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266 SECTION V Renal Disease
Therefore, the presence of small kidneys is not required to make a
diagnosis of CKD.
The echogenicity of the kidneys is compared with that of liver
parenchyma. Typically, the kidneys are less echogenic than the liver.
Increased echogenicity of the kidneys suggests the presence of scarring
and therefore CKD. Renal ultrasonography can also easily detect the
presence of cysts in the kidneys and therefore is a useful technique to
detect polycystic kidney disease.
Pulsed Doppler imaging is often used to calculate the resistive index
by estimating the systolic and diastolic Doppler velocities in the renal
cortex. A resistive index greater than 0.8 suggests that interventional
procedures to revascularize the kidney would be unlikely to benefit the
patient in terms of improving blood pressure or protecting the longterm decline in kidney function. If the two kidneys differ in size by
1.5 cm, it suggests the presence of renovascular disease in an adult.
In children, reflux nephropathy or congenital abnormalities are more
common causes of asymmetric kidney size.
Computed tomography (CT) of the kidney is often helpful to evaluate complex cysts. In contrast to simple cysts, complex cysts are suspicious for the presence of malignancy, and CT can evaluate them better
than ultrasonography. Likewise, CT is important for evaluating renal
masses, stones, retroperitoneal conditions (e.g., hemorrhage, tumor,
abscess), and renal vein thrombosis. In morbidly obese people, CT is
often used to guide kidney biopsy. The use of contrast agents to assess
vascular lesions of the kidney may be not be possible if kidney function is compromised due to fear of precipitating AKI. Limiting the volume of the contrast agent and volume repletion before radiocontrast
administration may minimize renal injury.
Although intravenous pyelography can image the structures in the
kidney, contrast CT has taken the place of classic intravenous pyelography in many centers because of the risk of inducing nephrotoxicity in
patients with CKD. In contrast, retrograde pyelography is often used by
urologists to define the site and nature of obstruction within the ureter
and the pelvis. In addition, during the procedure, ureteric stones can
be removed with the use of a basket device.
Magnetic resonance imaging (MRI) is useful for imaging of the vasculature and therefore for the diagnosis of renal vein thrombosis and
renal artery stenosis. Gadolinium-based contrast agents are often used
for MRI because of their paramagnetic properties. These agents should
be avoided if the GFR is less than 30 mL/min/1.73 m2, because in such
patients they have been implicated in causing a disabling and untreatable condition called nephrogenic systemic fibrosis. It is now believed
that the risk of this disabling condition is directly related to the release
of free gadolinium from gadolinium-based contrast agents. Stable
macrocyclic agents that minimize the release of free gadolinium after
administration such as gadoterate acid and godobutrol are preferred
over the older gadolinium-based contrast agents. MRI cannot be performed in patients who have metallic implanted devices with magnetic
properties such as pacemakers, artificial joints, or aneurysmal clips.
Although nonferrous surgical metal can distort an MRI image, most
are safe within the strong magnetic field of an MRI machine. Research
now reveals that MRI examination after a total joint replacement is
not only possible, but adjusting pulse sequences and parameters often
can provide accurate information on soft tissue tissues and causes of
joint failure.
After injection of a small amount of radioactive substance, radionu-
clide imaging can be performed to assess renal perfusion and function
of the kidneys. One advantage of this technique is that it can assess
kidney function and perfusion simultaneously for each kidney. It
therefore allows diagnosis of renal artery stenosis, especially when it is
performed before and after administration of angiotensin-converting
enzyme (ACE) inhibitors.
Renal arteriography is the reference standard for the diagnosis of
renal artery stenosis. It involves direct injection of a radiocontrast dye
into the renal arteries. In patients with CKD, contrast injection can
be limited and carbon dioxide can be injected to avoid nephrotoxicity. This technique is also useful for assessing vascular malformations
in the kidney and for making a diagnosis of polyarteritis nodosa. In
the latter condition, renal arteriography can detect the presence of
microaneurysms.
APPROACH TO THE PATIENT WITH ACUTE KIDNEY
INJURY
The initial approach to patients with AKI focuses on the following factors: (1) the evaluation of risk or susceptibility to renal injury, (2) the
cause(s) of the AKI, (3) the severity of injury, and (4) the presence
of distant organ effects or consequences. In all cases, it is important
to evaluate and optimize intravascular volume early in the course,
because this is a readily addressable factor that can prevent or minimize further injury.
Evaluation of Risk or Susceptibility to Renal Injury
The risk factors for AKI include, first and foremost, prior existence
of CKD; CKD can easily be detected by a low estimated GFR or the
presence of albuminuria. Other common risk factors for AKI include
advanced age, diabetes mellitus, hypertension (especially when treated
with inhibitors of the renin-angiotensin system), chronic liver disease
or cirrhosis, and multiple myeloma.
Causes of AKI
AKI is a challenging medical problem, and a careful and stepwise
approach to evaluation is essential. This approach is guided by knowledge of the causes of injury, which can be divided into five major
groups: ischemia, toxins, obstruction, inflammation, and infection.
Ischemia can be caused by volume loss from the gastrointestinal
system (vomiting or diarrhea), the skin (sweating, burns), or the kidneys (diuretics, Addison’s disease, and solute diuresis). Comparing the
body weight of the patient with those weights recorded in the medical record can be valuable. A substantial decrease in body weight may
point toward volume depletion as a possible cause of AKI. Third-space
fluid losses, as observed in patients with ascites, pancreatitis, or ileus,
can make the diagnosis of volume depletion challenging because such
patients may not have an overall loss in body weight. Ischemia is a
common cause of AKI due to poor perfusion associated with significant blood loss or sepsis or both. In the setting of ischemia, glomerular
hypoperfusion is aggravated when patients are taking inhibitors of the
renin-angiotensin system.
Nephrotoxins can be divided into two major groups: endogenous
and exogenous. The endogenous toxins include paraproteins, myoglobin, hemoglobin, uric acid (e.g., in tumor lysis syndrome), and bile
acids. Exogenous toxins include contrast agents, aminoglycosides, vancomycin, chemotherapeutic agents such as cisplatin, and NSAIDs.
Inflammation can involve the glomerular, interstitial, and vascular
compartments. Inflammation of these structures produces glomerulonephritis, interstitial nephritis, and vasculitis, respectively.
Infection is an important cause of injury to the nephron. Infectionassociated AKI is often diagnosed in the intensive care unit, where early
sepsis can manifest as a fall in urine output followed by an increase in
serum creatinine, confirming AKI. The causes of AKI in the setting of
sepsis are often multifactorial and include ischemia, direct tubular dysfunction due to sepsis, and concomitant administration of drugs such
as nephrotoxic antibiotics (commonly, high doses of vancomycin) and
procedures (radiocontrast imaging), often performed to reverse sepsis.
CHAPTER 24 Approach to the Patient With Renal Disease
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267
Therefore, declines in urine volume, especially in the intensive care
unit, should lead to a diligent search for a focus of infection.
