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.
Congestive heart failure and volume expansion
Edema formation in CHF is the result of increased filling pressure in the atrium and the venous circulation. This abnormality together with decline in cardiac output, because of a failing ventricle, reduces blood flow to the arterial sensors in the circulation that “perceive” a fall in effective arterial blood volume. The net effect is an increase in the capillary hydrostatic pressure and interstitial space fluid accumulation.
Nephrotic syndrome and volume expansion
The pathogenesis of edema formation in nephrotic syndrome relates to loss of albumin in the urine and hypoalbulinemia. The resulting fall in the capillary oncotic pressure causes flux of fluids from the vascular space into the interstitium and a fall in effective arterial blood volume. Increased sodium retention may also occur in those states with decreased GFR.
Clinical manifestations and diagnosis of Nephrotic syndrome
Patients with nephrotic syndrome may present with general and non-specific symptoms or those related to the primary cause of the nephrotic syndrome. Patients may experience fatigue, weakness, dyspnea, and leg and face swelling. The edema in nephrotic syndrome is often diffuse. Anasarca may be present with pleural effusion and ascites. Edema is often periorbital in the morning. Laboratory findings that define nephrotic syndrome are proteinuria in excess of 3.5 g/24 hrs., hypoalbulinemia, and hypercholesterolemia. Nephrotic syndrome has numerous causes. Among the secondary or systemic causes, more common etiologies include diabetes mellitus, systemic lupus erythematosus, amyloidosis, hepatitis B, syphilis, gold therapy, nonsteroidal anti-inflammatory agents, penicillamine, and Hodgkin’s lymphoma . Primary renal diseases that cause nephrotic syndrome are minimal change disease, focal sclerosis, membranoproliferative glomerulonephritis, and membranous nephropathy.
Cirrhosis and volume expansion
Underfilling of the arterial circulation in hepatic cirrhosis results from a combination of factors. Intrahepatic hypertension, portal hypertension, splanchnic vasodilation, and hypoalbuminemia characterize cirrhosis and lead to the underfilling of the arterial circulation. The effect is increased capillary hydrostatic pressure and decreased capillary oncotic pressure, and therefore loss of fluids into the interstitial compartment. Regardless of the initiating mechanism, a reduction in the EABV will ultimately lead to the activation of renal effector mechanisms in an attempt to “correct” the perceived arterial underfilling.
Treatment of volume expansion
The management of volume expansion depends on the diagnosis. Successful therapy is defined by the treatment of the underlying condition, salt restriction, and diuretics. Drugs (such as nonsteroidal anti-inflammatory agents) that predispose to salt retention or change the effects of diuretics should be avoided. Therapy that improves EABV will be most effective. Congestive heart failure is treated by improving contractility, afterload reduction with systemic vasodilators, and reduction of preload with diuretics and nitrates. With normalization of the cardiac output, EABV should improve and minimize the need to use diuretics to inhibit tubular reabsorption of sodium. Nephrotic syndrome has many causes. Again, addressing the underlying etiology is essential. For example, in diabetic nephropathy achieving normal blood pressure, glycemic control, and treatment of proteinuria with angiotensin converting enzyme inhibition are the key points of therapy. The use of corticosteroids and cytotoxic agents may be applicable in primary glomerular renal diseases. Cirrhosis complicated by ascites is treated with repeated large volume paracentesis, intravenous albumin administration and spironolactone. Salt restriction is very important in the treatment of these diseases. In mild cases, restriction of sodium intake to 4 g/day (172 mmol/day) may be adequate treatment. In more severe cases, sodium intake should be restricted to 2 g/day (86 mmol/day).
Diuretics
Diuretics may be used to treat symptomatic edema that persists in spite of salt restriction. It is important to recognize that diuretics should be used primarily to improve cardiac and respiratory function, and not merely to improve cosmetic appearance of edema. With regard to the latter, the physician should remember the potential for diuretic abuse in patients. Excessive use of diuretics can actually worsen kidney function by intravascular volume depletion. Several classes of diuretics are available for use: including diuretics acting at the proximal tubule, loop of henle, distal convoluted tubule, and collecting ducts.
Diuretics acting at the proximal tubule
Acetazolamide is a proximal tubular diuretic. It works by blocking carbonic anhydrase action and causes wastage of bicarbonate in the urine. It is a weak diuretic, because the distal parts of nephron compensate for the decrease proximal reabsorption of sodium. Acetazolamide is unique as a diuretic in that it causes metabolic acidosis, and can actually be used to treat cases of metabolic alkalosis when isotonic saline can not be given because of ECF volume expansion.
Diuretics acting at the loop of Henle
Examples of this class include furosemide, bumetanide, and torsemide. These agents work by inhibiting the coupled entry of sodium, potassium, and chloride across the apical membrane in the thick ascending limb of the loop of Henle (at the Na/2Cl/K co-transporter). Since 25% of the filtered load of sodium is reabsorbed at this site, this class of diuretics is very potent. The side effects of loop diuretics are metabolic alkalosis, hypokalemia, hypocalcemia, and hypomagnesemia.
Diuretics acting at the distal convoluted tubule
Examples of this class include the thiazide diuretics. Thiazides inhibit the sodium/chloride transporter and block sodium entry across the apical membrane into distal tubular cells. Therefore, they limit the diluting ability of the distal nephron, but have no effect on the concentrating gradient generated by the loop of Henle. They have the same side effects as the loop diuretics, except that they increase calcium reabsorption and decrease urinary calcium excretion.
Diuretics acting at the collecting ducts
Triamterene and amiloride are sodium channel blockers, and spironolactone is a competitive inhibitor of aldosterone. These diuretics cause mild natriuresis and potassium retention. Spironolactone can be used in states of secondary hyperaldosteronism such as cirrhosis with ascites. These potassium-sparing diuretics can be used together with other classes of diuretics to prevent hypokalemia.
The significance and range of potassium regulation
Even though it is a minor component of the ECF, potassium levels have critical effects on a number of vital physiological systems. Most primarily, the K+ concentration in the ECF determines the resting membrane potential of all excitable cells. As you have learned, this parameter has a strong influence on the generation and properties of the action potential found in the nervous system and in muscle cells. For the heart, abnormalities in potassium concentrations can be especially serious in causing cardiac arrhythmias. In addition, the status of potassium regulation has a major effect on acid/base balance. Finally, K+ is the most abundant ion within cells, and thus contributes to the osmotic properties of the cellular compartment as well as being a co-factor for a number of biochemical reactions. Since cellular levels of potassium must derive from the extracellular pool, ECF potassium regulation has an important indirect effect on cell K+ concentration. Normal ECF potassium concentration is generally considered to be between about 3.5 to 5.0mM. Probably individuals have their own set points that are more tightly regulated within this range. Pathological states in which potassium levels are below or above normal levels are called hypokalemia and hyperkalemia, respectively.
Potassium regulation by variable secretion.
As far as the renal handling of potassium goes, for our standard human about 30 grams of K+ are filtered each day at the glomerulus, while excretion can range anywhere from ~0 grams to as much as 45 grams. The very low level of potassium excretion possible in this range obviously suggests avid mechanisms for tubular reabsorption. But for the upper limit, how can excretion be greater than the rate of filtration? this must mean that there is a process of potassium secretion. Thus the range of possible potassium excretion relative to its range of filtration tells us that both reabsorption and secretion of potassium can take place in the tubule. In fact, the tubular scheme for regulated potassium excretion is like that for sodium and water, with a new twist: In the proximal segments, there is nearly complete obligatory reabsorption of the filtered load, so it is in the distal fine tuning segments that variable excretion is achieved through homeostatically varied secretion of potassium.
Potassium reabsorption in the proximal tubule and loop of Henle
The tubular handling of potassium is actually rather more complex than we’ll describe, but again the simplified scheme should be more than adequate for your understanding of the renal role in regulating this crucial ion. As for Na+ and water, the bulk of filtered potassium is reabsorbed in the proximal tube….about 80% of the filtered load. Basically, the reabsorption of K+ is paracellular and passive, simply driven by the bulk flow of water through the tight- junctions. Recall that the avid basolateral transport of Na+ results in passive movements of a lot of other solutes, hence there is bulk water flow through the paracellular pathway. Since potassium is freely permeable to these tight junctions, it is simply “swept along” with the water movement to the serosal side of the epithelium. Here the movement is largely transcellular, first using the Na/K/2Cl co- transporter at the apical membrane to gain access into the cell in a secondary active transport process. Potassium then passively runs down its electrochemical gradient through a K+ channel in the basolateral membrane to the serosal domain. This process accounts for the reabsorption of about 10-15% of the filtered load. Thus, when the tubular fluid enters the fine tuning segments, almost all (90-95%) of the filtered load has been obligatorily reabsorbed. The small amount of potassium remaining in the tubular fluid is reabsorbed in the so-called principal cells of these segments. Thus, to a first approximation, all of the filtered potassium is obligatorily reabsorbed, hence regulated potassium secretion in the fine tuning segments also determines potassium excretion and ECF potassium balance1.
Cellular mechanisms of potassium secretion in the fine-tuning segments
This process is believed to occur in the principal cells of the these segments. The key to understanding this topic is to separate the total secretory process for potassium into two parts, i.e. 1) the basolateral entry of K+ into the cell, and 2) the apical secretion of the ion into the tubular lumen. In essence it’s much like generic sodium transport, but in reverse. Hence, the first step in the process uses our old friend the sodium pump to cross the basolateral membrane into the cell. Thus this pump is actually a Na+/K+-ATPase exchanger, i.e. it extrudes sodium while pumping in potassium. Once within the cell, in the second step the potassium ion can flow passively down its electrochemical gradient through a potassium channel in the apical membrane into the lumen; from here it is then excreted in the final urine.
Feedback loops for the regulation of potassium secretion
includes mass-action effect, hormonal regulation via aldosterone, and the interdependence of sodium and potassium regulation
Mass-action effects
A rather passive mechanism that acts as a first-line regulator of potassium secretion. It is that a change in ECF potassium concentration will drive a commensurate change in its overall tubular secretion because of the chemical law of mass action. In this example, an ingestion-caused rise in ECF potassium causes the basolateral ATPase to run faster. This occurs simply because K+ is a required co-factor for pump operation (i.e. potassium ions have to be bound to the pump to activate the pump cycle that splits ATP and moves sodium). Here the binding of potassium to the pump is the rate limiting step in operation of the exchange pump, so the more potassium in the serosal fluid, the more quickly it is pumped into the tubular cell. (for those of you who remember your chemistry, since two K+ are transported per pump cycle, we would say that the kinetics of potassium entry via the pump are second order with respect to serosal potassium concentration). The increasing rate of basolateral K+ entry in step 1 will naturally cause intracellular concentration of potassium to rise. This will increase the electrochemical gradient for potassium across the apical membrane, and hence the second step of apical secretion will also accelerate to keep pace. The problem with this mass-action driven pathway is that since the pumping rate change is proportional to the change in potassium concentration, it is most effective for rather large changes in potassium concentration. For smaller concentrations or when a large change is reduced to lower levels, the mass-action effect slows down considerably. This would mean that deviations in potassium levels would persist rather chronically, and since their effect on membrane excitability is immediate, this situation would place one at risk for cardiac and other complications. Thus, although significant, mass-action alone probably isn’t adequate to achieve the tight level of potassium level needed.
Hormonal regulation via aldosterone
Working in parallel with the mass action effect is a hormonal pathway. Here the increased K+ works directly on same adrenal zona glomerulosa cells that synthesize aldosterone for the sodium regulatory pathway. The effect of elevated potassium is to increase the synthesis/secretion of aldosterone, which then circulates to the fine tuning cells.
how does aldosterone increase K+ secretion?
