Regulation of Sodium Excretion

June 25, 2016 Cardiology, Critical Care, Nephrology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , , , , , , , , , , , , ,

Percentage of Sodium Reabsorbed

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The Goals of Regulation

The overriding goals of regulating sodium and water excretion are to support the requirements of the cardiovascular system. This is manifested in 3 ways: 1.the kidneys maintain a sufficient ECF volume to fill the vascular space (mean circulatory filling pressure); 2.keep the osmolality of the ECF at a level consistent with cellular health; and 3.limit the changes in renal blood flow (RBF) and GFR that might otherwise reach deleterious levels. The kidneys and the CV system work cooperatively to ensure that peripheral tissue is sufficiently perfused. An adequate circulating volume is one of the essential requirements for tissue perfusion and it is the kidneys that control this volume. Osmolality is the ratio of solute content to water content. Sodium and chloride together account for 80% of the normal extracellular solute; thus the excretion of sodium and water by the kidneys regulates osmolality in the tight range that is needed for the health of tissue cells. There is a separate goal of regulation that differs from those stated above. Variations in RBF and GFR are major means of regulating sodium excretion. However, the kidney cannot change blood flow and filtration to such extreme values that they compromise the metabolic health of the kidneys or interfere with the excretion of substances other than sodium, particularly organic waste.

Formulas for ECF Volume

There are some formulas showing the relationship between ECF solute content, ECF osmolality, and ECF volume. Since almost all of the ECF solute is accounted for by sodium and an equivalent number of anions (mostly chloride and bicarbonate), the amount of ECF solute is approximately twice the sodium content.

ECF osmolality = ECF solute content / ECF volume (Equation 7-1)

ECF volume = ECF solute content / ECF osmolality (Equation 7-2)

ECF volume ≈ 2 x Na content / ECF osmolality (Equation 7-3)

Therefore, in the face of tightly controlled ECF osmolality, ECF volume varies directly with sodium content. But how do the kidneys know how much sodium there is in the ECF? The detection of sodium content is indirect, based on a combination of assessing sodium concentration and vascular pressures. Glial cells in regions of the brain called the circumventricular organs have sensory Na+ channels that respond to and act as detectors of extracellular sodium concentration. The glial cells modulate the activity of nearby neurons involved  in the control of body sodium. There are also neurons in the hypothalamus contain the sensory Na+ channels that respond to the sodium concentration in the cerebrospinal fluid. Thus cells in or near the hypothalamus monitor extracellular sodium concentration.

The volume affects pressure in different regions of the vasculature. It is the presssure baroreceptors in these regions of the vasculature detect the vascular pressures.

Major Controllers of Sodium Excretion

Sympathetic Stimulation 

Vascular pressures are so important in regard to sodium excretion and because volume affect pressure in different regions of the vasculature, so the changes in ECF affects pressures (arterial and/or venous) and changes in pressure affect sodium excretion (Thread "Regulation of Arterial Pressure" at and thread "Mean Circulatory Filling Pressure and CVP" at

The vasculature and tubules of the kidney are innervated by postganglionic sympathetic neurons that release norepinephrine. In most regions of the kidney, norepinephrine is recognized by alpha-adrenergic receptors. In the renal vasculature activation of alpha1-adrenergic recpetors causes vasoconstriction of afferent and efferent arterioles. This reduces RBF and GFR.

GFR is a crucial determinant of sodium excretion. However, except in body emergencies such as hypovolemic shock, GFR is kept within rather narrow limits due to autoregulatory processes (detail for vascular autoregulatory regulation Thus although neural control does affect GFR, this component of sympathetic control is probably less important in normal circumstances than its effect on sodium reabsorption. Neural control of the renal vasculature is exerted primarily on blood flow in the cortex, allowing preservation of medullary perfusion even when cortical blood flow is reduced.

The proximal tubule epithelial cells are innervated by alpha1- and alpha2-adrenergic receptors. Stimulation of these receptors in the proximal tubule by norepinephrine activates both components of the main transcellular sodium reabsorptive pathway, that is, the sodium-hydrogen antiporter NHE3 in the apical membrane and the Na-K-ATPase in the basolateral membrane. The effects of sympathetic stimulation on cells in the distal nephron are less straightforward. However, the overall outcome of sympathetic stimulation of the kidney is clearly reduced sodium excretion.

