CHAPTER 22 The Control of Ventilation 375 CASE STUDIES FOR PART V • • • CASE STUDY FOR CHAPTER 19 antiproteases. In emphysema, excess proteolytic activity de- stroys elastin and collagen, the major extracellular matrix Emphysema proteins responsible for maintaining the integrity of the A 65-year-old man went to the university hospital emer- alveolar-capillary membrane and the elasticity of the lung. gency department because of a 5-day history of shortness Cigarette smoke increases proteolytic activity, which may of breath and dyspnea on exertion. He also complained of arise through an increase in protease levels, a decrease in a cough productive of green sputum. He appeared pale antiprotease activity, or a combination of the two. and said he felt feverish at home, but denied any shaking Reference chills, sore throat, nausea, vomiting, or diarrhea. Having Hogg JC. Chronic obstructive pulmonary disease: An overview smoked two packs of cigarettes a day for the past 30 years, of pathology and pathogenesis. Novartis Found Symp he had recently decreased his habit to one pack a day. He 2001;234:4–26. had not been previously hospitalized. He is a retired cab driver and lives with his wife; they have no pets. Although CASE STUDY FOR CHAPTER 20 he has had dyspnea upon exertion for the last 2 years, he continues to maintain an active lifestyle. He still mows his Chest Pain lawn without much difficulty, and can walk 1 to 2 miles on A 27-year-old accountant recently drove cross-country to a flat surface at a moderate pace. The patient said he start a new job in Denver, Colorado. A week after her rarely drinks alcohol. He denied having had any other sig- move, she started to experience chest pains. She drove nificant past medical problems, including heart disease, to the emergency department after experiencing 24 hypertension, edema, childhood asthma, or any allergies. hours of right-sided chest pain, which was worse with in- He did state that his father, also a heavy smoker, died of spiration. She also experienced shortness of breath and emphysema at age 55. stated that she felt warm. She denied any sputum pro- An initial exam shows that the patient is thin but has duction, hemoptysis, coughing, or wheezing. She is ac- a large chest. He is in moderate respiratory distress. His tive and walks daily and never has experienced any blood pressure is 130/80 mm Hg; respiratory rate, 28 to swelling in her legs. She has never been treated for any 32 breaths/min; heart rate, 92/minute; and oral tempera- respiratory problems and has never undergone any sur- ture, 37.9C. His trachea is midline, and his chest ex- gical procedures. Her medical history is negative, and pands symmetrically. He has decreased but audible she has no known drug allergies. Oral contraceptives are breath sounds in both lung fields, with expiratory wheez- her only medication. She smokes a pack of cigarettes a ing and a prolonged expiratory phase. Head, eyes, ears, day and consumes wine occasionally. She does not use nose, and throat findings are unremarkable. A pulse intravenous drugs and has no other risk factors for HIV oximetry reading reveals his blood hemoglobin oxygen disease. Her family history is negative for asthma and saturation is 91% when breathing room air. any cardiovascular diseases. Pulmonary function tests reveal severe limitation of Physical examination reveals a mildly obese woman airflow rates, particularly expiratory airflow. The patient in moderate respiratory distress. Her respiratory rate is is diagnosed with pulmonary emphysema. 24 breaths/min and her pulse is 115 beats/min. Her blood Questions pressure is 140/80 mm Hg, and no jugular vein disten- 1. What are the common spirometry findings associated with sion is observed. Heart rate and rhythm are regular, with emphysema? normal heart sounds and no murmurs. Her chest is clear, 2. What are the mechanisms of airflow limitation in emphy- and her temperature is 38C. Her extremities show signs sema? of cyanosis, but no clubbing or edema is detected. Blood 3. What is the most commonly held theory explaining the de- gases, obtained while she was breathing room air, reveal velopment of emphysema? a PO 2 of 60 mm Hg and a PCO 2 of 32 mm Hg; her arterial blood pH is 7.49. Her alveolar-arterial (A-a)O 2 gradient is Answers to Case Study Questions for Chapter 19 40 mm Hg. A Gram’s stain sputum specimen exhibited a 1. The hallmark of emphysema is the limitation of airflow out normal flora. A chest X-ray study reveals a normal heart of the lungs. In emphysema, expiratory flow rates (FVC, shadow and clear lung fields, except for a small periph- FEV 1 , and FEV 1 /FVC ratio) are significantly decreased. How- eral infiltrate in the left lower lobe. A lung scan reveals ever, some lung volumes (TLC, FRC, and RV) are increased, an embolus in the left lower lobe. and the increase is a result of the loss of lung elastic recoil (increased compliance). Case Study Questions 2. The mechanisms that limit expiratory airflow in emphysema 1. What is the cause of a widened alveolar-arterial gradient in include hypersensitivity of airway smooth muscle, mucus patients with pulmonary embolism? hypersecretion, and bronchial wall inflammation and in- 2. What causes the decreased arterial PCO 2 and elevated arte- creased dynamic airway compression as a result of in- rial pH? creased compliance. 3. Why do oral contraceptives induce hypercoagulability? 3. Many of the pathophysiological changes in emphysema are Answers to Case Study Questions for Chapter 20 a result of the loss of lung elastic recoil and destruction of 1. A normal A-aO 2 gradient is 5 to 15 mm Hg. A pulmonary the alveolar-capillary membrane. This is thought to be a re- embolus will cause blood flow to be shunted to another re- sult of an imbalance between the proteases and antipro- gion of the lung. Because cardiac output is unchanged, the teases ( 1-antitrypsin) in the lower respiratory tree. Nor- shunting of blood causes overperfusion, which causes an mally, proteolytic enzyme activity is inactivated by abnormally low A/ ratio in another region of the lungs.
376 PART V RESPIRATORY PHYSIOLOGY Thus, blood leaving the lungs has a low PO 2 , resulting in hy- 2. DL CO decreases with anemia because there is less hemoglo- poxemia (a low arterial PO 2 ). The decrease in arterial PO 2 ac- bin available to bind CO. counts in part for the increase in the A-aO 2 gradient. How- 3. There are several causes of vitamin B 12 deficiency. In older ever, ventilation is also stimulated as a compensatory individuals, especially those who live alone, insufficient di- mechanism to hypoxemia, which leads to hyperventilation etary intake of animal protein may be the cause; other with a concomitant increase in alveolar PO 2 . The A-aO 2 gra- causes include loss of gastric mucosa or regional enteritis. dient is, therefore, further increased because of the in- creased alveolar PO 2 caused by hyperventilation. Reference 2. The decreased PCO 2 and increased pH are the result of hy- Wintrobe MM. Clinical Hematology. 9th Ed. Philadelphia: Lea & perventilation as a result of the hypoxic drive (low PO 2 ) that Febiger, 1993. stimulates ventilation. 3. The mechanisms by which oral contraceptives increase the CASE STUDY FOR CHAPTER 22. risk of thrombus formation are not completely understood. The risk appears to be correlated best with the estrogen Pickwickian Syndrome content of the pills. Hypotheses include increased endothe- A 45-year-old man was referred to the pulmonary func- lial cell proliferation, decreased rates of venous blood flow, tion laboratory because of polycythemia (hematocrit of and increased coagulability secondary to changes in 57%). At the time of referral, he weighs 142 kg (312 platelets, coagulation factors, and the fibrinolytic system. pounds) and his height is 175 cm (5 feet, 9 inches). A Furthermore, there are changes in serum lipoprotein levels brief history reveals that he frequently falls asleep during with an increase in LDL and VLDL and a variable effect on the day. His blood gas values are PaO 2 , 69 mm Hg; SaO 2 , HDL. Driving cross-country, with long sedentary periods, 94%; PCO 2 , 35 mm Hg, and pH, 7.44. A few days later, he may have exacerbated the patient’s condition. is admitted as an outpatient in the hospital’s sleep cen- Reference ter. He is connected to an ear oximeter and to a portable Cotes JE. Lung Function: Assessment and Application in Medi- heart monitor. Within 30 minutes, the patient falls asleep cine. 5th ed. Boston: Blackwell Scientific, 1993. and, within another 30 minutes, his SaO 2 decreases from 92% to 47% and his heart rate increases from 92 to 108 CASE STUDY FOR CHAPTER 21 beats/min, with two premature ventricular contractions. During this time, his chest wall continues to move, but Anemia airflow at the mouth and nose is not detected. A 68-year-old widow is seen by her physician because of Questions complaints of fatigue and mild memory loss. The patient 1. How would this patient’s test results be interpreted? does not abuse alcohol and has not had a history of sur- 2. What is the cause of the polycythemia? gery in the last 5 years. Blood gases (SaO 2, PO 2 , PCO 2 , and 3. How does hypoxia accelerate heart rate? pH) are normal. Blood analysis shows a white cell count 3 of 5,200 cells/mm ; Hb, 9.0 gm/dL; and a hematocrit of Answers to Case Study Questions for Chapter 22 27%. Her serum vitamin B 12 is low, but her serum folate, 1. This patient is suffering from what has been known as pick- thyroxin-stimulating hormone (TSH), and liver enzymes wickian syndrome, a disorder that occurs with severely are normal. Her peripheral blood smear is unremarkable. obese individuals because of their excessive weight. The Questions pickwickian syndrome was named after Joe, the fat boy 1. Why are SaO 2 and arterial PO 2 normal in anemic patients who was always falling asleep in Charles Dickens’ novel who have hypoxemia? The Pickwick Papers. Pickwickian patients suffer from hy- 2. How does anemia affect the oxygen diffusing capacity of poventilation and often suffer from sleep apnea as well. the lungs? Pickwickian syndrome is no longer an appropriate name be- 3. Why might this patient be deficient in vitamin B 12 ? cause it does not indicate what type of sleep disorder is in- volved. About 80% of sleep apnea patients are obese and Answers to Case Study Questions for Chapter 21 20% are of relatively normal weight. 1. Hemoglobin increases the oxygen carrying capacity of the 2. Polycythemia is the result of chronic hypoxemia from hy- blood, but has no effect on arterial PO 2 . By way of illustra- poventilation, as well as from sleep apnea. tion, if 100 mL of blood are exposed to room air, the PO 2 in 3. An increase in sympathetic discharge is often associated the blood will equal atmospheric PO 2 after equilibration. Re- with sleep apnea and is responsible for the accelerated moving the red cells, leaving only plasma, will not affect heart rate. PO 2 . An otherwise healthy patient with anemia will have a normal SaO 2 because both O 2 content and capacity are re- Reference duced proportionately. Hypoxemia in anemic patients is a Martin RJ, ed. Cardiorespiratory Disorders During Sleep. 2nd result of low oxygen content, not a low PO 2 . Ed. Mt. Kisco, NY: Futura, 1990.