The answer is that it works at several levels, which we can conveniently categorize as either step1 or step 2 effects. First, recall that aldosterone increase the number of Na/K/ATPase pumps on the basolateral surface. Obviously this increases the rate of potassium entry (enhanced step 1) and the intracellular concentration of K+ (enhanced step 2), as was seen in the mass action effect. Secondly, recall that aldosterone also increases the number of apical sodium channels. This will increase the rate of apical potassium secretion (step 2) because it enhances the passive counter flow of sodium inward across the apical membrane in exchange for outward potassium movement. Thirdly, aldosterone also increases the number of apical potassium channels, making it easier for potassium to flow into the lumen in step 2. The net effect is a strong enhancement of potassium secretion by aldosterone, and combined with the mass-action effects ensures that potassium is kept close to optimal levels in the face of significant gains or losses by other mechanisms.
The interdependence of sodium and potassium regulation
A point to keep in mind, especially for certain pathophysiological situations, is that since regulated sodium reabsorption and potassium secretion share the same hormonally-mediated pathway, one can expect a certain degree of interaction between these two homeostatic systems. Thus disorders affecting sodium regulation might be expected to also affect potassium levels too, and vice versa. This is often what happens, for example in hyperaldosteronism in which aldosterone levels are pathologically high, particularly for primary causes such as an adrenal tumor. However, there are often other processes that tend to attenuate such interactions between sodium and potassium. For example, while increased sodium reabsorption tends to increase the secretion of potassium simply based on charge exchange consideration, increased sodium also drives increased water reabsorption in the fine tuning segments, thus decreasing tubular flow. As we now discuss below, this has a very strong inhibitory effect on potassium secretion that offsets the stimulatory effect of sodium charge movement.
Effects of tubular flow on potassium secretion
Tubular flow has a very significant effect on potassium secretion, hence agents or situations that alter it strongly influence potassium levels in the ECF. One can see that the flow effect is an important determinant of the electrochemical gradient that drives the passive movement of K+ through potassium channels from the cell to the lumen in step 2. Thus with slow tubular flow, movement of potassium into the lumen causes it to build up in the tubular fluid before it is “washed away” by the flow of the tubular fluid downstream. Naturally as lumenal [K+] rises, the electrochemical gradient for subsequent secretion decreases, and thus secretion itself slows. The opposite effect is also true, namely that increased tubular flow will better wash away newly secreted potassium before it can build up and decrease the electrochemical gradient. Thus high tubular flows keep the gradient steep for passive apical flow of potassium.
How significant is the flow effect of potassium?
The answer is that such effects can be very important indeed. This is particularly the case for increased flows, since normally most potassium secretion takes place after much of the filtered water has been reabsorbed, hence the tubular flow is already quite slow. Take the example of loop diuretics, which you will learn more about in future lectures. This class of drugs selectively inhibits the ascending limb Na/K/2Cl co-transporter that we described above. As such, these drugs would be expected to inhibit the reabsorption of at most 15% of the filtered load, thus increasing secretion by this amount. However, treatment with loop diuretic often results in a massive increase of potassium secretion that can be well over 100% of the filtered load. Since these diuretics do not affect the 80% of filtered potassium obligatorily reabsorbed in the proximal tubule, one is left to conclude that these drugs are capable of stimulating huge increases in potassium secretion.
How potassium is fine tuned
Recall that the Na/K/2Cl co-transporter, through its transport of NaCl makes the interstitium hypertonic, thus creating an osmotic gradient for water reabsorption in both the descending limb and in the fine tuning segments. Thus inhibition of this process will diminish the osmotic gradient for the reabsorption of water, hence more water will remain in the tubule. Thus an increased flow of tubular fluid enters the fine-tuning segments due to the inhibition of descending limb water. Further, this increased flow will self-augment everywhere water is reabsorbed in the fine tuning segments themselves. In this way loop diuretics cause a large increase in tubular flow at the point of potassium secretion, greatly enhancing it. As you will learn, this enhancement of potassium secretion by this drug class class can often cause a dramatic lowering of ECF potassium, which can in turn result in a number of serious side effects that must be monitored or ameliorated. One might question whether loop diuretics, by virtue of the inhibition of potassium reabsorption in the ascending limb, would also increase the potassium concentration in the tubular fluid, thereby diminishing the gradient for potassium secretion, not enhancing it. However, the rise in potassium concentration that this entails is much smaller than the decrease in concentration afforded by a rapid wash out of secreted potassium at a high flow rate. On the other hand, things that decrease tubular flow in the fine tuning segments will have the opposite effect, i.e. a lowering, on potassium secretion and excretion rates. This effect can make the analysis of potassium handling in pathophysiological conditions a bit complex. As suggested above, a condition that elevates aldosterone will certainly tend to increase the molecular transporters that are involved in potassium secretion. However, this also increases sodium reabsorption, and thus more tubular water will follow this sodium into the interstitium, thus decreasing tubular flow and thus potassium secretion from this point of view.
which process dominates the potassium secretion picture?
primary hyperaldosteronism as usually causing an increased potassium secretion and loss. This is because this disease usually expands ECF volume and increases MAP, hence there is an increased filtration that keeps tubular flow normal or may make it elevated. This creates conditions where potassium secretion will indeed increase, particularly in the early stages of the disorder. On the other hand, cardiac insufficiency will also elevate aldosterone levels due to the fact that lowered MAP will stimulate the renin/angiotensin axis. This is sometimes known as “secondary hyperaldosteronism”, but it usually results in an elevation of potassium due to decreased potassium secretion. Why here, in the face of increased aldosterone, can potassium secretion decrease? Here the reason is that the decrease in MAP and potentially increased angiotensin result in a decreased GFR, hence the filtration flow is less than normal, and the reduced tubular flow causes a decrease in K+ secretion that more than offsets the effect of aldsoterone in increasing transporter number.
The effect of acid/base status on potassium secretion.
Another strong influence on potassium secretion, hence ECF potassium levels, is ECF pH. Alkalosis increases potassium secretion, hence tends to produce hypokalemia.
deep medullary K+-trapping mechanism
some of the reabsorbed K+ from the ascending loop and collecting duct is passively secreted into the descending loop. This is effectively a recycling mechanism for some reabsorbed K+ within the nephron. The significance of this phenomena is thought to lie in keeping the interstitial [K+] high to prevent passive reabsorptive leak of secreted K+ back into the deep medullary interstitium before it exits the papilla. While interesting, this process unnecessarily complicates our consideration of K+ regulation, and thus we will not consider it in the general picture of K+ homeostasis.
How alkalosis increases potassium secretion
Why this is so is not entirely understood, but the major features appear to be the following: First, high pH causes a shift of potassium ions into all cells from the ECF. This shift naturally includes the tubular cells, thus more potassium enters the cells, enhancing the electrochemical gradient for secretion via step 2. The mechanism for the shift into cells is not really known, but it should be noted that it will also reduce K+ generally throughout the ECF, thus contributing to the hypokalemic state. Secondly, the apical membrane potassium channels themselves are highly sensitive to pH, with increased H+ concentration inhibiting them from opening. Thus alkalosis, a lowering of the H+ concentration, releases some of the inhibition of these channels found at normal pH, hence allows faster flow of potassium into the lumen also in step 2. In summary, then, a state of alkalosis increases the rate of entry of potassium into the fine tuning epithelial cells at the same time it increases the apical membrane permeability to potassium. Thus the rate of potassium secretion is inappropriately elevated beyond that needed for ECF balance, and a state of hypokalemia results.
Acidosis and ECF potassium levels
So does a state of acidosis cause the opposite effect on potassium, namely decreased secretion and hyperkalemia? This is another of those “it depends” answers. In terms of the potassium shift and apical channel permeabilities that changed in alkalosis, the answer is indeed that these factors reverse in acidosis, i.e. these is a shift of K+ from cells to ECF, and the apical potassium channels become inhibited by the lowered pH. Thus the changes here argue for a decrease in potassium secretion, as expected. However, severe acidosis also inhibits the transporters involved in sodium reabsorption. Since this transport drives water reabsorption throughout the tubule, its inhibition increase tubular fluid flow, hence potassium secretion would also increase via the flow effect discussed above. Thus the final outcome really depends on the relative effects of a given acidosis on potassium secretion versus sodium reabsorption. This is why the effects of acidosis on ECF potassium are somewhat unpredictable, hence it is perhaps inadvisable to give a firm rule for the outcome as we can for the induction of hypokalemia by alkalosis. Finally, what if the primary event is a change in potassium levels (e.g. by the overuse of a potassium wasting diuretic?). As we will see in the next lecture, this indeed affects acid-base status with a converse correlation, as primary changes in K+ do affect pH levels.
Blood pH and plasma potassium regulation
plasma K rises with academia and fall with alkalemia. Anion-gap metabolic acidosis (e.g. lactic acidosis) does not generally cause as much of a shift as non-anion gap metabolic acidosis
Insulin and plasma potassium regulation
insulin is the first line of defense against hyperkalemia. A rise in plasma K stimulates insulin release which moves K into cells even without glucose. Insulin deficiency allows a mild rise in plasma K chronically and makes the patient liable to severe hyperkalemia if a potassium load is given. Conversely, potassium deficiency may cause decreased insulin release.
Adrenergic activity and plasma potassium regulation
beta two agonists stimulate the entry of K into cells. Beta blockers may potentiate hyperkalemia by preventing this internal shift. Alpha agonist also impair K entry into cells.
Physical Conditioning and Exercise and plasma potassium regulation
severe exertion may injure muscle cells and allow leakage of K into the ECF. Highly trained athletes may have normal total body K but redistribute K into muscles, thus producing hypokalemia.
Cell Membrane Na-K ATPase and plasma potassium regulation
These work to expel Na+ and take up K+. Thus, when Na/K exchange is inhibited, K may move out of cells. Digoxin intoxication causes hyperkalemia.
Hyperosmolality and plasma potassium regulation
Hyperosmolality may induce a shift of out of cells. The mechanisms involved are not clear
Renal excretion of K
K+ is freely filtered at the glomerulus and is reabsorbed predominantly through paracellular pathways in the proximal tubule so that 50% of the filtered K+ remains at the end ofthe proximal tubule. K+ is added to the proximal straight tubule and the descending limb of Henle’s loop so that at the hairpin turn100-120% of filtered K is present K+ is reabsorbed in the thick limb ofHenle’s loop by the Na+-K+-2cr cotransporter so that only 1 remains at the beginning of the cortical collecting tubule. K+ is into cortical collecting tubule through K+ channels but is reabsorbed in the medullary and papillary collecting duct by the KCI cotransporter and nonspecific cation channels so that about of filtered appears in urine. K+ reabsorbed in the medullary and papillary collecting duct is the source of the K that is added to the descending limb of henle. The pathophysiologic importance of renal K handling is that disorders of renal K handling almost always result from alterations in K addition of reabsorption from the collecting duct. The major site of regulation of renal potassium excretion occurs in the distal nephron.
How alkalosis increases potassium secretion
first high pH causes a shift of K ions into all cells from the ECF. This shift naturally includes the tubular cells, thus more K enters the cells, enhancing the electrochemical gradient for secretion via step 2. The shift into cells will also reduce K generally throughout the ECF, thus contributing to the hypokalemic state. Secondly, the apical membrane K channels themselves are highly sensitive to pH, with increased K concentration inhibiting them from opening, allowing for faster flow of K into the lumen also in step 2.
