This chapter will cover discussions on principles of external balance for electrolytes, and for acids and bases. The first section will deal with discussions on principles of electrolyte balance in general, and the second section discusses the acid–base balance.
This chapter will cover discussions on principles of external balance for electrolytes, and for acids and bases. The first section will deal with discussions on principles of electrolyte balance in general, and the second section discusses the acid–base balance.
Principles of Electrolyte Balance
Introduction
Prolonged imbalance between input and output of most quantifiable elements in a living organism is incompatible with life. The duration of imbalance varies, but eventually balance must be restored for maintenance of survival. This rule applies to all quantifiable elements in vivo as well as in vitro . Red cell destruction equals red cell production. Oxygen uptake equals oxygen utilization. Sodium intake must equal sodium output, and water input must match water loss. Yet transient discrepancies occur regularly in living organisms, but balance is ultimately achieved. The same rule applies to the balance of any quantifiable elements in nature. The duration of imbalance is usually quite short in living organisms, because protracted imbalance results in death. However, not limited by survival, the duration of imbalance in nature could be more protracted.
The main aim of this chapter is to describe the underlying principles for eventual restoration of balance in nature, and then to extrapolate these principles to the understanding of human physiology, particularly the principles of fluid and electrolyte balance.
Why is Balance Always Restored?
The underlying mechanism that allows eventual restoration of balance is perfect and foolproof. As an example, the kidney is a central player in the restoration and achievement of fluid and electrolyte balance in living organisms, but the smartness of the kidney is not the reason for perfect balance. The kidney merely accelerates the process by utilizing a principle ubiquitous in nature, but it does not determine its ultimate outcome. The most crucial element of the control system that restores ultimate balance is that a discrepancy between intake and output inevitably leads to a change in total content of the element in the system, and the uncorrected imbalance is cumulative. When input is greater than output the content increases, and the continued imbalance keeps increasing the content. When output is greater than input the content decreases, and the continuing imbalance keeps decreasing the content. In a system with a limited capacity, a change in content of a substance alters its concentration; this invariably affects output, and sometimes also input. The key points here are: (1) an uncorrected balance invariably leads to a change in content; (2) a change in content leads to a change in concentration; (3) an altered concentration affects output or input; and (4) these effects are cumulative.
Is the Capacity of any System Always Limited?
Is the capacity of any system always limited? The answer is yes. We often say: the sky has no limit. Yet there is a limit even to the capacity of atmospheric air volume. The apparent air volume is about 4.08×10 21 liters. (The apparent air volume is calculated considering that air is denser at sea level, and density declines progressively with rising altitude until there are no more air molecules. Thus, the apparent air volume is the theoretical volume that would be required if all the gases in the air were contained at the same concentrations as those at sea level at a pressure of 760 mmHg when the 1 mole of gas is contained in 22.4 liters.)
In recent years, the rising CO 2 concentration of the atmosphere and its impact on global warming is the source of a great deal of public concern. The rising CO 2 concentration implies that the amount of CO 2 added to the atmosphere is more than the amount eliminated from the atmosphere. However, the discrepancy will not and cannot remain permanent, because the CO 2 concentration in the atmosphere has a positive influence on the rate of its removal from the atmosphere. The main source of CO 2 addition to the air is the burning of fossil fuels (oil, gas, and coal). The total amount of CO 2 added is about 30 billion tons per year. This amount added to the air volume of 4.08×10 21 liters would increase atmospheric CO 2 concentration by about 3.74 ppm per year. Currently, the actual rise in CO 2 concentration is about 2 ppm per year. The difference, 1.74 ppm, is absorbed by the oceans, mostly by direct diffusion and some by diffusion into rain water entering the ocean. In the ocean, CO 2 is in equilibrium with bicarbonate and carbonate. As the atmospheric CO 2 concentration increases, the amount entering the ocean would increase progressively. Since the industrial revolution, the atmospheric CO 2 level has been rising rapidly, because the rate of CO 2 addition has been increasing rapidly with the progressively greater consumption of fossil fuel worldwide. Once the rate of fossil fuel consumption stops increasing further, the rate of CO 2 removal will eventually equal the rate of CO 2 addition. Of course, it is quite likely that at the time of new balance, the earth could be much warmer and the ocean much more acidic, with major ecological changes. Nevertheless, imbalance does not last forever, because imbalance always leads to a new balance.
Many substances in the human body utilize the same principles to reach a state of balance. For example, if creatinine production is doubled in the absence of any change in GFR, serum creatinine would exactly double, at which point the renal excretion of creatinine would also double. At this point a new balance is reached between production and excretion. For some substances, a new balance is accelerated by physiological control mechanisms. For example, if sodium intake is doubled, renal sodium excretion will also double, but doubling of renal sodium excretion does not require doubling of serum sodium or total body sodium content, only a slight increase in sodium content of the body, because of the excellent renal regulation of sodium balance. By the same token, a reduction in sodium intake to 1/10 of the usual amount does not require sodium content of the body to decrease to 1/10 of normal when the balance is restored.
In the human body, the capacity for most substances is quite limited, and daily variations for most electrolytes are quite large in relation to total body content. Furthermore, there is a limit to which the organism can tolerate a deviation in the content of these substances. Therefore, survival of the organism demands the existence of certain physiological mechanisms to accelerate the compensation processes, to prevent a deviation from occurring to a lethal level.
Following is the sequence of events in the control system: a certain amount of an element is contained in a compartment, if input of the element into the compartment exceeds its output, the content will increase. The higher content influences the control mechanisms to reduce input or to increase output. As long as the discrepancy remains, the content will keep increasing, because the consequence of discrepancy is cumulative; the higher the content, the greater the effect on input or output. A cumulative change stops only when input equals output. When input is less than output, the opposite sequence of events restores the balance ( Figure 10.1 ).
Restoration of salt balance will be used as an example. A person in a state of sodium balance has been ingesting 10 g of salt per day, and excreting 10 g of salt per day. Now, assume that a diuretic is given to this person. On the first day of diuretic therapy, salt output is 20 g per day, with net loss of 10 g of salt. The next day, although the diuretic dosage remains unchanged, salt excretion has to be less, for example, 15 g a day, because the reduction in effective vascular volume caused by the previous day’s salt loss has activated salt-retaining mechanisms, and has reduced salt losing hormones. Still, the overall result is an additional negative balance of 5 g of salt. Although the negative balance is less on the second day, the cumulative loss (15 g) is greater on the second day than on the first, and the effective vascular volume is even lower on the second day than the first. The lower effective volume reduces salt output further to 12 g per day on the third day, with an additional negative balance of 2 g. The overall cumulative loss is now 17 g, resulting in a further decrease in effective vascular volume. As long as the salt output remains greater than salt intake, cumulative salt loss becomes larger and larger, albeit less steeply than before. Cumulative salt loss stops only when salt output equals salt intake. Indefinite net salt loss is theoretically impossible, because continued salt loss will ultimately cause such severe volume depletion that the person will become hypotensive, and salt excretion would stop completely. Of course, long before reaching such an extreme state, renal excretion of salt would decrease to a level equaling intake.
In the example given, what causes restoration of balance is not the smartness of the kidney or the cleverness of humoral mechanisms, but the principle of balance restoration, which is ubiquitous in nature. For example, sodium balance in a person on chronic diuretic therapy would still be restored in the absence of aldosterone, in which case the person could be quite sick with dehydration when balance is attained.
The same control mechanism explains why urinary excretion of potassium does not remain greater than intake in patients with primary hyperaldosteronism. With increased aldosterone, K output will initially exceed K intake. The resulting negative K balance causes hypokalemia, which in turn reduces urine K excretion. As long as K excretion exceeds K intake, serum K will decrease progressively until K excretion equals K intake. Occasionally, a patient dies of a cardiac arrhythmia before balance is attained. In the vast majority of cases, balance is achieved before the patient dies.