Urinary tract obstruction is often a reversible cause of renal injury
and therefore important to diagnose. Although urine output is frequently reduced with obstruction, partial obstruction may be associated with an increase in urine output. Renal ultrasound is useful to
diagnose hydronephrosis; urinalysis may reveal hematuria or infection
or may be bland. Left untreated, renal atrophy may ensue.
In many ways, the severity of injury is best assessed at the bedside.
Oliguric renal failure (100-400 mL urine/24 hr) or anuric renal failure
(<100 mL urine/24 hr) has a worse prognosis than nonoliguric renal
failure (>400 mL urine/24 hr). A low fractional excretion of sodium
or, if the patient is taking diuretics, a low fractional excretion of urea
may suggest volume depletion as the likely cause. Fractional excretion
of any substance is simply calculated as the ratio of the clearance of
the analyte in question to the clearance of creatinine. However, a low
fractional excretion of urea or sodium may have causes other than volume depletion. For example, because of the heterogeneous nature of
nephronal injury, contrast-induced injury, sepsis, or burns often result
in a low fractional excretion of sodium despite intrinsic renal failure.
Intrinsic renal injury can be detected by examining the urine sediment. The classic manifestation of acute tubular necrosis (ATN) is the
presence of dirty-brown granular casts. However, in severe AKI, there
may be a large amount of amorphous granular material without cast
formation (see Figs. 24.3 and 24.5). This occurs because severe AKI
may result in failure to produce the Tamm-Horsfall protein that is now
called uromodulin, leading to no formation of casts. In the absence
of dirty-brown granular casts, a diagnosis of acute tubular injury can
still be made based on the presence of dysmorphic epithelial cells in
the urine. These epithelial cells, under hypoxic conditions, transform
from the round, fried-egg appearance of the tubular cell to angular
cells taking the shape of triangles or teardrops (see Fig. 24.3). A normal
sediment, on the other hand, suggests minimal or no kidney injury.
The individual elements that can be seen in the urine and may be of
diagnostic importance are as follows: dysmorphic RBCs, sterile pyuria
manifested by white blood cells (WBCs) in the urine without bacteria,
urinary tract infection characterized by both WBCs and bacteria in the
urine, dysmorphic tubular cells suggesting ATN, intact renal tubular
cells suggesting recovery from AKI, bubble cells, glitter cells, and oval
fat bodies (see Figs. 24.2 and 24.3).
Budding yeast in a patient with diabetes may suggest the need to
remove a long-standing indwelling catheter. Uric acid crystals in
large amount suggest tumor lysis syndrome, calcium oxalate crystals
may suggest ethylene glycol poisoning, and magnesium ammonium
phosphate (triple phosphate) crystals may suggest infection with urease-positive organisms (see Fig. 24.4).
Casts can occur in various forms, such as RBC, WBC, epithelial cell,
granular, hyaline, and dirty-brown granular casts. They can also occur
in various shapes, such as broad and narrow casts. Examples of these
are demonstrated in Fig. 24.5.
Severity of Injury
The severity of injury needs to be assessed, as well as its relationship to
the preexisting state of kidney health. Severe injury is required for AKI
to be manifested when the kidney is otherwise healthy. Little damage is
needed to produce a severe injury if CKD preexists. More important,
however, is the response to injury. It remains unclear why certain individuals have low GFR and others with the same extent of injury do not.
This likely reflects the protective nature of responses that can result in
poor or better GFR.
Presence of Distant Organ Effects on Consequences
End-organ manifestations of AKI include pulmonary edema or acute
respiratory distress syndrome, uremic encephalopathy as alteration of
mental status or asterixis, and uremic pericarditis or pleuritis manifested as pericardial or pleural friction rub. Although pulmonary
edema is still a common manifestation of uremia, uremic serositis and
encephalopathy are now rare.
For a deeper discussion on this topic, see Chapter 106, “Approach
to the Patient with Renal Disease,” in Goldman-Cecil Medicine, 26th
Edition.
SUGGESTED READINGS
Agarwal R, Delanaye P: Glomerular filtration rate: when to measure and in
which patients?, Nephrol Dial Transplant. https://doi.org/10.1093/ndt/
gfy363.
Earley A, Miskulin D, Lamb EJ: et al: Estimating equations for glomerular
filtration rate in the era of creatinine standardization: a systemic review,
Ann Intern Med 156:785–795, 2012.
Gansevoort RT, Matsushita K, van der Velde M, et al: Lower estimated GFR
and higher albuminuria are associated with adverse kidney outcomes: a
collaborative meta-analysis of general and high-risk population cohorts,
Kidney Int 80:93–104, 2011.
Maroni BJ, Steinman TI, Mitch WE: A method for estimating nitrogen intake
of patients with chronic renal failure, Kidney Int 27:58–65, 1985.
Perazella M, Coca S, Kanbay M, et al.: Diagnostic value of urine microscopy
for differential diagnosis of acute kidney injury in hospitalized patients,
Clin J Am Soc Nephrol 3:1615–1619, 2008.
Perrone RD, Madias NE, Levey AS: Serum creatinine as an index of renal
function: new insights into old concepts, Clin Chem 38:1933–1953, 1992.
Pickering TG, Miller NH, Ogedegbe G, et al.: Call to action on use and
reimbursement for home blood pressure monitoring: a joint scientific
statement from the American Heart Association, American Society
Of Hypertension, and Preventive Cardiovascular Nurses Association,
Hypertension 52:10–29, 2008.
Pickering TG, Shimbo D, Haas D: Ambulatory blood-pressure monitoring,
N Engl J Med 354:2368–2374, 2006.
Calculate
+
×2+
25
Fluid and Electrolyte Disorders
Biff F. Palmer
NORMAL VOLUME HOMEOSTASIS
In the average adult, the total body water is equal to 50% to 60% of
body weight: 60% for men and 50% for women because of extra body fat,
which is water free. Thus, in an average 70-kg male, total body water is
42 kg or 42 L, while in an average 70-kg female, total body water is 35
kg or L. Of the total body water, approximately two thirds is located
intracellularly while one third is located extracellularly. Of the extracellular fluid (ECF) volume, only one fourth is located within the intravascular space. In a 70-kg man with a total body water of 42 L, 28 of
these liters will be located intracellularly, while only 14 L are located in
the ECF, and only 3.5 L are located in the extracellular intravascular
compartment.
ECF volume is determined by the balance between sodium intake
and excretion. Under normal circumstances, wide variations in salt
intake lead to parallel changes in renal salt excretion, such that ECF
volume and total body salt is maintained within narrow limits. This
relative constancy of ECF volume is achieved by a series of afferent
sensing systems, central integrative pathways, and both renal and
extrarenal effector mechanisms acting in concert to modulate sodium
excretion by the kidney (Table 25.1).
The concentration of sodium chloride (NaCl) in the plasma
is regulated by renal water handling. The maintenance of plasma
tonicity is achieved by sensing and effector mechanisms that differ
from those that regulate volume. However, the systems that regulate
volume and plasma tonicity do work in concert. For example, if the
baroreceptors of the body detect that ECF volume is low, the kidney will respond by retaining NaCl. This will transiently lead to an
increase in the tonicity of the ECF that will stimulate arginine vasopressin (AVP) release, causing renal water retention and expansion
of the ECF volume.