Acidosis and ECF K levels
well, it depends. In terms of the K shift and apical channel permeabilities that changed in alkalosis, acidosis has the reverse effect—there is a shift of K from cells to ECF and the apical potassium channels become inhibited by the lowered pH. Thus working towards a decrease in K secretion. However, severe acidosis also inhibits the transporters involved in Na reabsorption. Since this transport drives water reabsorption throughout the tubule, its inhibition increases tubular fluid flow, hence K secretion would also increase via the flow effect. Thus the final outcome versus Na reabsorption. This is why the effects of acidosis on ECF K are somewhat unpredictable, hence it is perhaps inadvisable to give a firm rule for the outcome as we can for the induction of hypokalemia by alkalosis.
Aldosterone
binds to a plasma membrane and/or cytosolic receptor that translocates to the nucleus and activates a signaling system (not yet well characterized). This results in the production of transcription factors. These transcription factors stimulate the production of proteins (AIPs) that have a number of effects including: 1) activation of apical sodium channels (increased subunit synthesis, increased open probability and decreased removal of channels from the apical membrane); 2) increased expression of the basolateral Na+/K+ ATPase. Surprisingly, molecular studies have shown that aldosterone receptors have an equal aflinity for glucocorticoids and mineralocorticoids. Since glucocorticoids circulate at l 0- l 00 times the concentration of aldosterone, the aldosterone receptor is “protected” from glucocorticoids by the enzyme 11-P hydroxysteroid dehydrogenase. This enzyme metabolizes cortisol to cortisone, a glucocorticoid with very low affinity for the aldosterone receptor.
The major determinants of urinary potassium excretion
I) Normal Distal Tubule Function: This implies both a normal tubular epithelium as well as a dequate delivery of Na to this nephron segment. 2) Aldosterone Activity Aldosterone stimulates distal nephron secretion of potassium. In the absence of aldosterone, body potassium content and plasma K,_ are increased. In the presence of excess aldosterone, the reverse is true. In tum, increased plasma K stimulates aldosterone secretion and decreased plasma K suppresses it. 3) urine flow rate: increasing flow rate increases urinary K excretion, by creating a favorable electrochemical gradient for tubular secretion. 4) delivery of non-reabsorbed anions to distal nephron: urinary excretion of anion (e.g. sulphates, bicarbonate in proximal RTS) will drag K along as an obligate cation.
Gastrointertinal K excretion
gut excretes 10-15% of K intake. Diarrhea increases fecal K losses, particularly laxative-related diarrhea.
Skin K excretion
normally only a trivial amount of K is excreted in perspiration. However, working in hot temperatures may produce up to 10-12 liters of sweat containing 10 mEq/L of K. Thus major K losses may occur. Of interest, sweat K is also under control of the hormone aldosterone.
K adaptation
the physiologic components of adaptation include the ability to excrete a K load more quickly (renal K secretary rates are markedly enhanced) and the temporary storage of K in the intracellular fluid is more effective. It should be stressed that K adaptation, in contrast to Na adaptation, is a relatively slow process to turn on or off. The mechanisms responsible for K adaptation involve aldosterone, insulin and the induction of Na-K ATPase in the renal tubular cells. In chronic renal failure, glomerular filtration rate declines, but the dietary intake of K generally remains unchanged. Thus, each remaining nephron must increase its rate of K excretion in order that external K balance is maintained. This is why hyperkalemia is a problem in acute renal failure but in the chronic renal failure state it becomes a problem only when GFR is extremely depress (below 10ml/min).
K deficit without hypokalemia
causes include diabetic ketoacidosis or uremia.
Treatment of hypokalemia/ K deficiency
in emergency situations, such as a cardiac arrhythmia or paralysis, K may be given intravenously with caution general oral supplements are preferable. Diuretics that reduce renal K excretion may be useful at times (spironolactone, triamterene, amiloride).
Hypokalemia
is usually but not always a sign of K deficiency. Internal shifts due to pH, catecholamines, insulin and other factors must be considered in evaluating the change in K content.
Metabolic effects of hypokalemia/K deficiency
hypokalemia suppresses insulin release leading to glucose intolerance. K deficiency in children retards growth. Hypokalemia also causes intracellular acidosis. A compensatory response is increased renal ammonia production. In the patient with hepatic cirrhosis and encephalopathy, ammonia intoxication may exacerbate the situation.
Cardiovascular effects of hypokalemia/K deficiency
causes the appearance of U waves after the repolarization T wave on the EKG. Hypokalemia enhances the development of atrial and ventricular arrhythmias in patients on digitalis. Both digitalis and K might alter Na-k ATPase.
Neuromuscular effects of hypokalemia/K deficiency
causes muscle weakness, even paralysis. Muscle membranes may be injured producing rhabdomyolysis (muscle cell lysis). Ileus of the guts may occur.
Renal effects of hypokalemia/K deficiency
causes both increased thirst (unknown mechanism) and a renal concentrating defect (decreased adenylate cyclase activity and tissue solutes) resulting in polyuria. Prolonged hypokalemia causes proteinuria, proximal renal tubule vacuolization, interstitial fibrosis and decreased glomerular filtration rate.
Cause of hypokalemia without K deficit
alkalosis, familial hypokalemic periodic paralysis, beta 2 adrenergic drugs, insulin
Cause of hypokalemia with K deficit
poor dietary intake, cellular incorporation (e.g. treatment of megaloblastic anemia), gastrointestinal loss (e.g. protracted vomiting or diarrhea), urinary loss, excessive mineralocorticoid effect (e.g. hyperaldosteronism, licorice effect, bartter’s syndrome), renal tubular acidosis (I and II).
Hyperkalemia
is less common than hypokalemia but may be more dangerous. Plasma (or serum) levels above 7.0 mEq/L seriously derange organ function and levels above 10 are often fatal. Because of its emergent nature, every physician must be able to expediently manage hyperkalemia.
Cardiac effects of hyperkalemia
an acute rise in plasma K reduces the ratio of Ki/Ke that raises cell membrane potential toward the threshold potential. The EKG effects progress unpredictable through a tall T wave, decreased R wave, widened QRS complex, prolonged P-R interval, absent P wave, and lastly a sine wave QRS pattern with a ventricular fibrillation or cardiac arrest possible at any stage. Any EKG change with hyperkalemia is a medical emergency.
Neuromuscular effects of hyperkalemia
these resemble the changes in hypokalemia but are due to depolarization, not hyperpolization. Thus weakness progressing to paralysis may occur.
Causes of pseudohyperkalemia
hemolysis of drawn blood, massively increased WBC or platelet count, tourniquet applied too tightly.
Causes of true hyperkalemia
reversible shift from ICF to ECF: (e.g. acidosis, hyperkalemic familial periodic paralysis, digitalis intoxication, beta-adrenergic blockade, alpha-2-adrenergic agonists, hyperosmolality). Decreased excretion: chronic or acute renal failure, selective impairment in renal K excretion (K-sparing diuretics, ACEI, deficiency of adrenal steroids, type IV renal tubular acidosis). Increased input: endogenous input (e.g. hemolysis, rhabdomyolysis) and exogenous input (e.g. salt substitutes, K rich foods).
Treatment of hyperkalemia
is based on reversing physiological problems. Calcium infusion reverses depolarization. Glucose/insulin, beta 2 agonist, NaHCO3 infusion all shift K into cells. Kayexelate (ion exchange resin), diuretics, and hemodialysis removes K from body.
Normal and abnormal pH ranges
The usual ECF index of acidity, plasma pH, is considered to be normal when in the range of 7.35 to 7.45. This range represents a 25% difference in [H+], thus the regulation of hydrogen ion is fairly “tight”. pH values outside of this range suggest disorders in acid/base balance, with pH 7.45 indicating an alkalemia. Extremes for ECF pH that can be tolerated range from 7.0 (severe acidosis) to about 7.7 (severe alkalosis), a 5-fold range in hydrogen ion concentration. normal metabolism produces large quantities of potential acid in the form of carbon dioxide; since CO2 is a gas, it is eliminated very effectively under normal circumstances by the lungs. However, the body also produces a certain amount of “nonvolatile”, or nongaseous acid, mostly in the form of sulfuric or phosphoric acids (H2SO4 and H3PO4, respectively) that are produced from the catabolism of proteins and nucleic acids.
Production of nonvolatile acid and its potential consequences
Typically a 70kg person will produce 60 meq/day of nonvolatile acid, i.e. every day 60 mmol of H+ are added to the ECF. the amount of H+ produced daily is actually quite a lot if one is attempting to regulate ECF pH near neutrality.
ECF buffers for acid: The bicarbonate buffer system.
Obviously the ECF is not pure water, but is a complex mixture of solutes that includes buffers for hydrogen ions. Conceptually, any chemical substance capable of interacting with free hydrogen ion is a buffer in that it decreases the availability of protons for competing interactions with biologically important molecules such as enzymes or transporters. However, to be an effective buffer a compound must have the optimal combination of concentration and avidity for H+ to maintain a physiological pH. In this regard, a quantitatively important class of buffers are the proteins present in the ECF, particularly the plasma (e.g. albumins and immunoglobulins). Carboxylates, amines, and the histidine side group are all capable of binding hydrogen ions, thus are a large buffer component of the ECF. However, the pKa’s of most of these sites is far from physiological and on balance would only buffer nonvolatile acid to about pH5 or so. While this is more helpful to the general problem than an unbuffered ECF at pH2.4, ultimately the ECF needs a buffer system capable of reducing this acid to the required physiological level. Such a buffer is the bicarbonate anion, HCO3-.
bicarbonate anion, HCO3
As an anion with an affinity of hydrogen cations, bicarbonate can be expected to buffer simply by a complexing mechanism, i.e. H + HCO3 -> H2CO3. However, while bicarbonate is a more physiological buffer than protein, the pKa of this reaction is only about 6.8, thus high concentrations of HCO3- would be needed to buffer at pH~7.4. Furthermore, one would be left with the problem that every day would see the addition of 60 meq of nonvolatile acid, which would be building up constantly. Thus, the neat “twist” about the bicarbonate system is that it converts nonvolatile acid to a gaseous volatile form that can be eliminated, rather than simply buffered: H + HCO3 -> H2CO3 -> CO2+ H2O. In essence, then, the presence of bicarbonate converts H+ released from a nonvolatile acid anion to CO2, allowing it to be expelled from the ECF by the respiratory actions of the lungs.
The need for acid anion elimination and replacement of lost bicarbonate
Reaction scheme is fine for explaining how one can deal over time with the continued production of H+, but it is incomplete in two important aspects: First, one also has to eliminate the acid anions that produced the hydrogen ions in the first place, e.g. HSO4-, H2PO4- etc. . Since these entities are small, it will come as no surprise that they can be filtered at the glomerulus and excreted in the urine. However, the second consideration is a bit more problematic; this has to do with the obvious fact that by scheme elimination of each H+ requires the “suicide” destruction of a bicarbonate anion. Thus to maintain buffering capacity, the bicarbonate lost in this manner has to be replaced somehow. There is only a 5 days supply of ECF bicarbonate available (i.e. 300 total mmol HCO3/ 60mmol/day destroyed in reaction(1)). Clearly, then, the bicarbonate lost in the elimination of acid must be continuously replaced.
Role of the kidneys in nonvolatile acid elimination: Maintenance of ECF bicarbonate
So one simple aspect of the renal role in dealing with nonvolatile acid production is the removal of the acid anion from the ECF as urinary waste. However, this leaves the problem of bicarbonate maintenance. At a minimum, as a small solute bicarbonate is freely filtered at the glomerulus, hence it needs to be avidly reabsorbed lest it be rapidly lost in the urine. However, a new twist on how the kidneys regulate this ECF component is that they synthesize bicarbonate to replace exactly what is lost in the acid elimination process. Thus we will now discuss the tubular mechanisms that reabsorb filtered bicarbonate and those that synthesize it.