Speed of Balance Restoration
In a living organism, the speed of restoration of balance is teleologically determined. If an organism can tolerate protracted imbalance of a particular element without death or severe disability, balance need not be restored promptly. If quick restoration of balance is vital for survival, a mechanism for rapid restoration of balance is necessarily acquired in the process of evolution. Thus, the acceptable duration of discrepancy or alternatively speed with which restoration of balance is achieved, depends on the importance of maintaining the content of an element within a narrow range, in order to prevent the demise or serious disability of the organism. Four main factors influence the speed of balance restoration ( Table 10.1 ).
|
For example, an adult of average size has about 40 liters of total body water, and daily intake and output of water is about 2 liters. Obviously, water output exceeding water intake by one liter a day would lead to fatal dehydration in 10 days to two weeks. Conversely, water intake exceeding water output by the same magnitude would lead to water intoxication and death. An opposite example is calcium balance. The total body calcium content of an average adult man is about 1,200,000 mg (60,000 mEq), and net daily external flux is about 150 mg (7.5 mEq). A daily negative balance of calcium of 100 mg for one year would reduce total body calcium by mere 36,500 mg; 3% of total body calcium content. Obviously, a negative calcium balance of such a magnitude, even for a protracted period, is not incompatible with life. Indeed, during the period of development of osteoporosis, a substantial negative balance of calcium for 10 years or longer is a common occurrence. Similarly, a positive caloric balance of 500 calories a day for a year will result in a total positive balance of 182,500 calories (500×365=182,500). This amount would result in an increase in adipose tissue weight of about 50 lbs, an undesirable situation, but with no immediate effect on survival.
A large storage capacity does not guarantee a protracted imbalance. A quantitative analysis must be applied before that conclusion is reached. Once it was widely accepted that a large store of alkali of the bone was responsible for the maintenance of stable serum bicarbonate concentrations in chronic renal failure, despite a substantial daily positive balance of acid. However, this conclusion was reached without quantitative analysis. The bone content of alkali is indeed very large, but it is not sufficiently large to provide 19 mEq of alkali per day for six years in chronic renal failure. Since the total content of acid in the bone is about 25,000 mEq, a quick calculation would indicate that at a rate of consumption at 19 mEq per day, the entire bone content of alkali would be gone in about 3.6 years. Clearly, uremic patients with metabolic acidosis are in states of good or near acid–base balance, i.e., acid production equals acid excretion.
The cumulative net loss of a substance from the body cannot exceed the total amount of that substance contained in the body ( Table 10.2 ). For example, one can conclude with certainty that a person who has total body sodium content of 3500 mEq could not have been in daily negative balance of sodium by 10 mEq per day for one year, since the total loss of 3650 mEq (10×365=3650) would exceed the total body store of sodium. Even before exceeding the total body content, one cannot exceed a physiological limit of deficit for the substance. For example, potassium loss in excess of a third of the body store (3000 mEq) is usually fatal. Hence, you would reject a claim that a patient with Conn’s tumor has been losing 20 mEq of potassium daily for three months, since loss of such an amount (20×30×3=1800 mEq) would certainly be lethal. In contrast, the body can tolerate a greater fraction of sodium loss. A person who loses half of the body’s sodium would be gravely ill, but still alive.
| Body Elements | Total Body Content | Usual Daily Turnover | Days for 50% Turnover |
|---|---|---|---|
| Na | 3500 mEq | 4% | 12 |
| K | 3000 mEq | 2.3% | 22 |
| Ca | 60,000 mEq | 0.01% | 2700 |
| Mg | 2000 mEq | 0.5% | 100 |
| P | 18,000 mmol | 0.17% | 290 |
| Water | 40 L | 5% | 10 |
| Alkali | 28,000 mEq | 0.2% | 250 |
| Calories | 130,000 kcal | 1.5% | 33 |
| Creatinine | 400 mg | 400% | 0.12 |
| Urea-N | 4000 mg | 250% | 0.2 |
While the total stored amount sets the absolute upper limit on losses, the amount that can be gained depends on the additional storage capacity, which varies widely with electrolytes. In the case of sodium, the storage capacity for additional Na + in the body is enormous. In certain edema-forming states, the Na + content may increase by 300% of the basal amount. Caloric balance is another example. In a normally-built adult, the total stored in fat and protein is about 130,000 calories. At the caloric consumption rate of 1200 calories per day, about 50% of the stored calories would be consumed in 55 days. In contrast, a person can gain as much as 500 lbs of fat, which are equal to 4,500,000 calories, about 35 times the normal caloric storage.
Mechanism of Balance Restoration
All control mechanisms are activated by the introduction of a new influence into a system that causes imbalance between input and output of an element, and this leads to an alteration in a parameter of the element in the system. In biological systems, parameters that are most often disturbed are concentrations of elements in the plasma. Other disturbed parameters include pressure, volume, temperature, and body weight. Alterations in a parameter affect either input or output, which in turn affects the parameter directly or indirectly. Examples of an element that is directly responsible for a change in a parameter are balance of potassium (element) affecting plasma potassium concentration (parameter), and balance of magnesium (element) affecting the plasma magnesium concentration (parameter). Examples of an element that is indirectly responsible for a change in parameter include the balance of sodium (element) affecting the effective vascular volume (parameter), and the balance of calories (element) affecting body weight (parameter).
The effectiveness of the compensation mechanism determines the degree of deviation of a parameter from the baseline value when the balance is restored. A poor compensation mechanism restores balance with the parameter greatly deviated from the baseline value. An example of a poor compensation mechanism is a change in plasma urea concentration with a change in the rate of urea production. When urea production doubles, the renal excretion will eventually also double and equal the increased production rate. However, at equilibrium the plasma urea concentration will be twice the baseline value. An example of a good compensation mechanism is a change in a sodium content of the body in response to a change in sodium intake. When salt intake is doubled, renal excretion of salt will eventually double; at this point the total body sodium content would be very slightly greater than the baseline value.
Models of External Balance
The pattern of restoration of new balance for control of various elements in the human body is broadly classified into three models. The main source of input for most electrolytes in our body is oral intake and the main output the renal excretion, with some additional output through the GI tract.
Model A
This model is depicted in Figure 10.2 as a cylinder filled with water. Water enters from a faucet into the cylinder, and leaves through a hole at the bottom. The height of the water column depends on water input and water output, and water output in turn depends on the size of the hole at the bottom and the hydrostatic pressure. The hydrostatic pressure in turn depends on the height of water column. Under these conditions, only two factors can change the height of the water column permanently; the rate of water input and the size of the hole. If the rate of water input is doubled while the size of the outlet hole is kept constant, water output will also double when the balance is restored.
With the same size outlet hole, doubling of water output would require doubling of hydrostatic pressure, which in turn requires doubling of the water column height. Before balance is restored, the water column height rises, because water input exceeds water output. The rise in the water column height gradually increases the hydrostatic pressure, and therefore the water output. Hence the discrepancy between the water input and the water output gradually lessens. However, as long as water input remains greater than water output, the water level will keep rising, and the rise will stop only when the water output equals the water input; this occurs when the water column height is exactly doubled.
Conversely, decreasing the size of the outlet hole to double the resistance to water flow, with an unchanged rate in the water input, would initially reduce the water output to half. The ensuing imbalance between the water output and the water input would cause a rise in the water column height. A higher hydrostatic pressure resulting from the rise in the water column would allow more water to come out through a narrower hole. Thus, in this example, doubling of the water column height will restore the water output to the baseline value.
The main characteristic of this type of compensation is that the alteration in content or concentration caused by a disturbance is directly or inversely proportionate to the magnitude of the alteration in input or output function. For example, if the input of a substance is doubled, the content or concentration of the substance will be doubled when balance is restored. If input is increased three-fold, the content or concentration will be tripled. Similarly, if the output function is halved, the content or concentration will be doubled when balance is restored. If the output function is reduced to one tenth of the baseline, the content or concentration will be increased ten-fold when balance is restored.
Many substances in the body follow this pattern of compensation mechanism in order to achieve a new balance. When a substance follows this pattern of compensation, the body must have a high degree of tolerance for a large deviation in the body content or concentration for the substance. For example, if creatinine clearance diminishes to half of the baseline value with an unchanged creatinine production rate, serum creatinine concentration will double in order to achieve the same rate. Similarly, if creatinine production is reduced to half of the baseline value with the same renal creatinine clearance, serum creatinine concentration will be half of the original value. Likewise, if urea production is doubled, with unchanged kidney function, serum urea concentration is doubled when balance is restored.