Osmolality and Tonicity
Osmolality is defined as the number of particles per kilogram of solution. Plasma osmolality can be directly measured in an osmometer or
can be calculated using the following equation:
d osmolality = Na
where Na+ is the sodium ion concentration and BUN is the blood urea
nitrogen level.
The osmolar gap is the difference between the measured and calculated osmolality and is normally less than 10 mOsm/L. A higher value
indicates the accumulation of an unmeasured substance such as ethanol, methanol, ethylene glycol, and acetone.
It is important to distinguish osmolality from tonicity. Whereas
osmolality refers to all particles, tonicity describes whether the particles are effective or ineffective osmoles. Effective osmoles such as Na+,
glucose, or mannitol cannot penetrate cell membranes and thus can
glucose/18+BUN/ 2.8
lead to changes in cell volume. Ineffective osmoles such as urea and
alcohols are ineffective osmoles because they pass freely into and out
of cells and are unable to effect changes in cell volume. As an example,
chronic kidney disease patients with BUN levels greater than 100 mg/
dL have no cellular shifts of fluid due to the urea. The plasma osmolality is high, but plasma tonicity is normal.
HYPONATREMIA
Hyponatremia is one of the most common electrolyte abnormalities
encountered in clinical practice. Increasing age, medications, various
disease states, and administration of hypotonic fluids are among the
known risk factors for the disorder. Although hyponatremia is most
commonly a marker of hypo-osmolality, there are three general causes
of hyponatremia not associated with a hypo-osmolar state (Fig. 25.1).
The first of these is pseudohyponatremia. This condition occurs in the
setting of hyperglobulinemia or hypertriglyceridemia in which plasma
water relative to plasma solids is decreased in blood leading to less Na+
in a given volume of blood.
The second cause involves true hyponatremia but with elevations
in the concentration of an effective osmole. Clinical examples include
hyperglycemia as seen in uncontrolled diabetes or rarely hypertonic infusion of mannitol used in the treatment of cerebral edema.
Increased plasma glucose concentration raises serum osmolality,
which pulls water out of cells and dilutes the serum Na+. For every
100-mg/dL rise in glucose or mannitol the serum Na+ will quickly fall
by 1.6 mEq/L. The increased tonicity will also stimulate thirst and AVP
secretion, both of which contribute to further water retention. As the
plasma osmolality returns towards normal, the decline in serum Na+
will be 2.8 mEq/L for every 100-mg/dL rise in glucose. The net result is
a normal plasma osmolality but a low serum Na+.
The third cause of hyponatremia in the absence of a hypo-osmolar
state is the addition of an isosmotic (or near isosmotic) non-Na+ containing fluid to the extracellular space. This situation typically occurs
during a transurethral resection of the prostate or during laparoscopic
surgery when large amounts of a non-conducting flushing solution
containing glycine or sorbitol are reabsorbed systemically.
The presence of hypotonic hyponatremia implies that water intake
exceeds the ability of the kidney to excrete water. Because the normal kidney can excrete 20 to 30 L of water per day, the presence of
hyponatremia with normal renal water excretion implies the patient is
drinking at least those volumes of water. This condition is referred to
as primary polydipsia. Urine osmolality will be less than 100 mOsm/L
in this setting. Hyponatremia in association with a maximally dilute
urine can also result from more moderate fluid intake combined with
extremely limited solute intake, a condition often referred to as “beer
potomania” syndrome.
268
Plasma osmolality ?
TABLE 25.1 Sensors and Effectors That
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Determine Osmoregulation and Volume
Regulation
Factor Osmoregulation Volume Regulation
What is sensed Plasma osmolality Effective arterial volume
(EAV)
Sensors Hypothalamic osmore-
ceptors
Effectors Arginine vasopressin (AVP),
Thirst
What is effected Urine osmolality, Thirst Urine Na+ excretion
Low and high pressure
baroreceptors
Aldosterone, Angiotensin II,
Sympathetic nerves
CHAPTER 25 Fluid and Electrolyte Disorders
Decreased
Urine osmolality ?
Appropriately low
Primary polydipsia
Beer potomania syndrome
Inappropriately high
EABV ?
Normal
Pseudohyponatremia
*Hyperglycemia
Isosmotic irrigating solution
269
In the absence of primary polydipsia, hypotonic hyponatremia
results when water intake exceeds the renal capacity for water excretion due to an inappropriately concentrated urine (some value >100
mOsm/L). The effective arterial blood volume (EAV) must be defined
in this setting. Decreased EAV causes baroreceptor stimulation of AVP
secretion and leads to decreased distal delivery of filtrate to the tip of
the loop of Henle, accounting for the inability to maximally dilute the
urine. If EAV is low, ECF volume can be low in the volume-depleted
patient (hypovolemic hyponatremia) or can be high in the edematous
patient (hypervolemic hyponatremia). A normal EAV points to euvolemic causes of hyponatremia (isovolemic hyponatremia).
Approximately two thirds of diagnosed hyponatremia cases are
acquired in the hospital, where the common practices of monitoring daily
fluid intake, patient weight, and Na+ levels normally allow prompt diagnosis. Administration of hypotonic fluids in the postoperative period is
a risk factor for acute iatrogenic hyponatremia, particularly because AVP
levels remain increased several days after surgical procedures. Iatrogenic
cases can be prevented by close monitoring of electrolytes and urine output and by fluid restriction and avoidance of solutions with low-Na+
content; this approach applies particularly to elderly patients.
In neurosurgical patients, the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral salt wasting (CSW)
are two potential causes of hyponatremia. Distinguishing between
these two disorders can be challenging because there is considerable
overlap in the clinical presentation. The primary distinction lies in the
assessment of the EAV. SIADH is a volume-expanded state due to AVPmediated renal water retention. CSW is characterized by a contracted
EAV resulting from renal salt wasting. Making an accurate diagnosis
is important because the therapy of each condition is quite divergent.
Vigorous salt replacement is indicated in patients with CSW, and fluid
restriction is the treatment of choice in patients with SIADH.
Common causes of hyponatremia outside the hospital setting
include overhydration, diarrhea, vomiting, CNS infection, extreme
exercise, liver failure, renal failure, congestive heart failure, drugs,
SIADH, and combinations of these and other factors. Thiazide diuretics are the most common cause of drug-induced hyponatremia.
Hyponatremia typically develops in the first 2 weeks of drug initiation
and is most likely to occur in elderly women and during the summer
months because of the increased ingestion of hypotonic fluids when
it is hot. Concomitant use of nonsteroidal anti-inflammatory drugs
(NSAIDs) and selective serotonin reuptake inhibitors (SSRIs) can further increase the risk of thiazide-induced hyponatremia.
