Physiology - An Illustrated Review
16. Renal Tubular Transport
Renal excretion of any substance reflects the difference between the rate at which it enters the tubular lumen by filtration and secretion and the rate that it leaves the tubular lumen by reabsorption. For freely filtered solutes, the following expressions relate the various quantities:
Filtered load = glomerular filtration rate (GFR) × plasma concentration (mg/min)
Excretion rate = urine flow rate (U) × urine concentration (mg/min)
Net tubular transport = filtered load – excretion rate (mg/min)
Note: For solutes secreted but not reabsorbed, the net tubular transport is a negative number because more is excreted than filtered.
Example 1: Urea is a solute that is both secreted and reabsorbed. A patient has a GFR of 80 mL/min and plasma [urea nitrogen] of 0.12 mg/mL. The urine flow rate is 1 mL/min, and the urine [urea nitrogen] is 4.8 mg/mL.
Filtered load = 80 mL/min × 0.12 mg/mL = 9.6 mg/min
Excretion rate = 1 mL/min × 4.8 mg/mL = 4.8 mg/min
Net tubular transport = 9.6 mg/min – 4.8 mg/min = 4.8 mg/min (net reabsorption)
Example 2: Sodium is a solute that is reabsorbed but not secreted. For the patient above, the plasma sodium is 1.4 mEq/mL, and urine sodium is 1.12 mEq/mL.
Filtered load = 80 mL/min × 1.4 mEq/mL = 112 mEq/min
Excretion rate = 1 mL/min × 1.12 mEq/mL = 1.12 mEq/min
Net tubular transport = 112 mEq/min – 1.12 mEq/min = 110.9 mEq/min (99% reabsorption)
16.1 Mechanisms of Renal Tubular Transport
The renal epithelial cells use a large array of transport proteins (i.e., primary active transporters, multiporters, and uniporters) to reabsorb or secrete various substances. For the most part, this is transcellular transport—solutes travel through the epithelial cells using one transport species in the luminal membrane and a different one in the basolateral membrane. In some cases, secretion or reabsorption is paracellular transport (around the cells) where a concentration gradient between the tubular fluid and interstitial fluid drives diffusion through leaky tight junctions.
Na+ Transport Mechanisms
The transport of almost all substances is directly dependent on, or strongly influenced by, the reabsorption of Na+. Na+ enters tubular cells across the luminal membrane via an array of sym-porters, antiporters, and, in some places, Na+ channels. Na+ is then pumped out of tubular cells across the basolateral membrane primarily by the Na+−K+ ATPase and moves by a combination of diffusion and bulk flow into the peritubular capillaries. Some Na+ also leaks back to the lumen by the paracellular pathway if the limiting gradient is reached (Fig. 16.1).
– Water reabsorption is linked to Na+ because Na+ is the major osmotic particle in the tubular fluid—in most regions of the tubule, when Na+ is removed, water follows.
– Cl−, the major anion in the tubular fluid, follows Na+ because net transport of cations requires an equal net transport of anions.
– The transport of many other substances is linked to Na+ via a cascade of symporters and antiporters. The Na+ gradient set up by the Na+−K+ ATPase drives the secondary active transport of other substances (e.g., H+ ions). The gradient of the other substance then drives the secondary active transport of still other substances.
Fig. 16.1 Electrochemical Na+ gradient.
Na+−K+ ATPase pumps Na+ ions out of the cell while conveying K+ ions into the cell (1), thereby producing a chemical Na+ gradient (2). Back diffusion of K+ (3) also leads to the development of a membrane potentia l (4). Both combined result in a high electrochemical gradient that provides the driving force for passive Na+ influx into tubular cells from the lumen. (ATP, adenosine triphosphate.)
Glucose Transport. The electrochemical gradient established by the Na+−K+ ATPase in the basolateral membrane strongly favors inward movement of the Na+ from the lumen into tubular cells via Na+−glucose symporters (SGLTs) in the luminal membrane. As glucose begins to accumulate within the tubular cells, it moves out across the basolateral membrane into peritubular capillary blood via a glucose uniporter (GLUT2).
Transport of Organic Solutes. A huge number of organic solutes present in the blood at low concentrations are filtered at the glomerulus and then reabsorbed (e.g., amino acids and Krebs cycle intermediates). This process involves either active transport of substances from the lumen into tubular cells via the luminal membrane or active transport of substances from tubular cells into peritubular capillary blood via the basolateral membrane. In most cases, these processes consist of symport or antiport with Na+ or another organic solute.
