Fluid, Electrolyte & Acid-Base Balance
The balance of fluids, electrolytes (Elements in the blood that carry a positive or negative charge, including calcium, chloride, magnesium, potassium and sodium as the major ones) and acids and bases are all interrelated. The body, when functioning properly, maintains a state of homeostasis (Homeo= uniform; stasis= static, unchanging). Homeostasis refers to the maintenance of a “constant” internal environment for body cells. It is within this environment, where cellular activities involving nutrient uptake and waste elimination continually threaten the stability of chemical and physical parameters. In reality, the normal cellular environment is not static, but fluctuates within a normal range of values. For example, pH can normally vary between 7.35 and 7.45, so homeostasis actually involves a range of values that are considered “normal”.
The environment in which individual cells live is the interstitial fluid, (pertaining to being between things, especially between things that are normally closely spaced), or fluid between cells, which is formed by filtration from blood plasma across capillary walls to the interstitial spaces among cells, and is returned to circulation by osmosis at the venous ends of capillary beds. Interstitial fluid is one of the three different fluid compartments of the body. To maintain normal homeostasis (and health), it is essential that nutrients not become depleted nor may wastes be allowed to accumulate in this fluid environment. The two other fluid compartments that interact with the interstitial fluid are the intravascular (plasma or within the vascular system of capillaries veins and arteries) and intracellular (fluids within the cells that comprise cellular cytoplasm). Changes in one fluid compartment can result in changes in the others. These changes can be detrimental to cells and can constitute a disruption leading to a pathophysiological state. (disruption of normal physiological mechanisms to the extent that a disease state results.)
The three fluid compartments contain all the fluids of the human body, which combined represent 60% to 80% of the total body weight, which diminishes with age and other factors.
Fluids from blood plasma and interstitial compartments are exchanged very readily. Their compositions are very similar. Typical capillaries are fenestrated (have holes). As blood flows through an arteriole and into capillaries under pressure (hydrostatic blood pressure), plasma fluid, along with all small molecules dissolved in it, leak out into the interstitial spaces to form interstitial fluid. However, albumin protein (The major protein in plasma, with a large size) does not pass through capillary pores and becomes more concentrated in the capillaries, as fluid is lost around it. Since albumin is osmotically active (a solution that is osmotically active relative to another solution will transfer solute or solvent until the two substances have the same osmolarity- or concentration of solvents), its high concentration serves do draw interstitial fluid back into capillaries on the venous end of capillaries. This returning fluid has lost nutrients and gained wastes as it flowed through the interstitial spaces across cells. If filtration does not match reabsorption, interstitial spaces either swell (edema) or dry out (dehydration).
Changes in albumin concentration can change the osmolarity of blood plasma and cause fluid shifts into or out of this and other compartments. It is by this continuing process that cells are nourished and wastes are removed. Blood that has passed through tissue capillary beds must be purified to keep its composition constant and stable. This is homeostasis, and requires normal functioning organ systems for the process to continue.
The capillary wall separates plasma and interstitial fluid, whereas the interstitial and intracellular fluids are separated by cell membranes. Cell membranes are much more selective as to what crosses them accounting for the major differences between intracellular fluid composition and that of plasma and interstitial fluid. However, water crosses cell membranes readily and can cause cellular shrinking or swelling if osmotic differences should occur. Changes in osmolarity in one compartment can cause water to shift into or out of the other interconnected compartments.
The arteriolar ends of capillaries primarily filter fluids out since hydrostatic pressures exceed osmotic on that end. Conversely, the venous halves of capillaries have greater osmotic pressure and tend to favor reabsorption of fluids back into circulation.
Fluid balance is achieved primarily by balancing intake with output. Average water intake is 2000 ml/day, totaling water in food and fluids, so to be in balance the average output should also be 2000ml. If output is more than intake, possible dehydration results. If input is greater, possible edema results. The hormones ADH (Anti-Diuretic Hormone) and Aldosterone are the major controllers of water/fluid balance.
Normal water and solute concentrations in body fluids is referred to as an isotonic/isosmotic state where fluids and their dissolved solutes are balanced among the fluid compartments and water does not shift significantly from one to another. However, if water is selectively lost from a fluid compartment (usually blood), this tends to increase the concentration of solutes remaining and to cause water from other compartments to shift into the vascular compartment while stimulating thirst as a corrective measure to replace lost water. Lost water lowers blood volume and pressure to decrease kidney urine output via low glomerular filtration and increased ADH activity, both of which act to conserve fluids. If fluid balance is shifted toward the excess side, thirst should decrease and urine output should increase until normal isosmotic balance is again restored.
