Ganong's Review of Medical Physiology, 23rd Edition

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654 SECTION VIII Renal Physiology Interstitial fluid Na + K + K + Cl − Barttin ROMK K + Renal tubule cell ROMK Tubular lumen Na + 2Cl − K + FIGURE 38–15 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 38–2). vasopressin V 2 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 H 2 O, almost five times the osmolality of plasma, with a total of 99.7% of the filtered water being reabsorbed (Table 38–7). 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 H 2 O. 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. K + K + CLINICAL BOX 38–2 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 Ca 2+ 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 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 38–3). 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
TDL MI TAL A 300 300 300 300 300 300 300 300 E 300 300 350 350 350 350 500 500 300 300 300 300 300 300 300 300 300 300 350 350 350 350 500 500 300 300 300 300 300 300 300 300 150 150 300 300 300 300 500 500 B 400 400 400 400 400 400 400 400 F 325 325 425 425 425 425 600 600 400 400 400 400 400 400 400 400 325 325 425 425 425 425 600 600 200 200 200 200 200 200 200 200 125 125 225 225 225 225 400 400 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 38–16 for a cortical nephron with no thin ascending limb. Assume first a condition in which osmolality is 300 mOsm/kg of H 2 O throughout the descending and ascending limbs and the medullary interstitium (Figure 38–16A). 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 H 2 O. Water then moves out of the thin descending limb, and its contents equilibrate with the interstitium (Figure 38–16B). However, fluid containing 300 mOsm/kg of H 2 O is continuously entering this limb from the proximal tubule (Figure 38–16C), so the gradient against which the Na + and Cl – are pumped is reduced and more enters the interstitium (Figure 38–16D). 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. In juxtamedullary nephrons with longer loops and thin ascending limbs, the osmotic gradient is spread over a greater C 300 300 300 300 400 400 400 400 G 300 325 325 425 425 425 425 600 CHAPTER 38 Renal Function & Micturition 655 FIGURE 38–16 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.) 300 300 300 300 400 400 400 400 300 325 325 425 425 425 425 600 200 200 200 200 400 400 400 400 125 225 225 225 225 400 400 600 D 350 350 350 350 500 500 500 500 H 312 375 375 425 425 513 513 700 350 350 350 350 500 500 500 500 312 375 375 425 425 513 513 700 150 150 150 150 300 300 300 300 112 175 175 225 225 313 313 500 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 38–17). 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 countercurrent multiplication in the loops of Henle were to cease.
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Ranges of Normal Values in Human Wh
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Copyright © 2010 by The McGraw-Hil
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iv Key Features of the 23rd Edition
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About the Authors KIM E. BARRETT Ki
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viii CONTENTS 27. Digestion, Absorp
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2 SECTION I Cellular & Molecular Ba
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10 SECTION I Cellular & Molecular B
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80 SECTION II Physiology of Nerve &
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100 SECTION II Physiology of Nerve
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168 SECTION III Central & Periphera
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302 SECTION IV Endocrine & Reproduc
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430 SECTION V Gastrointestinal Phys
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490 SECTION VI Cardiovascular Physi
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588 SECTION VII Respiratory Physiol
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Page 652 and 653: 640 SECTION VIII Renal Physiology T
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Page 680 and 681: 668 SECTION VIII Renal Physiology p
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Page 684 and 685: 672 SECTION VIII Renal Physiology A
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Page 692 and 693: 680 SECTION VIII Renal Physiology I
Page 694 and 695: 682 SECTION VIII Renal Physiology C
Page 700 and 701: 688 Answers to Multiple Choice Ques
Page 702 and 703: 690 INDEX Angiotensin III, 671 Angi
Page 704 and 705: 692 INDEX Cannabinoids, 145, 179 Ca
Page 706 and 707: 694 INDEX Climbing fibers, 255 Clin
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704 INDEX Monoamines (continued) hi
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708 INDEX Proprioceptors, 632-633 P
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712 INDEX Supratentorial lesions, 2
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714 INDEX Vestibular system, 213-21
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