Section 2: Scientific Principles
Part D: Physiology and Anesthesia
Chapter 18: Renal Physiology

The Tubule

The tubule has four distinct segments: the proximal tubule, the loop of Henle, the distal tubule, and the connecting segment. The loop of Henle itself is divided into the pars recta (the straight portion of the proximal tubule), the descending and ascending thin limb segments, and the thick ascending limb. Each distal tubule drains into a collecting duct, which courses through the cortex, outer medulla, and inner medulla before entering the renal pelvis at the papilla (see Fig. 18–1).

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FIGURE 18–1 Anatomic relationships of the nephron and the renal vasculature. The left side of the diagram represents the renal vasculature as distributed through the inner medulla, outer medulla, and cortex. Arteries are drawn as solid lines, veins as hollow tubes. The renal artery divides serially into interlobar arteries (1), arcuate arteries (2), and interlobular arteries (3). The afferent arterioles (5) branch off laterally and provide the capillary tufts of the renal glomeruli in the outer cortex (7a), whose efferent arterioles (6) supply the cortical capillary network (not shown). In the juxtamedullary zone (7b), the efferent arterioles become the vasa recta, which are closely applied to the long loops of Henle (8, 8a, 9). The venous drainage consists of stellate veins (4), interlobular veins (3a), arcuate veins (2a), and interlobar veins (1a). The right side of the diagram represents two nephrons. On the left is the more numerous superficial cortical nephron with a short loop of Henle. On the right is the juxtamedullary nephron with a long loop of Henle, which dives deep into the inner medulla to generate the hyperosmotic interstitium required for tubular urine concentration. G, glomerulus; PT, proximal tubule; DTL, descending thin loop of Henle; ATL, ascending thin loop of Henle; TAL, thick ascending loop; DT, distal tubule; CCD, cortical collecting duct; OMCD, outer medullary collecting duct; IMCD, inner medullary collecting duct. (From Kriz and Bankir174 )

There are two populations of nephrons. Those that occupy the outer and middle renal cortex are far more numerous, receive about 85 percent of the renal blood flow, and have short loops of Henle. Their efferent arterioles drain into a peritubular capillary plexus. Those that occupy the juxtamedullary renal cortex receive about 10 percent of the RBF and have larger glomeruli and long loops of Henle, which dive deeply into the inner medulla. Their efferent arterioles drain into elongated vascular conduits, the vasa recta, which are closely applied to the loops of Henle. Although the vasa recta receive less than 1 percent of the renal blood flow, they play an important role in generating the countercurrent mechanism for medullary hypertonicity and renal concentrating ability (see below).

The Juxtaglomerular Apparatus

The juxtaglomerular apparatus provides a remarkable integration of tubular and glomerular structure and function (Fig. 18–4). A modified portion of the thick ascending loop, the macula densa, is applied to the glomerulus at the vascular pole between the afferent and efferent arterioles. The cells of the macula densa appear to have a chemoreceptor function, which senses the concentration of sodium chloride (NaCl) in the tubular lumen of the thick ascending loop. The juxtaposed segments of the afferent and efferent arterioles contain modified smooth muscle cells (granular cells), which produce renin. The arterioles are innervated with sympathetic nerve fibers and contain baroreceptors, which respond to intraluminal pressure changes. Renin catalyzes the formation of angiotensin, which modulates efferent and afferent arteriolar tone and GFR. The relationship of the juxtaglomerular apparatus to the sympathoadrenal system is discussed later in the section on neurohormonal regulation of renal function.

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FIGURE 18–4 The juxtaglomerular apparatus. (From Stanton and Koeppen2 )

Tubuloglomerular Feedback

When NaCl delivery to the macula densa is increased, renin-angiotensin elaboration is triggered, and arteriolar constriction ensues, which decreases GFR (tubuloglomerular feedback). The true role of tubuloglomerular feedback is unknown. Some have suggested that it is involved in renal autoregulation, 2  and others have postulated that it may be a compensatory mechanism to prevent polyuria in acute renal failure (“acute renal success”). When the thick ascending loop becomes ischemic, reabsorption of NaCl ceases, the ability of the tubule to concentrate urine is lost and, theoretically, intractable polyuria should result. Thurau and Boylan 8  suggested that the increased delivery of NaCl to the macula densa triggers angiotensin-mediated arteriolar constriction, which decreases GFR, induces oliguria, conserves intravascular volume, and protects the organism from dehydration.

Tubular Reabsorption and Secretion

The tubule has an enormous capacity for reabsorption of water and NaCl. Of the 180 L/d protein-free glomerular ultrafiltrate, 98 to 99 percent of the water and 99 percent of the sodium is reabsorbed. Many other filtered substances are completely reabsorbed, but some, such as glucose, have a maximum rate of tubular reabsorption (tubular maximum). Tubular reabsorption of glucose increases at a rate equal to that of the filtered load, which, if the GFR is constant, is directly proportional to that of plasma glucose. Once plasma glucose exceeds the tubular maximum (375 mg/dL), no further glucose is reabsorbed, and glycosuria results. Thereafter, the amount of glucose excreted in the urine increases in direct proportion to the filtered load.

