Renal2 Flashcards
Physiology of water balance
The kidneys normally maintain serum osmolality in a narrow range: 280-295 mOsm/kg. Water moves freely across cell membranes, in contrast to electrolytes.
What determines serum osmolality?
Sosm = 2x Na (mEq/L) + BUN (mg/dL):2.8 + Glucose (mg/dL):18
Hypertonicity
Can be caused by Hypernatremia, Uremia, Diabetic Coma, and Unmeasured osmoles, e.g. alcohols, glycin. When serum tonicity becomes elevated, Water moves freely across cell membranes, “Water shift hyponatremia”, and Hypertonic hyponatremia most often due to uncontrolled diabetes
ADH physiology
ADH causes water reabsorption in the renal collecting ducts. ADH increases if serum osmolality increases, to bring back serum osmolality to normal. ADH increases exponentially if blood volume decreases, despite a decrease in serum osmolality, leading to hyponatremia
How can blood volume decrease?
Hemorrhage. Plasma volume and EC fluid losses: Gastrointestinal loss, Renal loss (excessive use of diuretics, osmotic diuresis, mineralocorticoid deficiency), Excessive sweating, and Loss of sodium and water. This is hypovolemic hyponatremia
Signs of decreased blood volume
Low blood pressure and tachycardia. Orthostatic hypotension. Thirst, weakness, lethargy. Dry skin and mucous membranes. Low urine output, concentrated urine, low urine Na concentration (
Hypovolemic hyponatremia
Hypovolemia means decreased total body sodium. Total body water is also decreased, but to a lesser extent, because of appropriate ADH release. Treatment: Restore plasma volume by giving normal saline, ADH will fall, and normonatremia will follow
How else can “perceived” blood volume decrease?
There may be a decrease in “effective” blood volume, meaning decreased organ perfusion, due to a weak heart (congestive heart failure), or due to excessive vasodilatation such as in liver cirrhosis. The kidney increases tubular sodium and water reabsorption, leading to total body sodium and water excess, clinically manifest by edema.
ADH pathophysiology
In severe heart failure and liver cirrhosis “effective” blood volume is so low that ADH is stimulated and released, leading to more water reabsorption in the collecting duct, and hyponatremia develops. In these examples there is excess total body sodium (edema) and even more excess total body water. This is hypervolemic hyponatremia
Hypervolemic hyponatremia
Another mechanism (apart from ADH release) is intrinsic kidney disease. Either the diluting mechanism in the distal tubules does not work, or renal blood flow and glomerular filtration rate are too low, such as in advanced chronic kidney disease. Thiazide diuretics impair dilution and are a frequent cause of hyponatremia, particularly in the elderly (can be hypo-, hyper- or euvolemic)
Normal diluting system
- Normal function of ascending limb of Henle’s loop and of distal convoluted tubule. 2. Normal delivery of tubular fluid to the distal diluting segment of the nephron. 3. Normal suppression of ADH (vasopressin). Note: Free water excretion capacity is about 20% of GFR. Maximal urinary dilution: ~ 50 mOsm/kg
How to recognize and treat hypervolemic hyponatremia?
Edema, ascites, pleural effusions. History of heart, kidney or liver disease. Weight gain in short period of time. Treatment: Water restriction and loop diuretics, and treatment of the underlying condition. Note: Giving salt is a frequent mistake and makes the edema (and heart failure) worse!
Euvolemic hyponatremia
Hyponatremia is usually due to ADH secretion. Many stimuli can cause excessive ADH release: Hypothyroidism and adrenal insufficiency, nausea, pain, psychosis, and many medications, some of them commonly used (SSRI’s and antipsychotics, NSAIDS, and others). Syndrome of inappropriate ADH secretion (SIADH)
SIADH
Euvolemic hyponatremia and urine that is not maximally dilute (>50-100 mOsm/kg). Diagnosis of exclusion. Due to carcinomas (ectopic ADH production), CNS disorders, or pulmonary diseases
Symptoms of hyponatremia
Depend on rapidity with which hyponatremia develops (acute or chronic) and on severity. Anorexia, nausea, vomiting. Weakness, lethargy, confusion. Seizures, death. Symptoms likely due to cerebral edema
Treatment of euvolemic hyponatremia
If seizures, give hypertonic saline. If asymptomatic, water restriction and correction of underlying disorder or removal of offending drugs. If hyponatremia is chronic (> 48 hours) or unknown duration, slow correction to avoid central pontine myelinolysis (osmotic demyelination syndrome). ADH (vasopressin) antagonists
Hypernatremia
As with hyponatremia, total body sodium (volume) can be decreased, normal, or increased. Disorder of water balance, not primarily sodium. An increase in serum osmolality causes severe thirst. Therefore hypernatremia will only develop if the patient does not have access to water (often hospitalized patients) or has CNS pathology impairing thirst
What causes hypernatremia?
