4: Basic Transport Mechanisms

• ▸ Identify the major morphological components of an epithelial tissue including lumen, interstitium, apical and basolateral membranes, and tight junctions.

• ▸ State how transport mechanisms combine to achieve active transcellular reabsorption in epithelial tissues.

• ▸ Define iso-osmotic transport.

• ▸ Define paracellular transport and differentiate between transcellular and paracellular transport.

• ▸ Define the terms: channel, transporter, uniporter, multiporter, symporter, and antiporter.

• ▸ Describe qualitatively the forces that determine movement of reabsorbed fluid from the interstitium into peritubular capillaries.

• ▸ Explain why volume reabsorption in the proximal tubule depends on activity of the Na-K-ATPase.

• ▸ Compare the Starling forces governing glomerular filtration with those governing peritubular capillary absorption.

• ▸ Compare and contrast the concepts of T_m and gradient-limited transport.

As should be clear by now, the kidneys are transport machines, moving a large array of substances between the renal tubules and the nearby network of blood vessels. The basic process of moving these substances (secretion and reabsorption) requires that solutes and water cross 2 cell layers: (1) the epithelium that makes up the walls of the tubules and (2) the endothelium that makes up the vascular walls. Substances must also traverse the thin region of interstitial fluid between them. In the cortex, where the fluxes of many filtered substances are enormous, the vascular endothelium (peritubular capillaries) is fenestrated. The fenestrae and the loose underlying basement membrane offer virtually no resistance to the passive movement of water and small solutes. This facile permeation has 2 consequences. First, the rate of transport is governed almost exclusively by events in the tubular epithelium rather than the vascular endothelium; second, the cortical interstitium, which is the medium faced by the basolateral membranes of the tubular epithelia, has an osmolality and concentration of small solutes very close to those in plasma. In contrast, both blood flow and transport events are less rapid in the medulla. Only some regions of the medullary vasculature are fenestrated, so that (1) overall transport depends on both the properties of the vascular endothelium and tubular epithelium, and (2) the medullary interstitium is most definitely not plasma-like in its composition. In the rest of this chapter we will describe the principles of epithelial transport that apply to all parts of the kidney, with particular emphasis on events in the cortex. We will then see how these principles apply to the medulla in subsequent chapters.

Crossing the tubular epithelium can occur either through the cells or around the cells. The paracellular route is when the substance goes around the cells, that is, through the matrix of the tight junctions that link each epithelial cell to its neighbor. In most cases, however, a substance takes the transcellular route, a 2-step process through the cells. For reabsorption, this is entrance across the apical membrane facing the tubular lumen, through the cell cytosol, and then exit across the basolateral membrane facing the interstitium. For secretion the process is reversed. These structures and pathways are depicted in Figures 4–1A and B.

An array of mechanisms exists by which substances cross the various barriers. These are no different from transport mechanisms used elsewhere in the body. We can view these mechanisms as a physiological toolbox. Renal cells use whichever set of tools is most suitable for the task. The general classes of mechanisms for traversing the barriers are depicted in Figure 4–2.

The presence or absence of a given transport protein endows the tubular epithelium with selectivity, that is, the ability to choose which substance is permitted to move. Selectivity, obviously, applies to cell membranes containing different transport proteins. It also applies to paracellular flux through tight junctions. Key tight junction proteins, members of the claudin family, determine the degree to which various substances can travel paracellularly. In the proximal tubule, small ions such as sodium and potassium, water, and urea can move by the paracellular route. In the thick ascending limb, sodium and potassium, but not water or urea, can move paracellularly. Neither location permits the paracellular movement of glucose.

Movement by Diffusion

Diffusion is the frenzied random movement of free molecules in solution (like the Ping-Pong balls in a lottery drawing). Net diffusion occurs across a barrier (ie, more molecules moving one way than the other) if there is driving force (a concentration gradient or, for charged molecules, a potential gradient) and if the barrier is permeable. This applies to almost all substances crossing the endothelial barrier lining the peritubular capillaries. It applies to substances taking the paracellular route around the tubular epithelium and to some substances taking the transcellular route through membranes. Small neutral molecules that are lipid soluble, such as the blood gases, alcohol, and steroids, can diffuse directly through the lipid bilayer.