Renal Physiology and PART VI Body Fluids CHAPTER Kidney Function 23 George A. Tanner, Ph.D. 23 CHAPTER OUTLINE ■ FUNCTIONAL RENAL ANATOMY ■ TUBULAR TRANSPORT IN THE LOOPS OF HENLE ■ AN OVERVIEW OF KIDNEY FUNCTION ■ TUBULAR TRANSPORT IN THE DISTAL NEPHRON ■ RENAL BLOOD FLOW ■ URINARY CONCENTRATION AND DILUTION ■ GLOMERULAR FILTRATION ■ INHERITED DEFECTS IN KIDNEY TUBULE ■ TRANSPORT IN THE PROXIMAL TUBULE EPITHELIAL CELLS KEY CONCEPTS 1. The formation of urine involves glomerular filtration, tubu- 11. The transport of water and most solutes across tubu- lar reabsorption, and tubular secretion. lar epithelia is dependent upon active reabsorption of 2. The renal clearance of a substance is equal to its rate of ex- Na . cretion divided by its plasma concentration. 12. The thick ascending limb is a water-impermeable seg- 3. Inulin clearance provides the most accurate measure of ment that reabsorbs Na via a Na-K-2Cl cotransporter in glomerular filtration rate (GFR). the apical cell membrane and a vigorous Na /K -ATPase 4. The clearance of p-aminohippurate (PAH) is equal to the ef- in the basolateral cell membrane. fective renal plasma flow. 13. The distal convoluted tubule epithelium is water-imper- 5. The rate of net tubular reabsorption of a substance is equal meable and reabsorbs Na via a thiazide-sensitive apical to its filtered load minus its excretion rate. The rate of net membrane Na-Cl cotransporter. tubular secretion of a substance is equal to its excretion 14. Cortical collecting duct principal cells reabsorb Na and rate minus its filtered load. secrete K . 6. The kidneys, especially the cortex, have a high blood flow. 15. The kidneys save water for the body by producing urine 7. Kidney blood flow is autoregulated; it is also profoundly in- with a total solute concentration (i.e., osmolality) greater fluenced by nerves and hormones. than plasma. 8. The glomerular filtrate is an ultrafiltrate of plasma. 16. The loops of Henle are countercurrent multipliers; they 9. GFR is determined by the glomerular ultrafiltration coeffi- set up an osmotic gradient in the kidney medulla. Vasa cient, glomerular capillary hydrostatic pressure, hydro- recta are countercurrent exchangers; they passively static pressure in the space of Bowman’s capsule, and help maintain the medullary gradient. Collecting ducts glomerular capillary colloid osmotic pressure. are osmotic equilibrating devices; they have a low wa- 10. The proximal convoluted tubule reabsorbs about 70% of ter permeability, which is increased by arginine vaso- filtered Na , K , and water and nearly all of the filtered pressin (AVP). glucose and amino acids. It also secretes a large variety of 17. Genetic defects in kidney epithelial cells account for sev- organic anions and organic cations. eral disorders. 377
378 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS he kidneys play a dominant role in regulating the 6) They eliminate the waste products of metabolism, Tcomposition and volume of the extracellular fluid including urea (the main nitrogen-containing end-product (ECF). They normally maintain a stable internal environ- of protein metabolism in humans), uric acid (an end-prod- ment by excreting appropriate amounts of many sub- uct of purine metabolism), and creatinine (an end-product stances in the urine. These substances include not only of muscle metabolism). waste products and foreign compounds, but also many 7) They remove many drugs (e.g., penicillin) and for- useful substances that are present in excess because of eign or toxic compounds. eating, drinking, or metabolism. This chapter considers 8) They are the major production sites of certain hor- the basic renal processes that determine the excretion of mones, including erythropoietin (see Chapter 11) and various substances. 1,25-dihydroxy vitamin D 3 (see Chapter 36). The kidneys perform a variety of important functions: 9) They degrade several polypeptide hormones, in- 1) They regulate the osmotic pressure (osmolality) of the body fluids by excreting osmotically dilute or concen- cluding insulin, glucagon, and parathyroid hormone. trated urine. 10) They synthesize ammonia, which plays a role in 2) They regulate the concentrations of numerous ions acid-base balance (see Chapter 25). 2 2 in blood plasma, including Na , K , Ca , Mg , Cl , bi- 11) They synthesize substances that affect renal blood carbonate (HCO 3 ), phosphate, and sulfate. flow and Na excretion, including arachidonic acid deriv- 3) They play an essential role in acid-base balance by atives (prostaglandins, thromboxane A 2 ) and kallikrein (a excreting H , when there is excess acid, or HCO 3 , when proteolytic enzyme that results in the production of there is excess base. kinins). 4) They regulate the volume of the ECF by controlling When the kidneys fail, a host of problems ensue. Dialy- Na and water excretion. sis and kidney transplantation are commonly used treat- 5) They help regulate arterial blood pressure by adjust- ments for advanced (end-stage) renal failure (see Clinical ing Na excretion and producing various substances (e.g., Focus Box 23.1). renin) that can affect blood pressure. CLINICAL FOCUS BOX 23.1 Dialysis and Transplantation Dialysis can enable patients with otherwise fatal renal Chronic renal failure can result from a large variety of dis- disease to live useful and productive lives. Several physio- eases but is most often due to inflammation of the logical and psychological problems persist, however, in- glomeruli (glomerulonephritis) or urinary reflux and infec- cluding bone disease, disorders of nerve function, hyper- tions (pyelonephritis). Renal damage may occur over tension, atherosclerotic vascular disease, and many years and may be undetected until a considerable disturbances of sexual function. There is a constant risk of loss of nephrons has occurred. When GFR has declined to infection and, with hemodialysis, clotting and hemor- 5% of normal or less, the internal environment becomes so rhage. Dialysis does not maintain normal growth and de- disturbed that patients usually die within weeks or months velopment in children. Anemia (primarily a result of defi- if they are not dialyzed or provided with a functioning kid- cient erythropoietin production by damaged kidneys) was ney transplant. once a problem but can now be treated with recombinant Most of the signs and symptoms of renal failure can be human erythropoietin. relieved by dialysis, the separation of smaller molecules Renal transplantation is the only real cure for pa- from larger molecules in solution by diffusion of the small tients with end-stage renal failure. It may restore complete molecules through a selectively permeable membrane. health and function. In 1999, about 12,500 kidney trans- Two methods of dialysis are commonly used to treat pa- plant operations were performed in the United States. At tients with severe, irreversible (“end-stage”) renal failure. present, 94% of kidneys grafted from living donors related In continuous ambulatory peritoneal dialysis to the recipient function for 1 year; about 90% of kidneys (CAPD), the peritoneal membrane, which lines the abdom- from unrelated donors (cadaver) function for 1 year. inal cavity, acts as a dialyzing membrane. About 1 to 2 Several problems complicate kidney transplantation. liters of a sterile glucose-salt solution are introduced into The immunological rejection of the kidney graft is a major the abdominal cavity and small molecules (e.g., K and challenge. The powerful drugs used to inhibit graft rejec- urea) diffuse into the introduced solution, which is then tion compromise immune defensive mechanisms so that drained and discarded. The procedure is usually done sev- unusual and difficult-to-treat infections often develop. The eral times every day. limited supply of donor organs is also a major unsolved Hemodialysis is more efficient in terms of rapidly re- problem; there are many more patients who would benefit moving wastes. The patient’s blood is pumped through an from a kidney transplant than there are donors. The me- artificial kidney machine. The blood is separated from a bal- dian waiting time for a kidney transplant is currently more anced salt solution by a cellophane-like membrane, and than 900 days. Finally, the cost of transplantation (or dialy- small molecules can diffuse across this membrane. Excess sis) is high. Fortunately for people in the United States, fluid can be removed by applying pressure to the blood and Medicare covers the cost of dialysis and transplantation, filtering it. Hemodialysis is usually done 3 times a week (4 but these life-saving therapies are beyond the reach of to 6 hours per session) in a medical facility or at home. most people in developing countries.