- Renal or extrarenal water losses that exceed sodium loss (hypovolemic hypernatremia). 2. Addition of hypertonic fluids (hypervolemic hypernatremia), usually iatrogenic (hypertonic saline, TPN or bicarbonate infusion). 3. Lack of ADH effect: Diabetes insipidus (water diuresis, very dilute urine)
Diabetes insipidus
2 possible causes: No ADH is secreted (ADH deficiency), or the kidneys do not respond to ADH (ADH resistance). Clinical manifestation is polyuria and polydipsia. Hypernatremia develops only if the patient cannot drink water (often in the hospital)
Central DI
ADH deficiency. Diseases of hypothalamus or pituitary gland (head trauma, surgery, tumors, encephalitis). 30-50% of cases are idiopathic (autoimmune?). Complete or partial DI. Kidneys respond to exogenous ADH (=AVP). Treatment with a long-acting, nasally administered analogue (DDAVP)
Nephrogenic DI
ADH resistance. The renal collecting duct does not respond to ADH. Therefore exogenous ADH will not raise Uosm. Congenital nephrogenic DI: due to mutation in AVP-receptor (V2R) gene (X-linked recessive; 90%) or due to mutation in aquaporin 2 gene (autosomal recessive or dominant; 10%). Symptoms in infants are failure to thrive and polyuria, fever, vomiting, seizures, death
Acquired nephrogenic DI
Much more common than congenital disease and usually less severe, and at least partially reversible. Causes are hypercalcemia, chronic hypokalemia. Long-term therapy with lithium. Other drugs (cidofovir, foscarnet, amphotericin B, ifosfamide). Chronic kidney disease. Chronic kidney disease causes a concentrating defect due to tubular dysfunction (medulla not maximally hypertonic) as well as ADH resistance/ Sickle cell anemia and polycystic kidney disease cause early concentrating defects by disrupting the medulla. Urinary obstruction causes ADH resistance
Pregnancy (gestational DI)
release of vasopressinase from the placenta during second half of pregnancy. If treatment necessary, DDAVP is resistant to vasopressinase
Symptoms of hypernatremia
Extreme thirst. Neuromuscular irritability with twitches, hyperreflexia, seizures. Altered mental status, confusion, coma. Failure to thrive in infants. High mortality rate in adults and children. Often a marker of serious underlying disease
Treatment of hypernatremia
Calculate water deficit, replace deficit in addition to ongoing free water losses. Give D5W in most cases, not half-normal saline. Slow correction if hypernatremia is present for > 48 hours. For chronic management of nephrogenic DI thiazides may be helpful to reduce polyuria
Water needed (L)
= 0.6 x body weight (kg) x [actual Na:desired Na – 1]
The plasma sodium
is simply a concentration term and as such reflects only the relative amounts of sodium and water present in the sample. This concentration is not a measure of total body sodium content. [ECF Na+] = ECF Na+ /ECF H2O. Therefore, a low plasma sodium concentration simply denotes a relative deficit of sodium and/or a relative excess of water. As can be seen from the above formulae hyponatremia may result from either a decrease in the numerator or an increase in the denominator. Although one might conclude that hyponatremia would be more likely the result of a decrease in the numerator, in clinical practice the opposite is true. Hyponatremia is most commonly caused by a relative excess of water. The key pathophysiological process at work in the majority of cases is the non-osmotic release of vasopressin.
the tonicity of ECF
Since sodium is the most abundant cation in extracellular fluid (ECF), its concentration is the major determinant of tonicity or osmolality (the number of particles of solute per unit of solution) of this fluid. Furthermore, water moves freely across cellular membranes allowing osmotic equilibrium to be maintained between various compartments. Therefore, the tonicity of ECF reflects the tonicity of cells.
Calculating serum osmolality (Sosm)
may be calculated from the following formula: Sosm (mOsm/kg) = 2 X [Na (mEq/L)] + BUN (mg/dL)/2.8 + Glucose (mg/dL)/18. It may also be measured directly by determining freezing point depression or vapor pressure techniques.
Regulation of sodium balance
the kidneys maintain serum osmolality within a very narrow range of 280-295 mOsm/kg. The kidney is able to achieve this tight control by producing urine which varies tremendously in its concentration. If serum osmolality increases (e.g. during volume contraction), the kidney reabsorbs water to produce a concentrated urine with high specific gravity and osmolality. The net result is a restoration of serum osmolality back to its normal range. If serum osmolality falls, the kidney excretes free water to produce urine that is dilute with a low specific gravity and osmolality. The kidney is therefore equipped with concentrating and diluting segments.
The major factor controlling water metabolism
is renal excretion of water. The major factor controlling renal excretion of water in man is antidiuretic hormone (ADH), also known as arginine vasopressin (AVP). Osmoreceptors in the hypothalamus regulate the secretion of AVP from the posterior pituitary gland. AVP secretion increases by 0.38 pg/ml for every 1 mOsm/kg increase in serum osmolality above > 283 mOsm/kg. In turn, urine osmolality (Uosm) rises in response to AVP increments. A rise in AVP of 1 pg/ml produces an increase in Uosm of about 225 mOsm/kg. The increase in AVP causes reabsorption of water in the collecting duct and the production of a concentrated urine with an increased urine osmolality. The reabsorbed water returns serum osmolality back towards normal.
Renal water excretion
The three essential features of a normal diluting system are: normal function of diluting segment, normal delivery of tubular fluid to the distal diluting segment of the nephron, absence of vasopressin.
Normal function of the diluting segment
Tubular fluid is diluted in the water- impermeable ascending limb of Henle’s loop and the distal convoluted tubule by the reabsorption of sodium chloride. Sodium is transported on the Na+-K+-2Cl- cotransporter in the thick ascending limb and by the thiazide-sensitive NaCl cotransporter in the distal convoluted tubule.
Normal delivery of tubular fluid to the distal diluting segment of the nephron
i.e. normal glomerular filtration rate and proximal reabsorption of tubular fluid. Although tubular fluid remains isotonic in the proximal tubule, proximal reabsorption is an important determinant of water excretion. Thus, if proximal reabsorption increases and causes decreased distal delivery, the volume of dilute urine excreted will be decreased.
Abscence of vasopressin
This factor is of primary importance. Vasopressin renders the collecting duct water-permeable. Therefore, when vasopressin is present, osmotic equilibration of fluid between the tubule lumen and interstitium occurs. This causes the urine to become concentrated and impairs water excretion. In the absence of vasopressin, the collecting duct is impermeable to water. Water therefore remains in the collecting duct, and the diluting system functions normally to produce a dilute urine. Note that in subjects with normal renal function excessive water intake alone does not cause hyponatremia unless it exceeds about 1 liter per hour. As a general rule one’s maximal free water excretion is equal to about 20% of one’s GFR. With a glomerular filtration rate of 120 L/d, distal delivery to the diluting site of 20% of the filtered load = 24 L; hence 1 L/h equals maximal free water excretion. Thus, in people with a normal GFR, hyponatremia due to excessive water intake is observed only rarely (usually in psychotic patients who drink from faucets or showers). Note, however, that a reduction in GFR will limit free water excretion. An individual whose GFR is 20% of normal will become hyponatremic upon drinking anything over 4 liters per day.
The normal renal concentrating mechanism
in man allows for the excretion of a urine as much as four times as concentrated as plasma (1200 mOsm per kg H2O). Since the average daily solute load (i.e. the amount of solute that needs to be excreted in urine) is approximately 600 mOsm, this solute can be excreted in as little as 0.5 liters (600 mOsm /1200 mOsm per kg H2O = 0.5 kg H2O or 0.5 liters H2O). Note that even under maximal antidiuretic conditions, man has to drink at least this volume of water (0.5 liters) per day in order to maintain water balance. Thirst is thus an integral component of the water regulatory system. The normal function of the concentrating mechanism requires that its various components be intact. These include: the ability to generate a hypertonic interstitium, the secretion of ADH, and normal collecting duct responsiveness to vasopressin.