Transport of p -Aminohippuric Acid and Toxic Substances. P-aminohippuric acid (PAH) moves from peritubular capillary blood into tubular cells across the basolateral membrane via an anion antiporter and secreted from tubular cells into the tubular lumen across the luminal membrane via a multidrug-resistant protein. This transport system is also used by the body to rid itself of organic toxic substances.
16.2 Progress of Renal Tubular Transport
The progress of transport (reabsorption or secretion) for any substance that is freely filtered can be followed by looking at the ratio of its concentration in the tubular fluid, TFx, to its concentration in the plasma, Px. This ratio, [TF]x/[P]x, may rise, fall, or stay constant depending on the transport of the substance and on how much water is reabsorbed. Water is reabsorbed in most regions of the nephron and this has the effect of concentrating any solutes in the tubular fluid even if they are not transported at all. Therefore, we simultaneously have to take into account the reabsorption of water. This is achieved by measuring the [TF]/[P] ratio of inulin. Given that inulin is neither secreted nor reabsorbed, the rise in [TF]inulin/[P]inulin reflects the reabsorption of water. For example, if 75% of the filtered water has been reabsorbed (the original amount of inulin is now dissolved in only 25% of the water), the value of [TF]inulin/[P]inulin will be 4.
– The fractional reabsorption of water can be expressed as
1 – 1/([TF]inulin/[P]inulin)
For example, when 75% of the water is reabsorbed, the expression becomes
1 – 0.25 = 0.75
– For any solute (other than inulin itself), an expression that corrects the [TF]/[P] ratio for water reabsorption is
Fractional reabsorption of solute × = 1 – ([TF]x/[P]x)/([TF]inulin/[P]inulin)
– This expression calculates the fraction of a substance that has been reabsorbed. Consider as an example the reabsorption of urea. Suppose at a given point in the nephron the [TF]x/[P]x for urea is 1.2 (its concentration is now 20% greater than in plasma), and the [TF]inulin/[P]inulin for inulin is 4 (75% of the water has been reabsorbed). Then the fractional reabsorption of urea is
1 – 1.2/4 = 0.7
– This tells us that 70% of the urea has been reabsorbed even though its concentration has actually increased. This follows because a slightly smaller fraction of urea has been reabsorbed than water.
– If a solute undergoes net secretion, there will be more of that substance in the tubular fluid than was filtered. Its concentration will rise both because water is reabsorbed and because amounts are added to the fluid. The expression for fractional reabsorption will then result in a negative number. For example, if the fractional reabsorption is –0.5, it means that an amount equal to 50% of the filtered load has been secreted.
16.3 Limitations of Tubular Transport
The capacity of the tubules to secrete and reabsorb is not infinite. Rates reach an upper limit either because the transporters saturate (Tm-limited transport processes) or because the substance leaks back across leaky tight junctions (gradient-limited transport processes).
Saturation of Transporters: Tm-limited Transport Processes
Maximum tubular transport capacity (Tm) is the highest attainable rate of tubular transport of any given solute. Tm is reached due to saturation of the transport carriers and/or saturation of transport sites for a particular substance along the renal tubules.
– Substances with a reabsorptive Tm include glucose, phosphate, and sulfate ions, many amino acids, and Krebs cycle intermediates.
– Substances with a secretory Tm include PAH, uric acid, creatinine, histamine, and drugs (e.g., penicillin and morphine).
Reabsorptive Tm: Glucose.
Filtered load of glucose = GFR × plasma glucose
– If GFR remains constant, the filtered load of glucose will be proportional to the plasma glucose concentration.
– Glucose is not normally excreted, because filtered glucose is reabsorbed into blood in the proximal tubules by SGLT. As plasma glucose concentration, and consequently the filtered load, increases, renal Na+−glucose carriers become saturated, and the Tm for glucose is reached (400 mg/min). Increases in plasma glucose concentration above Tm will cause glucose to be excreted in urine (Fig. 16.2).
Osmotic diuresis with diabetes
Glucose is normally completely reabsorbed in the proximal tubule. In diabetes, however, high plasma glucose levels exceed their maximum tubular transport capacity (Tm), causing glucose to pass on to the loop of Henle and distal nephron, where it causes an osmotic diuresis. Net reabsorption of Na+ is also reduced (causing hyponatremia, or low blood [Na+]), because the large amount of tubular water accompanying the glucose also contains large amounts of Na+. These factors explain polyuria (excessive urination), polydipsia (excessive thirst), and dehydration, which are common presenting symptoms in diabetes.