Many important endogenous and exogenous solutes are secreted into the tubular lumen from the capillary blood. Some also have a tubular maximum for secretion, such as para-amino hippurate (PAH), which is used to calculate renal plasma flow. This is discussed further in the section on renal function tests.

There is a striking relationship between the structure and function of the different segments of the tubule (Fig. 18–5). The most metabolically active components of the tubule are the proximal tubule, the thick ascending loop of Henle, and the first part of the distal tubule. Figure 18–6 illustrates a tubular cell in the thick ascending loop of Henle, which encompasses all the major mechanisms of reabsorption and secretion. The tubular lumen abuts the apical cell membrane, which joins adjacent cells at the right junctions. The remainder of the cell is lined by the basolateral cell membrane, which interfaces with the lateral interstitial spaces on either side and with the peritubular capillary at its base. There are a number of protein-based active transport systems. Of these the most important is the sodium-potassium adenosine triphosphatase (Na-K-ATPase) system, situated in the basolateral membrane, which, in exchange for potassium from inside the tubular cell, pumps sodium out of the tubular cell into the interstitial fluid (and capillary blood) against a concentration and an electrical gradient. The consequent decrease in intracellular sodium concentration in turn facilitates passive reabsorption of sodium from the tubular lumen into the cell. The transport of virtually all solutes is coupled to that of sodium. Active transport systems that move solutes in the same direction into or out of the cell are called symporter systems, and those that move solutes in opposite directions are called antiporter systems. Whereas solutes are transported by both active and passive mechanisms, water always diffuses passively along an osmotic gradient.

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FIGURE 18–5 Structure-function relationships in the renal tubule. The most metabolically active components of the tubule are the proximal tubule, the thick ascending loop of Henle, and the first part of the distal tubule. Their cells are large, and on the capillary surface (basolateral membrane) there are many invaginations rich in mitochondria. The cells of the proximal tubule have a brush-border on the luminal surface (apical cell membrane), whereas the cells of the descending and thin ascending loops of Henle are flattened with few mitochondria. The second part of the distal tubule and collecting duct are intermediate in nature. The intercalated cells of the distal tubule have many mitochondria, the principal cells few. (From Stanton and Koeppen2 )

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FIGURE 18–6 Mechanisms of tubular secretion and reabsorption. This tubular cell in the thick ascending loop of Henle encompasses the major mechanisms of secretion and reabsorption, one or more of which is used by various segments of the tubule. The most ubiquitous and important transport mechanism is the energy-requiring Na-K-ATPase pump in the basolateral cell membrane (1), which pumps sodium out into the interstitium against its concentration gradient and maintains a low intracellular concentration. This favors inward movement of sodium from the tubular lumen, facilitated by a sodium chloride symporter system on the apical cell membrane (2), which creates enough potential energy to draw in potassium against its concentration gradient and which is the primary inhibitory site of action of loop diuretics. A sodium-H+ antiporter system on the apical cell membrane (3) aids sodium reabsorption and extrudes H+, thereby promoting reaction of water with carbon dioxide to form H+ and bicarbonate ion under the influence of carbonic anhydrase (CA). Bicarbonate diffuses out into the capillary. Sodium reabsorption is thereby coupled to H+ loss and bicarbonate reabsorption. The transport proteins create a positive charge in the lumen, which drives ions such as sodium, calcium, potassium, and magnesium passively through the tight junctions by paracellular diffusion. The thick ascending loop of Henle is uniquely highly water-impermeable so that luminal osmolality progressively falls to less than 150 mOsm/kg (the “diluting segment”). (Modified from Stanton and Koeppen2 )

Proximal Tubule

The first part of the proximal tubule reabsorbs about 100 percent of the filtered glucose, lactate, and amino acids as well as some phosphate by coupling with sodiumsymporter systems. 2  Hydrogen ions are extruded into the tubule by a sodium-H+ antiporter system in exchange for bicarbonate. The absorption of organic anions and bicarbonate in the first part of the proximal tubule results in a relatively high chloride concentration downstream, promoting passive ingress of chloride. This leaves the tubular fluid positively charged relative to blood, further promoting the movement of sodium from the tubular fluid into the cell.