CHAPTER 23 Kidney Function 379 Cortical radial artery convoluted tubules, and cortical collecting ducts are located and glomeruli in the cortex. The medulla is lighter in color and has a stri- Arcuate artery Interlobar ated appearance that results from the parallel arrangement of artery the loops of Henle, medullary collecting ducts, and blood vessels of the medulla. The medulla can be further subdi- Pyramid vided into an outer medulla, which is closer to the cortex, Outer and an inner medulla, which is farther from the cortex. medulla The human kidney is organized into a series of lobes, Renal Inner usually 8 to 10. Each lobe consists of a pyramid of artery medulla medullary tissue and the cortical tissue overlying its base Papilla and covering its sides. The tip of the medullary pyramid forms a renal papilla. Each renal papilla drains its urine into Hilum Segmental Renal a minor calyx. The minor calices unite to form a major ca- vein artery lyx, and the urine then flows into the renal pelvis. The Minor calyx Pelvis urine is propelled by peristaltic movements down the Major calyx ureters to the urinary bladder, which stores the urine until Cortex Renal the bladder is emptied. The medial aspect of each kidney is capsule indented in a region called the hilum, where the ureter, Ureter blood vessels, nerves, and lymphatic vessels enter or leave the kidney. The human kidney, sectioned vertically. FIGURE 23.1 (From Smith HW. Principles of Renal Physiol- ogy. New York: Oxford University Press, 1956.) The Nephron Is the Basic Unit of Renal Structure and Function Each human kidney contains about one million nephrons (Fig. 23.2), which consist of a renal corpuscle and a renal FUNCTIONAL RENAL ANATOMY tubule. The renal corpuscle consists of a tuft of capillaries, the Each kidney in an adult weighs about 150 g and is roughly glomerulus, surrounded by Bowman’s capsule. The renal the size of one’s fist. If the kidney is sectioned (Fig. 23.1), two tubule is divided into several segments. The part of the tubule regions are seen: an outer part, called the cortex, and an in- nearest the glomerulus is the proximal tubule. This is subdi- ner part, called the medulla. The cortex typically is reddish vided into a proximal convoluted tubule and proximal brown and has a granulated appearance. All of the glomeruli, straight tubule. The straight portion heads toward the Connecting Distal tubule convoluted tubule Cortex Proximal Juxtaglomerular convoluted apparatus tubule Cortical Renal corpuscle collecting containing duct Bowman's capsule and glomerulus Proximal straight Outer medulla Outer Thick tubule medullary ascending collecting limb Descending duct thin limb Inner medulla FIGURE 23.2 Components of the nephron and the collect- Inner ing duct system. On the left is a long- Ascending medullary thin limb collecting looped juxtamedullary nephron; on the right duct is a superficial cortical nephron. (Modified from Kriz W, Bankir L. A standard nomen- Papillary clature for structures of the kidney. Am J duct Physiol 1988;254:F1–F8.)
380 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS medulla, away from the surface of the kidney. The loop of Henle includes the proximal straight tubule, thin limb, and Cortex Glomerulus thick ascending limb. The next segment, the short distal con- voluted tubule, is connected to the collecting duct system by Cortical connecting tubules. Several nephrons drain into a cortical Afferent radial collecting duct, which passes into an outer medullary col- arteriole vein lecting duct. In the inner medulla, inner medullary collecting Cortical Efferent ducts unite to form large papillary ducts. arteriole radial The collecting ducts perform the same types of func- artery tions as the renal tubules, so they are often considered to be part of the nephron. The collecting ducts and nephrons dif- Outer Juxtamedullary fer, however, in embryological origin, and because the col- medulla glomerulus lecting ducts form a branching system, there are many more nephrons than collecting ducts. The entire renal Arcuate tubule and collecting duct system consists of a single layer vein of epithelial cells surrounding fluid (urine) in the tubule or Ascending Arcuate duct lumen. Cells in each segment have a characteristic his- vasa recta artery tological appearance. Each segment has unique transport Descending properties (discussed later). vasa recta Interlobar Inner artery Not All Nephrons Are Alike medulla Interlobar vein Three groups of nephrons are distinguished, based on the location of their glomeruli in the cortex: superficial, mid- cortical, and juxtamedullary nephrons. The jux- Renal From renal artery tamedullary nephrons, whose glomeruli lie in the cortex pelvis next to the medulla, comprise about one-eighth of the To renal nephron population. They differ in several ways from the vein other nephron types: they have a longer loop of Henle, longer thin limb (both descending and ascending portions), FIGURE 23.3 The blood vessels in the kidney; peritubu- lar capillaries are not shown. (Modified from larger glomerulus, lower renin content, different tubular Kriz W, Bankir L. A standard nomenclature for structures of the permeability and transport properties, and a different type kidney. Am J Physiol. 1988;254:F1–F8.) of postglomerular blood supply. Figure 23.2 shows superfi- cial and juxtamedullary nephrons; note the long loop of the juxtamedullary nephron. Some vasa recta reach deep into the inner medulla. In the outer medulla, descending and ascending vasa recta are The Kidneys Have a Rich Blood Supply grouped in vascular bundles and are in close contact with and Innervation each other. This arrangement greatly facilitates the ex- change of substances between blood flowing in and out of Each kidney is typically supplied by a single renal artery that branches into anterior and posterior divisions, which the medulla. give rise to a total of five segmental arteries. The seg- The kidneys are richly innervated by sympathetic nerve mental arteries branch into interlobar arteries, which pass fibers, which travel to the kidneys, mainly in thoracic toward the cortex between the kidney lobes (see Fig. spinal nerves T10, T11, and T12 and lumbar spinal nerve 23.1). At the junction of cortex and medulla, the interlo- L1. Stimulation of sympathetic fibers causes constriction of bar arteries branch to form arcuate arteries. These, in renal blood vessels and a fall in renal blood flow. Sympa- turn, give rise to smaller cortical radial arteries, which thetic nerve fibers also innervate tubular cells and may pass through the cortex toward the surface of the kidney. cause an increase in Na reabsorption by a direct action on Several short, wide, muscular afferent arterioles arise these cells. In addition, stimulation of sympathetic nerves from the cortical radial arteries. Each afferent arteriole increases the release of renin by the kidneys. Afferent (sen- gives rise to a glomerulus. The glomerular capillaries are sory) renal nerves are stimulated by mechanical stretch or followed by an efferent arteriole. The efferent arteriole by various chemicals in the renal parenchyma. then divides into a second capillary network, the per- Renal lymphatic vessels drain the kidneys, but little is itubular capillaries, that surrounds the kidney tubules. known about their functions. Venous vessels, in general, lie parallel to the arterial ves- sels and have similar names. The Juxtaglomerular Apparatus Is the Site The blood supply to the medulla is derived from the ef- of Renin Production ferent arterioles of juxtamedullary glomeruli. These ves- sels give rise to two patterns of capillaries: peritubular Each nephron forms a loop, and the thick ascending limb capillaries, which are similar to those in the cortex, and touches the vascular pole of the glomerulus (see Fig. 23.2). At vasa recta, which are straight, long capillaries (Fig. 23.3). this site is the juxtaglomerular apparatus, a region com-
CHAPTER 23 Kidney Function 381 Macula densa space of Bowman’s capsule and then flows downstream through the tubule lumen, where its composition and vol- Thick ume are altered by tubular activity. Tubular reabsorption ascending involves the transport of substances out of tubular urine; limb these substances are then returned to the capillary blood, Granular which surrounds the kidney tubules. Reabsorbed sub- 2 cell Efferent stances include many important ions (e.g., Na , K , Ca , arteriole Mg 2 , Cl , HCO 3 , phosphate), water, important Nerve metabolites (e.g., glucose, amino acids), and even some waste products (e.g., urea, uric acid). Tubular secretion in- Extraglomerular mesangial cell volves the transport of substances into the tubular urine. Afferent For example, many organic anions and cations are taken up arteriole Bowman's by the tubular epithelium from the blood surrounding the capsule tubules and added to the tubular urine. Some substances (e.g., H , ammonia) are produced in the tubular cells and Mesangial cell secreted into the tubular urine. The terms reabsorption and se- Glomerular capillary cretion indicate movement out of and into tubular urine, re- spectively. Tubular transport (reabsorption, secretion) may Histological appearance of the juxta- FIGURE 23.4 be active or passive, depending on the particular substance glomerular apparatus. A cross section and other conditions. through a thick ascending limb is on top and part of a glomerulus Excretion refers to elimination via the urine. In general, is below. The juxtaglomerular apparatus consists of the macula the amount excreted is expressed by the following equation: densa, extraglomerular mesangial cells, and granular cells. (From Taugner R, Hackenthal E. The Juxtaglomerular Apparatus: Struc- Excreted Filtered Reabsorbed Secreted (1) ture and Function. Berlin: Springer, 1989.) The functional state of the kidneys can be evaluated using several tests based on the renal clearance concept. These tests measure the rates of glomerular filtration, renal blood flow, prised of the macula densa, extraglomerular mesangial cells, and tubular reabsorption or secretion of various substances. and granular cells (Fig. 23.4). The macula densa (dense spot) Some of these tests, such as the measurement of glomerular consists of densely crowded tubular epithelial cells on the filtration rate, are routinely used to evaluate kidney function. side of the thick ascending limb that faces the glomerular tuft; these cells monitor the composition of the fluid in the tubule lumen at this point. The extraglomerular mesangial Renal Clearance Equals Urinary Excretion Rate cells are continuous with mesangial cells of the glomerulus; Divided by Plasma Concentration they may transmit information from macula densa cells to the granular cells. The granular cells are modified vascular A useful way of looking at kidney function is to think of the smooth muscle cells with an epithelioid appearance, located kidneys as clearing substances from the blood plasma. mainly in the afferent arterioles close to the glomerulus. When a substance is excreted in the urine, a certain volume These cells synthesize and release renin, a proteolytic en- of plasma is, in effect, freed (or cleared) of that substance. zyme that results in angiotensin formation (see Chapter 24). The renal clearance of a substance can be defined as the volume of plasma from which that substance is completely removed (cleared) per unit time. The clearance formula is: AN OVERVIEW OF KIDNEY FUNCTION V ˙ C x U x (2) Three processes are involved in forming urine: glomerular P x filtration, tubular reabsorption, and tubular secretion (Fig. where X is the substance of interest, C X is the clearance of 23.5). Glomerular filtration involves the ultrafiltration of substance X, U X is the urine concentration of substance, P X ˙ plasma in the glomerulus. The filtrate collects in the urinary is the plasma concentration of substance X, and V is the ˙ urine flow rate. The product U X Vequals the excretion rate per minute and has dimensions of amount per unit time Filtration Kidney tubule (e.g., mg/min or mEq/day). The clearance of a substance can easily be determined by measuring the concentrations of a substance in urine and plasma and the urine flow rate Reabsorption Secretion Excretion (urine volume/time of collection) and substituting these values into the clearance formula. Glomerulus Peritubular capillary Inulin Clearance Equals the Glomerular Filtration Rate Processes involved in urine formation. This FIGURE 23.5 highly simplified drawing shows a nephron and An important measurement in the evaluation of kidney its associated blood vessels. function is the glomerular filtration rate (GFR), the rate at