Diabetes mellitus is a leading cause of chronic renal failure. The main pathogenic feature is glomerular disease with thickening of the glomerular basement membrane and glomerulosclerosis. This causes proteinuria (proteins in urine) to develop, and eventually the GFR is irreversibly reduced. Clinically, signs and symptoms include those seen with diabetes and its associated disorders, for example, retinopathy, neuropathy, hypertension, peripheral vascular disease, coronary artery disease, and nonhealing ulcers, as well as frothy urine, proteinuria, and edema (if nephrotic syndrome develops). Diagnosis is made with albuminuria (< 300 mg/dL) on two occasions, 3 to 6 months apart, decline in GFR, and elevated arterial blood pressure. Treatment involves meticulous glycemic control and angiotensin-converting enzyme (ACE) inhibitors to slow progression to chronic renal failure. Ultimately, dialysis or renal transplantation may be needed.
Secretory Tm: p-Aminohippuric Acid
Filtered PAH = GFR × plasma [PAH]
Fig. 16.2 Reabsorption of glucose and amino acids.
Fractional excretion of d-glucose is very low (~0.4%). This virtually complete reabsorption is achieved by secondary active transport (Na+−glucose symport) at the luminal cell membrane. About 95% of this activity occurs in the proximal tubule. If the plasma glucose concentration exceeds 10 to 15 mmol/L, as in diabetes mellitus (normally 5 mmol/L), glycosuria develops. (GFR, glomerular filtration rate)
– If GFR remains constant, the filtered load of PAH will be proportional to plasma [PAH].
– PAH is normally secreted into urine from peritubular capillary blood by carriers in the proximal tubule. As plasma [PAH] increases, these carriers become saturated, the secretion of PAH reaches its Tm, and the renal clearance of PAH decreases toward the value of GFR. The amount of PAH that is excreted is therefore the sum of the [PAH] that is filtered across the glomerular membrane and the [PAH] that is secreted from peritubular capillary blood into urine (Fig. 16.3).
Determination of Tm -limited Transport Processes Using Renal Clearance. Renal clearance can be used to determine whether or not renal transport of a substance is a Tm-limited transport process. This is done by constructing a renal titration curve, a combined plot of the filtered load, the urinary excretion rate, and the transport rate of substance X against the increasing plasma concentrations of X. If the transport rate becomes constant at high plasma concentrations of X, then it is a Tm-limited transport process.
Gradient-limited Transport Processes
For some solutes, rates of transport are limited by the concentration gradient between the filtrate and the peritubular capillary blood because the leakiness of the tight junctions does not allow a large gradient to exist. In this case, the solute diffuses back as fast as it is transported. — Na+ reabsorption along the nephron is an example of a gradient-limited transport process.
Fig. 16.3 Secretion and excretion of p-aminohippuric acid (PAH).
The proximal tubule uses active transport mechanisms to secrete numerous waste products. This is done with carriers for organic anions (e.g., PAH) and organic cations. This makes it possible to raise their clearance level above that of inulin and thus raise their fractional excretion above 1.0 to eliminate them more effectively (compare red and blue curves). Secretion is carrier-mediated and is therefore subject to saturation kinetics (saturation = maximum tubular transport capacity). The fractional excretion of organic anions or cations decreases when their plasma concentrations rise (PAH secretion curve reaches a plateau, and the slope of the PAH excretion curve decreases).
16.4 Renal Handling of Na+ and Its Accompanying Solutes
Refer to Fig. 16.4.
– About 67% of the filtered load of Na+ is reabsorbed from tubular fluid into peritubular capillary blood in the proximal tubule.
– Na+ enters the tubular cells from the lumen mostly via the Na+−H+ antiporter (NHE-3) in the luminal membrane.
Fig. 16.4 Na+ and Cl− reabsorption.