Reabsorption of filtered bicarbonate
As with other important metabolites that are “swept up” in the indiscriminate flow of the glomerular filtrate, most of the recapture of bicarbonate takes place in the proximal tubule (i.e. about 85% of the filtered load) and is obligatory. the main cellular basis for bicarbonate reabsorption, which is defined as the transport of HCO3- from the tubule lumen to the serosa. In this process, the primary event is the secretion of an H+ from the inside of the cell into the lumen. In the proximal tubule this takes place primarily through a sodium- hydrogen exchanger (NHE) located in the apical membrane. Once in the lumen it rapidly combines with bicarbonate to form carbonic acid (H2CO3), which according to scheme (1) breaks down to CO2 and water. The apical membrane is highly permeable to CO2, a neutral molecule, and so carbon dioxide diffuses into the cell. Inside the cell, CO2 recombines with a water molecule to reform carbonic acid. This is possible because reaction(1) is actually highly reversible. Within the cell bicarbonate and H+ concentrations are low, hence the reaction drives toward the left, resulting in the regeneration of these two reactants. Finally, the intracellular bicarbonate thus created is transported across the basolateral membrane by a sodium-bicarbonate co-transporter (NBC).
important points about reversibility of the carbonic acid reaction
First, note that this process does not change ECF acid/base balance. In particular, the original H+ that was secreted into the lumen simply recycles with each HCO3- that is transported into the cell. Thus no acid is created or lost in the process, but rather bicarbonate is merely returned to the ECF from the filtrate. Second, note also that the process causes the transepithelial movement of negatively-charged bicarbonate; thus electroneutrality demands the corresponding movement of a cation or the exchange for an anion. In the proximal tubule, electroneutrality is largely satisfied by the co-movement of sodium. Mostly such movements are directly coupled to the process by the NHE’s and the NBC’s. This is significant to mention, since the reabsorption of bicarbonate at 20mM couples to the reabsorption of about 15% of the filtered Na+. Third, ordinarily the breakdown or formation of carbonic acid from water and carbon dioxide is rather slow. To speed up the process an enzyme called carbonic anhydrase is localized at critical points on the apical membrane surface and within the cell cytoplasm. This fact, along with the large amount of NaHCO3 transported by the processes, will become important for you to think about when you study a class of diuretic known as carbonic anhydrase inhibitors.
Cellular mechanisms of bicarbonate synthesis by tubular cells
This is primarily a process of the epithelial intercalated cells in the distal segments. One could regenerate lost bicarbonate simple by taking a CO2 and reversing reaction. Well, of course this creates a bicarbonate, but in reality the process creates carbonic acid which also yields H+ when it dissociates. Thus we are actually worse off with this scheme. However, what if we did indeed use this scheme, but at the end of it all we could get rid of the hydrogen ion itself? This is exactly what happens in renal bicarbonate synthesis; a carbon dioxide is taken from the ECF into the cell, where like the reabsorptive process it is turned into carbonic acid and then H+ and HCO3-. Here the cellular trick is that the acid and its base pair are physically separated, with the hydrogen ion transported into the lumen for excretion in the urine and the newly synthesized bicarbonate transported out from the cell to the serosal ECF.
Trapping of secreted hydrogen ion by urinary buffers in synthesis of bicarbonate by tubular cells
However, the secretion of hydrogen into the tubular fluid will tend to drastically lower its pH. Since 60 mmol of hydrogen from nonvolatile acid are produced each day, this same amount must be secreted into the tubule to stay in balance. But this amount of acid must be excreted in the typical urine volume of 1.5 liters. If the urine were unbuffered, its average pH would then be about 1.4. This fall in pH cannot be allowed to occur for two basic reasons. First, a urinary pH that low would be highly injurious to the cells lining the urinary tract. Second, it would be energetically very expensive to secret hydrogen ions from the cell into the lumen given the approximately 1 million-fold hydrogen ion concentration gradient across the apical membrane (i.e. pH 1.4 versus pH 7.4 inside cell). As you will learn, the parietal cells of the stomach have solved these problems for digestion, however, the solutions of the stomach would be very deleterious for the other transport and regulatory functions of the kidney. Instead, the kidney’s solution is to neutralize most of this secreted acid with urinary buffers. There are two main buffering mechanisms recognized in this processes, respectively termed titratable acid and ammonia trapping.
Titratable acid
refers to the complexing of hydrogen ion to a filtered acid anion, such as HPO42- . Actually, the real acid anion will be of no help in buffering, since its pKa by definition is very acid (e.g. around 2 for phosphoric acid), so it’s usually other forms of the anion or a weak acid that will significantly interact with hydrogen ion at pHs near 5 or so. In this case much of the HPO42- actually derives from bone calcium phosphate desorption, not from phosphoric acid production from nucleic acid catabolism. In Figure 3 the example is one of titrating the doubly-charged phosphoric acid anion, which is a weak acid, to the monovalent form (which is a strong acid and can’t be titrated further at urinary pH’s). However, titratable acid buffering is merely incidental to the needs of bicarbonate synthesis, since the buffers involved exist for other reasons not related to acid/base balance. Thus a second urinary buffer mechanism exists that can be varied in response to chronic changes in acid/base balance. This mechanism is ammonia trapping.
Mechanism of ammonia trapping
Basically, the tubular cells break down the amino acid glutamine to free ammonia (NH3). Since this substance is readily soluble and neutral, it diffuses very readily through the apical membranes of the epithelium into the tubule. Once in the tubule, it has a very high affinity for H+, buffering it to form ammonium ion (NH4+). In this way conversion of neutral, lipid soluble ammonia to charged ammonium renders the compound impermeant to the apical membrane, hence the ammonia is now trapped with the buffered hydrogen ion in the tubule, to be excreted in the urine. The significance of ammonia trapping is that it can be up or down regulated if hydrogen ion secretion chronically changes. For example, in the case of a prolonged metabolic acidosis, one of the enzymes responsible for glutamine catabolism, glutaminase, is upregulated, hence the production of ammonia from glutamine increases to buffer the increased secretion of hydrogen ion.
Similarities to reabsorption with synthesis of bicarbonate by tubular cells
From a transport point of view, the synthesis process can use the very same transporters and enzymes used by reabsorption. The main difference is that synthesis starts with CO2 entry from the serosa, whereas with reabsorption the CO2 comes from tubule lumen. However, it is important to realize that, unlike bicarbonate reabsorption, this process is not neutral in acid/base terms, but results in the elimination of acid in the urine. Further, other apical H+ secretion mechanisms and basolateral HCO3- transporters are usually involved in addition to the NHE’s and NBC’s that we saw in the proximal tubule reabsorption process. For example, there is an apical hydrogen ion pump that uses the energy in ATP to secrete H+, while in the basolateral membrane bicarbonate is extruded in exchange for chloride entry via a HCO3/Cl exchanger. However, these details do not change the fundamental concepts of bicarbonate handling and synthesis: Both processes require apical secretion of hydrogen ion and basolateral extrusion of bicarbonate from the cell interior, and it doesn’t matter which of these transporter variants are involved. In fact, given these H+ secretion and HCO3- extrusion characteristics, any cell can reabsorb and/or synthesize bicarbonate
Reabsorption of bicarbonate is a much larger process than synthesis
Since any cell with the requisite transporters can run in the bicarbonate reabsorption or synthesis modes, we next explore the relative magnitudes of these processes and the conditions that specify which modality the tubule executes. Under normal circumstances a healthy individual must make 60mmol of HCO3- each day to replace that lost neutralizing nonvolatile acid. Thus the tubular cells must secrete this amount of hydrogen across the apical membrane and transport this much bicarbonate across the basolateral membrane. For reabsorption, however, the amount of filtered bicarbonate that must be reabsorbed is 20mmol/liter times the GFR of 190 liters/day = 3800mmol of hydrogen ion and bicarbonate that must be transported using the same secretory and basolateral processes as for bicarbonate synthesis. Thus the reabsorption of bicarbonate requires over 60 times the capacity of the tubular cell NHE’s, NBC’s, H+ pumps, etc. as does synthesis.
Reabsorption of bicarbonate always takes priority over bicarbonate synthesis
An essential rule to understand in considering how bicarbonate is regulated is the following: “Essentially no bicarbonate synthesis can take place until bicarbonate reabsorption is complete.” If the urinary buffer were bicarbonate, the hydrogen ion is not trapped, but instead causes conversion of luminal bicarbonate to CO2, thus the process occurs to reabsorb the tubular bicarbonate. Doing so results in the hydrogen ion reforming inside the cell, instead of staying in the lumen and being excreted as it has to. In particular, this recycling from the reabsorption process will inhibit synthesis competitively, since the intracellular formation of CO2, H+, and bicarbonate during this process will inhibit the entry of CO2 from the blood side and will compete for the secretory and bicarbonate extrusion transporters required for the synthesis pathway. To summarize, any cell with apical H+ secretion and basolateral HCO3- extrusion mechanisms can serve to reabsorb bicarbonate or to synthesize it. However, as long as there is bicarbonate in the tubular fluid, only reabsorption will take place; bicarbonate synthesis can only occur after all the filtered load has been reabsorbed. In reality, the filtered load of bicarbonate is so large that it is only the cells in the very distal parts of the tubule that will end up synthesizing bicarbonate under normal circumstances.
The regulatory range of bicarbonate handling
As with the other ECF substances that we have discussed, we now consider the limits of bicarbonate processing possible for our 70kg person. For normal health, all of the filtered bicarbonate, i.e. 3800 mmol, must be reabsorbed plus 60 mmol/day synthesized. At one end of the limit is severe metabolic acidosis when up to 200 mmol/day of H+ from nonvolatile acid can be eliminated by the bicarbonate system, thus requiring 140 additional mmol of bicarbonate to be synthesized each day. At the other end of the limit is severe metabolic alkalosis in which excess base in produced. The kidneys help out here by excreting up to 80 mmol of bicarbonate per day in the urine, this time retaining the hydrogen ion formed during their creation in reaction(2), thus adding needed acid to the ECF. So the entire range of bicarbonate handling goes from 3720 mmol/day reabsorbed to 4000mmol/day reabsorbed plus synthesized.
Bicarbonate homeostasis during acid/base imbalances
in the normal situation for acid/base balance the production of nonvolatile acid and the tubular secretion of hydrogen ion are relatively constant. However, in acidosis the production of acid increases, while in alkalosis there is decrease in acid production below normal, or indeed, a net production of base. Since bicarbonate reabsorption and synthesis must involve the apical secretion of hydrogen ions and the basolateral extrusion of bicarbonate, it is these processes that are rate limiting for bicarbonate homeostasis. The rates of apical hydrogen ion secretion and basolateral bicarbonate extrusion depend on ECF pH and CO2 levels. The reason for this is simply that the levels of acid or carbon dioxide determine the number of the relevant transporters in the apical and basolateral membrane. The mechanisms for this are not known, but an increase in either (e.g. CO2 in respiratory acidosis, H+ in metabolic acidosis) causes the cell to insert more transporters into the apical and basolateral membrane.