Treatment of Hyponatremia
Symptoms of hyponatremia include nausea and malaise, which can be
followed by headache, lethargy, muscle cramps, disorientation, restlessness, and obtundation. When treating a patient with hyponatremia,
Low
ECF volume ?
hgiH woL
Diarrhea
Diuretics
Cerebral salt wasting
Mineralocorticoid deficiency
Fig. 25.1 Approach to the patient with hyponatremia. Assessment of
effective arterial blood volume (EAV) is key to understanding the mechanism of renal NaCl retention and whether it is primary or in response
to a low EAV. By definition, EAV is the arterial volume sensed by the
kidney. Thus, if the kidney is working normally and it is retaining NaCl,
EAV must be low, and if a normally functioning kidney is excreting large
amounts of NaCl, the EAV is large. The physical examination is the most
reliable way to assess EAV. The presence or absence of edema and
orthostatic changes in blood pressure and pulse are particularly useful
findings indicative of EAV. Laboratory tests are also useful in the assessment of EAV. Collection of a spot urinary sample for Na+, Cl−, and creatinine allows calculation of the fractional excretion of Na+ or fractional
excretion of Cl− using the following equations: FENa (%) = [(urine Na+
× plasma creatinine)/(plasma Na+ × urine creatinine)] × 100 FECl (%) =
[(urine Cl− × plasma creatinine)/(Plasma Cl− × urine creatinine)] × 100.
If these parameters are low (<0.5 to 1%), a low EAV is indicated. Other
findings suggestive of a low EAV include an increase in the blood urea
nitrogen (BUN)/creatinine ratio (>20:1), increased serum uric acid concentration (due to increased proximal tubular reabsorption), and increased
hematocrit and serum albumin concentration secondary to hemoconcentration. *Osmolality can be normal or increased with hyperglycemia.
Edematous states
Normal
SIADH
Glucocorticoid deficiency
Hypothyroidism
Drugs
the Na+ concentration should be raised at the rate at which it fell. In
patients with chronic hyponatremia (>48 hours duration), the serum
Na+ concentration has fallen slowly. Neurologic symptoms are generally minimal, brain size is normal, and the number of intracellular
osmoles is decreased. Sudden return of ECF osmolality to normal values will lead to cell shrinkage and possibly precipitate osmotic demyelination. This complication can be avoided by limiting correction to
less than 10 to 12 mEq/L in 24 hours and to less than 18 mEq/L in
48 hours. In a patient whose serum Na+ concentration has decreased
rapidly (<48 hours), neurologic symptoms are frequently present, and
there is cerebral edema. In this setting, there has not been enough time
to remove osmoles from the brain, and rapid return to normal ECF
osmolality merely returns brain size to normal.
In general, the development of hyponatremia in the outpatient setting is more commonly chronic in duration and should be corrected
slowly. By contrast, hyponatremia of short duration is more likely to be
270 SECTION V Renal Disease
*All are associated with impairment of thirst or access to water
Hypernatremia*
Clinically assess extracellular fluid volume
Hypovolemia
(Hypotonic fluid loss)
I. Renal losses
A. Osmotic diuresis
1. Hyperglycemia
2. Mannitol
3. Relief of acute
obstruction
B. Diuretics
II. Extrarenal losses
A. Skin
B. Respiratory tract
C. Gastrointestinal tract
Fig. 25.2 Approach to the patient with hypernatremia.
Isovolemia
(Pure water loss)
I. Renal losses
A. Central D.I.
B. Nephrogenic D.I.
II. Extrarenal losses
A. Respiratory
B. Skin
encountered in hospitalized patients receiving intravenous free water.
Use of “ecstasy,” exercise-induced hyponatremia, or patients with primary polydipsia can also lead to acute hyponatremia and if symptomatic may similarly require rapid correction.
HYPERNATREMIA
Hypernatremia is a relatively common problem, particularly among
the elderly and critically ill. Hypernatremia always indicates hypertonicity and shrinkage of cells. It is an independent risk factor for mortality in the ICU setting.
The initial approach to any patient with hypernatremia is to determine
why there has been inadequate intake of water (Fig. 25.2). Hypernatremia
is rare in conscious patients who have free access to water because of the
extreme sensitivity of the thirst mechanism. Usually there is inadequate
water intake due to an alteration in the level of consciousness so that
patients become unaware of thirst or cannot adequately communicate
the need for water or there is restricted access to water. Only rarely is
there a specific lesion of the thirst center. A reduced sensation of thirst
occurs in otherwise normal individuals as a feature of increasing age.
The next step is to search for the presence of accelerated water loss or
increased Na+ gain, both of which will increase the likelihood of a patient
developing hypernatremia. This can be accomplished by clinical assessment
of EAV. Hypovolemic hypernatremia results from fluid losses in which the
Na+ concentration is less than the plasma concentration. Hypervolemic
hypernatremia can be due to iatrogenic administration of hypertonic NaCl
or hypertonic NaHCO3 or from mineralocorticoid excess.
Pure water loss, whether from mucocutaneous routes or from the
kidneys, causes isovolemic hypernatremia. Because two thirds of pure
water loss is sustained from within cells, patients will not become clinically volume depleted unless the water deficit becomes substantial.
Insensible losses from the respiratory tract or skin result in concentrated urine. Inappropriate water loss by the kidney, whether from central or nephrogenic diabetes insipidus, results in dilute urine. Although
renal water loss can lead to hypernatremia in patients with impaired
thirst or access to water, most patients with diabetes insipidus have
neither of these defects and typically present with polyuria, polydipsia,
and a normal serum sodium concentration.
Hypervolemia
(Hypertonic fluid gain)
I. Iatrogenic
A. Hypertonic saline
B. Hypertonic sodium
Bicarbonate
II. Mineralocorticoid excess
Evaluation of Polyuria and Polydipsia
Polyuria can be the result of an osmotic diuresis or a water diuresis.
In turn, a water diuresis may result from inappropriate water loss as
in either central or nephrogenic diabetes insipidus or may represent
appropriate water loss as in primary polydipsia. The clinical setting and
urine osmolality help to differentiate between these processes (Fig. 25.3).
Osmotic diuresis causing polyuria is often evident from the clinical setting. Poorly controlled glucose levels in a patient with diabetes
mellitus, administration of mannitol to a patient with increased intracranial pressure, and high-protein enteral feedings (urea diuresis) are
all examples in which polyuria is the result of osmotic diuresis. Urine
osmolality greater than 300 mOsm/L) in the polyuric patient is suggestive of solute or osmotic diuresis.
After excluding the presence of osmotic diuresis, one must then discriminate between the causes of water diuresis. In patients with central
diabetes insipidus, the onset of symptoms is characteristically abrupt
in nature, whereas patients with nephrogenic diabetes insipidus typically have a more gradual onset of symptoms. Patients with primary
polydipsia are more vague in dating the onset of their symptoms. Both
nephrogenic and central diabetes insipidus are characterized by severe
and frequent nocturia, a feature that is typically absent in patients with
primary polydipsia. Patients with central diabetes insipidus seem to
have a predilection for ice water, which is not typically described in
the other two conditions. A serum Na+ concentration less than 140
mEq/L is suggestive of primary polydipsia because these patients tend
to be in mild positive water balance. By contrast, a value greater than
140 mEq/L is more suggestive of either central or nephrogenic diabetes insipidus because these patients tend to be in mild negative water
balance. Finally, urine osmolality will increase in response to water
deprivation in primary polydipsia but show no response in diabetes
insipidus. Central and nephrogenic diabetes insipidus are distinguished
by the change in urine osmolality following subcutaneous administration of AVP (increased in central with no change in nephrogenic).