In the proximal tubule, Na+ ions diffuse passively from the tubular lumen into cells via the electroneural Na+−H+ antiporter (NHE-3) and various Na+ symporters for reabsorption of glucose and other substances (1). Because most of these symporters are electrogenic, the luminal membrane is depolarized, and an early lumen-negative transepithelial potential (LNTP) develops (2). This LNTP drives Cl− through paracellular spaces out of the lumen and into peritubular capillary blood (3). The reabsorption of Cl− lags behind that of Na+ and H2O, so luminal [Cl−] rises. As a result, Cl−starts to diffuse down its concentration gradient paracellularly along the middle and late proximal tubule (4), thereby producing a lumen-positive transepithelial potential (LPTP) (5). The LPTP drives Na+ and other cations into peritubular capillary blood. In the thick ascending limb of the loop of Henle (6), Na+ is reabsorbed via the Na+−K+−2Cl− symporter (7). This symporter is primarily electroneutral, but K+ recirculates back into the lumen through K+ channels. This hyperpolarizes the membrane, resulting in an LPTP. In the distal convoluted tubule, Na+ is reabsorbed via an electroneutral Na+−Cl− symporter (8). In principal cells of the collecting duct, Na+ exits the lumen via Na+ channels activated by aldosterone and antidiuretic hormone (ADH) and inhibited by prostaglandins and atrial natriuretic peptide (ANP) (9). On the basolateral membrane side, Na+ ions exit cells and enter peritubular capillary blood via Na+−K+ ATPase and an Na+−HCO3− symport carrier. In the latter case, Na+ exits the cell as H+ is secreted by the cell, resulting in the intracellular accumulation of HCO3−. (ANP, atrial natriuretic peptide; BSC, bumetanide-sensitive cotransporter; TSC, thiazide-sensitive cotransporter)
– Na+ leaves the tubular cells and enters peritubular capillary blood primarily via the Na+−K+ ATPase on the basolateral membrane.
– The proximal tubule has a high permeability to water, resulting in water following Na+ in equal proportions. The reabsorbed fluid then moves from interstitial space into peritubular capillaries by bulk flow caused by the net balance of hydrostatic and oncotic pressures acting across the capillaries.
– Cl−, HCO3−, glucose, phosphate, sulfate, amino acids, and many other solutes are reabsorbed along with Na+ and H2O. Cl−, the major anion in the filtrate, is mostly passively reabsorbed. The concentration gradient favors the movement of Cl− from lumen to peritubular capillary blood. This gradient is established by the reabsorption of water.
– In the early part of the proximal tubular lumen, the potential difference across the luminal membrane is slightly negative (−4 mV). In the late part of the proximal tubule, the potential difference becomes slightly positive (+3 mV).
– Organic acids and NH3 are secreted.
– H+ ions are actively secreted via the Na+−H+ antiporter in the luminal membrane.
Glomerulotubular Balance. Under steady-state conditions, a relatively constant fraction (two-thirds, or 67%) of the filtered Na+ and H2O is reabsorbed from tubular fluid into peritubular capillary blood in the proximal tubule despite variations in GFR. The absolute rate of Na+ reabsorption in the proximal tubule changes proportionately to the change in GFR (Na+ and H2O filtered load). This helps to minimize changes in Na+ and H2O excretion that follow changes in GFR.
Loop of Henle
– Twenty-five percent of Na+ is reabsorbed, along with Cl− and K+, in the thick ascending limb via an Na+−K+−2Cl− symporter in the luminal membrane. Net K+ reabsorption in this segment is very small compared with net reabsorption of Na+ and Cl−. K+ diffuses back to the tubular lumen.
– About 10% of the water is reabsorbed in the thin descending limb, and virtually none in the thick ascending limb. The relatively greater reabsorption of NaCl than water in the loop as a whole dilutes the tubular fluid. The loop of Henle is therefore the primary site for dilution of urine.
– The transepithelial potential difference is 10 mV lumen positive in the thick ascending limb, which helps promote cation reabsorption.
Distal Tubule and Collecting Duct
– Eight percent of Na+ is reabsorbed into tubular cells, along with Cl− in the early distal tubule, via an Na+−Cl− cotransporter in the luminal membrane. The early distal tubule is also impermeable to water, allowing NaCl to be reabsorbed without water. It is therefore a secondary site for dilution of urine.
– NaCl is reabsorbed along with water in the late distal tubule.
– H+ is actively secreted into the tubular lumen from peritubular capillary blood against a concentration gradient of 1000:1 via an H+−ATPase system in luminal membrane of the late distal tubule. Tubular fluid can be significantly acidified in the distal nephron.