The kidneys and skin comprise a complex system for waste removal. The liver and lungs also remove wastes. A waste material by definition is one that the body cannot further use. The nitrogenous wastes, urea (from amino acid metabolism) and uric acid (from DNA and RNA metabolism) are examples of these materials. Yet, the definition is much broader. Any material that occurs in the body in quantities greater than those needed become wastes. Excess water, salt, excess acid (Hydrogen) or alkaline (bicarbonate) ions, vitamins, amino acids and other nutrients that exist at levels above those required by the body must be excreted. Consequently, urine composition is constantly changing as different materials occur in excess in the body.
Since different materials can occur in excess at different times, excretory organs must be able to selectively eliminate them. The specific structure and function of the kidney makes this possible. Specialized regions of the nephron, the functional unit of the kidney, consisting of the renal corpuscle, the proximal and distal convoluted tubules, and the nephronic loop) provide for three major processes in urine formation: (1) glomerular filtration; (2) tubular reabsorption; and (3) tubular secretion.
Glomerular Filtration. The kidney nephrons possess a membrane surface, the glomerular membrane, with an extensive surface area. Glomerular filtration is poorly selective and resembles that which occurs in interstitial fluid formation. Basically, everything except blood cells and high molecular weight proteins will cross the membrane. This filtrate contains both nutrients and wastes. If allowed to remain in the nephron, essential nutrients would be lost with the urine.
Tubular Reabsorption. To prevent this potential loss of essential materials, nephron tubule cells, especially those of the proximal tubule, selectively reabsorb the nutrients back into blood leaving only the wastes in the nephron. The tubular reabsorption of materials occurs by selective membrane transport mechanisms and each material exhibits a maximal threshold of reabsorption. Reabsorption, since it is an active process, requires energy. If the concentration of a material in the filtrate is greater than the maximal threshold, the excess will not be reabsorbed and will appear in the urine. In normal kidneys only the excesses (wastes) will be excreted.
Tubular Secretion. Nephron tubule cells also have the ability to actively transport wastes from blood and excrete them directly into urine. This process also requires energy. A classic example of this process is the acid- base (pH) regulation involving the kidney’s capacity to excrete hydrogen ions into the urine during acidosis and retain them during alkalosis.
Assessing Basic Kidney Function. Two screening blood tests are used to detect initial kidney problems. Elevated levels of Blood Urea Nitrogen (BUN) show excess nitrogenous wastes, which may be indicative of early stage kidney failure among other things. Elevated creatinine level screen for accumulation of the muscle waste product creatinine, which is derived from muscle stores of creatine phosphate and is normally excreted by the kidneys.
Kidney function is regulated by extrinsic (outside the kidney) and intrinsic (within the kidney) sources. Extrinsic sources include: systemic blood pressure; aldosterone; and Antidiuretic Hormone (ADH).
Since the rate of glomerular filtration is directly related to the hydrostatic blood pressure in glomerular capillaries, any increase in blood pressure results in a corresponding increase in filtration and urine output. Since this process ultimately decreases blood volume, the kidneys are a powerful means of controlling long- term blood pressure. Conversely, drops in blood pressure have the opposite effect. Thus, a negative feedback loop occurs in relationship to blood pressure and kidney function. One may appreciate how chronic high blood pressure may negatively affect kidney function.
Aldosterone is a steroid hormone (meaning it is ultimately made from Cholesterol), released from the adrenal cortex in response to elevated levels of potassium, causes nephrons to secrete potassium into the urine. But, since potassium and sodium share the same transport carrier, as potassium is excreted sodium is retained. Chloride ions and water follow the retained sodium to cause an increase in fluid retention and expansion of blood volume with corresponding increases in blood pressure. (Recall that fluid retention is a common side effect of steroid hormone activity). Since it is often the case in the modern world that diets have been stripped of much of their potassium, this exchange of excreting potassium while retaining sodium may lead to long-term deficiencies of potassium. This may be worsened if a person is placed on a low sodium diet. The body will try to preserve the sodium at the expense of already marginal or low potassium. Individuals under prolonged stress who have elevated levels of the stress hormone cortisol will also often have elevated aldosterone levels, which have the effects of increasing blood pressure and increasing potassium loss in the urine.