The ability to generate a hypertonic interstitium
Henle’s loop acts as a countercurrent multiplier with energy derived from the active transport of chloride in the water impermeable thick ascending limb of the loop (mediated via the Na+-K+-2Cl- cotransporter). This purpose serves the dual process of diluting tubular fluid and rendering the interstitium progressively hypertonic from cortex to papilla. If the collecting duct is made permeable to water (i.e. by vasopressin), the hypertonic interstitium draws water from the collecting duct. The collecting duct fluid therefore becomes concentrated.
The secretion of ADH
This hormone renders the collecting duct permeable to water and allows the dilute fluid delivered from the distal tubule to equilibrate with the concentrated interstitium.
Normal collecting duct responsiveness to vasopressin
Abnormalities in the renal concentrating process obligate excretion of a larger volume of urine to maintain solute balance, e.g. if one has to excrete the average daily solute load of 600 mosm but the kidney cannot increase Uosm above 300 mosm (approximately the level of serum osmolality), a urine flow of 2 liters per day is obligated (i.e. 600 mOsm /300 mOsm per kg H2O = 2.0 kg H2O or 2.0 liters H2O). Failure to replace these water losses orally leads to progressive water depletion and hypernatremia.
Antidiuretic Hormone
ADH (release is stimulated not only by changes in Sosm (osmotic release of vasopressin), but also to changes in effective intravascular blood volume or actual blood volume (non- osmotic release of vasopressin) . Defense of volume has priority in that ADH will rise to increase renal water reabsorption and thus protect volume even if Posm is compromised. It is more important for the organism to maintain blood volume than it is to maintain tonicity. ADH also has a pressor effect, contributing perhaps 10% to mean arterial pressure during volume depletion. The response of AVP to volume depletion is less sensitive initially than to increases in Sosm. However, after about 6-7% volume depletion, the “volume response” dominates the “osmolality response.” Thus, ADH is normally osmoregulatory, but during stress becomes a volume regulatory hormone. ADH (AVP) exerts its effect on the kidney by reacting with a tubular cell membrane receptor. This activates adenylate cyclase which generates cyclic AMP. This, in turn, activates a cascade of messages that results in the insertion of water channels (aquaporins) that increase tubular luminal membrane permeability to water.
Hyponatremia
disorders of renal diluting capacity. Hyponatremia is the most common electrolyte disturbance in hospitalized patients. It is the result of an inability to maximally dilute the urine coupled with continued water intake. Therefore, ECF water increases causing a fall in plasma sodium concentration. The first step in the evaluation of hyponatremia is determining the serum osmolality. This will help you differentiate the 3 main categories of hyponatremia – hypertonic, isotonic, or hypotonic.
Hypertonic
> 300 mOsm/kg
Isotonic
~280-300 mOsm/kg
Hypertonic Hyponatremia
Hyponatremia is due to the shift of water from cells in response to a non-sodium solute (elevated serum osmolality). Common causes of this type of hyponatremia are hyperglycemia and mannitol or glycerol administration. For each increase in serum glucose of 100 mg/dL, serum sodium will fall by about 1.6 mEq/L ignoring renal losses due to glycosuric osmotic diuresis. This is a calculated number based on the molecular weight of glucose and the distribution of total body water, 2/3 intracellular and 1/3 extracellular. Of all the causes of hyponatremia associated with an increased serum osmolality, hyperglycemia is by far the most common. When considering the answer to the question “what is the serum osmolality” one must always ask the question “what is the serum glucose?”
Isotonic Hyponatremia
This form of hyponatremia is associated with normal plasma osmolality. It is due to a lab artifact caused by hyperlipidemia or hyperproteinemia.. Plasma is comprised of approximately 93% H2O and 7 % non-water components such as lipids and protein. The common method of sodium analysis, flame photometry, measures the sodium per 1 liter of total plasma. Thus, conditions that reduce plasma water below the usual 93% of plasma will decrease the sodium content per liter of plasma. Two conditions that reduce plasma water are hyperlipidemia and hyperproteinemia (i.e. multiple myeloma). This is not a common problem. A clue to the presence of hyperlipidemia is a report from the lab of lipemic serum. Lipemic serum means that after centrifugation of cells to the bottom of the tube the supernatant or serum is cloudy. This type of hyponatremia is a laboratory artifact of flame photometry and direct measurement of serum sodium by ion- sensitive electrode will yield a normal value.
Hypotonic Hyponatremia
The causes of hyponatremia involve alteration of the ratio between ECF Na and ECF water. The most common pathophysiologic mechanism of hyponatremia is the non- osmotic release of ADH that prevents maximal urinary dilution. As you will see, the clue to the cause of the increased ADH levels lies in the volume status. We will discuss the specific varieties of hypotonic hyponatremia below.
Specific Varieties of Hypotonic hyponatremia
The next step in the evaluation of hyponatremia is determining the volume status. States of increased ECF volume (hypervolemia) are easy to identify on physical exam because they are characterized by the presence of edema. However, it may be difficult to differentiate milder cases of ECF volume contraction (hypovolemia) from euvolemia on physical exam. Serum uric acid may help sometimes – high serum uric acid levels suggest volume depletion while low levels suggest euvolemia. States of severe ECF volume contraction are often apparent on physical exam (i.e. hypotension, tachycardia, or orthostasis).
Hypovolemia
Low total body sodium (clinically low ECF volume). ADH release is non-osmotic and “appropriate” to help defend ECF volume. Causes of hypovolemic hyponatremia are as follows: Gastrointestinal losses (Excessive salt and water loss cause sufficient hypovolemia to stimulate hypothalamic baroreceptors to increase ADH release.). Diuretic overuse or abuse. Salt-losing nephritis. Mineralocorticoid deficiency (ADH secretion is increased with deficiency of
either gluco- or mineralocorticoid hormones. Mineralocorticoid deficiency typically causes hypovolemic hyponatremia, while glucocorticoid deficiency generally causes euvolemic hyponatremia). Osmotic diuresis (Solutes such as glucose, mannitol or urea increase urine flow rate and urinary sodium concentration thus prohibiting maximal dilution.)
