologically active angiotensin II ( ).

Angiotensin II has numerous important hemodynamic functions that are mediated largely by binding to angiotensin-II T1 receptors in endothelial cells, tubular epithelial cells, and smooth muscle ( Box 6.1 ) ( ). It plays a key role in regulating blood volume and long-term blood pressure through stimulation of several tubular transporters of Na ⁺ that are mainly located in the proximal tubule and through its effects in enhancing aldosterone secretion and Na ⁺ reabsorption in the distal tubule. As a potent direct smooth-muscle vasoconstrictor and as an enhancer of ADH and sympathetic nervous system activity, angiotensin II also participates in short-term blood pressure regulation in disorders associated with volume depletion or circulatory depression. Research has uncovered multiple nonhemodynamic functions that are primarily mediated by binding to T1 receptors of angiotensin II, which are particularly important in the pathophysiology of progressive renal injury ( ).

A rise in plasma aldosterone concentration stimulates urinary K ⁺ secretion, thus allowing maintenance of K ⁺ balance. Aldosterone also increases the excretion of ammonium (NH ⁴⁺ ) and magnesium (Mg ²⁺ ) and increases the absorption of Na ⁺ in the distal tubule, both by increasing the permeability of the apical membrane and by increasing the activity of Na ⁺ , K ⁺ -adenosine triphosphatase (ATPase) ( ). The net effect is to generate more negative potential in the lumen, a driving force for increased K ⁺ secretion. In addition, aldosterone enhances reabsorption of sodium in the cortical collecting duct through activation of the epithelial sodium-specific channel (ENaC) ( ). In performing these functions, aldosterone plays a key role in regulating fluid and electrolyte balance. Long-term aldosterone administration to healthy volunteers increases the ECF volume. Clinical edema does not occur, however, because after several days, the kidneys “escape” from the Na ⁺ -retaining effect while maintaining the K ⁺ -secretory effect ( ).

The kidneys and atrial natriuretic peptide

ANP is secreted by atrial monocytes in response to local stretching of the atrial wall in cases of hypervolemia (e.g., congestive heart failure or renal failure) and ultimately results in the reduction of intravascular volume and systemic blood pressure ( ). In the kidneys, ANP acts in the medullary collecting duct to inhibit sodium reabsorption during ECF expansion. ANP induces hyperfiltration, natriuresis, and suppression of renin release, and it inhibits receptor-mediated aldosterone biosynthesis ( ). In the cardiovascular system, it diminishes cardiac output and stroke volume and reduces peripheral vascular resistance. Some of these effects are mediated through the influence of ANP on vagal and sympathetic nerve activity.

Body fluid compartments

The internal environment of the body consists of fluids contained within compartments. Water accounts for 50% to 80% of the human body by weight. The variation in water content depends on tissue type: Adipose tissue contains only 10% water, whereas muscle contains 75% water. Total body water (TBW) decreases with age, mainly as a result of loss of water in ECF. For clinical purposes, TBW is estimated at 60% of body weight in infants older than age 6 months, as well as in children and adolescents. This value is very inaccurate for low-birth-weight premature infants, in whom TBW constitutes as much as 80% of total body weight ( ; ). In term infants younger than 6 months of age, TBW may be approximated as 75% of total body weight ( ). Newer formulas that consider the height (cm) and weight (kg) but not the degree of adiposity or the child’s surface area have improved the estimation of TBW, particularly in healthy children between 3 months and 13 years of age ( ; ). TBW can be determined as follows:

Parenteral and oral fluids and electrolytes

Except for the first 3 postnatal days when full-term neonates require only 40 to 60 mL/kg fluid per day, in general, 100 mL of water is needed for each 100 kcal expended. Notably, an additional 15 mL of water is generated endogenously for each 100 kcal used (water of oxidation), which is also available for body functions. In preterm infants, fluid intake may be gradually increased to 150 mL/kg per day, whereas 100 to 125 mL/kg per day generally suffices for infants weighing less than 10 kg. The fluid requirement decreases to 50 mL/kg per day for those weighing 11 to 20 kg and to 20 mL/kg per day for those with body weights above 20 kg, thus the derivation of the 4, 2, 1 rule for calculating fluid maintenance. These fluid volumes are sufficient to allow excretion of dietary solute load and to replace insensible fluid loss through the skin, lungs, and intestines ( Table 6.5 ) ( ). It should be noted that energy expenditure and, therefore, fluid intake may be significantly increased with stress ( Table 6.6 ) ( ).

