Ganong’s Review of Medical Physiology, 24th Edition
CHAPTER 37 Renal Function & Micturition
After reading this chapter, you should be able to:
Describe the morphology of a typical nephron and its blood supply.
Define autoregulation and list the major theories advanced to explain autoregulation in the kidneys.
Define glomerular filtration rate, describe how it can be measured, and list the major factors affecting it.
Outline tubular handling of Na+ and water.
Discuss tubular reabsorption and secretion of glucose and K+.
Describe how the countercurrent mechanism in the kidney operates to produce hypertonic or hypotonic urine.
List the major classes of diuretics; understand how each operates to increase urine flow.
Describe the voiding reflex and draw a cystometrogram.
Each individual renal tubule and its glomerulus is a unit (nephron). The size of the kidneys between species varies, as does the number of nephrons they contain. Each human kidney has approximately 1 million nephrons. The specific structures of the nephron are shown in diagrammatic fashion in Figure 37–1.
FIGURE 37–1 Diagram of a nephron. The main histologic features of the cells that make up each portion of the tubule are also shown.
The glomerulus, which is about 200 μm in diameter, is formed by the invagination of a tuft of capillaries into the dilated, blind end of the nephron (Bowman’s capsule). The capillaries are supplied by an afferent arteriole and drained by the efferent arteriole (Figure 37–2), and it is from the glomerulus that the filtrate is formed. The diameter of the afferent arteriole is larger than the efferent arteriole. Two cellular layers separate the blood from the glomerular filtrate in Bowman’s capsule: the capillary endothelium and the specialized epithelium of the capsule. The endothelium of the glomerular capillaries is fenestrated, with pores that are 70–90 nm in diameter. The endothelium of the glomerular capillaries is completely surrounded by the glomerular basement membrane along with specialized cells called podocytes. Podocytes have numerous pseudopodia that interdigitate (Figure 37–2) to form filtration slits along the capillary wall. The slits are approximately 25 nm wide, and each is closed by a thin membrane. The glomerular basement membrane, the basal lamina, does not contain visible gaps or pores. Stellate cells called mesangial cells are located between the basal lamina and the endothelium. They are similar to cells called pericytes, which are found in the walls of capillaries elsewhere in the body. Mesangial cells are especially common between two neighboring capillaries, and in these locations the basal membrane forms a sheath shared by both capillaries (Figure 37–2). The mesangial cells are contractile and play a role in the regulation of glomerular filtration. Mesangial cells secrete the extracellular matrix, take up immune complexes, and are involved in the progression of glomerular disease.
FIGURE 37–2 Structural details of glomerulus. A) Section through vascular pole, showing capillary loops. B) Relation of mesangial cells and podocytes to glomerular capillaries. C) Detail of the way podocytes form filtration slits on the basal lamina, and the relation of the lamina to the capillary endothelium. D) Enlargement of the rectangle in C to show the podocyte processes. The fuzzy material on their surfaces is glomerular polyanion.
Functionally, the glomerular membrane permits the free passage of neutral substances up to 4 nm in diameter and almost totally excludes those with diameters greater than 8 nm. However, the charge on molecules as well as their diameters affects their passage into Bowman’s capsule. The total area of glomerular capillary endothelium across which filtration occurs in humans is about 0.8 m2.
The general features of the cells that make up the walls of the tubules are shown in Figure 37–1; however, there are cell sub-types in all segments, and the anatomic differences between them correlate with differences in function.
The human proximal convoluted tubule is about 15 mm long and 55 μm in diameter. Its wall is made up of a single layer of cells that interdigitate with one another and are united by apical tight junctions. Between the cells are extensions of the extracellular space called the lateral intercellular spaces. The luminal edges of the cells have a striated brush border due to the presence of many microvilli.
The convoluted proximal tubule straightens and the next portion of each nephron is the loop of Henle. The descending portion of the loop and the proximal portion of the ascending limb are made up of thin, permeable cells. On the other hand, the thick portion of the ascending limb (Figure 37–1) is made up of thick cells containing many mitochondria. The nephrons with glomeruli in the outer portions of the renal cortex have short loops of Henle (cortical nephrons), whereas those with glomeruli in the juxtamedullary region of the cortex (juxtamedullary nephrons) have long loops extending down into the medullary pyramids. In humans, only 15% of the nephrons have long loops.
The thick end of the ascending limb of the loop of Henle reaches the glomerulus of the nephron from which the tubule arose and nestles between its afferent and efferent arterioles. Specialized cells at the end form the macula densa, which is close to the efferent and particularly the afferent arteriole (Figure 37–2). The macula, the neighboring lacis cells, and the renin-secreting granular cells in the afferent arteriole form the juxtaglomerular apparatus(see Figure 38–8).
The distal convoluted tubule, which starts at the macula densa, is about 5 mm long. Its epithelium is lower than that of the proximal tubule, and although a few microvilli are present, there is no distinct brush border. The distal tubules coalesce to form collecting ducts that are about 20 mm long and pass through the renal cortex and medulla to empty into the pelvis of the kidney at the apexes of the medullary pyramids. The epithelium of the collecting ducts is made up of principal cells (P cells) and intercalated cells (I cells). The P cells, which predominate, are relatively tall and have few organelles. They are involved in Na+ reabsorption and vasopressin-stimulated water reabsorption. The I cells, which are present in smaller numbers and are also found in the distal tubules, have more microvilli, cytoplasmic vesicles, and mitochondria. They are concerned with acid secretion and transport. The total length of the nephrons, including the collecting ducts, ranges from 45 to 65 mm.
Cells in the kidneys that appear to have a secretory function include not only the granular cells in the juxtaglomerular apparatus but also some of the cells in the interstitial tissue of the medulla. These cells are called renal medullary interstitial cells (RMICs) and are specialized fibroblast-like cells. They contain lipid droplets and are a major site of cyclooxygenase 2 (COX-2) and prostaglandin synthase (PGES) expression. PGE2 is the major prostanoid synthesized in the kidney and is an important paracrine regulator of salt and water homeostasis. PGE2 is secreted by the RMICs, by the macula densa, and by cells in the collecting ducts; prostacyclin (PGI2) and other prostaglandins are secreted by the arterioles and glomeruli.
The renal circulation is diagrammed in Figure 37–3. The afferent arterioles are short, straight branches of the interlobular arteries. Each divides into multiple capillary branches to form the tuft of vessels in the glomerulus. The capillaries coalesce to form the efferent arteriole, which in turn breaks up into capillaries that supply the tubules (peritubular capillaries) before draining into the interlobular veins. The arterial segments between glomeruli and tubules are thus technically a portal system, and the glomerular capillaries are the only capillaries in the body that drain into arterioles. However, there is relatively little smooth muscle in the efferent arterioles.
FIGURE 37–3 Renal circulation. Interlobar arteries divide into arcuate arteries, which give off interlobular arteries in the cortex. The inter-lobular arteries provide an afferent arteriole to each glomerulus. The efferent arteriole from each glomerulus breaks up into capillaries that supply blood to the renal tubules. Venous blood enters interlobular veins, which in turn flow via arcuate veins to the interlobar veins. (Modified from Boron WF, Boulpaep EL: Medical Physiology. Saunders, 2009.)
The capillaries draining the tubules of the cortical nephrons form a peritubular network, whereas the efferent arterioles from the juxtamedullary glomeruli drain not only into a peritubular network, but also into vessels that form hairpin loops (the vasa recta). These loops dip into the medullary pyramids alongside the loops of Henle (Figure 37–3). The descending vasa recta have a nonfenestrated endothelium that contains a facilitated transporter for urea, and the ascending vasa recta have a fenestrated endothelium, consistent with their function in conserving solutes.
The efferent arteriole from each glomerulus breaks up into capillaries that supply a number of different nephrons. Thus, the tubule of each nephron does not necessarily receive blood solely from the efferent arteriole of the same nephron. In humans, the total surface of the renal capillaries is approximately equal to the total surface area of the tubules, both being about 12 m2. The volume of blood in the renal capillaries at any given time is 30–40 mL.
The kidneys have an abundant lymphatic supply that drains via the thoracic duct into the venous circulation in the thorax.
The renal capsule is thin but tough. If the kidney becomes edematous, the capsule limits the swelling, and the tissue pressure (renal interstitial pressure) rises. This decreases the glomerular filtration rate (GFR) and is claimed to enhance and prolong anuria in acute renal failure.
INNERVATION OF THE RENAL VESSELS
The renal nerves travel along the renal blood vessels as they enter the kidney. They contain many postganglionic sympathetic efferent fibers and a few afferent fibers. There also appears to be a cholinergic innervation via the vagus nerve, but its function is uncertain. The sympathetic preganglionic innervation comes primarily from the lower thoracic and upper lumbar segments of the spinal cord, and the cell bodies of the postganglionic neurons are in the sympathetic ganglion chain, in the superior mesenteric ganglion, and along the renal artery. The sympathetic fibers are distributed primarily to the afferent and efferent arterioles, the proximal and distal tubules, and the juxtaglomerular apparatus (see Chapter 38). In addition, there is a dense noradrenergic innervation of the thick ascending limb of the loop of Henle.
Nociceptive afferents that mediate pain in kidney disease parallel the sympathetic efferents and enter the spinal cord in the thoracic and upper lumbar dorsal roots. Other renal afferents presumably mediate a renorenal reflex by which an increase in ureteral pressure in one kidney leads to a decrease in efferent nerve activity to the contralateral kidney. This decrease permits an increase in its excretion of Na+ and water.
In a resting adult, the kidneys receive 1.2–1.3 L of blood per minute, or just under 25% of the cardiac output. Renal blood flow can be measured with electromagnetic or other types of flow meters, or it can be determined by applying the Fick principle (see Chapter 30) to the kidney; that is, by measuring the amount of a given substance taken up per unit of time and dividing this value by the arteriovenous difference for the substance across the kidney. Because the kidney filters plasma, the renal plasma flow (RPF) equals the amount of a substance excreted per unit of time divided by the renal arteriovenous difference as long as the amount in the red cells is unaltered during passage through the kidney. Any excreted substance can be used if its concentration in arterial and renal venous plasma can be measured and if it is not metabolized, stored, or produced by the kidney and does not itself affect blood flow.