The 2004 guidelines of the Institute of Medicine specifies an RDAof 4700 mg of potassium for adults, based on intake levels that have been found to lower blood pressure, reduce salt sensitivity, and minimize the risk of kidney stones. However, most Americans consume only half that amount per day. Similarly, in the European Union, particularly inGermany and Italy, insufficient potassium intake is widespread. The RDA for sodium on the other hand is much lower, at 1500mg/day. The FDA’s recommendation for adults “safe” daily sodium intake is 2,300 mg. In reality most Americans consume anywhere from 3,000-4,000 mg daily. Therefore the combination of excess sodium and low intake of potassium can lead to a potassium deficiency. This could be made worse by then eliminating sodium from the diet without simultaneously increasing potassium. Further complicating the picture is that aldosterone levels increase with stress, causing further loss of potassium. As will be discussed below, potassium is a major alkaline mineral. Deficiencies can aggravate acidosis (a state of too much acid).
Antidiuretic Hormone (ADH) is produced by the hypothalamus and released from the posterior pituitary when the osmotic pressure of blood and body fluids increases. Increased osmotic pressure correlates directly with solute concentration, indicating that water retention and/or intake is required to correct the situation. Membrane pores for water transport increase in nephrons cells under ADH influence. Because of the high sodium ion concentration in the kidney interstitial fluids, increasing the number of these pores increases the rate of water reabsorption from the urine back into blood. Only water is reabsorbed under ADH influence allowing this mechanism to “fine tune” the osmolarity of body fluids and blood while concentrating or diluting the urine output.
pH is a number describing the relative acidity or alkalinity of a solution. As hydrogen ion concentration goes up, pH values go down. The normal pH is slightly on the alkaline side of neutral (a pH of 7.0 is neutral) in the range of 7.35-7.45. Acidic body pH’s, below 7.0, are not usually compatible with life.
In order to understand acid-base balance, some knowledge of elementary chemistry is essential. An acid is a substance that can donate a Hydrogen ion (H+); a base is a substance that can accept a Hydrogen ion. A buffer is a substance that resists changes in pH by accepting or donating hydrogen ions when they are excessive or deficient, respectively. Thus, buffers become the body’s first line of defense against pH changes and are considered responsible for pH “regulation.”
pH Regulation. In normal individuals, two major and related processes; pH regulation and pH compensation control pH. Regulation is a function of the buffer systems of the body whereas compensation requires further intervention of the lungs and kidneys to restore homeostasis. Given that normal body pH is slightly alkaline and that normal metabolism produces acidic waste products such as carbonic acid (carbon dioxide reacted with water) and lactic acid, body pH is constantly threatened with shifts toward acidity. This is where buffers play a vital role by guarding against this shift toward acidosis and helping keep blood and body pH in the normal range. Systemic venous blood, which is blood returning from the tissues after oxygen has been delivered and carbon dioxide picked up by red blood cells; is high in acidic carbon dioxide and should be lower in pH. Arterial blood is lower in carbon dioxide, higher in oxygen and should be alkaline. In fact, the two are strikingly similar in pH primarily due to buffers.
The two metabolic acids, carbonic and lactic, are chemically different in an important way. Carbonic acid is described as a volatile acid since it has a vapor phase, which exists because it can be converted into carbon dioxide and water vapor, (H2CO3> CO2 +H2O), both of which are gasses and can be expelled from the lungs. Since carbon dioxide is a common waste product, this is a valuable process in both pH regulation and compensation. The kidneys participate in normal pH regulation by the excretion of hydrogen ions into the urine as blood is processed by nephrons. Lactic acid is nonvolatile and must be eliminated via the kidneys.
The lungs are important for excretion of carbon dioxide (the respiratory acid) and there is a huge amount of this to be excreted: at least 12,000 to 13,000 mmols/day. (millimoles- a measure of concentration or quantity, meaning 1/1000 of a Mole).
In contrast the kidneys are responsible for excretion of the fixed acids (like lactic acid) and this is also a critical role even though the amounts involved (70-100 mmols/day) are much smaller. The main reason for this renal importance is because there is no other way to excrete these acids and it should be appreciated that the amounts involved are still very large when compared to the plasma hydrogen ion concentration of only 40 nanomoles/litre. (a nanomole is 1,000,000 times less than a millimole).
