Diseases of Water MetabolismSumit Kumar Tomas Berl

T

he maintenance of the tonicity of body fluids within a very narrow physiologic range is made possible by homeostatic mechanisms that control the intake and excretion of water. Critical to this process are the osmoreceptors in the hypothalamus that control the secretion of antidiuretic hormone (ADH) in response to changes in tonicity. In turn, ADH governs the excretion of water by its end-organ effect on the various segments of the renal collecting system. The unique anatomic and physiologic arrangement of the nephrons brings about either urinary concentration or dilution, depending on prevailing physiologic needs. In the first section of this chapter, the physiology of urine formation and water balance is described. The kidney plays a pivotal role in the maintenance of normal water homeostasis, as it conserves water in states of water deprivation, and excretes water in states of water excess. When water homeostasis is deranged, alterations in serum sodium ensue. Disorders of urine dilution cause hyponatremia. The pathogenesis, causes, and management strategies are described in the second part of this chapter. When any of the components of the urinary concentration mechanism is disrupted, hypernatremia may ensue, which is universally characterized by a hyperosmolar state. In the third section of this chapter, the pathogenesis, causes, and clinical settings for hypernatremia and management strategies are described.

CHAPTER

1

1.2

Disorders of Water, Electrolytes, and Acid-Base

Physiology of the Renal Diluting and Concentrating MechanismsFIGURE 1-1 Principles of normal water balance. In most steady-state situations, human water intake matches water losses through all sources. Water intake is determined by thirst (see Fig. 1-12) and by cultural and social behaviors. Water intake is finely balanced by the need to maintain physiologic serum osmolality between 285 to 290 mOsm/kg. Both water that is drunk and that is generated through metabolism are distributed in the extracellular and intracellular compartments that are in constant equilibrium. Total body water equals approximately 60% of total body weight in young men, about 50% in young women, and less in older persons. Infants total body water is between 65% and 75%. In a 70-kg man, in temperate conditions, total body water equals 42 L, 65% of which (22 L) is in the intracellular compartment and 35% (19 L) in the extracellular compartment. Assuming normal glomerular filtration rate to be about 125 mL/min, the total volume of blood filtered by the kidney is about 180 L/24 hr. Only about 1 to 1.5 L is excreted as urine, however, on account of the complex interplay of the urine concentrating and diluting mechanism and the effect of antidiuretic hormone to different segments of the nephron, as depicted in the following figures.

Normal water intake (1.01.5 L/d)

Water of cellular metabolism (350500 mL/d) Intracellular compartment (27 L) Extracellular compartment (15 L) Total body water 42L (60% body weight in a 70-kg man)

Fixed water excretion

Variable water excretion

Filtrate/d 180L Stool 0.1 L/d Sweat 0.1 L/d Pulmonary 0.3 L/d

Total insensible losses ~0.5 L/d

Total urine output 1.01.5 L/d

Water excretion

Water intake and distribution

Diseases of Water Metabolism

1.3

GFR

Determinants of delivery of NaCl to distal tubule: GFR Proximal tubular fluid and solute (NaCl) reabsorption

;; ;;

Water delivery NaCl movement Solute concentration

;;;;;;;;;;;;;;; ;;;;;;;;;;; ;;;;;;;;;;;;;;; ;;;;;;;;;;;;;;; ;;;;;;;;;;;;;;; ;;;;;;;;;;;;;;; ;;;;;;;;;;;;;;; ;;;;;;;;;;;;;;; ;;;;;;;;;;;;;;; ;;;; ;;;;;;;;;;;;;;; ;;;; ;;;;;;;;;;; ;;;; ;;;;;;;;;;; ;;;; ;;; ;;;;;;;;;;; ;;;; ;;; ;;;;;;;;;;; ;;;; ;;; ;;;;;;;;;;; ;;;; ;;; ;;;; ;;; ;;;NaCl H 2OH 2O

Generation of medullary hypertonicity Normal function of the thick ascending limb of loop of Henle Urea delivery Normal medullary blood flow

ADH

ADH H 2O

NaCl NaCl NaCl NaCl

NaCl NaCl

H 2O

ADH H 2O

H 2O

H 2O

H 2O

Collecting system water permeability determined by Presence of arginine vasopressin Normal collecting system

FIGURE 1-2 Determinants of the renal concentrating mechanism. Human kidneys have two populations of nephrons, superficial and juxtamedullary. This anatomic arrangement has important bearing on the formation of urine by the countercurrent mechanism. The unique anatomy of the nephron [1] lays the groundwork for a complex yet logical physiologic arrangement that facilitates the urine concentration and dilution mechanism, leading to the formation of either concentrated or dilute urine, as appropriate to the persons needs and dictated by the plasma osmolality. After two thirds of the filtered load (180 L/d) is isotonically reabsorbed in the proximal convoluted tubule, water is handled by three interrelated processes: 1) the delivery of fluid to the diluting segments; 2) the separation of solute and water (H2O) in the diluting segment; and 3) variable reabsorption of water in the collecting duct. These processes participate in the renal concentrating mechanism [2].1. Delivery of sodium chloride (NaCl) to the diluting segments of the nephron (thick ascending limb of the loop of Henle and the distal convoluted tubule) is determined by glomerular filtration rate (GFR) and proximal tubule function. 2. Generation of medullary interstitial hypertonicity, is determined by normal functioning of the thick ascending limb of the loop of Henle, urea delivery from the medullary collecting duct, and medullary blood flow. 3. Collecting duct permeability is determined by the presence of antidiuretic hormone (ADH) and normal anatomy of the collecting system, leading to the formation of a concentrated urine.

1.4

Disorders of Water, Electrolytes, and Acid-BaseFIGURE 1-3 Determinants of the urinary dilution mechanism include 1) delivery of water to the thick ascending limb of the loop of Henle, distal convoluted tubule, and collecting system of the nephron; 2) generation of maximally hypotonic fluid in the diluting segments (ie, normal thick ascending limb of the loop of Henle and cortical diluting segment); 3) maintenance of water impermeability of the collecting system as determined by the absence of antidiuretic hormone (ADH) or its action and other antidiuretic substances. GFRglomerular filtration rate; NaClsodium chloride; H2Owater.

GFR

Determinants of delivery of H2O to distal parts of the nephron GFR Proximal tubular H2O and NaCl reabsorption

;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;;NaCl H 2O NaCl NaCl NaCl NaCl H 2O H 2O H 2O H 2O Collecting duct impermeability depends on Absence of ADH Absence of other antidiuretic substances H 2O Distal tubule Urea

Normal functioning of Thick ascending limb of loop of Henle Cortical diluting segment

Impermeable collecting duct

Cortex Na+ K+ 2Cl2 NaCl Na+ K+ 2Cl2 H 2O Urea

H 2O

2 H 2O

Na+ 1 K+ 2Cl2 Na+ K+ 2Cl2 Urea Outer medullary collecting duct

Outer medulla

H 2O 4 3 H 2O Urea NaCl NaCl 5 NaCl Inner medulla Loop of Henle

Inner medullary collecting duct

Urea

Collecting tubule

FIGURE 1-4 Mechanism of urine concentration: overview of the passive model. Several models of urine concentration have been put forth by investigators. The passive model of urine concentration described by Kokko and Rector [3] is based on permeability characteristics of different parts of the nephron to solute and water and on the fact that the active transport is limited to the thick ascending limb. 1) Through the Na+, K+, 2 Cl cotransporter, the thick ascending limb actively transports sodium chloride (NaCl), increasing the interstitial tonicity, resulting in tubular fluid dilution with no net movement of water and urea on account of their low permeability. 2) The hypotonic fluid under antidiuretic hormone action undergoes osmotic equilibration with the interstitium in the late distal tubule and cortical and outer medullary collecting duct, resulting in water removal. Urea concentration in the tubular fluid rises on account of low urea permeability. 3) At the inner medullary collecting duct, which is highly permeable to urea and water, especially in response to antidiuretic hormone, the urea enters the interstitium down its concentration gradient, preserving interstitial hypertonicity and generating high urea concentration in the interstitium. (Legend continued on next page)

Diseases of Water MetabolismFIGURE 1-4 (continued) 4) The hypertonic interstitium causes abstraction of water from the descending thin limb of loop of Henle, which is relatively impermeable to NaCl and urea, making the tubular fluid hypertonic with high NaCl concentration as it arrives at the bend of the loop of

1.5

Henle. 5) In the thin ascending limb of the loop of Henle, NaCl moves passively down its concentration gradient into the interstitium, making tubular fluid less concentrated with little or no movement of water. H2Owater. FIGURE 1-5 Pathways for urea recycling. Urea plays an important role in the generation of medullary interstitial hypertonicity. A recycling mechanism operates to minimize urea loss. The urea that is reabsorbed into the inner medullary stripe from the terminal inner medullary collecting duct (step 3 in Fig. 1-4) is carried out of this region by the ascending vasa recta, which deposits urea into the adjacent descending thin limbs of a short loop of Henle, thus recycling the urea to the inner medullary collecting tubule (pathway A). Some of the urea enters the descending limb of the loop of Henle and the thin ascending limb of the loop of Henle. It is then carried through to the thick ascending limb of the loop of Henle, the distal collecting tubule, and the collecting duct, before it reaches the inner medullary collecting duct (pathway B). This process is facilitated by the close anatomic relationship that the hairpin loop of Henle and the vasa recta share [4].

Cortex Urea

Urea

Urea

Urea Outer stripe Inner stripe Urea

Outer medulla

Urea

Collecting duct

Urea Urea Ascending vasa recta Pathway A Pathway B Urea Inner medulla

150020 mL 0.3 mL

1200 Osmolality, mOsm/kg H2O

900

600

300100 mL 30 mL 20 mL

Maximal ADH 2.0 mL no ADH 16 mL

0 Proximal tubule Loop of Henle Distal tubule and cortical collecting tubule Outer and inner medullary collecting ducts

FIGURE 1-6 Changes in the volume and osmolality of tubular fluid along the nephron in diuresis and antidiuresis. The osmolality of the tubular fluid undergoes several changes as it passes through different segments of the tubules. Tubular fluid undergoes marked reduction in its volume in the proximal tubule; however, this occurs iso-osmotically with the glomerular filtrate. In the loop of Henle, because of the aforementioned countercurrent mechanism, the osmolality of the tubular fluid rises sharply but falls again to as low as 100 mOsm/kg as it reaches the thick ascending limb and the distal convoluted tubule. Thereafter, in the late distal tubule and the collecting duct, the osmolality depends on the presence or absence of antidiuretic hormone (ADH). In the absence of ADH, very little water is reabsorbed and dilute urine results. On the other hand, in the presence of ADH, the collecting duct, and in some species, the distal convoluted tubule, become highly permeable to water, causing reabsorption of water into the interstitium, resulting in concentrated urine [5].