RPF can be measured by infusing p-aminohippuric acid (PAH) and determining its urine and plasma concentrations. PAH is filtered by the glomeruli and secreted by the tubular cells, so that its extraction ratio (arterial concentration minus renal venous concentration divided by arterial concentration) is high. For example, when PAH is infused at low doses, 90% of the PAH in arterial blood is removed in a single circulation through the kidney. It has therefore become commonplace to calculate the “RPF” by dividing the amount of PAH in the urine by the plasma PAH level, ignoring the level in renal venous blood. Peripheral venous plasma can be used because its PAH concentration is essentially identical to that in the arterial plasma reaching the kidney. The value obtained should be called the effective renal plasma flow (ERPF) to indicate that the level in renal venous plasma was not measured. In humans, ERPF averages about 625 mL/min.
Concentration of PAH in urine (UPAH): 14 mg/mL
Urine flow (): 0.9 mL/min
Concentration of PAH in plasma (PPAH): 0.02 mg/mL
It should be noted that the ERPF determined in this way is the clearance of PAH. The concept of clearance is discussed in detail below.
ERPF can be converted to actual renal plasma flow (RPF):
Average PAH extraction ratio: 0.9
From the renal plasma flow, the renal blood flow can be calculated by dividing by 1 minus the hematocrit:
Hematocrit (Hct): 45%
PRESSURE IN RENAL VESSELS
The pressure in the glomerular capillaries has been measured directly in rats and has been found to be considerably lower than predicted on the basis of indirect measurements. When the mean systemic arterial pressure is 100 mm Hg, the glomerular capillary pressure is about 45 mm Hg. The pressure drop across the glomerulus is only 1–3 mm Hg, but a further drop occurs in the efferent arteriole so that the pressure in the peritubular capillaries is about 8 mm Hg. The pressure in the renal vein is about 4 mm Hg. Pressure gradients are similar in squirrel monkeys and presumably in humans, with a glomerular capillary pressure that is about 40% of systemic arterial pressure.
REGULATION OF THE RENAL BLOOD FLOW
Norepinephrine (noradrenaline) constricts the renal vessels, with the greatest effect of injected norepinephrine being exerted on the interlobular arteries and the afferent arterioles. Dopamine is made in the kidney and causes renal vasodilation and natriuresis. Angiotensin II exerts a constrictor effect on both the afferent and efferent arterioles. Prostaglandins increase blood flow in the renal cortex and decrease blood flow in the renal medulla. Acetylcholine also produces renal vasodilation. A high-protein diet raises glomerular capillary pressure and increases renal blood flow.
FUNCTIONS OF THE RENAL NERVES
Stimulation of the renal nerves increases renin secretion by a direct action of released norepinephrine on β1-adrenergic receptors on the juxtaglomerular cells (see Chapter 38) and it increases Na+ reabsorption, probably by a direct action of norepinephrine on renal tubular cells. The proximal and distal tubules and the thick ascending limb of the loop of Henle are richly innervated. When the renal nerves are stimulated to increasing extents in experimental animals, the first response is an increase in the sensitivity of the granular cells in the juxtaglomerular apparatus (Table 37–1), followed by increased renin secretion, then increased Na+ reabsorption, and finally, at the highest threshold, renal vasoconstriction with decreased glomerular filtration and renal blood flow. It is still unsettled whether the effect on Na+ reabsorption is mediated via α- or β-adrenergic receptors, and it may be mediated by both. The physiologic role of the renal nerves in Na+ homeostasis is also unsettled, in part because most renal functions appear to be normal in patients with transplanted kidneys, and it takes some time for transplanted kidneys to acquire a functional innervation.
TABLE 37–1 Renal responses to graded renal nerve stimulation.
Strong stimulation of the sympathetic noradrenergic nerves to the kidneys causes a marked decrease in renal blood flow. This effect is mediated by α1-adrenergic receptors and to a lesser extent by postsynaptic α2-adrenergic receptors. Some tonic discharge takes place in the renal nerves at rest in animals and humans. When systemic blood pressure falls, the vasoconstrictor response produced by decreased discharge in the baroreceptor nerves includes renal vasoconstriction. Renal blood flow is decreased during exercise and, to a lesser extent, on rising from the supine position.
AUTOREGULATION OF RENAL BLOOD FLOW
When the kidney is perfused at moderate pressures (90–220 mm Hg in the dog), the renal vascular resistance varies with the pressure so that renal blood flow is relatively constant (Figure 37–4). Autoregulation of this type occurs in other organs, and several factors contribute to it (see Chapter 32). Renal autoregulation is present in denervated and in isolated, perfused kidneys, but is prevented by the administration of drugs that paralyze vascular smooth muscle. It is probably produced in part by a direct contractile response to stretch of the smooth muscle of the afferent arteriole. NO may also be involved. At low perfusion pressures, angiotensin II also appears to play a role by constricting the efferent arterioles, thus maintaining the GFR. This is believed to be the explanation of the renal failure that sometimes develops in patients with poor renal perfusion who are treated with drugs that inhibit angiotensin-converting enzyme.
FIGURE 37–4 Autoregulation in the kidneys.
REGIONAL BLOOD FLOW & OXYGEN CONSUMPTION
The main function of the renal cortex is filtration of large volumes of blood through the glomeruli, so it is not surprising that the renal cortical blood flow is relatively great and little oxygen is extracted from the blood. Cortical blood flow is about 5 mL/g of kidney tissue/min (compared with 0.5 mL/g/min in the brain), and the arteriovenous oxygen difference for the whole kidney is only 14 mL/L of blood, compared with 62 mL/L for the brain and 114 mL/L for the heart (see Table 33–1). The PO2 of the cortex is about 50 mm Hg. On the other hand, maintenance of the osmotic gradient in the medulla requires a relatively low blood flow. It is not surprising, therefore, that the blood flow is about 2.5 mL/g/min in the outer medulla and 0.6 mL/g/min in the inner medulla. However, metabolic work is being done, particularly to reabsorb Na+ in the thick ascending limb of Henle, so relatively large amounts of O2 are extracted from the blood in the medulla. The PO2 of the medulla is about 15 mm Hg. This makes the medulla vulnerable to hypoxia if flow is reduced further. NO, prostaglandins, and many cardiovascular peptides in this region function in a paracrine fashion to maintain the balance between low blood flow and metabolic needs.
Glomerular filtration rate (GFR) is the amount of plasma ultrafiltrate formed each minute and can be measured in intact experimental animals and humans by measuring the plasma level of a substance and the amount of that substance that is excreted. A substance to be used to measure GFR must be freely filtered through the glomeruli and must be neither secreted nor reabsorbed by the tubules.
In addition to the requirement that it be freely filtered and neither reabsorbed nor secreted in the tubules, a substance suitable for measuring the GFR should be nontoxic and not metabolized by the body. Inulin, a polymer of fructose with a molecular weight of 5200, meets these criteria in humans and most animals and can be used to measure GFR.
Renal plasma clearance is the volume of plasma from which a substance is completely removed by the kidney in a given amount of time (usually minutes). The amount of that substance that appears in the urine per unit of time is the result of the renal filtering of a certain number of milliliters of plasma that contained this amount. GFR and clearance are measured in mL/min.
Therefore, if the substance is designated by the letter X, the GFR is equal to the concentration of X in urine (UX) times the urine flow per unit of time divided by the arterial plasma level of X (PX), or . This value is called the clearance of X (CX).
In practice, a loading dose of inulin is administered intravenously, followed by a sustaining infusion to keep the arterial plasma level constant. After the inulin has equilibrated with body fluids, an accurately timed urine specimen is collected and a plasma sample obtained halfway through the collection. Plasma and urinary inulin concentrations are determined and the clearance is calculated:
Clearance of creatinine (CCr) can also be used to determine GFR, however some creatinine is secreted by the tubules thus the clearance of creatinine will be slightly higher than inulin. In spite of this, the clearance of endogenous creatinine is a reasonable estimate of GFR as the values agree quite well with the GFR values measured with inulin (see Table 37–2). More common though is the use of PCr values as an index of renal function (normal=1 mg/dL).
TABLE 37–2 Normal clearance values of different solutes.
The GFR in a healthy adult of average size is approximately 125 mL/min. Its magnitude correlates fairly well with surface area, but values in women are 10% lower than those in men even after correction for surface area. A rate of 125 mL/min is 7.5 L/h, or 180 L/d, whereas the normal urine volume is about 1 L/d. Thus, 99% or more of the filtrate is normally reabsorbed. At the rate of 125 mL/min, in 1 day the kidneys filter an amount of fluid equal to four times the total body water, 15 times the ECF volume, and 60 times the plasma volume.
CONTROL OF GFR
The factors governing filtration across the glomerular capillaries are the same as those governing filtration across all other capillaries (see Chapter 31), that is, the size of the capillary bed, the permeability of the capillaries, and the hydrostatic and osmotic pressure gradients across the capillary wall. For each nephron:
where Kf, the glomerular ultrafiltration coefficient, is the product of the glomerular capillary wall hydraulic conductivity (ie, its permeability) and the effective filtration surface area. PGC is the mean hydrostatic pressure in the glomerular capillaries, PT the mean hydrostatic pressure in the tubule (Bowman’s space), πGC the oncotic pressure of the plasma in the glomerular capillaries, and πT the oncotic pressure of the filtrate in the tubule (Bowman’s space).