Regulation of Na+ Reabsorption
Na+ is the most abundant solute in extracellular fluid (ECF). Consequently, the status of Na+ balance critically determines the volume of the ECF compartment and the long-term regulation of blood pressure. The renin–angiotensin−aldosterone system is the most important regulator of Na+ balance. The kidney regulates Na+ balance by adjusting the amount of Na+ excretion according to Na+ intake. Na+ excretion is the result of two processes: glomerular filtration and tubular reabsorption. The kidneys conserve Na+ by normally reabsorbing 99.4% of filtered Na+. Autoregulation of GFR automatically prevents excessive changes in the rate of Na+ excretion in response to spontaneous changes in blood pressure. In addition, glomerulotubular balance compensates for changes in the filtered load of Na+ due to acute changes in GFR under normal Na+ and volume status. When there is a chronic change in GFR due to a change in the size of the ECF compartment, glomerulotubular balance is abolished, and Na+ excretion varies more directly with GFR, such that Na+ balance and ECF volume are restored.
Renin–Angiotensin−Aldosterone System Regulation
Renin, synthesized in the juxtaglomerular cells of renal afferent arterioles, acts on angiotensinogen (synthesized in the liver) to form angiotensin I in the bloodstream (Fig. 16.5). Angiotensin I is converted to angiotensin II by ACE. ACE is located primarily in pulmonary capillary endothelium but is also present in systemic capillary endothelial cells. Angiotensin II stimulates the release of aldosterone from the adrenal cortex. Aldosterone stimulates Na+reabsorption in the distal tubules and collecting ducts. Angiotensin II is a potent vasoconstrictor and simulates the renal tubules to reabsorb Na+.
Renin release is stimulated by the following:
– ↓volume of the ECF compartment. This is detected by baroreceptors in renal afferent arterioles.
– ↑sympathetic nervous system activation
Fig. 16.5 Renin–angiotensin−aldosterone system (RAS).
If the mean renal blood pressure acutely drops below 99 mm Hg or so, renal baroreceptors will trigger the release of renin, thereby increasing the systemic plasma renin concentration. Renin is a peptidase that catalyzes the cleavage of angiotensin I from angiotensinogen. Angiotensin-converting enzyme (ACE) cleaves two amino acids from angiotensin I to produce angiotensin II. Angiotensin II and aldosterone are the most important effectors of the RAS. Angiotensin II stimulates the release of aldosterone by the adrenal cortex. Both hormones directly and indirectly lead to a renewed increase in arterial blood pressure, and in response, renin release decreases to normal levels. Moreover, both hormones directly inhibit renin release (negative feedback). (GFR, glomerular filtration rate; RBF, renal blood flow)
Sympathetic Nervous System and Humoral Regulation
– Increased sympathetic nervous system activation directly stimulates Na+ reabsorption in the proximal tubule.
– Atrial natriuretic peptide (ANP) is a hormone that is released from atrial myocardial cells in response to stretch of the atria. This stretch is due to an expansion of the ECF compartment. ANP increases Na+ excretion by
– ↓tubular reabsorption of Na+ in collecting ducts
– ↓renin and aldosterone secretion
Figure 16.6 shows overall regulation of NaCl balance.
Effects of Diuretics on Na+ Reabsorption
Diuretics decrease the absorption of Na+ and water by various mechanisms and thereby increase their excretion
Fig. 16.6 Regulation of salt (NaCl) balance.
(1) Salt deficit. When there is low blood Na+ (hyponatremia) (e.g., in aldosterone deficiency) in the presence of a primarily low water content of the body, blood osmolality and therefore antidiuretic hormone (ADH) secretion decrease, thereby transiently increasing the excretion of water. Although the hyposmolality is elevated, the extracellular fluid (ECF) volume, plasma volume, and blood pressure consequently decrease. This, in turn, activates the renin–angiotensin−aldosterone system (RAS), which stimulates thirst by secreting angiotensin II and induces Na+ retention by secreting aldosterone. The retention of Na+ increases plasma osmolality, leading to the secretion of ADH and, ultimately, to the retention of water. The additional intake of fluids in response to thirst also helps normalize ECF volume. (2) Salt excess. An abnormally high NaCl content of the body leads to increased plasma osmolality (thirst → drinking), as well as ADH secretion (retention of water). Thus, the ECF volume increases, and RAS activity is decreased. The additional secretion of atrial natriuretic peptide (ANP) leads to increased excretion of NaCl and water. (STN, solitary tract nucleus)
Carbonic Anhydrase Inhibitors. Carbonic anhydrase inhibitors (e.g., acetazolamide) d ecrease the production and reabsorption of HCO3− in tubular cells.
– ↑HCO3− excretion
– ↓Na+ reabsorption because fewer H+ ions are available for the Na+−H+ antiporter.
