Physical Address

304 North Cardinal St.
Dorchester Center, MA 02124

Tubular transport


Introduction

The body faces multiple challenges met by the kidneys, including acid base balance, regulation of the concentrations of electrolytes such as potassium, and control of blood pressure. Two of the most critical are (1) the management of extracellular fluid volume by the handling of sodium and water and (2) the removal of metabolites and dietary components that are useful at low concentrations but toxic at high concentrations. Evolutionarily, animal species did not have a mechanism to concentrate urine until the arrival of mammals.

As we saw in chapter 17 , the glomerular filtration rate (GFR) in mL/min is normally approximately 20% of renal plasma flow (RPF). That means that ingested toxins or metabolic waste products cannot be removed completely from the body by the kidney by filtration alone. Since their accumulation would be lethal to the organism, a necessary component of normal renal function is the secretory mechanisms involving membrane transport in the tubular structures of the nephron. Operating on low concentrations of toxic substances in the renal plasma, the transporters can secrete close to 100% of these solutes if they are working at the unsaturated portion of their transport kinetic relationships. Such is the case with para-amino hippurate (PAH, see Ch. 17 ).

These renal tubular transporters, however, are not limited to the secretion of ingested toxins, and therefore have other functions – namely, to secrete similar but normal endogenous metabolites that are useful within a physiologic range. For these molecules, removing them entirely would cause disease, but allowing them to accumulate above a certain concentration would also cause disease. The kidney must therefore regulate the serum concentrations of these molecules by a combination of filtration, secretion, and reabsorption. These same mechanisms allow the kidney to control the movement of water, saving it when extracellular fluid volume (and thus blood pressure) is too low or when the concentration of electrolytes like sodium is too high by concentrating the urine, and removing it when extracellular fluid volume (and thus blood pressure) is too high or when the concentration of electrolytes like sodium is too low by diluting the urine. The reason for high filtration rates in most mammals is that reabsorption of solutes in excess of water allows the kidney to produce dilute urine in the late distal nephron under appropriate circumstances.

In general, the control of osmolality is achieved by the handling of free water. The control of extracellular fluid volume is achieved by the handling of sodium.

The body faces a major dilemma concerning ingested nitrogen containing substances. On the one hand, molecules such as ammonia are toxic at sufficiently high concentrations. On the other hand, nitrogen containing substances also perform critical metabolic functions. The turnover of proteins requires a critical mass of protein precursors, so some organic nitrogen must be available to form amino acids. Ammonia, a waste product produced by protein catabolism, is converted by the urea cycle to urea, mostly in the liver. Urea is also critical to the concentrating mechanism of the kidney. Glomerular filtration allows for large amounts of filtered nitrogen products to be excreted into the urine while some (but not complete) reabsorption of urea occurs by the renal tubules. A large portion of the filtered urea is not eliminated – it is saved to maintain the ability of the kidney to concentrate the urine – and the amount that is eliminated must match the amount ingested to maintain nitrogen balance. Since most protein is approximately 1⁄6th nitrogen by weight, the mass of urea nitrogen (there are two nitrogen atoms per molecule of urea) excreted daily must equal 1⁄6th of the mass of protein ingested. Thus, for example, if 10 gm of nitrogen appear in the urine in a 24 hour period, that means that the patient is consuming 60 gm of protein daily. This is known as the protein catabolic rate, which in a healthy person is equivalent to the daily protein intake and requires that the concentration of urea in the blood be constant. Azotemia results when too much urea is retained. Uremia ensues when this increased urea concentration causes toxicity.

The processes of glomerular filtration, tubular reabsorption, and tubular secretion determine the composition of the urine and the blood leaving the kidney. This enables the kidney to maintain blood volume and solute levels within the body regardless of external conditions.

Homeostasis is achieved through regulated tubular transport of solutes in both directions (reabsorption and secretion), as well as reabsorption of water. This chapter will describe:

  • Mechanisms of reabsorption and secretion

  • Specialization of different parts of the tubule for transporting various substances

  • Cellular transporters that convey substances across the tubule walls

System structure: Functional anatomy of the kidney tubule

Recall that the nephron is the functional unit of the kidney, composed of ( Fig. 18.1 ):

  • Glomerulus, where the initial filtration of blood occurs

  • Tubule, where reabsorption and secretion occur

Fig. 18.1, The nephron. Although only depicted on the proximal tubule cell, tight junctions and the lateral intercellular space are present in the epithelium in all parts of the tubule. The pars recta is the straight portion of the proximal tubule.