The Renin-Angiotensin System

AII's function

  • Reduces the RBF and GFR
  • Stimulation of sodium tubular reabsorption
  • Stimulation of the CNS: salt appetite, thirst, and sympathetic drive
  • Stimulation of aldosterone secretion

The major determinant of circulating AII is the amount of renin available to form angiotensin I.

PS: "Control of the Circulating RAAS" is ready at

AII is a potent vasoconstrictor, acting on the vasculature of many peripheral tissues, the effect of which is to raise arterial pressure. It also vasoconstricts both cortical and medullary vessels in the kidney. This reduces total RBF and reduces GFR, thus decreasing the filtered load of sodium.

AII stimulates sodium reabsorption in both the proximal tubule and distal nephron. In the proximal tubule it stimulates the same transcellular transport pathway as does norepinephrine, namely NHE3 sodium/hydrogen antiporter in the apical membrane and the Na-K-ATPase in the basolateral membrane. In the distal tubule and connecting tubule, it stimulates the activity of sodium/chloride symporters and sodium channels (ENaC) that reabsorb sodium.

AII stimulates behavioral actions in response to fluid loss that increase salt appetite and thirst. AII acts on the circumventricular organs in the brain. These function as detectors of many substances in the blood and convey information to various areas of the brain. In situations of volume depletion and low blood pressure, when circulating levels of AII are high, a key effect, in addition to vascular and tubular actions is increased thirst and salt appetite. These pathways also increase sympathetic drive.

Aldosterone is a major stimulator of sodium reabsorption in the distal nephron, that is, regions of the tubule beyond the proximal tubule and loop of Henle. We focus here on the role of aldosterone in sodium reabsorption, but aldosterone has many other important actions, including stimulation of potassium excretion and acid excretion. The most important physiological factor controlling secretion of aldosterone is the circulating level of AII, which stimulates the adrenal cortex to produce aldosterone. But keep in mind that elevated plasma potassium concentration, atrial natriuretic factors are other stimulators of aldosterone secretion. The aldosterone has enough lipid character to freely cross principal cell membrane in the collecting ducts, after which it combines with mineralocorticoid receptors (aldosterone receptors) in the cytoplasm. After being transported to the nucleus, the receptor acts as a transcription factor that promotes gene expression of specific proteins. The effect of these proteins is to increase the activity or number of luminal membrane sodium channels (ENaCs) and basolateral membrane Na-K-ATPase pumps.


Dopaimine inhibits sodium reabsorption in the kidney. The dopamine that acts in the kidney is not released from neurons; rather it is synthesized in proximal tubule cells from the precursor l-DOPA. l-DOPA is taken up from the renal circulation and glomerular filtrate and converted to dopamine in the proximal tubule epithelium, and then released to act in a paracrine manner on nearby cells. Although the signaling path is not clear, it is known that increases in sodium intake lead to increased production of intrarenal dopamine. Dopamine has 2 actions, both of which reduce sodium reabsorption. First, it causes retraction of NHE antiporters and Na-K-ATPase pumps into intracellular vesicles, thereby reducing transcellular sodium reabsorption. Second, it reduces the expression of AII receptors, thereby decreasing the ability of AII to stimulate sodium reabsorption.

Other Controllers of Sodium Excretion


When ADH binds to V2 reecptors in tubular cells, it increases the production of c-AMP. This results in increased activity of the NKCC multiporter in the thick ascending limb and increased sodium channel (ENaC) presence in principal cells of the distal nephron, thereby increasing the uptake of sodium that, in both regions, is actively transported into the interstitium by the Na-K-ATPase. Interestingly, in the distal nephron the mechanism proceeds, not by moving ENaCs into the membrane, but rather by decreasing their removal and degradation.

