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How is hyponatremia diagnosed? What are two things that will give a false low sodium diagnosis? How do they differ from normal hyponatremia?

Definitive diagnosis of hyponatremia requires laboratory determination of the serum sodium concentration. However, a falsely low-serum sodium concentration is observed in two scenarios:

1. Hypertonic hyponatremia
2. Pseudohyponatremia

Hypertonic hyponatremia is caused by an increase in
the plasma glucose concentration. The rise in glucose concentration
increases the plasma osmolality, which promotes
passive diffusion of water from the cellular compartment
to the extracellular compartment. The gain in extracellular
water lowers the concentration of sodium. An important distinction
between this phenomenon and classic hypoosmolar
hyponatremia is that the plasma osmolality is increased, not
decreased. In addition, hypoosmolar hyponatremia induces
cell swelling, not shrinkage, because water moves into the
cellular compartment. The effects of hyperglycemia on the
serum sodium concentration are fairly predictable. Thus, a
100 mg/dL increase in glucose typically lowers the sodium
concentration by ~1.6 mEq/L.
Pseudohyponatremia is caused by an increase in the
concentration of proteins or lipids (Fig. 10.1). The decrease
in plasma sodium concentration occurs when dilution-based
methodologies are employed to measure the sodium concentration.
Dilution-based techniques underestimate the true plasma
sodium concentration since the volume of diluent used to prepare
the sample for analysis is increased as the concentration
of proteins or lipids rise. However, since the sodium concentration
in the aqueous-phase remains unchanged, the osmolality
is unaffected by hyperlipidemia or hyperproteinemia. Measure
of osmolality using freezing point depression confirms the normal
osmolality, hence, the designation pseudohyponatremia.


What are the principal manifestations of hyponatremia? What mediates them? What extent of hyponatremia will cause this mediation?

The principal manifestations of hyponatremia are the result of
altered cell volume. While most systems can tolerate a modest
increase in volume, the inelastic cranium is associated with a
rise in intracerebral pressure when brain cells swell beyond
5%. Intracranial pressure rises exponentially with as little as a
10% decrease in the plasma osmolality (Fig. 10.2). Therefore,
the cardinal clinical manifestations of hypoosmolar hyponatremia
are secondary to central nervous system (CNS) swelling.
These symptoms include
• Nausea and vomiting
• Behavioral changes
• Decreased level of consciousness, advancing to coma
• Seizures


Describe cellular adaption to hyponatremia including the stages and how it is accomplished. When can hyponatremia be asymptomatic? Why should correcting serum sodium for these patients be done very carefully?

Most cells are endowed with an intrinsic osmotic regulatory
system that maintains cell volume constant. Cellular adaptation occurs acutely (within 24 hours), but several days
are required to achieve near-normal cell volume. In the complete
absence of adaptation, life-threatening cerebral edema
may occur with as little as a 5%-10% decrease in osmolality.
Acute adaptation is principally secondary to extrusion of
intracellular sodium and water. It is effective, albeit limited.
Chronic adaptation depends on the cell extrusion of specific
organic compounds known as osmolytes. Chronic adaptation
can completely normalize intracerebral pressure. Therefore,
the rate of decrease in serum sodium concentration is far more
important in governing symptoms than the absolute decline.

Even extreme decreases in the serum sodium
concentration (


Describe some etiologies and pathophysiologies of hyponatremia.

An increase in water intake relative to water excretion is
required for the development of hyponatremia (Eq. [10.1]).
Since ADH is the primary determinant of water excretion, it
is frequently involved in the pathogenesis of this clinical syndrome.
Although there are many clinical conditions that produce
hyponatremia, the pathogenesis is similar—water imbalance.
Understanding the factors that regulate water intake and
excretion permits a rationale approach to the differential diagnosis
of hyponatremia.
Water Intake > Water Excretion (10.1)
Although it is theoretically possible to ingest sufficient water to
produce hyponatremia, most instances are secondary to a combination
of impaired renal free water excretion and a normal or
slightly increased water intake. The maximal urine flow rate is
quite impressive under normal circumstances and provides an
extraordinary buffer against the development of hyponatremia
from water intake alone. The maximal urine flow rate can be
calculated from knowledge of (1) the minimum urine osmolality
(~50 mOsm/kg H2O in normal humans) and, (2) the average
urinary solute excretion (~600 mOsm/d, which comprises
sodium, potassium, and urea). Therefore, a simple calculation
yields a maximum urine volume of 12 L/d (Eq.10.2):
Urine Volume
600 mOsm Solute per Day
50 mOsm
Solute in each Liter of Urine