Hypervolemia
Increased total body sodium (clinically increased ECF volume). For heart failure, cirrhosis and nephrotic syndrome, the effective vascular volume is compromised which activates volume/pressure receptors to release ADH (note the similarity to signal for sodium retention). Thus a decreased volume is sensed despite an absolute increase in total body salt and water. The increase in ADH is “appropriate” to the sensed signal. For acute or chronic renal failure, the hypervolemic hyponatremic state is caused by the inability to lose free water because of the compromised glomerular filtration rate. All of these disorders are characterized by the presence of edema on physical exam. The etiology can generally be determined by history and physical exam. The urine sodium may help sometimes as patients with heart failure, cirrhosis and nephrotic syndrome generally (not always, because they can be on diuretics) have low urine sodium.
the major causes of hypervolemic hyponatremia
congestive heart failure, hepatic cirrhosis, nephrotic syndrome, advanced chronic or acute renal failure.
Euvolemia
Normal total body sodium (clinically normal ECF volume). In this state, ADH secretion is increased despite the absence of the two physiologic stimuli for its release: increased Posm and decreased effective vascular volume. Thus ADH secretion is inappropriate. Hypothyroidism (ADH secretion is increased inappropriately and accounts for the hyponatremia.). Pharmacological agents (A variety of drugs impair renal water excretion. A partial list is shown below.). Adrenal insufficiency (ADH secretion is increased with deficiency of glucocorticoid hormones). Primary Polydispsia – excessive water intake usually in a person with some degree of renal insufficiency. SIADH (syndrome of inappropriate ADH secretion)- This diagnosis can be made with hypoosmolality and a less than maximally dilute urine in the absence of cardiac, hepatic, renal, adrenal, and thyroid disease. Three categories of disease may cause SIADH.
SIADH
is a diagnosis of exclusion. Before making this diagnosis it is necessary to establish the presence of normal adrenal and thyroid function and the absence of drugs that impair urinary dilution. Note that the urinary sodium concentration is of little value in SIADH. As a new steady-state of sodium and water balance is achieved urinary sodium excretion may be high, normal or low depending on the individual’s sodium intake.
Signs of hyponatremia
Gastrointestinal complaints of anorexia, nausea and vomiting occur early. Thereafter altered sensorium develops. Seizures occur with severe or acute hyponatremia. This is a general principle. The severity of symptoms correlate both with the magnitude of the disorder and the rapidity of its onset. These central nervous system complaints are likely due to cerebral edema.
Treatment of hyponatremia
Treatment depends on the effects and severity of hyponatremia. Dietary water restriction and correction of the causative disorder suffice in most circumstances. At times, hypertonic sodium chloride (3%) may be given with or without furosemide (which increases free water excretion) to prevent further or new seizures. Caution must be used not to raise the serum sodium concentration too quickly as a devastating neurological syndrome, central pontine myelinolysis, has been postulated to result from overaggressive correction. Drugs such as lithium or demeclocycline will antagonize the end-organ effect of AVP, but unfortunately are toxic. Specific antagonists to the hydroosmotic effect of AVP have been developed and are currently undergoing clinical trials.
Hypernatremia
disorders of concentrating ability. Hypernatremia occurs only when (1) ADH is decreased or ineffective or (2) daily water intake is less than that required to compensate for normal insensible, gastrointestinal and renal losses. Although many problems are listed, decreased thirst, inability to obtain water and medications are the most common causes. Hypernatremia is always associated with increased serum osmolality (re: Posm = 2 x [Na] + BUN/2.8 + Glucose/18)
Causes of hypernatremia with decreased total body NA
This occurs when total body water loss is»_space; total body salt loss. Examples include GI loss (diarrhea), skin loss (burns) or diuretic use without sufficient water intake. Another common example is a patient who is on a mechanical ventilator without access to water and no water replacement is given.
Causes of hypernatremia with increased total body Na
This is rare and usually occurs when people receive hypertonic fluid, usually sodium bicarbonate or hypertonic saline.
Normal total body Na
This can be broken down to ADH deficiency (Central Diabetes Insipidus) or ADH resistance (Nephrogenic Diabetes Insipidus).
Central Diabetes Insipidus (DI)
50% of cases are idiopathic. Head trauma, surgery and neoplasms constitute most of the rest. Urine volume ranges from 3-15 L/day. Patients tend to be young with nocturia and a predilection for cold water. Since central DI is due to ADH deficiency, the kidneys should respond to exogenous AVP with a rise in Uosm of 100 mOsm/kg above the levels achieved following water deprivation. Patients with complete central DI are not able to concentrate urine above 200 mOsm/kg with dehydration, whereas patients with partial DI are able to concentrate urine but not maximally. Treatment consists of supplying AVP; the best therapy is long-acting, nasally administered DDAVP (1-desamino-8-D-AVP). An interesting point is that thirst is stimulated by the increased Sosm so effectively that plasma sodium may well be normal and the main complaint is polyuria. The main differential diagnosis is often polydipsic water drinking.
Nephrogenic DI
In this condition the renal collecting duct does not respond appropriately to ADH, hence exogenous AVP will not change the Uosm significantly. Congenital nephrogenic DI is a rare sex-linked (male) disorder in which cyclic AMP is not generated in response to AVP. Treatment consists of large fluid intake and the use of a thiazide diuretic to decrease urine flow by causing sodium loss and volume depletion. Acquired nephrogenic DI is much more common but less severe. Chronic renal failure, hypercalcemia and hypokalemia are causes of this disorder. A number of drugs may cause a renal concentrating defect. Ethanol and phenytoin impair ADH release resulting in a water diuresis. Lithium and demeclocycline cause tubular resistance to ADH while amphotericin B and methoxyflurane injure the renal medulla.
Causes of an inability to conserve water
a concentrating defect can be due to lack of ADH, unresponsiveness to ADH, or renal tubular dysfunction. Other specific causes and mechanisms for concentrating defects include sickle cell anemia or trait (medullary vascular injury), excessive water intake or primary polydipsia (decreased medullary tonicity), severe protein restriction (decreased medullary urea), and a variety of disorders affecting renal medullary vessels and tubules. Treatment is directed at the underlying disorder. Water deficits may be corrected preferably with increased oral intake or with intravenous administration of hypotonic solutions. Recently, a condition of diabetes insipidus caused by peripheral degradation of vasopressin has been reported in some peripartum women. Vasopressinase is an enzyme that degrades ADH and oxytocin. This enzyme appears in the plasma of women early in pregnancy and increases in activity throughout pregnancy. Following delivery, vasopressinase rapidly becomes undetectable. Although only case reports of diabetes insipidus from vasopressinase have been published to date, it is not clear how frequently this condition actually occurs.