Movement Through Channels

Most substances of biological importance cannot penetrate lipid membranes fast enough to meet cellular needs. To speed up the process their transmembrane flux is mediated by integral membrane proteins, which are divided into categories of channels and transporters (see Figure 4–2). Channels are small pores (proteins with a “hole” through the interior of the protein) that permit, depending on their structure, water or specific solutes to diffuse through them. Thus, we use the terms sodium channel and potassium channel to designate channels that permit diffusion of these molecular species. Aquaporins are channels that are permeable to water. Some species of aquaporin also permit diffusion of small neutral molecules including carbon dioxide (CO₂) and nitric oxide (NO). Channels typically flicker open and closed like camera shutters, so that the permeability of a membrane containing many channels is proportional to the number of channels and the probability of their being open. Movement through channels is passive, that is, no external energy is required. The energy to drive the diffusion is inherent in the concentration gradient or, strictly speaking, the electrochemical gradient, because charged ions are driven through channels and around cells via the paracellular route not only by gradients of concentration but also by gradients of voltage. Channels represent a mechanism for rapid movement of specific substances across membranes, which would otherwise diffuse slowly or not at all.

A characteristic of channels critical for renal function is the regulation of their permeability by a number of environmental factors and signaling cascades (Figure 4–3). First, many channel types can be gated, meaning that the probability that the channel is open can be increased or decreased. The topic of channel gating is a whole story by itself, but several ways of gating channels include reversible binding of small molecules that are components of signaling cascades (ligand-gated channels), changes in membrane potential (voltage-gated channels), and mechanical distortion (stretch-gated channels). Second, many channel types have phosphorylation sites such that phosphorylation either locks the channel shut or allows it to be gated by one the mechanisms above. Third, some channel species can be moved back and forth between the surface membrane and intracellular vesicles, thereby regulating the number of the existing channels actually functioning as permeability pathways. Finally, and on a slower time scale, the genomic expression of channels is regulated so that the total number of channels, whether in the membrane or sequestered in vesicles, is altered up or down. Channel and transporter proteins are not permanent fixtures in the membrane. Their lifetimes in the membrane are generally in the range of a few hours. All of these regulatory processes are controlled by intricate signaling cascades that are the subject of current research.

Movement by Transporters

Our genome codes for a large array of proteins that function as transporters, all with names and acronyms that suffuse the physiological literature. Transporters, like channels, permit the transmembrane flux of a solute that is otherwise impermeable in the lipid bilayer. Channels can move large amounts of materials across membranes in a short period of time, but most transporters have a lower rate of transport because the transported solutes bind much more strongly to the transport protein. Furthermore, the protein must undergo a more elaborate cycle of conformational change to move the solute from one side of the membrane to the other. However, overall flux rate depends not only on the kinetics of individual transporters, but also on the density of transporters in the membrane. Total flux via transporters can be very high if the transporter density is high. As is the case for channels, the amount of substance moved via transporters is highly regulated. The regulation includes changes in phosphorylation of the transporter (thereby turning its activity on or off), sequestration into vesicles, and of course, changes in genomic expression. As described next, we group transporters into categories according to basic functional properties.

UNIPORTERS

Uniporters permit movement of a single solute species through the membrane. The basic difference between a channel and a uniporter is that a channel is a tiny hole, whereas a uniporter requires that the solute bind to a site that is alternately available to one side and then the other side of the membrane (like entering a vestibule through an outside door and then leaving the vestibule to enter a hallway through an inside door). Movement through a uniporter is often called facilitated diffusion because, like diffusion, it is driven by concentration gradients, but the transported solute moves through the uniporter protein rather than the membrane lipid. A set of uniporters crucial for all cells includes those that facilitate the movement of glucose across cell membranes. These are members of the GLUT (glucose transporter) family of proteins that permit, in the kidney's proximal tubule epithelial cells, glucose to move from the cytosol across the basolateral membrane into the interstitium.