The renal response to a metabolic acidosis
As you have already learned, during imbalances of a metabolic nature the kidney and the lungs work together to deal with the threat. This example illustrates how healthy renal and respiratory systems can respond coordinately to the primary event of the metabolic overproduction of H+. In the short term this threat is dealt with passively through the buffering action of bicarbonate and the production of CO2 (which is eliminated by the lungs). However, this also results in a reduction in the filtered load of bicarbonate, hence less hydrogen ion secretion is used to reabsorb bicarbonate and there is now an excess of secretory capacity to allow increased bicarbonate synthesis to replace that which is lost by increased acid neutralization
The renal response to a respiratory acidosis
In this situation, ventilation is inadequate due to a pulmonary problem (usually obstructive disease), hence CO2 levels rise in the plasma and in the ECF, causing acidemia/acidosis. Thus the normal partnership between the lungs and kidney that compensates for metabolic acidosis (i.e. increased ventilation by lungs, increased HCO3- synthesis by the kidney) doesn’t work in respiratory acidosis, since the lungs themselves are the source of the problem. How do the kidneys respond to this state of affairs? This is a more complex response to analyze. At first, when CO2 levels in the ECF first become elevated, HCO3- levels rise due to a simply mass-action conversion of carbon dioxide to bicarbonate. This process is comparatively rapid (i.e. follows the onset of hypoventilation closely in time) and is not compensatory but rather results in acidification of the plasma and the ECF since each mass action-produced HCO3- is also accompanied by one H+. Following the induction of the acidosis, the kidney responds via the increased expression of H+ pumps in the apical membrane of tubular cells (largely in intercalated cells of the collecting duct). This process occurs relatively slowly, i.e. over the course of several days, resulting in an increased hydrogen ion secretion. Since at this early stage all filtered HCO3- has been reabsorbed proximally, these additional hydrogen ions are derived from CO2 entering from the ECF, i.e. resulting in the synthesis of additional HCO3- . More importantly, this secreted H+ stays in the tubule and is excreted, thus compensating the primary acidosis. However, this mechanism of compensation is ultimately limited by the fact that for each compensating H+ secreted an HCO3- is synthesized. Also adding to the HCO3- pool is the bicarbonate formed by the original retention of CO2, adding to the filtered load of HCO3-. Thus in the final phase of the renal response, most of the additional secreted H+ now goes to reabsorb this newly added HCO3- and H+ excretion returns toward normal. So to summarize, in the short term the kidneys respond to a respiratory acidosis by increasing their excretion of hydrogen ion to counteract the acidosis. Eventually, however, this compensation is limited by the increased filtered load of bicarbonate that results. Thus in the case of a prolonged respiratory acidosis, one generally sees a partial renal compensation with elevated bicarbonate.
Effects of potassium imbalances on acid/base status
In the previous lecture we discussed the effects that primary acid/base imbalances have on potassium homeostasis, noting particularly that alkalosis leads to increased potassium excretion and a tendency to hypokalemia. The opposite is also true, namely that a primary hypokalemia will cause an alkalosis. Part of the reason for this can be seen as the opposite of the mechanism, since lowered ECF potassium results in a shift of hydrogen ion into all cells; in the tubular cells this means more H+ is available for secretion, thus by mass action more will be moved into the lumen and then excreted. In addition, a chronic fall in pH in the tubular cells caused by this shift stimulates the same mechanism discussed above that increases transporter number. Thus the hypokalemia-induced shift of H+ into tubular cells results in inappropriately increased H+ secretion and urinary excretion, inducing the alkalosis. On the other limb, it is also the case that hyperkalemia tends to induce an acidosis. Naturally a hyperkalemic induced shift of H+ out of cells will have the opposite effects for hydrogen ion secretion as described for hypokalemia above, i.e. there will be a reduced intracellular concentration of H+ for apical secretion and the insertion of apical H+ secretory transports will decrease. However, there appear to be other less well understood mechanisms that decrease hydrogen ion secretion, including a direct inhibitory effect of potassium on ammonia production, thus a decrease in the ammonia trapping process. In this latter case, the tubular fluid pH will fall, thus representing an increase in the apical H+ ion gradient that hydrogen ions must be secreted against, and the secretion rate thus falls. Overall, the effect of hyperkalemia is to reduce the rate of H+ secretion and subsequent excretion, and H+ is inappropriately retained in the ECF to produce an acidosis.
Four categories of acid base disturbances
a change in pH can only occur if there is a change in HCO3- or PCO2. Thus, there are four, and only four, types of acid base disturbances: 1. Respiratory alkalosis (decrease in CO2 resulting in a increase in pH) 2. Respiratory acidosis (increase in CO2 resulting in a decrease in pH) 3. Metabolic alkalosis (increase in HCO3 resulting in an increase in pH) 4. Metabolic acidosis (decrease in HCO3 resulting in decrease in pH). So, if you are breathing too fast for some reason (pneumonia, asthma exacerbation) this decreases PCO2 resulting in a primary respiratory alkalosis; based on the ABC formula and Henderson Hasselbalch, it should be clear that the mechanism to compensate for this primary respiratory alkalosis and return the pH toward normal would be to decrease the bicarbonate concentration. In ALL cases, the compensation is in the same direction as the primary change.
Definition of respiratory alkalosis
Respiratory alkalosis is a respiratory process that causes a primary decrease in the PCO2.
Differential diagnosis of respiratory alkalosis
Primary respiratory alkalosis is ALWAYS from breathing too much, i.e., respiratory alkalosis is ALWAYS from hyperventilation. Hyperventilation can occur due to pulmonary diseases, hypoxemia, voluntary, mechanical ventilation, and miscellaneous causes that directly simulate the respiratory center such as fever, liver disease, pregnancy, head injuries, salicylate toxicity (salicylate toxicity results in a concomitant metabolic acidosis).
Compensation for respiratory alkalosis
Decreased HCO3 from 1) cell H+ release (acute) and 2) renal H+ retention (chronic). Compensation for respiratory alkalosis is by a decrease in HCO3 which occurs in two steps: 1) buffering from cells (H+ release from cells) and 2) renal H+ retention. In both cases the H+ binds HCO3, consuming and lowering HCO3, and driving the Henderson-Hasselbalch equation toward the formation of CO2 and H2O. Renal compensation takes 3 to 5 days to become complete, thus, respiratory alkalosis may be acute (drop in bicarbonate from cell buffering with H+ release from cell alone) or chronic (drop in bicarbonate from cell buffering and renal H+ retention). In acute respiratory alkalosis, the bicarbonate is expected to fall by 2 mEq/L for every 10 mmHg fall in PCO2; in chronic respiratory alkalosis, the bicarbonate is expected to fall by 4 mEq for every 10 mmHg fall in PCO2.
Compensation rules for respiratory alkalosis
The expected decrease in bicarbonate in respiratory alkalosis is predicted by the following: Acute: ΔHCO3- = ↓ 2 meq/L for every 10 mmHg ↓ in PCO2 [↓(2:10)]
Chronic (3 to 5 days): ΔHCO3- = ↓4 meqL for every 10 mmHg ↓ in PCO2 [↓(4:10)]
Lab abnormalities with respiratory alkalosis
decreased potassium (small); decreased phosphorus (may be large). Symptoms: neurologic (paresthesias, carpopedal spasms). Consequences: decreased intracranial pressure, cardiac arrhythmias.
Treatment of respiratory alkalosis
Treat the underlying cause. If alkalemia is severe (pH >7.55), then depressing ventilation with a sedative could be considered to prevent arrhythmias, tetany, etc.
Definition of respiratory acidosis
Respiratory acidosis is a respiratory process that causes a primary increase in the PCO2.
Differential diagnosis of respiratory acidosis
Primary respiratory acidosis is ALWAYS from inadequate respiration which can occur due to problems in any of the 4 steps in respiration: 1) sensing and signaling, 2) muscles and motion, 3) free flow, 4) gas exchange. Sensing and signaling refers to processes that impair the medullary control center (e.g., sedatives, obesity hypoventilation syndrome) or impair neurologic signals to the muscle of respiration (e.g., amyotrophic lateral sclerosis, Guillian-Barre syndrome). Muscles and motion refers to processes that impair function of the respiratory muscles (e.g., hypokalemia, periodic paralysis). Free flow refers to processes that impair the free flow of air resulting in airway obstruction (e.g., foreign body). Gas exchange refers to processes that impair the exchange of CO2 and O2 in the alveoli (e.g., pneumonia, acute lung injury, COPD).
Compensation for respiratory acidosis
Increased HCO3 from 1) Cell buffering (acute) and 2) Renal H+ excretion (HCO3 resorption) (chronic). As with respiratory alkalosis, cell buffering occurs first, this time H+ is absorbed by cell buffers resulting in the generation of HCO3. Renal compensation occurs by the renal excretion of H+ which results in the generation of new HCO3 (see pages 11 to 12, below). Renal compensation takes 3-5 days to reach completion, thus, respiratory acidosis may be acute (increase in bicarbonate from cell buffering alone) or chronic (increase in bicarbonate from cell buffering and renal H+ excretion/renal bicarbonate production). In acute respiratory acidosis, the bicarbonate is expected to increase by 1 mEq/L for every 10 mmHg increase in PCO2; in chronic respiratory acidosis, the bicarbonate is expected to increase by 4 mEq for every 10 mmHg rise in PCO2. The pH does not fall below 7.20 in appropriately compensated chronic respiratory acidosis.
Rules for compensation for respiratory acidosis
The expected increase in bicarbonate in respiratory acidosis is predicted by the following: Acute: ΔHCO3- = ↑ 1 meq/L for every 10 mmHg ↑ in PCO2 [↑ (1:10)]
Chronic (3 to 5 days): ΔHCO3- = ↑4 meqL for every 10 mmHg ↑ in PCO2 [↑ (4:10)]
Symptoms of respiratory acidosis
Neurologic: headache, decreased arousal/sleepiness (aka CO2 narcosis)
Consequences of respiratory acidosis
Increased intracranial pressure, cardiac arrhythmias, hypotension from peripheral vasodilatation
Treatment of respiratory acidosis
Treat underlying causes and pay attention to the PO2. In patients with COPD, titrate oxygen saturation to about 88 to 92%. In the chronic state, no specific treatment of the acid-base disorder is indicated.
Definition of metabolic alkalosis
Metabolic alkalosis is a metabolic process that causes a primary increase in the HCO3.
Differential Diagnosis of metabolic alkalosis
A primary increase in plasma bicarbonate leading to metabolic alkalosis is classically considered to be two step process that requires generation and maintenance.
Generation of metabolic alkalosis
can occur in a number of ways: 1) addition of HCO3- , 2) loss of H+, 3) loss of chloride rich fluids (previously known as contraction alkalosis), 4) post-hypercapneia, and 5) hypokalemia.
Maintenance of metabolic alkalosis
is ALWAYS the kidney’s fault and is due to factors that impair the ability of the kidney to excrete the excess HCO3; maintenance is most often due to chloride depletion or potassium depletion which affects ion channels in the kidney and impairs bicarbonate excretion.
Addition of HCO3- can occur due to
Direct administration of bicarbonate e.g. to treat metabolic acidosis. Direct administration of a substrate that is metabolized to bicarbonate (e.g.,lactated ringers which contains lactate, which is metabolized to bicarbonate).
Loss of H+ can occur due to
GI loss: vomiting, nasogastric suctioning.
Renal loss: Loop and thiazide diuretics, mineralocorticoid excess (Diuretics inhibit Na+ resorbtion in the thick ascending loop of Henle (loop diuretics) or distal tubule (thiazides) resulting in an increased delivery of Na+ to the distal nephron. The distal nephron resorbs some of the Na+, generating a negatively charged tubular lumen which favors H+ secretion.)
Loss of chloride rich fluid
(formerly known as contraction alkalosis) can be due to: Loop diuretics, possibly also congenital chloride diarrhea, sweat loss in cystic fibrosis,
Post-hypercapnia
is the development of metabolic alkalosis in a patient with chronic respiratory acidosis (low pH; high CO2 and high bicarbonate to compensate) who has received mechanical ventilation with a rapid lowering of CO2; in this setting the CO2 is newly normal but the bicarbonate remains high as it takes longer for the kidneys to excrete the bicarbonate. Chloride depletion is a feature of chronic respiratory acidosis as retention of bicarbonate by the kidneys occurs with secretion and excretion of chloride. Thus, after mechanical ventilation and the development of metabolic alkalosis, the alkalosis is maintained by chloride depletion which prevents excretion of the excess HCO3-.