Glomerulotubular Balance

Glomerulotubular balance (not to be confused with TG feedback described previously) refers to the phenomenon whereby sodium reabsorption in the proximal tubule varies in parallel with the filtered load, such that approximately two thirds of the filtered sodium is reabsorbed even when GFR varies. The mechanism by which reabsorption varies with filtered load appears to be via mechanotransduction by the microvilli on the apical surface of the proximal tubule cells, similar in principle to mechanotransduction by primary cilia in the macula densa. As flow changes, the amount of bending of the microvilli changes, and this is converted by cellular mechanisms into changes in transport.

Pressure Natriuresis and Diuresis

Because the kidneys are responsive to arterial pressure, there are situations in which elevated blood pressure can lead directly to increased excretion of sodium. This phenomenon is called pressure natriuresis, and because natriuresis is usually accompanied by water, it is often called pressure diuresis. This is an intrarenal phenomenon, not requiring external signaling. However, external signals normally override pressure natriuresis.

Natriuretic Peptides

Several tissues in the body synthesize members of a hormone family called natriuretic peptides. Key among these are atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). The main source of both natriuretic peptides is the heart. The natriuretic peptides have both vascular and tubular actions. The relax the afferent arteriole, thereby promoting increased filtration, and act at several sites in the tubule. They inhibit release of renin, inhibit the actions of AII that normally promote reabsorption of sodium, and act in the medullary collecting duct to inhibit sodium absorption. The major stimulus for increased secretion of the natriuretic peptides is distention of the atria, which occurs during plasma volume expansion. This is probably the stimulus for the increased natriuretic peptides that occurs in persons on a high salt diet.

Factors That Affect GFR

April 16, 2014 Physiology and Pathophysiology 1 comment , , ,

Glomerular filtration rate (GFR) is the amount of plasma ultrafiltrate formed each minute in both kidneys. For substances that are nontoxic and not metabolized by the body can be used to measure GFR. Renal plasma clearance of this substance can be the GFR. The renal plasma clearance is the volume of plasma from which a substance is completely removed by the kidney in a given amount of time. The amount of that substance that appears in the urine per unit of time is the result of the renal filtering of a certain number of milliliters of plasma that contained this amount.

The GFR in a healthy adult of average size is approximately 125 mL/min.

The factors governing filtration across the glomerular capillaries are the size of the capillary bed, the permeability of the capillaries, and the hydrostatic and osmotic pressure gradients across the capillary wall. That is,

GFR = k[(PGC –  PT) – (πGC – πT)]

PGC is the mean hydrostatic pressure in the glomerular capillaries, PT is the mean hydrostatic pressure in the tubule, πGC is the oncotic pressure of the plasma in the glomerular capillaries, and πT is the oncotic pressure of the filtrate in the tubule. Normally, the πT is negligible and can be ignored. So the GFR can be calced as follows:

GFR = k[(PGC –  PT) – πGC]

Factors that affect parameters in the formula above can affect GFR.

Renal plasma flow would alter GFR positively. Since the increase of renal plasma flow increase the amount of volume of plasma filtrated by glomerular in every unit of time. Besides, as the renal plasma flow increases, the rate of increase in πGC is slow down (flow-limited exchange) and the distance along the glomerular capillaries is prolonged, which makes filtrate increased and the GFR.Screen Shot 2015-02-11 at 6.19.00 PM

Factors that alter renal plasma flow such as constriction of renal blood arterial vessels, afferent arteriolar, low effective circulatory volume etc affect GFR as described above, and stimulation of the renal nerves (sympathetic efferent fibers) also cause the vasoconstriction of renal blood arterial vessels. Note that when the kidney is perfused at moderate pressures (90-220 mm Hg in the dog), the renal vascular resistance varies with the pressure so that renal blood flow is relative constant (auto-regualtion).

PS: the stimulation of renal sympathetic fibers increases secretion of renin, increases reabsorption of sodium by tubule directly, and decreases GFR.

Changes in glomerular capillary hydrostatic pressure would affect GFR directly as explained in the formula above. The constriction of efferent arteriolar would increase the glomerular capillary hydrostatic pressure and to maintain the GFR to some degree (When renal blood flow decreases, the constriction of efferent arteriolar due to effect of AngII help to maintain the GFR). Changes in Kf and hydrostatic pressure in Bowman's capsule would affect GFR.