– Treatment of glaucoma (↓intraocular pressure via inhibition of aqueous humor formation)
Loop Diuretics. Loop diuretics (e.g., furosemide, bumetanide, and ethacrynic acid) inhibit the Na+−K+−2Cl− symporter in the thick ascending limb of the loop of Henle.
– ↑excretion of NaCl, K+, and Ca2+
– ↓ability to concentrate urine (by ↓ corticomedullary gradient)
– ↓ability to dilute urine (by inhibition of diluting segment of the loop of Henle)
– Pulmonary edema due to left ventricular failure
–Chronic congestive heart failure
–Acute oliguria (by maintaining urine formation)
–Acute hypercalcemia (with fluid replacement therapy)
Thiazide Diuretics. Thiazide diuretics (e.g., hydrochlorothiazide) inhibit the Na+−Cl− sym-porter in the early distal tubule.
– ↑NaCl and K+ excretion
– ↓Ca2+ excretion
– ↓ability to dilute urine (by inhibition of the cortical diluting segment of the loop of Henle)
– Mild to moderate hypertension
– Idiopathic hypercalciuria
Potassium-sparing Diuretics. Potassium-sparing diuretics (e.g., spironolactone, triamterene, and amiloride) act on the late distal tubule and collecting duct.
–Spironolactone competitively antagonizes aldosterone, thus inhibiting the synthesis of Na+ channel proteins and Na+−K+ ATPases.
– Triamterene and amiloride directly block Na+ channels, thus inhibiting Na+ reabsorption and K+ secretion.
– Na+ excretion
– ↓ K+ secretion
– Hypertension (spironolactone, triamterene, and amiloride). Triamterene and amiloride are weak diuretics and have little hypotensive action when given alone. However, they are useful when given along with the thiazides to prevent K+ depletion.
– Primary aldosteronism (spironolactone)
–Hyperuricemia, hypokalemia, or glucose intolerance (spironolactone)
Figure 16.7 summarizes the site and mechanism of action of diuretics.
Fig. 16.7 Site of action of diuretics.
(ECF, extracellular fluid)
Osmotic diuretics and their role in head injury management
Osmotic diuretics (e.g., mannitol) are solutes that cannot be reabsorbed from the tubular lumen into pericapillary blood and thus increase tubular fluid osmolarity. This increased osmolality causes water retention in the lumen, which is subsequently excreted. The excretion of other electrolytes (e.g., Na+, K+, Cl−, HCO3−, Ca2+, Mg2+, and PO43−) is also increased due to dilution of their tubular concentration by retained water. Mannitol is widely used to manage head injuries where there is a need for the acute reduction of intracranial pressure (ICP), for example, if the patient shows signs of brain herniation, a situation when brain tissue, cerebrospinal fluid, and blood vessels are moved or pressed away from their usual position. When given as a bolus, an osmotic gradient is set up so that fluid is drawn out of cells, thus decreasing edema (and ICP). Then circulating blood volume increases, and blood viscosity decreases. This has the beneficial effect of increasing cerebral blood flow and oxygen delivery.
16.5 Renal Handling of K+
Refer to Fig. 16.8.
– Sixty-seven percent of K+ is reabsorbed, along with Na+ and H2O.
– K+ is reabsorbed passively by its concentration gradient established by the reabsorption of water.
Thick Ascending Loop of Henle
– Twenty percent of K+ is reabsorbed along with Na+ and Cl− via the Na+−K+−2Cl− symporter in the luminal membrane.
Distal Tubule and Collecting Duct
– K+ is reabsorbed in the distal tubule via H+−K+ ATPase in the luminal membrane of α-intercalated cells. This occurs only on a low-K+ diet when the body tries to retain as much of the filtered load of K+ as possible. A diet that is low in K+ also decreases the number of channels; thus, K+ secretion is decreased.
– The relative amount of K+ secretion in the distal tubule depends on dietary intake of K+, aldosterone levels, acid–base status, tubular flow, and diuretics (Fig. 16.9).
– At normal and high K+ diets, K+ is secreted by principal cells into the cortical collecting ducts by active uptake from the interstitium via Na+−K+ ATPase on the basolateral membrane. K+ is then secreted from tubular cells into the lumen by passive transport, which is driven by the prevailing electrochemical gradient. Because most filtered K+ is reabsorbed in prior nephron segments, the rate of K+ excretion is proportional to its secretory rate in the distal nephron.
– A diet that is high in K+ increases the number of K+ channels in the luminal membrane, so K+ secretion is increased.