Hypokelemia
By incompletely understood mechanisms, hypokalemia of any cause can both generate and maintain metabolic alkalosis.
Maintenance of a metabolic alkalosis
Under normal circumstances, the kidney responds to an elevation in serum HCO3- by increasing bicarbonate excretion, the maintenance of metabolic alkalosis is ALWAYS due to the inability of the kidney to excrete excess HCO3-. This occurs by a number of mechanisms: chloride depletion, potassium depletion, increased mineralocorticoid activity, and hypovolemia.
Chloride depletion and maintenance of a metabolic alkalosis
Chloride depletion results in the resorption of bicarbonate by the kidney thus maintaining metabolic alkalosis. Since this is such a major contributor to the maintenance of metabolic alkalosis, the disorders of metabolic alkalosis are clinically divided into chloride responsive versus non-chloride responsive as identified by the urine chloride concentration (Urine chloride less than 20 mEq/L denotes a chloride responsive alkalosis). Since chloride depletion is frequently accompanied by volume depletion, chloride responsive metabolic alkalosis is also referred to as saline (NaCl) responsive metabolic alkalosis. Experiments have convincingly demonstrated that replacement of chloride and not volume replacement is the key factor that corrects the metabolic alkalosis in these settings. Although it is incompletely understood why chloride depletion results in bicarbonate resorption (thus generating and maintaining metabolic alkalosis), one explanation is that chloride/bicarbonate exchangers exist along the nephron and that chloride needs to be present for the exchanger to work and for bicarbonate to be excreted.
Potassium depletion and maintenance of a metabolic alkalosis
May maintain metabolic alkalosis due to increased aldosterone release (see increased mineralocorticoid activity, below), but can also maintain metabolic alkalosis in the absence of hyperaldosteronism (unclear mechanisms).
Increased mineralocorticoid activity and maintenance of a metabolic alkalosis
Mineralocorticoid activity may be increased appropriately (e.g., aldosterone release in response to hypovolemia as described above) or inappropriately in disease states (e.g., Cushing’s syndrome). Mineralocorticoids act on the H+-ATPase pump of the intercalated cell in the distal tubule. Stimulation of the H+-ATPase pump leads to secretion of H+ into the tubule lumen which is accompanied by bicarbonate resorption and thus maintains the metabolic alkalosis (see figure below).
Hypovolemia and maintenance of a metabolic alkalosis
The role of hypovolemia in maintaining metabolic alkalosis is less important than previously thought. However, clinically, hypovolemia commonly accompanies metabolic alkalosis associated with chloride depletion and administration of saline is necessary to correct the chloride deficit as well as the hypovolemia. The mechanisms by which hypovolemia might contribute to the maintenance of metabolic alkalosis is by the release of aldosterone and other factors in order to correct volume contraction by increasing renal Na+ resorption; as a consequence, HCO3- resorption also increases to maintain electroneutrality.
Secretion of H+ results in the generation and maintenance of metabolic alkalosis
In the intercalated cell of the distal nephron, H2O dissociates into free H+ and OH-. The H+ ion is secreted into the tubule lumen by H+-ATPase. The OH- combines with free CO2 to form HCO3-, which is reabsorbed into the blood. H+-ATPase activity increases under the influence of aldosterone and other mineralocorticoids, thus generating and maintaining a metabolic alkalosis.
Diagnosis of metabolic alkalosis
Clinically, metabolic alkalosis is divided into 2 categories:chloride responsive (also known as saline responsive) and chloride unresponsive (also known as saline resistant)
To differentiate between the 2 categories, urine [Cl-] is measured. If the urine [Cl-] is 20 mEq/L, metabolic alkalosis is categorized as chloride resistant (aka saline resistant).
Diuretics and chloride responsive metabolic alkalosis
Generated by renal Cl- loss in excess of HCO3 loss, plus increased H+ secretion and loss. Maintained by chloride depletion, volume depletion, aldosterone, hypokalemia.
Vomiting, gastric drainage and chloride responsive metabolic alkalosis
Generated by HCl loss, maintained by chloride depletion, volume depletion, aldosterone, hypokalemia.
Villous adenomas (some) and chloride responsive metabolic alkalosis
Generated by loss of chloride rich fluid (formerly known as contraction alkalosis) maintained by chloride depletion.
Congenital chloride losing diarrhea and chloride responsive metabolic alkalosis
Generated by loss of chloride rich fluid (formerly known as contraction alkalosis) maintained by chloride depletion.
Cystic fibrosis and chloride responsive metabolic alkalosis
(rare) Generated by loss of chloride rich fluid (formerly known as contraction alkalosis) through the skin maintained by chloride depletion.
Post-Hypercapnia and chloride responsive metabolic alkalosis
Correction of PCO2 to normal by mechanical ventilation in a patient with chronic respiratory acidosis (increased PCO2 and increased HCO3); the [HCO3] remains high due to delayed renal compensation and by chloride depletion (chloride depletion occurs during the development of chronic respiratory acidosis – HCO3 resorption increases at the expense of chloride excretion).
Causes of chloride resistant metabolic alkalosis
(aka saline/NaCl resistant) (Urine Cl- >20 mEq /L). it is due to excess mineralocorticoid due either to hyperaldosteronism, cushing’s syndrom. Generated and maintained by renal H+ loss from aldosterone action. Another mechanism is licorice ingestion. Generated and maintained by renal H+ loss from glycyrrhetinic acid contained in some licorice. Glycyrrhetinic inhibits the enzymatic breakdown of aldosterone and cortisol thus increasing aldosterone action.
Compensation for metabolic alkalosis
increased CO2 from hypoventilation. The rise in pH from the increase in [HCO3-] is sensed by respiratory system chemoreceptors which leads to a decrease in ventilation, retention of CO2, and a rise in CO2.
Rules for compensation for metabolic alkalosis
The expected increase in CO2 in metabolic alkalosis is predicted by the following: ΔCO2 (in mmHg) = 0.25 – 1.0 X Δ HCO3. ΔPCO2 (in mmHg) = 0.25 – 1.0 x (measured HCO3- – 24). This means that the PCO2 increases from 40 by 0.25 to 1.0 times the increase in HCO3- over 24.
Treatment of metabolic alkalosis
There are two main reasons to consider urgent treatment a metabolic alkalemia: (1) Cardiac arrhythmias. Alkalemia increases sensitivity to catecholamines and may precipitate life- threatening arrhythmias. (2) Hypocalcemia. Calcium circulates in two forms: free and active ionized calcium and ‘bound’ which refers primarily to inactive calcium bound to albumin. Alkalosis increases the binding of free calcium to albumin, thereby lowering plasma ionized calcium concentration. This may increase neuromuscular irritability with the possibility of tetany. In an emergency, any acid-base state may be altered quickly with mechanical ventilation, thus hypoventilation may be considered to correct alkalemia if adequate oxygenation is maintained. The treatment options for the different categories of metabolic alkalosis are as follows: Chloride responsive (aka saline responsive): Infusions of NaCl (most common method of treatment) and/or KCl. Chloride resistant (aka saline resistant): In some cases, blocking mineralocorticoid effect with spironolactone or amiloride will be effective. In general, will need to identify specific cause to identify the appropriate therapy.
Definition of metabolic acidosis
Metabolic acidosis is a metabolic process that causes a primary decrease in the HCO3.
Differential Diagnosis of metabolic acidosis
A primary decrease in plasma HCO3- leading to metabolic acidosis occurs in two major ways: 1) Loss of bicarbonate
2) Addition of acid. If the serum anion gap is normal, metabolic acidosis is due to a loss in bicarbonate; if the serum anion gap is increased, metabolic acidosis is due to the addition of acid, thus, the differential diagnosis of metabolic acidosis is based on whether it is a non-anion gap metabolic acidosis (normal serum anion gap) or an anion gap metabolic acidosis (increased serum anion gap).
Calculating the serum anion gap
The serum anion gap is calculated as follows: [Na+] – [Cl-] – [HCO3] and is usually 9±3 (for example 140-108-24 = 8). The implications of the serum anion gap are based on the concept of electroneutrality; that is, if the concentration of all the cations were subtracted from the concentration of all the anions, the anion gap would be zero as the number of cations equals the number of anions to maintain electoneutrality.
Metabolic acidosis caused by loss of bicarbonate (non-anion gap)
Loss of bicarbonate causes academia by shifting the equation below towards the production of HCO3- and H+ thus increasing H+ concentration (i.e., decreasing pH); the increase in HCO3- is not enough to replace the HCO3- that was lost and the overall net effect is academia: 1) Decrease in bicarbonate: H+ + ↓HCO3- H2 CO3 H2O + CO2. 2) Increase in H+ (i.e. decrease in pH, acidosis): increased H+ + increased HCO3-
Example of metabolic acidosis caused by loss of bicarbonate (non-anion gap)
For example, normally serum sodium is 140 mEq/L, serum chloride is 108, and serum bicarbonate is 24, thus, the normal serum anion gap is 140-108-24, or 8. In a non-anion gap netabolic acidosis, a loss of bicarbonate occurs and chloride increases to compensate; thus the new values might be: sodium 140, chloride 124, bicarbonate 12 and the serum anion gap is 140-120-12, or 8 and the serum anion gap remains normal and thus a non anion gap metabolic acidosis is present:
Metabolic acidosis caused by addition of acid (anion gap)
An acid is composed of a hydrogen ion (H+) and it accompanying anion (A-). Thus, the addition of an acid directly increases the H+ concentration (lowers pH) which consumes HCO3- (lowering bicarbonate): increased H+ + decreased HCO3- -> H2 CO3 ->H2O + CO2. With a decrease in HCO3- concentration, there is a loss of negative charge (anion) from plasma. In order to maintain electroneutrality another anion must increase. In this case, the anions which accompanied the added H+ provide the negative charge and the Cl- concentration remains the same
Example of metabolic acidosis caused by addition of acid (anion gap)
For example, normally serum sodium is 140 mEq/L, serum chloride is 108, and serum bicarbonate is 24, thus, the normal serum anion gap is 140-108-24, or 8. In an anion gap netabolic acidosis, addition of acid (H+A-) occurs, bircobante is consumed and lowered, chloride concentration remains the same, and the A- are increased (i.e., “other anions” are increased) to compensate; thus the new values are: sodium 140, chloride 110, bicarbonate 10 and the serum anion gap is 140-110-10, or 20 and the serum anion gap is increased and an anion gap metabolic acidosis is present. Generally, the anion gap is considered “increased” when it is 18 or higher. Of note, a major contributor to the anion gap is the serum albumin concentration. A change in serum albumin of 1.0 g/dl from the normal 4.0 g/dl changes the anion gap by 2.5 mEq/L. Hence, when the albumin is 3.0 g/dl and the AG is 15, the corrected anion gap is 17.5 mEq/L.