Model B
In this model, the cylinder has a wedge-shaped slit on its side instead of a hole at the bottom ( Figure 10.3 ). Water enters the cylinder from a faucet, and leaves through the slit. As in model A, water output depends on the height of the water column. But, because of the wedge shaped slit, the effect of a rise in water level on water output is exponential. Therefore, when water intake doubles, doubling of water output does not require doubling of the water column height. Depending on the shape of the slit, the water level may rise only slightly before a new balance is restored. In other words, an increase in water output in response to a change in the height of water column is magnified in this system. Furthermore, unlike model A, when the water level drops below the lowest part of the slit, water output stops altogether.
The regulation of the body content or plasma concentration of most electrolytes and other essential body elements utilizes this type of compensation. For example, when potassium intake is increased five-fold, plasma potassium concentration does not increase five-fold when balance is restored. In the presence of normal renal function and normal aldosterone response, plasma potassium concentration will increase only slightly. Likewise, a five-fold increase in sodium intake causes only a slight increase in body sodium content or plasma sodium concentration; when sodium intake is greatly reduced, the body sodium content decreases only slightly before renal sodium excretion ceases.
Model C
The pattern of water excretion in model C ( Figure 10.4 ) is similar to model A, but in this model two cylinders, one big (A) and the other small (B), are connected at the bottom. Water enters only into cylinder A, but once it enters, it equilibrates with cylinder B. Ordinarily, because cylinder A has a bigger hole than cylinder B, the water output is determined primarily by the size of hole A. However, as the size of hole A decreases, the role of hole B increases. When water input is doubled, the height of the water column will have to be doubled in order to permit establishment of a new steady-state. On the other hand, when the resistance to flow through hole A is doubled, the height of the water column will be less than doubled when balance is restored, provided that the size of hole B is unchanged.
When the excretion rate through hole A decreases, the excretion through hole B becomes more important. The regulation of plasma concentration of uric acid follows the pattern in model C. Uric acid is cleared by the kidney, and is also cleared metabolically by colonic bacteria. The renal clearance of uric acid is normally about 8 liters per day, and the colonic clearance is about 4 liters per day. Thus, 2/3 of the uric acid produced is cleared by the kidney and 1/3 by the colon. If the plasma concentration of uric acid is 5 mg/dl (50 mg/L), renal excretion of uric acid would be 400 mg per day (uric acid clearance of 8 liters per day), and the amount cleared by the colonic bacteria would be 200 mg, with a total uric acid removal rate of 600 mg per day. If chronic renal disease reduces the renal clearance of uric acid to 4 L a day (half of normal), total uric acid clearance would now be 8 liters per day, if the colonic clearance remained unchanged at 4 liters per day. If the rate of production remained the same (600 mg/day), plasma uric acid concentration would not double to 10 mg/dl, but would increase to 7.5 mg/dl, because total body uric acid clearance would be 8 liters per day (4+4=8 liters); at this concentration, the total amount of uric acid cleared would be 600 mg/day (75 mg/L×8 L/day=600 mg/day).
The regulation of plasma creatinine concentration follows the same type of compensation as shown in model C. Normally, creatinine is cleared mainly by the kidney, with a daily clearance of about 180 liters, but the colonic bacteria also remove a small amount of creatinine, providing about 3 liters of creatinine clearance per day. Thus, normally the colonic clearance, which constitutes less than 2% of the total creatinine clearance, has little impact on the plasma concentration of creatinine. However, in the presence of advanced renal failure, which does not diminish the colonic clearance of creatinine, it could have a substantial impact on plasma concentration of creatinine. For example, in a person who has 5 ml/min of renal creatinine clearance (7.2 liters per day), 3 liters of colonic clearance would now represent about 30% of the total creatinine clearance. For these reasons, the rate of rise in serum creatinine in advanced renal failure is not exactly inversely proportionate to the reduction in renal clearance of creatinine.
Infinite Gain Control Mechanism
The ultimate aim of all compensation mechanisms is restoration of balance between input and output, after balance is disturbed by introduction of an abnormality. In most instances restoration of balance is possible only when the abnormality persists. For example, increased renal excretion of potassium by primary hyperaldosteronism will result in imbalance between input and output, with output exceeding input. Development of hypokalemia is needed for output to decrease to match input, and hypokalemia is the price that must paid in order to restore balance. Similarly, an increase salt intake would result in chronic volume expansion, in order for salt excretion to increase to equal the increased intake. The infinite gain control mechanism, to be discussed below, is unique in that the abnormality is corrected completely when a balance is restored.
This principle is well illustrated in Figure 10.5 . In this model system, water enters the tank from a faucet at the top, and leaves the tank through a hole at the bottom. The input is independently regulated, but the water output depends on two factors, the size of the outlet hole and the hydrostatic pressure. The hydrostatic pressure in turn depends on the water level, which is determined by the balance between the water input and water output. At equilibrium, the water input is equal to the water output. What would happen if the capacity of the tank is suddenly altered at this point by, for example, placing a brick in the tank, without a change in the water input or the size of outlet hole (i.e., output function)? Initially, the water level would rise and hydrostatic pressure at the bottom of the tank would be increased. The higher pressure with the same size outlet hole would cause the output of water to exceed water input. The consequent imbalance between the input and output would cause a gradual decline in the water level. But, as long as the water level is higher, even slightly, than the baseline value, the water output will exceed the water input. Only when the water level decreases to the original level, will the water input equal the water output. A sudden increase in the capacity of the tank, for example by creating a pouch on the tank, would cause an imbalance between the water input and the water output because of the initial reduction in the water level and the hydrostatic pressure, but the discrepancy would be only transient. At equilibrium, the water level will return to the original level.
This type of compensation mechanism is ubiquitous in various physiological and pathological states in the human body, but the importance of this mechanism was first recognized by Guyton, who presented the concept in his discussion of the regulation of arterial blood pressure. He boldly predicted that in the absence of an altered function of renal excretion of salt, no abnormality will sustain hypertension chronically. This prediction was made on the basis of the observation that the arterial blood pressure is normally a powerful regulator of renal salt excretion, and that a minute increase in blood pressure results in a large increase in salt excretion, and salt excretion in excess of salt intake will continue until the blood pressure returns to normal .
Suppose hypertension develops as a result of increased systemic vascular resistance, while the responsiveness of the kidney to changes in blood pressure to influence salt output (i.e., renal function curve in response to blood pressure) remains unchanged; the higher the pressure, the higher the renal salt output. Increased salt output caused by a higher blood pressure in the absence of commensurate increase in salt intake would lead to a negative salt balance. The negative salt balance would reduce effective vascular volume, circulating blood volume, and eventually cardiac output. A lower cardiac output will reduce blood pressure to a lower level, but as long as the blood pressure is still higher than the baseline, salt output will remain greater than the basal salt output. The salt output in excess of salt intake progressively reduces the salt content of the body. Only when blood pressure returns to the original value will the renal salt output return to the baseline value. At this point, balance is restored between salt intake and salt output, and the abnormality in blood pressure is completely dissipated.
In Guyton’s use, the term “gain” is defined as the fraction of abnormality that has been corrected divided by the fraction yet to be corrected. For example, if an abnormality causes an increase in blood pressure, and a control system brings it back halfway to the original value, the feedback gain is one (0.5/0.5=1). Gain is zero if a control system does not correct at all (0/1=0). Gain is infinite if the abnormality is almost all corrected completely with virtually nothing left to be corrected, because division of a number with an infinitely small number results in an infinitely large number.
What is the reason why an abnormality disappears completely in the infinite gain control mechanism, but not in other control mechanisms? The main difference is in the nature of the influence that causes disturbances in the system. When the disturbance affects either input or responsiveness of the system to change in a parameter for the output (i.e., output function), the abnormality will not be corrected completely, and the compensation mechanism does not involve the infinite gain control mechanism. On the other hand, when the disturbance introduced is not one of these two kinds, the compensation mechanism is an infinite gain control mechanism.