The kidneys play an equally important second role in acid-base balance, namely the reabsorption of the filtered bicarbonate (4,000 to 5,000 mmol/day). This is a HUGE quantity of bicarbonate; 5,000 mmol equals 5 moles. A mole of bicarbonate ion weighs about 63 grams. Five moles weigh more than 2/3 of a pound! Remember that bicarbonate is the major extracellular buffer against the fixed acids and it is important that its plasma concentration should be defended against renal loss.
Both these processes involve secretion of H+ into the lumen by the renal tubule cells but only the second leads to excretion of H+ from the body. In the first part of the nephron, called the proximal tubule, bicarbonate is reabsorbed. In addition, ammonium ion (NH4+) is produced. The reactions that occur consist of formation of hydrogen ion or acid (H+) and bicarbonate ion (HCO3- ) are from CO2 and H2O in a reaction catalyzed by the enzyme carbonic anhydrase. Note that this enzyme requires zinc as a co-factor to function properly, so a zinc deficiency could impair its function.
The excretion of acid from the kidney occurs mainly by exchanging the hydrogen ion for sodium, which is reabsorbed. Bicarbonate is reabsorbed also by exchange for sodium. For every three bicarbonates reabsorbed, one sodium is lost. Since, in our evolutionary past, sodium was generally scarce and potassium abundant, it was critical to preserve sodium, so further down the nephron, a mechanism evolved that exchanges the lost sodium for potassium. Unfortunately, as noted above, the traditional sodium/potassium balance has now shifted in favor of sodium, creating the possibility of potassium deficiencies. We love the taste of salty foods as an evolutionary mechanism to obtain as much sodium as possible, due to its scarcity in the non-modern world.
The net effect is the reabsorption of one molecule of bicarbonate and one molecule of sodium from the tubular lumen into the blood stream for each molecule of H+ secreted. This mechanism does not lead to the net excretion of any H+ from the body as the H+ is consumed in the reaction with the filtered bicarbonate in the tubular lumen. Although no net excretion of H+ from the body occurs yet as a result of bicarbonate reabsorption, this proximal mechanism is extremely important in acid-base balance. Loss of bicarbonate is equivalent to an acidifying effect and the potential amounts of bicarbonate lost if this mechanism fails are very large.
Ammonium (NH4) is produced predominantly within the proximal tubular cells. The major source is from the amino acid glutamine (which is one of many reasons why glutamine is such an important amino acid). Ammonium is produced from glutamine by the action of the enzyme glutaminase. Further ammonium is produced when the glutamate is metabolized to produce alpha-ketoglutarate. This molecule contains 2 negatively charged carboxylate groups so further metabolism of it in the cell results in the production of 2 bicarbonate anions!
The subsequent situation with ammonium is complex. Simply, the lower the urine pH, the higher the ammonium excretion and this ammonium excretion tend to increase extracellular pH towards normal. If the ammonium returns to the blood stream it is metabolized in the liver to urea with net production of one hydrogen ion per ammonium molecule. Increased ammonium therefore can increase the lab values for BUN, an indicator of possible liver or kidney stress.
Distal Tubular Mechanism. This part of the nephron system accounts for the excretion of the daily fixed acid load (the non- gaseous acids like lactic acid), of 70 mmols/day. The maximal capacity of this system is as much as 700 mmols/day but this is still low compared to the capacity of the proximal tubular mechanism to secrete H+. It can however decrease the pH down to a limiting pH of about 4.5: this represents a thousand-fold (i.e. 3 pH units) gradient for H+ across the distal tubular cell.
The processes involved are:
Formation of titratable acidity (TA)
Addition of ammonium (NH4+) to luminal fluid
Reabsorption of Remaining Bicarbonate
1. Titratable Acidity- H+ is produced from CO2 and H2O (as in the proximal tubular cells) and actively transported out of the nephron. Titratable acidity represents the H+, which is buffered mostly by phosphate, which is present in significant concentration. Creatinine may also contribute to TA. At the minimum urinary pH, it will account for some of the titratable acidity. If ketoacids are present, they also contribute to titratable acidity. In severe diabetic ketoacidosis, beta-hydroxybutyrate is the major component of TA. The TA can be measured in the urine from the amount of sodium hydroxide needed to titrate the urine pH back to 7.4 hence the term ‘titratable acidity’. Titratable acid is a term to describe acids such as phosphoric and sulfuric acids which are involved in renal physiology. It is used to explicitly exclude ammonium(NH4+) as a source of acid, and is part of the calculation for net acid excretion.