Fig. 16.8 Reabsorption and secretion of K+ in the kidney.
Approximately 67% of K+ is reabsorbed in the proximal tubule (comparable to the percentage of Na+ and H2O reabsorbed). This type of K+ transport is mainly paracellular and therefore passive. Solvent drag (when solute particles are carried along with the water flow or filtration) and the lumen-positive transepithelial potential (LPTP) (1) in the middle and late proximal tubule are responsible for it. In the loop of Henle, an other 15% of the filtered K+ is reabsorbed by trans- and paracellular routes (2). The amount of K+ secreted is determined in the collecting ducts. Larger or smaller quantities of K+ are then either reabsorbed or secreted according to need. The collecting duct contains principal cells (3) that reabsorb Na+ and secrete K+. Accumulated intracellular K+ can exit the cell through K+ channels on either side of the cell. The electrochemical K+ gradient across the membrane in question is decisive for the efflux of K+. The luminal membrane of principal cells also contains Na+ channels through which Na+ enters the cell. This depolarizes the luminal membrane, which reaches a potential of ~−20 mV. The driving force for K+ efflux is therefore higher on the luminal side than on the opposite side. Hence, K+ preferentially exits the cell toward the lumen (secretion). This is mainly why K+ secretion is coupled with Na+ reabsorption; that is, the more Na+ reabsorbed by the principal cell, the more K+ secreted. Type A (α) intercalated cells can actively reabsorb K+ in addition to secreting H+ due to a H+−K+ ATPase in the luminal membrane (like the parietal cells in the stomach) (4). (CA, carbonic anhydrase)
– Aldosterone increases K+ secretion and stimulates Na+ reabsorption into cells in the distal tubule and collecting duct. The intracellular Na+ is then pumped out of the tubular cell in exchange for K+ by the Na+−K+ ATPase pump. This increases the intracellular [K+], which provides a favorable electrochemical gradient for the passive secretion of K+ into the lumen via K+ channels. Aldosterone also increases the number of K+ channels in the luminal membrane.
Acid–base Status. Acidosis decreases K+ secretion; alkalosis increases K+ secretion.
– In acidosis, there is an excess of H+ ions in the bloodstream. H+ ions enter cells in exchange for K+ via the H+−K+ ATPase pump. This decreases the intracellular [K+], so K+ secretion is decreased.
– In alkalosis, there is a deficiency of H+ ions in the bloodstream, causing H+ to enter the blood from the cell in exchange for K+. This increases the intracellular [K+], so K+ secretion is increased.
Fig. 16.9 Factors that affect K+ secretion and excretion.
An increased K+ intake raises the intracellular and plasma [K+], which thereby increases the chemical driving force for K+ secretion. The intracellular [K+] in renal cells rises in alkalosis and falls in acute acidosis. This leads to a simultaneous fall in K+ excretion, which again rises in chronic acidosis. This is because acidosis-related inhibition of Na+−K+ ATPase reduces proximal Na+ reabsorption, resulting in in creased distal urinary flow, and the resulting hyperkalemia (high blood [K+]) stimulates aldosterone secretion. If there is increased urinary flow in the collecting duct (e.g., due to a high Na+ intake, osmotic diuresis, or other factors that inhibit Na+ reabsorption upstream), larger quantities of K+ will be excreted. Aldosterone leads to retention of Na+, an increase in extracellular fluid (ECF) volume, a moderate increase in H+ secretion, and increased K+ secretion. It also increases the number of Na+−K+ ATPase molecules in the target cells.
– Increased fluid flow in the distal nephron, detected by mechanosensitive elements in principal cells, increases K+ permeability and therefore increases K+ secretion.
– Thiazide and loop diuretics increase K+ secretion because of increased fluid flow past the principal cells. This can cause decreased blood K+ levels (hypokalemia) unless they are combined with a K+-sparing diuretic, which decreases K+ secretion.
16.6 Renal Handling of Urea, Phosphate, Calcium, and Magnesium
– Fifty percent of the filtered load of urea undergoes passive net reabsorption into peritubular capillary blood in the proximal tubule. The remaining 50% is excreted in urine.
– Urea is secreted from interstitial fluid into tubular fluid in the deep medullary regions of the loop of Henle, thereby restoring the urea content of the tubular fluid.
– The distal tubule, cortical, and outer medullary collecting ducts are relatively impermeable to urea, so no reabsorption occurs in these segments.