Therefore, water intake must be prodigious to generate hyponatremia
without a concomitant defect in urine dilution. Since
the urinary volume depends on the total solute excreted, it is
possible to dramatically limit free water excretion by restricting
solute intake. Although, relatively uncommon, such a phenomenon
has been described in the elderly and the alcoholic
in whom solute intake can be less than 100 mOsm/d.
Figure 10.3 depicts the steps involved in renal excretion
of water. In step 1 sodium and water are reabsorbed in the
proximal tubule. Therefore, water delivery to the remainder
of the nephron is linked to proximal tubular fluid reabsorption.
Conditions characterized by increased proximal tubular
fluid reabsorption can reduce the renal capacity to excrete
water. For example, low cardiac output states such as heart
failure or dehydration increase proximal tubular reabsorption
of sodium and water. In step 2 the urine undergoes dilution
(see Fig. 7.4) in the medullary thick ascending limb of Henle.

Electrolyte free water is generated at this site. Loop diuretics interfere with maximal urinary dilution by inhibiting NKCC2. In step 3, water is either excreted (suppressed ADH) or conserved (increased ADH). Step 3 is the most important step in renal excretion of water. The majority of hyponatremic states are characterized by an increase in circulating ADH and water conservation via step 3. The prevailing level of ADH reflects the effects of multiple factors that may stimulate or inhibit secretion (see Table 9.1). When the stimulus for ADH secretion is unknown the syndrome of inappropriate ADH secretion (SIADH) is established.
In summary, water intake must exceed water excretion for hyponatremia to develop. Recognition of the factors that influence water balance is essential to formulate a logical differential diagnosis. Water drinking alone is unlikely to produce hyponatremia. ADH plays a prominent role in water excretion, and is, therefore, frequently implicated in the pathogenesis of hyponatremia. Since many clinical conditions influence ADH secretion, hyponatremia is relatively common in the clinical arena.


What are the two categories in the differential diagnosis of hyponatremia? How do they differ?

Hyponatremia can be classified into two major categories based on the effective circulating volume (ECV): (1) conditions associated with a low ECV, and (2) conditions associated with a normal ECV. The distinction between total body volume and ECV is subtle, yet critical. The total body volume reflects the combined volume of all major body fluid compartments (intravascular, interstitial, and intracellular). In contrast, the ECV reflects, generally the intravascular volume, and specifically implies a decrease in perfusion to vital organs. It is possible to develop total body volume expansion, yet manifest a decreased ECV. For example, congestive heart failure is accompanied by total volume expansion (manifested as edema) but is also accompanied by a decrease in cardiac output, which is tantamount to a fall in ECV. Any condition that decreases the ECV triggers a neurohumoral response that is associated with an increase in circulating ADH and renal retention of sodium.


What are 4 clinical syndromes of hyponatremia associated with a low ECV? How do they cause a low ECV? How do they cause hyponatremia? How should they be managed?

Four clinical syndromes account for the vast majority of these states (Fig. 10.4):
• Volume contraction
• Congestive heart failure
• Nephrotic syndrome
• Cirrhosis
All of these disorders are characterized by an increase in circulating ADH because of a decrease in ECV. The mechanism responsible for the fall in ECV is intuitive in volume contraction and heart failure. Nephrotic syndrome and cirrhosis are accompanied by moderate to severe hypoalbuminemia.

The attendant decrease in serum oncotic pressure promotes diffusion of solute and water from the intravascular to interstitial compartment, thus decreasing ECV. The fall in ECV reduces renal perfusion, which, in turn, increases the reabsorption of sodium and water in the proximal tubule. This reduces urine flow, and therefore, water excretion. The retention of sodium lowers the urine sodium concentration (usually <10 mEq/L), which is an excellent biomarker of decreased ECV. Although the pathophysiology of hyponatremia with these syndromes is similar, the management varies depending on the underlying cause. Volume contraction should be managed with simple hydration (0.9% or isotonic saline if intravenous fluids
are required). Ideally, treatment of congestive heart failure, nephrotic syndrome, or cirrhosis should be aimed at correcting
the underlying disorder. However, response rates vary
depending on the extent and severity of illness, as well as
the specific pathology. Unfortunately, many of these conditions
are not amenable to therapy. In such cases the approach
involves using measures to increase free water excretion while
restricting water intake.