The high fractional excretion of Na ⁺ (FE _{Na +} ) in premature infants can lead to negative Na ⁺ balance, hyponatremia, neurologic disturbances, and poor growth unless an Na ⁺ intake of 3 to 5 mmol/kg per day is given; in full-term infants and older children, 2 to 3 mmol/kg per day is sufficient ( ). Premature infants have a lower renal threshold for bicarbonate. In addition, several functional and anatomic factors combine to limit tubular excretion of weak organic acids ( ). Consequently, premature infants may need small supplements of base. Sodium bicarbonate at 1 to 2 mmol/kg per day is generally recommended for the very small premature infant. Clinically important disturbances in acid-base status are unusual in full-term neonates unless they consume excessive amounts of protein.

Evaluation and management of dehydration

The clinical signs of dehydration are a manifestation of extracellular volume depletion ( Table 6.7 ). Three factors determine the amount of extracellular volume depletion and therefore the severity of dehydration: fluid deficit, electrolyte deficit, and the speed with which dehydration occurs. The fluid deficit or antecedent deficit is the total amount of body water lost expressed as a percent decrease in body weight and can be estimated based on physical findings. The serum sodium can be normal, high, or low in children with dehydration. The severity of dehydration is affected by the electrolyte deficit, which is reflected in the serum sodium. In general, the electrolyte deficit parallels extracellular fluid losses. Therefore for the same fluid deficit, the severity of extracellular volume depletion is inversely proportional to the serum sodium. Stated differently, given the same volume loss, hyponatremic dehydration results in more severe signs than hypernatremic dehydration. Signs of volume depletion are less pronounced in patients with hypernatremia due to better preservation of the extracellular volume. This is the basis for classifying dehydration according to the serum sodium as isonatremic (130–150 mEq/L), hyponatremic (<130 mEq/L), or hypernatremic (>150 mEq/L). Isonatremic dehydration is the most commonly encountered in approximately 70% to 80% of children, followed by hyponatremic in 15% and hypernatremic in 5%. The most important factor that will determine the type of dehydration is the amount of oral intake to balance the free water losses. In most instances the amount of free water losses and free water ingested are of similar magnitude, resulting in little change in serum sodium. In infants where water intake may be decreased due to limited access or vomiting, free water losses will result in hypernatremic dehydration. In older children who may be able to satisfy their thirst or who are taking very hypotonic oral fluids, free water intake in excess of free water losses will result in hyponatremic dehydration. This is exacerbated by the stimulation of AVP secretion due to the intravascular volume depletion.

The primary goal of rehydration is to rapidly expand the intravascular volume to reestablish hemodynamic stability and tissue perfusion. If dehydration is severe, this is done by administering 20 to 40 mL/kg of a balanced salt solution (0.9% sodium chloride, plasmalyte, or lactated Ringer’s solution) rapidly and repeating the bolus fluid administration as necessary until the patient is hemodynamically stable. Further volume depletion can generally be corrected by administering 40 mL/kg of 0.9% sodium chloride over 2 to 4 hours, followed by administering the remainder of the deficit and maintenance as 0.9% sodium chloride. Caution must be taken to avoid hypotonic fluids such as 0.45% and 0.22% sodium chloride until the dehydration is corrected and AVP secretion is no longer stimulated. Hypotonic fluids may be necessary AFTER the initial phase of fluid therapy if hypernatremia is present and is associated with ongoing free water losses from high fever, voluminous diarrhea, or a renal concentrating defect such as congenital nephrogenic diabetes insipidus or renal dysplasia. Hypotonic fluids may also be required in a child with severe hyponatremic dehydration (Na <120 mEq/L) after the initial therapy with 0.9% sodium chloride. The hypotonic solution is used in order to prevent rapid correction of hyponatremia from a free water diuresis. In addition to intravenous fluid administration, oral rehydration solutions are an effective therapy for mild to moderate dehydration. The compositions of select parenteral solutions are shown in Table 6.8 .

In most infants and children receiving parenteral solutions for brief periods, the normal fluid and electrolyte needs can be easily satisfied. The caloric needs, however, are not readily met. It is customary to provide 5% dextrose in parenteral solutions. Although this concentration provides only a fraction of the optimal number of calories (20% of total kilocalories needed by infants younger than 1 year of age), it is sufficient to prevent ketosis. In less mature neonates, higher infusion rates of 5% dextrose generally suffice to maintain blood glucose concentrations between 50 and 90 mg/dL ( ; ).