1.6

Disorders of Water, Electrolytes, and Acid-BaseParaventricular neurons Baroreceptors Supraoptic neuron SON

Osmoreceptors Pineal Third ventricle VP,NP Tanycyte

Optic chiasm Superior hypophysial artery Portal capillaries in zona externa of median eminence Long portal vein Systemic venous system Anterior pituitary Short portal vein VP,NP Mammilary body Posterior pituitary

VP,NP

FIGURE 1-7 Pathways of antidiuretic hormone release. Antidiuretic hormone is responsible for augmenting the water permeability of the cortical and medullary collecting tubules, thus promoting water reabsorption via osmotic equilibration with the isotonic and hypertonic interstitium, respecively. The hormone is formed in the supraoptic and paraventricular nuclei, under the stimulus of osmoreceptors and baroreceptors (see Fig. 1-11), transported along their axons and secreted at three sites: the posterior pituitary gland, the portal capillaries of the median eminence, and the cerebrospinal fluid of the third ventricle. It is from the posterior pituitary that the antidiuretic hormone is released into the systemic circulation [6]. SONsupraoptic nucleus; VPvasopressin; NPneurophysin.

Exon 1

Exon 2

Exon 3

Pre-pro-vasopressin (164 AA)

AVP Signal peptide

Gly

Lys

Arg

Neurophysin II

Arg

Glycopeptide

(Cleavage site)

Pro-vasopressin

AVP

Gly

Lys

Arg

Neurophysin II

Arg

Glycopeptide

Products of pro-vasopressin

AVP

NH2

+

Neurophysin II

+

Glycopeptide

FIGURE 1-8 Structure of the human arginine vasopressin (AVP/antidiuretic hormone) gene and the prohormone. Antidiuretic hormone (ADH) is a cyclic hexapeptide (mol. wt. 1099) with a tail of three amino acids. The biologically inactive macromolecule, pre-pro-vasopressin is cleaved into the smaller, biologically active protein. The protein of vasopressin is translated through a series of signal transduction pathways and intracellular cleaving. Vasopressin, along with its binding protein, neurophysin II, and the glycoprotein, are secreted in the form of neurosecretory granules down the axons and stored in nerve terminals of the posterior lobe of the pituitary [7]. ADH has a short half-life of about 15 to 20 minutes and is rapidly metabolized in the liver and kidneys. Glyglycine; Lyslysine; Argarginine.

Diseases of Water Metabolism

1.7

AQP-3 Recycling vesicle Endocytic retrieval AQP-2 AQP-2 PKA Gs Gs AQP-2 Exocytic insertion Recycling vesicle H 2O

cAMP ATP

AVP

AQP-4 Basolateral Luminal

FIGURE 1-9 Intracellular action of antidiuretic hormone. The multiple actions of vasopressin can be accounted for by its interaction with the V2 receptor found in the kidney. After stimulation, vasopressin binds to the V2 receptor on the basolateral membrane of the collecting duct cell. This interaction of vasopressin with the V2 receptor leads to increased adenylate cyclase activity via the stimulatory G protein (Gs), which catalyzes the formation of cyclic adenosine 3, 5monophosphate (cAMP) from adenosine triphosphate (ATP). In turn, cAMP activates a serine threonine kinase, protein kinase A (PKA). Cytoplasmic vesicles carrying the water channel proteins migrate through the cell in response to this phosphorylation process and fuse with the apical membrane in response to increasing vasopressin binding, thus increasing water permeability of the collecting duct cells. These water channels are recyled by endocytosis once the vasopressin is removed. The water channel responsible for the high water permeability of the luminal membrane in response to vasopressin has recently been cloned and designated as aquaporin-2 (AQP-2) [8]. The other members of the aquaporin family, AQP-3 and AQP-4 are located on the basolateral membranes and are probably involved in water exit from the cell. The molecular biology of these channels and of receptors responsible for vasopressin action have contributed to the understanding of the syndromes of genetically transmitted and acquired forms of vasopressin resistance. AVParginine vasopressin.

AQUAPORINS AND THEIR CHARACTERISTICSAQP-1Size (amino acids) Permeability to small solutes Regulation by antidiurectic hormone Site Cellular localization Mutant phenotype 269 No No Proximal tubules; descending thin limb Apical and basolateral membrane Normal

AQP-2271 No Yes Collecting duct; principal cells Apical membrane and intracellular vesicles Nephrogenic diabetes insipidus

AQP-3285 Urea glycerol No Medullary collecting duct; colon Basolateral membrane Unknown

AQP-4301 No No Hypothalamicsupraoptic, paraventricular nuclei; ependymal, granular, and Purkinje cells Basolateral membrane of the prinicpal cells Unknown

FIGURE 1-10 Aquaporins and their characteristics. An ever growing family of aquaporin (AQP) channels are being described. So far, about seven

different channels have been cloned and characterized; however, only four have been found to have any definite physiologic role.

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Disorders of Water, Electrolytes, and Acid-BaseFIGURE 1-11 Osmotic and nonosmotic regulation of antidiuretic hormone (ADH) secretion. ADH is secreted in response to changes in osmolality and in circulating arterial volume. The osmoreceptor cells are located in the anterior hypothalamus close to the supraoptic nuclei. Aquaporin-4 (AQP-4), a candidate osmoreceptor, is a member of the water channel family that was recently cloned and characterized and is found in abundance in these neurons. The osmoreceptors are sensitive to changes in plasma osmolality of as little as 1%. In humans, the osmotic threshold for ADH release is 280 to 290 mOsm/kg. This system is so efficient that the plasma osmolality usually does not vary by more than 1% to 2% despite wide fluctuations in water intake [9]. There are several other nonosmotic stimuli for ADH secretion. In conditions of decreased arterial circulating volume (eg, heart failure, cirrhosis, vomiting), decrease in inhibitory parasympathetic afferents in the carotid sinus baroreceptors affects ADH secretion. Other nonosmotic stimuli include nausea, which can lead to a 500-fold rise in circulating ADH levels, postoperative pain, and pregnancy. Much higher ADH levels can be achieved with hypovolemia than with hyperosmolarity, although a large fall in blood volume is required before this response is initiated. In the maintenance of tonicity the interplay of these homeostatic mechanisms also involves the thirst mechanism, that under normal conditions, causes either intake or exclusion of water in an effort to restore serum osmolality to normal.

50 45 40 Plasma AVP, pg/mL 35 30 25 20 15 10 5 0

Isotonic volume depletion Isovolemic osmotic increase

0

5

10 15 Change, %

20

Control of Water Balance and Serum Sodium ConcentrationIncreased plasma osmolality or decreased arterial circulating volume Decreased plasma osmolality or increased arterial circulating blood volume

Increased thirst

Increased ADH release

Decreased thirst

Decreased ADH release

Increased water intake Water retention

Decreased water excretion

Decreased water intake Water excretion

Decreased water excretion

Decreased plasma osmolality or increased arterial circulating volume

Increased plasma osmolality and decreased arterial circulating volume

A

Decreased ADH release and thirst

B

Increased ADH release and thirst

FIGURE 1-12 Pathways of water balance (conservation, A, and excretion, B). In humans and other terrestrial animals, the thirst mechanism plays an important role in water (H2O) balance. Hypertonicity is the most potent stimulus for thirst: only 2% to 3 % changes in plasma osmolality produce a strong desire to drink water. This absolute level of osmolality at which the sensation of thirst arises in healthy persons, called the osmotic threshold for thirst, usually averages about 290 to 295 mOsm/kg H2O (approximately 10 mOsm/kg H2O above that of antidiuretic hormone [ADH] release). The socalled thirst center is located close to the osmoreceptors but is

anatomically distinct. Between the limits imposed by the osmotic thresholds for thirst and ADH release, plasma osmolality may be regulated still more precisely by small osmoregulated adjustments in urine flow and water intake. The exact level at which balance occurs depends on various factors such as insensible losses through skin and lungs, and the gains incurred from eating, normal drinking, and fat metabolism. In general, overall intake and output come into balance at a plasma osmolality of 288 mOsm/kg, roughly halfway between the thresholds for ADH release and thirst [10].

Diseases of Water Metabolism

1.9

Plasma osmolality 280 to 290 mOsm/kg H2O Decrease Supression of thirst Supression of ADH release Increase Stimulation of thirst Stimulation of ADH release

Dilute urine

Concentrated urine

FIGURE 1-13 Pathogenesis of dysnatremias. The countercurrent mechanism of the kidneys in concert with the hypothalamic osmoreceptors via antidiuretic hormone (ADH) secretion maintain a very finely tuned balance of water (H2O). A defect in the urine-diluting capacity with continued H2O intake results in hyponatremia. Conversely, a defect in urine concentration with inadequate H2O intake culminates in hypernatremia. Hyponatremia reflects a disturbance in homeostatic mechanisms characterized by excess total body H2O relative to total body sodium, and hypernatremia reflects a deficiency of total body H2O relative to total body sodium [11]. (From Halterman and Berl [12]; with permission.)

Disorder involving urine dilution with H2O intake

Disorder involving urine concentration with inadequate H2O intake Hypernatremia

Hyponatremia

Approach to the Hyponatremic PatientEFFECTS OF OSMOTICALLY ACTIVE SUBSTANCES ON SERUM SODIUMSubstances that increase osmolality and decrease serum sodium (translocational hyponatremia)Glucose Mannitol Glycine Maltose

Substances the increase osmolality without changing serum sodiumUrea Ethanol Ethylene glycol Isopropyl alcohol Methanol

FIGURE 1-14 Evaluation of a hyponatremic patient: effects of osmotically active substances on serum sodium. In the evaluation of a hyponatremic patient, a determination should be made about whether hyponatremia is truly hypo-osmotic and not a consequence of translocational or

pseudohyponatremia, since, in most but not all situations, hyponatremia reflects hypo-osmolality. The nature of the solute plays an important role in determining whether or not there is an increase in measured osmolality or an actual increase in effective osmolality. Solutes that are permeable across cell membranes (eg, urea, methanol, ethanol, and ethylene glycol) do not cause water movement and cause hypertonicity without causing cell dehydration. Typical examples are an uremic patient with a high blood urea nitrogen value and an ethanolintoxicated person. On the other hand, in a patient with diabetic ketoacidosis who is insulinopenic the glucose is not permeant across cell membranes and, by its presence in the extracellular fluid, causes water to move from the cells to extracellular space, thus leading to cell dehydration and lowering serum sodium. This can be viewed as translocational at the cellular level, as the serum sodium level does not reflect changes in total body water but rather movement of water from intracellular to extracellular space. Glycine is used as an irrigant solution during transurethral resection of the prostate and in endometrial surgery. Pseudohyponatremia occurs when the solid phase of plasma (usually 6% to 8%) is much increased by large increments of either lipids or proteins (eg, in hypertriglyceridemia or paraproteinemias).