2. Addition of Ammonium- Proximal tubular cells predominantly produce ammonium. Ammonium excretion is extremely important in increasing acid excretion in systemic acidosis. The titratable acidity is mostly due to phosphate buffering and the amount of phosphate present is limited by the amount filtered (and thus the plasma concentration of phosphate). This cannot increase significantly in the presence of acidosis (though some additional phosphate could be released from bone, which offers an explanation of why chronic, low grade acidosis may contribute to osteoporosis). In comparison, the amount of ammonium excretion can and does increase markedly in acidosis. The ammonium excretion increases as urine pH falls.
Production of ammonium is dependent upon the urea cycle, so adequate quantities of the amino acids involved are critical. (Arginine, citrulline and ornithine). Elevated orotate levels on an organic acids test are a marker for excess ammonia buildup. Elevation of the first three organic acids in the Kreb’s Cycle; Ctrate, cis-Anonitate and Isocitrate), may also be an indicator of increased ammonium ion demand, in the absence of increases in the remaining Kreb’s Cycle intermediates.
3. Reabsorption of Remaining Bicarbonate- Due to it’s acidity, a typical Western diet filters the entire load of bicarbonate, which is reabsorbed, . The net acid excretion in the urine is equal to the sum of the TA and [NH4+] minus [HCO3] (if present in the urine). The major factors, which regulate renal bicarbonate reabsorption and acid excretion, are:
A) Extracellular volume (ECF)- Volume depletion is associated with Na+ retention and this also enhances HCO3 reabsorption. Conversely, ECF volume expansion results in renal Na+ excretion and secondary decrease in HCO3 reabsorption.
B) Arterial Concentration of Carbon Dioxide (pCO2)- An increase in arterial pCO2 results in increased renal H+ excretion and increased bicarbonate reabsorption. This renal bicarbonate retention is compensation for a chronic respiratory acidosis the converse also applies. Hypercapnia (Increased levels of carbon dioxide), results in an intracellular acidosis and this results in enhanced H+ excretion.
C) Potassium & Chloride Deficiency- Potassium has a role in bicarbonate reabsorption. Low intracellular K+ levels result in increased HCO3 reabsorption in the kidney. Chloride deficiency is extremely important in the maintenance of a metabolic alkalosis because it prevents excretion of the excess HCO3 (i.e., now the bicarbonate instead of chloride is reabsorbed with Na+ to maintain electroneutrality).
D) Aldosterone & Cortisol- Aldosterone at normal levels has no role in renal regulation of acid-base balance. Aldosterone depletion or excess does have indirect effects. High aldosterone levels result in increased Na+ reabsorption and increased urinary excretion of H+ and K+ resulting in a metabolic alkalosis. Conversely, it might be thought that hypoaldosteronism would be associated with a metabolic acidosis.
E) Reduction in Glomerular Filtration Rate (GFR)- A reduction in GFR is important mechanism responsible for the maintenance of a metabolic alkalosis. The filtered load of bicarbonate is reduced proportionately with a reduction in GFR.
F) Ammonium- The kidney responds to an acid load by increasing tubular production and urinary excretion of NH4+. The mechanism involves an acidosis-stimulated increase of glutamine utilization by the kidney resulting in increased production of NH4+ and HCO3. This is very important in increasing renal acid excretion during a chronic metabolic acidosis. There is a lag period: the increase in ammonium excretion takes several days to reach its maximum following an acute acid load. The key to understanding the role of ammonium in acid secretion involves the liver. Protein turnover results in amino acid degradation, which results in production of HCO3- and NH4+. For a typical 100g/day protein diet, this is a net production of 1,000mmol/day of HCO3- and 1,000mmol/day of NH4+. (These are produced in equal amounts by neutral amino acids as each contains one carboxylic acid group and one amino group.)