Changes in glomerular capillary permeability and effective filtration surface area would affect GFR.

PS: At low perfusion pressures, angII also appears to play a role by constricting the efferent arterioles, thus maintaining the GFR. This is believed to be the explanation of the renal failure that sometimes develops in patients with poor renal perfusion who are treated with drugs that inhibit angiotensin-converting enzyme (that is, ACEIs).

Screen Shot 2016-07-10 at 7.32.03 PMWrite Again – GFR and Its Determinants

The glomerular filtrate contains most inorganic ions and low-molecular-weight organic solutes in virtually the same concentrations as in the plasma. It also contains small plasma peptides and a very limited amount of albumin. Filtered fluid must pass through a 3-layered glomerular filtration barrier. The first layer, the endothelial cells of the capillaries, is perforated by many large fenestrae ("windows"), like a slice of Swiss cheese, which occupy about 10% of the endothelial surface area. They are freely permeable to everything in the blood except cells and platelets. The middle layer, the capillary basement membrane, is a gel-like acellular meshwork of glycoproteins and proteoglycans, with a structure like a kitchen sponge. The third layer consists of epithelial cells (podocytes) that surround the capillaries and rest on the capillary basement membrane. The podocytes have an unusual octopus-like structure. Small "fingers," called pedicels (or foot processes), extend from each arm of the podocyte and are embedded in the basement membrane. Pedicels from a given podocyte inter-digitate with the pedicels from adjacent podocytes. The pedicels are coated by a thick layer of extracellular material, which partially occludes the slits. Extremely thin processes called slit diaphragms bridge the slits between the pedicels. Slit diaphragms are widened versions of the tight junctions and adhering junctions that link all contiguous epithelial cells together and are like miniature ladders. The pedicels form the sides of the ladder, and the slit diaphragms are the rungs. Spaces between slit diaphragms constitute the path through which the filtrate, once it has passed through the endothelial cells and basement membrane, travels to enter Bowman's space.

Both the slit diaphragms and basement membrane are composed of an array of proteins, and while the basement membrane may contribute to the selectivity of the filtration barrier, integrity of the slit diaphragms is essential to prevent excessive leak of plasma protein. Some protein-wasting diseases are associated with abnormal slit diaphragm structure. The selectivity of the filtration barrier is crucial for renal function. The barrier has to be leaky enough to permite free passage of everything that should be filtered, such as organic waste, yet restrictive to plasma proteins that should not be filtered. Selectivity of the barrier is based on both molecular size and electrical charge. The filtration barrier of the renal corpuscle provides no hindrance to the movement of molecules with molecular weights less than 7000 Da, including all small ions, glucose, urea, amino acids, and many hormones. The filtration barrier almost totally excludes plasma albumin. The hindrance to plasma albumin is not 100%, howevver, and the glomerular filtrate does contain extremely small quantities of albumin, on the order of 10 mg/L or less. This is only about 0.02% of the concentration of albumin in plasma. Some small substances are partly or mostly bound to large plasma proteins and are thus not free to be filtered, even though the unbound fractions can easily move through the filtration barrier. This includes hydrophobic hormones of the steroid and thyroid categories and about 40% of the calcium in the blood.

For molecules with a molecular weight ranging from 7000 to 70,000 Da, the amount filtered becomes progressively smaller as teh molecule becomes larger. Thus, many normally occurring small- and medium-sized plasma peptides and proteins are actually filtered to a significant degree. Moreover, when certain small proteins appear in the plasma because of disease, considerable filtration of these may occur as well.

Electrical charge is the second variable determining filterability of macromolecules. For any given size, negatively charged macromolecules are filtered to a lesser extent, and positively charged macromolecules to a greater extent, than neutral molecules. This is because the surfaces of all the components of the filtration barrier (the cell coats of the endothelium, the basement membrane, and the cell coats of the slit diaphragms) contain fixed polyanions, which repel negatively charged macromolecules during filtration. Because almost all plasma proteins bear net negative charge, this electrical repulsion plays a very important restrictive role, enhancing that of purely size hindrance. In other words, if either albumin or the filtration barrier were not charged, even albumin would be filtered to a considerable degree. It must be emphasized that the negative charges in teh filtration membranes act as a hindrance only to macromolecules, not to mineral anions or low-molecular-weight organic anions. Thus, chloride and bicarbonate ions, despite their negative charge, are freely filtered.

