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ECF Volume Regulation

  • Changes to the volume of the extracellular fluid (ECF) require addition or subtraction of not only water but also osmolytes. The dominant ECF osmolyte is sodium and thus ECF volume regulation is achieved largely by modulating the amount of ECF sodium. However, an under-appreciated aspect of ECF volume regulation is that following addition or subtraction of sodium to ECF, proper functioning of osmoregulatory mechanisms are required to ensure that a corresponding volume of water is added to or subtracted from the ECF. The physiological mechanisms that ultimately sense ECF volume and effect changes to ECF sodium are multiple but several important themes exist in how they assess the ECF volume and modify the amount of ECF sodium.
ECF Volume: Water with osmolytes
  • Overview
    • ECF volume is ultimately made up of the molecules within it; however, the largest and most important contributor is water. This may lead one to think that the task of modulating ECF volume is one of controlling free water intake and excretion. While intuitive, this thought is wrong. In fact, it the presence of osmolytes that control the presence of ECF volume.
  • Free Water does not modulate ECF Volume
    • Addition and subtraction of free water from the ECF yields only minor changes to the ECF volume. The reason is that any free water added to the ECF rapidly osmotically equilibrates with the intracellular space, a fluid compartment that is much larger than the extracellular fluid compartment (See: Body Fluid Compartments). For example, if one were to add a liter of free water to the ECF, this would reduce the ECF osmolarity compared to that of the intracellular fluid (ICF). In response, free water would osmotically move into the ICF to equilibrate the ECF and ICF osmolarities. Because the ICF is nearly twice the size of the ECF, most of the 1 liter of free water added to the ECF would move to the ICF, yielding little in the way of additional ECF volume.
  • ECF Volume depends on the presence of osmolytes
    • Given the tendency of free water to rapidly equilibrate between the ECF and ICF, how can water be kept within the ECF? The answer is that the free water must be added with osmolytes. If 1 liter of water is added to the ECF and osmolytes are added with it so that the added fluid is isoosmotic with that of the ICF then there would be no osmotic driving force for the added fluid volume to leave the ECF. Therefore, the key to controlling the ECF volume is the regulated addition and subtraction of omsolytes with water, not free water on its own.
Sodium: The dominant ECF osmolyte
  • The major cationic osmolyte of the ECF is sodium with negligible contributions from potassium, calcium, and magnesium. The major anionic osmolyte of the ECF is chloride with important but minor contributions from bicarbonate and negatively-charged plasma proteins.
  • While all of these ions are osmotically active, the body solely uses its control of sodium to modulate ECF volume. The reason involves the fact that the extracellular fluid ultimately must be electroneutral, meaning the that the numbers of positively and negatively charged osmolytes must be equivalent. Extracellular fluid electroneutrality is achieved automatically because tubular resorption of chloride largely follows that of sodium passively. Thus, whatever amount of sodium is resorbed, a sufficient amount of chloride will automatically be resorbed to achieve electroneutrality of the extracellular fluid.
  • Given this property, sole control over sodium is sufficient to modulate the addition and subtraction of osmolytes to the ECF. In this way, sodium can be thought of as the dominant extracellular osmolyte and clinically the blood sodium concentration is followed as the primary proxy for total ECF osmolarity.
ECF Volume Regulation: A two-step mechanism
  • Overview
    • How does the body coordinate regulated addition and subtraction of water together with sodium to the ECF? It appears to do so by a two-step mechanism: First, the total amount of ECF sodium is changed, then a corresponding volume of free water is added or subtracted from the ECF. A deep understanding of this two-step mechanism is perhaps one of the key points in understanding renal physiology so careful attention to the following should be payed.
  • Step 1: Modulation of total ECF sodium amount
    • When the body wishes to change the ECF volume its first step is to modify the total amount of sodium in the extracellular fluid. Because the body cannot control how much sodium is being added to the ECF (i.e. there is no equivalent of "thirst" for sodium), the only mechanism available is to modulate the rate of urinary sodium excretion and hope for the best in terms of behavorial sodium ingestion. For example, when ECF volume is low, the body reduces urinary sodium excretion to a minimum and hopes that more sodium will be ingested. Conversely, when the ECF volume is excessive, the body increases urinary sodium excretion and hopes that the individual will not eat incredible amounts of salt. In this way, the body can exert control of the total amont of sodium in the ECF by modulating urinary sodium excretion.