MULTIPORTERS: SYMPORTERS AND ANTIPORTERS

Multiporters move 2 or more solute species across a membrane simultaneously. Symporters move them together in the same direction. Antiporters move them in opposite directions. In the literature, symporters are sometimes called cotransporters, and antiporters are called exchangers. Important symporters for the handling of glucose move sodium and glucose together into cells (members of the SGLT protein family). Each transport cycle moves 1 glucose molecule and either 1 or 2 sodium ions depending on the particular species of SGLT. Another key symporter in the kidney is one that moves sodium, potassium, and chloride all together into a cell (N-K-2Cl). Important antiporters in the kidneys and many other organs move sodium into a cell and protons out of a cell, often called sodium-hydrogen exchangers, members of the NHE (sodium-hydrogen exchange) protein family. Yet another family of antiporters in many cells, including the kidney, moves chloride in one direction and bicarbonate in the opposite direction. In later chapters, we will see how these and other transporters play defined roles in specific nephron segments.

All molecular transport requires energy. In the case of diffusion through a channel or movement via a uniporter, the energy is inherent in the electrochemical gradient of the solute. With symporters and antiporters, at least 1 of the solutes moves down its electrochemical gradient and provides the energy to move 1 or more of the other solutes up its electrochemical gradient (like a pulley system where a weight is raised by the downward movement of a heavier weight on the other side of the pulley). Movement of any solute up its electrochemical gradient is called active transport. In the case of symporters and antiporters that do not hydrolyze adenosine triphosphate (ATP), the active transport is called secondary active transport because the energy is provided indirectly from the transport of another solute rather than directly from a chemical reaction. In a large number of cases, sodium is 1 of the solutes moved by a symporter or antiporter. The electrochemical gradient of sodium in all cells favors entrance. Passive movement of sodium is therefore always inward. When sodium movement is coupled to that of another solute, as in sodium-proton antiport (exchange), sodium will normally enter. The stoichiometry is important here. The energy available from a gradient is multiplied by the number of molecules that move per transport cycle. For example, sodium/calcium antiporters move 3 sodium ions per calcium ion. Calcium has a larger electrochemical gradient than sodium, but this difference is overcome by moving 3 sodium ions per cycle of the antiporter.

Another example where the stoichiometry plays an essential role is the coupled transport of bicarbonate and sodium. An important symporter in the proximal tubule is the NBCe transporter, which moves 3 bicarbonate ions and 1 sodium ion out of the cell, per transport cycle. The electrochemical gradient for bicarbonate is directed outward, and the energy gained from moving 3 bicarbonate ions outward is greater than the energy it takes to move 1 sodium ion outward against its electrochemical gradient. Therefore, this transporter moves both solutes outward, up the electrochemical gradient for sodium. This is a rare case of sodium removal by something other than an ATPase.

PRIMARY ACTIVE TRANSPORTERS

Primary active transporters are membrane proteins that move 1 or more solutes up their electrochemical gradients using the energy obtained from the hydrolysis of ATP. All transporters that move solutes in this manner are ATPases, that is, their structure is both that of an enzyme that splits ATP, and a transporter that has binding sites that alternately are open to one side and then the other side of the membrane. Among the key primary active transporters in the kidney is the ubiquitous Na-K-ATPase, often called the “sodium pump,” some isoform of which is present in virtually all cells of the body. This transporter simultaneously moves sodium against its electrochemical gradient out of a cell and potassium against its gradient into a cell. The stoichiometry is 3 sodium ions out and 2 potassium ions for every ATP molecule hydrolyzed. Other crucial primary active transport systems are H-ATPases, which move protons out of cells, and Ca-ATPases, which move calcium out of cells. All of these ATPases belong to a large family of homologous transporter proteins. Yet another important class of primary active transporters are the multidrug resistance proteins (MDR, also called ATP binding cassette proteins), named for their ability to remove therapeutic drugs from cells. Unlike the inorganic ion ATPases, which are quite selective for the ion species they move, the MDR transporters unselectively transport a wide variety of organic anions.