Direct Determinants of Glomerular Filtration Rate

The rate of filtration in any capillary bed, including the glomeruli, is determined by the hydraulic permeability of the capillaries, their surface are, and the net filtration pressure acting (NFP) across them.

Rate of filtration = hydraulic permeability X surface area X NFP

Because it is difficult to estimate the surface area of a capillary bed, a parameter called the filtration coefficient (Kf) is used to denote the product of the hydraulic permeability and surface area. The NFP is the algebraic sum of the hydrostatic pressures and the osmotic pressures resulting from protein – the oncotic, or colloid osmotic pressures, – on the 2 sides of the capillary wall. There are 4 pressures to consider: 2 hydrostatic pressures and 2 oncotic pressures. These are known as Starling forces. In the glomerular capillaries

NFP = (PGC – PBC) – (πGC – πBC)

where PGC is glomerular capillary hydrostatic pressure, πBC is the oncotic pressure of fluid in Bowman's capsule, PBC is the hydrostatic pressure in Bowman's capsule, and πGC is the oncotic pressure in glomerular capillary plasma. Because there is normally little total protein in Bowman's capsulre, πBC may be taken as zero. Accordingly, the overall equation for GFR becomes

GFR = Kf X (PGC – PBC – πGC)

Figure 2-5 shows that the hydrostatic pressure is nearly constant within the glomeruli. This is because there are so many capillaries in parallel, and collectively they provide only a small resistance to flow, but the oncotic pressure in the glomerular capillaries does change substantially along the length of the glomeruli. As water is filtered out of the vascular space it leaves most of the protein behind, thereby increasing protein concentration and, hence, the oncotic pressure of the unfiltered plasma remaining in the glomerular capillaries. Mainly because of this large increase in oncotic pressure, the NFP decreases from the beginning of the glomerular capillaries to the end.

Screen Shot 2016-07-11 at 3.38.42 PMThe NFP when averaged over the whole length of the glomerulus is about 16 mm Hg. This average NFP is higher than that found in most nonrenal capillary beds. Taken together with a very high value for Kf, it accounts for the enormous filtration of 180 L of fluid/day (compared wtih 3L/day or so in all other capillary beds combined).

The GFR is not constant but shows fluctuations in differing physiological states and in disease. Its value must be tightly controlled. To understand control of the GFR, it is essential to see how a change in any one factor affects GFR under the assumption that all other factors are held constant. It provides a checklist to review when trying to understand how diseases or vasoactive chemical messengers and drugs change GFR. It should be noted that the major cause of decreased GFR in renal disease is not a change in these parameters within individual nephrons, but rather a decrease in the number of functioning nephrons. This reduces Kf.

Filtration coefficient (Kf)

  • Glomerular diseases
  • Contraction of glomerular mesangial cells

Changes in Kf are caused most often by glomerular disease, but also by normal physiological control. The detials are still not completely clear, but chemical messengers released within the kidneys cause contraction of glomerular mesangial cells. Such contraction may restrict flow through some of the capillary loops, effectively reducing the area available for filtration, Kf, and hence GFR.

Glomerular Capillary Hydrostatic Pressure (PGC)

  • Renal artery pressure
  • Renal blood flow
  • Changes in the resistance of the AAs and EAs