Treatment of Hypernatremia
Signs and symptoms of hypernatremia include lethargy, weakness,
fasciculations, seizures, and coma. Increased ECF osmolality initially
causes cell shrinkage within the brain. In response, cells generate
CHAPTER 25 Fluid and Electrolyte Disorders
Water decit = Current body water ( 0. 6 in men and 0. 5
TTKG = U
× Serum
/Serum
× U
osmolality
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Approach to the patient with polyuria
?, Clinical setting
U
osm
271
>300 mOsm/Kg U
U
osm
Osmotic diuresis
U
remains <100 mOsm/Kg
osm
AVP response
Inappropriately dilute Appropriately concentrated
Nephrogenic diabetes insipidus Central diabetes insipidus
Fig. 25.3 Approach to the patient with polyuria. AVP, Arginine vasopressin; U, urine.
intracellular osmoles, which pull water back into the cells, returning
brain size to normal. If extracellular osmolality is returned rapidly to
normal, the extra intracellular osmoles will pull water into the brain
cells, resulting in cerebral edema. Thus, in general, hypernatremia
should be corrected slowly by water administration at a rate that leads
to half correction in 24 hours. The water deficit can be estimated from
the following formula:
in women × body weight) × N
+
a
plasma
/140 − 1
Calculation of the amount of water to give must add insensible
losses and any ongoing losses from the urinary and gastrointestinal
tract. This formula also does not include the volume of isotonic saline
required in those patients who may be concomitantly volume depleted.
Careful monitoring of the serum Na+ is required to ensure the rate of
correction is appropriate.
HYPOKALEMIA
Hypokalemia is a common clinical disorder. Decreases in total body
K+ are usually due to gastrointestinal or renal losses whereas hypokalemia in the setting of normal total body K+ is due to cell shift. In
most cases, the cause can be determined by history, measurement of
blood pressure, examination of acid-base balance, and measurement
of urinary K+ levels.
Cellular Shift With Normal Total Body Potassium
In the absence of physical and historical evidence of gastrointestinal
or renal K+ losses, either a redistribution of K+ at the cellular level or
laboratory error will account for a low serum K+. Spurious causes of
hypokalemia can be seen in leukemia patients with leukocyte counts of
100 to 250,000 × 109/L, in which still-viable leukocytes extract K+ from
the serum in the sample tube. Interestingly, some patients with acute
myeloid leukemia develop kidney K+ wasting due to increased urinary
excretion of lysozyme. This protein increases the luminal electronegativity in the collecting duct, providing a greater driving force for K+
secretion.
The regulation of K+ distribution between the intracellular and
extracellular space is referred to as internal K+ balance. Although the
kidney is ultimately responsible for maintenance of total body K+,
factors that modulate internal balance are important in the disposal
of acute K+ loads. A large potassium meal could potentially double
<100 mOsm/Kg
osm
Water deprivation response
Appropriately concentrated
Primary polydipsia
extracellular K+ were it not for the rapid shift of the K+ load into cells.
The kidney cannot excrete K+ rapidly enough in this setting to prevent
life-threatening hyperkalemia. Thus, it is important that this excess K+
be rapidly shifted and stored in cells until the kidney has successfully
excreted the K+ load. The major regulators of K+ shift into cells are
insulin and catecholamines.
Insulin excess, whether given exogenously in a patient with diabetes
mellitus or endogenous secretion as seen in a normal person given a
high glucose load, will lower the serum K+. β-Adrenergic agonists used
in the treatment of bronchospasm or in treating premature labor will
cause similar K+ shifts. In the setting of an acute myocardial infarction, hypokalemia may result as a sequela of high circulating epinephrine levels and might predispose to arrhythmias in this clinical setting.
Other clinical disorders resulting in intracellular sequestration of K+
are treatment of megaloblastic anemia with vitamin B12, hypothermia,
and barium poisoning. Hypokalemic periodic paralysis is inherited
in an autosomal dominant pattern and is characterized by episodic
hypokalemia resulting in muscle weakness. An acquired form of the
disorder is seen in thyrotoxic patients, who are often of Japanese or
Mexican descent.
Decreased Total Body Potassium
In the absence of cell shift, low serum K+ can result from inadequate
dietary intake, extrarenal losses through the gastrointestinal tract or
skin, or renal losses. The urinary K+ concentration serves as a useful
guide in discerning between these possibilities. A urine K+ concentration of less than 20 mEq/L is suggestive of extrarenal losses, whereas a
urine concentration of greater than 40 mEq/L suggests renal K+ losses.
A limitation of a random value is the degree of urinary concentration.
A urine K+ concentration of 40 mEq/L may be an appropriate response
in a hypokalemic patient with maximally concentrated urine due to
decreased water intake. By the same token, a random urine value of
less than 15 mEq/L may represent renal K+ wasting if obtained in the
setting of water diuresis.
The transtubular potassium gradient (TTKG) is a method designed
to overcome the limitations of a random urine K+ concentration in the
evaluation of a dyskalemic patient:
potassium
The formula estimates the ratio of K+ in the lumen of the cortical
collecting duct to that in the peritubular capillaries at a point where
tubular fluid is isotonic relative to plasma. While still often used, the
osmolality
potassium
272 SECTION V Renal Disease
relationship
Decreased EABV Increased EABV
Increased
proximal Na
reabsorption
Decreased distal
+
Na
Fig. 25.4 The relationship between effective arterial volume and distal Na+ delivery in determining renal K+
excretion.
+
delivery
Increased
renin
Increased
aldosterone
Increased
aldosterone
+
↑ Kidney K
excretion
Increased distal
Increased distal
Na
+
assumptions on which the formula is based have been called into question. For this reason, a urine K+ to creatinine ratio is now the preferred way to assess renal K+ handling. A ratio of less than 13 mEq
K+/g creatinine or less than 2.5 mEq K+/mmol creatinine is considered
an appropriate response to gastrointestinal potassium loss, remote use
of diuretics, decreased dietary intake, and potassium shift into cells.
Higher values suggest an inappropriate response of the kidney.
Inadequate dietary intake is an unusual cause of hypokalemia.
Clinical situations associated with extreme K+-deficient diets include
anorexia nervosa, crash diets, alcoholism, and intestinal malabsorption. Increased renal K+ excretion owing to magnesium deficiency
(which is often present in these clinical situations) may contribute to
the observed hypokalemia.
Extrarenal Potassium Losses
Sweat, with its low concentration of K+, is an unusual cause of K+ depletion. However, during physical training sweat losses can become substantial and K+ depletion may result. Gastrointestinal syndromes are the
most common clinical disorders of extrarenal K+ losses. Diarrhea leads
to fecal K+ wastage and is associated with a normal anion gap acidosis.