Manifestations of hypernatremia
Cellular dehydration occurs as water shifts out of cells. This causes neuromuscular irritability with twitches, hyperreflexia, seizures, coma and death. In children, severe acute hypernatremia (plasma sodium >160 mEq/L) has a mortality rate of 45%. Two- thirds of survivors have permanent neurological injury. In adults, acute hypernatremia has a mortality of 75%, chronic hypernatremia 60%. However, in adults, hypernatremia is a marker of serious underlying disease. Of note, the brain protects itself from the insult of dehydration by increasing its own osmolality, in part due to increases in free amino acids. The mechanism is unclear, but the phenomenon is referred to as “idiogenic osmoles.” The therapeutic corollary is that water repletion must be slow to allow inactivation of these solutes and thus avoid cerebral edema.
Treatment of the hypernatremic patient
Treatment is directed at restoring serum tonicity to normal and correcting sodium imbalances. Thus, sodium may need to be added or removed while providing water. A formula to calculate the total amount of water needed to lower plasma sodium from one level to another can be used. However, this does not take into account changes in sodium balance as it is based on a rough estimate of total body water as 60% of weight (kg): Water needed (L) = 0.6 x body weight in kg x [(actual sodium/desired sodium) - 1 ]. Water deficits should be restored slowly in order to avoid sudden shifts in brain cell water. It should also be pointed out that this formula calculates the amount of free water that would need to be replaced at the time the patient is first seen. It does not take into account any ongoing free water losses that may be occurring from the kidney while you are attempting to replace the deficit.
Some facts about salt
Typical intake of sodium in the U.S. = 3-7 g/day (150-300 mEq/day).A “no added salt” diet = 4 g of sodium/day. This is often ordered for patients with
hypertension or renal failure. A “low salt” diet = 2 g of sodium/day. Total body sodium = 50 g. Sodium filtered at the glomerulus = 600 g/day. Intracellular fluid (ICF) sodium concentration = 10 mEq/L. Extracellular fluid (ECF) sodium concentration = 140 mEq/L. The sodium ion and its accompanying anions (chloride and bicarbonate) form more than 90% of the total solute in the ECF space. Sodium and these anions are the osmotically active solutes and are therefore the major determinants of the ECF volume. Disorders of “sodium balance” relate to disorders of ECF volume. Note that at steady state, the osmolality of the ECF and ICF volumes is the same. In addition, at steady state the amount of sodium intake equals the amount of sodium that is excreted. The vast majority (>99%) of sodium that is consumed in the diet is excreted in the urine by the kidney under normal conditions.
Body fluid compartments
Living organisms are composed largely of water. A lean, healthy human is approximately 60% water by weight. Fat tissue contains less water. Therefore, in an obese person, the fraction of body weight that is water is lower, about 55%. Newborn babies have much less fat, and their water content is about 75% to 80% of their respective body weight.
The total body water distribution
The total body water (TBW) exists in two compartments. The intracellular fluid (ICF) compartment contains 2/3 of TBW, and the extracellular fluid (ECF) compartments have the remaining 1/3. The latter is further divided by the vascular capillary endothelial membrane into two more compartments: 1⁄4 of which is contained within the intravascular (IV) or plasma fluid compartment, and the remaining 3⁄4 is found in the extravascular or the interstitial fluid (IF) compartment. Figure 1 shows the distribution of water in a 70 kg man. If he has approximately 60% water by weight, then he will have a total body water of 42 L.
Water movement between between ICF and ECF compartments
Cell membranes throughout most of the body are freely permeable to water but are impermeable to many solutes. If different concentrations of impermeable solutes in the ICF and ECF compartments exist, an osmotic gradient is created. Freely permeable water then moves from the compartment with a high concentration of impermeable solutes to the compartment with a lower concentration until equilibrium is established. In other words, the ICF and ECF compartments are in OSMOTIC EQUILIBRIUM.
Rules of osmotic fluid movement
A water-permeable membrane must separate two compartments with different concentration of impermeable solutes. Water moves into the compartment with the higher solute concentration. Freely permeable solutes (like urea) do not affect this movement. The magnitude of the concentration gradient determines the magnitude of the water movement. Movement of water occurs until either the concentration gradient dissipates or the resulting increase in hydrostatic pressure balances out the osmotic pressure.
Water movement between vascular and interstitial compartments
The capillary wall is the barrier between these two compartments. Because this barrier is highly fenestrated, small molecules move easily between the two compartments and osmotic gradients do not develop. Instead, as discussed in the introductory section of the syllabus, Starling forces determine fluid movement i.e. the balance between the net hydrostatic pressure and the net oncotic pressure (determined by plasma protein concentration) determines the rate of water movement. It is important to realize that large molecules such as protein in the blood, albumin, and dextran cannot cross the fenestrated capillary wall. Therefore, intravenous infusions of these substances remain within the blood vessels and do not distribute to the interstitial space. One of the most commonly used intravenous solutions is normal saline, which is comprised of 0.9% NaCl in water. In contrast to blood and albumin, Na+ and Cl- are small molecules which move easily across the capillary barrier. Normal saline therefore distributes evenly across the vascular and interstitial compartments. This has important implications for which fluid is used to treat ECF volume contraction.
Most important determinant of ECF
sodium is the most abundant solute in the ECF. It is therefore the most important determinant of the ECF volume. The concentration of sodium in the ECF is tightly regulated (please see chapter on Water Balance). ECF sodium deficiency leads to renal sodium retention, and excess ECF sodium results in increased urinary excretion of sodium. When we talk about disorders of sodium balance, what we are referring to is the disorders of ECF volume. The inability to regulate ECF volume would threaten the very existence of the organism, because it would jeopardize circulatory stability. Maintenance of ECF volume determines the mean arterial pressure and left ventricular filling volume.
Effective arterial blood volume (EABV)
This is the volume of blood that is detected by volume sensors, located in the arterial side of the circulation. It is that amount of arterial blood volume required to adequately “fill” the capacity of arterial circulation.
Components of the homeostatic response
An adequate response involves two key components: an afferent limb that detects changes in EABV and an efferent limb that regulates the rate of sodium excretion by the kidney.
The afferent limb (volume sensors)
Volume sensors are located at various locations throughout the vasculature. They are classified into four categories: Low-pressure baroreceptors. High-pressure baroreceptors. Intrarenal sensors. Hepatic and central nervous system sensors.