382 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS are desired. The clearance of iothalamate, an iodinated or- ganic compound, also provides a reliable measure of GFR. It is not common, however, to use these substances in the clinic. They must be infused intravenously, and because short urine collection periods are used, the bladder is usu- ally catheterized; these procedures are inconvenient. It would be simpler to use an endogenous substance (i.e., one Filtered inulin = Excreted inulin native to the body) that is only filtered, is excreted in the P x GFR U x V urine, and normally has a stable plasma value that can be ac- IN IN U V curately measured. There is no such known substance, but GFR = IN = C IN creatinine comes close. P IN Creatinine is an end-product of muscle metabolism, a The principle behind the measurement of derivative of muscle creatine phosphate. It is produced con- FIGURE 23.6 glomerular filtration rate (GFR). P IN tinuously in the body and is excreted in the urine. Long plasma [inulin], U IN urine [inulin], V urine flow rate, C IN urine collection periods (e.g., a few hours) can be used be- inulin clearance. cause creatinine concentrations in the plasma are normally stable and creatinine does not have to be infused; conse- which plasma is filtered by the kidney glomeruli. If we had quently, there is no need to catheterize the bladder. Plasma a substance that was cleared from the plasma only by and urine concentrations can be measured using a simple glomerular filtration, it could be used to measure GFR. colorimetric method. The endogenous creatinine clear- The ideal substance to measure GFR is inulin, a fructose ance is calculated from the formula: polymer with a molecular weight of about 5,000. Inulin is U CREATININE V ˙ suitable for measuring GFR for the following reasons: C CREATININE (3) • It is freely filterable by the glomeruli. P CREATININE • It is not reabsorbed or secreted by the kidney tubules. There are two potential drawbacks to using creatinine • It is not synthesized, destroyed, or stored in the kidneys. to measure GFR. First, creatinine is not only filtered but • It is nontoxic. also secreted by the human kidney. This elevates urinary • Its concentration in plasma and urine can be determined excretion of creatinine, normally causing a 20% increase by simple analysis. in the numerator of the clearance formula. The second The principle behind the use of inulin is illustrated in drawback is due to errors in measuring plasma [creati- Figure 23.6. The amount of inulin (IN) filtered per unit nine]. The colorimetric method usually used also meas- time, the filtered load, is equal to the product of the plasma ures other plasma substances, such as glucose, leading to [inulin] (P IN) GFR. The rate of inulin excretion is equal a 20% increase in the denominator of the clearance for- ˙ to U IN V. Since inulin is not reabsorbed, secreted, syn- mula. Because both numerator and denominator are 20% thesized, destroyed, or stored by the kidney tubules, the fil- too high, the two errors cancel, so the endogenous crea- tered inulin load equals the rate of inulin excretion. The tinine clearance fortuitously affords a good approxima- equation can be rearranged by dividing by the plasma [in- tion of GFR when it is about normal. When GFR in an ˙ ulin]. The expression U IN V /P IN is defined as the inulin adult has been reduced to about 20 mL/min because of re- clearance. Therefore, inulin clearance equals GFR. nal disease, the endogenous creatinine clearance may Normal values for inulin clearance or GFR (corrected to overestimate the GFR by as much as 50%. This results 2 a body surface area of 1.73 m ) are 110 15 (SD) mL/min from higher plasma creatinine levels and increased tubu- for young adult women and 125 15 mL/min for young lar secretion of creatinine. Drugs that inhibit tubular se- adult men. In newborns, even when corrected for body sur- cretion of creatinine or elevated plasma concentrations 2 face area, GFR is low, about 20 mL/min per 1.73 m body of chromogenic (color-producing) substances other than surface area. Adult values (when corrected for body surface creatinine may cause the endogenous creatinine clear- area) are attained by the end of the first year of life. After ance to underestimate GFR. the age of 45 to 50 years, GFR declines, and is typically re- duced by 30 to 40% by age 80. If GFR is 125 mL plasma/min, then the volume of plasma Plasma Creatinine Concentration Can Be Used filtered in a day is 180 L (125 mL/min 1,440 min/day). as an Index of GFR Plasma volume in a 70-kg young adult man is only about 3 Because the kidneys continuously clear creatinine from the L, so the kidneys filter the plasma some 60 times in a day. plasma by excreting it in the urine, the GFR and plasma The glomerular filtrate contains essential constituents [creatinine] are inversely related. Figure 23.7 shows the (salts, water, metabolites), most of which are reabsorbed by steady state relationship between these variables—that is, the kidney tubules. when creatinine production and excretion are equal. Halv- ing the GFR from a normal value of 180 L/day to 90 L/day The Endogenous Creatinine Clearance Is Used results in a doubling of plasma [creatinine] from a normal Clinically to Estimate GFR value of 1 mg/dL to 2 mg/dL after a few days. Reducing GFR from 90 L/day to 45 L/day results in a greater increase Inulin clearance is the highest standard for measuring GFR in plasma creatinine, from 2 to 4 mg/dL. Figure 23.7 shows and is used whenever highly accurate measurements of GFR that with low GFR values, small absolute changes in GFR
CHAPTER 23 Kidney Function 383 creted, so it is nearly completely cleared from all of the plasma Steady state for creatinine 16 flowing through the kidneys. The renal clearance of PAH, at Produced Filtered Excreted low plasma PAH levels, approximates the renal plasma flow. 1.8 g/day 1.8 g/day10 mg/L 180 L/day The equation for calculating the true value of the renal 1.8 g/day 20 mg/L 90 L/day 1.8 g/day plasma flow is: RPF C PAH /E PAH (5) Plasma [creatinine] (mg/dL) 8 1.8 g/day 160 mg/L 11 L/day 1.8 g/day where C PAH is the PAH clearance and E PAH is the extrac- 1.8 g/day 40 mg/L 45 L/day 1.8 g/day 12 1.8 g/day 80 mg/L 22 L/day 1.8 g/day tion ratio (see Chapter 16) for PAH—the arterial plasma a rv [PAH] (P PAH) minus renal venous plasma [PAH] (P PAH) divided by the arterial plasma [PAH]. The equation is de- rived as follows. In the steady state, the amounts of PAH per unit time entering and leaving the kidneys are equal. The PAH is supplied to the kidneys in the arterial plasma and leaves the kidneys in urine and renal venous plasma, or 4 PAH entering kidneys is equal to PAH leaving kidneys: a ˙ rv RPF P PAH U PAH V RPF P PAH (6) Rearranging, we get: 0 ˙ 04590135 180 RPF U PAH V/(P PAH P PAH)(7) a rv GFR (L/day) If we divide the numerator and denominator of the right The inverse relationship between plasma a FIGURE 23.7 side of the equation by P PAH , the numerator becomes [creatinine] and GFR. If GFR is decreased by C PAH and the denominator becomes E PAH . half, plasma [creatinine] is doubled when the production and ex- If we assume extraction of PAH is 100% (E PAH 1.00), cretion of creatinine are in balance in a new steady state. then the RPF equals the PAH clearance. When this assump- tion is made, the renal plasma flow is usually called the effec- lead to much greater changes in plasma [creatinine] than tive renal plasma flow and the blood flow calculated is called occur at high GFR values. the effective renal blood flow. However, the extraction of The inverse relationship between GFR and plasma [cre- PAH by healthy kidneys at suitably low plasma PAH con- atinine] allows the use of plasma [creatinine] as an index of centrations is not 100% but averages about 91%. Assuming GFR, provided certain cautions are kept in mind: 100% extraction underestimates the true renal plasma flow by 1) It takes a certain amount of time for changes in GFR about 10%. To calculate the true renal plasma flow or blood to produce detectable changes in plasma [creatinine]. flow, it is necessary to cannulate the renal vein to measure its 2) Plasma [creatinine] is also influenced by muscle plasma [PAH], a procedure not often done. mass. A young, muscular man will have a higher plasma [creatinine] than an older woman with reduced muscle Net Tubular Reabsorption or Secretion of a mass. 3) Some drugs inhibit tubular secretion of creatinine, Substance Can Be Calculated From Filtered leading to a raised plasma [creatinine] even though GFR and Excreted Amounts may be unchanged. The rate at which the kidney tubules reabsorb a substance The relationship between plasma [creatinine] and GFR can be calculated if we know how much is filtered and how is one example of how a substance’s plasma concentration much is excreted per unit time. If the filtered load of a sub- can depend on GFR. The same relationship is observed for stance exceeds the rate of excretion, the kidney tubules several other substances whose excretion depends on GFR. must have reabsorbed the substance. The equation is: For example, when GFR falls, the plasma [urea] (or blood ˙ urea nitrogen, BUN) rises in a similar fashion. T reabsorbed P x GFR U x V (8) where T is the tubular transport rate. p-Aminohippurate Clearance Nearly The rate at which the kidney tubules secrete a substance Equals Renal Plasma Flow is calculated from this equation: ˙ T secreted U x V P x GFR (9) Renal blood flow (RBF) can be determined from measure- ments of renal plasma flow (RPF) and blood hematocrit, us- Note that the quantity excreted exceeds the filtered load ing the following equation: because the tubules secrete X. In equations 8 and 9, we assume that substance X is RBF RPF/(1 Hematocrit) (4) freely filterable. If, however, substance X is bound to the The hematocrit is easily determined by centrifuging a plasma proteins, which are not filtered, then it is necessary blood sample. Renal plasma flow is estimated by measuring to correct the filtered load for this binding. For example, the clearance of the organic anion p-aminohippurate (PAH), about 40% of plasma Ca 2 is bound to plasma proteins, so infused intravenously. PAH is filtered and vigorously se- 60% of plasma Ca 2 is freely filterable.