Provided that infants and children are less than 10% dehydrated and have minimal electrolyte abnormalities, a good level of consciousness, adequate bowel sounds, and absence of signs of hypovolemia, oral rehydration may be used to replace deficits and maintain fluid volume. Commercially available preparations, such as Pedialyte RS (Ross) with an Na ⁺ content of 45 mmol/L may be used. In children with diarrhea in developing countries, the World Health Organization (WHO) has recommended the use of an inexpensive and effective oral rehydration solution consisting of 90 mmol/L Na ⁺ and 111 mmol/L of glucose (total osmolarity, 311 mOsmol/L). However, glucose-based solutions with a lower osmolality may further optimize fluid and glucose-sodium coupled absorption in the small intestine ( ).

Isotonic solution versus balanced solution for fluid resuscitation and in the perioperative setting

There has been a growing concern that 0.9% sodium chloride has a supraphysiologic chloride concentration and may result in untoward complications such as hyperchloremic metabolic acidosis, renal vasoconstriction, delayed micturition, hyperkalemia, an increased incidence of acute kidney injury, and the need for renal-replacement therapy ( ). The benefit of balanced solutions over isotonic saline seems to be primarily in critically ill adult patients with sepsis and those with preceding acute kidney injury and previous renal replacement therapy ( ; ). It is unclear if this is applicable to children with volume depletion. Balanced solutions differ from normal saline primarily in having variable amounts of a buffering agent, such as lactate, acetate, or gluconate. Balanced solutions do not have bicarbonate as it is not stable in polyvinyl chloride bags. Balanced solutions also have variable amounts of potassium, calcium, and magnesium and have a lower sodium concentration and osmolarity in comparison to normal saline ( Table 6.8 ). A solution of 0.9% sodium chloride (Na 154 mmol/L) has a higher sodium concentration than plasma but results in normal osmolarity, whereas Plasma-Lyte (Na 140 mmol/L) and lactated Ringer’s (Na 130 mmol/L) are slightly hypotonic in relationship to plasma. Lactated Ringer’s in particular may aggravate hyponatremia and should be avoided in hyponatremic patients or those at high risk for cerebral edema. It has not been clearly established that balanced solutions are superior to 0.9% sodium chloride for fluid resuscitation or in the perioperative state, with large clinical trials yielding conflicting results. The Saline Against Lactated Ringers or Plasma-Lyte in the Emergency Department (SALT-ED) and Isotonic Solutions and Major Adverse Renal Events (SMART) trials were able to demonstrate a 1% decrease in a composite of major kidney events ( ; ). The Saline versus Plasma-Lyte 148 for ICU Fluid Therapy (SPLIT) and the Saline or Lactated Ringer’s (SOLAR) trial were unable to determine a clinically meaningful difference between the two solutions, as was a recent Cochrane review ( ; see also ; ). At the current moment, both fluids are appropriate for resuscitation and perioperative fluid management.

Perioperative fluid management of premature and full-term neonates

Guidelines for the intraoperative fluid and electrolyte management of premature and full-term neonates are largely based on available knowledge of renal physiology rather than on data obtained from clinical investigations (see Chapter 27 , “Neonatology for Anesthesiologists”). The physiology of the healthy neonate is influenced by the short tubular length and is characterized by immature reabsorption mechanisms, an activated renin-angiotensin-aldosterone system, and low circulating ADH concentrations ( ; ). Thus healthy preterm neonates weighing less than 1300 g, or of fewer than 32 weeks’ gestation, have FE _{Na +} rates that range from 8.2% to 2.1% between 28 and 32 weeks’ gestation, with further gradual decrease to less than 1% at term; such rates may increase to 15% with stress ( ; ). The high FE _{Na +} in preterm infants is ascribed to decreased Na ⁺ reabsorption in the proximal tubule, together with hyporesponsiveness of the distal tubule to aldosterone ( ). When combined with a negative Na ⁺ balance that results from inadequate Na ⁺ supplementation and decreased sensitivity of the collecting duct to ADH, up to one-third of such infants develop significant hyponatremia (Na ⁺ <130 mEq/L), often manifesting with neurologic disturbances during the first 6 weeks of life ( ).