Loss of bicarbonate causing metabolic acidosis (non-anion gap)
Non-anion gap (or hyperchloremic) metabolic acidosis is due to the loss of bicarbonate which can either be from the GI tract or kidney. GI loss of bicarbonate causing a non-anion gap metabolic acidosis is most commonly due to diarrhea, although certain surgical procedures such as bowel resection can also result in significant loss of HCO3- from the body. Renal loss of bicarbonate causing a non-anion gap metabolic acidosis is due to a defect in renal bicarbonate or hydrogen ion handling resulting in a renal tubular acidosis (RTA). There are three major forms of RTAs: a) proximal, b) distal, and c) hyperkalemic. To understand the RTA, it is necessary to understand the normal handling of bicarbonate and hydrogen ion handling by the kidney
Renal bicarbonate and hydrogen ion handling
Normal acid base balance is maintained by the kidney in two steps: 1) Bicarbonate reabsorption (performed primarily in the proximal tubule)
2. H+ excretion (performed primarily in the distal tubule) which generates new bicarbonate.
Bicarbonate resorption
is necessary to reclaim all of the filtered bicarbonate, if the proximal tubule is damaged in a way that this cannot occur, bicarbonate is lost in the urine and a proximal RTA is present. Normally, the proximal tubule reabsorbs about 90% of filtered HCO3-.
H+ excretion
Every day, about 60 mEq of H+ is generated via metabolism, and is known as the daily acid load (estimated to be approximately 1 mEq/kg/day). The 60 mEq of H+ consumes 60 mEq of bicarbonate, thus, new bicarbonate needs to be generated every day by the distal tubule, generation of new bicarbonate occurs by the excretion of H+.
Mechanism of H+ excretion
H+ excretion (bicarbonate generation) is accomplished through 3 mechanisms: Excretion of ‘titratable’ acids. Titratable acids are anions that are filtered at the glomerulus and then bind to H+. The primary anion in this process is phosphate which binds hydrogen to form H2PO4. The amount of anion filtered by the glomerulus is relatively constant and does not increase when the H+ level in the body increases. Excretion of nontitratable acid (NH4+). Ammonia (NH3+) is produced by the proximal tubule and binds to H+ to form ammonium (NH4+). Ammonia production (and therefore ammonium generation) can be increased in response to an increase in H+ level in the body. As you will see, this method of H+ excretion is measured clinically using the urine anion gap. Ammonia production is inhibited by hyperkalemia, thus hyperkalemia can inhibit ammoniagenesis and cause an RTA. Free hydrogen excretion by the distal tubule (measured by pH).
Determining if renal acid excretion is appropriate
The urine pH and the urine anion gap can be used to determine if renal acid excretion
(new bicarbonate generation) is appropriate.
Urine pH in determining if renal acid excretion is appropriate
Normally, if a metabolic acidosis is present, urine H+ excretion should increase. Thus, if the urine pH is not acidic (i.e., is greater than 5.3) in the setting of a non-anion gap metabolic acidosis, this suggests that an RTA is present. If the urine pH is acidic (i.e., is less than 5.3), this suggests that the kidneys are functioning normally, and that a GI loss of bicarbonate (e.g., diarrhea) is present.
Urine anion gap in determining if renal acid excretion is appropriate
If a metabolic acidosis is present, NH4+ production should increase. Unfortunately, NH4+ is difficult to measure directly; to indirectly assess whether NH4+ is present, the urine anion gap is calculated. The urine anion gap is = urine [Na+] + urine [K+] - urine [Cl-]. If NH4+ production is increased, then urine chloride (Cl-) should also increases to maintain electroneutrality; as chloride increases, the urine anion gap becomes a negative number. Thus, a negative urine anion gap suggests that ammonia production in the kidney is occurring and that the non-anion gap metabolic acidosis is due to GI loss. If the urine anion gap is a positive number, is suggests that renal ammonia production is impaired and that an RTA is present.
Causes of non-anion gap metabolic acidosis
can be due to GI loss of HCO3 or renal tubular acidosis
GI loss of HCO3
Diarhea causes loss of HCO3 rich (30-50 mEq/L) and K+ rich bowel fluid (urine pH
Renal Tubular Acidosis
proximal problems includes decreased ability to reclaim filtered HCO3. Distal problems include inability to excrete H+ (and therefore produce new HCO3-). Urine pH > 5.3; urine anion gap a positive number. Hyperkalemia can cause increased potassium, which inhibits ammonia production (Urine anion gap a positive number).
Ureterosigmoidostomy
is a surgical procedure in which the ureters are diverted to the sigmoid colon. It is often performed in conjunction with bladder resection for bladder cancer.
Ileal loop conduit
is a surgical procedure in which the ureters are diverted to a portion of ileum instead of colon.
Addition of acid (H+A-) causing metabolic acidosis (anion gap)
Anion gap metabolic acidosis is due to the addition of acid which can be due to the following: Ingestion of toxins that interfere with intermediary metabolism (aspirin) or are metabolized to organic acids (methanol and ethylene glycol). Overproduction of organic acids due to a defect in intermediary metabolism (e.g., lactic acidosis or ketoacidosis). Failure to excrete both the H+ and anions derived from metabolism due to renal failure (acute or chronic).
The largest anion gaps occur in conditions caused by accumulation of organic acids like lactic acid. The classic mnemonic physicians use to remember the causes of anion gap metabolic acidosis is MUDPILES (methanol, uremia, diabetic ketoacidosis, propylene glycol, iron poisoning or isoniazid, lactic acidosis, ethylene glycol, salicylates).
conditions that result in a low serum anion gap
Overproduction of abnormal cations (e.g., paraproteins in multiple myeloma) · Low serum albumin (remember that albumin is the major contributor to the AG. If your patient has a low serum albumin, the AG should be corrected.
Physiologic Effects of Metabolic Acidosis
With marked acidemia (i.e., pH less than 7.00-7.10) myocardial contractility is depressed and peripheral resistance falls. This combination may produce hypotension, pulmonary edema and ventricular fibrillation. These manifestations may result from the metabolic acidosis decreasing vascular and myocardial responsiveness to catecholamines, and depressing myocardial contractractility. Respirations become deep and rapid (Kussmaul’s) especially at pH less than 7.20. Chronic metabolic acidosis causes hypercalciuria (excess excretion of calcium in the urine) and bone disease because bone buffering of acid leads to marked calcium losses from bone. This aspect is extremely important in treating renal tubular acidosis or the acidosis of chronic renal failure.
Respiratory Compensation
The body compensates for a metabolic acidosis by increasing ventilation and causing a fall in PCO2. The primary fall in [HCO3-] results in a fall in serum pH. This stimulates the respiratory system via peripheral carotid chemoreceptors and central nervous system receptors to increase ventilation and thereby CO2 excretion. The resultant fall in PCO2 somewhat balances the primary decreases in [HCO3-] and returns the pH toward normal, but not all the way to normal. The amount of change in PCO2 is the key to determining the presence of simple metabolic acidosis.
Equation for the appropriate degree of respiratory compensation
Δ PaCO2 (in mmHg) = 1.0 – 1.5 x Δ [HCO3-] (in mEq/L) This means that in simple metabolic acidosis [normal PaCO2 minus actual PaCO2] should equal 1.0 to 1.5x (normal [HCO3-] – actual [HCO3-]). (40- actual PaCO2) mmHg = 1.0 –1.5 x (24- actual [HCO3-]) (in mEq/L). As a quick evaluation in simple metabolic acidosis, the respiratory compensation should equal the last 2 digits of the pH (PCO2 = last 2 digits of pH). Remember, HCO3- and PaCO2 should go in the same direction i.e. if serum HCO3- falls, PaCO2 should fall. If this does not occur or if the above relationship is not seen, then a mixed disorder is very likely to be present. A mixed disorder refers to the concurrent existence of 2 separate acid-base abnormalities For example, if Δ PaCO2 (in mmHg) > 1.0 – 1.5 x Δ [HCO3-] (in mEq/L), a primary respiratory alkalosis coexists with a metabolic acidosis. This concept will become clearer as you complete the small-group questions.
Treatment of Metabolic Acidosis
Treatment is directed at correcting the underlying disorder that generated and maintained the low [HCO3-]. For chronic acidotic states, oral sodium bicarbonate therapy is generally well tolerated and indicated. Rapid correction of pH by administration of intravenous bicarbonate in acute acidotic states may be accompanied by cardiovascular compromise. It is thought that the administered bicarbonate may cause a paradoxical intracellular acidosis induced by CO2 generation. This effect may subsequently impair cardiac performance. Therefore, the use of bicarbonate to treat acute metabolic acidosis is extremely controversial.
Rules of compensation for simple acid-base disorders
In general, the pH will change by 0.08 for every 10 mmHg change in PCO2 in acute situations and 0.03 in chronic conditions. As you recall, the pH is inversely proportional to the PCO2 (pH α [HCO3-] /[PCO2] ) so it will change in the opposite direction as the PCO2 (↑ PCO2, ↓ pH).
A mixed acid base disturbance
is the coexistence of two or more primary acid-base disorders. In this setting, the expected compensation will be less than or greater than expected. The pH does not return to normal with compensation. If the PCO2 and [HCO3-] differ from normal in opposite directions, a mixed disorder is always present (i.e. increased PaCO2 and decreased [HCO3]). Metabolic alkalosis and metabolic acidosis may coexists. The clue to this set of disorders is the presence of an enormous increase in the serum anion gap that is either out of proportion to the decrease in [HCO3] seen with metabolic acidosis (e.g., an anion gap of 50 with a [HCO3] of 15) or seen in concert with a normal or increased [HCO3]. A more concrete way to put this is as follows. If the anion gap were 50, it would have increased approximately 41 mEq/L (from a normal of 9). However, a [HCO3] of 15 is only 9 mEq/L decreased from a normal of 24. If each anion generated has an accompanying proton, then there must be some other process which is eliminating the other 32 protons per liter and is generating HCO3. Hence, there must be a simultaneous metabolic alkalosis (e.g., vomiting). The combination of metabolic acidosis and metabolic alkalosis with either a respiratory alkalosis or acidosis constitutes the so-called “triple acid- base disturbance”. This does occur clinically.
Pathogenesis of essential hypertension
can result from an increase in either cardiac output or the total peripheral resistance, or both. Factors that affect these two variable, such as the stroke volume and heart rate, will also affect the MAP. The kidney has a major influence on BG because of its central role in the regulation of extracellular fluid (ECF) volume. The frank starling mechanism suggests that an increase in ECF volume due to renal Na and water retention should result in increased blood volume, venous return and stroke volume. According to MAP, cardiac output should then increase and hypertension may develop. Volume expansion resulting from excess Na intake or an underlying abnormality in renal Na excretory mechanisms, has been considered to be an important mechanism for the development of early HTN with essential HTN or primary renal disease. However, the circulatory system is dynamic and a perturbation, such as an increase in ECF volume due to renal Na and water retention may result in compensatory responses that ultimately restore Na balance and thus normalize ECF volume and CO. this restoration of Na balance results from a phenomenon called “pressure natriuresis” that occurs in the setting of systemic HTN. During early stage of HTN, ECF volume and CO are seen to increase. However, over the long term, the initial increase in ECF volume normalizes and HTN is subsequently maintained by an increase in total peripheral resistance (TPR). The increase in TPR arises primarily at the level of precapillary arterioles.
Mechanisms of impaired natriuresis
loss of nephron mass, activation of the sympathetic nervous system and the neurohormonal axis, abnormal blood vessel response to vasoconstrictors.
pressure natriuresis
increased urinary excretion of sodium along with water when there is an increase of arterial pressure, a compensatory mechanism to maintain blood pressure within the normal range.
If an inability to excrete Na excess Na leads to volume expansion and a high BP, why doesn’t this high BP lead to increased Na excretion with subsequent return of BP to normal?
It is believed that in hypertensive states, there is a shift of the usual pressure-natriuresis relationship such that a higher perfusion pressure is required to result in natriuresis.
How does a shift in the pressure-natriuresis curve result in an increase in TPR and not a persistent increase in CO?
the pattern of initially high CO giving way to persistently elevated TPR occurred in animals with reduced renal mass that were given excess salt. Blood pressure initially increased as a consequence of the high CO. within a few days however, TPR rose and CO returned to near basal levels. This changeover occurs because of autoregulation, an intrinsin property of vascular beds that allow them to regulate the blood flow depending on the metabolic need of tissues.