Common Misconceptions and New Insights
A series of topics discussed in the following section deals with widespread misconceptions regarding principles related to restoration of balance states.
There is no Set Point for Renal Salt Excretion
Hollenberg, citing the earlier writing on the same subject by Straus and colleagues proposed a hypothesis for the existence of a set point for the regulation of body sodium content by the kidney. The set point is defined in his writings as the level of sodium content in the body that the kidney tries to maintain as the normal and desirable level. Henceforth, this hypothesis will be called the set point hypothesis . The evidence for the set point hypothesis follows.
First, when sodium intake is suddenly reduced, the rate of decrease in urine sodium excretion is exponential. The authors of the hypothesis consider the exponential decline thermodynamically unsound. If the decline were in response to progressive volume depletion, the authors argued, the decline should be accelerating, not declining exponentially. Second, when patients in sodium balance on a low sodium diet (10 mEq/day) were given a small amount of extra sodium (e.g., 30 mEq), the extra sodium was promptly excreted. It is further argued that if the patient had been volume depleted at the time, he should not have excreted the extra sodium. Finally, when a patient who was volume depleted by chronic diuretic therapy was given sodium, no sodium diuresis occurred until the body sodium content was brought back to the level that was achieved on zero sodium intake.
On the basis of these observations, the set point for renal sodium excretion was defined as the amount of sodium in the body when the subject is in balance on a salt-free diet. Accordingly, most humans are in a state of sodium excess, and hence the unloading of excess sodium diminishes the stimulus for sodium diuresis, producing an exponential decrease in renal sodium excretion. It was further argued that the absence of a set point would lead to chaos, and a control system without a reference point is unimaginable. The possibility of a set point being higher or lower than the level defined above was dismissed; the exponential decrease in sodium excretion on a salt-free diet is considered to be evidence against a higher set point, whereas the absence of sodium diuresis upon salt administration in patients pretreated with a diuretic was thought to be evidence against the existence of a lower set point. The set point hypothesis has been debated in the public forum previously – but the uniqueness of the current argument against the hypothesis is that it is advanced by the use of counter examples (three counter examples follow).
- 1.
When water intake is suddenly stopped after a period of normal water intake, the pattern of urine water output follows the same pattern as the renal salt output after sudden curtailment of salt intake. With increasing water deficit on a zero water intake, urine output declines exponentially, not accelerating, despite progressive water deficit and progressive activation of the water-conserving mechanism. Clearly, the water content of the body on zero water intake cannot be the desirable water content.
- 2.
When a patient is on a potassium-free diet, urinary excretion of potassium declines exponentially, not accelerating, despite a progressive increase in potassium deficit. Again, no one would argue that the potassium content of the body on zero potassium intake is the desirable body potassium content.
- 3.
The arterial pCO 2 declines exponentially with increasing severity of metabolic acidosis, despite metabolic acidosis becoming more and more severe.
These counter examples indicate that the finding that urinary sodium declines exponentially neither supports nor argues against the existence of a set point, as previously defined. When sodium intake is stopped, urine sodium decreases progressively because effective vascular volume declines progressively, and as a result sodium reabsorption mechanisms in the kidney are activated progressively. Whether the body sodium content at usual sodium intake is normal or excessive is not a question that can be decided by the pattern of renal sodium excretion, just as we cannot decide the normal plasma potassium concentration by the pattern of renal potassium output in response to a change in potassium intake.
In an attempt to define a normal value in the set point hypothesis, a special meaning has been attached to the pattern of renal sodium excretion. However, normalcy of any physiological values must ultimately be decided by their relation to morbidity and mortality. Given the well-known effects of the body salt content on blood pressure, it may be more advantageous to have a salt content that is achieved on a near salt-free diet than the content attained on the current usual salt intake. The fact that the body’s sodium content attained on a near salt free diet is more advantageous to human health is, in my opinion, pure chance, but may have contributed to the set point hypothesis. At different times in human history, a slight excess in sodium content might have been beneficial to survival, when salt was not readily available in many parts of the world and salt loss was a common occurrence from gastroenteritis and sweating. This scenario seems more plausible when one realizes that the main adverse effect of excess salt content in the body is increase in blood pressure, and hypertension was not the main cause of death when the average lifespan was 30 to 40 years. Normally, urine sodium excretion decreases when effective vascular volume declines. Thus, the relationship between effective vascular volume and renal sodium excretion can be summed up in one sentence: the lower the effective vascular volume, the lower the renal sodium output, and the higher the effective vascular volume, the higher the renal sodium output.
As explained in model B ( Figure 10.3 ), the relationship between renal sodium excretion and effective vascular volume is not continuous; below a certain level of effective vascular volume, renal sodium output virtually disappears, and this happens before any overt signs of clinical dehydration. When effective vascular volume decreases further, renal sodium excretion cannot decrease further because renal sodium excretion cannot be a negative number, even though the sodium retaining mechanisms are even more activated. Administration of sodium in such a state would not cause sodium diuresis until effective vascular volume increases to a higher level. The proponent of the set point hypothesis asks the question: “if a subject is volume depleted on 10 mEq per day sodium diet, why would he excrete the administered sodium?” The simple answer would be “because he is less volume depleted now.”
It is the central core of the set point hypothesis that the kidney stops excreting sodium at the set point, i.e., the salt content attained at near zero sodium intake, in order to preserve the most desirable value of body sodium content. However, that is not the consistent behavior of the kidney. Urine output never becomes zero until the kidney is completely shut off, despite progressive water deficit and clear clinical evidence of dehydration. Likewise, renal potassium output does not cease on a zero potassium intake, despite clinically evident hypokalemia.
Renal Salt Output Does Not Exceed Salt Intake in Salt Losing Nephropathy
An often-cited diagnostic criterion for salt losing nephropathy is urine sodium excretion in excess of sodium intake. This is obviously impossible on a chronic basis, just as chronic diuretic therapy cannot produce persistent net sodium loss. Salt intake must equal salt output in the long run, but transient imbalance often occurs. Salt output exceeds intake while volume depletion develops, but the reverse occurs when volume depletion is being corrected. If a patient with salt-losing nephropathy who had been on a high-salt diet reduces salt intake because of an illness, the patient will develop volume depletion, and during this period urine salt output exceeds salt intake, and hence a negative salt balance occurs. On the other hand, when the same patient resumes his usual salt intake or receives intravenous fluid, salt balance will be positive during the period of recovery. The diagnosis of salt losing nephropathy requires documentation of inappropriate urinary salt excretion in the presence of volume depletion.
Mechanism of Low Urea Nitrogen Concentration in Liver Disease
It is often stated that serum urea nitrogen level is very low in chronic liver disease because urea is produced in the liver, and the diseased liver cannot produce urea at the normal rate. It is obvious that a low serum urea concentration without increased urea clearance must be due to reduced production, but impaired liver function is not the reason for reduced production. Once ingested protein is broken down to individual amino acids, and is absorbed into the bloodstream, it has three metabolic pathways: (1) metabolism to urea to be excreted in urine; (2) metabolism to non-urea nitrogen compounds to be excreted in urine; and (3) protein synthesis. Patients with chronic liver disease are not in a state of net protein synthesis, i.e., an anabolic state. Major non-urea nitrogen compounds normally excreted in urine include ammonia, amino acids, creatinine, and uric acid, and urinary excretion of these compounds is not increased in chronic liver disease. One might suggest that nitrogen could accumulate as ammonia in the blood as metabolic conversion of ammonia to urea is impaired in liver disease. In severe liver disease, ammonia concentration in plasma is indeed increased, but the total amount of nitrogen that can accumulate in the body in the form of ammonia without fatal consequences is extremely small. The concentrations of ammonia in plasma are expressed in micrograms per dl, whereas those of urea are in milligrams per dl. Accumulation of only 10% of ingested nitrogen as ammonia instead of its conversion to urea would lead to fatal hyper-ammonemia within hours.