Both premature and term neonates have a limited capacity to excrete K ⁺ , possibly because of distal tubular insensitivity to aldosterone. Hence, baseline reference plasma K ⁺ concentrations range from 3.9 to 5.9 mEq/L. Moreover, both preterm and term neonates are capable of producing maximally diluted urine while concentrating capacity is limited. Yet hyponatremia may develop after administration of large volumes of hypotonic fluids, because fluid excretion may be limited mainly because of low GFR. Stress may cause profound reduction in GFR in premature and term neonates through release of various extrarenal vasoactive and hormonal substances that modify the response of “immature kidneys,” thereby further disturbing fluid and electrolyte homeostasis. The higher body content of water and the higher metabolic rate, as well as a propensity to metabolic acidosis and hypocalcemia in premature newborns, are other important factors in deciding the volume and composition of intraoperative fluids.

Such considerations support the avoidance of boluses of hypotonic fluids, while keeping in mind the lower age- and size-appropriate circulatory pressures that may serve as the goal of fluid management. In the absence of the expected physiologic fluid loss, which may range from 5% to 15% of body weight during the first 3 days of postnatal life, fluid volume during this time period may be limited to 60 mL/kg per day, whereas blood pressure support may be sustained with small infusions (5 mL/kg) of 5% albumin or other blood products as needed. Beyond 3 days of life, maintenance fluid volume is gradually increased to 150 mL/kg per day. Deficits beyond the expected physiologic losses and ongoing losses and allowance for surgical trauma may be replaced by a similar fluid composition, but the volume replacement may be more gradual or less rapid than outlined for older infants and children (see Table 6.9 ). Na ⁺ bicarbonate and calcium may be supplemented, whereas K ⁺ should be limited. Also, a higher glucose concentration is generally desirable in premature infants. Prospective studies have demonstrated the safety of using isotonic fluids in neonates ( ).

Fluid management of children undergoing renal transplantation

The key goal of intraoperative management is to expand the circulatory volume and to maintain systemic blood pressure between the 90th and 95th percentiles for age, gender, and height percentile, so as to allow for adequate perfusion of the renal allograft ( ). Regarding fluid management, there is no difference between a cadaveric and a living related renal transplant (see Chapter 38 , “Solid Organ Transplantation”). An adult kidney may sequester up to 250 mL of blood, and in infants, nearly 50% of the cardiac output may be directed toward perfusion of the allograft. To ensure adequate perfusion of the allograft, the anesthesiologist actually needs to maximize the circulatory volume of the recipient, mainly with crystalloid or packed cytomegalovirus-safe, leukocyte-poor red blood cells if hemoglobin is below 9 g/dL, while closely monitoring the central venous pressure (CVP) and systemic MABP during vessel anastomosis. Near the completion of the vascular anastomoses, 20% mannitol (0.5 to 1.0 g/kg) and intravenous furosemide (1 mg/kg) may be given before the cross-clamps are released. Before cross-clamp release, CVP should be maintained at 8 to 12 cm H ₂ O (some have suggested as much as 18 to 20 cm H ₂ O), and the systolic blood pressure and MABP should be kept above 120 mm Hg and 70 mm Hg, respectively. If the MABP is inadequate to achieve good renal perfusion of the adult kidneys, a constant dopamine infusion of up to 5 mcg/kg per minute may be started. Intraoperative blood gases may be monitored frequently, because clamping of the aorta and accumulation of lactic acid can result in metabolic acidosis and vasoconstriction. The critical goal is to obtain immediate allograft function; hypotension after cross-clamp release in an infant with inadequate circulatory volume and an underperfused allograft is a potential catastrophe ( ).

Intravenous furosemide (1 to 2 mg/kg per dose), 25% salt-poor albumin (0.5 g/kg per dose), 20% mannitol (0.3 to 0.5 g/kg per dose), or isotonic solutions (10 mL/kg bolus) may be given to help promote urine output in the immediate postoperative period.