The high pK of the ammonium means it cannot dissociate to produce one H+ to neutralize the HCO3- so consequently amino acid metabolism is powerfully alkalinizing to the body. The body now has two major problems: How to get rid of 1,000mmol/day of alkali and highly toxic ammonium? The solution is to react the two together and get rid of both at once. This is the process of hepatic urea synthesis. The overall reaction in urea synthesis is:
2 NH4+ + 2 HCO3- => urea + CO2 + 3 H2O
The body has two ways in which it can remove NH4+, urea synthesis in the liver and excretion of NH4+ by the kidney. The key thing here is that the acid-base implications of these 2 mechanisms are different. For each ammonium converted to urea in the liver one bicarbonate is consumed. For each ammonium excreted in the urine, there is one bicarbonate that is not neutralized by it (during urea synthesis) in the liver. So overall, urinary excretion of ammonium is equivalent to net bicarbonate production- but by the liver! Indeed in a metabolic acidosis, an increase in urinary ammonium excretion results in an exactly equivalent net amount of hepatic bicarbonate (produced from amino acid degradation) available to the body. So the true role of renal ammonium excretion is to serve as an alternative route for nitrogen elimination that has a different acid-base effect from urea production.
The role of glutamine is to act as the non-toxic transport molecule to carry NH4+ to the kidney. The bicarbonates consumed in the production of glutamine and then released again with renal metabolism of ketoglutarate are not important, as there is no net gain of bicarbonate.
As pH falls, the 3 factors involved in increased H+ excretion are:
1. Increased ammonium excretion (increases steadily with decrease in urine pH and this effect is augmented in acidosis) [This is the major and regulatory factor because it can be increased significantly].
2. Increased titratable acidity: Increased buffering by phosphate (but negligible further effect on H+ excretion if pH < 5.5 as too far from pKa so minimal amounts of HPO4-2 remaining). Increased buffering by other organic acids (if present) may be important at lower pH values as their pKa is lower (e.g., creatinine, ketoanions).
3. Bicarbonate reabsorption is complete at low urinary pH so none is lost in the urine
Most of the carbon dioxide transported in circulating blood is carried as the bicarbonate ion as a result of the bicarbonate buffer system. This ion is in itself alkaline since it can accept a hydrogen ion to become carbonic acid and contributes to normal base excess in the body. There is about 20 times as much bicarbonate as carbon dioxide in blood of a normal human, and this “excess” keeps body pH at the normal alkaline level of about 7.4. Loss of this base excess occurs as the buffer systems become overwhelmed by excess hydrogen ions and serves as a good index of body buffer status.
Bicarbonate ion is also nonvolatile, and must be eliminated or retained by the kidneys as pH changes dictate. When a bicarbonate ion is formed in blood or body fluid from carbonic acid, a free hydrogen ion is generated which must be taken up by hemoglobin to prevent pH shifts toward the acid side of the scale
Once hydrogen ion concentration becomes excessive (acidosis) or deficient (alkalosis) as a result of failure of the buffer systems, mechanisms of compensation must take over. Given that the respiratory and renal systems are essential for pH regulation and compensation, they are often the causes of serious pH imbalances. For example, poor lung ventilation can cause carbon dioxide to accumulate in blood and generate excess hydrogen ions driving the pH toward acidosis. If the lungs are impaired sufficiently to cause a pH imbalance, it is not likely that they will be very helpful in correcting the situation. In this case, the kidneys must intervene to compensate for a respiratory problem. A failure in one organ system results in the other assuming the compensatory role.
Potassium is an essential mineral macronutrient and is the main intracellular ion for all types of cells. It is important in maintaining fluid and electrolyte balance. Potassium ion is found in especially high concentrations within plant cells, and in a mixed diet, it is most highly concentrated in fruits. The high concentration of potassium in plants means that heavy crop production rapidly depletes soils of potassium, and agricultural fertilizers consume 93% of the potassium chemical production of the modern world economy.
The functions of potassium and sodium in living organisms are quite different. Animals, in particular, employ sodium and potassium differentially to generate electrical potentials in animal cells, especially in nervous tissue. Potassium depletion in animals, including humans, results in various neurological dysfunctions.
Potassium is the major cation (positive ion) inside animal cells, while sodium is the major cation outside animal cells. (i.e.,- in the interstitial fluid). The concentration differences of these charged particles causes a difference in electrical potential between the inside and outside of cells, known as the membrane potential. Ion pumps in the cell membrane maintain the balance between potassium and sodium. The cell membrane potential created by potassium and sodium ions allows the cell to generate an action potential critical for body functions such as neurotransmission, muscle contraction, and heart function.