The permeability of the glomerular capillaries is about 50 times that of the capillaries in skeletal muscle. Neutral substances with effective molecular diameters of less than 4 nm are freely filtered, and the filtration of neutral substances with diameters of more than 8 nm approaches zero. Between these values, filtration is inversely proportional to diameter. However, sialoproteins in the glomerular capillary wall are negatively charged, and studies with negatively and positively charged dextrans indicate that the negative charges repel negatively charged substances in blood, with the result that filtration of anionic substances 4 nm in diameter is less than half that of neutral substances of the same size. This probably explains why albumin, with an effective molecular diameter of approximately 7 nm, normally has a glomerular concentration only 0.2% of its plasma concentration rather than the higher concentration that would be expected on the basis of diameter alone; circulating albumin is negatively charged. Conversely, filtration of cationic substances is greater than that of neutral substances.
The amount of protein in the urine is normally less than 100 mg/d, and most of this is not filtered but comes from shed tubular cells. The presence of significant amounts of albumin in the urine is called albuminuria. In nephritis, the negative charges in the glomerular wall are dissipated, and albuminuria can occur for this reason without an increase in the size of the “pores” in the membrane.
SIZE OF THE CAPILLARY BED
Kf can be altered by the mesangial cells, with contraction of these cells producing a decrease in Kf that is largely due to a reduction in the area available for filtration. Contraction of points where the capillary loops bifurcate probably shifts flow away from some of the loops, and elsewhere, contracted mesangial cells distort and encroach on the capillary lumen. Agents that have been shown to affect the mesangial cells are listed in Table 37–3. Angiotensin II is an important regulator of mesangial contraction, and there are angiotensin II receptors in the glomeruli. In addition, some evidence suggests that mesangial cells make renin.
TABLE 37–3 Agents causing contraction or relaxation of mesangial cells.
HYDROSTATIC & OSMOTIC PRESSURE
The pressure in the glomerular capillaries is higher than that in other capillary beds because the afferent arterioles are short, straight branches of the interlobular arteries. Furthermore, the vessels “downstream” from the glomeruli, the efferent arterioles, have a relatively high resistance. The capillary hydrostatic pressure is opposed by the hydrostatic pressure in Bowman’s capsule. It is also opposed by the oncotic pressure gradient across the glomerular capillaries (πGC – πT). πT is normally negligible, and the gradient is essentially equal to the oncotic pressure of the plasma proteins.
The actual pressures in one strain of rats are shown in Figure 37–5. The net filtration pressure (PUF) is 15 mm Hg at the afferent end of the glomerular capillaries, but it falls to zero—that is, filtration equilibrium is reached—proximal to the efferent end of the glomerular capillaries. This is because fluid leaves the plasma and the oncotic pressure rises as blood passes through the glomerular capillaries. The calculated change in Δπ along an idealized glomerular capillary is also shown in Figure 37–5. It is apparent that portions of the glomerular capillaries do not normally contribute to the formation of the glomerular ultrafiltrate; that is, exchange across the glomerular capillaries is flow-limited rather than diffusion-limited. It is also apparent that a decrease in the rate of rise of the Δ curve produced by an increase in RPF would increase filtration because it would increase the distance along the capillary in which filtration was taking place.
FIGURE 37–5 Hydrostatic pressure (PGC) and osmotic pressure (πGC) in a glomerular capillary in the rat. PT, pressure in Bowman’s capsule; PUF, net filtration pressure. πT is normally negligible, so . . (Reproduced with permission from Mercer PF, Maddox DA, Brenner BM: Current concepts of sodium chloride and water transport by the mammalian nephron. West J Med 1974;120:33.)
There is considerable species variation in whether filtration equilibrium is reached, and some uncertainties are inherent in the measurement of Kf. It is uncertain whether filtration equilibrium is reached in humans.
CHANGES IN GFR
Variations in the factors discussed in the preceding paragraphs and listed in Table 37–4 have predictable effects on the GFR. Changes in renal vascular resistance as a result of autoregulation tend to stabilize filtration pressure, but when the mean systemic arterial pressure drops below the autoregulatory range (Figure 37–4), GFR drops sharply. The GFR tends to be maintained when efferent arteriolar constriction is greater than afferent constriction, but either type of constriction decreases blood flow to the tubules.
TABLE 37–4 Factors affecting the GFR.
The ratio of the GFR to the RPF, the filtration fraction, is normally 0.16–0.20. The GFR varies less than the RPF. When there is a fall in systemic blood pressure, the GFR falls less than the RPF because of efferent arteriolar constriction, and consequently the filtration fraction rises.
The amount of any substance (X) that is filtered is the product of the GFR and the plasma level of the substance (ClnPX). The tubular cells may add more of the substance to the filtrate (tubular secretion), may remove some or all of the substance from the filtrate (tubular reabsorption), or may do both. The amount of the substance excreted per unit of time equals the amount filtered plus the net amount transferred by the tubules. This latter quantity is conveniently indicated by the symbol TX (Figure 37–6). The clearance of the substance equals the GFR if there is no net tubular secretion or reabsorption, exceeds the GFR if there is net tubular secretion, and is less than the GFR if there is net tubular reabsorption.
FIGURE 37–6 Tubular function. For explanation of symbols, see text.
Much of our knowledge about glomerular filtration and tubular function has been obtained by using micropuncture techniques. Micropipettes can be inserted into the tubules of the living kidney and the composition of aspirated tubular fluid determined by the use of microchemical techniques. In addition, two pipettes can be inserted in a tubule and the tubule perfused in vivo. Alternatively, isolated perfused segments of tubules can be studied in vitro, and tubular cells can be grown and studied in culture.
MECHANISMS OF TUBULAR REABSORPTION & SECRETION
Small proteins and some peptide hormones are reabsorbed in the proximal tubules by endocytosis. Other substances are secreted or reabsorbed in the tubules by passive diffusion between cells and through cells by facilitated diffusion down chemical or electrical gradients or active transport against such gradients. Movement is by way of ion channels, exchangers, cotransporters, and pumps. Many of these have now been cloned, and their regulation is being studied.
It is important to note that the pumps and other transporters in the luminal membrane are different from those in the basolateral membrane. As was discussed for the gastrointestinal epithelium, it is this polarized distribution that makes possible net movement of solutes across the epithelia.
Like transport systems elsewhere, renal active transport systems have a maximal rate, or transport maximum (Tm), at which they can transport a particular solute. Thus, the amount of a particular solute transported is proportional to the amount present up to the Tm for the solute, but at higher concentrations, the transport mechanism is saturated and there is no appreciable increment in the amount transported. However, the Tms for some systems are high, and it is difficult to saturate them.
It should also be noted that the tubular epithelium, like that of the small intestine, is a leaky epithelium in that the tight junctions between cells permit the passage of some water and electrolytes. The degree to which leakage by this paracellular pathway contributes to the net flux of fluid and solute into and out of the tubules is controversial since it is difficult to measure, but current evidence seems to suggest that it is a significant factor in the proximal tubule. One indication of this is that paracellin-1, a protein localized to tight junctions, is related to Mg2+ reabsorption, and a loss-of-function mutation of its gene causes severe Mg2+ and Ca2+ loss in the urine.
The reabsorption of Na+ and Cl– plays a major role in body electrolyte and water homeostasis. In addition, Na+ transport is coupled to the movement of H+, glucose, amino acids, organic acids, phosphate, and other electrolytes and substances across the tubule walls. The principal cotransporters and exchangers in the various parts of the nephron are listed in Table 37–5. In the proximal tubules, the thick portion of the ascending limb of the loop of Henle, the distal tubules, and the collecting ducts, Na+ moves by cotransport or exchange from the tubular lumen into the tubular epithelial cells down its concentration and electrical gradients, and is then actively pumped from these cells into the interstitial space. Na+ is pumped into the interstitium by Na, K ATPase in the basolateral membrane. Thus, Na+ is actively transported out of all parts of the renal tubule except the thin portions of the loop of Henle. The operation of the ubiquitous Na+ pump is considered in detail in Chapter 2. It extrudes three Na+ in exchange for two K+ that are pumped into the cell.
TABLE 37–5 Transport proteins involved in the movement of Na+ and Cl– across the apical membranes of renal tubular cells.a
The tubular cells along the nephron are connected by tight junctions at their luminal edges, but there is space between the cells along the rest of their lateral borders. Much of the Na+ is actively transported into these lateral intercellular spaces (Figure 37–7).
FIGURE 37–7 Mechanism of Na+ reabsorption in the proximal tubule. Na+ moves out of the tubular lumen by cotransport and exchange mechanism through the apical membrane of the tubule (dashed line). The Na+ is then actively transported into the interstitial fluid by Na, K ATPase in the basolateral membrane (solid lines). K+ enters the interstitial fluid via K+ channels. A small amount of Na+, other solutes, and H2O re-enter the tubular lumen by passive transport through the tight junctions (dotted lines).
Normally about 60% of the filtered Na+ is reabsorbed in the proximal tubule, primarily by Na–H exchange. Another 30% is absorbed via the Na–2Cl–K cotransporter in the thick ascending limb of the loop of Henle. In both of these segments of the nephron, passive paracellular movement of Na+ also contributes to overall Na+ reabsorption. In the distal convoluted tubule 7% of the filtered Na+ is absorbed by the Na–Cl cotransporter. The remainder of the filtered Na+, about 3%, is absorbed via ENaC channels in the collecting ducts, and this is the portion that is regulated by aldosterone to permit homeostatic adjustments in Na+ balance.
Glucose, amino acids, and bicarbonate are reabsorbed along with Na+ in the early portion of the proximal tubule (Figure 37–8). Glucose is typical of substances removed from the urine by secondary active transport. It is filtered at a rate of approximately 100 mg/min (80 mg/dL of plasma × 125 mL/min). Essentially all of the glucose is reabsorbed, and no more than a few milligrams appear in the urine per 24 h. The amount reabsorbed is proportional to the amount filtered and hence to the plasma glucose level (PG) times the GFR up to the transport maximum (TmG). When the TmG is exceeded, the amount of glucose in the urine rises (Figure 37–9). The TmG is about 375 mg/min in men and 300 mg/min in women.