The volume and composition of intravenous fluid administered during the first 48 postoperative hours are essential to ensure continued renal function. The urine output often exceeds 5 mL/kg per hour. Thus insensible losses are quantitatively less important. Urine output is replaced on a milliliter-for-milliliter basis for approximately the first 24 hours postoperative and then can be changed to a fixed rate thereafter. In infants and children with body weight below 30 kg, the CVP should be maintained in the range of 5 to 10 cm H ₂ O, and the MABP should be at greater than 70 mm Hg. One fluid solution that may be used during the first 24 to 48 hours consists of 1% dextrose, 0.45 mEq/L NaCl solution, and 10 to 20 mEq sodium bicarbonate per liter. During the first 24 to 36 hours, additional fluid boluses of 10 mL/kg of normal saline or a 5% albumin solution may be given if CVP falls below 5 cm H ₂ O, with the goal of maintaining a urine output above certain arbitrary limits (5, 4, and 3 mL/kg per hour for body weight <10 kg, <20 kg, and <30 kg, respectively). It should be noted that excess fluid replacement with 0.45% NaCl has resulted in hyponatremic encephalopathy ( ). In conjunction with such fluid boluses, intravenous furosemide (1 mg/kg) is also administered because renal allografts tend to be dependent on diuretics in the early perioperative setting.

Serum electrolytes (Na ⁺ , K ⁺ , Cl ⁻ , HCO ₃ ⁻ , Ca ²⁺ , P ²⁻ , Mg ²⁺ ) may be monitored at 8- to 12-hour intervals during the first 2 postoperative days. Potassium chloride is given separately as needed when the plasma K ⁺ decreases below 3.5 mEq/L. In infants and young children, close monitoring of fluid balance and cardiovascular examination are essential to prevent electrolyte imbalance and fluid overload, which may result in severe hypertension or pulmonary edema or in reduction of intravascular volume and acute tubular necrosis (ATN). A bladder catheter inserted intraoperatively is necessary for accurate measurement of urine volume. Unless there are specific urologic indications, the catheter is removed after 4 to 5 days.

Immediate measures must be undertaken to improve postoperative oliguria. Besides the most easily correctable causes of oliguria, such as hypovolemia or a malfunctioning catheter, other potential causes include vascular bleeding or occlusion, ATN caused by prolonged cold ischemia storage, hyperacute rejection, or urinary extravasation or obstruction. In patients with oxalosis, precipitation of calcium oxalate crystals in the graft may cause acute allograft failure. Children with delayed graft function, congestive heart failure, or marked electrolyte abnormalities may require removal of fluid by hemodialysis or peritoneal dialysis. Fluid removal should be performed cautiously to avoid allograft hypoperfusion.

Hyponatremia

Hyponatremia, defined as a serum less than 135 mEq/L, is a common disorder that occurs in both the outpatient and inpatient settings ( Table 6.10 ) ( ). The body’s primary defense against developing hyponatremia is the kidney’s ability to generate a dilute urine and excrete free water. Rarely is excess ingestion of free water alone the cause of hyponatremia, as an adult with normal renal function can typically excrete over 15 L of free water per day. It is also rare to develop hyponatremia from excess urinary sodium losses in the absence of free water ingestion. For hyponatremia to develop, it typically requires a relative excess of free water in conjunction with an underlying condition that impairs the kidney’s ability to excrete free water. Renal water handling is primarily under the control of arginine vasopressin (AVP), which is produced in the hypothalamus and released from the posterior pituitary. AVP release impairs water diuresis by increasing the permeability to water in the collecting tubule. There are osmotic, hemodynamic, and nonhemodynamic stimuli for AVP release. In most cases of hyponatremia, there is a stimulus for vasopressin production that results in impaired free water excretion. The body will attempt to preserve the extracellular volume at the expense of the serum sodium, so a hemodynamic stimulus for AVP production will override an inhibitory effect of hyponatremia. There are numerous stimuli for AVP production that occur in hospitalized patients, so all hospitalized patients are at risk for hyponatremia.

Hypernatremia

Hypernatremia is defined as a serum sodium greater than 145 mEq/L. In both children and adults hypernatremia is primarily seen in the hospital setting in individuals who have restricted access to water for a variety of reasons ( ). In most instances these patients are either debilitated by an acute or chronic illness or neurologic impairment or are at the extremes of age. Hypernatremia is a particularly common problem in the intensive care unit because most patients are either intubated or moribund and have restricted access to fluids. Additional contributing factors for hypernatremia in the intensive care setting are excess sodium administration, renal concentrating defects, gastrointestinal fluid losses, and dialysis-related complications. A serum sodium greater than 145 mmol/L should always be considered abnormal and evaluated thoroughly to prevent the development of significant hypernatremia.