Describe some hyponatremic conditions associated with a normal ECV. What is the pathophysiology? Treatments?

Hyponatremia accompanied by a normal volume exam (euvolemia)
should alert the clinician to the presence of SIADH.
This syndrome is characterized by an increase in circulating
ADH; however, there is no known stimulus to ADH secretion
(Fig. 10.5). Since the volume status and, accordingly, ECV
is normal, the urine sodium concentration is not low (it usually
exceeds 40 mEq/L). Although treatment of the underlying
clinical disorder is desirable, it is often not feasible as many
of these conditions are refractory. Therefore, water restriction
has been the mainstay of therapy. Additional treatment strategies
include increasing solute intake (with sodium tablets)
to facilitate free water excretion and demeclocycline. Demeclocycline
(a tetracycline antibiotic) antagonizes the action of
ADH, however, the incidence of photosensitivity is a significant
adverse effect.


Describe the functions of the ADH receptors. What are some drugs that take advantage of these receptors?

Recently, V2R antagonists have emerged as a new approach to
the management of hyponatremia. These agents competitively inhibit binding of ADH with the vasopressin receptor. Three
vasopressin receptors have been characterized over the past
decade. V2R mediates the effects of ADH on water permeability.
V1R comprises two receptor subtypes, V1Ra and V1Rb.
V1Ra is expressed on vascular smooth muscle cells (vasoconstriction),
platelets (aggregation), hepatocytes (glycogenolysis),
and the myometrium (uterine contractions). V1Rb is
widely expressed in the brain, although, it’s exact role remains
incompletely understood.
Conivaptan was the first agent approved for use in the
United States in 2006. Conivaptan is a non-selective vasopressin
antagonist (inhibiting V2R and V1Ra) only approved
for use in SIADH. Conivaptan may reduce blood pressure
because of its effect on V1Ra. It is contraindicated in patients
with heart failure and cirrhosis. Several newer agents (tolvaptan,
relcovaptan, lixivaptan) with greater receptor selectivity
have emerged. For example, tolvaptan is V2R-specific and is
approved for use in SIADH as well as hyponatremia associated
with heart failure and cirrhosis.


What are some steps taken that are usually sufficient to establish the etiology of hyponatremia. Describe various unusual causes of hyponatremia. Describe other causes of hyponatremia. Which pts. might suffer from these things? Describe reset osmostat. What are 3 others?

One must first establish that the serum sodium concentration is
not an artifact or secondary to hyperglycemia (Fig. 10.6). Fortuitously,
the serum glucose is routinely reported on a standard
electrolyte panel. If in doubt, measuring the plasma osmolality
via freezing-point depression will discriminate pseudohyponatremia
and hypertonic hyponatremia from hypotonic hyponatremia. Clinical assessment of volume including, neck vein distension, skin turgor, and peripheral edema, coupled with urine chemistries (osmolality and sodium concentration) is usually sufficient to establish the etiology of hyponatremia.
There are several unusual causes of hyponatremia that should also be considered. Psychogenic water drinking has been described in young women receiving psychotropic agents. This condition is characterized by excessive water intake; however, these individuals also exhibit impaired maximal urine dilution. The mechanism of increased thirst is not well understood, although, the anticholinergic effect of the psychotropic agents are often implicated.
Adrenal insufficiency and hypothyroidism have long been described in patients with hyponatremia. Increased sensitivity to the action of ADH is thought to underlie the water retention in these conditions. Correction of the endocrine disturbance cures the hyponatremia.
Chronic administration of thiazide diuretics is a very common cause of hyponatremia in the elderly. The thiazide diuretics promote volume contraction, which increases ADH. In addition, the thiazide diuretics interfere with sodium reabsorption in the early DCT. Since urine is further diluted at this site, the thiazide diuretics interfere with maximal urine dilution and water excretion. Since the loop diuretics interfere with urine concentration via blockade of NKCC2, they are less commonly associated with hyponatremia.
Decreased intake of solute (sodium and potassium) or protein (which is metabolized to urea) can markedly reduce water excretion (see Eq. 10.1). This is common in the elderly, or in the alcoholic on a binge. During a binge, the alcoholic is largely consuming water with little solute. Importantly, since the circulating level of ADH is not increased in these patients (unless they have concomitant volume contraction), the urine osmolality is usually


Describe general treatment strategies for more chronic hyponatremia. What are some difficulties in doing so? What about acute hyponatremia? What things must be kept in mind with that?