The tubule is further broken down into:

  • Proximal tubule

  • Loop of Henle

  • Distal tubule

  • Collecting duct

  • Juxtaglomerular apparatus (regulatory structure)

Transport takes place in every part of the tubule. The epithelial cells are connected to each other along the entire tubule by tight junctions, which separate the cell surface into ( Fig. 18.2 ):

  • An apical-luminal side facing the tubule lumen

  • A basolateral side facing the interstitium and the peritubular capillaries

  • Between the cells is an area known as the lateral intercellular space.

Fig. 18.2, Two distinct surfaces of tubular cells. The apical-luminal side refers to the inside of the tubule, where the ultrafiltrate flows. The basolateral side constitutes the outside of the tubule and faces the peri-tubular capillaries. The tight junctions in between the epithelial cells separate the tubule lumen from the outside.

The proximal tubule is located in the cortex of the kidney along with the glomerulus:

  • Ultrafiltrate from the glomerulus flows directly into the proximal tubule

  • The initial convoluted portion, the proximal convoluted tubule, has more surface area for transport than the straight portion

  • The following straight portion—the pars recta—conducts less transport

The loop of Henle is a U-shaped structure that dips into the medulla of the kidney. The filtrate in the lumen encounters the three sections of the loop of Henle in the following order:

  • The thin descending limb is permeable to water but impermeable to salt.

  • The thin ascending limb is impermeable to water, but the passive permeability to salt is high.

  • The thick ascending limb actively, rather than passively, transports salt out of the lumen into the interstitium. As the filtrate passes through the thick ascending limb, sodium is pumped out, the fluid becomes hypotonic, and it eventually passes into the distal tubule.

The distal convoluted tubule is located in the cortex of the kidney.

  • Cells located in the distal tubule are cuboidal and have extensive infoldings of the basolateral membranes and numerous mitochondria.

  • Multiple neighboring distal convoluted tubules empty into a common collecting duct.

Collecting ducts receive fluid from distal convoluted tubules in the cortex and transport the fluid through the medulla. The portion of the duct that receives fluid from the distal tubule is known as the cortical collecting duct, which becomes the medullary collecting duct as it passes into the medulla.

  • The cortical collecting duct has a large lumen and is composed of two main cell types (with distinct roles that will be discussed later in the chapter):

    • Principal cells

    • Intercalated cells

  • The medullary collecting duct has important transport functions for urea, Na + , NH 3 , and water.

Note energy for filtration is from cardiac mechanical energy sustaining blood whereas tubule energetics emanate from electrochemical gradients set up by adenosine triphosphatases (ATPases).

System function: Reabsorption and secretion

To understand the epithelial secretion and reabsorption that are critical to the homeostasis of the body, we must first review the concept of mass balance.

This concept, which relates to the net results of secretion and reabsorption, prepares the way for a discussion of the more minute mechanisms of secretion and reabsorption and the specialization of transport in the different segments of the tubule.

Mass balance

Mass balance is a straightforward and intuitive principle: what goes in must come out.

  • “What goes in” is the blood supplied to the kidney by the renal artery. This blood contains plasma, which consists of water, ions, proteins, and other solutes.

  • “What comes out” is 2-fold: that which leaves the kidney via the renal vein and that which leaves the kidney via the urine (for the moment, we will assume no production or metabolism of a given solute).

The Fick equation is one way to express mass balance for any specific substance S:

The first term in the equation is the incoming mass of S:Q, the flow per minute through the renal artery, multiplied by the concentration of S in the artery.

  • The terms on the other side of the equation represent the outgoing mass of S: the mass of S in urine plus the mass of S in the vein.

  • The distribution of renal output between the vein and urine is determined by glomerular filtration, reabsorption, and secretion (see Fig. 17.7 ).

Tubular secretion refers to the transport of substances from the peritubular capillaries to the tubular lumen via the nephron’s epithelial cells. Tubular reabsorption, the opposite of secretion, refers to the transport of substances from the tubular lumen to the interstitium.

It is important to remember the direction of solute movement attached to these terms. Secretion means transport to the lumen, and reabsorption implies reabsorption from the lumen.