384 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS port maximum (Tm) for glucose (G). At Tm G , the limited number of tubule glucose carriers are all saturated and transport glucose at the maximal rate. The glucose threshold is not a fixed plasma concentration 800 but depends on three factors: GFR, Tm G , and amount of splay. A low GFR leads to an elevated threshold because the filtered glucose load is reduced and the kidney tubules can reabsorb all the filtered glucose despite an elevated plasma Glucose (mg/min) [glucose]. A reduced Tm G lowers the threshold because the Filtered 600 tubules have a diminished capacity to reabsorb glucose. Splay is the rounding of the glucose reabsorption curve; Figure 23.8 shows that tubular glucose reabsorption does Reabsorbed 400 not abruptly attain Tm G when plasma glucose is progres- Tm G sively elevated. One reason for splay is that not all nephrons have the same filtering and reabsorbing capaci- ties. Thus, nephrons with relatively high filtration rates and Splay 200 low glucose reabsorptive rates excrete glucose at a lower Excreted plasma concentration than nephrons with relatively low fil- tration rates and high reabsorptive rates. A second reason Threshold for splay is that the glucose carrier does not have an infi- 0 nitely high affinity for glucose, so glucose escapes in the 0 200 400 600 800 urine even before the carrier is fully saturated. An increase Plasma glucose (mg/dL) in splay results in a decrease in glucose threshold. Glucose titration study in a healthy man. In uncontrolled diabetes mellitus, plasma glucose levels FIGURE 23.8 The plasma [glucose] was elevated by infusing are abnormally elevated, and more glucose is filtered than glucose-containing solutions. The amount of glucose filtered per can be reabsorbed. Urinary excretion of glucose, gluco- unit time (top line) is determined from the product of the plasma suria, produces an osmotic diuresis. A diuresis is an increase [glucose] and GFR (measured with inulin). Excreted glucose (bot- in urine output; in osmotic diuresis, the increased urine flow tom line) is determined by measuring the urine [glucose] and flow results from the excretion of osmotically active solute. Di- rate. Reabsorbed glucose is calculated from the difference be- tween filtered and excreted glucose. Tm G tubular transport abetes (from the Greek for “syphon”) gets its name from maximum for glucose. this increased urine output. Equations 8 and 9 for quantitating tubular transport The Tubular Transport Maximum for rates yield the net rate of reabsorption or secretion of a PAH Provides a Measure of Functional substance. It is possible for a single substance to be both Proximal Secretory Tissue reabsorbed and secreted; the equations do not give unidi- rectional reabsorptive and secretory movements, but only p-Aminohippurate is secreted only by proximal tubules in the net transport. the kidneys. At low plasma PAH concentrations, the rate of secretion increases linearly with the plasma [PAH]. At high plasma PAH concentrations, the secretory carriers are sat- The Glucose Titration Study Assesses urated and the rate of PAH secretion stabilizes at a constant Renal Glucose Reabsorption maximal value, called the tubular transport maximum for PAH (Tm PAH ). The Tm PAH is directly related to the num- Insights into the nature of glucose handling by the kidneys ber of functioning proximal tubules and, therefore, pro- can be derived from a glucose titration study (Fig. 23.8). vides a measure of the mass of proximal secretory tissue. The plasma [glucose] is elevated to increasingly higher lev- Figure 23.9 illustrates the pattern of filtration, secretion, els by the infusion of glucose-containing solutions. Inulin is and excretion of PAH observed when the plasma [PAH] is infused to permit measurement of GFR and calculation of progressively elevated by intravenous infusion. the filtered glucose load (plasma [glucose] GFR). The rate of glucose reabsorption is determined from the differ- ence between the filtered load and the rate of excretion. At RENAL BLOOD FLOW normal plasma glucose levels (about 100 mg/dL), all of the filtered glucose is reabsorbed and none is excreted. When The kidneys have a very high blood flow. This allows them to the plasma [glucose] exceeds a certain value (about 200 filter the blood plasma at a high rate. Many factors, both in- mg/dL, see Fig. 23.8), significant quantities of glucose ap- trinsic (autoregulation, local hormones) and extrinsic (nerves, pear in the urine; this plasma concentration is called the bloodborne hormones), affect the rate of renal blood flow. glucose threshold. Further elevations in plasma glucose lead to progressively more excreted glucose. Glucose ap- The Kidneys Have a High Blood Flow pears in the urine because the filtered amount of glucose ex- ceeds the capacity of the tubules to reabsorb it. At very In resting, healthy, young adult men, renal blood flow av- high filtered glucose loads, the rate of glucose reabsorption erages about 1.2 L/min. This is about 20% of the cardiac reaches a constant maximal value, called the tubular trans- output (5 to 6 L/min). Both kidneys together weigh about
CHAPTER 23 Kidney Function 385 240 Cortex 4 5 200 Outer p-Aminohippurate (mg/min) 160 Excreted Secreted Tm PAH 0.2 0.25 medulla 0.7 1 120 Inner medulla 80 40 Filtered Blood flow rates (in mL/min per gram of tis- FIGURE 23.10 sue) in different parts of the kidney. (Modi- 0 0 20 40 60 80 100 fied from Brobeck JR, ed. Best & Taylor’s Physiological Basis of Medical Practice. 10th Ed. Baltimore: Williams & Wilkins, 1979.) Plasma [p-aminohippurate] (mg/dL) Rates of excretion, filtration, and secretion FIGURE 23.9 of p-aminohippurate (PAH) as a function of plasma [PAH]. More PAH is excreted than is filtered; the difference rep- The Kidneys Autoregulate Their Blood Flow resents secreted PAH. Despite changes in mean arterial blood pressure (from 80 to 180 mm Hg), renal blood flow is kept at a relatively constant level, a process known as autoregulation (see Chapter 16). Autoregulation is an intrinsic property of the kidneys and is 300 g, so blood flow per gram of tissue averages about 4 observed even in an isolated, denervated, perfused kidney. mL/min. This rate of perfusion exceeds that of all other GFR is also autoregulated (Fig. 23.11). When the blood organs in the body, except the neurohypophysis and pressure is raised or lowered, vessels upstream of the carotid bodies. The high blood flow to the kidneys is nec- glomerulus (cortical radial arteries and afferent arterioles) essary for a high GFR and is not due to excessive meta- constrict or dilate, respectively, maintaining relatively con- bolic demands. stant glomerular blood flow and capillary pressure. Below or The kidneys use about 8% of total resting oxygen above the autoregulatory range of pressures, blood flow and consumption, but they receive much more oxygen than GFR change appreciably with arterial blood pressure. they need. Consequently, renal extraction of oxygen is Two mechanisms account for renal autoregulation: the low, and renal venous blood has a bright red color (be- myogenic mechanism and the tubuloglomerular feedback cause of a high oxyhemoglobin content). The anatomi- mechanism. In the myogenic mechanism, an increase in cal arrangement of the vessels in the kidney permits a pressure stretches blood vessel walls and opens stretch-ac- large fraction of the arterial oxygen to be shunted to the tivated cation channels in smooth muscle cells. The ensu- veins before the blood enters the capillaries. Therefore, ing membrane depolarization opens voltage-dependent the oxygen tension in the tissue is not as high as one Ca 2 channels and intracellular [Ca 2 ] rises, causing might think, and the kidneys are certainly sensitive to is- smooth muscle contraction. Vessel lumen diameter de- chemic damage. creases and vascular resistance increases. Decreased blood pressure causes the opposite changes. Blood Flow Is Higher in the Renal Cortex In the tubuloglomerular feedback mechanism, the and Lower in the Renal Medulla transient increase in GFR resulting from an increase in blood pressure leads to increased solute delivery to the Blood flow rates differ in different parts of the kidney (Fig. macula densa (Fig. 23.12). This produces an increase in the 23.10). Blood flow is highest in the cortex, averaging 4 to tubular fluid [NaCl] at this site and increased NaCl reab- 5 mL/min per gram of tissue. The high cortical blood flow sorption by macula densa cells. By mechanisms that are permits a high rate of filtration in the glomeruli. Blood still uncertain, constriction of the nearby afferent arteriole flow (per gram of tissue) is about 0.7 to 1 mL/min in the results. The vasoconstrictor agent may be adenosine or outer medulla and 0.20 to 0.25 mL/min in the inner ATP; it does not appear to be angiotensin II, although medulla. The relatively low blood flow in the medulla feedback sensitivity varies directly with the local concen- helps maintain a hyperosmolar environment in this region tration of angiotensin II. Blood flow and GFR are lowered of the kidney. to a more normal value. The tubuloglomerular feedback