1.10

Disorders of Water, Electrolytes, and Acid-BaseFIGURE 1-15 Pathogenesis of hyponatremia. The normal components of the renal diluting mechanism are depicted in Figure 1-3. Hyponatremia results from disorders of this diluting capacity of the kidney in the following situations:1. Intrarenal factors such as a diminished glomerular filtration rate (GFR), or an increase in proximal tubule fluid and sodium reabsorption, or both, which decrease distal delivery to the diluting segments of the nephron, as in volume depletion, congestive heart failure, cirrhosis, or nephrotic syndrome. 2. A defect in sodium chloride transport out of the water-impermeable segments of the nephrons (ie, in the thick ascending limb of the loop of Henle). This may occur in patients with interstitial renal disease and administration of thiazide or loop diuretics. 3. Continued secretion of antidiuretic hormone (ADH) despite the presence of serum hypo-osmolality mostly stimulated by nonosmotic mechanisms [12].

Reabsorption of sodium chloride in distal convoluted tubule Thiazide diuretics

GFR diminished Age Renal disease Congestive heart failure Cirrhosis Nephrotic syndrome Volume depletion

Reabsorption of sodium chloride in thick ascending limb of loop of Henle Loop diuretics Osmotic diuretics Interstitial disease

NaCl

ADH release or action Drugs Syndrome of inappropriate antidiuretic hormone secretion, etc.

NaClsodium chloride.

Assessment of volume status

Hypovolemia Total body water Total body sodium

Euvolemia (no edema) Total body water Total body sodium

Hypervolemia Total body water Total body sodium

UNa >20

UNa 20

UNa >20

UNa 100 mOsm/kg H2O) Clinical euvolemia Elevated urinary sodium concentration (U[Na]), with normal salt and H2O intake Absence of adrenal, thyroid, pituitary, or renal insufficiency or diuretic use Supplemental Abnormal H2O load test (inability to excrete at least 90% of a 20mL/kg H2O load in 4 hrs or failure to dilute urinary osmolality to < 100 mOsm/kg) Plasma antidiuretic hormone level inappropriately elevated relative to plasma osmolality No significant correction of plasma sodium with volume expansion, but improvement after fluid restriction

1.12

Disorders of Water, Electrolytes, and Acid-BaseFIGURE 1-20 Signs and symptoms of hyponatremia. In evaluating hyponatremic patients, it is important to assess whether or not the patient is symptomatic, because symptoms are a better determinant of therapy than the absolute value itself. Most patients with serum sodium values above 125 mEq/L are asymptomatic. The rapidity with which hyponatremia develops is critical in the initial evaluation of such patients. In the range of 125 to 130 mEq/L, the predominant symptoms are gastrointestinal ones, including nausea and vomiting. Neuropsychiatric symptoms dominate the picture once the serum sodium level drops below 125 mEq/L, mostly because of cerebral edema secondary to hypotonicity. These include headache, lethargy, reversible ataxia, psychosis, seizures, and coma. Severe manifestations of cerebral edema include increased intracerebral pressure, tentorial herniation, respiratory depression and death. Hyponatremia-induced cerebral edema occurs principally with rapid development of hyponatremia, typically in patients managed with hypotonic fluids in the postoperative setting or those receiving diuretics, as discussed previously. The mortality rate can be as great as 50%. Fortunately, this rarely occurs. Nevertheless, neurologic symptoms in a hyponatremic patient call for prompt and immediate attention and treatment [16,17].

SIGNS AND SYMPTOMS OF HYPONATREMIACentral Nervous SystemMild Apathy Headache Lethargy Moderate Agitation Ataxia Confusion Disorientation Psychosis Severe Stupor Coma Pseudobulbar palsy Tentorial herniation Cheyne-Stokes respiration Death

Gastrointestinal SystemAnorexia Nausea Vomiting

Musculoskeletal SystemCramps Diminished deep tendon reflexes

FIGURE 1-21 Cerebral adaptation to hyponatremia. 3 Na+/H2O Na+/H2O Na+/H2O A, Decreases in extracellular osmolality 2 cause movement of water (H2O) into the cells, increasing intracellular volume and K+, Na+ K+, Na+ K+, Na+ thus causing tissue edema. This cellular H 2O H2O H 2O osmolytes osmolytes osmolytes edema within the fixed confines of the cranium causes increased intracranial pressure, leading to neurologic symptoms. To prevent this from happening, mechanisms geared toward volume regulation come into operaNormonatremia Acute hyponatremia Chronic hyponatremia A tion, to prevent cerebral edema from developing in the vast majority of patients with hyponatremia. After induction of extracellular fluid hypo-osmolality, H2O moves into the brain in response to osmotic gradients, producing cerebral edema (middle panel, 1). However, within 1 to 3 hours, a decrease in cerebral extracellular volume occurs by movement of K+ fluid into the cerebrospinal fluid, which is then shunted back into the systemic circulation. Glutamate This happens very promptly and is evident by the loss of extracellular and intracellular solutes (sodium and chloride ions) as early as 30 minutes after the onset of hyponatremia. Na+ As H2O losses accompany the losses of brain solute (middle panel, 2), the expanded brain Urea volume decreases back toward normal (middle panel, 3) [15]. B, Relative decreases in individual osmolytes during adaptation to chronic hyponatremia. Thereafter, if hyponatremia persists, other organic osmolytes such as phosphocreatine, myoinositol, and amino acids Inositol like glutamine, and taurine are lost. The loss of these solutes markedly decreases cerebral Cl swelling. Patients who have had a slower onset of hyponatremia (over 72 to 96 hours or Taurine longer), the risk for osmotic demyelination rises if hyponatremia is corrected too rapidly Other B [18,19]. Na+sodium; K+potassium; Cl-chloride.1

Diseases of Water Metabolism

1.13

HYPONATREMIC PATIENTS AT RISK FOR NEUROLOGIC COMPLICATIONSComplicationAcute cerebral edema

SYMPTOMS OF CENTRAL PONTINE MYELINOLYSISInitial symptoms Mutism Dysarthria Lethargy and affective changes Classic symptoms Spastic quadriparesis Pseudobulbar palsy Lesions in the midbrain, medulla oblongata, and pontine tegmentum Pupillary and oculomotor abnormalities Altered sensorium Cranial neuropathies Extrapontine myelinolysis Ataxia Behavioral abnormalities Parkinsonism Dystonia

Persons at RiskPostoperative menstruant females Elderly women taking thiazides Children Psychiatric polydipsic patients Hypoxemic patients Alcoholics Malnourished patients Hypokalemic patients Burn victims Elderly women taking thiazide diuretics

Osmotic demyelination syndrome

FIGURE 1-22 Hyponatremic patients at risk for neurologic complications. Those at risk for cerebral edema include postoperative menstruant women, elderly women taking thiazide diuretics, children, psychiatric patients with polydipsia, and hypoxic patients. In women, and, in particular, menstruant ones, the risk for developing neurologic complications is 25 times greater than that for nonmenstruant women or men. The increased risk was independent of the rate of development, or the magnitude of the hyponatremia [21]. The osmotic demyelination syndrome or central pontine myelinolysis seems to occur when there is rapid correction of low osmolality (hyponatremia) in a brain already chronically adapted (more than 72 to 96 hours). It is rarely seen in patients with a serum sodium value greater than 120 mEq/L or in those who have hyponatremia of less than 48 hours duration [20,21]. (Adapted from Lauriat and Berl [21]; with permission.)

FIGURE 1-23 Symptoms of central pontine myelinolysis. This condition has been described all over the world, in all age groups, and can follow correction of hyponatremia of any cause. The risk for development of central pontine myelinolysis is related to the severity and chronicity of the hyponatremia. Initial symptoms include mutism and dysarthria. More than 90% of patients exhibit the classic symptoms of myelinolysis (ie, spastic quadriparesis and pseudobulbar palsy), reflecting damage to the corticospinal and corticobulbar tracts in the basis pontis. Other symptoms occur on account of extension of the lesion to other parts of the midbrain. This syndrome follows a biphasic course. Initially, a generalized encephalopathy, associated with a rapid rise in serum sodium, occurs. This is followed by the classic symptoms 2 to 3 days after correction of hyponatremia, however, this pattern does not always occur [22]. (Adapted from Laureno and Karp [22]; with permission.)

A

Bimages, hypointense. These lesions do not enhance with gadolinium. They may not be apparent on imaging until 2 weeks into the illness. Other diagnostic tests are brainstem auditory evoked potentials, electroencephalography, and cerebrospinal fluid protein and myelin basic proteins [22]. B, Gross appearance of the pons in central pontine myelinolysis. (From Laureno and Karp [22]; with permission.)

FIGURE 1-24 A, Imaging of central pontine myelinolysis. Brain imaging is the most useful diagnostic technique for central pontine myelinolysis. Magnetic resonance imaging (MRI) is more sensitive than computed tomography (CT). On CT, central pontine and extrapontine lesions appear as symmetric areas of hypodensity (not shown). On T2 images of MRI, the lesions appear as hyperintense and on T1

1.14

Disorders of Water, Electrolytes, and Acid-BaseFIGURE 1-25 Treatment of severe euvolemic hyponatremia ( 24 mg/24 hrs)

Increased vasomotor tone

Na+ reabsorption

No Mg deficiency

Mg deficiency present Check for nonrenal causes Mg deficiency present Renal Mg wasting

Hypertension Tolerance Mg test (see Figure 418)

FIGURE 4-16 Mechanism whereby magnesium (Mg) deficiency could lead to hypertension. Mg deficiency does the following: increases angiotensin II (AII) action, decreases levels of vasodilatory prostaglandins (PGs), increases levels of vasoconstrictive PGs and growth factors, increases vascular smooth muscle cytosolic calcium, impairs insulin release, produces insulin resistance, and alters lipid profile. All of these results of Mg deficiency favor the development of hypertension and atherosclerosis [10,11]. Na+ionized sodium; 12-HETEhydroxy-eicosatetraenoic [acid]; TXA2thromboxane A2. (From Nadler and coworkers [17].)