Filtration and secretion can also be confused. Although they both refer to adding to the tubular lumen:

  • Filtration only describes the bulk-flow process in the glomerulus.

  • Secretion can and does happen all along the rest of the tubule.

Be aware, too, that some substances (such as K + and uric acid) are both secreted into and reabsorbed from the lumen in different segments of the tubule, but these terms usually refer to net secretion or net reabsorption.

Finally, a note of qualification about the mass balance equation: the equation assumes no consumption or creation of substances in the kidney, but consumption (metabolism) and creation of substances do occur in some cases. To account for this, the mass balance equation can be rewritten:

Epithelial transport

Recall that tight junctions separate the cell surface into an apical-luminal side and a basolateral side that faces the interstitium. To secrete or reabsorb, the nephron must convey substances across this boundary from lumen to interstitium or vice versa. It does so by various forms of epithelial transport, and there are two basic routes this transport can take.

  • Paracellular transport ( Fig. 18.3 ) is a passive process where solutes and ions can pass through the tight junctions between cells along their electrochemical gradient.

    Fig. 18.3, Paracellular and transcellular transport routes across the wall of the renal tubule.

  • Transcellular transport occurs with specific transporter proteins on the apical and basolateral membranes of the epithelial cells, which transport substances cross the apical membrane, through the cell, then across the basolateral membrane and vice versa. It can be either active or passive.

Most solute transport is essentially driven by the Na + ,K + -ATPase in the basolateral membrane. When the ATPase pumps Na + out toward the interstitium in exchange for potassium and at the expense of adenosine triphosphate (ATP), it is conducting primary active transport ( Fig. 18.4 A). Specialized proteins then couple this Na + transport to the transport of other solutes. This process works in the following manner:

  • Primary active transport of Na + out of the cell creates low intracellular [Na + ]

  • Na + flows down favorable electrochemical gradient into the cell through apical Na + channels

  • Apical symporters couple solute transport to Na + movement in the same direction

  • Antiporters couple solute transport to Na + movement in the opposite direction

  • This process is termed secondary active transport because there is an indirect requirement for ATP ( Fig. 18.4 B).

Fig. 18.4, Transcellular active transport. A, Primary active transport of Na + by the basolateral Na + ,K + -ATPase. B, Secondary active transport of a solute S 1 , coupled to Na + movement by a symporter, and another solute S 2 , coupled to Na + movement by an antiporter. S 1 is actively reabsorbed, and S 2 is actively secreted.

Transcellular transport may, in turn, drive paracellular transport. Transcellular translocation of cations and anions can create electrical and osmolar gradients across the tight junction that promote the movement of ions and water.

  • For instance, if mostly cations have crossed transcellularly, an electrical gradient is set up that promotes the movement of anions (such as Cl – or HCO 3 – ) across the tubular epithelium via the paracellular route.

  • Also as solutes cross the membrane, they establish an osmolar gradient; water then crosses the epithelium paracellularly.

While the entire tubule makes use of the transport mechanisms mentioned previously, each epithelial segment of the nephron has unique transport properties. This is because different parts of the tubule have various types of pumps and channels.

Reabsorption

Reabsorption is the transport of substances from the tubule lumen to the interstitium and peritubular capillary. Owing to the large rate of filtration, there is a burden on the tubule to prevent valuable solutes, such as glucose and amino acids, from becoming lost in the urine. Consequently, the tubule must perform a large amount of reabsorption and must expend a great deal of energy doing so.

As a rule, solutes are initially reabsorbed in bulk, followed by a regulated titration, to achieve the urinary excretion required to maintain balance. An important aspect of bulk reabsorption is the concept of transport maximum (T m ).

  • Simple diffusion across a membrane obeys the electrochemical gradient without limitation.

  • Carrier-mediated diffusion, however, is limited by the capacity of the carrier proteins (transporters).

  • As the concentration of a substance climbs, the transport rate for that substance climbs until the substance saturates its transport proteins, at which point the transport rate reaches its maximum, T m ( Fig. 18.5 ).

    Fig. 18.5, Nonsaturable and saturable transport. C , A constant; K m , the concentration of S at which the transport rate is half-maximum; [ S ], the concentration of substance S in the compartment from which S is being transported (e.g., the tubule lumen); T , transport rate; T m , maximum transport rate for substance S.