386 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS mechanism is a negative-feedback system that stabilizes renal blood flow and GFR. Autoregulatory If NaCl delivery to the macula densa is increased exper- range imentally by perfusing the lumen of the loop of Henle, fil- 1.5 tration rate in the perfused nephron decreases. This sug- gests that the purpose of tubuloglomerular feedback may be to control the amount of Na presented to distal nephron segments. Regulation of Na delivery to distal parts of the nephron is important because these segments Flow rate (L/min) 1.0 have a limited capacity to reabsorb Na . Renal blood flow Renal autoregulation minimizes the impact of changes in arterial blood pressure on Na excretion. Without renal autoregulation, increases in arterial blood pressure would lead to dramatic increases in GFR and potentially serious losses of NaCl and water from the ECF. 0.5 Renal Sympathetic Nerves and Various Hormones GFR Change Renal Blood Flow Renal blood flow may be changed by the stimulation of re- nal sympathetic nerves or by the release of various hor- 0 mones. Sympathetic nerve stimulation causes renal vasocon- 0 40 80 120 160 200 240 striction and a consequent decrease in renal blood flow. Mean arterial blood pressure (mm Hg) Renal sympathetic nerves are activated under stressful condi- Renal autoregulation, based on measure- tions, including cold temperatures, deep anesthesia, fearful FIGURE 23.11 ments in isolated, denervated, and perfused situations, hemorrhage, pain, and strenuous exercise. In these kidneys. In the autoregulatory range, renal blood flow and GFR conditions, the decrease in renal blood flow may be viewed stay relatively constant despite changes in arterial blood pressure. as an emergency mechanism that makes more of the cardiac This is accomplished by changes in the resistance (caliber) of pre- output available to perfuse other organs, such as the brain glomerular blood vessels. The circles indicate that vessel radius (r) and heart, which are more important for short-term survival. is smaller when blood pressure is high and larger when blood Several substances cause vasoconstriction in the kidneys, 4 pressure is low. Since resistance to blood flow varies as r , including adenosine, angiotensin II, endothelin, epineph- changes in vessel caliber are greatly exaggerated in this figure. rine, norepinephrine, thromboxane A 2 , and vasopressin. Other substances cause vasodilation in the kidneys, includ- ing atrial natriuretic peptide, dopamine, histamine, kinins, nitric oxide, and prostaglandins E 2 and I 2 . Some of these substances (e.g., prostaglandins E 2 and I 2 ) are produced lo- cally in the kidneys. An increase in sympathetic nerve activ- ity or plasma angiotensin II concentration stimulates the production of renal vasodilator prostaglandins. These prostaglandins then oppose the pure constrictor effect of sympathetic nerve stimulation or angiotensin II, reducing the fall in renal blood flow, preventing renal damage. GLOMERULAR FILTRATION Glomerular filtration involves the ultrafiltration of plasma. This term reflects the fact that the glomerular filtration bar- rier is an extremely fine molecular sieve that allows the fil- tration of small molecules but restricts the passage of macromolecules (e.g., the plasma proteins). The Glomerular Filtration Barrier The tubuloglomerular feedback mecha- Has Three Layers FIGURE 23.12 nism. When single nephron GFR is in- creased—for example, as a result of an increase in arterial blood An ultrafiltrate of plasma passes from glomerular capillary pressure—more NaCl is delivered to and reabsorbed by the mac- blood into the space of Bowman’s capsule through the ula densa, leading to constriction of the nearby afferent arteriole. glomerular filtration barrier (Fig. 23.13). This barrier con- This negative-feedback system plays a role in renal blood flow sists of three layers. The first, the capillary endothelium, is and GFR autoregulation. called the lamina fenestra because it contains pores or win-
CHAPTER 23 Kidney Function 387 Urinary space of TABLE 23.1 Restrictions to the Glomerular Filtration Bowman's of Molecules capsule Molecular Molecular [Filtrate]/ Substance Weight Radius (nm) [Plasma Water] Water 18 0.10 1.00 Slit Glucose 180 0.36 1.00 pore Inulin 5,000 1.4 1.00 Myoglobin 17,000 2.0 0.75 Hemoglobin 68,000 3.3 0.03 Cationic dextran a 3.6 0.42 Neutral dextran 3.6 0.15 Foot processes Endothelium Fenestra Anionic dextran 3.6 0.01 Serum albumin 69,000 3.6 0.001 Basement membrane Capillary lumen a Dextrans are high-molecular-weight glucose polymers available in cationic (amine), neutral (uncharged), or anionic (sulfated) forms. Electron micrograph showing the three lay- (Adapted from Pitts RF. Physiology of the Kidney and Body Fluids. 3rd FIGURE 23.13 Ed. Chicago: Year Book, 1974; and Brenner BM, Bohrer MP, Baylis C, ers of the glomerular filtration barrier: en- dothelium, basement membrane, and podocytes. (Courtesy Deen WM. Determinants of glomerular permselectivity: Insights de- of Dr. Andrew P. Evan, Indiana University.) rived from observations in vivo. Kidney Int 1977;12:229–237.) dows (fenestrae). At about 50 to 100 nm in diameter, these tion barrier. Very large molecules (e.g., molecular weight, pores are too large to restrict the passage of plasma pro- 100,000) cannot get through at all. Most plasma proteins teins. The second layer, the basement membrane, consists are large molecules, so they are not appreciably filtered. of a meshwork of fine fibrils embedded in a gel-like matrix. From studies with molecules of different sizes, it has been The third layer is composed of podocytes, which consti- calculated that the glomerular filtration barrier behaves as tute the visceral layer of Bowman’s capsule. Podocytes though it were penetrated by cylindric pores of about 7.5 (“foot cells”) are epithelial cells with extensions that termi- to 10 nm in diameter. However, no one has ever seen pores nate in foot processes, which rest on the outer layer of the of this size in electron micrographs of the glomerular filtra- basement membrane (see Fig. 23.13). The space between tion barrier. adjacent foot processes, called a slit pore, is about 20 nm Molecular shape influences the filterability of macromol- wide and is bridged by a filtration slit diaphragm. A key ecules. For a given molecular weight, a slender and flexible component of the diaphragm is a molecule called molecule will pass through the glomerular filtration barrier nephron, which forms a zipper-like structure; between the more easily than a spherical, nondeformable molecule. prongs of the zipper are rectangular pores. The nephron is Electrical charge influences the passage of macromole- mutated in congenital nephrotic syndrome, a rare, inher- cules through the glomerular filtration barrier because the ited condition characterized by excessive filtration of barrier bears fixed negative charges. Glomerular endothe- plasma proteins. The glomerular filtrate normally takes an lial cells and podocytes have a negatively charged surface extracellular route, through holes in the endothelial cell coat (glycocalyx), and the glomerular basement membrane layer, the basement membrane, and the pores between ad- contains negatively charged sialic acid, sialoproteins, and jacent nephron molecules. heparan sulfate. These negative charges impede the pas- sage of negatively charged macromolecules by electrostatic repulsion and favor the passage of positively charged Size, Shape, and Electrical Charge Affect macromolecules by electrostatic attraction. This is sup- the Filterability of Macromolecules ported by the finding that the filterability of dextran is low- The permeability properties of the glomerular filtration est for anionic dextran, intermediate for neutral dextran, barrier have been studied by determining how well mole- and highest for cationic dextran (see Table 23.1). cules of different sizes pass through it. Table 23.1 lists sev- In addition to its large molecular size, the net negative eral molecules that have been tested. Molecular radii were charge on serum albumin at physiological pH is an impor- calculated from diffusion coefficients. The concentration of tant factor that reduces its filterability. In some glomerular the molecule in the glomerular filtrate (fluid collected from diseases, a loss of fixed negative charges from the glomeru- Bowman’s capsule) is compared to its concentration in lar filtration barrier causes increased filtration of serum al- plasma water. A ratio of 1 indicates complete filterability, bumin. Proteinuria, abnormal amounts of protein in the and a ratio of zero indicates complete exclusion by the urine, results. Proteinuria is the hallmark of glomerular dis- glomerular filtration barrier. ease (see Clinical Focus Box 23.2 and the Case Study). Molecular size is an important factor affecting filterabil- The layer of the glomerular filtration barrier primarily ity. All molecules with weights less than 10,000 are freely responsible for limiting the filtration of macromolecules is filterable, provided they are not bound to plasma proteins. a matter of debate. The basement membrane is probably Molecules with weights greater than 10,000 experience the principal size-selective barrier, and the filtration slit di- more restriction to passage through the glomerular filtra- aphragm forms a second barrier. The major electrostatic