Normal Mg retention No Mg deficiency Normal

Mg retention Mg deficiency present Check for nonrenal causes

FIGURE 4-17 Evaluation in suspected magnesium (Mg) deficiency. Serum Mg levels may not always indicate total body stores. More refined tools used to assess the status of Mg in erythrocytes, muscle, lymphocytes, bone, isotope studies, and indicators of intracellular Mg, are not routinely available. Screening for Mg deficiency relies on the fact that urinary Mg decreases rapidly in the face of Mg depletion in the presence of normal renal function [2,6,815,18]. (Adapted from Al-Ghamdi and coworkers [11].) FIGURE 4-18 The magnesium (Mg) tolerance test, in various forms [2,6,812,18], has been advocated to diagnose Mg depletion in patients with normal or near-normal serum Mg levels. All such tests are predicated on the fact that patients with normal Mg status rapidly excrete over 50% of an acute Mg load; whereas patients with depleted Mg retain Mg in an effort to replenish Mg stores. (From Ryzen and coworkers [18].)

MAGNESIUM (Mg) TOLERANCE TEST FOR PATIENTS WITH NORMAL SERUM MAGNESIUM

Time0 (baseline) 04 h 024 h End %M=1 (24-h urine Mg)

ActionUrine (spot or timed) for molar Mg:Cr ratio IV infusion of 2.4 mg (0.1 mmol) of Mg/kg lean body wt in 50 mL of 50% dextrose Collect urine (staring with Mg infusion) for Mg and Cr Calculate % Mg retained (%M) ([Preinfusion urine Mg:Cr] Total Mg infused [24-h urine Cr]) 100

Mg retained, %>50 2050 20 mEq/L)

Vomiting, gastric suction Postdiuretic phase of loop and distal agents Posthypercapnic state Villous adenoma of the colon Congenital chloridorrhea Post alkali loading

Urinary [K+] Low (< 20 mEq/L) Laxative abuse Other causes of profound K+ depletion

Abundant (> 30 mEq/L)

Diuretic phase of loop and distal agents Bartter's and Gitelman's syndromes Primary aldosteronism Cushing's syndrome Exogenous mineralocorticoid agents Secondary aldosteronism malignant hypertension renovascular hypertension primary reninism Liddle's syndrome

Disorders of Acid-Base Balance

6.25

SIGNS AND SYMPTOMS OF METABOLIC ALKALOSISCentral Nervous SystemHeadache Lethargy Stupor Delirium Tetany Seizures Potentiation of hepatic encephalopathy

Cardiovascular SystemSupraventricular and ventricular arrhythmias Potentiation of digitalis toxicity Positive inotropic ventricular effect

Respiratory SystemHypoventilation with attendant hypercapnia and hypoxemia

Neuromuscular SystemChvosteks sign Trousseaus sign Weakness (severity depends on degree of potassium depletion)

Metabolic EffectsIncreased organic acid and ammonia production Hypokalemia Hypocalcemia Hypomagnesemia Hypophosphatemia

Renal (Associated Potassium Depletion)Polyuria Polydipsia Urinary concentration defect Cortical and medullary renal cysts

FIGURE 6-38 Signs and symptoms of metabolic alkalosis. Mild to moderate metabolic alkalosis usually is accompanied by few if any symptoms, unless potassium depletion is substantial. In contrast, severe metabolic alkalosis ([HCO3] > 40 mEq/L) is usually a symptomatic disorder. Alkalemia, hypokalemia, hypoxemia, hypercapnia, and decreased plasma ionized calcium concentration all contribute to

these clinical manifestations. The arrhythmogenic potential of alkalemia is more pronounced in patients with underlying heart disease and is heightened by the almost constant presence of hypokalemia, especially in those patients taking digitalis. Even mild alkalemia can frustrate efforts to wean patients from mechanical ventilation [23,24]. of hypercalcemia after primary hyperparathyroidism and malignancy. Another common presentation of the syndrome originates from the current use of calcium carbonate in preference to aluminum as a phosphate binder in patients with chronic renal insufficiency. The critical element in the pathogenesis of the syndrome is the development of hypercalcemia that, in turn, results in renal dysfunction. Generation and maintenance of metabolic alkalosis reflect the combined effects of the large bicarbonate load, renal insufficiency, and hypercalcemia. Metabolic alkalosis contributes to the maintenance of hypercalcemia by increasing tubular calcium reabsorption. Superimposition of an element of volume contraction caused by vomiting, diuretics, or hypercalcemia-induced natriuresis can worsen each one of the three main components of the syndrome. Discontinuation of calcium carbonate coupled with a diet high in sodium chloride or the use of normal saline and furosemide therapy (depending on the severity of the syndrome) results in rapid resolution of hypercalcemia and metabolic alkalosis. Although renal function also improves, in a considerable fraction of patients with the chronic form of the syndrome serum creatinine fails to return to baseline as a result of irreversible structural changes in the kidneys [27].

Ingestion of large amounts of calcium

Ingestion of large amounts of absorbable alkali

Augmented body content of calcium

Increased urine calcium excretion (early phase)

Urine alkalinization

Augmented body bicarbonate stores

Nephrocalcinosis Reduced renal bicarbonate excretion

Hypercalcemia

Renal vasoconstriction

Renal insufficiency

Metabolic alkalosis

Decreased urine calcium excretion Increased renal H+ secretion

Increased renal reabsorption of calcium

FIGURE 6-39 Pathophysiology of the milk-alkali syndrome. The milk-alkali syndrome comprises the triad of hypercalcemia, renal insufficiency, and metabolic alkalosis and is caused by the ingestion of large amounts of calcium and absorbable alkali. Although large amounts of milk and absorbable alkali were the culprits in the classic form of the syndrome, its modern version is usually the result of large doses of calcium carbonate alone. Because of recent emphasis on prevention and treatment of osteoporosis with calcium carbonate and the availability of this preparation over the counter, milk-alkali syndrome is currently the third leading cause

6.26Clinical syndrome Bartter's syndrome Type 1

Disorders of Water, Electrolytes, and Acid-Baseand hypercalciuria and nephrocalcinosis are present. In contrast, Gitelmans syndrome is a milder disease presenting later in life. Patients often are asymptomatic, or they might have intermittent muscle spasms, cramps, or tetany. Urinary concentrating ability is maintained; hypocalciuria, renal magnesium wasting, and hypomagnesemia are almost constant features. On the basis of certain of these clinical features, it had been hypothesized that the primary tubular defects in Bartters and Gitelmans syndromes reflect impairment in sodium reabsorption in the thick ascending limb (TAL) of the loop of Henle and the distal tubule, respectively. This hypothesis has been validated by recent genetic studies [28-31]. As illustrated here, Bartters syndrome now has been shown to be caused by loss-of-function mutations in the loop diureticsensitive sodium-potassium-2chloride cotransporter (NKCC2) of the TAL (type 1 Bartters syndrome) [28] or the apical potassium channel ROMK of the TAL (where it recycles reabsorbed potassium into the lumen for continued operation of the NKCC2 cotransporter) and the cortical collecting duct (where it mediates secretion of potassium by the principal cell) (type 2 Bartters syndrome) [29,30]. On the other hand, Gitelmans syndrome is caused by mutations in the thiazide-sensitive Na-Cl cotransporter (TSC) of the distal tubule [31]. Note that the distal tubule is the major site of active calcium reabsorption. Stimulation of calcium reabsorption at this site is responsible for the hypocalciuric effect of thiazide diuretics.

Affected gene

Affected chromosome

Localization of tubular defect TAL

NKCC2

15q15-q21 TAL CCD

Type 2 Gitelman's syndrome

ROMK

11q24

DCT TSC 16q13

Tubular lumen Na+ K+,NH+ 4 Cl Loop diuretics H+

Cell+

Peritubular space 2K+ ATPase

Tubular lumen Na+

Cell 3Na+ + K Cl Cl

Peritubular space 2K+ ATPase

Tubular lumen Na+

Cell

Peritubular space Cl

3Na

3Na K+ K+

+

K 3HCO 3 Na+

+

Cl Thiazides

ATPase + 2K

K+

3Na+ Ca2+

Ca

2+

Ca2+ Mg2+ Thick ascending limb (TAL) Distal convoluted tuble (DCT) Cortical collecting duct (CCD)

FIGURE 6-40 Clinical features and molecular basis of tubular defects of Bartters and Gitelmans syndromes. These rare disorders are characterized by chloride-resistant metabolic alkalosis, renal potassium wasting and hypokalemia, hyperreninemia and hyperplasia of the juxtaglomerular apparatus, hyperaldosteronism, and normotension. Regarding differentiating features, Bartters syndrome presents early in life, frequently in association with growth and mental retardation. In this syndrome, urinary concentrating ability is usually decreased, polyuria and polydipsia are present, the serum magnesium level is normal,

Disorders of Acid-Base Balance

6.27

Management of metabolic alkalosis

For alkali gain

For H+ loss Eliminate source of excess alkali

For H+ shift

Discontinue administrationof bicarbonate or its precursors. via gastric route Administer antiemetics; discontinue gastric suction; administer H2 blockers or H+-K+ ATPase inhibitors. via renal route Discontinue or decrease loop and distal diuretics; substitute with amiloride, triamterene, or spironolactone; discontinue or limit drugs with mineralocorticoid activity. Potassium repletion ECF volume repletion; renal replacement therapy

For decreased GFR

FIGURE 6-41 Metabolic alkalosis management. Effective management of metabolic alkalosis requires sound understanding of the underlying pathophysiology. Therapeutic efforts should focus on eliminating or moderating the processes that generate the alkali excess and on interrupting the mechanisms that perpetuate the hyperbicarbonatemia. Rarely, when the pace of correction of metabolic alkalosis must be accelerated, acetazolamide or an infusion of hydrochloric acid can be used. Treatment of severe metabolic alkalosis can be particularly challenging in patients with advanced cardiac or renal dysfunction. In such patients, hemodialysis or continuous hemofiltration might be required [1].