Almost all the secretion and reabsorption of solutes discussed throughout this textbook use some combination of the just-mentioned set of membrane permeability mechanisms. One other solute transport process of some importance is receptor-mediated endocytosis. In this case, a solute, usually a protein, binds to a site on the apical surface of an epithelial cell, and then a patch of membrane with the solute bound to it is internalized as a vesicle in the cytoplasm. Subsequent processes then degrade the protein into its constituent amino acids, which are transported across the basolateral membrane and into the blood.

For a few proteins, particularly immunoglobulins, endocytosis can occur at either the apical or basolateral membranes, after which the endocytic vesicles remain intact and are transported to the opposite cellular membrane, where they undergo exocytosis to release the protein intact. Such transcytosis is very important in the host defense mechanisms of the kidney and in the prevention of urinary tract infections.

Osmosis and Osmotic Pressure

OSMOTIC VOCABULARY

The vocabulary of osmotic matters is often used loosely leading to some confusion, but the central concept is straightforward. Solutes dissolved in water displace some of the water and lower its concentration. Therefore, solutions differing in solute concentration also differ in water concentration. Given the opportunity to do so, water diffuses from where its concentration is higher (dilute solutions) into solutions where its concentration is lower (concentrated solutions), a process called osmosis.

Dissolved solutes that displace water are called osmoles. One mole of any dissolved solute (an Avogadro number of it; about 6.02 × 10²³) is 1 osmole. The sum of the moles in a mixture gives us the total number of osmoles. For example, one half mole of urea and one half mole of sucrose together make 1 total osmole. As salts dissociate in solution, 1 mole of salt molecules that split into 2 ions (eg, NaCl) becomes 2 osmoles, and a mole of salt that splits into 3 ions (eg, CaCl₂) becomes 3 osmoles.

The concentration of osmoles is expressed by the terms osmolarity and osmolality. Osmolarity is the number of osmoles per liter of solution; most commonly, it is expressed in “milli” units (mOsm/L). A solution containing 50 mM urea and 100 mM NaCl has an osmolarity of 250 mOsm/L (50 urea, 100 Na⁺, and 100 Cl⁻). Osmolarity is a convenient unit because we can easily calculate it from the known ingredients in solution. Osmolality is the concentration of osmoles per kg of water, for example, 300 mOsm/kg H₂O. As a liter of solution contains almost 1 kg of water, the values of osmolarity and osmolality are nearly the same.

All of the above assumes that solutions are ideal (ie, any dissolved solute particle is the same as any other and is fully active osmotically), but real solutions are not ideal. Solutes interact with each other in mysterious ways such that a mole of most solutes, when dissolved, results in less than 1 osmole. It is the real osmolality that determines the movement of water between fluid compartments. These concepts are illustrated in the case of physiological saline (0.9% NaCl, or 154 mmol/L NaCl). This solution is commonly used as a hospital infusion solution because it matches the normal osmolality of human plasma (280 − 290 mOsm/kg H₂O). The osmolarity of this solution, assuming ideality, is 154 + 154 = 308 mOsm/L, but the measured osmolality is 287 mOsm/kg H₂O. Any solution with the same real osmolality as normal human plasma is said to be an isosmotic solution. For convenience, physiologists often calculate osmolarity assuming the solution to be ideal and then call it osmolality, and accept the error in this calculation as the price paid for convenience.

Osmotic pressure is another confusing concept. Despite its name, osmotic pressure is not a pressure in the sense of hydrostatic pressure—it just means osmolality. A beaker of water and a beaker of glucose solution with a high osmolality, both have the same hydrostatic pressure, but different osmotic pressures. By definition, osmotic pressure is the pressure that theoretically would have to be applied to a solution to prevent the movement of water by osmosis across a semipermeable barrier from pure water into the solution. (A semipermeable barrier is permeable to water, but not solute.) Numerically, it is the just real osmolality expressed in pressure units. This equivalence is expressed by the van't Hoff equation where π is the osmotic pressure, R and T are the gas constant and absolute temperature, and C is the osmolality (osmolarity is usually used as an approximation for osmolality).

To calculate a numerical value for osmotic pressure in units of mm Hg, multiply the osmolality by 19.3. Thus, an osmolality difference of only 1 mOsm/kg H₂O is actually a significant driving force for the movement of water.