  • Step 2: Modulation of Free Water
    • However, simply changing the total amount of sodium in the ECF would be useless if it were not accompanied by a corresponding change in the volume of ECF water. As discussed above, to change the ECF volume both sodium and water must be coordinately added or subtracted from the ECF. The key concept to understand is that this Step 2 of volume regulation is essentially automatically preformed by the mechanisms of ECF Osmoregulation. When the total amount of ECF sodium is increased (Step 1), this boosts the ECF osmolarity, triggering the thirst sensation and renal generation of a concentrated urine. Together the thirst mechanism along with urine concentration yield rapid net addition of free water to the ECF, an amount perfectly osmotically matched to the amont of sodium added by Step 1. Together, Step 1 (sodium regulation) and Step 2 (osmoregulation) work together to coordinately add/subtract sodium and water to the ECF and thus control its volume.
  • Final Points
    • In discussions of ECF volume regulation, nearly all the focus is on Step 1 (sodium regulation) and little attention is payed to Step 2 (osmoregulation), yielding confusion for some students. Part of this may result from the following quirk of physiology: Step 1 (sodium regulation) is often dysregulated in pathological contexts; however, Step 2 (osmoregulation) almost always works perfectly. As discussed below, part of the reason for this is that while cells can directly sense the osmolarity of the ECF, the total ECF volume is essentially impossible to measure directly. Thus, a variety of physiological proxy variables are used to assess the ECF volume and these proxy variables can become invalid in certain pathological situations.
ECF Volume Regulatory Sensor-Effector Mechanisms
  • Overview
    • As seen above, changing the amount of ECF sodium (Step 1) will put into motion an eventual corresponding change in ECF volume. Consequently, it is no surprise that the body uses its capacity to modulate ECF sodium as its primary mechanism for regulating ECF volume. However, a major question is how ECF volume is sensed, and how is this information used to modulate the quantity of ECF sodium. It appears that multiple independent physiological sensors exist for assessing the ECF volume, each with its own mechanism for modulating ECF sodium. Working together these sensor-effector pairs are largely able to maintain fairly good control over ECF volume. Although these mechanisms are distinct there are several important themes to what they are actually sensing and how they ultimately control the quantity of ECF sodium.
  • What is sensed: Arterial Pressure
    • A major concept to appreciate is that there is no clear way for any of these sensors to actually assess the ECF volume. As a result, these sensors use a variety of physiological proxy variables that under normal circumstances track changes in ECF volume. The common theme to these proxy variables is that they largely assess the systemic arterial pressure at the anatomical location where these sensors exist. As discussed in the 'ECF Volume and Arterial Pressure' section of Systemic Arterial Pressure - Long-term Regulation the systemic arterial pressure varies proportionally with the ECF volume under normal circumstances. Consequently, when the blood pressure is high, these sensors assume that there is excessive ECF volume and when the blood pressure is low they assume that there is insufficient ECF volume.
    • The key caveat to this assumption is the phrase under normal circumstances as there are a variety of pathological scenarios in which the relationship between ECF volume and arterial pressure does not hold. In these scenarios, the body may begin to add sodium to the ECF even when the ECF volume is already expanded. Common clinical examples include left heart failure, nephrotic syndrome, and cirrhosis.
  • What is effected: Renal Sodium Excretion
    • Although each of these effector mechanisms utilizes a distinct mechanism for modulating ECF sodium, their common theme is they largely exert their effect by changing the rate of tubular sodium resorption. When ECF volume is high and thus arterial pressure is excessive, these sensor-effector mechanisms together yield reduced tubular sodium resorption and in turn a reduction in the ECF sodium amount. When ECF volume is low and thus arterial pressure is insufficient, these sensor-effector mechanisms together yield enhanced sodium resorption and in turn boost the ECF sodium amount.
  • Sensor-Effector Mechanisms