Treating the underlying disturbance is always the optimal approach. If the underlying condition cannot be improved, water restriction and judicious use of a vasopressin antagonist may prove useful. Water restriction is difficult to enforce in patients with heart failure, nephrotic syndrome, or cirrhosis, since the disease state is characterized by a marked increase in circulating ANG II. ANG II is a potent stimulus of thirst. Solute administration is also not effective in these conditions, because they are associated with retention of sodium (see Fig. 10.5).

Life-threatening (acute) hyponatremia, usually accompanied by coma, seizures, lethargy, and confusion, requires a more aggressive initial strategy. Typically a modest (5-7 mEq/L) increase in serum sodium is adequate to prevent permanent neurologic sequelae. Careful intravenous administration of hypertonic saline (3%-5% saline) is used to quickly raise the serum sodium concentration. Loop diuretics have also been employed in this setting. Acutely, loop diuretics increase water excretion because of their potent diuretic properties, although they interfere with urine dilution. Acute administration of a loop diuretic must be monitored carefully, since the simultaneous loss of sodium can produce severe dehydration and hemodynamic collapse. Moreover, overcorrection of the serum sodium concentration can produce osmotic demyelination syndrome. Paradoxically, chronic daily administration of diuretics is implicated in the development of hyponatremia. Since these patients are mildly volume contracted, the circulating level of ADH and ANG II is increased, which increases water retention and thirst, respectively.


What is ODS? What cuases it? What are the symptoms? How do they present? How can it be treated? How can it be avoided? Which pts are high risk?

It is extremely important to avoid rapid restoration or overcorrection of the serum sodium concentration, because this has been associated with demyelination. This condition was originally coined “central pontine myelinolysis” because the pattern of myelin loss was confined to the central pons (Fig. 10.8). The classic clinical features included quadriparesis and pseudobulbar palsies. Recent evidence suggests that the lesions may also involve extrapontine regions. Thus, the more general term osmotic demyelination syndrome (ODS) has been adopted.
ODS was first described in the alcoholic, but more recent studies have documented myelin loss in many other disorders, including liver transplantation, malnutrition, and AIDS. Post-mortem studies indicate that the majority of cases are clinically asymptomatic; therefore, the exact incidence is difficult to ascertain. The onset of symptoms is usually delayed, typically requiring 24-48 hours to manifest. Therefore, patients inadvertently subjected to rapid correction must be monitored carefully. Unfortunately, the treatment of symptomatic ODS is ineffective, although spontaneous recovery has been reported in a small number of cases. Recent studies suggest that lowering the serum sodium with water should be considered in patients in whom the serum sodium has increased to rapidly. Based on observational studies in patients and animal studies, a prudent approach to the correction of hyponatremia is outlined below:
• Manage asymptomatic patients conservatively.
• A 5-7 mEq/L increase in plasma sodium concentration should reverse cerebral edema.
• The correction rate should not exceed 0.5-1.0 mEq/h.
• The absolute correction should not exceed 10-12 mEq/d.

The above guidelines should be adhered to strictly in high-risk groups including, the alcoholic, liver transplant recipients, or those with previous CNS disease.


What is the pathophysiology of hypernatremia. Who is at higher risk for this pathophys? What are two common clinical settings in which this pathophys is very common? How does it differ from diabetes insipidus?

The pathophysiology of hypernatremia is conceptually analogous to the hyponatremic states since the prerequisite for developing this disorder is an imbalance in water homeostasis (Eq. [10.3]).


What is invaluable in establishing the pathogenesis of hypernatremia? What will the levels be like if the hypernatremia is secondary to an isolated thirst disturbance? What are the levels like in DI? When will an osmotic diuresis occur? How do you know if a diuresis is osmotic? What causes it? What happens when the levels are in a grey zone? What two categories of disease should be considered then?