Low-pressure baroreceptors
Cardiac atria receptors. Left ventricular receptors. Pulmonary vascular bed receptors.
These sensors are located on the venous side of the circulation and protect the body against ECF volume expansion and contraction. These are the receptors in the cardiac atria and cardiopulmonary sensors. Volume expansion and increased venous return to the right side of the heart stimulate atrial wall stretch receptors to signal hypothalamic and medullary centers in the brain (via cranial nerves IX and X) to decrease renal sympathetic nerve (SNS) activity. The net result is loss of sodium and water in the kidney and reduction in the initial ECF volume expansion. (See figure 3). The opposite occurs in a state of volume reduction. Similarly, cardiopulmonary receptors in the left ventricle and the pulmonary vascular bed are sensitive to changes in the central venous pressure (CVP) and adjust their rate of discharge in an attempt to normalize ECF volume by altering natriuresis, diuresis, heart rate, and peripheral vascular resistance.
High-pressure baroreceptors
Carotid sinus body at the bifurcation of the carotid artery. Aortic body in the aortic arch.
These receptors are situated on the arterial side of the circulation and protect the body against volume contraction and expansion. These sensors assess the pressure of the arterial circulation and work to maintain the mean arterial pressure (MAP) and protect vital organs from wide fluctuations in perfusion pressure. In a state of volume contraction, or in any condition that lowers EABV, these receptors send signals to brain centers and increased renal sympathetic nerve activity results. The net effects are anti-natriuresis and anti-diuresis. In severe volume contraction, norepinephrine (noradrenaline) is also released. This catecholamine response raises blood pressure by increasing heart rate and vascular resistance. Overfilling of the arterial tree has the opposite effect. Over all, the attempt is to normalize ECF volume in response to volume expansion or contraction.
Intrarenal sensors
Intrarenal sensors are formed by the renal juxtaglomerular apparatus (JGA) that releases renin. The latter is an enzyme whose function culminates in the formation of angiotensin II and aldosterone. Changes in renal perfusion pressure, sodium chloride delivery to the JGA, and renal sympathetic nerves influence release of renin.
Efferent limb (effector elements)
The kidney is the major effector organ involved in fluid volume homeostasis. ECF volume is mainly regulated by changes in renal sodium excretion. The factors that influence the latter are: Glomerular filtration. Physical factors at the level of the proximal tubule. Humoral effector mechanisms. Renal sympathetic nerves.
Glomerular filtration
How much sodium is excreted in the urine depends on how much sodium is filtered in the first place. The filtered load depends on the GFR and the serum sodium concentration. In a normal kidney, about 23 g of sodium (1000 mmol) are filtered per hour, approximately 600 g per day. Of the total hourly filtered load, 22.8 g (990 mmol) are re-absorbed. So as you can see, any fluctuation in the GFR will influence the renal handling of sodium. As stated earlier, the single nephron GFR is determined by the Starling forces. However, there are physiologic processes that serve to maintain GFR relatively constant and mitigate against large changes in filtered sodium load. these are: renal autoregulation, tubuloglomerular feedback (tgf), glomerulo-tubular balance
Renal autoregulation
an ability of the kidney to keep RBF (renal blood flow) and GFR constant by the contraction of the vascular smooth muscle of the stretched afferent arteriole in response to a higher intravascular pressure or dilatation when perfusion pressure decreases.
TGF refers to a phenomenon whereby increased distal delivery of sodium chloride to the macula densa (part of the JGA) increases afferent arteriolar tone and returns the RBF and GFR towards normal values.
Glomerulo-tubular balance is a fundamental property of the kidney whereby changes in GFR automatically induce a proportional change in the rate of proximal tubular sodium reabsorption. Thus, the fractional excretion of sodium is maintained constant in the setting of increases or decreases in GFR.
Humoral effector mechanisms
There are two groups of hormones that regulate the renal handling of sodium: In a state of ECF volume contraction, angiotensin II, aldosterone, and catecholamines act to
retain sodium.In conditions of volume overload, the other group of hormones- prostaglandins, bradykinin,
an atrial natriuretic peptide-work to induce natriuresis.
Renal sympathetic nerves
The sympathetic nervous system innervates the afferent and efferent arterioles of the glomerulus. This nerve activity is stimulated in a state of volume contraction and is needed for sodium conservation. Activation of these nerves has an anti-natriuretic effect. In addition, this nerve stimulation enhances the release of renin from the JGA which causes release of the anti-natriuretic hormones angiotensin II and aldosterone.
Sodium reabsorption in the kidney
As stated above, the goal of the integrated homeostatic response is to maintain ECF volume, in part by modifying sodium reabsorption. Now we will discuss how the kidney responds to the effector mechanisms to alter tubular sodium reabsorption. There are 4 major areas for sodium handling in the kidney. They are: Proximal tubule, Thick ascending limb of the loop of Henle, Distal convoluted tubule, Principal cell of the cortical collecting duct
Proximal tubule
The kidneys filter about 180 L of plasma daily. Most of the ultrafiltrate is reclaimed by various segments of the nephron. Only 1 to 2 L of urine is excreted daily. The kidneys filter approximately 25,000 mEq of sodium daily (GFR x serum sodium concentration = 180 L x 140 mEq/L). The proximal tubule reabsorbs about 60% of the glomerular filtrate, including the sodium. Sodium reabsorption in the proximal tubule occurs by both passive and active mechanisms. The former occurs down the electrochemical gradient of sodium because the sodium concentration in the tubule lumen is approximately 140 mEq/L compared to 15-35 mEq/L inside the cell. This gradient is maintained by the action of the ubiquitous sodium pump (Na/K/ATPase) at the basolateral membrane (plasma side). Na/K/ATPase moves Na+ from within the cell into the plasma, thus keeping intracellular Na+ concentrations low. The active entry of sodium into the cell is coupled to chloride, phosphate, glucose, amino acids, and lactate sodium-dependent co-transport. Another active mechanism of sodium transport is through the Na/H antiporter, which pumps sodium ion into and hydrogen ion out of the cell. This process leads to the generation and reabsorption of bicarbonate via the enzyme carbonic anhydrase.
Loop of Henle
About 30% of the filtered sodium is reabsorbed in the thick ascending limb of the loop of Henle (TALH). This part of the nephron is virtually impermeable to water but highly permeable to sodium. This characteristic makes the tubular fluid more dilute with a low NaCl concentration. Thus the osmolality of the tubular fluid at the end of TALH is about 150 mOsm/Kg water, or half that of plasma. The reabsorption of sodium at the apical membrane occurs by Na/K/2Cl co-transporter, an active transport process.