Interrupt perpetuating mechanisms

For Cl responsive acidification defect

Administer NaCl and KCl

For Cl resistant acidification defect

Adrenalectomy or other surgery, potassiuim repletion, administration of amiloride, triamterene, or spironolactone.

References1. Adrogu HJ, Madias NE: Management of life-threatening acid-base disorders. N Engl J Med, 1998, 338:2634, 107111. 2. Madias NE, Adrogu HJ: Acid-base disturbances in pulmonary medicine. In Fluid, Electrolyte, and Acid-Base Disorders. Edited by Arieff Al, DeFronzo RA. New York: Churchill Livingstone; 1995:223253. 3. Madias NE, Adrogu HJ, Horowitz GL, et al.: A redefinition of normal acid-base equilibrium in man: carbon dioxide tension as a key determinant of plasma bicarbonate concentration. Kidney Int 1979, 16:612618. 4. Adrogu HJ, Madias NE: Mixed acid-base disorders. In The Principles and Practice of Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St. Louis: Mosby-Year Book; 1995:953962. 5. Krapf R: Mechanisms of adaptation to chronic respiratory acidosis in the rabbit proximal tubule. J Clin Invest 1989, 83:890896. 6. Al-Awqati Q: The cellular renal response to respiratory acid-base disorders. Kidney Int 1985, 28:845855. 7. Bastani B: Immunocytochemical localization of the vacuolar H+ATPase pump in the kidney. Histol Histopathol 1997, 12:769779. 8. Teixeira da Silva JC Jr, Perrone RD, Johns CA, Madias NE: Rat kidney band 3 mRNA modulation in chronic respiratory acidosis. Am J Physiol 1991, 260:F204F209. 9. Respiratory pump failure: primary hypercapnia (respiratory acidosis). In Respiratory Failure. Edited by Adrogu HJ, Tobin MJ. Cambridge, MA: Blackwell Science; 1997:125134. 10. Krapf R, Beeler I, Hertner D, Hulter HN: Chronic respiratory alkalosis: the effect of sustained hyperventilation on renal regulation of acidbase equilibrium. N Engl J Med 1991, 324:13941401. 11. Hilden SA, Johns CA, Madias NE: Adaptation of rabbit renal cortical Na+-H+-exchange activity in chronic hypocapnia. Am J Physiol 1989, 257:F615F622. 12. Adrogu HJ, Rashad MN, Gorin AB, et al.: Arteriovenous acid-base disparity in circulatory failure: studies on mechanism. Am J Physiol 1989, 257:F1087F1093. 13. Adrogu HJ, Rashad MN, Gorin AB, et al.: Assessing acid-base status in circulatory failure: differences between arterial and central venous blood. N Engl J Med 1989, 320:13121316. 14. Madias NE: Lactic acidosis. Kidney Int 1986, 29:752774. 15. Kraut JA, Madias NE: Lactic acidosis. In Textbook of Nephrology. Edited by Massry SG, Glassock RJ. Baltimore: Williams and Wilkins; 1995:449457. 16. Hindman BJ: Sodium bicarbonate in the treatment of subtypes of acute lactic acidosis: physiologic considerations. Anesthesiology 1990, 72:10641076. 17. Adrogu HJ: Diabetic ketoacidosis and hyperosmolar nonketotic syndrome. In Therapy of Renal Diseases and Related Disorders. Edited by Suki WN, Massry SG. Boston: Kluwer Academic Publishers; 1997:233251. 18. Adrogu HJ, Barrero J, Eknoyan G: Salutary effects of modest fluid replacement in the treatment of adults with diabetic ketoacidosis. JAMA 1989, 262:21082113. 19. Bastani B, Gluck SL: New insights into the pathogenesis of distal renal tubular acidosis. Miner Electrolyte Metab 1996, 22:396409. 20. DuBose TD Jr: Hyperkalemic hyperchloremic metabolic acidosis: pathophysiologic insights. Kidney Int 1997, 51:591602. 21. Madias NE, Bossert WH, Adrogu HJ: Ventilatory response to chronic metabolic acidosis and alkalosis in the dog. J Appl Physiol 1984, 56:16401646. 22. Gennari FJ: Metabolic alkalosis. In The Principles and Practice of Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St Louis: Mosby-Year Book; 1995:932942.

6.28

Disorders of Water, Electrolytes, and Acid-Base28. Simon DB, Karet FE, Hamdan JM, et al.: Bartters syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet 1996, 13:183188. 29. Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic heterogeneity of Bartters syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet 1996, 14:152156. 30. International Collaborative Study Group for Bartter-like Syndromes. Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence for genetic heterogeneity. Hum Mol Genet 1997, 6:1726. 31. Simon DB, Nelson-Williams C, et al.: Gitelmans variant of Bartters syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet 1996, 12:2430.

23. Sabatini S, Kurtzman NA: Metabolic alkalosis: biochemical mechanisms, pathophysiology, and treatment. In Therapy of Renal Diseases and Related Disorders Edited by Suki WN, Massry SG. Boston: Kluwer Academic Publishers; 1997:189210. 24. Galla JH, Luke RG: Metabolic alkalosis. In Textbook of Nephrology. Edited by Massry SG, Glassock RJ. Baltimore: Williams & Wilkins; 1995:469477. 25. Madias NE, Adrogu HJ, Cohen JJ: Maladaptive renal response to secondary hypercapnia in chronic metabolic alkalosis. Am J Physiol 1980, 238:F283289. 26. Harrington JT, Hulter HN, Cohen JJ, Madias NE: Mineralocorticoidstimulated renal acidification in the dog: the critical role of dietary sodium. Kidney Int 1986, 30:4348. 27. Beall DP, Scofield RH: Milk-alkali syndrome associated with calcium carbonate consumption. Medicine 1995, 74:8996.

Disorders of Phosphate BalanceMoshe Levi Mordecai Popovtzer

T

he physiologic concentration of serum phosphorus (phosphate) in normal adults ranges from 2.5 to 4.5 mg/dL (0.801.44 mmol/L). A diurnal variation occurs in serum phosphorus of 0.6 to 1.0 mg/dL, the lowest concentration occurring between 8 AM and 11 AM. A seasonal variation also occurs; the highest serum phosphorus concentration is in the summer and the lowest in the winter. Serum phosphorus concentration is markedly higher in growing children and adolescents than in adults, and it is also increased during pregnancy [1,2]. Of the phosphorus in the body, 80% to 85% is found in the skeleton. The rest is widely distributed throughout the body in the form of organic phosphate compounds. In the extracellular fluid, including in serum, phosphorous is present mostly in the inorganic form. In serum, more than 85% of phosphorus is present as the free ion and less than 15% is protein-bound. Phosphorus plays an important role in several aspects of cellular metabolism, including adenosine triphosphate synthesis, which is the source of energy for many cellular reactions, and 2,3-diphosphoglycerate concentration, which regulates the dissociation of oxygen from hemoglobin. Phosphorus also is an important component of phospholipids in cell membranes. Changes in phosphorus content, concentration, or both, modulate the activity of a number of metabolic pathways. Major determinants of serum phosphorus concentration are dietary intake and gastrointestinal absorption of phosphorus, urinary excretion of phosphorus, and shifts between the intracellular and extracellular spaces. Abnormalities in any of these steps can result either in hypophosphatemia or hyperphosphatemia [37]. The kidney plays a major role in the regulation of phosphorus homeostasis. Most of the inorganic phosphorus in serum is ultrafilterable at the level of the glomerulus. At physiologic levels of serum phosphorus and during a normal dietary phosphorus intake, approximately 6 to 7 g/d of phosphorous is filtered by the kidney. Of that

CHAPTER

7

7.2

Disorders of Water, Electrolytes, and Acid-Base(type I and type II Na-Pi cotransport proteins). Most of the hormonal and metabolic factors that regulate renal tubular phosphate reabsorption, including alterations in dietary phosphate content and parathyroid hormone, have been shown to modulate the proximal tubular apical membrane expression of the type II Na-Pi cotransport protein [1116].FIGURE 7-1 Summary of phosphate metabolism for a normal adult in neutral phosphate balance. Approximately 1400 mg of phosphate is ingested daily, of which 490 mg is excreted in the stool and 910 mg in the urine. The kidney, gastrointestinal (GI) tract, and bone are the major organs involved in phosphorus homeostasis.

amount, 80% to 90% is reabsorbed by the renal tubules and the rest is excreted in the urine. Most of the filtered phosphorus is reabsorbed in the proximal tubule by way of a sodium gradient-dependent process (Na-Pi cotransport) located on the apical brush border membrane [810]. Recently two distinct Na-Pi cotransport proteins have been cloned from the kidney

Bone

GI intake 1400 mg/d

Digestive juice phosphorus 210 mg/d

Formation 210 mg/d

Resorption 210 mg/d

Extracellular fluid Total absorbed intestinal phosphorus 1120 mg/d

Urine 910 mg/d Stool 490 mg/d

Major determinants of ECF or serum inorganic phosphate (Pi) concentration Dietary intake Intestinal absorption

FIGURE 7-2 Major determinants of extracellular fluid or serum inorganic phosphate (Pi) concentration include dietary Pi intake, intestinal Pi absorption, urinary Pi excretion and shift into the cells.

Serum Pi Urinary excretion

Cells

Disorders of Phosphate Balance

7.3

Renal Tubular Phosphate Reabsorption100% PCT 55-75%

DCT 5-10%

FIGURE 7-3 Renal tubular reabsorption of phosphorus. Most of the inorganic phosphorus in serum is ultrafilterable at the level of the glomerulus. At physiologic levels of serum phosphorus and during a normal dietary phosphorus intake, most of the filtered phosphorous is reabsorbed in the proximal convoluted tubule (PCT) and proximal straight tubule (PST). A significant amount of filtered phosphorus is also reabsorbed in distal segments of the nephron [7,9,10]. CCTcortical collecting tubule; IMCDinner medullary collecting duct or tubule; PSTproximal straight tubule.

PST 10-20%

CCT 2-5%

IMCD 0.5 mg/dL/d Previous SCr normal

FIGURE 8-9 Discovering the cause of acute renal failure (ARF). This is a great challenge for clinicians. This algorithm could help to determine the cause of the increase in blood urea nitrogen (BUN) or serum creatinine (SCr) in a given patient.