FIGURE 37–8 Reabsorption of various solutes in the proximal tubule. TF/P, tubular fluid:plasma concentration ratio. (Courtesy of FC Rector Jr)
FIGURE 37–9 Renal glucose transport. Top: Relation between the plasma level (P) and excretion (UV) of glucose and inulin. Bottom: Relation between the plasma glucose level (PG) and amount of glucose reabsorbed (TG).
The renal threshold for glucose is the plasma level at which the glucose first appears in the urine in more than the normal minute amounts. One would predict that the renal threshold would be about 300 mg/dL, that is, 375 mg/min (TmG) divided by 125 mL/min (GFR). However, the actual renal threshold is about 200 mg/dL of arterial plasma, which corresponds to a venous level of about 180 mg/dL. Figure 37–9 shows why the actual renal threshold is less than the predicted threshold. The “ideal” curve shown in this diagram would be obtained if the TmG in all the tubules was identical and if all the glucose were removed from each tubule when the amount filtered was below the TmG. This is not the case, and in humans, for example, the actual curve is rounded and deviates considerably from the “ideal” curve. This deviation is called splay. The magnitude of the splay is inversely proportional to the avidity with which the transport mechanism binds the substance it transports.
GLUCOSE TRANSPORT MECHANISM
Glucose reabsorption in the kidneys is similar to glucose reabsorption in the intestine (see Chapter 26). Glucose and Na+ bind to the sodium-dependent glucose transporter (SGLT) 2 in the apical membrane, and glucose is carried into the cell as Na+ moves down its electrical and chemical gradient. The Na+ is then pumped out of the cell into the interstitium, and the glucose exits by facilitated diffusion via glucose transporter (GLUT) 2 into the interstitial fluid. At least in the rat, there is some transport by SGLT 1 and GLUT 1 as well.
SGLT 2 specifically binds the D isomer of glucose, and the rate of transport of D-glucose is many times greater than that of L-glucose. Glucose transport in the kidneys is inhibited, as it is in the intestine, by the plant glucoside phlorhizin, which competes with D-glucose for binding to the carrier.
ADDITIONAL EXAMPLES OF SECONDARY ACTIVE TRANSPORT
Like glucose reabsorption, amino acid reabsorption is most marked in the early portion of the proximal convoluted tubule. Absorption in this location resembles absorption in the intestine (see Chapter 26). The main carriers in the apical membrane cotransport Na+, whereas the carriers in the basolateral membranes are not Na+-dependent. Na+ is pumped out of the cells by Na, K ATPase and the amino acids leave by passive or facilitated diffusion to the interstitial fluid.
Some Cl– is reabsorbed with Na+ and K+ in the thick ascending limb of the loop of Henle. In addition, two members of the family of Cl channels have been identified in the kidney. Mutations in the gene for one of the renal channels is associated with Ca2+-containing kidney stones and hypercalciuria (Dent disease), but how tubular transport of Ca2+ and Cl– are linked is still unsettled.
The dynamics of PAH transport illustrate the operation of the active transport mechanisms that secrete substances into the tubular fluid (see Clinical Box 37–1). The filtered load of PAH is a linear function of the plasma level, but PAH secretion increases as PPAH rises only until a maximal secretion rate (TmPAH) is reached (Figure 37–10). When PPAH is low, CPAH is high; but as PPAH rises above TmPAH, CPAH falls progressively. It eventually approaches the clearance of inulin (CIn) (Figure 37–11), because the amount of PAH secreted becomes a smaller and smaller fraction of the total amount excreted. Conversely, the clearance of glucose is essentially zero at PG levels below the renal threshold; but above the threshold, CG rises to approach CIn as PG is raised.
CLINICAL BOX 37–1
Substances Secreted by the Tubules
Derivatives of hippuric acid in addition to PAH, phenol red and other sulfonphthalein dyes, penicillin, and a variety of iodinated dyes are actively secreted into the tubular fluid. Substances that are normally produced in the body and secreted by the tubules include various ethereal sulfates, steroid and other glucuronides, and 5-hydroxyindoleacetic acid, the principal metabolite of serotonin.
The loop diuretic, furosemide, and the thiazide diuretics are organic anions which gain access to their tubular sites of action (thick ascending limb and distal convoluted tubule, respectively) when they are secreted into the urine by the proximal tubule.
FIGURE 37–10 Relation between plasma levels (P) and excretion (UV) of PAH and inulin.
FIGURE 37–11 Clearance of inulin, glucose, and PAH at various plasma levels of each substance in humans.
The use of CPAH to measure ERPF is discussed above.
TUBULOGLOMERULAR FEEDBACK & GLOMERULOTUBULAR BALANCE
Signals from the renal tubule in each nephron feed back to affect filtration in its glomerulus. As the rate of flow through the ascending limb of the loop of Henle and first part of the distal tubule increases, glomerular filtration in the same nephron decreases, and, conversely, a decrease in flow increases the GFR (Figure 37–12). This process, which is called tubuloglomerular feedback, tends to maintain the constancy of the load delivered to the distal tubule.
FIGURE 37–12 Mechanisms of glomerulotubular balance and tubuloglomerular feedback.
The sensor for this response is the macula densa. The amount of fluid entering the distal tubule at the end of the thick ascending limb of the loop of Henle depends on the amount of Na+ and Cl– in it. The Na+ and Cl– enter the macula densa cells via the Na–K–2Cl cotransporter in their apical membranes. The increased Na+ causes increased Na, K ATPase activity and the resultant increased ATP hydrolysis causes more adenosine to be formed. Presumably, adenosine is secreted from the basal membrane of the cells. It acts via adenosine A1 receptors on the macula densa cells to increase their release of Ca2+ to the vascular smooth muscle in the afferent arterioles. This causes afferent vasoconstriction and a resultant decrease in GFR. Presumably, a similar mechanism generates a signal that decreases renin secretion by the adjacent juxtaglomerular cells in the afferent arteriole (see Chapter 38), but this remains unsettled.
Conversely, an increase in GFR causes an increase in the reabsorption of solutes, and consequently of water, primarily in the proximal tubule, so that in general the percentage of the solute reabsorbed is held constant. This process is called glomerulotubular balance, and it is particularly prominent for Na+. The change in Na+ reabsorption occurs within seconds after a change in filtration, so it seems unlikely that an extrarenal humoral factor is involved. Alternatively, one mediating factor is the oncotic pressure in the peritubular capillaries. When the GFR is high, there is a relatively large increase in the oncotic pressure of the plasma leaving the glomeruli via the efferent arterioles and hence in their capillary branches. This increases the reabsorption of Na+ from the tubule. However, other as yet unidentified intrarenal mechanisms are likely also involved.
Normally, 180 L of fluid is filtered through the glomeruli each day, while the average daily urine volume is about 1 L. The same load of solute can be excreted per 24 h in a urine volume of 500 mL with a concentration of 1400 mOsm/kg or in a volume of 23.3 L with a concentration of 30 mOsm/kg (Table 37–6). These figures demonstrate two important facts: First, at least 87% of the filtered water is reabsorbed, even when the urine volume is 23 L; and second, the reabsorption of the remainder of the filtered water can be varied without affecting total solute excretion. Therefore, when the urine is concentrated, water is retained in excess of solute; and when it is dilute, water is lost from the body in excess of solute. Both facts have great importance in the regulation of the osmolality of the body fluids. A key regulator of water output is vasopressin acting on the collecting ducts.
TABLE 37–6 Alterations in water metabolism produced by vasopressin in humans. In each case, the osmotic load excreted is 700 mOsm/d.
Rapid diffusion of water across cell membranes depends on the presence of water channels, integral membrane proteins called aquaporins. To date, 13 aquaporins have been cloned; however, only four aquaporins (aquaporin-1, -2, -3, and -4) play a key role in the kidney. The roles played by aquaporin-1 and aquaporin-2 in renal water transport are discussed below.
Active transport of many substances occurs from the fluid in the proximal tubule, but micropuncture studies have shown that the fluid remains essentially iso-osmotic until the end of the proximal tubule (Figure 37–8). Aquaporin-1is localized to both the basolateral and apical membrane of the proximal tubules and its presence allows water to move rapidly out of the tubule along the osmotic gradients set up by active transport of solutes, and isotonicity is maintained. Because the ratio of the concentration in tubular fluid to the concentration in plasma (TF/P) of the nonreabsorbable substance inulin is 2.5 to 3.3 at the end of the proximal tubule, it follows that 60–70% of the filtered solute and 60–70% of the filtered water have been removed by the time the filtrate reaches this point (Figure 37–13).
FIGURE 37–13 Changes in the percentage of the filtered amount of substances remaining in the tubular fluid along the length of the nephron in the presence of vasopressin. (Modified from Sullivan LP, Grantham JJ: Physiology of the Kidney, 2nd ed. Lea & Febiger, 1982.)
When aquaporin-1 was knocked out in mice, proximal tubular water permeability was reduced by 80%. When the mice were subjected to dehydration, their urine osmolality did not increase (< 700 mOsm/kg), even though other renal aquaporins were present. In humans with mutations that eliminate aquaporin-1 activity, the defect in water homeostasis is not as severe, though their response to dehydration is defective.
LOOP OF HENLE
As noted above, the loops of Henle of the juxtamedullary nephrons dip deeply into the medullary pyramids before draining into the distal convoluted tubules in the cortex, and all the collecting ducts descend back through the medullary pyramids to drain at the tips of the pyramids into the renal pelvis. There is a graded increase in the osmolality of the interstitium of the pyramids in humans: The osmolality at the tips of the papillae can reach about 1200 mOsm/kg of H2O, approximately four times that of plasma. The descending limb of the loop of Henle is permeable to water, due to the presence of aquaporin-1 in both the apical and basolateral membranes, but the ascending limb is impermeable to water. Na+, K+, and Cl– are cotransported out of the thick segment of the ascending limb. Therefore, the fluid in the descending limb of the loop of Henle becomes hypertonic as water moves out of the tubule into the hypertonic interstitium. In the ascending limb it becomes more dilute because of the movement of Na+ and Cl– out of the tubular lumen, and when fluid reaches the top of the ascending limb (called the diluting segment) it is now hypotonic to plasma. In passing through the descending loop of Henle, another 15% of the filtered water is removed, so approximately 20% of the filtered water enters the distal tubule, and the TF/P of inulin at this point is about 5.