388 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS CLINICAL FOCUS BOX 23.2 Glomerular Disease tein excretion in the urine. The loss of protein (mainly The kidney glomeruli may be injured by several immuno- serum albumin) leads to a fall in plasma [protein] (and col- logical, toxic, hemodynamic, and metabolic disorders. loid osmotic pressure). The edema results from the hy- Glomerular injury impairs filtration barrier function and, poalbuminemia and renal Na retention. Also, a general- consequently, increases the filtration and excretion of ized increase in capillary permeability to proteins (not just plasma proteins (proteinuria). Red cells may appear in the in the glomeruli) may lead to a decrease in the effective urine, and sometimes GFR is reduced. Three general syn- colloid osmotic pressure of the plasma proteins and may dromes are encountered: nephritic diseases, nephrotic dis- contribute to the edema. The hyperlipidemia (elevated eases (nephrotic syndrome), and chronic glomeru- serum cholesterol and, in severe cases, elevated triglyc- lonephritis. erides) is probably a result of increased hepatic synthesis In the nephritic diseases, the urine contains red blood of lipoproteins and decreased lipoprotein catabolism. cells, red cell casts, and mild to modest amounts of pro- Most often, nephrotic syndrome in young children cannot tein. A red cell cast is a mold of the tubule lumen formed be ascribed to a specific cause; this is called idiopathic when red cells and proteins clump together; the presence nephrotic syndrome. Nephrotic syndrome in children or of such casts in the final urine indicates that bleeding had adults can be caused by infectious diseases, neoplasia, occurred in the kidneys (usually in the glomeruli), not in certain drugs, various autoimmune disorders (such as lu- the lower urinary tract. Nephritic diseases are usually as- pus), allergic reactions, metabolic disease (such as dia- sociated with a fall in GFR, accumulation of nitrogenous betes mellitus), or congenital disorders. wastes (urea, creatinine) in the blood, and hypervolemia The distinctions between nephritic and nephrotic dis- (hypertension, edema). Most nephritic diseases are due to eases are sometimes blurred, and both may result in immunological damage. The glomerular capillaries may chronic glomerulonephritis. This disease is characterized be injured by antibodies directed against the glomerular by proteinuria and/or hematuria (blood in the urine), hyper- basement membrane, by deposition of circulating immune tension, and renal insufficiency that progresses over years. complexes along the endothelium or in the mesangium, or Renal biopsy shows glomerular scarring and increased num- by cell-mediated injury (infiltration with lymphocytes and bers of cells in the glomeruli and scarring and inflammation macrophages). A renal biopsy and tissue examination by in the interstitial space. The disease is accompanied by a pro- light and electron microscopy and immunostaining are of- gressive loss of functioning nephrons and proceeds relent- ten helpful in determining the nature and severity of the lessly even though the initiating insult may no longer be disease and in predicting its most likely course. present. The exact reasons for disease progression are not Poststreptococcal glomerulonephritis is an exam- known, but an important factor may be that surviving ple of a nephritic condition that may follow a sore throat nephrons hypertrophy when nephrons are lost. This leads to caused by certain strains of streptococci. Immune com- an increase in blood flow and pressure in the remaining plexes of antibody and bacterial antigen are deposited in nephrons, a situation that further injures the glomeruli. Also, the glomeruli, complement is activated, and polymor- increased filtration of proteins causes increased tubular re- phonuclear leukocytes and macrophages infiltrate the absorption of proteins, and the latter results in production of glomeruli. Endothelial cell damage, accumulation of leuko- vasoactive and inflammatory substances that cause is- cytes, and the release of vasoconstrictor substances re- chemia, interstitial inflammation, and renal scarring. Dietary duce the glomerular surface area and fluid permeability manipulations (such as a reduced protein intake) or antihy- and lower glomerular blood flow, causing a fall in GFR. pertensive drugs (such as angiotensin-converting enzyme Nephrotic syndrome is a clinical state that can de- inhibitors) may slow the progression of chronic glomeru- velop as a consequence of many different diseases caus- lonephritis. Glomerulonephritis in its various forms is the ing glomerular injury. It is characterized by heavy protein- major cause of renal failure in people. uria (3.5 g/day per 1.73 m 2 body surface area), hypoalbuminemia (3 g/dL), generalized edema, and hy- Reference perlipidemia. Abnormal glomerular leakiness to plasma Falk RJ, Jennette JC, Nachman PH. Primary glomerular proteins leads to increased catabolism of the reabsorbed diseases. In: Brenner BM, ed. Brenner & Rector’s The Kid- proteins in the kidney proximal tubules and increased pro- ney. 6th Ed. Philadelphia: WB Saunders, 2000;1263–1349. barriers are probably the layers closest to the capillary lu- eral. In the glomerulus, the driving force for fluid filtration men, the lamina fenestra and the innermost part of the is the glomerular capillary hydrostatic pressure (P GC ). basement membrane. This pressure ultimately depends on the pumping of blood by the heart, an action that raises the blood pres- sure on the arterial side of the circulation. Filtration is op- GFR Is Determined by Starling Forces posed by the hydrostatic pressure in the space of Bow- Glomerular filtration rate depends on the balance of hy- man’s capsule (P BS ) and by the colloid osmotic pressure drostatic and colloid osmotic pressures acting across the (COP) exerted by plasma proteins in glomerular capillary glomerular filtration barrier, the Starling forces (see blood. Because the glomerular filtrate is virtually protein- Chapter 16); therefore, it is determined by the same fac- free, we neglect the colloid osmotic pressure of fluid in tors that affect fluid movement across capillaries in gen- Bowman’s capsule. The net ultrafiltration pressure gradi-
CHAPTER 23 Kidney Function 389 ent (UP) is equal to the difference between the pressures to blood flow, resulting in an appreciable fall in capillary favoring and opposing filtration: hydrostatic pressure with distance. Finally, note that in the glomerulus, the colloid osmotic pressure increases substan- GFR K f UP K f (P GC P BS COP) (10) tially along the length of the capillary because a large vol- where K f is the glomerular ultrafiltration coefficient. Esti- ume of filtrate (about 20% of the entering plasma flow) is mates of average, normal values for pressures in the human pushed out of the capillary and the proteins remain in the kidney are: P GC , 55 mm Hg; P BS , 15 mm Hg; and COP, 30 circulation. The increase in colloid osmotic pressure op- mm Hg. From these values, we calculate a net ultrafiltration poses the outward movement of fluid. pressure gradient of 10 mm Hg. In the skeletal muscle capillary, the colloid osmotic pres- sure hardly changes with distance, since little fluid moves across the capillary wall. In the “average” skeletal muscle The Pressure Profile Along a Glomerular capillary, outward filtration occurs at the arterial end and Capillary Is Unusual absorption occurs at the venous end. At some point along the skeletal muscle capillary, there is no net fluid move- Figure 23.14 shows how pressures change along the length ment; this is the point of so-called filtration pressure equi- of a glomerular capillary, in contrast to those seen in a cap- librium. Filtration pressure equilibrium probably is not at- illary in other vascular beds (in this case, skeletal muscle). tained in the normal human glomerulus; in other words, the Note that average capillary hydrostatic pressure in the outward filtration of fluid probably occurs all along the glomerulus is much higher (55 vs. 25 mm Hg) than in a glomerular capillaries. skeletal muscle capillary. Also, capillary hydrostatic pres- sure declines little (perhaps 1 to 2 mm Hg) along the length Several Factors Can Affect GFR of the glomerular capillary because the glomerulus contains many (30 to 50) capillary loops in parallel, making the re- The GFR depends on the magnitudes of the different terms sistance to blood flow in the glomerulus very low. In the in equation 10. Therefore, GFR varies with changes in K f , skeletal muscle capillary, there is a much higher resistance hydrostatic pressures in the glomerular capillaries and Bow- A. Skeletal muscle capillary B. Glomerular capillary FIGURE 23.14 Pressure profiles along a skeletal muscle Bowman’s capsule (P BS ). The middle line is the sum of P BS and the capillary and a glomerular capillary. A, In glomerular capillary colloid osmotic pressure (COP). The differ- the typical skeletal muscle capillary, filtration occurs at the arte- ence between P GC and P BS COP is equal to the net ultrafiltra- rial end and absorption at the venous end of the capillary. Inter- tion pressure gradient (UP). In the normal human glomerulus, fil- stitial fluid hydrostatic and colloid osmotic pressures are neg- tration probably occurs along the entire capillary. Assuming that lected here because they are about equal and counterbalance each K f is uniform along the length of the capillary, filtration rate other. B, In the glomerular capillary, glomerular hydrostatic pres- would be highest at the afferent arteriolar end and lowest at the sure (P GC) (top line) is high and declines only slightly with dis- efferent arteriolar end of the glomerulus. tance. The bottom line represents the hydrostatic pressure in