T m is equivalent to V max in Michaelis-Menten kinetics.

A substance’s K m is the concentration at which the transport rate is half-maximum (see Clinical Correlation Box 18.1 ). Note that in the saturable transport condition, for solute concentrations well below K m , the transport is mostly unidirectional, but as the concentration increases, and the curve is clearly non-linear, there starts to be more bidirectional until forward transport is halted (transporter saturation).

Clinical Correlation Box 18.1

D-Glucose is a valuable solute that is almost completely reabsorbed under normal circumstances (zero clearance). In a person with a normal plasma glucose level, the amount of glucose filtered does not elevate the tubular glucose concentration high enough to saturate the glucose transporters; the tubular glucose transport rate is below transport maximum (T m ), and nearly all the glucose is reabsorbed. A patient with diabetes mellitus, however, has an abnormally high plasma glucose concentration, which leads to more filtered glucose, and a tubular glucose concentration that exceeds capacity; the transporters become saturated and cannot reabsorb all of the glucose. As a result, some glucose is excreted into urine, which can be seen on urine dipstick testing.

Whether a substance has a high or a low T m may reflect whether the kidney regulates the level of that solute in the blood.

  • For instance, phosphate has a lower T m that is easily reached if plasma phosphate rises just slightly above normal. This creates de facto regulation of phosphate, for when plasma levels rise too high, transport capacity is exceeded and the excess phosphate is excreted into the urine.

  • By contrast, the kidneys are not the primary regulator of glucose levels in the blood (that is accomplished by pancreatic insulin-secreting cells). (See Fast Fact Box 18.1 and Clinical Correlation Box 18.2 ). FLOAT NOT FOUND

Fast Fact Box 18.1

At normal glomerular filtration, spillage of glucose into the urine does not occur until the blood sugar exceeds approximately 180 mg/dL, a higher-than-normal fasting value.

Clinical Correlation Box 18.2
Sodium-Glucose Linked Transporter 2 Inhibitor

Sodium-glucose linked transporter 2 (SGLT2) is the glucose transporter responsible for the majority of glucose reabsorption in the proximal tubule. SGLT2 inhibitors, such as canagliflozin and dapagliflozin, are designed to treat type 2 diabetes by decreasing glucose reabsorption in the first segment of the proximal tubule. Effects of SGLT2 inhibitors also include weight loss (through calorie leakage into the urine) and lowering blood pressure (through osmotic diuresis). Osmotic diuresis occurs because the proximal tubule must reabsorb isosmotic fluid—sodium reabsorption rises as glucose reabsorption falls. Because of the increased sodium reabsorption in the earlier segments of proximal, leading to the fall of sodium in tubular fluid, fewer amounts of sodium and fluid are reabsorbed in the later segments of the tubule. The net effect is decreased sodium and water reabsorption leading to diuresis.

Secretion

Secretion is the process of transport of substances from the peritubular capillaries to the tubular lumen.

  • Many substances that are freely filtered by the glomeruli—organic anions and metabolic products (such as choline and creatinine)—are also eliminated from the body by this route.

  • Because substances that are highly protein-bound in the plasma will not be freely filtered by the glomerulus, these solutes need to be secreted to be cleared.

    • To be filtered or secreted, protein-bound solutes must coexist with an unbound or “free” component in the plasma.

    • The kidney also secretes H + , K + , and foreign compounds, such as drugs. Most substances, including H + , are secreted in the proximal tubule, whereas H + and K + are secreted in the distal tubule and collecting ducts (information to follow).

Recall that one example of an exogenous substance that is actively secreted in the proximal tubule is the organic anion para-aminohippurate (PAH).

  • Like glucose reabsorption, PAH secretion has a T m . As long as T m is not reached, virtually all PAH that reaches the kidney is secreted and thus excreted.

  • Therefore the amount of plasma cleared of PAH is a good estimate of the renal plasma flow, as all the blood that passes through the kidney is cleared of PAH.

The proximal tubule

Now we will consider the specialized reabsorptive and secretory functions of each tubule segment ( Fig. 18.6 ). Our journey begins in the proximal tubule, where two-thirds of Na + and H 2 O reabsorption takes place.

Fig. 18.6, Key transporters along the renal tubule.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here

Related Posts