In the thick ascending limb, a carrier cotransports one Na+, one K+, and 2Cl– from the tubular lumen into the tubular cells. This is another example of secondary active transport; the Na+ is actively transported from the cells into the interstitium by Na, K ATPase in the basolateral membranes of the cells, keeping the intracellular Na+ low. The Na–K–2Cl cotransporter has 12 transmembrane domains with intracellular amino and carboxyl terminals. It is a member of a family of transporters found in many other locations, including salivary glands, the gastrointestinal tract, and the airways.
The K+ diffuses back into the tubular lumen and back into the interstitium via ROMK and other K+ channels. The Cl– moves into the interstitium via ClC-Kb channels (Figure 37–14).
FIGURE 37–14 NaCl transport in the thick ascending limb of the loop of Henle. The Na–K–2Cl cotransporter moves these ions into the tubular cell by secondary active transport. Na+ is transported out of the cell into the interstitium by Na, K ATPase in the basolateral membrane of the cell. Cl– exits in basolateral ClC-Kb Cl– channels. Barttin, a protein in the cell membrane, is essential for normal ClC-Kb function. K+ moves from the cell to the interstitium and the tubular lumen by ROMK and other K+ channels (see Clinical Box 37–2).
CLINICAL BOX 37–2
Genetic Mutations in Renal Transporters
Mutations of individual genes for many renal sodium transporters and channels cause specific syndromes such as Bartter syndrome, Liddle syndrome, and Dent disease. A large number of mutations have been described.
Bartter syndrome is a rare but interesting condition that is due to defective transport in the thick ascending limb. It is characterized by chronic Na+ loss in the urine, with resultant hypovolemia causing stimulation of renin and aldosterone secretion without hypertension, plus hyperkalemia and alkalosis. The condition can be caused by loss-of-function mutations in the gene for any of four key proteins: the Na–K–2Cl cotransporter, the ROMK K+ channel, the ClC–Kb Cl– channel, or barttin, a recently described integral membrane protein that is necessary for the normal function of ClC–Kb Cl– channels.
The stria vascularis in the inner ear is responsible for maintaining the high K+ concentration in the scala media that is essential for normal hearing. It contains both ClC–Kb and ClC–Ka Cl– channels. Bartter syndrome associated with mutated ClC–Kb channels is not associated with deafness because the Clc–Ka channels can carry the load. However, both types of Cl– channels are barttin-dependent, so patients with Bartter syndrome due to mutated barttin are also deaf.
Another interesting example involves the proteins polycystin-1 (PKD-1) and polycystin-2 (PKD-2). PKD-1 appears to be a Ca2+ receptor that activates a nonspecific ion channel associated with PKD-2. The normal function of this apparent ion channel is unknown, but both proteins are abnormal in autosomal dominant polycystic kidney disease, in which the renal parenchyma is progressively replaced by fluid-filled cysts until there is complete renal failure.
The distal tubule, particularly its first part, is in effect an extension of the thick segment of the ascending limb. It is relatively impermeable to water, and continued removal of the solute in excess of solvent further dilutes the tubular fluid.
The collecting ducts have two portions: a cortical portion and a medullary portion. The changes in osmolality and volume in the collecting ducts depend on the amount of vasopressin acting on the ducts. This antidiuretic hormone from the posterior pituitary gland increases the permeability of the collecting ducts to water. The key to the action of vasopressin on the collecting ducts is aquaporin-2. Unlike the other aquaporins, this aquaporin is stored in vesicles in the cytoplasm of principal cells. Vasopressin causes rapid insertion of these vesicles into the apical membrane of cells. The effect is mediated via the vasopressin V2 receptor, cyclic adenosine 5-monophosphate (cAMP), and protein kinase A. Cytoskeletal elements are involved, including microtubule-based motor proteins (dynein and dynactin) as well as actin filament-binding proteins such as myosin-1.
In the presence of enough vasopressin to produce maximal antidiuresis, water moves out of the hypotonic fluid entering the cortical collecting ducts into the interstitium of the cortex, and the tubular fluid becomes isotonic. In this fashion, as much as 10% of the filtered water is removed. The isotonic fluid then enters the medullary collecting ducts with a TF/P inulin of about 20. An additional 4.7% or more of the filtrate is reabsorbed into the hypertonic interstitium of the medulla, producing a concentrated urine with a TF/P inulin of over 300. In humans, the osmolality of urine may reach 1400 mOsm/kg of H2O, almost five times the osmolality of plasma, with a total of 99.7% of the filtered water being reabsorbed (Table 37–6). In other species, the ability to concentrate urine is even greater. Maximal urine osmolality is about 2500 mOsm/kg in dogs, about 3200 mOsm/kg in laboratory rats, and as high as 5000 mOsm/kg in certain desert rodents.
When vasopressin is absent, the collecting duct epithelium is relatively impermeable to water. The fluid therefore remains hypotonic, and large amounts flow into the renal pelvis. In humans, the urine osmolality may be as low as 30 mOsm/kg of H2O. The impermeability of the distal portions of the nephron is not absolute; along with the salt that is pumped out of the collecting duct fluid, about 2% of the filtered water is reabsorbed in the absence of vasopressin. However, as much as 13% of the filtered water may be excreted, and urine flow may reach 15 mL/min or more.
THE COUNTERCURRENT MECHANISM
The concentrating mechanism depends upon the maintenance of a gradient of increasing osmolality along the medullary pyramids. This gradient is produced by the operation of the loops of Henle as countercurrent multipliers and maintained by the operation of the vasa recta as countercurrent exchangers. A countercurrent system is a system in which the inflow runs parallel to, counter to, and in close proximity to the outflow for some distance. This occurs for both the loops of Henle and the vasa recta in the renal medulla (Figure 37–3).
The operation of each loop of Henle as a countercurrent multiplier depends on the high permeability of the thin descending limb to water (via aquaporin-1), the active transport of Na+ and Cl– out of the thick ascending limb, and the inflow of tubular fluid from the proximal tubule, with outflow into the distal tubule. The process can be explained using hypothetical steps leading to the normal equilibrium condition, although the steps do not occur in vivo. It is also important to remember that the equilibrium is maintained unless the osmotic gradient is washed out. These steps are summarized in Figure 37–15 for a cortical nephron with no thin ascending limb. Assume first a condition in which osmolality is 300 mOsm/kg of H2O throughout the descending and ascending limbs and the medullary interstitium (Figure 37–15A). Assume in addition that the pumps in the thick ascending limb can pump 100 mOsm/kg of Na+ and Cl– from the tubular fluid to the interstitium, increasing interstitial osmolality to 400 mOsm/kg of H2O. Water then moves out of the thin descending limb, and its contents equilibrate with the interstitium (Figure 37–15B). However, fluid containing 300 mOsm/kg of H2O is continuously entering this limb from the proximal tubule (Figure 37–15C), so the gradient against which the Na+ and Cl– are pumped is reduced and more enters the interstitium (Figure 37–15D). Meanwhile, hypotonic fluid flows into the distal tubule, and isotonic and subsequently hypertonic fluid flows into the ascending thick limb. The process keeps repeating, and the final result is a gradient of osmolality from the top to the bottom of the loop.
FIGURE 37–15 Operation of the loop of Henle as a countercurrent multiplier producing a gradient of hyperosmolarity in the medullary interstitium (MI). TDL, thin descending limb; TAL, thick ascending limb. The process of generation of the gradient is illustrated as occurring in hypothetical steps, starting at A, where osmolality in both limbs and the interstitium is 300 mOsm/kg of water. The pumps in the thick ascending limb move Na+ and Cl– into the interstitium, increasing its osmolality to 400 mOsm/kg, and this equilibrates with the fluid in the thin descending limb. However, isotonic fluid continues to flow into the thin descending limb and hypotonic fluid out of the thick ascending limb. Continued operation of the pumps makes the fluid leaving the thick ascending limb even more hypotonic, while hypertonicity accumulates at the apex of the loop. (Modified and reproduced with permission from Johnson LR [editor]: Essential Medical Physiology. Raven Press, 1992.)
In juxtamedullary nephrons with longer loops and thin ascending limbs, the osmotic gradient is spread over a greater distance and the osmolality at the tip of the loop is greater. This is because the thin ascending limb is relatively impermeable to water but permeable to Na+ and Cl–. Therefore, Na+ and Cl– move down their concentration gradients into the interstitium, and there is additional passive countercurrent multiplication. The greater the length of the loop of Henle, the greater the osmolality that can be reached at the tip of the medulla.
The osmotic gradient in the medullary pyramids would not last long if the Na+ and urea in the interstitial spaces were removed by the circulation. These solutes remain in the pyramids primarily because the vasa recta operate as countercurrent exchangers (Figure 37–16). The solutes diffuse out of the vessels conducting blood toward the cortex and into the vessels descending into the pyramid. Conversely, water diffuses out of the descending vessels and into the fenestrated ascending vessels. Therefore, the solutes tend to recirculate in the medulla and water tends to bypass it, so that hypertonicity is maintained. The water removed from the collecting ducts in the pyramids is also removed by the vasa recta and enters the general circulation. Countercurrent exchange is a passive process; it depends on movement of water and could not maintain the osmotic gradient along the pyramids if the process of counter-current multiplication in the loops of Henle were to cease.