WATER MOVEMENT ACROSS SEMIPERMEABLE BARRIERS

If the solutions on either side of a semipermeable barrier differ in osmolality, water moves by osmosis toward the solution with the higher osmolality. Although water is driven by its own concentration gradient, it is convenient to think of solute as “pulling” water. The kidneys make use of this concept by reabsorbing solutes across the renal tubules (from lumen to the interstitium) and allowing water to follow, that is, “water follows the osmoles.” Differences in osmolality are only effective in driving osmosis when the barrier is less permeable to solutes than to water, that is, it is semipermeable. (Imagine a barrier made of chicken wire. Regardless of osmolalities, there would be no osmosis because there would be no restriction on the diffusion of solute.)

In the fenestrated endothelial barriers of glomerular capillaries and peritubular capillaries, most of the solutes are as permeable through the fenestrae as water and thus do not influence water movement. However, the large plasma proteins are not permeable, and they do indeed influence water movement. The osmotic pressure resulting from the proteins only (ignoring everything else) is called the colloid osmotic pressure or oncotic pressure. Colloid osmotic pressure is a component of the Starling forces governing filtration and absorption across endothelial layers. In other barriers, specifically the epithelial lining of the renal tubules, the permeabilities of all solutes are generally lower than water permeability. Therefore, all solutes contribute to driving a water flux. Here, all of the osmolality, not just the component resulting from proteins, is important.

Virtually all of the 180 L of water and several pounds of salt and other solutes filtered each day into Bowman's space are reabsorbed, along with large amounts of many other substances. Most of this reabsorption occurs in the proximal tubule. Almost all solutes (except large plasma proteins) are filtered from plasma into Bowman's space in the same proportion as water; thus, their concentrations in the glomerular filtrate are the same as in the plasma. By the end of the proximal tubule, about two third of the water and solutes have been reabsorbed. The rates of reabsorption, and thus concentrations in the lumen at the end of the proximal tubule, vary from solute to solute, but the summed total of solutes (osmoles) reabsorbed is proportional to water reabsorbed. This is called iso-osmotic reabsorption. In the later portions of the nephron, beyond the proximal tubule, reabsorption is generally not iso-osmotic, meaning that water and total solute reabsorption are usually not proportional. This is crucial for our ability to independently regulate solute and water balance.

Sodium and Water

Sodium accounts for nearly half of the total solute load appearing in the glomerular filtrate, and most of the rest consists of the anions (primarily chloride and bicarbonate) that must accompany sodium to maintain electroneutrality. Similarly, sodium and its accompanying anions account for the vast majority of solutes reabsorbed in the proximal tubule. The large amount of sodium and anions transferred from lumen to interstitium sets up an osmotic gradient that favors the parallel movement of water. The proximal tubule epithelium is very permeable to water, which follows the osmoles across in equal proportions. Thus, both the fluid removed from the lumen and that remaining behind are essentially iso-osmotic with the original filtrate. We say “essentially” because there must be some difference in osmolality to induce water movement, but for an epithelial barrier like the proximal tubule that is very permeable to water, a difference of less than 1 mOsm/kg is sufficient to drive reabsorption of water. (Recall that an osmolality difference of 1 mOsm/kg is equal in driving force to 19.3 mm Hg of hydrostatic pressure). Once in the interstitium, the solutes and water move from interstitium into the peritubular capillaries and are returned to the systemic circulation Table 4–1.

Epithelial transport requires that the cells be polarized, that is, the proteins present in the apical and the basolateral membranes are not the same. In the case of sodium, polarization of the proximal tubule epithelium promotes net flux from lumen to interstitium. Movement of sodium is the linchpin around which the transport of virtually every other substance depends. Figure 4–4 shows the morphology of a generalized proximal tubule epithelium in which salt and water transport can be viewed as a multi-step process.

Step 1 is the active extrusion of sodium from epithelial cell to interstitium across the basolateral membrane. Step 2 is the passive entrance of sodium from the tubular lumen across the apical membrane into the cell to replace the sodium removed in step 1. Step 3 is the parallel movement of anions that must accompany the sodium to preserve electroneutrality. Step 4 is the osmotic flow of water from tubular lumen to interstitium. Finally, step 5 is the bulk flow of water and solute from interstitium into the peritubular capillary. Let us examine these steps more closely.