SCr < 0.5 mg/dL/d Previous SCr increased

and/or

and/or

CRF

ARF

+Echography SCr < 0.5 mg/dL/d Normal Flare of previous disease Acute-on-chronic renal failure

Urinary tract dilatation Repeat echograph after 24 h

Normal No Parenchymatous glomerular or systemic ARF Vascular ARF Acute tubulointerstitial nephritis Tumor lysis Sulfonamides Amyloidosis Other Data indicating glomerular or systemic disease? Great or small vessel disease? Data indicating interstitial disease? Crystals or tubular deposits? Prerenal factors? No Yes Obstructive ARF

Yes

Improvement with specific treatment? Yes Prerenal ARF

Yes

No

Yes

No Acute tubular necrosis

Yes

No No

Acute Renal Failure: Causes and Prognosis

8.5

BIOPSY RESULTS IN THE MADRID STUDYDiseasePrimary GN Extracapillary Acute proliferative Endocapillary and extracapillary Focal sclerosing Secondary GN Antiglomerular basement membrane Acute postinfectious Diffuse proliferative (systemic lupus erythematosus) Vasculitis Necrotizing Wegeners granulomatosis Not specified Acute tubular necrosis Acute tubulointerstitial nephritis Atheroembolic disease Kidney myeloma Cortical necrosis Malignant hypertension ImmunoglobulinA GN + ATN Hemolytic-uremic syndrome Not recorded * One patient with acute-on-chronic renal failure.

Patients, n12 6 3 2 1 6 3 2 1* 10 5* 3 2 4* 4 2 2* 1 1 1 1 2

FIGURE 8-10 Biopsy results in the Madrid acute renal failure (ARF) study. Kidney biopsy has had fluctuating roles in the diagnostic work-up of ARF. After extrarenal causes of ARF are excluded, the most common cause is acute tubular necrosis (ATN). Patients with well-established clinical and laboratory features of ATN receive no benefit from renal biopsy. This histologic tool should be reserved for parenchymatous ARF cases when there is no improvement of renal function after 3 weeks evolution of ARF. By that time, most cases of ATN have resolved, so other causes could be influencing the poor evolution. Biopsy is mandatory when a potentially treatable cause is suspected, such as vasculitis, systemic disease, or glomerulonephritis (GN) in adults. Some types of parenchymatous non-ATN ARF might have histologic confirmation; however kidney biopsy is not strictly necessary in cases with an adequate clinical diagnosis such as myeloma, uric acid nephropathy, or some types of acute tubulointerstitial nephritis . Other parenchymatous forms of ARF can be accurately diagnosed without a kidney biopsy. This is true of acute post-streptococcal GN and of hemolytic-uremic syndrome in children. Kidney biopsy was performed in only one of every 16 ARF cases in the Madrid ARF Study [1]. All patients with primary GN, 90% with vasculitis and 50% with secondary GN were diagnosed by biopsy at the time of ARF. As many as 15 patients were diagnosed as having acute tubulointerstitial nephritis, but only four (27%) were biopsied. Only four of 337 patients with ATN (1.2%) underwent biopsy. (Data from Liao et al. [1].)

Predisposing Factors for Acute Renal FailureRenal insult Advanced age Proteinuria 20% Volume depletion Myeloma Diuretic use 39% Diabetes mellitus Previous cardiac or renal insufficiency 48% 56% Very elderly 11% Elderly 12% 11% 29% 30% Young 17% 7% 21%Other Obstructive Prerenal Acute tubular necrosis

(n=103)

(n=256)

(n=389)

Higher probability for ARF

FIGURE 8-11 Factors that predispose to acute renal failure (ARF). Some of them act synergistically when they occur in the same patient. Advanced age and volume depletion are particularly important.

FIGURE 8-12 Causes of acute renal failure (ARF) relative to age. Although the cause of ARF is usually multifactorial, one can define the cause of each case as the most likely contributor to impairment of renal function. One interesting approach is to distribute the causes of ARF according to age. This

figure shows the main causes of ARF, dividing a population diagnosed with ARF into the very elderly (at least 80 years), elderly (65 to 79), and young (younger than 65). Essentially, acute tubular necrosis (ATN) is less frequent (P=0.004) and obstructive ARF more frequent (P1); THF + alloTHF/THEratio of the combined urinary tetrahydrocortisol and allotetrahydrocortisol to urinary tetrahydrocortisone (normal: 90%) inherit NDI as an X-linked recessive trait. In these patients, defects in the V2 receptor have been identified. In the remaining patients, the disease is transmitted as either an autosomal recessive or autosomal dominant trait involving mutations in the AQP2 gene [38,39]. ADH antidiuretic hormone; ATPadenosine triphosphate.

Renal Tubular Disorders

12.15

UrolithiasesINHERITED CAUSES OF UROLITHIASESDisorderCystinuria Dents disease X-linked recessive nephrolithiasis X-linked recessive hypophosphatemic rickets Hereditary renal hypouricemia Hypoxanthine-guanine phosphoribosyltransferase deficiency Xanthinuria Primary hyperoxaluria

Stone characteristicsCystine Calcium-containing Calcium-containing Calcium-containing Uric acid, calcium oxalate Uric acid Xanthine Calcium oxalate

TreatmentHigh fluid intake, urinary alkalization Sulfhydryl-containing drugs High fluid intake, urinary alkalization High fluid intake, urinary alkalization High fluid intake, urinary alkalization High fluid intake, urinary alkalization Allopurinol High fluid intake, urinary alkalization Allopurinol High fluid intake, dietary purine restriction High fluid intake, dietary oxalate restriction Magnesium oxide, inorganic phosphates

FIGURE 12-23 Urolithiases are a common urinary tract abnormality, afflicting 12% of men and 5% of women in North America and Europe [40]. Renal stone formation is most commonly associated with hypercalciuria. Perhaps in as many as 45% of these patients, there seems to be a familial predisposition. In comparison, a group of relatively rare disorders exists, each of which is transmitted as a Mendelian trait and causes a variety of different crystal nephropathies. The most common of these disorders is cystinuria, which involves defective cystine and dibasic

amino acid transport in the proximal tubule. Cystinuria is the leading single gene cause of inheritable urolithiasis in both children and adults [41,42]. Three Mendelian disorders, Dents disease, X-linked recessive nephrolithiasis, and X-linked recessive hypophosphatemic rickets cause hypercalciuric urolithiasis. These disorders involve a functional loss of the renal chloride channel ClC-5 [43]. The common molecular basis for these three inherited kidney stone diseases has led to speculation that ClC-5 also may be involved in other renal tubular disorders associated with kidney stones. Hereditary renal hypouricemia is an inborn error of renal tubular transport that appears to involve urate reabsorption in the proximal tubule [16]. In addition to renal transport deficiencies, defects in metabolic enzymes also can cause urolithiases. Inherited defects in the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase (HPRT) and adenine phosphoribosyltransferase (APRT) or in the catabolic enzyme xanthine dehydrogenase (XDH) all can lead to stone formation [44]. Finally, defective enzymes in the oxalate metabolic pathway result in hyperoxaluria, oxalate stone formation, and consequent loss of renal function [45].

AcknowledgmentThe author thanks Dr. David G. Warnock for critically reviewing this manuscript.

References1. Wells R, Kanai Y, Pajor A, et al.: The cloning of a human cDNA with similarity to the sodium/glucose cotransporter. Am J Physiol 1992, 263:F459F465. 2. Hediger M, Coady M, Ikeda T, Wright E: Expression cloning and cDNA sequencing of the Na/glucose co-transporter. Nature 1987, 330:379381. 3. Woolf L, Goodwin B, Phelps C: Tm-limited renal tubular reabsorption and the genetics of renal glycosuria. J Theor Biol 1966, 11:1021. 4. Meuckler M: Facilitative glucose transporters. Euro J Biochem 1994, 219:713725. 5. Morris JR, Ives HE: Inherited disorders of the renal tubule. In The Kidney. Edited by Brenner B, Rector F. Philadelphia: WB Saunders, 1996:17641827. 6. Kanai Y, Hediger M: Primary structure and functional characterization of a high affinity glutamate transporter. Nature 1992, 360:467471. 7. Oynagi K, Sogawa H, Minawi R,et al.: The mechanism of hyperammonemia in congenital lysinuria. J Pediatr 1979, 94:255. 8. Smith A, Strang L: An inborn error of metabolism with the urinary excretion of -hydroxybutric acid and phenyl-pyruvic acid. Arch Dis Child 1958, 33:109. 9. Rosenberg LE, Downing S, Durant JL, Segal S: Cystinuria: biochemical evidence for three genetically distinct diseases. J Clin Invest 1966, 45:365371. 10. Pras E, Arber N, Aksentijevich I, et al.: Localization of a gene causing cystinuria to chromosome 2p. Nature Genet 1994, 6:415419. 11. Calonge MJ, Gasparini P, Chillaron J, et al.: Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. Nature Genet 1994, 6:420425. 12. Calonge M, Volpini V, Bisceglia L, et al.: Genetic heterogeneity in cystinuria: the SLC3A1 gene is linked to type I but not to type III cystinuria. Proc Am Acad Sci USA 1995, 92:96679671.