FIGURE 37–16 Operation of the vasa recta as countercurrent exchangers in the kidney. NaCl and urea diffuse out of the ascending limb of the vessel and into the descending limb, whereas water diffuses out of the descending and into the ascending limb of the vascular loop. (Modified and reproduced with permission from Pitts RF: Physiology of the Kidney and Body Fluid, 3rd ed. Chicago: Yearbook Medical Publications, 1974.)
It is worth noting that there is a very large osmotic gradient in the loop of Henle and, in the presence of vasopressin, in the collecting ducts. It is the countercurrent system that makes this gradient possible by spreading it along a system of tubules 1 cm or more in length, rather than across a single layer of cells that is only a few micrometers thick. There are other examples of the operation of countercurrent exchangers in animals. One is the heat exchange between the arteries and venae comitantes of the limbs. To a minor degree in humans, but to a major degree in mammals living in cold water, heat is transferred from the arterial blood flowing into the limbs to the adjacent veins draining blood back into the body, making the tips of the limbs cold while conserving body heat (see Chapter 33).
ROLE OF UREA
Urea contributes to the establishment of the osmotic gradient in the medullary pyramids and to the ability to form a concentrated urine in the collecting ducts. Urea transport is mediated by urea transporters, presumably by facilitated diffusion. There are at least four isoforms of the transport protein UT-A in the kidneys (UT-A1 to UT-A4); UT-B is found in erythrocytes and in the descending limbs of the vasa recta. Urea transport in the collecting duct is mediated by UT-A1 and UT-A3, and both are regulated by vasopressin. During antidiuresis, when vasopressin is high, the amount of urea deposited in the medullary interstitium increases, thus increasing the concentrating capacity of the kidney. In addition, the amount of urea in the medullary interstitium and, consequently, in the urine varies with the amount of urea filtered, and this in turn varies with the dietary intake of protein. Therefore, a high-protein diet increases the ability of the kidneys to concentrate the urine and a low-protein diet reduces the kidneys’ ability to concentrate the urine.
The presence of large quantities of unreabsorbed solutes in the renal tubules causes an increase in urine volume called osmotic diuresis. Solutes that are not reabsorbed in the proximal tubules exert an appreciable osmotic effect as the volume of tubular fluid decreases and their concentration rises. Therefore, they “hold water in the tubules.” In addition, the concentration gradient against which Na+ can be pumped out of the proximal tubules is limited. Normally, the movement of water out of the proximal tubule prevents any appreciable gradient from developing, but Na+ concentration in the fluid falls when water reabsorption is decreased because of the presence in the tubular fluid of increased amounts of unreabsorbable solutes. The limiting concentration gradient is reached, and further proximal reabsorption of Na+ is prevented; more Na+ remains in the tubule, and water stays with it. The result is that the loop of Henle is presented with a greatly increased volume of isotonic fluid. This fluid has a decreased Na+ concentration, but the total amount of Na+ reaching the loop per unit time is increased. In the loop, reabsorption of water and Na+ is decreased because the medullary hypertonicity is decreased. The decrease is due primarily to decreased reabsorption of Na+, K+, and Cl– in the ascending limb of the loop because the limiting concentration gradient for Na+ reabsorption is reached. More fluid passes through the distal tubule, and because of the decrease in the osmotic gradient along the medullary pyramids, less water is reabsorbed in the collecting ducts. The result is a marked increase in urine volume and excretion of Na+ and other electrolytes.
Osmotic diuresis is produced by the administration of compounds such as mannitol and related polysaccharides that are filtered but not reabsorbed. It is also produced by naturally occurring substances when they are present in amounts exceeding the capacity of the tubules to reabsorb them. For example, in diabetes mellitus, if blood glucose is high, glucose in the glomerular filtrate is high, thus the filtered load will exceed the TmG and glucose will remain in the tubules causing polyuria. Osmotic diuresis can also be produced by the infusion of large amounts of sodium chloride or urea.
It is important to recognize the difference between osmotic diuresis and water diuresis. In water diuresis, the amount of water reabsorbed in the proximal portions of the nephron is normal, and the maximal urine flow that can be produced is about 16 mL/min. In osmotic diuresis, increased urine flow is due to decreased water reabsorption in the proximal tubules and loops and very large urine flows can be produced. As the load of excreted solute is increased, the concentration of the urine approaches that of plasma (Figure 37–17) in spite of maximal vasopressin secretion, because an increasingly large fraction of the excreted urine is isotonic proximal tubular fluid. If osmotic diuresis is produced in an animal with diabetes insipidus, the urine concentration rises for the same reason.
FIGURE 37–17 Approximate relationship between urine concentration and urine flow in osmotic diuresis in humans. The dashed line in the lower diagram indicates the concentration at which the urine is isosmotic with plasma. (Reproduced with permission from Berliner RW, Giebisch G: In Best and Taylor’s Physiological Basis of Medical Practice, 9th ed. Brobeck JR [editor]. Williams & Wilkins, 1979.)
RELATION OF URINE CONCENTRATION TO GFR
The magnitude of the osmotic gradient along the medullary pyramids is increased when the rate of flow of fluid through the loops of Henle is decreased. A reduction in GFR such as that caused by dehydration produces a decrease in the volume of fluid presented to the countercurrent mechanism, so that the rate of flow in the loops declines and the urine becomes more concentrated. When the GFR is low, the urine can become quite concentrated in the absence of vasopressin. If one renal artery is constricted in an animal with diabetes insipidus, the urine excreted on the side of the constriction becomes hypertonic because of the reduction in GFR, whereas that excreted on the opposite side remains hypotonic.
“FREE WATER CLEARANCE”
In order to quantitate the gain or loss of water by excretion of a concentrated or dilute urine, the “free water clearance” (CH2O) is sometimes calculated. This is the difference between the urine volume and the clearance of osmoles (COsm):
where is the urine flow rate and UOsm and POsm the urine and plasma osmolality, respectively. COsm is the amount of water necessary to excrete the osmotic load in a urine that is isotonic with plasma. Therefore, CH2O is negative when the urine is hypertonic and positive when the urine is hypotonic. For example, using the data in Table 37–6, the values for CH2O are –1.3 mL/min (–1.9 L/d) during maximal antidiuresis and 14.5 mL/min (20.9 L/d) in the absence of vasopressin.
REGULATION OF Na+ EXCRETION
Na+ is filtered in large amounts, but it is actively transported out of all portions of the tubule except the descending thin limb of Henle’s loop. Normally about 99% of the filtered Na+ is reabsorbed. Because Na+ is the most abundant cation in ECF and because Na+ salts account for over 90% of the osmotically active solute in the plasma and interstitial fluid, the amount of Na+ in the body is a prime determinant of the ECF volume. Therefore, it is not surprising that multiple regulatory mechanisms have evolved in terrestrial animals to control the excretion of this ion. Through the operation of these regulatory mechanisms, the amount of Na+ excreted is adjusted to equal the amount ingested over a wide range of dietary intakes, and the individual stays in Na+ balance. When Na intake is high, or saline is infused, natriuresis occurs, whereas when ECF is reduced (for example, fluid loss following vomiting or diarrhea) a decrease in Na+ excretion occurs. Thus, urinary Na+ output ranges from less than 1 mEq/d on a low-salt diet to 400 mEq/d or more when the dietary Na+ intake is high.
Variations in Na+ excretion are brought about by changes in GFR (Table 37–7) and changes in tubular reabsorption, primarily in the 3% of filtered Na+ that reaches the collecting ducts. The factors affecting GFR, including tubuloglomerular feedback, have been discussed previously. Factors affecting Na+ reabsorption include the circulating level of aldosterone and other adrenocortical hormones, the circulating level of ANP and other natriuretic hormones, and the rate of tubular secretion of H+ and K+.
TABLE 37–7 Changes in Na+ excretion that would occur as a result of changes in GFR if there were no concomitant changes in Na+ reabsorption.
EFFECTS OF ADRENOCORTICAL STEROIDS
Adrenal mineralocorticoids such as aldosterone increase tubular reabsorption of Na+ in association with secretion of K+ and H+ and also Na+ reabsorption with Cl–. When these hormones are injected into adrenalectomized animals, a latent period of 10–30 min occurs before their effects on Na+ reabsorption become manifest, because of the time required for the steroids to alter protein synthesis via their action on DNA. Mineralocorticoids may also have more rapid membrane-mediated effects, but these are not apparent in terms of Na+ excretion in the whole animal. The mineralocorticoids act primarily in the collecting ducts to increase the number of active epithelial sodium channels (ENaCs) in this part of the nephron. The molecular mechanisms believed to be involved are discussed in Chapter 20 and summarized in Figure 37–18.
FIGURE 37–18 Renal principal cell. Na+ enters via the ENaCs in the apical membrane and is pumped into the interstitial fluid by Na, K ATPases in the basolateral membrane. Aldosterone activates the genome to produce serum- and glucocorticoid-regulated kinase (sgk) and other proteins, and the number of active ENaCs is increased.
In Liddle syndrome, mutations in the genes that code for the β subunit and less commonly the γ subunit of ENaC cause the channels to become constitutively active in the kidney. This leads to Na+ retention and hypertension.
OTHER HUMORAL EFFECTS
Reduction of dietary intake of salt increases aldosterone secretion (see Figure 20–24), producing marked but slowly developing decreases in Na+ excretion. A variety of other humoral factors affect Na+ reabsorption. PGE2 causes a natriuresis, possibly by inhibiting Na, K ATPase and possibly by increasing intracellular Ca2+, which in turn inhibits Na+ transport via ENaCs. Endothelin and IL-1 cause natriuresis, probably by increasing the formation of PGE2. ANP and related molecules increase intracellular cyclic 3’,5’-guanosine monophosphate (cGMP), and this inhibits transport via ENaC. Inhibition of Na, K ATPase by another natriuretic hormone, which appears to be endogenously produced ouabain, also increases Na+ excretion. Angiotensin II increases reabsorption of Na+ and by an action on the proximal tubules. There is an appreciable amount of angiotensin-converting enzyme in the kidneys, and the kidneys convert 20% of the circulating angiotensin I to angiotensin II. In addition, angiotensin I is generated in the kidneys.