The only logical explanation for low urea production, therefore, is reduced protein intake. Chronic alcoholics often have persistently low protein ingestion, and they have low plasma urea nitrogen. However, any normal person ingesting a low protein diet will also have low urea nitrogen production, and therefore low plasma urea nitrogen. A strict vegetarian often has a low urea nitrogen concentration, for these reasons. When a patient with a liver disease has a G-I hemorrhage, serum urea nitrogen concentration rises promptly, indicating that the diseased liver can produce urea rapidly when substrate is available. If a person with severe liver disease ingests a normal amount of protein, urea production will be normal, but plasma ammonia will be higher.
It is a general rule that an impaired metabolic pathway does not reduce the output of its metabolic product unless there is another pathway to which the precursor of the product can be shunted. In the absence of another pathway, at equilibrium the concentration of the precursor will be increased, and the rate of output of the metabolic product will return to the baseline. The situation is analogous to the quantity of creatinine excretion in chronic renal failure. When the kidney function is impaired, the amount of creatinine excreted in the urine does not decrease, as long as creatinine production remains unchanged. The amount excreted will decrease at the onset of renal failure, but at equilibrium it will return to baseline. One does not measure the rate of urinary creatinine excretion as a means of determining renal function; one looks at serum creatinine concentration instead. Likewise, the rate of production of urea by the liver does not offer any clue to the level of liver function, but serum ammonia level does.
Sodium Intake and Sodium Balance are Poor Predictors of Effective Vascular Volume
The assessment of effective vascular volume by urinary sodium excretion is a widely used and useful clinical tool. Most physicians, however, believe that knowledge of both sodium intake and urine sodium output provides a better clue to the status of effective vascular volume. The following example explains why this reasoning is flawed.
Question: Two subjects, A and B, have been admitted to the hospital with unknown status of their effective vascular volume. Subject A is given a diet containing 100 mEq of sodium per day, and subject B gets a sodium intake of 20 mEq a day. In the next 24 hours, subject A excretes 60 mEq of sodium per day, and subject B excretes 40 mEq of sodium per day. On the basis of this information, which subject do you believe has a higher effective vascular volume? You should assume that neither subject has any renal or hormonal disorder that would affect renal sodium excretion.
Answer and discussion: The most common answer is that A has a lower effective vascular volume than B. The reasoning for the answer: person A is in positive sodium balance because the “smart kidney,” sensing volume depletion, retains sodium, whereas person B is in negative sodium balance because the “smart kidney,” sensing the volume expansion, compels him to excrete the excess sodium. It is true that the balance data indicates that A is in a state of sodium retention and B in a state of sodium loss. However, sodium retention need not indicate the presence of volume depletion, and sodium loss not does prove the state of expanded volume. The following examples will make these points obvious.
A person in salt balance while ingesting 100 mEq of sodium per day suddenly increased sodium intake to 200 mEq per day. Salt excretion will eventually increase to the same level as intake, but not on the first day. If adjustment in salt excretion matched intake immediately, there would be no retention of sodium, and there would be no harmful effect of a high salt intake. Instead, there would be some sodium retention. On the first day he may excrete only 150 mEq, causing net retention of 50 mEq of sodium. The positive sodium balance in this instance is due to increased intake, not to reduced excretion. Furthermore, a positive sodium balance increases the effective vascular volume to a higher level than the previous day, and the higher effective vascular volume is indeed the reason for the greater urinary sodium excretion. Clearly, positive sodium balance does not necessarily mean low effective vascular volume.
In another example, a patient with intractable heart failure is ingesting 50 mEq of sodium per day and excretes only 10 mEq per day. He is retaining sodium avidly, and hence the term renal sodium retention would be appropriate in this setting, as positive sodium balance in this instance is due to low effective vascular volume. Frustrated by relentless sodium retention, the physician prescribes a salt-free diet, and urine sodium drops further to 5 mEq per day. At this point, however, his overall sodium balance is −5 mEq per day. Can we say, then, that his effective vascular volume is no longer diminished, since he is no longer retaining sodium?
Sodium intake itself has no direct effect on renal sodium output. Any influence of sodium intake on renal sodium output is always mediated through effective vascular volume, because balance between sodium intake and sodium output influences effective vascular volume. If we think of renal sodium output in terms of model B ( Figure 10.3 ), the height of the water column represents effective vascular volume. Just as the only factor that influences water output in model B is the height of water column, the only factor that influences renal sodium excretion directly is effective vascular volume. The higher the effective vascular volume, the higher is the urine sodium; the lower the effective vascular volume, the lower is the urine sodium. Once this relationship is understood, the question regarding subjects A and B is easy; subject A has higher effective vascular volume, because he is excreting more sodium in urine than subject B.
The reason for the widespread belief that sodium intake and output is a better predictor of effective vascular volume is likely to be due to the misuse of the term renal sodium retention. The train of logic goes as follows. First, sodium intake in excess of sodium output represents sodium retention. Second, sodium retention in most clinical situations is due to reduced renal excretion of sodium. Third, reduced renal excretion of sodium is most often due to low effective vascular volume. Fourth, therefore sodium retention is most often due to low effective vascular volume. Finally, any sodium retention, i.e., positive sodium balance, signifies low effective vascular volume. Although the fatal error in reasoning is in the final step, the major mistake occurred in the thinking that sodium retention is always due to reduced renal sodium output, instead of thinking that it is usually due to reduced renal sodium output.
Does Overflow Mechanism Explain Ascites Formation?
The overflow theory of ascites formation states that an important mechanism of sodium retention in ascites formation in cirrhosis of the liver is primary renal sodium retention due to a diseased liver. The argument is based on the data from drug-induced cirrhosis of the liver in dogs, which developed ascites and salt retention in the absence of signs of reduced effective vascular volume, such as elevated PRA and plasma aldosterone concentration. On the basis of these observations, the authors of the study concluded that renal sodium retention could not have been a response to volume depletion caused by loss of fluid to the peritoneal cavity (i.e., under-filling), and therefore renal salt retention was a primary event that led to increased effective vascular volume resulting in the ascites formation (i.e., overflow). Two major errors were made in this line of thinking.
The first error is the assumption that the proof of salt retention (i.e., positive salt balance) due to the under-filling mechanism requires the presence of overt volume depletion. The following example will demonstrate how effective vascular volume could remain “normal” during the period of positive salt balance by an under-filling mechanism. Assume that a person, who has been in salt balance while ingesting 15 g of salt a day and excreting 15 g a day, develops chronic diarrhea and loses 5 g of salt in the stool daily. The net GI absorption of salt after subtracting the amount lost in the stool would then be 10 g per day, and he would excrete 10 g of salt in the urine per day. His effective vascular volume during diarrhea will be lower than it was before the start of diarrhea, but not lower than that of a person ingesting only 10 g of salt per day without diarrhea. Likewise, if a person ingesting 15 g of salt per day develops ascites slowly, and sequesters 5 g of salt daily in the peritoneal space, his effective vascular volume would not be lower than a person who ingests 10 g of salt a day without development of ascites. In both cases, ingestion of 15 g of salt, in the absence of abnormal salt loss, would have resulted in excretion of 15 g of salt. With ascites formation or diarrhea, the kidney excretes 10 g instead of 15 g, because the effective vascular volume is slightly lower than in a person without ascites formation or diarrhea. In both cases, the reduction in renal sodium output clearly was in response to “under-filling,” even though there would be no discernible volume depletion. In both examples, effective vascular volume was maintained sufficiently high to allow renal excretion of 10 g of salt a day. If plasma renin activity were measured during the period of sodium retention in these examples, it would have been normal. The absence of apparent volume depletion in any edema-forming conditions does not prove that the kidney did not retain sodium in response to a volume stimulus.