12.16

Tubulointerstitial Disease30. White P, Mune T, Rogerson F, et al.: 11- -hydroxysteroid dehydrogenase and its role in the syndrome of apparent mineralocorticoid excess. Pediatr Res 1997, 41:2529. 31. Yiu V, Dluhy R, Lifton R, Guay-Woodford L: Low peripheral plasma renin activity as a critical marker in pediatric hypertension. Pediatr Nephrol 1997, 11:343346. 32. Chang S, Grunder S, Hanukoglu A, et al.: Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalemic acidosis, pseudohypoaldosteronism type 1. Nature Genet 1996, 12:248253. 33. Kuhle U: Pseudohypoaldosteronism: mutation found, problem solved? Mol Cell Endocrinol 1997, 133:7780. 34. Gordon R: Syndrome of hypertension and hyperkalemia with normal glomerular filtration rate. Hypertension 1986, 8:93102. 35. Mansfield T, Simon D, Farfel Z, et al.: Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q2. Nature Genet 1997, 16:202205. 36. Robertson GL, et al: Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma. J Clin Invest 1973, 52:23402352. 37. Bichet D, Osche A, Rosenthal W: Congenital nephrogenic diabetes insipidus. JASN 1997, 12:19511958. 38. van Lieburg A, Verdijk M, Knoers N, et al.: Patients with autosomal recessive nephrogenic diabetes insipidus homozygous for mutations in the aquaporin 2 water channel gene. Am J Hum Genet 1994, 55:648652. 39. Bichet D, Arthus M-F, Lonergan M, et al.: Autosomal dominant and autosomal recessive nephrogenic diabetes insipidus: novel mutations in the AQP2 gene. J Am Soc Nephrol 1995, 6:717A. 40. Coe F, Parks J, Asplin J: The pathogenesis and treatment of kidney stones. N Engl J Med 1992, 327:11411152. 41. Segal S, Thier S: Cystinuria. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. York: McGraw-Hill; 1995:35813602. 42. Polinsky MS, Kaiser BA, Baluarte HJ: Urolithiasis in childhood. Pediatr Clin North Am 1987, 34:683710. 43. Lloyd S, Pearce S, Fisher S, et al.: A common molecular basis for three inherited kidney stone diseases. Nature 1996, 379:445449. 44. Cameron J, Moro F, Simmonds H: Gout, uric acid and purine metabolism in paediatric nephrology. Pediatr Nephrol 1993, 7:105118. 45. Danpure C, Purdue P: Primary Hyperoxaluria. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 1995:23852424.

13. Wartenfeld R, Golomb E, Katz G, Bale S, et al.: Molecular analysis of cystinuria in Libyan Jews: exclusion of the SLC3A1 gene and mapping a new locus on 19q. Am J Med Genet 1997, 60:617624. 14. Stephens AD: Cystinuria and its treatment: 25 years experience at St. Bartholomews Hospital. J Inherited Metab Dis 1989, 12:197209. 15. Perazella M, Buller G: Successful treatment of cystinuria with captopril. Am J Kidney Dis 1993, 21:504507. 16. Grieff M: New insights into X-linked hypophosphatemia. Curr Opin Nephrol Hypertens 1997, 6:1519. 17. Robertson GL: Vasopressin in osmotic regulation in man. Annu Rev Med 1974, 25:315. 18. Econs M, Drezner M: Tumor-induced osteomalacia: unveiling a new hormone. N Engl J Med 1994, 330:16791681. 19. The HYP Consortium: A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nature Genet 1995, 11:130136. 20. Bergeron M, Gougoux A, Vinay P: The renal Fanconi syndrome. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill, 1995:36913704. 21. Sly W, Hu P: The carbonic anhydrase II deficiency syndrome: osteopetrosis with renal tubular acidosis and cerebral calcification. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 1965:35813602. 22. Bastani B, Gluck S: New insights into the pathogenesis of distal renal tubular acidosis. Miner Electrolyte Metab 1996, 22:396409. 23. Bruce L, Cope D, Jones G, et al.: Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (band 3, AE1) gene. J Clin Invest 1997, 100:16931707. 24. Jarolim P, Shayakul C, Prabakaran D, et al.: Autosomal dominant distal renal tubular acidosis is associated in three families with heterozygosity for the R589H mutation in the AE1 (band 3) Cl-/HCO-3 exchanger. J Biol Chem, 1998, 273:63806388. 25. Guay-Woodford L: Bartter syndrome: unraveling the pathophysiologic enigma. Am J Med, 1998, 105:151161. 26. Spiegel A, Weinstein L: Pseudohypoparathyroidism. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 1995:30733085. 27. Van Dop C: Pseudohypoparathyroidism: clinical and molecular aspects. Semin Nephrol 1989, 9:168178. 28. Lifton RP, Dluhy RG, Powers M., et al.: A chimaeric 11- -hydroxylase aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992, 355:262265. 29. Shimkets RA, Warnock DG, Bositis CM, et al.: Liddles syndrome: heritable human hypertension caused by mutations in the subunit of the epithelial sodium channel. Cell 1994, 79:407414.

The Kidney in Blood Pressure RegulationL. Gabriel Navar L. Lee Hamm

D

espite extensive animal and clinical experimentation, the mechanisms responsible for the normal regulation of arterial pressure and development of essential or primary hypertension remain unclear. One basic concept was championed by Guyton and other authors [14]: the long-term regulation of arterial pressure is intimately linked to the ability of the kidneys to excrete sufficient sodium chloride to maintain normal sodium balance, extracellular fluid volume, and blood volume at normotensive arterial pressures. Therefore, it is not surprising that renal disease is the most common cause of secondary hypertension. Furthermore, derangements in renal function from subtle to overt are probably involved in the pathogenesis of most if not all cases of essential hypertension [5]. Evidence of generalized microvascular disease may be causative of both hypertension and progressive renal insufficiency [5,6]. The interactions are complex because the kidneys are a major target for the detrimental consequences of uncontrolled hypertension. When hypertension is left untreated, positive feedback interactions may occur that lead progressively to greater hypertension and additional renal injury. These interactions culminate in malignant hypertension, stroke, other sequelae, and death [7]. In normal persons, an increased intake of sodium chloride leads to appropriate adjustments in the activity of various humoral, neural, and paracrine mechanisms. These mechanisms alter systemic and renal hemodynamics and increase sodium excretion without increasing arterial pressure [3,8]. Regardless of the initiating factor, decreases in sodium excretory capability in the face of normal or increased sodium intake lead to chronic increases in extracellular fluid volume and blood volume. These increases can result in hypertension. When the derangements also include increased levels of humoral or neural factors that directly cause vascular smooth muscle constriction, these effects increase peripheral vascular resistance or decrease vascular capacitance. Under these conditions the effects of subtle increases in blood volume are compounded because of increases in the blood volume relative to

CHAPTER

1

1.2

Hypertension and the Kidneyextrinsic influences and intrarenal derangements can lead to reduced sodium excretory capability. Many factors also exist that alter cardiac output, total peripheral resistance, and cardiovascular capacitance. Accordingly, hypertension is a multifactorial dysfunctional process that can be caused by a myriad of different conditions. These conditions range from stimulatory influences that inappropriately enhance tubular sodium reabsorption to overt renal pathology, involving severe reductions in filtering capacity by the renal glomeruli and associated marked reductions in sodium excretory capability. An understanding of the normal mechanisms regulating sodium balance and how derangements lead to altered sodium homeostasis and hypertension provides the basis for a rational approach to the treatment of hypertension.

the capacitance, often referred to as the effective blood volume. Through the mechanism of pressure natriuresis, however, the increases in arterial pressure increase renal sodium excretion, allowing restoration of sodium balance but at the expense of persistent elevations in arterial pressure [9]. In support of this overall concept, various studies have demonstrated strong relationships between kidney disease and the incidence of hypertension. In addition, transplantation studies have shown that normotensive recipients from genetically hypertensive donors have a higher likelihood of developing hypertension after transplantation [10]. This unifying concept has helped delineate the cardinal role of the kidneys in the normal regulation of arterial pressure as well as in the pathophysiology of hypertension. Many different

160 Aortic pressure, mm Hg

Arterial pressure, mm Hg

Isolated systolic hypertension (61 y)

120

80 Aortic blood flow, mL/s 400 0Normotensive (56 y)

200 180 160 140 120 100 80 60 40 20

C

A

B

HEMODYNAMIC DETERMINANTSFor any vascular bed: Arterial pressure gradient Blood flow = Vascular resistance For total circulation averaged over time: Blood flow = cardiac output Therefore, Arterial pressure - right atrial pressure Cardiac output = Total peripheral resistance and: Mean arterial pressure = Cardiac output total peripheral resistance

PP = 72 mm Hg PP = 40 mm Hg PP = 30 mm Hg

A

B

500

600 700 800 900 Arterial volume, mL

FIGURE 1-1 Aortic distensibility. The cyclical pumping nature of the heart places a heavy demand on the distensible characteristics of the aortic tree. A, During systole, the aortic tree is rapidly filled in a fraction of a second, distending it and increasing the hydraulic pressure. B, The distensibility characteristics of the arterial tree determine the pulse pressure (PP) in response to a specific stroke volume. The normal relationship is shown in curve A, and arrows designate the PP. A highly distensible arterial tree, as depicted in curve B, can accommodate the stroke volume with a smaller PP. Pathophysiologic processes and aging lead to decreases in aortic distensibility. These decreases lead to marked increases in PP and overall mean arterial pressure for any given arterial volume, as shown in curve C. Decreased distensibility is partly responsible for the isolated systolic hypertension often found in elderly persons. Recordings of actual aortic pressure and flow profiles in persons with normotension and systolic hypertension are shown in panel A [11,12]. (Panel B Adapted from Vari and Navar [4] and Panel A from Nichols et al. [12].)

FIGURE 1-2 Hemodynamic determinants of arterial pressure. During the diastolic phase of the cardiac cycle, the elastic recoil characteristics of the arterial tree provide the kinetic energy that allows a continuous delivery of blood flow to the tissues. Blood flow is dependent on the arterial pressure gradient and total peripheral resistance. Under normal conditions the right atrial pressure is near zero, and thus the arterial pressure is the pressure gradient. These relationships apply for any instant in time and to timeintegrated averages when the mean pressure is used. The time-integrated average blood flow is the cardiac output that is normally 5 to 6 L/min for an adult of average weight (70 to 75 kg).

The Kidney in Blood Pressure Regulation

1.3

Dietary Insensible losses Urinary intake (skin, respiration, fecal) excretion

+

Net sodium and fluid balance

ECF volume Arterial pressure Blood volume Interstitial fluid volume

Arterial baroreflexes Atrial reflexes Renin-angiotensin-aldosterone Adrenal catecholamines Vasopressin Natriuretic peptides Endothelial factors: nitric oxide, endothelin kallikrein-kinin system Prostaglandins and other eicosanoids (Autoregulation) Total peripheral resistance

Neurohumoral systems

Mean circulatory pressure

Venous return

Cardiac output Cardiovascular capacitance

Heart rate and contractility

FIGURE 1-3 Volume determinants of arterial pressure. The two major determinants of arterial pressure, cardiac output and total peripheral resistance, are regulated by a combination of short- and long-term mechanisms. Rapidly adjusting mechanisms regulate peripheral vascular resistance, cardiovascular capacitance, and cardiac performance. These mechanisms include the neural and humoral mechanisms listed. On a long-term basis, cardiac output is determined by venous return, which is regulated primarily by the mean circulatory pressure. The mean circulatory pressure depends on blood volume and overall cardiovascular capacitance. Blood volume is closely linked to extracellular fluid (ECF) volume and sodium balance, which are dependent on the integration of net intake and net losses [13]. (Adapted from Navar [3].)