Laboratory determination of the urine osmolality is invaluable in establishing the pathogenesis of hypernatremia (Fig. 10.10). When secondary to an isolated thirst disturbance, the urine will be appropriately concentrated (>800 mOsm/kg H2O in healthy adults). A urine osmolality of


What are the features and causes of the two categories of Diabetes Insipidus?

Although the fundamental mechanism responsible for diabetes
insipidus is relatively straightforward (ADH deficiency
or resistance), the etiology is diverse (Fig. 10.11). Generally,
conditions affecting the CNS such as trauma, infection, or
tumors, are common causes of CDI (Low circulating ADH, responsive to ADH). Conversely, certain drugs,
electrolyte disturbances, or renal damage are responsible for
the nephrogenic variants of diabetes insipidus. Lithium is an
important and common cause of NDI (normal or high circulating ADH, not responsive to ADH). NDI has been described
in >40% of patients receiving lithium for bipolar affective disorder,
however, most have minimal symptoms. Lithium interferes
with the expression of aquaporin 2 in the collecting duct.
Some, but not all, resolve after discontinuing the drug.


What is considered polyuria? What are two categories of causes of polyuria? How can they be differentiated?

Since patients with diabetes insipidus exhibit polyuria rather than hypernatremia, the clinical evaluation of polyuria must be understood. A urine output in excess of 2.5 L/d is the generally accepted definition of polyuria. Generally, polyuria is mediated by increased excretion of water or solute (sodium, glucose, urea, or mannitol). Clinically, it is useful to classify polyuria into three categories based on the composition of the urine (Fig. 10.12). Patients exhibiting polyuria because of a water diuresis will manifest dilute urine (<150 mOsm). This group comprises patients with complete diabetes insipidus and psychogenic polydipsia. Measurement of the urine sodium and potassium concentration permits differentiation of an electrolyte-mediated diuresis from an osmotic diuresis. Since the solutes in urine are composed of electrolytes (sodium, potassium, and a counterbalancing anion) and osmotic compounds (glucose and urea) it is relatively straightforward to estimate the likely culprit by comparing the measured osmolality to the calculated osmolality (Eq. [10.4]).
CalculatedUrineOsmolalityNaK=×+++2() (10.4)
If the calculated osmolality is equal to the measured osmolality, it is likely that the polyuria is secondary to an electrolyte diuresis (usually sodium). Conversely, when the calculated osmolality is significantly less than the measured osmolality, an osmotic agent such as glucose should be considered. The most common osmotic agents include glucose, urea, and mannitol. These compounds can be directly assayed in the urine.


How should hypernatremia be managed? CDI? NDI? What guidelines should be followed to avoid cerebral edema?

Treating the underlying disorder is the optimal approach. Since the majority of these individuals are not consuming adequate water, one need simply provide sufficient water to replace the deficit. In addition, ongoing losses of water must be accounted for. Calculation of the water deficit (Eq. [10.5]) provides a useful starting point for replacement fluids.

 1401- (10.5)
Aqueous vasopressin (administered nasally or via the subcutaneous route) is useful in patients with central diabetes insipidus, while the chronic administration of thiazide diuretics reduces free water excretion in patients with nephrogenic diabetes insipidus. Thiazide diuretics appear to exert their effects via two mechanisms. Mild volume contraction promotes increased water reabsorption in the proximal, thereby, decreasing water excretion. In addition, recent studies demonstrate that thiazide diuretics increase expression of aquaporin 2 in the collecting duct.
Rapidly lowering the sodium concentration in plasma may precipitate cerebral edema as water redistributes into the intracellular compartment. This can be avoided if the serum sodium concentration is reduced gradually. Hence, the following guidelines should be employed in all patients with hypernatremia:
• First restore volume contraction with normal saline before initiating therapy with dilute solutions. Correction of the volume status is essential to prevent cardiovascular collapse.
• Correct the at a rate not to exceed 12 mEq/d or 0.5 mEq/h (to prevent life-threatening cerebral edema) with 5% dextrose in water (D5W).
• Replace ongoing water and sodium losses (urine, sweat) with an intravenous solution of comparable tonicity. This is particularly important when the urine output is high, as might occur with an osmotic diuresis.