The active extrusion of sodium in step 1 is via the Na-K-ATPase, which is the major energy consumer in the cell. The action of the Na-K-ATPase has several consequences, the key one being that it keeps the concentration of sodium within the cell low enough to favor the passive entrance of sodium from lumen to cell in all the processes of step 2.

The entrance of sodium into the cell in step 2 is via multiple pathways. Quantitatively, most of sodium enters via the sodium-proton antiporter (NHE3 isoform). As we will see later, regulation of this transporter is a key player in regulating sodium excretion.

Step 3, the movement of anions is more complex, as it involves 2 ions (chloride and bicarbonate) and a variety of transcellular and paracellular processes. We will examine the details later, but for now, we emphasize that the movement of sodium, which is a cation, must be matched quantitatively by the equal movement of anions.

Step 4 is the osmotic movement of water. The tubular cells possess a complement of aquaporins in both the apical and basolateral membranes, and the tight junctions are also permeable to water. Therefore, as steps 1 to 3 lower the local luminal osmotic concentration by even a few milliosmoles per liter, water flows osmotically from lumen to interstitium.

The movement of water into the interstitium in step 4 promotes step 5. This is the bulk flow of fluid from interstitium to peritubular capillary driven by Starling forces (hydrostatic and oncotic pressure gradients). The capillary hydraulic pressure opposes the uptake of interstitial fluids, but its value of 15 to 20 mm Hg is much lower than the 60 mm Hg in the glomerular capillaries, where there is net filtration. Meanwhile, the plasma oncotic pressure has risen to more than 30 mm Hg because loss of water by filtration in the glomerular capillaries concentrates the large plasma proteins. There is also a small but significant, interstitial pressure. The sum of these Starling forces is a net absorptive pressure, and it drives fluid movement into the peritubular capillaries. The reader can appreciate the fact that if cortical Starling forces are abnormal (eg, low plasma oncotic pressure as when liver disease prevents normal production of serum albumin), absorption of fluid from the cortical interstitium can be slowed, causing a backup of fluid that inhibits fluid movement from tubular lumen to interstitium. Ultimately, this can lead to increased excretion of water and electrolytes from the body.

Consequences for Other Solutes

The events just described have consequences for all the other solutes filtered along with sodium and its anions. As water follows sodium and its anions across the epithelium, the luminal volume decreases, thereby concentrating all remaining solutes. If two thirds of the water is removed, any solute not previously removed will increase in concentration by a factor of 3. As its luminal concentration rises, this generates a concentration gradient across the tight junctions between the lumen and the interstitium (The interstitial concentration of transported substances is essentially clamped to the plasma value because of the high peritubular blood flow and high permeability of the fenestrated capillaries.). If the tight junctions are permeable to the substance in question (“leaky”), the substance diffuses from the lumen to the interstitium and then into the peritubular capillaries along with sodium and water. This is precisely what happens to many solutes (eg, urea, potassium, calcium, and magnesium) in the proximal tubule. The exact fractions that are reabsorbed depend on the permeability of the tight junctions, but are generally in the range of one half to two thirds. As indicated earlier, one substance that does not move by the paracellular route is glucose, which is impermeable in the tight junctions. We will describe the fate of filtered glucose in Chapter 5.

Limits on Rate of Transport: T_m and Gradient-limited Systems

Even though the transport capacity of the renal tubules is huge, it is not infinite. There are upper limits to the rate at which any given solute can be reabsorbed or secreted. In situations in which unusually large amounts of a substance are filtered, these limits are reached with the consequence that larger than normal amounts of solute are not reabsorbed (ie, left in the lumen and passed on to the next nephron segment). In general, transport mechanisms can be classified by the properties of these limits as either (1) tubular maximum-limited (T_m) systems or (2) gradient-limited systems.