Prolonged exposure to high levels of circulating mineralocorticoids does not cause edema in otherwise normal individuals because eventually the kidneys escape from the effects of the steroids. This escape phenomenon, which may be due to increased secretion of ANP, is discussed in Chapter 20. It appears to be reduced or absent in nephrosis, cirrhosis, and heart failure, and patients with these diseases continue to retain Na+ and become edematous when exposed to high levels of mineralocorticoids.
REGULATION OF WATER EXCRETION
The feedback mechanism controlling vasopressin secretion and the way vasopressin secretion is stimulated by a rise and inhibited by a drop in the effective osmotic pressure of the plasma are discussed in Chapter 17. The water diuresis produced by drinking large amounts of hypotonic fluid begins about 15 min after ingestion of a water load and reaches its maximum in about 40 min. The act of drinking produces a small decrease in vasopressin secretion before the water is absorbed, but most of the inhibition is produced by the decrease in plasma osmolality after the water is absorbed.
During excretion of an average osmotic load, the maximal urine flow that can be produced during a water diuresis is about 16 mL/min. If water is ingested at a higher rate than this for any length of time, swelling of the cells because of the uptake of water from the hypotonic ECF becomes severe and, rarely, the symptoms of water intoxication may develop. Swelling of the cells in the brain causes convulsions and coma and leads eventually to death. Water intoxication can also occur when water intake is not reduced after administration of exogenous vasopressin or when secretion of endogenous vasopressin occurs in response to nonosmotic stimuli such as surgical trauma. Administration of oxytocin after parturition (to contract the uterus) can also lead to water intoxication if water intake is not monitored carefully.
REGULATION OF K+ EXCRETION
Much of the filtered K+ is removed from the tubular fluid by active reabsorption in the proximal tubules, and K+ is then secreted into the fluid by the distal tubular cells. The rate of K+ secretion is proportional to the rate of flow of the tubular fluid through the distal portions of the nephron, because with rapid flow there is less opportunity for the tubular K+ concentration to rise to a value that stops further secretion. In the absence of complicating factors, the amount secreted is approximately equal to the K+ intake, and K+ balance is maintained. In the collecting ducts, Na+ is generally reabsorbed and K+ is secreted. There is no rigid one-for-one exchange, and much of the movement of K+ is passive. However, there is electrical coupling in the sense that intracellular migration of Na+ from the lumen tends to lower the potential difference across the tubular cell, and this favors movement of K+ into the tubular lumen. K+ excretion is decreased when the amount of Na+ reaching the distal tubule is small. In addition, if H+ secretion is increased, K+ excretion will decrease as K+ is reabsorbed in collecting duct cells in exchange for H+, via the action of the H,K-ATPase.
Although a detailed discussion of diuretic agents is beyond the scope of this book, consideration of their mechanisms of action constitutes an informative review of the factors affecting urine volume and electrolyte excretion. These mechanisms are summarized in Table 37–8. Water, alcohol, osmotic diuretics, xanthines, and acidifying salts have limited clinical usefulness, and the vasopressin antagonists are currently undergoing clinical trials. However, many of the other agents on the list are used extensively in medical practice.
TABLE 37–8 Mechanism of action of various diuretics.
The carbonic anhydrase-inhibiting drugs are only moderately effective as diuretic agents, but because they inhibit acid secretion by decreasing the supply of carbonic acid, they have far-reaching effects. Not only is Na+ excretion increased because H+ secretion is decreased, but reabsorption is also depressed; and because H+ and K+ compete with each other and with Na+, the decrease in H+ secretion facilitates the secretion and excretion of K+.
Furosemide and the other loop diuretics inhibit the Na–K–2Cl cotransporter in the thick ascending limb of Henle’s loop. They cause a marked natriuresis and kaliuresis. Thiazides act by inhibiting Na–Cl cotransport in the distal tubule. The diuresis they cause is less marked, but both loop diuretics and thiazides cause increased delivery of Na+ (and fluid) to the collecting ducts, facilitating K+ excretion. Thus, over time, K+ depletion and hypokalemia are common complications in those who use them if they do not supplement their K+ intake. On the other hand, the so-called K+-sparing diuretics act in the collecting duct by inhibiting the action of aldosterone or blocking ENaCs.
EFFECTS OF DISORDERED RENAL FUNCTION
A number of abnormalities are common to many different types of renal disease. The secretion of renin by the kidneys and the relation of the kidneys to hypertension are discussed in Chapter 38. A frequent finding in various forms of renal disease is the presence in the urine of protein, leukocytes, red cells, and casts, which are proteinaceous material precipitated in the tubules and washed into the bladder. Other important consequences of renal disease are loss of the ability to concentrate or dilute the urine, uremia, acidosis, and abnormal retention of Na+ (see Clinical Box 37–3).
CLINICAL BOX 37–3
In many renal diseases and in one benign condition, the permeability of the glomerular capillaries is increased, and protein is found in the urine in more than the usual trace amounts (proteinuria). Most of this protein is albumin,and the defect is commonly called albuminuria. The relation of charges on the glomerular membrane to albuminuria has been discussed above. The amount of protein in the urine may be very large, and especially in nephrosis, the urinary protein loss may exceed the rate at which the liver can synthesize plasma proteins. The resulting hypoproteinemia reduces the oncotic pressure, and the plasma volume declines, sometimes to dangerously low levels, while edema fluid accumulates in the tissues.
A benign condition that causes proteinuria is a poorly understood change in renal hemodynamics, which in some otherwise normal individuals, causes protein to appear in urine when they are in the standing position (orthostatic albuminuria). Urine formed when these individuals are lying down is protein-free.
LOSS OF CONCENTRATING & DILUTING ABILITY
In renal disease, the urine becomes less concentrated and urine volume is often increased, producing the symptoms of polyuria and nocturia (waking up at night to void). The ability to form a dilute urine is often retained, but in advanced renal disease, the osmolality of the urine becomes fixed at about that of plasma, indicating that the diluting and concentrating functions of the kidney have both been lost. The loss is due in part to disruption of the countercurrent mechanism, but a more important cause is a loss of functioning nephrons. When one kidney is removed surgically, the number of functioning nephrons is halved. The number of osmoles to be excreted is not reduced to this extent, and so the remaining nephrons must each be filtering and excreting more osmotically active substances, producing what is in effect an osmotic diuresis. In osmotic diuresis, the osmolality of the urine approaches that of plasma.
The same thing happens when the number of functioning nephrons is reduced by disease. The increased filtration in the remaining nephrons eventually damages them, and thus more nephrons are lost. The damage resulting from increased filtration may be due to progressive fibrosis in the proximal tubule cells, but this is unsettled. However, the eventual result of this positive feedback is loss of so many nephrons that complete renal failure with oliguria, or even anuria, results.
When the breakdown products of protein metabolism accumulate in the blood, the syndrome known as uremia develops. The symptoms of uremia include lethargy, anorexia, nausea and vomiting, mental deterioration and confusion, muscle twitching, convulsions, and coma. The blood urea nitrogen (BUN) and creatinine levels are high, and the blood levels of these substances are used as an index of the severity of the uremia. It probably is not the accumulation of urea and creatinine per se but rather the accumulation of other toxic substances—possibly organic acids or phenols—that produces the symptoms of uremia.
The toxic substances that cause the symptoms of uremia can be removed by dialyzing the blood of uremic patients against a bath of suitable composition in an artificial kidney (hemodialysis). Patients can be kept alive and in reasonable health for many months on dialysis, even when they are completely anuric or have had both kidneys removed. However, the treatment of choice today is certainly transplantation of a kidney from a suitable donor.
Other features of chronic renal failure include anemia, which is caused primarily by failure to produce erythropoietin, and secondary hyperparathyroidism due to 1,25-dihydroxycholecalciferol deficiency (see Chapter 21).
Acidosis is common in chronic renal disease because of failure to excrete the acid products of digestion and metabolism (see Chapter 39). In the rare syndrome of renal tubular acidosis, there is specific impairment of the ability to make the urine acidic, and other renal functions are usually normal. However, in most cases of chronic renal disease the urine is maximally acidified, and acidosis develops because the total amount of H+ that can be secreted is reduced because of impaired renal tubular production of .
ABNORMAL Na+ HANDLING
Many patients with renal disease retain excessive amounts of Na+ and become edematous. Na+ retention in renal disease has at least three causes. In acute glomerulonephritis, a disease that affects primarily the glomeruli, the amount of Na+ filtered is decreased markedly. In the nephrotic syndrome, an increase in aldosterone secretion contributes to salt retention. The plasma protein level is low in this condition, and so fluid moves from the plasma into the interstitial spaces and the plasma volume falls. The decline in plasma volume triggers an increase in aldosterone secretion via the renin–angiotensin system. A third cause of Na+ retention and edema in renal disease is heart failure.Renal disease predisposes to heart failure, partly because of the hypertension it frequently produces.
The walls of the ureters contain smooth muscle arranged in spiral, longitudinal, and circular bundles, but distinct layers of muscle are not seen. Regular peristaltic contractions occurring one to five times per minute move the urine from the renal pelvis to the bladder, where it enters in spurts synchronous with each peristaltic wave. The ureters pass obliquely through the bladder wall and, although there are no ureteral sphincters as such, the oblique passage tends to keep the ureters closed except during peristaltic waves, preventing reflux of urine from the bladder.
The smooth muscle of the bladder, like that of the ureters, is arranged in spiral, longitudinal, and circular bundles. Contraction of the circular muscle, which is called the detrusor muscle, is mainly responsible for emptying the bladder during urination (micturition). Muscle bundles pass on either side of the urethra, and these fibers are sometimes called the internal urethral sphincter, although they do not encircle the urethra. Farther along the urethra is a sphincter of skeletal muscle, the sphincter of the membranous urethra (external urethral sphincter). The bladder epithelium is made up of a superficial layer of flat cells and a deep layer of cuboidal cells. The innervation of the bladder is summarized in Figure 37–19.