Distal Convoluted Tubule
In the distal tubule, sodium is reabsorbed across the apical membrane by three mechanisms: 1) Na ions enter the cell via Na-channels. This creates a negative potential difference in the lumen. The negative potential difference drives Cl ions across the paracellular pathway. 2) NaCl reabsorption occurs by a Na/Cl co-transporter. 3) Na transport involves parallel Na/H antiport and Cl/base exchange with recycling of hydrogen ions and base
Cortical Collecting Duct
The cortical collecting duct contains 2 types of cells: principal cells and intercalated cells. The intercalated cells (type A and B) are involved in hydrogen ion secretion and bicarbonate secretion, respectively. In the principal cell, sodium enters from the tubule lumen in exchange for potassium.
Extracellular volume contraction
ECF volume loss is shared equally by the two ECF compartments (the intravascular and interstitial compartments), unless the Starling forces across the capillary membranes are altered.
Etiology of extracellular volume contraction
ECF volume contraction can be due to renal or extra-renal causes. The renal losses are due to salt and water loss, or water loss alone. The renal losses are secondary to either a loss of effector mechanism (see earlier discussion) for salt and water preservation or an intrinsic kidney disease that causes a change in the output mechanism, e.g. kidney failure (see table 1) Extra-renal losses can occur from (1) the gastrointestinal tract (2) through the skin (3) due to hemorrhage, or (4) by “third- spacing”. “Third-spacing” refers to accumulation of fluid into areas outside of the ECF and ICF compartments, e.g the peritoneal cavity.
Renal losses of sodium and water
Two unusual mechanisms of renal sodium loss that involve failure of the effector mechanism occur in Bartter’s syndrome and Gitelman’s syndrome.
Bartter’s syndrome
presents early in life, and is caused by a mutation in the Na/K/2Cl co-transporter in the TALH. This syndrome is characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, high plasma renin and aldosterone levels, increased calcium excretion, and normal blood pressure.
Gitelman’s syndrome
occurs usually in older individuals, and is caused by a mutation in NaCl co- transporter in the distal tubule. It is characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, and reduced urinary excretion of calcium.
Extra-renal losses
ECF volume contraction results when extra-renal losses are not replaced.
Gastrointestinal (GI) tract fluid losses
can occur anywhere along the alimentary canal. Fluid loss from the upper GI tract (e.g. due to vomiting or nasogastric suction) is associated with concomitant loss of acidic gastric fluid, resulting in metabolic alkalosis(se acid-base chapter). Lower GI tract fluid loss (e.g due to diarrhea) is associated with concomitant loss of bicarbonate-rich pancreatic fluid, and can result in metabolic acidosis.
Dermal fluid losses
can occur due to profound sweating, burns (fluid loss occurs through damaged skin) and fever. Fluid lost during profuse sweating or high fever is hypotonic whereas interstitial fluid loss from burns is usually isotonic.
Fluid losses into a “third space”
occur when fluid is sequestered in an area outside of the ECF and ICF compartments. Common examples include loss of fluid within the bowel lumen during intestinal obstruction, or in the retroperitoneal area during pancreatitis.
Cardiovascular response to extracellular volume contraction
Baroreceptors detect volume contraction and reduced intravascular pressure. In an attempt to maintain blood pressure, the following activities result: Increased sympathetic activity which causes increased heart rate, cardiac inotropic function, and systemic vascular resistance. Increased secretion of vasoconstrictor hormones such as angiotensin II, A VP , endothelin.
Renal response to extracellular volume contraction
The renal response is an attempt to replenish the lost fluids and to conserve and re-absorb salt and water: Decreased GFR resulting in a smaller filtered load of sodium. Activation of the renal sympathetic nerves (see section on volume sensors above):
This leads to vasoconstriction of the afferent arteriole (decreases GFR) and increased tubular
re-absorption of sodium. Decreased hydrostatic pressure and increased oncotic pressure in the peritubular capillaries.
These enhance fluid reabsorption into the peritubular capillaries. Stimulation of renin-angiotensin-aldosterone system. Increased secretion of arginine vasopressin (AVP) from the posterior pituitary gland. AVP
increases water reabsorption in the collecting ducts. Inhibited secretion of atrial natriuretic peptide (ANP) from the atrial myocytes. An anti-
natriuretic effect.
Clinical manifestation and diagnosis
of extracellular volume contraction
Signs and symptoms of volume contraction will depend on the following major factors: the magnitude, the rate, the nature of the losses, and the responsiveness of the vasculature to the volume reduction.
History and physical examination of extracellular volume contraction
An accurate history and physical examination is important in your approach to the diagnosis. The symptoms are often non-specific. In mild volume contraction or when volume loss is gradual, the patient may have only thirst, postural dizziness, and weakness. In more severe or acute volume loss, the sensation of lightheadedness or dizziness may be worse. The patient may have palpitations or decreased urinary output. In severe volume contraction, the patient may experience confusion, lack of urine output, and profound weakness.
Physical signs of volume depletion
may not be easy to find when losses have been mild or gradual. However, look for any weight changes and make comparisons with baseline weights and obtain orthostatic blood pressure and heart rate. Orthostatic hypotension or tachycardia may be the first clinical sign of mild volume contraction. It is assessed by taking the patient’s blood pressure and pulse in a supine position, and then re-measuring it in the upright position after the patient has stood for 5 minutes.
Orthostatic hypotension
is present if there is: A decrease of greater than 10 mmHg in systolic blood pressure between supine and standing blood pressure or an increase of greater than 20 beats/minute in heart rate.
Interstitial fluid loss can be detected by decreased elasticity or turgor of the skin, but this sign may be difficult to interpret in the elderly who have lost subcutaneous tissue elasticity. Another sign is dry mucous membranes, but in a mouth-breather this sign may be insignificant. In more severe volume losses, one may find on examination lack of alertness, disorientation, hypotension, tachycardia, oliguria, decrease in the external venous pressure in the external jugular veins, cold and clammy extremities, and cyanosis. All of the clinical findings we have described may be unreliable in moderate degrees of volume contraction or in critically ill patients. Therefore, invasive hemodynamic monitoring may be required to assess volume state. This is accomplished by placing catheters into the venous circuit and measuring pressures within various compartments. The expected hemodynamic changes are decreased right atrial and central venous pressures, decreased pulmonary capillary wedge pressure, decreased cardiac output, and increased systemic vascular resistance.