The classification is based on the leakiness of the tight junctions. Consider first gradient-limited systems. When the tight junctions are very leaky to a given substance, for example, sodium, it is impossible for the removal of the substance from the lumen to reduce its luminal concentration very much below that in the cortical interstitium. As the substance is removed and the luminal concentration starts to fall, the gradient between these 2 media increases, causing the substance to leak back as fast as it is removed (like bailing a very leaky boat). Thus for sodium and all other substances whose reabsorption is characterized by a gradient-limited system, the luminal concentration remains close to the interstitial concentration. Be aware that the existence of a limiting rate does not stop reabsorption in normal circumstances because water is being reabsorbed simultaneously. Even though the luminal concentration does not decrease very much, large amounts are still being removed. In contrast, if unusual osmotic conditions retard water reabsorption, then removal of the substance is not accompanied by a corresponding amount of water. Consequently its concentration does decrease, the limiting gradient is indeed reached, and now the substance leaks back, leaving unusually high amounts of the substance in the large volume of unreabsorbed water.

Now consider T_m-limited systems. In this case the tight junctions are impermeable to the solutes in question. There is no back leak and no limit on the size of the difference in concentration between lumen and interstitium. The limit on transport rate instead is placed on the capacity of the transporters to remove the substance (the inherent kinetic properties of the transport proteins and their density in the membrane). As the filtered load rises, the amount reabsorbed increases in parallel up to the point of saturating the transporters. For loads below the T_m, virtually all is reabsorbed. But any increase in filtered load above the T_m does not increase transport out of the lumen. Consequently, the excess is left behind. In most cases, the amount that escapes reabsorption in the proximal tubule is excreted.

The functional reason for differentiating between T_m and gradient-limited systems is that solutes handled by T_m systems will, if the filtered load is below the T_m, be reabsorbed essentially completely, whereas solutes handled by gradient-limited systems are never reabsorbed completely, that is, a substantial amount always remains in the tubule to be passed on to the next nephron segment.

Osmotic Diuresis

If the normal tight coupling between sodium and water reabsorption in the proximal tubule is disrupted, we have a phenomenon known as osmotic diuresis. The term diuresis simply means increased urine flow, and osmotic diuresis denotes the situation in which the increased urine flow is due to an abnormally high amount of any solute that is not reabsorbed at all (eg, mannitol) or is filtered at such a high rate that much is left in the tubule (eg, very high plasma glucose), leaving large amounts of solute (osmoles) in the lumen. As water is reabsorbed from the tubule, the concentration of any unreabsorbed solute rises. Its osmotic presence retards the further reabsorption of water, that is, it is “holding” water in the lumen. If this occurs in the proximal tubule, it also retards net sodium reabsorption. Sodium transport per se continues unabated. But as water is being held in the lumen, the sodium transport causes an initial fall in luminal sodium concentration. This drives a passive back leak of sodium via tight junctions because the limiting gradient for sodium transport is reached. At this point there is little net sodium transport because the amount reabsorbed is matched by the amount leaking back. The result is that high amounts of sodium, water, and the unusual solute pass on to the loop of Henle. Osmotic diuresis can occur in persons with uncontrolled diabetes mellitus, in which the filtered load of glucose exceeds the tubular maximum (T_m), and the unreabsorbed glucose then acts as an osmotic diuretic. In other cases, it can be due to an infused solute such as mannitol that is filtered, but not transported at all.

• Flux from lumen to interstitium can be transcellular; using separate transport steps in the apical and basolateral membranes, or paracellular, around the cells through tight junctions.

• The kidneys move solutes across membranes by multiple transport mechanisms including channels, uniporters, multiporters, and primary active transporters.

• The kidneys regulate excretion by regulating channels and transporters in epithelial cell membranes.

• Water crosses epithelial barriers by movement down osmotic gradients (from regions of lower to higher osmolality).

• Volume reabsorption is a multistep process involving transport across epithelial membranes from lumen to interstitium, and bulk flow from interstitium to peritubular capillaries driven by Starling forces.

• The reabsorption of water concentrates all remaining tubular solutes, increasing the driving force for their passive reabsorption by diffusion.

• All reabsorptive processes have a limit on how fast they can occur, either because the substance leaks back into the lumen (gradient-limited systems), or because the transporters saturate (T_m systems).