Acidosis will result in K+ redistribution out of cells, leading to a degree of
hypokalemia that is not as severe as the degree of total body K+ depletion.
Renal Potassium Losses
Increased distal delivery of Na+ and water and increased mineralocorticoid activity can each stimulate renal K+ secretion. Under normal
physiologic conditions, these two determinants are inversely regulated
by EAV (Fig. 25.4). Decreases in EAV are associated with increased
aldosterone secretion but lower distal delivery of Na+ and water secondary to enhancement of reabsorption in the proximal nephron. It
is for this reason that renal K+ excretion is relatively independent of
volume status. It is only under pathophysiologic conditions that distal
Na+ delivery and aldosterone become coupled. In this setting, renal K+
wasting will occur. This coupling can be due to a primary increase in
mineralocorticoid activity or a primary increase in distal Na+ delivery.
The term primary means that the changes are not secondary to changes
in EAV. The causes of hypokalemia, grouped according to the physiologic determinants of renal K+ excretion, are given in Fig. 25.5.
Decreased
proximal Na
reabsorption
Na+ delivery
+
delivery
+
Decreased
renin
Decreased
aldosterone
Underlying cause of
kidney K
+
wasting
Normal
reciprocal
Primary Increase in Mineralocorticoid Activity
Increases in mineralocorticoid activity can be due to primary increases
in renin secretion, primary increases in aldosterone secretion, or
increases in a non-aldosterone mineralocorticoid or increased mineralocorticoid-like effect. In all of these conditions, ECF volume is
expanded and hypertension is typically present. The differential diagnosis for the patient with hypertension, hypokalemia, and metabolic
alkalosis rests on the measurement of plasma renin activity and plasma
aldosterone levels.
Primary Increase in Distal Sodium Delivery
Conditions that give rise to primary increases in distal Na+ delivery are
characterized by normal or low ECF volume. Blood pressure is typically normal. Increases in distal Na+ delivery are most frequently due
to diuretics that act proximal to the cortical collecting duct. Increased
delivery can also be the result of non-reabsorbed anions such as bicarbonate as with active vomiting or a type II proximal renal tubular
acidosis. Ketoanions (β-hydroxybutyrate and acetoacetate) and the
+
salts of penicillins are other examples. The inability to reabsorb
Na
these anions in the proximal tubule results in increased delivery of Na+
to the distal nephron. Because these anions also escape reabsorption
in the distal nephron, a more lumen-negative voltage develops and
the driving force for K+ excretion into the tubular fluid is enhanced.
Disorders of hypokalemia due to primary increases in distal Na+ delivery can best be categorized by the presence of metabolic acidosis or
metabolic alkalosis.
Clinical Presentation
The most important clinical manifestations of hypokalemia occur
in the neuromuscular system. Low serum K+ leads to cell hyperpolarization that impedes impulse conduction and muscle contraction.
Typically, a flaccid paralysis develops in the hands and feet that moves
proximally to eventually include the trunk and respiratory muscles.
Death may occur from respiratory insufficiency. A myopathy may
also occur that can evolve to rhabdomyolysis (muscle cell lysis) and
acute kidney injury. Hypokalemia can also lead to smooth muscle
dysfunction including paralytic ileus. Changes in electrocardiogram
(ECG) include ST depression, T-wave flattening, and an increase in
Urine K
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CHAPTER 25 Fluid and Electrolyte Disorders
+
273
<13 mEq K
<2.5 mEq K+/mmol creatinine)
Cell shift Gastrointestinal loss
Hypokalemic periodic paralysis
Administration of inulin
B2-adrenergic stimulation
+
/g creatinine or
+
>13 mEq K
>2.5 mEq K+/mmol creatinine)
Assess blood pressure, EABV
Diarrhea
High Low-normal
↑ Renin, ↑ Aldosterone
Renal artery stenosis
Renin secreting tumor
↓ Renin, ↑ Aldosterone
Adrenal adenoma
Bilateral cortical hyperplasia
Glucocorticoid suppressible
hyperaldosteronism
↓ Renin, ↓ Aldosterone
Cushing syndrome
11 β-hydroxylase deficiency
17 α-hydroxylase deficiency
Syndrome of apparent
mineralocorticoid excess
Liddle syndrome
Fig. 25.5 Clinical approach to the hypokalemic patient.
/g creatinine or
Plasma [HCO
Low
Proximal RTA
Distal RTA
Non-reabsorbable
Low
anion effect
Vomiting
Ticarcillin,
Carbenicillin,
Piperacillin
–
]
3
High
Urine [Cl–]
High
Loop diuretics
Thiazide diuretics
2+
deficiency
Mg
Bartter syndrome
Gitelman syndrome
the amplitude of the U wave. Patients treated with cardiac glycosides
are at increased risk for premature ventricular contractions, and supraventricular and ventricular tachyarrhythmias, when hypokalemic.
Hypokalemia also causes a renal concentrating defect due both to
a decrease in the medullary gradient and resistance of the cortical collecting tubule to AVP. This leads to polyuria and polydipsia. Prolonged
hypokalemia can also lead to tubulointerstitial nephritis and renal failure (kaleopenic nephropathy). Because insulin release is regulated partially by serum K+, hypokalemia can lead to glucose intolerance.
Treatment of Hypokalemia
The serum K+ levels can at times be misleading as to the degree of deficit because a normal or even increased K+ level can occur with significant total body K+ depletion. In the absence of significant K+ shifts, a
decline in the serum K+ from 4 to 3 mEq/L generally is associated with
a deficit of 300 to 400 mEq intracellular K+ per 70 kg body weight. A
serum K+ concentration of 2 mEq/L reflects a deficit of roughly 600
mEq. Despite these guidelines, the serum K+ level should be monitored
frequently during replacement therapy.
K+ can be given orally or intravenously as the potassium chloride
(KCl) salt. Potassium bicarbonate or citrate can be given if there is concomitant metabolic acidosis. The safest way to administer KCl is orally.
KCl can be given in doses of 100 to 150 mEq/day. Liquid KCl is bitter
tasting and, like the tablet, can be irritating to the gastric mucosa. The
microencapsulated or wax-matrix forms of KCl are better tolerated.
Intravenous administration of K+ may be necessary if the patient
cannot take oral medications or if the K+ deficit is large and is resulting in cardiac arrhythmias, respiratory paralysis, or rhabdomyolysis.
Intravenous KCl should be given at a maximum rate of 20 mEq/hour
and maximum concentration of 40 mEq/L. Higher concentrations will
result in phlebitis. Replacement of KCl in dextrose-containing solutions can lower the serum K+ further secondary to insulin release. Thus,
saline solutions are preferred. Depending on the specific cause, additional therapy of chronic hypokalemia involves the use of K+-sparing
diuretics such as amiloride, spironolactone or triamterene. These
agents must be used cautiously in patients with renal insufficiency or
in patients with other disorders that impair renal K+ excretion.