NaCl intake

Antidiuretic hormone release If increased

Concentrated urine: Increased free water reabsorption Thirst: Increased water intake

6 5 Blood volume, L 4 3 2 0 10

Edema

Na+ and Cl Quantity of Extracellular concentrations fluid volume = NaCl in ECF in ECF volume

+

If decreased NaCl losses (urine insensible) Antidiuretic hormone inhibition

Decreased water intake Increased salt intake Dilute urine: Increased solute-free water excretion

A

B

15 Extracellular fluid volume, L

20

FIGURE 1-4 A, Relationship between net sodium balance and extracellular fluid (ECF) volume. Sodium balance is intimately linked to volume balance because of powerful mechanisms that tightly regulate plasma and ECF osmolality. Sodium and its accompanying anions constitute the major contributors to ECF osmolality. The integration of sodium intake and losses establishes the net amount of sodium in the body, which is compartmentalized primarily in the ECF volume. The quotient of these two parameters (sodium and volume) determines the sodium concentration and, thus, the osmolality. Osmolality is subject to very tight regulation by vasopressin and other mechanisms. In particular, vasopressin is a very powerful regulator of plasma osmolality; however, it achieves this regulation primarily by regulating the relative solute-free water retention or excretion by the kidney [1315]. The important point is that the osmolality is rapidly regulated by adjusting the ECF volume to the total solute present. Corrections of excesses in extracellular fluid volume involve more complex interactions that regulate the sodium excretion rate.

B, Relationship between the ECF volume and blood volume. Under normal conditions a consistent relationship exists between the total ECF volume and blood volume. This relationship is consistent as long as the plasma protein concentration and, thus, the colloid osmotic pressure are regulated appropriately and the microvasculature maintains its integrity in limiting protein leak into the interstitial compartment. The shaded area represents the normal operating range [13]. A chronic increase in the total quantity of sodium chloride in the body leads to a chronic increase in ECF volume, part of which is proportionately distributed to the blood volume compartment. When accumulation is excessive, disproportionate distribution to the interstitium may lead to edema. Chronic increases in blood volume increase mean circulatory pressure (see Fig. 1-3) and lead to an increase in arterial pressure. Therefore, the mechanisms regulating sodium balance are primarily responsible for the chronic regulation of arterial pressure. (Panel B adapted from Guyton and Hall [13].)

1.4

Hypertension and the Kidney

Intrarenal Mechanisms Regulating Sodium Balance6 Sodium excretion, normal 5 4 3 2 1 0 60 80 100 120 140 160 Renal arterial pressure, mm Hg 180 200Normal sodium intake Reduced 1 3 Elevated sodium intake 2 4 High sodium intake Normal sodium intake Low sodium intake B

A

5

C

FIGURE 1-5 Arterial pressure and sodium excretion. In principle, sodium balance can be regulated by altering sodium intake or excretion by the kidney. However, intake is dependent on dietary preferences and usually is excessive because of the abundant salt content of most foods. Therefore, regulation of sodium balance is achieved primarily by altering urinary sodium excretion. It is therefore of major significance that, for any given set of conditions and neurohumoral environment, acute elevations in arterial pressure produce natriuresis, whereas

reductions in arterial pressure cause antinatriuresis [9]. This phenomenon of pressure natriuresis serves a critical role linking arterial pressure to sodium balance. Representative relationships between arterial pressure and sodium excretion under conditions of normal, high, and low sodium intake are shown. When renal function is normal and responsive to sodium regulatory mechanisms, steady state sodium excretion rates are adjusted to match the intakes. These adjustments occur with minimal alterations in arterial pressure, as exemplified by going from point 1 on curve A to point 2 on curve B. Similarly, reductions in sodium intake stimulate sodiumretaining mechanisms that prevent serious losses, as exemplified by point 3 on curve C. When the regulatory mechanisms are operating appropriately, the kidneys have a large capability to rapidly adjust the slope of the pressure natriuresis relationship. In doing so, the kidneys readily handle sodium challenges with minimal long-term changes in extracellular fluid (ECF) volume or arterial pressure. In contrast, when the kidney cannot readjust its pressure natriuresis curve or when it inadequately resets the relationship, the results are sodium retention, expansion of ECF volume, and increased arterial pressure. Failure to appropriately reset the pressure natriuresis is illustrated by point 4 on curve A and point 5 on curve C. When this occurs the increased arterial pressure directly influences sodium excretion, allowing balance between intake and excretion to be reestablished but at higher arterial pressures. (Adapted from Navar [3].)

Filtered sodium load, mol/min/g

150 100 50 0 100Low Normal High

Fractional sodium reabsorption, %

98 96 94 92 8

FIGURE 1-6 Intrarenal responses to changes in arterial pressure at different levels of sodium intake. The renal autoregulation mechanism maintains the glomerular filtration rate (GFR) during changes in arterial pressure, GFR, and filtered sodium load. These values do not change significantly during changes in arterial pressure or sodium intake [3,16]. Therefore, the changes in sodium excretion in response to arterial pressure alterations are due primarily to changes in tubular fractional reabsorption. Normal fractional sodium reabsorption is very high, ranging from 98% to 99%; however, it is reduced by increased sodium chloride intake to effect the large increases in the sodium excretion rate. These responses demonstrate the importance of tubular reabsorptive mechanisms in modulating the slope of the pressure natriuresis relationship. (Adapted from Navar and Majid [9].)

Fractional sodium excretion, %

6 4 2 0 75 100 125 150 175 Renal arterial pressure, mm Hg

The Kidney in Blood Pressure Regulation

1.5

RA

ga=25

B140/90 mm Hg) is common and almost universally observed in patients with acute glomerulonephritis (GN). Many of these patients have lower pressures as the course of acute renal injury subsides, although residual abnormalities in renal function and sediment may remain. Blood pressure returns to normal in some but not all of these patients. Overall, 39% of patients with acute renal failure develop new hypertension. INinterstitial nephritis. (Adapted from RodriguezIturbe and coworkers [3]; with permission.)

FIGURE 2-6 (see Color Plate) Micrograph of an onion skin lesion from a patient with malignant hypertension.

2.4

Hypertension and the Kidney

Pathophysiology of Hypertension in Renal DiseasexFIGURE 2-7 Pathophysiologic mechanisms related to hypertension in parenchymal renal disease: schematic view of candidate mechanisms. The balance between cardiac output and systemic vascular resistance determines blood pressure. Numerous studies suggest that cardiac output is normal or elevated, whereas overall extracellular fluid volume is expanded in most patients with chronic renal failure. Systemic vascular resistance is inappropriately elevated relative to cardiac output, reflecting a net shift in vascular control toward vasoconstricting mechanisms. Several mechanisms affecting vascular tone are disturbed in patients with chronic renal failure, including increased adrenergic tone and activation of the reninangiotensin system, endothelin, and vasoactive prostaglandins. An additional feature in some disorders appears to depend on reduced vasodilation, such as in impaired production of nitric oxide.

Blood pressure =

Cardiac output

Systemic vascular resistance

Increased extracellular fluid volume Decreased glomerular filtration rate Impaired sodium excretion Increased renal nerve activity Ineffective natriuresis, eg, atrial natriuretic peptide resistance

Increased contraction Increased adrenergic activation

Increased vasoconstriction Increased adrenergic stimuli Inappropriate renin-endothelin release Increased endothelin-derived contracting factor Increased thromboxane

Decreased vasodilation Decreased prostacyclin Decreased nitric oxide

7 Intake and output of water and salt (x normal) Intake and output of water and salt (x normal) 6 5 4 3NormalD

7kid G o ld ne blat t ys Al do ste ron e-s tim ula ted

6 5 4 3 2 1 0Normal intake Low intake A H B

High intake

E s se n hyp tial erte nsio n

Normal

High intake

F G

2 1 0 0 50Normal intake Low intake

A C

B

ss ma al ren of ss D Lo C

E

A

100 150 Arterial pressure, mm Hg

200

0

50

B

100 150 Arterial pressure, mm Hg

200

FIGURE 2-8 A, The relationship between renal artery perfusion pressure and sodium excretion (which defines pressure natriuresis) has been the subject of extensive research. Essential hypertension is characterized by higher renal perfusion pressures required to achieve daily sodium balance. B, Distortion of this relationship routinely occurs in patients with parenchymal renal disease, illustrated here

as loss of renal mass. Similar effects are observed in conditions with disturbed hormonal effects on sodium excretion (aldosterone-stimulated kidneys) or reduced renal blood flow as a result of an arterial stenosis (Goldblatt kidneys). In all of these instances, higher arterial pressures are required to maintain sodium balance.

Renal Parenchymal Disease and Hypertension200 Percentage of body weight, kg Total blood volume, mL/cm 130Hemodialysis

2.5

40

Cumulative daily sodium intake

0Cumulative urinary sodium loss

126

35

400 Sodium, mEq 800

122

30

118 F 10.0 S S M T W TH Days F S S M

Sodium losses during hemodialysis or ultrafiltration Net sodium loss

1200

1600

Plasma renin activity, mg/mL/h

5.0

Uremic control subjects

Total net loss of sodium=1741 mEq

F

S

S

M T

B

W TH F Days

S

S M

T

Blood pressure, mm Hg

180Captopril, 25 mg

140

A

100

FIGURE 2-9 Sodium expansion in chronic renal failure. The degree of sodium expansion in patients with chronic renal failure can be difficult to ascertain. A, Shown are data regarding body weight, plasma renin

activity, and blood pressure (before and after administration of an ACE inhibitor) over 11 days of vigorous fluid ultrafiltration. Sequential steps were undertaken to achieve net negative sodium and volume losses by means of restricting sodium intake (10 mEq/d) and initiating ultrafiltration to achieve several liters of negative balance with each treatment. A negative balance of nearly 1700 mEq was required before evidence of achieving dry weight was observed, specifically a reduction of blood pressure. Measured levels of plasma renin activity gradually increased during sodium removal, and blood pressure became dependent on the renin-angiotensin system, as defined by a reduction in blood pressure after administration of the angiotensin-converting enzyme inhibitor captopril. Achieving adequate reduction of both extracellular fluid volume and sodium is essential to satisfactory control of blood pressure in patients with