The second error is the failure to recognize that the infinite gain control mechanism operates in ascites formation by the under-filling mechanism. If the salt intake and the function curve for renal salt output remain unchanged, effective vascular volume would return to the baseline when steady-state is achieved. The sequence of events would be as follows. Ascites formation by the transudation of fluid from the vascular space into the peritoneal cavity would reduce effective vascular volume, which reduces renal salt output. The normal salt intake with reduced renal salt output causes salt retention, which would tend to increase effective vascular volume. However, as long as effective vascular volume remains lower than the baseline value, renal salt output will remain lower than the baseline, and the positive salt balance will continue. Only when effective vascular volume returns to the baseline, will renal salt output return to the baseline, and the salt retention will stop. Thus, at equilibrium, effective vascular volume in any patient with ascites would be normal, unless he is treated with a low-salt diet or a diuretic.
Main Mechanism of Nephrotic Edema: Low Oncotic Pressure versus Primary Renal Salt Retention
It has been suggested that primary renal salt retention plays a more important role in the formation of nephrotic edema than low oncotic pressure which would cause secondary renal salt retention. This belief is based on the observation that in untreated subjects with nephrotic syndrome, plasma renin activity is often reduced. The reasoning goes this way: if low oncotic pressure is the primary cause of edema formation, transudation of fluid from the vascular space into the interstitial space would reduce effective vascular volume, which is expected to increase plasma renin activity; the suppressed plasma renin activity, therefore, is the evidence for primacy of primary salt retention in the pathogenesis of nephrotic edema.
The flaw of this reasoning lies in the faulty assumption that edema due to low oncotic pressure must be accompanied by low effective vascular volume. The truth is that nephrotic edema entirely due to low oncotic pressure would not maintain low effective vascular volume, unless the patient is treated with salt restriction or a diuretic. The compensation mechanism against a low effective vascular volume in such situations would be the infinite gain control mechanism.
Imagine a patient in a third world country develops nephrotic syndrome. The patient is not treated with a diuretic, and he does not know the value of a low-salt diet in treating edema. He continues to ingest a diet that contains the usual amount of salt. Yet almost invariably, his renal salt output returns to the baseline and salt retention stops. Otherwise, the patient will develop relentless sodium retention and progressive edema, and will die in a relatively short period with massive edema. Since a slight reduction in effective vascular volume diminishes renal sodium excretion to virtually zero, restoration of renal sodium excretion to a usual normal value is proof that effective vascular volume has been restored to normal. Plasma renin activity at this point would be normal.
If a patient now develops a renal disease that results in primary renal salt retention, edema will be worse and effective vascular volume will be greater than the usual value, which would cause suppression of plasma renin activity. When the natriuretic effect of the increased effective vascular volume is sufficient to counterbalance the sodium retaining effect of the renal disease, renal sodium output will increase further to achieve a new balance. At this point, edema will not progress any further. The presence of suppressed plasma renin activity in a patient with nephrotic syndrome is a strong indication for the presence of primary renal sodium retention, but it does not prove that low oncotic pressure is not the main cause of edema formation. Indeed, primary renal Na retention alone, e.g., acute glomerulonephritis, rarely causes as severe edema as a non-nephrotic cause of low oncotic pressure, such as severe protein malnutrition.
Clinical Application of External Balance
A serious topic discussed below utilizes the principles of external balance to explain physiological concepts and clinical manifestations of certain disorders of fluid and electrolyte balance.
Determinants of Sodium Delivery to the Cortical Collecting Duct and Renal K Excretion
According to the principles outlined at the beginning of this chapter, in the steady-state, sodium output is equal to sodium intake, including all salt-retaining and salt-wasting conditions, such as hyperaldosteronism and hypoaldosteronism. One might therefore conclude that sodium delivery to the cortical collecting duct cannot remain chronically abnormal unless intake is altered. However, the principles discussed in earlier sections predict that total sodium output will eventually equal intake; it does not predict that sodium delivery to any particular nephron site cannot remain chronically altered.
In the steady-state, a patient receiving chronic diuretic therapy or one with primary hyperaldosteronism will excrete the same amount of sodium as before the abnormalities developed, if the intake remains the same. In both states, however, a greater amount of sodium would be reabsorbed at the collecting duct because of the increased aldosterone effect, but the amount excreted in the final urine cannot be more or less than the intake. To satisfy both conditions, sodium delivery to the collecting duct at the time of balance restoration must be increased in hyperaldosteronism, and decreased in hypoaldosteronism. Primary hyperaldosteronism will be used as an example to explain this.
The initial abnormality in primary hyperaldosteronism is increased salt reabsorption, mainly at the cortical collecting duct, resulting in reduced salt output. The consequent positive salt balance increases effective vascular volume, which inhibits the proximal tubular salt reabsorption, resulting in increased delivery of salt to the cortical collecting duct. With the increased delivery of salt, the amount of salt that escapes into the urine is more now than at the beginning, but still less than intake because of increased salt reabsorption in the collecting duct. As long as urinary excretion of salt is less than intake, net positive salt retention continues, causing further increase in effective vascular volume. A higher effective vascular volume further inhibits proximal tubular salt reabsorption, causing even greater increase in the distal delivery of salt. The process will continue, with progressive increase in effective vascular volume and further increase in salt excretion. Only when excretion of salt is equal to intake will positive salt balance stop. At equilibrium, salt output equals salt intake, but the quantity of salt delivered to the collecting duct remains increased.
In the case of therapy with a loop diuretic or a thiazide diuretic, initially salt delivery to the collecting duct would be greatly increased; during this period salt balance will be negative. The ensuing volume depletion activates salt-retaining mechanisms at the proximal tubule, and also stimulates aldosterone secretion causing increased reabsorption of salt in the cortical collecting duct. One might predict that in a steady-state, sodium delivery to the collecting duct would be normalized as the two opposing effects cancel out each other’s effect. However, as long as the increased aldosterone secretion caused by volume depletion increases reabsorption of Na in the cortical collecting duct, Na delivery to the collecting duct must remain increased, in order to have a normal amount of Na excretion in the final urine. In other words, the combined effect of increased proximal Na reabsorption and decreased Na reabsorption by the diuretics would be chronic increase in Na delivery to the cortical collecting duct. Normal delivery of sodium accompanied by increased reabsorption of sodium at the cortical collecting duct would result in reduced excretion of sodium in the final urine; this is impossible.
For the same reasons, sodium delivery to the cortical collecting duct remains reduced chronically in states of hypoaldosteronism, such as Addison’s disease. Because the Na reabsorption at the cortical collecting duct is reduced, the only way to have the same normal amount of Na excretion in the final urine is to have reduced delivery of Na to the collecting duct.
Two most important factors that influence renal K excretion are the amount of Na delivery to the cortical collecting duct and aldosterone concentration. Most clinical states that cause increased renal excretion of K are accompanied by increased Na delivery and increased aldosterone, whereas conditions characterized by reduced renal K excretion are accompanied by reduced Na delivery and a low plasma aldosterone or an impaired aldosterone effect. Renal K excretion is unaffected when these two factors are altered in opposite directions. In a high-salt diet sodium delivery to the cortical collecting duct is increased, but aldosterone secretion is reduced, resulting in a normal K excretion. A salt restriction reduces sodium delivery to the cortical collecting duct, but the aldosterone secretion is increased, resulting in a normal K excretion ( Table 10.3 ).
| Clinical States | Na Delivery to CCD | Aldosterone Effect | Urine K Excretion |
|---|---|---|---|
| Hyperaldosteronism | Increased | Increased | Increased |
| Diuretics | Increased | Increased | Increased |
| Hypoaldosteronism | Decreased | Decreased | Decreased |
| K sparing diuretics | Decreased | Decreased | Decreased |
| Pendred syndrome | Decreased | Increased | Normal |
| High-salt diet | Increased | Decreased | Normal |
| Low-salt diet | Decreased | Increased | Normal |
Enigma of Pendred Syndrome
Pendred syndrome is a genetic disorder characterized by goiter and sensorineural hearing loss, responsible for about 7.5% of congenital hearing loss. The disease is named after Vaughan Pendred, an English physician who first described the condition in 1896. The mechanism of the disease is a defect in an anion exchanger pendrin, which is located in the inner ear, thyroid gland, and the cortical collecting duct. The exchanger, located on the luminal membrane of beta-intercalated cells, appears to play an important role in the reabsorption of chloride, and therefore indirectly of sodium.
