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
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;;;;;;;;;;; ;;;; ;;; ;;;;;;;;;;; ;;;; ;;; ;;;;;;;;;;; ;;;; ;;;
;;;;;;;;;;; ;;;; ;;; ;;;; ;;; ;;;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
;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;;
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;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;;
;;;;;;;;;;;;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.
1.8
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.
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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
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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
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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
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Diseases and Related Disorders Edited by Suki WN, Massry SG.
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RG: Metabolic alkalosis. In Textbook of Nephrology. Edited by
Massry SG, Glassock RJ. Baltimore: Williams & Wilkins;
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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.
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tubular acidosis is associated in three families with
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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