Hydrostatic pressure in the glomerular capillaries is influenced by many factors. We can depict the situation using the analogy of a leaking garden hose. If pressure in the pipes feeding the hose changes, the pressure in the hose and, hence, the rate of leak will be altered. Resistances in the hose also affect the leak. If we hink the hose upstream from the leak, pressure at the reigon of leak decreases and less water leaks out. However, if we hink the hose beyond the leak, this increase pressure at the region of leak and increases the leak rate. These same principles apply to PGC and GFR. First, change in renal arterial pressure causes a change in PGC in the same direction. If resistance remain constant, PGC rises and falls as renal artery pressure (and renal blood flow) rises and falls. This is a crucial point because arterial blood pressure shows considerable variability. Second, changes in the resistance of the afferent and EAs have opposite effects on PGC. An increase in afferent arteriolar resistance, which is upstream from the glomerulus, is like kinking the hose above the leak – it decrease PGC. An increase in efferent arteriolar resistance is down-stream from the glomerulus and is like kinking the hose beyond the leak – it increases PGC. Of course dialation of the AA raises PGC, and hence GFR, whereas dialation of the EA lowers PGC and GFR. It should also clear that when the afferent and efferent arteriolar resistances both change in the same direction, they exert opposing effects on PGC.

´╝Ěhat is the significance of this? It means the kidney can regulate PGC and, hence, GFR independently of RBF.

Hydrostatic Pressure in Bowman's Capsule (PBC)

  • Urinary obstruction

Changes in pressure within Bowman's space are usually of very minor importance. However, obstruction anywhere along the tubule or in the external portions of the urinary system (e.g., the ureter) increases the tubular pressure everywhere proximal to the occlusion, all the way back to Bowman's capsulre. The result is to decrease GFR.

Oncotic Pressure in Glomerular Capillary PlasmaGC)

  • Arterial plasma protein concentration
  • Renal plasma flow

Oncotic pressure in the plasma at the very beginning of the glomerular capillaries is the oncotic pressure of systemic arterial plasma. Accordingly, a decrease in arterial plasma protein concentration, as occurs, for example, in liver disease, decreases arterial oncotic pressure and tends to increase GFR, whereas increased arterial oncotic pressure tends to reduce GFR.

However, recall that πGC is the same as arterial oncotic pressure only at the very begining of the glomerular capillaries; πGC then increases somewhat along the glomerular capillaries as protein-free flid filters out of the capillary, concentrating the protein left behind. This means that NFP and, hence, filtration progressively decrease along the capillary length. Accordingly, anything that causes a steeper increase in πGC tends to lower average NFP and hence GFR.

Such a steep increase in oncotic pressure occurs in conditions of low RBF. When RBF is low, the filtration process removes a relatively larger fraction of the plasma, leaving a smaller vlume of plasma behind in the glomeruli still containing all the plasma protein. The πGC reaches a final value at the end of the glomerular capillaries that is higher than normal. This lowers average NFP and, hence, GFR. Conversely, a high RBF, all other factors remaining constant, causes πGC to increase less steeply and reach a final value at the end of the capillaries that is less than normal, which increases the GFR.

As blood is composed of cells and plasma, we can describe the flow of plasma per se, the renal plasma flow (RPF). Variations in the relative amounts of plasma that are filtered can be expressed as a filtration fraction: the ratio RPF/GFR, which is normally about 20%, that is, about 20% of the plasma entering the kidney is removed from the blood and put into the Bowman's space. The increase in πGC along the glomerular capillaries is directly proportional to the filtration fraction (i.e., if relatively more of the plasma is filtered, the increase in πGC is greater). If the filtration fraction has changed, it is certain that there has also been a proportional change in πGC and that this has played a role in altering GFR.

Filtered Load

A term we use in other chapters is filtered load. It is the amount of substance that is filtered per unit time. For freely filtered substances, the filtered load is the product of GFR and plasma concentration. Consider sodium. Its normal plasma concentration is 140 mEq/L, or 0.14 mEq/mL. A normal GFR in healthy young adult males is 125 mL/min, so the filtered load of sodium is 0.14 mEq/mL X 125 mL/min = 17.5 mEq/min. We can do the same calculation for any other substance, being careful in each case to be aware of the unit of measure in which concentration is expressed. The filtered load is what is presented to the rest of the nephron to handle. The filtered load varies with plasma concentration and GFR. An increase in GFR, at constant plasma concentration, increases the filtered load, as does an increase in plasma concentration at constant GFR. Variations in filtered load play a major role in the renal handling of many substances.