HYPERKALEMIA
Like the hypokalemic disorders, a high serum K+ can occur in the setting of normal or altered body stores of K+. The body has a marked
ability to protect against hyperkalemia. This includes regulatory mechanisms that will excrete excess K+ quickly and mechanisms that will
redistribute excess K+ into cells until it is excreted. All causes of hyperkalemia therefore involve abnormalities in these mechanisms.
Pseudohyperkalemia is an in vitro phenomenon due to the
mechanical release of K+ from cells during the phlebotomy procedure,
specimen processing, or in the setting of marked leukocytosis and
thrombocytosis. (As noted above, with certain leukemias with high
WBC counts, extraction of K+ from the serum by cells in the sample
tube can result in spurious hypokalemia.)
Excessive Dietary Intake
In the presence of normal renal and adrenal function, it is difficult to
ingest enough K+ in the diet to produce hyperkalemia. Rather, dietary
274 SECTION V Renal Disease
intake of K+ as a contributor to hyperkalemia is usually observed in
the setting of impaired kidney function. Dietary sources particularly
enriched with K+ include melons, citrus juice, and commercial salt
substitutes containing K+.
Cellular Redistribution
Cellular redistribution is a more important cause of hyperkalemia than
of hypokalemia. Tissue damage is probably the most important cause
of hyperkalemia due to redistribution of K+ out of cells. This can be
due to rhabdomyolysis, trauma, burns, massive intravascular coagulation, and tumor lysis (either spontaneous or following treatment). The
effect of metabolic acidosis to cause K+ exit from cells is dependent
upon the type of acid present. Mineral acidosis (NH4Cl or HCl) by
virtue of the relative impermeability of the chloride anion results in
the greatest efflux of K+ from cells. By contrast, organic acidosis (lactic
or β-hydroxybutyric) results in no significant efflux of K+. Increased
osmolality as in uncontrolled diabetes causes K+ to move out of cells. In
fact, it is the hypertonic state as well as insulin deficiency that accounts
for hyperkalemia often seen in patients with diabetic ketoacidosis who
are total body K+ depleted. β-Adrenergic blocking agents can interfere with the disposal of acute K+ loads. Other drugs that can result in
hyperkalemia include the depolarizing muscle relaxant succinylcholine
and severe digitalis poisoning.
Decreased Renal Excretion of Potassium
Decreased renal excretion of K+ can occur because of one or more of
three abnormalities: a primary decrease in distal delivery of salt and
water, abnormal cortical collecting duct function, and a primary
decrease in mineralocorticoid levels.
Primary Decrease in Distal Delivery (Acute and
Chronic Kidney Disease)
Acute decreases in glomerular filtration rate (GFR), as occur in acute kidney injury, lead to marked decreases in distal delivery of salt and water that
may secondarily decrease distal K+ secretion. When acute kidney injury is
oliguric, distal delivery of NaCl and volume are low and hyperkalemia is
a frequent problem. When kidney injury is nonoliguric, however, distal
delivery is usually sufficient and hyperkalemia is unusual. Decreased distal
Na+ delivery is a risk factor for hyperkalemia in patients with decompensated congestive heart failure. In chronic kidney disease patients, hyperkalemia is unusual until the GFR falls to less than 10-20 mL/min. The
occurrence of hyperkalemia with a GFR of greater than 10 mL/min should
raise the question of decreased aldosterone levels or a specific lesion of the
cortical collecting duct.
Primary Decrease in Mineralocorticoid Activity
Decreased mineralocorticoid activity can result from disturbances that
originate at any point along the renin-angiotensin-aldosterone system.
Such disturbances can be the result of a disease state or be due to effects
of various drugs. Hyperkalemia most commonly develops when one or
more of these drugs are administered in a setting where the renin-angiotensin-aldosterone system is already impaired. One common example is the use of angiotensin-converting enzyme inhibitors (ACEI) or
angiotensin-receptor blockers (ARB) in patients with diabetes mellitus
with hyporeninemic hypoaldosteronism.
Distal Tubular Defects
Certain interstitial renal diseases can affect the distal nephron specifically and lead to hyperkalemia in the presence of only mild decreases
in GFR and normal aldosterone levels. Amiloride and triamterene
inhibit Na+ transport, which makes the luminal potential more positive and secondarily inhibits K+ secretion. A similar effect occurs with
trimethoprim and accounts for the development of hyperkalemia
following the administration of the antibiotic trimethoprim-sulfamethoxazole. Spironolactone and eplerenone compete with aldosterone
and thus block the mineralocorticoid effect.
Clinical Presentation
Hyperkalemia leads to depolarization of the resting membrane because
the potential across cell membranes is in part determined by the ratio
of intracellular to extracellular K+. The heart is particularly sensitive to
this depolarizing effect. The progressive changes of hyperkalemia on the
electrocardiogram are peaking of T waves, widening of the PR and QRS
interval, development of a sine wave pattern, and eventually ventricular
fibrillation and asystole. In general, ECG changes appear at a serum K+
of 6 mEq/L with acute onset of hyperkalemia, whereas the ECG may
remain normal up to a concentration of 8 to 9 mEq/L with chronic
hyperkalemia. Hyperkalemia can also cause neuromuscular manifestations such as ascending paralysis and eventual flaccid quadriplegia.
Hyperkalemia also decreases ammonia availability to act as a buffer for
distal H+ secretion. This effect impairs bicarbonate regeneration, leading to the development of a normal anion gap metabolic acidosis.
Treatment of Acute Hyperkalemia
The immediate treatment of life-threatening hyperkalemia is the
administration of calcium, usually in the form of calcium gluconate
or calcium chloride. ECG changes such as increasing PR interval or a
widening QRS complex warrant treatment with calcium. Glucose and
insulin therapy will shift K+ into cells. Acute administration of glucose
without insulin can potentially worsen hyperkalemia in patients with
diabetes mellitus by raising extracellular osmolality and causing K+
to shift into the extracellular space. NaHCO3 administration through
expansion of the ECF space results in dilution of the serum K+.
Additionally, K+ is shifted into cells whenever concomitant metabolic
acidosis is corrected. Inhalation of β2-agonists such as albuterol or parenteral use of salbutamol can cause significant K+ shifts into cells.
The effects of calcium, bicarbonate, glucose and insulin, and β2-agonist therapy will provide immediate relief of acute toxicity but will
not decrease total body K+. Measures to reduce total body K+ include
the administration of K+ binding drugs and dialysis.
Treatment of Chronic Hyperkalemia
After review of the patient’s medication profile, drugs that can impair
renal K+ excretion should be discontinued if possible. Nonsteroidal
anti-inflammatory drugs, either prescribed or those over-the-counter,
are common offenders in this regard. Patients should be placed on a
low K+ diet with specific counseling against the use of K+-containing
salt substitutes. Diuretics are particularly effective in minimizing
hyperkalemia. In patients with an eGFR less than 30 mL/min, thiazide
diuretics can be used, but loop diuretics are required with more severe
renal insufficiency. In chronic kidney disease patients with metabolic
acidosis (bicarbonate concentration < 22 mEq/L), NaHCO3 should be
given. K+-binding drugs can be utilized when hyperkalemia is refractory to the approaches outlined above. Sodium polystyrene sulfonate
(Kayexalate) has been available for over 50 years but is poorly tolerated
and has been linked to gastrointestinal toxicity. Patiromer and sodium
zirconium cyclosilicate (ZS-9) are new K+-binding drugs that are well
tolerated when used chronically and can maintain normokalemia in
the setting of renin-angiotensin-aldosterone system inhibitors.