A severe shortage of potassium in body fluids may cause a potentially fatal condition known as hypokalemia. Hypokalemia typically results from loss of potassium through diarrhea, diuresis or vomiting. Symptoms are related to alterations in membrane potential and cellular metabolism. Symptoms include muscle weakness and cramps, EKG abnormalities, intestinal paralysis, decreased reflex response and (in severe cases) respiratory paralysis, and arrhythmia.
Less severe shortages may be due to chronic over-ingestion of sodium, which can “wash out” potassium and lead to milder forms of dysfunction. In rare cases, habitual consumption of large amounts of black licorice has resulted in hypokalemia. Licorice contains a compound (Glycyrrhizin) that increases urinary excretion of potassium. Although low dietary intake of potassium does not lead to overt hypokalemia in healthy individuals, many long-term health risks are related to insufficient dietary potassium. Diseases that may be prevented by adequate potassium intake include stroke, osteoporosis, kidney stones and hypertension.
Hyperkalemia is the most serious adverse reaction to potassium. Hyperkalemia occurs when potassium builds up faster than the kidneys can remove it. It is most common in individuals with renal failure. Symptoms of hyperkalemia may include tingling of the hands and feet, muscular weakness, and temporary paralysis. The most serious complication of hyperkalemia is the development of an abnormal heart rhythm (arrhythmia), which can lead to cardiac arrest. Hyperkalemia is rare in healthy individuals, oral doses greater than 18 grams taken at one time in individuals not accustomed to high intakes can lead to hyperkalemia. Most supplements sold in the U.S. contain no more than 99 mg of potassium; a healthy individual would need to consume more than 180 such pills to experience severe health risks.
Nothing in the human body exists in isolation. There is an interconnectedness that must be appreciated. Recent studies show that taking either potassium bicarbonate or citrate, but not sodium bicarbonate or potassium chloride reduces urinary calcium excretion. Thus, when evaluating a patient for osteoporosis, it is critical to evaluate potassium and acid-base balance.
Another study showed that when acid production was experimentally increased among healthy subjects, renal net acid excretion does not increase as much as acid production so that acid balances become positive (i.e.- low grade metabolic acidosis). This caused loss of bone calcium into the urine that was due to bone buffering of retained H+. They also showed that when acid production was experimentally reduced during the administration of the alkaline buffer, potassium bicarbonate, that net acid excretion by the kidney did not decrease as much as the decrease in acid production so that acid balances become negative, or to put it another way, alkaline balance becomes positive. Equivalently positive potassium and calcium balances, and thus positive charge balances, accompany these negative acid imbalances. This is the equivalent of acidosis leading to bone loss and a more normal alkaline state improving bone density.
Not only do alkaline diets help improve bone balance, they increase lean muscle mass. Another current study showed that there was an association of 24-hour urinary potassium and the fruit and vegetable content of the diet with the percentage lean body mass in older subjects. Maintaining muscle mass while aging is important to prevent falls and fractures.
Metabolic acidosis promotes muscle wasting, and the net acid load from diets that are rich in net acid-producing protein and cereal grains relative to their content of net alkali-producing fruit and vegetables may therefore contribute to a reduction in lean tissue mass in older adults. They concluded that higher intake of foods rich in potassium, such as fruit and vegetables, favors the preservation of muscle mass in older men and women.
Not only is potassium important in osteoporosis and maintaining lean muscle mass, it is critical in cardiovascular disease. McDonald and Struthers took the following excerpts from a review article. I have modified their verbiage in certain places to make it easier to understand. “Humans evolved ingesting a potassium-rich, sodium-poor diet, and mechanisms developed to retain sodium and excrete potassium. The sodium-rich diet of modern humans produces sodium overload and potassium depletion. Hypokalemia contributes to cardiovascular disease, and many cardiovascular disorders and drugs aggravate hypokalemia. Hypokalemia is therefore a common, reversible factor in the natural history of cardiovascular disease.”
Total body potassium is 3,500 mmol, with 98% found inside the cells and only 1-2% in the serum. Serum potassium is maintained between 3.5 and 5.3 mmol/l by renal excretion and shift between intracellular and extracellular fluid compartments. A high intracellular potassium concentration is maintained, despite the fact that there is almost 50 times the amount of potassium on the inside of cells versus outside. This occurs by an energy requiring pump system that exchanges potassium for sodium. This sodium-potassium pump is stimulated by hyperkalemia, aldosterone, catecholamines, (adrenalin) and insulin. There is an electrical potential difference depends between the inside and outside of cells maintained by the sodium-potassium balance. Hypokalemia increases this resting potential, and causes cellular hyper-excitability. Because cardiac repolarization relies on potassium influx, hypokalemia lengthens the electrical discharge. Heartbeats originating from the wrong part of the ventricle can be suppressed by potassium replacement. Thus, hypokalemia increases risk of ventricular arrhythmia and sudden cardiac death.