FIGURE 37–19 Innervation of the bladder. Dashed lines indicate sensory nerves. Parasympathetic innervation is shown at the left, sympathetic at the upper right, and somatic at the lower right.
The physiology of bladder emptying and the physiologic basis of its disorders are subjects about which there is much confusion. Micturition is fundamentally a spinal reflex facilitated and inhibited by higher brain centers and, like defecation, subject to voluntary facilitation and inhibition. Urine enters the bladder without producing much increase in intravesical pressure until the viscus is well filled. In addition, like other types of smooth muscle, the bladder muscle has the property of plasticity; when it is stretched, the tension initially produced is not maintained. The relation between intravesical pressure and volume can be studied by inserting a catheter and emptying the bladder, then recording the pressure while the bladder is filled with 50-mL increments of water or air (cystometry). A plot of intravesical pressure against the volume of fluid in the bladder is called a cystometrogram (Figure 37–20). The curve shows an initial slight rise in pressure when the first increments in volume are produced; a long, nearly flat segment as further increments are produced; and a sudden, sharp rise in pressure as the micturition reflex is triggered. These three components are sometimes called segments Ia, Ib, and II. The first urge to void is felt at a bladder volume of about 150 mL, and a marked sense of fullness at about 400 mL. The flatness of segment Ib is a manifestation of the law of Laplace. This law states that the pressure in a spherical viscus is equal to twice the wall tension divided by the radius. In the case of the bladder, the tension increases as the organ fills, but so does the radius. Therefore, the pressure increase is slight until the organ is relatively full.
FIGURE 37–20 Cystometrogram in a normal human. The numerals identify the three components of the curve described in the text. The dashed line indicates the pressure–volume relations that would have been found had micturition not occurred and produced component II. (Modified and reproduced with permission from Tanagho EA, McAninch JW: Smith’s General Urology, 15th ed. McGraw-Hill, 2000.)
During micturition, the perineal muscles and external urethral sphincter are relaxed, the detrusor muscle contracts, and urine passes out through the urethra. The bands of smooth muscle on either side of the urethra apparently play no role in micturition, and their main function in males is believed to be the prevention of reflux of semen into the bladder during ejaculation.
The mechanism by which voluntary urination is initiated remains unsettled. One of the initial events is relaxation of the muscles of the pelvic floor, and this may cause a sufficient downward tug on the detrusor muscle to initiate its contraction. The perineal muscles and external sphincter can be contracted voluntarily, preventing urine from passing down the urethra or interrupting the flow once urination has begun. It is through the learned ability to maintain the external sphincter in a contracted state that adults are able to delay urination until the opportunity to void presents itself. After urination, the female urethra empties by gravity. Urine remaining in the urethra of the male is expelled by several contractions of the bulbocavernosus muscle.
The bladder smooth muscle has some inherent contractile activity; however, when its nerve supply is intact, stretch receptors in the bladder wall initiate a reflex contraction that has a lower threshold than the inherent contractile response of the muscle. Fibers in the pelvic nerves are the afferent limb of the voiding reflex, and the parasympathetic fibers to the bladder that constitute the efferent limb also travel in these nerves. The reflex is integrated in the sacral portion of the spinal cord. In the adult, the volume of urine in the bladder that normally initiates a reflex contraction is about 300–400 mL. The sympathetic nerves to the bladder play no part in micturition, but in males they do mediate the contraction of the bladder muscle that prevents semen from entering the bladder during ejaculation.
The stretch receptors in the bladder wall have no small motor nerve system. However, the threshold for the voiding reflex, like the stretch reflexes, is adjusted by the activity of facilitatory and inhibitory centers in the brainstem. There is a facilitatory area in the pontine region and an inhibitory area in the midbrain. After transection of the brain stem just above the pons, the threshold is lowered and less bladder filling is required to trigger it, whereas after transection at the top of the midbrain, the threshold for the reflex is essentially normal. There is another facilitatory area in the posterior hypothalamus. Humans with lesions in the superior frontal gyrus have a reduced desire to urinate and difficulty in stopping micturition once it has commenced. However, stimulation experiments in animals indicate that other cortical areas also affect the process. The bladder can be made to contract by voluntary facilitation of the spinal voiding reflex when it contains only a few milliliters of urine. Voluntary contraction of the abdominal muscles aids the expulsion of urine by increasing the intra-abdominal pressure, but voiding can be initiated without straining even when the bladder is nearly empty.
EFFECTS OF DEAFFERENTATION
When the sacral dorsal roots are cut in experimental animals or interrupted by diseases of the dorsal roots, such as tabes dorsalis in humans, all reflex contractions of the bladder are abolished. The bladder becomes distended, thin-walled, and hypotonic, but some contractions occur because of the intrinsic response of the smooth muscle to stretch.
EFFECTS OF DENERVATION
When the afferent and efferent nerves are both destroyed, as they may be by tumors of the cauda equina or filum terminale, the bladder is flaccid and distended for a while. Gradually, however, the muscle of the “decentralized bladder” becomes active, with many contraction waves that expel dribbles of urine out of the urethra. The bladder becomes shrunken and the bladder wall hypertrophied. The reason for the difference between the small, hypertrophic bladder seen in this condition and the distended, hypotonic bladder seen when only the afferent nerves are interrupted is not known. The hyperactive state in the former condition suggests the development of denervation hypersensitization even though the neurons interrupted are preganglionic rather than postganglionic (see Clinical Box 37–4).
CLINICAL BOX 37–4
Abnormalities of Micturition
Three major types of bladder dysfunction are due to neural lesions: (1) due to interruption of the afferent nerves from the bladder, (2) due to interruption of both afferent and efferent nerves, and (3) due to interruption of facilitatory and inhibitory pathways descending from the brain. In all three types the bladder contracts, but the contractions are generally not sufficient to empty the viscus completely, and residual urine is left in the bladder.
EFFECTS OF SPINAL CORD TRANSECTION
During spinal shock, the bladder is flaccid and unresponsive. It becomes overfilled, and urine dribbles through the sphincters (overflow incontinence). After spinal shock has passed, the voiding reflex returns, although there is, of course, no voluntary control and no inhibition or facilitation from higher centers when the spinal cord is transected. Some paraplegic patients train themselves to initiate voiding by pinching or stroking their thighs, provoking a mild mass reflex (see Chapter 12). In some instances, the voiding reflex becomes hyperactive, bladder capacity is reduced, and the wall becomes hypertrophied. This type of bladder is sometimes called the spastic neurogenic bladder.The reflex hyperactivity is made worse by, and may be caused by, infection in the bladder wall.
Plasma enters the kidneys and is filtered in the glomerulus. As the filtrate passes down the nephron and through the tubules its volume is reduced and water and solutes are removed (tubular reabsorption) and waste products are secreted (tubular secretion).
A nephron consists of an individual renal tubule and its glomerulus. Each tubule has several segments, beginning with the proximal tubule, followed by the loop of Henle (descending and ascending limbs), the distal convoluted tubule, the connecting tubule, and the collecting duct.
The kidneys receive just under 25% of the cardiac output and renal plasma flow can be measured by infusing p-aminohippuric acid (PAH) and determining its urine and plasma concentrations.
Renal blood flow enters the glomerulus via the afferent arteriole and leaves via the efferent arteriole (whose diameter is smaller). Renal blood flow is regulated by norepinephrine (constriction, reduction of flow), dopamine (vasodilation, increases flow), angiotensin II (constricts), prostaglandins (dilation in the renal cortex and constriction in the renal medulla), and acetylcholine (vasodilation).
Glomerular filtration rate can be measured by a substance that is freely filtered and neither reabsorbed nor secreted in the tubules, is nontoxic, and is not metabolized by the body. Inulin meets these criteria and is extensively used to measure GFR.
Urine is stored in the bladder before voiding (micturition). The micturition response involves reflex pathways, but is under voluntary control.
For all questions, select the single best answer unless otherwise directed.
1. In the presence of vasopressin, the greatest fraction of filtered water is absorbed in the
A. proximal tubule.
B. loop of Henle.
C. distal tubule.
D. cortical collecting duct.
E. medullary collecting duct.
2. In the absence of vasopressin, the greatest fraction of filtered water is absorbed in the
A. proximal tubule.
B. loop of Henle.
C. distal tubule.
D. cortical collecting duct.
E. medullary collecting duct.
3. If the clearance of a substance which is freely filtered is less than that of inulin,
A. there is net reabsorption of the substance in the tubules.
B. there is net secretion of the substance in the tubules.
C. the substance is neither secreted nor reabsorbed in the tubules.
D. the substance becomes bound to protein in the tubules.
E. the substance is secreted in the proximal tubule to a greater degree than in the distal tubule.
4. Glucose reabsorption occurs in the
A. proximal tubule.
B. loop of Henle.
C. distal tubule.
D. cortical collecting duct.
E. medullary collecting duct.
5. On which of the following does aldosterone exert its greatest effect?
B. Proximal tubule
C. Thin portion of the loop of Henle
D. Thick portion of the loop of Henle
E. Cortical collecting duct
6. What is the clearance of a substance when its concentration in the plasma is 10 mg/dL, its concentration in the urine is 100 mg/dL, and urine flow is 2 mL/min?
A. 2 mL/min
B. 10 mL/min
C. 20 mL/min
D. 200 mL/min
E. Clearance cannot be determined from the information given.
7. As urine flow increases during osmotic diuresis
A. the osmolality of urine falls below that of plasma.
B. the osmolality of urine increases because of the increased amounts of nonreabsorbable solute in the urine.
C. the osmolality of urine approaches that of plasma because plasma leaks into the tubules.
D. the osmolality of urine approaches that of plasma because an increasingly large fraction of the excreted urine is isotonic proximal tubular fluid.
E. the action of vasopressin on the renal tubules is inhibited.
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