METABOLIC ACIDOSIS
Metabolic acidosis is diagnosed by a low pH, a reduced HCO
centration, and respiratory compensation resulting in a decrease in the
−
3
con-
CHAPTER 25 Fluid and Electrolyte Disorders
Anio
−
−
−
)
UAG
+
+
+
−
−
Urine osmolal gap = calculated urine osmolality ( mOsmol/kg)
+
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275
Assessment of ↓ [HCO
Check arterial blood gas to exclude
chronic respiratory alkalosis
Calculate serum anion gap
Lactic acidosis
Diabetic acidosis
Alcoholic ketoacidosis
Starvation ketoacidosis
Poisoning
salicylate
ethylene glycol
methanol
Uremic acidosis
Fig. 25.6 Approach to the patient with a reduced serum HCO
centration.
High
Renal tubular
partial pressure of carbon dioxide (Pco2). A low HCO
–
]
3
Normal
Calculate urine anion gap
Positive
acidosis
Negative
Diarrhea
External loss of
pancreatic or
biliary secretions
−
concentration
3
−
3
con-
alone is not diagnostic of metabolic acidosis because it also results from
the renal compensation to chronic respiratory alkalosis. Measurement
of the arterial pH differentiates between these two possibilities. The pH
is low in hyperchloremic metabolic acidosis and high in chronic respiratory alkalosis. The clinical approach to a patient with a low serum
−
HCO
concentration is given in Fig. 25.6.
3
After confirming the presence of metabolic acidosis, calculation
of the serum anion gap is a useful step in determining the differential diagnosis of the disorder. The anion gap is equal to the difference
between the plasma concentrations of the major cation (Na+) and the
major measured anions (Cl− + HCO
n gap = Na
−
).
3
+
( CI
)−( HCO
3
The normal value of the anion gap is approximately 12 ± 2 mEq/L.
Most of the unmeasured anions consist of albumin; therefore, the normal anion gap changes in the setting of hypoalbuminemia (normal
anion gap is approximately three times the serum albumin in g/dL).
Because the total number of cations must equal the total number of
anions, a fall in the serum HCO
−
concentration must be offset by a
3
rise in the concentration of other anions. If the anion accompanying
excess H+ is Cl−, the fall in the serum HCO
−
concentration is matched
3
by an equal rise in the serum Cl− concentration. The acidosis is classified as a normal gap or hyperchloremic metabolic acidosis. By contrast,
if excess H+ is accompanied by an anion other than Cl−, the fall in
−
HCO
is balanced by a rise in the concentration of the unmeasured
3
anion. The Cl− concentration remains the same. In this setting, the
acidosis is said to be a high anion gap metabolic acidosis.
A useful method for differentiating extrarenal from renal causes of
metabolic acidosis is to measure urinary NH
+
excretion. Extrarenal
4
causes of metabolic acidosis are associated with an appropriate increase
in net acid excretion, primarily reflected by high levels of urinary NH
excretion. By contrast, net acid excretion and urinary NH
+
4
4
levels are
low in metabolic acidosis of renal origin. Unfortunately, measurement
of urinary NH
medicine. However, the amount of urinary NH
+
is not a test that is commonly available in clinical
4
+
can be indirectly
4
assessed by calculating the urinary anion gap (UAG).
= UNa
UK
UCI
Under normal circumstances, the UAG is positive, with values
ranging from 30 to 50. Metabolic acidosis of extrarenal origin is associated with a marked increase in urinary NH
+
excretion and, therefore,
4
a large negative value will be obtained for the UAG. If the acidosis is of
renal origin, urinary NH
+
excretion will be minimal and the UAG will
4
usually be positive.
The UAG can be misleading when other unmeasured ions are
excreted. For example, increased urinary excretion of sodium keto acid
salts in diabetic and alcoholic ketoacidosis and urinary excretion of
sodium hippurate and sodium benzoate in toluene exposure can keep
the UAG positive despite an appropriate increase in urinary ammonium
excretion. Increased urinary excretion will also be missed when NH
excreted with an anion other than Cl− such as β-hydroxybutyrate or hippurate. In these settings, calculation of the urine osmolal gap is used as
an indirect measure of ammonium excretion. The urine osmolal gap is
the difference between the measured and the calculated urine osmolality:
+
+
2 × Na++ K
=
mg/dL]
/2.8
[urea nitrogen in
glucose in mg/dL
[
The urine osmolal gap normally ranges from approximately 10 to 100
mOsmol/kg. Because NH
+
salts are generally the only other major uri-
4
nary solute that contribute significantly to the urine osmolality, values
appreciably greater than 100 mOsmol/kg reflect increased excretion of
+
NH
salts.
4
Urine pH cannot reliably differentiate acidosis of renal origin
from that of extrarenal origin. For example, an acid urine pH does
not necessarily indicate an appropriate increase in net acid excretion. With a significant reduction in the availability of NH
serve as a buffer, only a small amount of distal H+ secretion will
lead to a maximal reduction in urine pH. In this setting, the pH
of the urine is acid but the quantity of H+ secretion is insufficient
to meet daily acid production. By contrast, alkaline urine does not
necessarily imply a renal acidification defect. In conditions where
availability of NH
+
is not limiting, distal H+ secretion can be mas-
4
sive and yet the urine remains relatively alkaline because of the
buffering effects of NH
+
.
4
Hyperchloremic or Normal Anion Gap Metabolic
Acidosis
Hyperchloremic (normal anion gap metabolic) acidosis can be of renal
or extrarenal origin. Metabolic acidosis of renal origin is the result of
abnormalities in tubular H+ transport. Metabolic acidosis of extrarenal
origin is most commonly caused by gastrointestinal losses of HCO
Other causes include the external loss of biliary and pancreatic secretions and ureteral diversion procedures. Fig. 25.7 provides a clinical
approach to metabolic acidosis of renal origin.
Renal Origin
Proximal renal tubular acidosis (type II). The diagnosis of
proximal RTA is suspected in a patient with a normal anion gap acidosis,
hypokalemia, and an intact ability to acidify the urine to a pH of less
+
than 5.5 while in a steady state. In the steady state, the serum HCO
concentration is usually in the range of 16 to 18 mmol/L. Proximal
RTA can be an isolated finding but most commonly is accompanied by
generalized dysfunction of the proximal tubule (Fanconi syndrome).
The urine anion gap is positive because proximal tubular dysfunction
also impairs ammoniagenesis.
]
/ 18
4
4
+
+
is
to
−
3
−
3
.
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