Despite the common belief that chloride reabsorption in the collecting tubule duct depends mainly on the paracellular chloride channel, supportive evidence is not very strong. For example, in severe volume depletion states, urine chloride concentration is as low as 2 mEq/L. The Nernst Equation would predict that such a low chloride concentration, to be explained entirely by a passive mechanism through the paracellular pathway, would require the transepithelial voltage of over 100 mV. The highest transepithelial voltage observed in states of high aldosterone effect is about 60 mV. It is likely that other mechanisms exist for reabsorption of chloride in the cortical collecting duct, and the most likely one is pendrin-mediated chloride reabsorption. If pendrin were such an important transporter for reabsorption of chloride in the cortical collecting duct, why isn’t a pendrin defect associated with any electrolyte abnormality? Indeed, the apparent absence of electrolyte abnormalities is one of the reasons why Pendred syndrome, well-known among specialists of ENT, is not widely appreciated among nephrologists.
The most common and apparent electrolyte abnormality associated with impaired renal salt transport is hypokalemia, but Pendred syndrome is not known to be associated with hypokalemia. The following is the likely scenario. A pendrin defect would reduce the overall reabsorption of NaCl in the cortical collecting duct, and the ensuing volume depletion would stimulate renin and hence aldosterone. However, unlike defects in salt transport caused by impaired salt reabsorption in the distal convoluted tubule (Gitelman’s syndrome) or the thick ascending limb of Henle (Bartter’s syndrome), both of which are characterized by increased salt delivery to the cortical collecting duct, the delivery of salt to the cortical collecting duct in Pendred syndrome would be reduced. That is because the site of defect in salt transport is the cortical collecting duct itself. According to the principle of external balance, in the long run salt intake must equal salt output, no matter what and where defects in renal salt transport may be. Thus, a patient with Pendred syndrome would be excreting the normal amount of salt in the final urine. The excretion of the normal amount of salt and the reduced salt reabsorption at the cortical collecting duct is possible if the amount delivered to the cortical collecting duct is reduced. The end result is that patients with Pendred syndrome would have hyperaldosteronism, but reduced delivery of salt to the collecting duct. There has been no measurement of plasma aldosterone in patients with Pendred syndrome, but effective vascular volume is likely to be reduced and plasma aldosterone is likely to be increased. As supportive evidence, in a study of 21 patients with Pendred syndrome, not a single subject was shown to have hypertension.
Is it possible that salt reabsorption at the cortical collecting duct is not reduced in Pendred syndrome because of the two opposite influences, a high aldosterone state increasing salt reabsorption and a defective pendrin impairing salt reabsorption? That is unlikely because reduced salt delivery with normal salt reabsorption at the cortical collecting duct would mean reduced salt excretion. Remember that in a steady-state final urine sodium excretion is always normal. Is it possible that salt delivery to the cortical collecting duct is normalized in a steady-state? Again, it is unlikely, because normal salt delivery would mean normal effective vascular volume, and then aldosterone secretion cannot be increased. In the end, in a steady-state in Pendred syndrome, there must be some volume depletion accompanied by hyperaldosteronism. At equilibrium renal K excretion in Pendred syndrome would be normal, because two main regulators of renal K excretion are altered in opposite directions; aldosterone is increased and Na delivery to the cortical collecting duct is reduced. The situation would be analogous to a person on a low-salt diet, in which aldosterone is increased but sodium delivery is reduced ( Table 10.3 ). Thus, the patient with Pendred syndrome would be normotensive (low normal blood pressure) and normokalemic, and have no apparent electrolyte abnormalities.
In a recent case report, a patient with Pendred syndrome treated with a thiazide diuretic developed severe hypokalemia (serum K 2.2 mEq/L) and signs of profound volume depletion. The likely explanation for severe potassium depletion is that the patient has impaired salt transport in both the distal convoluted tubule and collecting duct. Severe renal K-wasting occurred because sodium delivery to the cortical collecting duct was increased by a thiazide diuretic in the setting of high aldosterone. In another report, a patient with Pendred syndrome developed life-threatening metabolic alkalosis during intercurrent illnesses, indicating the importance in chloride reabsorption.
Hypoxemia is necessary to restore balance between oxygen supply and oxygen demand
While the principle of external balance is most useful in explaining homeostatic mechanisms of fluid and electrolyte balance, the same principle applies to restoration of balances in other homeostatic mechanisms. The following example illustrates the mechanism by which a patient with severe lung disease can maintain the normal supply of oxygen necessary to sustain life.
The basal oxygen consumption of a person with advanced lung disease is no less, perhaps slightly greater because of the increased work of breathing, than that of a healthy individual. This means that the diseased lung somehow takes up a normal amount of oxygen. How does this happen? Here is the explanation. A normal person who has alveolar ventilation of 4 liters a minute needs an uptake of 200 ml of oxygen per minute at the basal state. The oxygen content of one liter of inspired air at an atmospheric pO 2 of 150 mmHg is 200 ml, and the oxygen content the expired air is about 150 ml per liter with the pO 2 at 110 mmHg. With an alveolar–arterial pO 2 gradient of 10 mmHg, the arterial pO 2 would be about 100 mmHg. This means that each liter of ventilated air has resulted in uptake of 50 ml of oxygen or total of 200 ml of oxygen by 4 liters of alveolar ventilation. When alveolar ventilation is reduced to 2 liters per minute, how is it possible to extract the same 200 ml of oxygen? A quick calculation will indicate that, in order to extract the same 200 ml of oxygen, each of 2 liters of alveolar ventilation must result in an uptake of 100 ml of oxygen. Since the inspired air has still the same oxygen content at pO 2 150 mmHg, the expired air must have a pO 2 of 70 mmHg. This requires alveolar pO 2 to decrease to 70 mmHg. Since arterial pO 2 is about 10 mmHg lower, it must decrease to 60 mmHg. In other words, hypoxemia is a necessary condition for restoring oxygen uptake to normal.
How does the body know to reduce the arterial pO 2 precisely to the right level to restore oxygen balance? The body does not know, but the general principle of external balance allows automatic restoration of balance. Let us suppose that alveolar ventilation drops to half that of normal. Initially there will be a discrepancy between the body’s demand for oxygen and oxygen supply. The reduced supply in the face of unchanged demand will decrease arterial pO 2 . A lower arterial pO 2 means a lower alveolar pO 2 , which permits greater uptake of oxygen for a given volume of alveolar ventilation. As long as oxygen uptake is less than oxygen demand, arterial pO 2 will keep decreasing, with further reduction in alveolar pO 2 . Only when the alveolar pO 2 decreases sufficiently to allow oxygen uptake to meet oxygen demand, is a new balance achieved between oxygen demand and oxygen uptake.
Will this mechanism of external balance restore oxygen uptake at any severity of lung disease? The answer is no. What would happen if the alveolar ventilation decreased to 1 liter per minute? In order to have an uptake of 200 ml of oxygen by 1 liter of alveolar ventilation, each liter now extracts the entire oxygen content of the inspired air, since the total content of oxygen at pO 2 of 150 mmHg is 200 ml. This would mean that alveolar pO 2 must be 0 mmHg, clearly an impossible situation, since arterial pO2, always lower than alveolar pO2, must be a negative number. Long before the alveolar pO 2 drops to 0 mmHg, the person will die of severe hypoxia.
Mechanism of Volume Expansion in SIADH
Ample evidence exists that patients with SIADH with chronic hyponatremia are volume expanded. Evidence for expanded volume includes low plasma creatinine, low plasma urea, and low plasma uric acid, all caused by increased renal clearances. However, persistence of chronic volume expansion in SIADH would seem paradoxical. In the absence of disorders that cause primary renal Na retention, such as renal diseases and primary hyperaldosteronism, would the normal kidney not promptly eliminate the excess Na until the volume is restored to normal?