Hypomagnesemia (low serum magnesium) occurs commonly and when there is too much of the hormone aldosterone, which increases magnesium excretion. Thus, hyperaldosteronism causes hypomagnesemia. Diuretics and digoxin also cause magnesium loss. In heart failure and hypertension, magnesium depletion is common. Hypomagnesemia increases potassium excretion, and hypokalemia is difficult to remedy with concurrent hypomagnesemia because the sodium-potassium-ATPase pump requires the presence of magnesium ions (emphasis is mine). Hypomagnesemia increases ventricular ectopic activity and is related to prognosis in heart failure. This may be partly due to potassium depletion. Potassium-sparing diuretics prevent urinary magnesium wasting. Hypomagnesemia should be remembered as a cause of refractory hypokalemia. It is desirable to avoid hypokalemia in cardiovascular patients. It seems beneficial to aim for serum potassium levels above 4.5 mmol/l. and to avoid potassium levels above 5.5 mmol/l”.
Chronic acidosis may lead to increased loss of magnesium from the urine, which may be partially corrected with bicarbonate. In addition, potassium depletion, phosphate deficiency and metabolic acidosis may be additive. Furthermore, net acid production in the normal homeostatic state is reflected by net acid excretion (NAE). NAE is implicated in bone loss because it is positively associated with urinary calcium loss. Protein is one of the main sources of dietary acid load, whereas fruit and vegetables provide alkaline potassium salts that counteract the dietary acid load. Daily sodium intake and the ratio of sodium to potassium in urine show a significant correlation with fasting calcium excretion.
Conditions that lead to low-grade metabolic acidosis are chronic, inflammatory ones, such as insulin resistance, diabetes, low bone density, high urinary sulfates, dysbiosis, leaky gut, chemical toxicity, poor liver Phase 1 and 2 detoxification, high levels of heavy metals, genetic variations, and anti-oxidant deficiencies.
Standard lab testing may be instructive in revealing potential chronic, low-grade metabolic acidosis. Multiple abnormalities of the following tests can point one in the right direction: elevated cholesterol and cholesterol/triglyceride ratio (ideal 2:1), high liver enzymes (ALT, AST, GGT), elevated WBC with high PMN’s or lymphocytes, high C-RP, TSH outside normal range (1-8-3.0), abnormal T3 and T4, high blood pressure, low first morning salivary pH and urine pH (below 7.0 and 6.4 respectively), low normal serum potassium with high normal serum sodium, low RBC potassium and magnesium, high urine calcium, magnesium and sodium, low to low-normal serum CO2, High normal to high BUN with a normal creatinine, low serum calcium to phosphorus ratio (ideal is 10:4), multiple high levels of organic acids on an organic acids test, elevated orotate on an organic acids test, low arginine, citrulline, and ornithine and a high glutamate to glutamic acid on an amino acids test.
Testing serum CO2 is actually a test for bicarbonate, since most CO2 in the body is in the form of bicarbonate. Therefore, a low level of CO2 implies low bicarbonate levels and implies a situation of acidosis, which could be ketoacidosis, lactic acidosis, metabolic acidosis kidney disease, diarrhea or poisoning with aspirin, ethylene glycol or methanol.
Another test for acidosis is the Anion Gap. An electrolyte imbalance is often the first sign of an acid-base disorder. The Anion Gap calculates the sum of cation electrolytes (Sodium + Potassium) minus the anion electrolytes (Chloride +Bicarbonate). AG = (Na + K) – (Cl + HCO3). Electrically, the body is neutral. The anion gap exists because not all electrically charged particles are measured. Because there are more unmeasured anions (Proteins, Organic Acids, Phosphates, Sulfates) than cations (Calcium, Magnesium) this artificial number exists. If they were all measured there would be no gap. The most common cause for an elevated anion gap is the presence of excess cations caused by acidosis- metabolic, lactic, kidney failure, and ketoacidosis. The most common cause for a low anion gap is a decrease in serum albumin. For every 1 gm/dl albumin drops, the anion gap is reduced by 2.5mEq/L.
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