Serum indices in volume contraction
The following serum indices may be seen in states of volume contraction: Increased BUN: plasma creatinine ratio. A normal BUN: plasma creatinine ratio is 10-
15:1. During volume contraction, the kidney avidly reabsorbs Na+ in the proximal tubule.
Urea passively follows the Na+ causing the BUN: plasma creatinine ratio to rise to ≥ 20:1.Metabolic alkalosis during upper GI loss of fluid. Metabolic acidosis during lower GI loss of fluid. Increased hematocrit and serum albumin because of hemoconcentration.
Fibroblast growth factor 23
The main function of FGF23 seems to be regulation of phosphate concentration in plasma. FGF23 is secreted by Osteocytes in response to elevated Calcitriol. FGF23 acts on the kidneys, where it decreases the expression of NPT2, a sodium-phosphate cotransporter in the proximal tubule. Thus, FGF23 decreases the reabsorption and increases excretion of phosphate.
Urinary sodium (UNa+) in volume contraction
UNa+ is usually low (40 meq/L) in part because the tubules are injured and cannot reabsorb sodium.
Fractional excretion of sodium (FENa) in volume contraction
As discussed in the chapter on ARF, the FENa simply reflects that amount of filtered sodium that is ultimately excreted in the urine. In prerenal azotemia, this value will be less than 1%. In oliguric acute renal failure it will be > 2 % (see equation below)
Equation: FE Na = Urinary Na x Plasma Cr x 100 / Plasma Na x Urinary Cr
Urine specific gravity and urine osmolality in volume contraction
These values are routinely obtained from urine dipsticks or from urinalysis performed by the lab. Urine specific gravity and osmolality indicate how dilute or concentrated a specimen of urine is. The specific gravity is a measure of the proportion of dissolved solid components to the total volume of the specimen (i.e. it reflects the density of the specimen). Osmolality indicates the number of particles of solute per unit of solution.
Serum osmolality is maintained within a very narrow range (285-295 mOsm/kg) by the kidneys in order to keep cells functioning optimally. The kidney is able to achieve this tight control by producing urine which varies tremendously in its concentration. If serum osmolality increases (e.g. during volume contraction), the kidney reabsorbs Na+ and water to produce a concentrated urine with high specific gravity and osmolality. The net result is a restoration of serum osmolality back to its normal range. If serum osmolality falls, the kidney excretes free water to produce urine that is dilute with a low specific gravity and osmolality. Both of these indices have been found to be reliable indicators of hydration status. the kidney’s ability to vary urine specific gravity, resulting in urine that consistently has a specific gravity of approximately 1.010. This is called isosthenuria and reflects severe renal injury that has caused disruption of both concentrating and diluting abilities.
Urine to plasma creatinine ratio (U/P Cr) in volume contraction
U/P Cr will be higher than 40:1 in pre-renal azotemia and less than 20:1 in acute tubular necrosis.
Treatment of extracellular volume contraction
The most important objective is the expansion of the ECF volume. Remember that ECF volume is made up of two compartments: intravascular and interstitial compartments. In general, the replacement fluid should resemble the lost fluid. The rate, amount, and route of replacement will depend on the situation. Some specific circumstances will be discussed. In acute hemorrhage blood should be given to correct hypovolemic shock. If blood is not immediately available, plasma volume expanders such as albumin and dextran solutions are alternative choices. Blood, albumin and dextran solutions contain large molecules preferentially expand the intravascular volume (see section: Water movement between vascular and interstitial compartments). Solutions containing sodium can be given in many situations. Isotonic normal saline (which is comprised of 0.9% NaCl or 154 mEq/L of NaCl) preferentially expands the ECF volume i.e. 20% remains intravascular and 80% in the interstitium (see Figure 11). Potassium loss from serum can be treated by adding potassium chloride to the intravenous solution. The rate of volume correction should match the clinical situation for each patient. In cases of hypovolemic shock, fluids must be given more rapidly. Care must be taken not only to provide what is lost but also to replace the ongoing losses, including insensible losses.
Extravascular volume expansion
ECF volume expansion is characterized by an increase in total body water, usually accompanied by an increase in total body salt. It is associated with edema formation, which refers to localized or generalized fluid accumulation in the interstitial compartment.
Etiology of extravascular volume expansion
Volume expansion occurs when renal and extrarenal fluid losses do not match water and salt intake. Three general kinds of derangements account for edematous states. Disturbed Starling forces lead to reduced effective arterial circulating volume and edema formation. Examples include: Congestive heart failure: increased venous pressure causes increased capillary hydrostatic pressure, and forces fluid into the interstitial compartment. Nephrotic syndrome: urinary protein loss causes decreased capillary oncotic pressure, and a reduction in the ability of the vessels to retain water. Water then moves into the interstitial compartment. Cirrhosis: hypoalbuminemia (due to malnutrition) and increased splanchnic vasodilation (seen in cirrhosis) cause a combined disorder in the Starling forces. The former results in less oncotic pressure within the vessels and the latter causes an increased in capillary hydrostatic pressure. The net result is movement of fluid from vessels into the interstitium. Primary hormone excess (overproduction of mineralocorticoids or vasopressin). Examples include: Primary hyperaldosteronism, Cushing’s syndrome, Syndrome of inappropriate secretion of anti-diuretic hormone (SIADH).
As discussed in the section Humoral effector mechanisms, mineralocorticoids promote Na+ reabsorption and vasopressin promotes water reabsorption. Primary renal sodium retention. Example: Acute glomerulonephritis.
Disturbance in Starling forces and volume expansion
Edema is a result of a decrease in capillary oncotic pressure and/or an increase in capillary hydrostatic pressure. Such disturbance in the Starling forces initiates edema formation. What maintains edema is that baroreceptors (discussed earlier in the section: The afferent limb, Volume sensors) perceive a reduced effective arterial circulating volume. This “arterial underfilling” stimulates the kidney (via mechanisms discussed in the section Efferent limb: effector elements) to retain sodium and water in an effort to maintain ECF volume via the integrated homeostatic response. Therefore, formation and persistence of edema results from a combination of:Alteration in Starling forces. Arterial underfilling resulting in decreased effective arterial circulating volume. Excessive renal sodium and water retention.