The explanation for the persistence of volume expansion in SIADH lies in the antinatriuretic effect of hyponatremia. The sequence of events is as follows. Initially, water retention causes hyponatremia and volume expansion. Volume expansion causes sodium diuresis, resulting in further reduction in serum sodium. But as serum sodium declines, the antinatriuretic effect of hyponatremia opposes the natriuretic effect of volume expansion. When these two opposing effects are equal, renal Na excretion returns to the baseline value, and a new balance is established, with renal Na excretion equaling salt intake. In other words, when renal Na excretion returns to the baseline, the effective vascular volume must be expanded.
Mechanism of Volume Depletion in Chronic Hypernatremia
In the presence of normal renal function, chronic hypernatremia is always accompanied by reduced effective vascular volume, and the degree of reduction in effective vascular volume is proportionate to the level of serum sodium. Exceptions are chronic hypernatremia in renal failure or hypernatremia that develops as a result of chronic administration of a large amount of sodium. Even in the latter condition, the effective vascular volume would be lower with high serum sodium than with normal serum sodium for the same amount of sodium administered. Although some authors postulate that the effective vascular volume is normal in essential hypernatremia, this rule applies to all hypernatremic states including essential hypernatremia. The following analysis will elaborate on the mechanism.
As hyponatremia is antinatriuretic, hypernatremia is natriuretic. For this reason, renal sodium excretion would be increased in normovolemic hypernatremia, as long as the kidney function is normal. Increased renal sodium excretion with the usual intake of sodium would reduce effective vascular volume. Volume depletion would reduce renal sodium excretion and oppose the natriuretic effect of hypernatremia. As long as renal sodium excretion exceeds sodium intake, volume depletion will become progressively greater. Only when volume depletion is sufficiently great to exactly oppose the natriuretic effect of hypernatremia, does renal sodium excretion return to the baseline, equaling the intake. At this point, a new sodium balance is struck between sodium intake and output, but at the expense of volume depletion. Since the natriuretic effect of hypernatremia is proportionate to the degree of hypernatremia, the magnitude of volume depletion needed to counterbalance the natriuretic effect of hypernatremia must also be proportionately great, to match the degree of hypernatremia when the new sodium balance is achieved. In other words, the more severe the hypernatremia, the greater is the volume depletion in a steady-state.
It has been suggested that patients with essential hypernatremia are euvolemic, because hypernatremia in this condition is a result of the resetting of the osmostat. Resetting means that the osmostat is regulated normally, but at higher than usual serum sodium concentrations. More recent evidence indicates that essential hypernatremia is caused by defects in the osmoreceptors, not the resetting. However, regardless of its pathogenetic mechanism, chronic volume depletion is inevitable in essential hypernatremia if renal function is normal. Mild volume depletion can escape detection even by careful physical examination. For example, a small amount of a diuretic, e.g., 50 mg hydrochlorothiazide, can reduce effective vascular volume sufficiently for the kidney to sense a reduction in volume, and thereby reduce clearances of urea, creatinine, and uric acid. Yet a careful physical examination by an astute physician will not detect signs of dehydration without the help of laboratory tests, e.g., a higher serum urate. Indeed, it has been shown that most patients with essential hypernatremia have laboratory evidence of volume depletion when the data are carefully analyzed.
External Balance of Protons
Determination of external balance of most univalent ions such as sodium, potassium, and chloride is straightforward; intestinal absorption is complete and they are eventually eliminated from the body since none is metabolized. Balance of polyvalent inorganic ions such as calcium, magnesium and phosphate is more complicated, because of incomplete intestinal absorption. External balance of acids and bases is even more complicated than that of polyvalent ions, because of uncertainties in their intestinal absorption and variations in their metabolism after absorption.
In the steady-state, hydrogen ions enter the body through ingestion of acid or are created endogenously through metabolism. The pH of food offers little guidance to its character as a donor of acid or alkali. Most fruit juices have low pH because of the organic acids in them, but overall they are contributors of alkali, because organic acid is metabolized to CO 2 , while organic anions are metabolized to bicarbonate. Sulfur-containing amino acids are mostly metabolized to produce sulfuric acid, but not all sulfur is metabolized to sulfuric acid.
Under steady-state conditions, net acid production must equal net acid excretion, and the traditional view of the external balance of acid–base has been as follows. Acids are produced from three main sources: sulfuric acid derived from the metabolism of sulfur-containing amino acids; incompletely metabolized organic acids; and acid (or alkali) from the diet absorbed in the intestine. Acids are excreted either in the form of ammonium or titratable acid, while a small amount of alkali is lost in the urine as bicarbonate. Hence, the total acid excretion measured as the sum of urine ammonium and titratable acid minus bicarbonate is called net acid excretion. However, this traditional view of the acid–base balance must be re-evaluated in light of conceptual uncertainties of this approach, and methodological limitations in the measurement of parameters of acid–base balance by conventional techniques. The following discussion will shed some light on these uncertainties and limitations.
Measurement of Net Acid Excretion
The concept of titratable acid is straightforward. The pH of urine following glomerular ultrafiltration is the same as that of plasma, but decreases progressively with addition of H + by tubular secretion. Most of the secreted H + is buffered by HCO 3 − , and this represents indirect reabsorption of HCO 3 − . As urine pH falls further with tubular secretion of H + , other urinary buffers are titrated to retard a fall in urine pH. Addition of alkali to the urine until its pH is the same as that of the plasma measures the titratable acid. This back-titration of urine releases all the H + titrated by non-bicarbonate buffers except those in the form of NH 4 + , which is not titrated because of its high pK (9.2), and therefore is measured separately.
However, the measurement of titratable acid, ammonium, and bicarbonate does not accurately reflect net acid excretion by the kidney, for the following reasons. First, there is a technical problem with the measurement of titratable acid. Addition of alkali to the urine causes partial precipitation of some urine calcium with HPO 4 2− . Selective depletion of HPO 4 2− causes conversion of H 2 PO 4 − to HPO 4 2− with liberation of protons, leading to overestimation of titratable acid. Furthermore, titration of urine to the plasma pH results in titration of 1/64th of urinary ammonium (calculated with the pKa of ammonium of 9.2), resulting in further overestimation of titratable acid; this error is usually negligible, but would be substantial when urine contains a large amount of ammonium.
A potentially more serious source of error is the presence of buffers other than ammonium that are not titrated when urine pH is increased to 7.4. The original assumption that ammonium is the only urinary buffer that escapes titration during the measurement of titratable acid has not been fully proven. Normal urine contains various amines such as ethanolamine, phosphoethanolamine, methylamine, and dimethylamine. Urinary excretion of these substances would represent acid excretion, as does the excretion of ammonium. However, titration of urine to pH 7.4 would not detect the presence of such substances. The individual urine concentration of each of these substances appears to be quite low individually, but the amount might be substantial collectively.
Sources of Acid
Sulfuric Acid
The metabolism of sulfur-containing amino acids produces sulfuric acid:
RN − S → CO 2 + UREA + H 2 SO 4 .
The resulting H 2 SO 4 is buffered by the body alkali, mainly HCO 3 − . Previously it was assumed that virtually all urinary sulfates originate from sulfur-containing amino acids. However, this assumption is wrong, since soft drinks regularly contain sulfate as a preservative, and persons consuming large quantities of soft drinks could acquire a substantial amount of sulfate. In one such study, the average amount of urinary sulfate originating from soft drinks was estimated to be 15 mEq/day. Furthermore, the metabolism of sulfur-containing amino acids does not always result in production of sulfuric acid, because some of the sulfur is excreted in a neutral form, such as cystine, taurine or sulfate conjugate. Each mmol of sulfur metabolized to H 2 SO 4 produces 2 mEq of protons in the following reaction:
H 2 SO 4 → SO 4 = + 2 H +
On the other hand, the sulfate conjugation reaction consumes a proton; the result is net production of only 1 mEq of proton for each mole of sulfur oxidized when the final product is sulfate conjugate.
R − OH + SO 4 = + H + → R − O − SO 3 −
Related posts:
Solute Transport, Energy Consumption, and Production in the Kidney
Mechanisms of Ion Transport across Cell Membranes
Molecular and Cellular Mechanisms of Kidney Development
Physiopathology of Potassium Deficiency
Clinical Disturbances of Phosphate Homeostasis
Pathogenesis and Treatment of Nephrolithiasis
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