– The inner medullary collecting duct is permeable to urea in the presence of antidiuretic hormone (ADH), and urea is reabsorbed a second time. Some of the urea that is reabsorbed is recycled back to the loop of Henle and in doing so sets up the corticopapillary osmotic gradient (see page 179 and Fig. 17.3).
Fig. 16.10 Reabsorption of phosphate, Ca2+, and Mg2+.
Inorganic phosphate (Pi) is filtered, and a large part of this is reabsorbed (1). Pi is reabsorbed at the proximal tubule (2,3). Its luminal membrane contains an Na+−Pi symporter. Pi excretion rises in the presence of a Pi excess and falls during a Pi deficit. Acidosis also results in the excretion of phosphate and H+ ions. Hypocalcemia (low blood [Ca2+]) also induces a rise in Pi excretion. Parathyroid hormone (PTH) inhibits P↑ reabsorption (3). Ca2+ reabsorption occurs practically throughout the entire nephron (1,2) and is paracellular, that is, passive (4a) The lumen-positive transepithelial potential (LPTP) provides most of the driving force for this activity. Because Ca2+ reabsorption in the thick ascending limb of the loop of Henle (TAL) depends on NaCl reabsorption, loop diuretics inhibit Ca2+ reabsorption there. Parathyroid hormone (PTH) promotes Ca2+ reabsorption in TAL, as well as in the distal convoluted tubule, where Ca2+ is reabsorbed by transcellular active transport (4b). Thus, Ca2+ influx into the cell is passive and occurs via luminal Ca2+ channels, and Ca2+ efflux is active and occurs via Ca2+ ATPase and via the Na+−Ca2+ antiporter. The majority of Mg2+ is subject to paracellular reabsorption in the TAL (4a). Another 10% of Mg2+ is subject to transcellular reabsorption in the distal tubule (4b), probably like Ca2+.
– Eighty-five percent of filtered phosphate is reabsorbed in the proximal tubule by Na+−phosphate cotransport. The remaining 15% is excreted in urine.
– Parathyroid hormone (PTH) inhibits phosphate reabsorption in the proximal tubule by activating adenylate cyclase and increasing cyclic adenosine monophosphate (cAMP) production (↑ urinary cAMP). This inhibits Na+−phosphate cotransport.
– Phosphate is an important urinary buffer. It combines with excess H+ ions, which are excreted as phosphoric acid (H2PO4). This is also called titratable acid and is discussed further on page 188.
– Sixty percent of plasma Ca2+ is filtered across the glomerulus.
– Ninety percent of the filtered load of Ca2+ is reabsorbed into peritubular capillaries by passive transport in the proximal tubule and in the thick ascending loop of Henle. Although not coupled mechanistically, the amount reabsorbed depends on Na+ reabsorption because of its effects on driving forces.
– PTH facilitates further active Ca2+ reabsorption in the distal tubule by activating adenylate cyclase and ↑ cAMP.
– Loop diuretics (e.g., furosemide) inhibit Na+ reabsorption (via inhibition of the Na+−K+−2Cl− symporter) in the thick ascending loop of Henle. Because Ca2+ reabsorption depends on Na+ reabsorption, Ca2+ reabsorption decreases, and more Ca2+ is excreted. Loop diuretics can therefore be used in the treatment of hypercalcemia (with appropriate fluid replacement).
– Thiazide diuretics (e.g., hydrochlorothiazide) decrease Na+ reabsorption but actually stimulate Ca2+ reabsorption. They act in the early distal tubule to inhibit the Na+−Cl− symporter. Blocking Na+ uptake lowers the cytostolic [Na+] and stimulates Na+−Ca2+ antiport at the basolateral membrane. This increases Ca2+ reabsorption. Thiazides are used for the treatment of idiopathic hypercalciuria.
– The thick ascending loop of Henle is the major site for Mg2+ reabsorption through tight junctions, although reabsorption also occurs in the proximal and distal tubules.
– Mg2+ and Ca2+ compete for reabsorption in the thick ascending loop of Henle.
– Hypercalcemia inhibits Mg2+ reabsorption; therefore, more Mg2+ is excreted.
– Hypermagnesemia inhibits Ca2+ reabsorption; therefore, more Ca2+ is excreted.
Figure 16.10 shows the reabsorption of phosphate, Ca2+, and Mg2+.
Table 16.1 and Fig. 16.11 summarize the renal handling of solutes.
Fig. 16.11 Summary of the transport of substances along the nephron. (PAH, p-aminohippuric acid)