Mechanism of the antihypertensive effect of thiazide diuretics
the acute effect of diuretic administration is a decrease in ECF and plasma volume with a reduction in cardiac output. However, over a period of weeks to months of chronic thiazide diuretic administration, the negative Na balance is attenuated such that plasma volume and cardiac output are normalized. Nevertheless, the antihypertensive effect persists, implying a concomitant decreased in peripheral vascular resistance. The secondary decrease in peripheral vascular resistance appears to be the long-term mechanism of the antihypertensive action of thiazides and related diuretics. A reduction of peripheral resistance and BP as an indirect result of the natriuretic action of the diuretics is easy to conceptualize. Restoration of the renal natriuretic capacity to normal means that HTN is no longer necessary to maintain Na balance.
Secondary hypertension
hypertension due to an identifiable underlying etiology. Often these patients have a history of hypertension refractory to the maximal dosage of several drugs. Newly diagnosed hypertension deserves a search for contributing factors: history should include review of current medications (oral contraceptives, NSAIDs, antidepressants, glucocorticoids, decongestants, stimulants), recreational drug use, and questions about the signs and symptoms that suggest an underlying condition (Cushing disease, pheochromocytoma, obstructive sleep apnea, etc.). To remember some common medications which cause elevations in blood pressure, it may help to recall the mnemonicGONADS: Glucocorticoids, OCPs (oral contraceptive pills), NSAIDs (non-steroidal anti-inflammatory agents), Antidepressants (particularly SNRIs), Decongestants (pseudoephedrine), Stimulants (methylphenidate, amphetamines)
The causes of secondary hypertension
can be organized into several categories: Drug- or medication-related, Renal failure (renal parenchymal disease)–most common non-medication-related etiology, Anatomic (vascular) anomalies: aortic coarctation, renal artery stenosis (fibrodysplasia, renal artery stenosis/atherosclerosis), Pheochromocytoma, and Endocrinopathies: hyperaldosteronism (Conn Syndrome), hypercortisolism (Cushing Syndrome), hyperparathyroidism, Grave’s disease. Using the mnemonic DRAPEmay help you recall the various etiologies of secondary hypertension when deciding on the next best step in management. Renal artery stenosis is more common in female patients less than 25 years of age (fibromuscular dysplasia) and inpatients over the age of 50(atherosclerosis). Combination oral contraceptive pills (OCPs) are more likely to cause hypertension in women over 35 years of age, obese women, and in patients with a history of long-term OCP use. Pheochromocytomas occur more commonly in younger patients with a history of endocrine tumors. Aorta coarctation is more common in patients with Turner syndrome, especially on test questions.
Pathophysiology of two kidney renovascular HTN
in unilateral renovascular HTN, the decrease in renal blood flow (due to atherosclerosis or fibromuscular disease) results in decreased renal perfusion pressure and activation of renal baroreceptors. This results in increased proximal tubule Na reabsorption PTna, which in turn activates the macula densa mechanism by causing a reduced delivery of sodium to the macula densa. As a result of activation of baroreceptors and decreased distal Na delivery, renin secretion is increased. This generates angiotensin II, which causes the rise in BP. An increase in renal perfusion pressure results in suppression of PTNa in the normal kidney. Hence the normal kidney excretes increased amounts of sodium, while the kidney with arterial stenosis excretes decreased amounts of sodium. Therefore, net sodium excretion is normalized and a normal ECF volume is maintained in this type of HTN. When HTN is produced with the contralateral normal kidney in situ, the state may be referred as two kidney renovascular HTN. An important aspect of this model of HTN is that the factors responsible for maintenance of BP elevation may change with time. Although BP is elevated during the entire course, renin is elevated initially but falls with time. Initially, BP normalizes with removal of the stenosis but eventually treatment of the stenosis may have no effect on BP. Presumably with time, the BP elevation causes vascular damage and injury to the contralateral kidney such that sodium retention with renin suppression and fixed HTN develops. Clearly the natural history has implications for human renovascular HTN in which the proper timing of surgical repair is crucial for success.
renal parenchymal hypertension
there are two broad mechanisms by which chronic renal disease could lead to HTN: 1. A decrease in the vasodepressor effect of the kidney or 2. An increase in the vasopressor effect of the kidney.
Hyperaldosteronism (excess aldosterone)
may be primary or secondary in etiology. The most common cause of hyperaldosteronism isprimary hyperaldosteronism. High aldosterone (and hypertension) suppresses the secretion of renin. Therefore, in primary hyperaldosteronism, low levels of renin are seen. In contrast, ahigh renin level suggests secondary hyperaldosteronism. Both primary and secondary hyperaldosteronism are treated with spironolactone and eplerenone (competitive aldosterone receptor antagonists). Surgical removal of aldosterone-secreting adrenal adenoma is curative in Conn’s syndrome.Secondary hyperaldosteronism is treated by correcting inciting causes (e.g, CHF), and spironolactone (K+-sparing diuretic).
Hyperaldosteronism (primary and secondary) presents
Hypertension (due to sodium retention), Hypokalemia, and Metabolic alkalosis
Causes of primary hyperaldosteronism
Sporadichyperplasia of the adrenal glands (most common), ConnSyndrome:asingle, benign adrenal tumor or adenoma, Adrenal carcinoma
Secondary hyperaldosteronism
is caused by an increase in the activity of the renin-angiotensin system. This is most commonly seen in cases of renal artery stenosis, which impairs renal blood flow. The low intravascular volume stimulates the renin-angiotensin system and increases aldosterone production.Other causes of secondary hyperaldosteronism include: Congestive heart failure, Cirrhosis, Chronic renal failure, and Nephrotic syndrome. In both primary and secondary hyperaldosteronism, elevated aldosterone levels lead to Na+/H2O retention and K+/H+ wastingbecause aldosterone: Increases the number of Na+(reabsorbed)and K+ (excreted)channels, Increases the numberof Na+-K+ATPase pumps (basolateral). Increases the activity of the H+-ATPasein the intercalated cells renal collecting duct. Hypertension results from increased Na+(and therefore, H2O) retention. Elevated aldosterone leads to an increase in the number of K+channels in the cortical collecting duct, and an increase in H+-ATPase activity in the alpha intercalated cells. Thus, excess aldosterone leads to alkalosis and hypokalemia. Hypokalemia results in a metabolic alkalosis due to increased H+/K+transcellular exchange(K+is reclaimed at the expense of H+excretion). Alkalosis causes the – COOH side groups of serum albumin to become deprotonated (– COO-). Thiscauses increased binding of Ca2+, whichdecreases free Ca2+ concentration. Hypokalemia resulting from hyperaldosteronism can lead to symptoms of muscle weakness, as well as cardiac changes visible on EKG (classically described as U-waves). Diagnosis is often based on measurement of serum renin levels (in addition to an elevated aldosterone level).
Pheochromocytoma
A rare neuroendocrine tumor of adrenal medulla chromaffin cells that secretes catecholamines. The classic presentation for a pheochromocytoma is resistant hypertension.Patients may also experience “paroxysms” or sudden episodes of: worsening hypertension, intermittent tachycardia, diaphoresis, headache, palpitations, chest pain, nausea and vomiting, anxiety. These paroxysms are due to the sudden episodic release of catecholamines from the tumor
Pheo Crisis
is rare, but is the most feared complication in a patient with a pheochromocytoma; mortality rates approach 85%. It results in an adrenergic hypertensive crisis leading to multiple system organ failure. Conditions that may induce a Pheo Crisis Include: Anesthesia induction agents, Drugs (Corticosteroids, metoclopramine, morphine, glucagon, chemotherapeutic drugs, sympathomimetics, and TCAs), Emotional stress, IV urographic contrast
Treatment of Pheochromocytoma
First choice is surgical resection. Medical management of HTN is achieved with an irreversible, non-competitive, non-selective α-blocker such as phenoxybenzamine. Prazosin and Terazosin may also be used with similar effect. Note: This is crucial because it prevents the surges of catecholamines pre and post surgical resection of the tumor. A β-blocker may be added for rate control AFTER α-blockade is established. Note:Used after because if used before, theß-blockade would lead to unopposedα-stimulation from the Pheo’s catecholamines, leading to a hypertensive crisis. Note: Do not confuse phenoxybenzamine (irreversible α-blocker) with phentolamine (reversible α-blocker). Adequateα-blockade is achieved with a BP less than 120/80 sitting but not less than 90 systolic standing. To reduce complication during surgery, the BP is controlled with adequate α-blockade FIRST, and then aß-blocker may be added for rate control, as discussed previously. Post-operative hypotension is the most common complication, but can be managed with IV fluids in the first 24 hours.
Hypertensive crisis
Hypertensive urgency is defined as a systolic blood pressure (SBP) > 180 mm Hg or a diastolic blood pressure (DBP) > 120 mm Hgwithout physical evidence of target organ damage. Patients with hypertensive urgency present withnon-progressive symptomsincludinghead ache,shortness of breath,epistaxis, orpedal edema. The immediate goal of treatment is reduction of SBP to 120 mm Hg, but may occur at lower pressures if there has been a rapid increase above baseline.
Causes of hypertensive crises
Most hypertensive crises are due to an acute exacerbation of underlying hypertension, frequently brought on by noncompliance with antihypertensive therapy. Additional causes include: Medication side effect:oral contraceptives, attention deficit hyperactivity disorder (ADHD) drugs, nonsteroidal anti-inflammatory agents (NSAIDs), linezolid, and monoamine oxidase inhibitors (MAOIs). Recreational drug use:cocaine, amphetamines, and phencyclidine (PCP, angel dust). Pregnancy:pre-eclampsia/eclampsia, HELLP syndrome. Any cause of secondary hypertension(recall theGONADSmnemonic).
Malignant hypertension
is a subset ofhypertensive emergencymarked by anaccelerated course of rapidly rising BP and the presence ofpapilledemaon physical exam. Renal pathological changes associated with malignant hypertension include a flea bittenkidney(multiple hemorrhages due to ruptured arterioles on large swollen kidney).
Evaluation of hypertensive crisis
Initial evaluation of hypertensive crisis should include: Serum electrolytes to rule out hypokalemia or hypomagnesemia, Serum BUN and creatinine to assess renal function, Liver function tests (AST, ALT, alkaline phosphatase, PT/INR), Complete blood count (CBC) with peripheral smear, Urinalysis with microscopy, Electrocardiogram (ECG), Chest x-ray if patient complains of chest pain, Non-contrast CT in patients with neurological symptoms or complaining of head ache
The treatment of hypertensive emergency
requires three steps: 1. Immediate admission to an intensive care unit (ICU). 2. Parenteral (IV) administration of a titratable anti-hypertensive agent. 3. Continuous monitoring of blood pressure, neurological status, and urine output. BP should be reduced by 20% to 25% of the presenting level over the first hour, followed by reduction to 160/100-110 mm Hg over the next 2 to 6 hours. The most appropriate IV agent(s) to treat hypertensive emergency are dictated by the presentation: Hypertensive encephalopathy: labetalol, Pregnancy: hydralazine, and Aortic dissection: 2 IV agents–e.g. labetalol + esmolol
Papilledema
represents a large cotton-wool spot resulting from ischemia of the optic nerve. It is important to recognize that papilledema in the setting of malignant hypertension is almost always accompanied by flame-shaped hemorrhages and cotton-wool spots. If papilledema occurs in isolation, one must consider that a primary intracranial process such as tumor or cerebrovascular accident in the differential diagnosis.