Most NaCl is absorbed transcellularly by a sodium-H+ and chloride-based antiporter system in the apical cell membrane. Sodium is pumped into the interstitial space by the Na-K-ATPase pump, and chloride is pumped by a potassium-chloride symporter system, and the resulting increase in osmolality draws water across as well. In all, about two-thirds of the filtered water, chloride, and potassium are reabsorbed by the proximal tubule, coupled with and strongly influenced by sodium absorption. 2 

The proximal tubule is also an important site of secretion of many endogenous anions (bile salts, urate), cations (creatinine, dopamine) and drugs (diuretics, penicillin, probenecid, cimetidine). Organic ions compete for protein transport systems. Thus, administration of probenecid impairs tubular secretion of penicillin and prolongs its action. In chronic renal insufficiency there is an accumulation of organic acids that compete with drugs such as furosemide for secretor proteins, thereby conferring the “resistance” to loop diuretics encountered in this condition.

Thick Ascending Loop of Henle

The metabolically active component of the loop of Henle is the thick ascending loop, which reabsorbs about 20 percent of the filtered sodium, chloride, potassium, and bicarbonate. Only the descending loop is permeable to water. In the water-impermeable thick ascending loop, sodium is actively reabsorbed, but water remains. In this so-called diluting segment of the kidney, tubular fluid osmolality decreases to less than 150 mOsm/kg H2 O.

As in the proximal tubule, the Na-K-ATPase pump in the basolateral membrane is the engine that drives the resorptive capacity of the thick ascending loop. 2  Sodium moves from the tubular lumen by passive diffusion along its concentration gradient. A sodium-H+ antiporter system in the apical cell membrane mediates the net secretion of H+ and reabsorption of bicarbonate.

An important symporter protein system couples the reabsorption of sodium, chloride, and potassium (the latter against its concentration gradient) across the apical membrane. This system is the major site of action of loop diuretics in their inhibition of NaCl reabsorption in the thick ascending loop of Henle.

Oxygen Balance in the Medullary Thick Ascending Loop

The kidneys receive 20 percent of the total cardiac output but extract relatively little oxygen. The renal arteriovenous oxygen difference [(a-v)O2 ] is only 1.5 mL/dL. However, there is a marked discrepancy between the renal cortex and medulla with regard to blood flow, oxygen delivery, and oxygen consumption (Table 18–1). The medulla receives only 6 percent of the RBF and has an average oxygen tension (PO2) of 8 mm Hg. Thus, it is possible that severe hypoxia could develop in the medulla despite a relatively adequate total RBF, and the metabolically active medullary thick ascending loop of Henle is particularly vulnerable. 9 

TABLE 18–1. Distribution of Renal Blood Flow Between Cortex and Medulla

The medullary thick ascending loop is also a potential site for nephrotoxic injury. Intrarenal blood flow is regulated by endogenous vasoactive compounds. In the outer cortex, adenosine induces vasoconstriction. In the juxtamedullary zone, generation of prostaglandins and nitric oxide promote vasodilation. The net effect is to direct as much available blood flow to the medulla as possible. Drugs that inhibit prostaglandin synthesis, such as nonsteroidal antiinflammatory agents, can upset this compensatory mechanism and result in medullary ischemia.

Any stress resulting in activation of the sympathoadrenal system (pain, trauma, hemorrhage, hypoperfusion, sepsis, congestive heart failure) results in renal cortical constriction and potential tubular ischemia. The kidney is relatively devoid of b2 -receptors so that endogenous or exogenous epinephrine induces vasoconstriction through alpha receptors or angiotensin activation. In hemodynamically mediated renal injury, the initial response to renal hypoperfusion is increased active NaCl absorption in the thick ascending limb. This increases oxygen consumption in the face of decreased oxygen delivery. Subsequent sympathoadrenal responses and renal cortical vasoconstriction may be a compensatory attempt to redistribute blood flow to the medulla. Ultimately, ATP stores become depleted, and active NaCl reabsorption winds down. This increases the NaCl concentration in tubular fluid reaching the macula densa in the distal tubule, resulting in angiotensin release and afferent arteriolar constriction (i.e., tubuloglomerular feedback). Teleologically, the resultant decrease in GFR benefits renal oxygen balance by decreasing solute reabsorption and oxygen consumption in the medullary thick ascending loop and by preserving intravascular volume. 9 

This hypothesis implies that ischemic or nephrotoxic insults to the renal tubules could be alleviated by the administration of loop diuretics or dopaminergic agents. These drugs inhibit active sodium reabsorption in the thick ascending limb, thereby decreasing oxygen consumption and enhancing tubular oxygen balance. 10 

Distal Tubule and Collecting Duct

The proximal segment of the distal tubule is structurally and functionally similar to the thick ascending loop. An apical cell membrane NaCl symporter system is the site of action of thiazide diuretics.

The last part of the distal tubule is composed of two types of cells. Principal cells reabsorb sodium and water and secrete potassium via the Na-K-ATPase pump. Intercalated cells secrete H+ and reabsorb bicarbonate by an H+ -ATPase pump in the apical cell membrane.