390 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS man’s capsule, and the glomerular capillary colloid osmotic plasma proteins (e.g., by intravenous infusion of a large pressure. These factors are discussed next. volume of isotonic saline) lowers the plasma COP and leads to an increase in GFR. Part of the reason glomeru- The Glomerular Ultrafiltration Coefficient. The glomeru- lar blood flow has important effects on GFR is that the lar ultrafiltration coefficient (K f ) is the glomerular equiva- COP profile is changed along the length of a glomerular lent of the capillary filtration coefficient encountered in capillary. Consider, for example, what would happen if Chapter 16. It depends on both the hydraulic conductivity glomerular blood flow were low. Filtering a small volume (fluid permeability) and surface area of the glomerular filtra- out of the glomerular capillary would lead to a sharp rise tion barrier. In chronic renal disease, functioning glomeruli in COP early along the length of the glomerulus. As a are lost, leading to a reduction in surface area available for fil- consequence, filtration would soon cease and GFR would tration and a fall in GFR. Acutely, a variety of drugs and hor- be low. On the other hand, a high blood flow would al- mones appear to change glomerular K f and, thus, alter GFR, low a high rate of filtrate formation with a minimal rise in but the mechanisms are not completely understood. COP. In general, renal blood flow and GFR change hand in hand, but the exact relation between GFR and renal Glomerular Capillary Hydrostatic Pressure. Glomerular blood flow depends on the magnitude of the other fac- capillary hydrostatic pressure (P GC ) is the driving force for tors that affect GFR. filtration; it depends on the arterial blood pressure and the resistances of upstream and downstream blood vessels. Be- cause of autoregulation, P GC and GFR are maintained at rel- Several Factors Contribute to the High GFR atively constant values when arterial blood pressure is var- in the Human Kidney ied from 80 to 180 mm Hg. Below a pressure of 80 mm Hg, The rate of plasma ultrafiltration in the kidney glomeruli however, P GC and GFR decrease, and GFR ceases at a blood (180 L/day) far exceeds that in all other capillary beds, for pressure of about 40 to 50 mm Hg. One of the classic signs several reasons: of hemorrhagic or cardiogenic shock is an absence of urine 1) The filtration coefficient is unusually high in the output, which is due to an inadequate P GC and GFR. glomeruli. Compared with most other capillaries, the The caliber of afferent and efferent arterioles can be glomerular capillaries behave as though they had more altered by a variety of hormones and by sympathetic pores per unit surface area; consequently, they have an un- nerve stimulation, leading to changes in P GC , glomerular usually high hydraulic conductivity. The total glomerular 2 blood flow, and GFR. Some hormones act preferentially filtration barrier area is large, about 2 m . on afferent or efferent arterioles. Afferent arteriolar dila- 2) Capillary hydrostatic pressure is higher in the tion increases glomerular blood flow and P GC and, there- glomeruli than in any other capillaries. fore, produces an increase in GFR. Afferent arteriolar 3) The high rate of renal blood flow helps sustain a high constriction produces the exact opposite effects. Efferent GFR by limiting the rise in colloid osmotic pressure, favoring arteriolar dilation increases glomerular blood flow but filtration along the entire length of the glomerular capillaries. leads to a fall in GFR because P GC is decreased. Constric- In summary, glomerular filtration is high because the tion of efferent arterioles increases P GC and decreases glomerular capillary blood is exposed to a large porous sur- glomerular blood flow. With modest efferent arteriolar face and there is a high transmural pressure gradient. constriction, GFR increases because of the increased P GC . With extreme efferent arteriolar constriction, however, TRANSPORT IN THE PROXIMAL TUBULE GFR decreases because of the marked decrease in glomerular blood flow. Glomerular filtration is a rather nonselective process, since both useful and waste substances are filtered. By contrast, tubular transport is selective; different substances are trans- Hydrostatic Pressure in Bowman’s Capsule. Hydrosta- ported by different mechanisms. Some substances are reab- tic pressure in Bowman’s capsule (P BS ) depends on the input sorbed, others are secreted, and still others are both reab- of glomerular filtrate and the rate of removal of this fluid by sorbed and secreted. For most, the amount excreted in the the tubule. This pressure opposes filtration. It also provides urine depends in large measure on the magnitude of tubu- the driving force for fluid movement down the tubule lu- lar transport. Transport of various solutes and water differs men. If there is obstruction anywhere along the urinary in the various nephron segments. Here we describe trans- tract—for example, stones, ureteral obstruction, or prostate port along the nephron and collecting duct system, starting enlargement—then pressure upstream to the block is in- with the proximal convoluted tubule. creased, and GFR consequently falls. If tubular reabsorp- The proximal convoluted tubule comprises the first 60% tion of water is inhibited, pressure in the tubular system is of the length of the proximal tubule. Because the proximal increased because an increased pressure head is needed to straight tubule is inaccessible to study in vivo, most quanti- force a large volume flow through the loops of Henle and tative information about function in the living animal is collecting ducts. Consequently, a large increase in urine confined to the convoluted portion. Studies on isolated output caused by a diuretic drug may be associated with a tubules in vitro indicate that both segments of the proximal tendency for GFR to fall. tubule are functionally similar. The proximal tubule is re- sponsible for reabsorbing all of the filtered glucose and amino acids; reabsorbing the largest fraction of the filtered 2 Glomerular Capillary Colloid Osmotic Pressure. The Na , K , Ca , Cl , HCO 3 , and water and secreting var- COP opposes glomerular filtration. Dilution of the ious organic anions and organic cations.
CHAPTER 23 Kidney Function 391 little higher than 3, indicating that about 70% of the filtered water was reabsorbed in the proximal convoluted tubule. The ratio is about 5 at the beginning of the distal tubule, in- dicating that 80% of the filtered water was reabsorbed up to this point. From these measurements, we can conclude that the loop of Henle reabsorbed 10% of the filtered water. The urine/plasma inulin concentration ratio in the ureter is greater than 100, indicating that more than 99% of the fil- tered water was reabsorbed. These percentages are not fixed; they can vary widely, depending on conditions. Proximal Tubular Fluid Is Essentially Isosmotic to Plasma Samples of fluid collected from the proximal convoluted tubule are always essentially isosmotic to plasma, a conse- quence of the high water permeability of this segment (Fig. 23.16). Overall, 70% of filtered solutes and water are reab- sorbed along the proximal convoluted tubule. Na salts are the major osmotically active solutes in the plasma and glomerular filtrate. Since osmolality does not change appreciably with proximal tubule length, it is Tubular fluid (or urine) [inulin]/plasma [in- FIGURE 23.15 4.0 PAH ulin] ratio as a function of collection site (data from micropuncture experiments in rats). The increase in this ratio depends on the extent of tubular water reabsorption. The distal tubule is defined in these studies as beginning at the macula densa and ending at the junction of the tubule and a col- lecting duct and it includes distal convoluted tubule, connecting Inulin tubule, and initial part of the collecting duct. (Modified from Giebisch G, Windhager E. Renal tubular transfer of sodium, chlo- 3.0 ride, and potassium. Am J Med 1964;36:643–669.) The Proximal Convoluted Tubule Reabsorbs About 70% of the Filtered Water The percentage of filtered water reabsorbed along the nephron has been determined by measuring the degree to which inulin is concentrated in tubular fluid, using the kidney [Tubular fluid]/[Plasma ultrafiltrate] 2.0 micropuncture technique in laboratory animals. Samples of tubular fluid from surface nephrons are collected and ana- lyzed, and the site of collection is identified by nephron mi- Urea crodissection. Because inulin is filtered but not reabsorbed by Cl the kidney tubules, as water is reabsorbed, the inulin becomes increasingly concentrated. For example, if 50% of the filtered water is reabsorbed by a certain point along the tubule, the [in- 1.0 Osmolality, Na , K ulin] in tubular fluid (TF IN ) will be twice the plasma [inulin] (P IN ). The percentage of filtered water reabsorbed by the tubules is equal to 100 (SNGFR V TF )/SNGFR, where SN (single nephron) GFR gives the rate of filtration of water and HCO 3 ˙ V TF is the rate of tubular fluid flow at a particular point. The SNGFR can be measured from the single nephron inulin clear- Amino acids ˙ ance and is equal to TF IN V TF /P IN . From these relations: 0 Glucose 0 20 40 60 80 100 % of filtered water [1 1/(TF IN /P IN )] 100 (11) % Proximal tubule length Figure 23.15 shows how the TF IN /P IN ratio changes along Tubular fluid-plasma ultrafiltrate concen- the nephron in normal rats. In fluid collected from Bow- FIGURE 23.16 tration ratios for various solutes as a func- man’s capsule, the [inulin] is identical to that in plasma (in- tion of proximal tubule length. All values start at a ratio of 1, ulin is freely filterable), so the concentration ratio starts at 1. since the fluid in Bowman’s capsule (0% proximal tubule length) By the end of the proximal convoluted tubule, the ratio is a is a plasma ultrafiltrate.
392 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS not surprising that [Na ] also does not change under or- Tubular Proximal tubule cell Interstitial Blood dinary conditions. urine space If an appreciable quantity of nonreabsorbed solute is present (e.g., the sugar alcohol mannitol), proximal tubular Na + Cl - H O 2 fluid [Na ] falls to values below the plasma concentration. This is evidence that Na can be reabsorbed against a con- Na + ATP Na + centration gradient and is an active process. The fall in ADP + P i K + proximal tubular fluid [Na ] increases diffusion of Na Glucose, K + into the tubule lumen and results in reduced net Na and amino acids, Solute phosphate + water reabsorption, leading to increased excretion of Na Na + H O 2 and water, an osmotic diuresis. Two major anions, Cl and HCO 3 , accompany Na Glucose, in plasma and glomerular filtrate. HCO 3 is preferentially H + K + amino acids, phosphate reabsorbed along the proximal convoluted tubule, leading Base - Cl - to a fall in tubular fluid [HCO 3 ], mainly because of H Na + secretion (see Chapter 25). The Cl lags behind; as water - is reabsorbed, [Cl ] rises (see Fig. 23.16). The result is a tu- Cl - 3HCO 3 bular fluid-to-plasma concentration gradient that favors Cl diffusion out of the tubule lumen. Outward movement H 2 O H O 2 of Cl in the late proximal convoluted tubule creates a small (1–2 mV), lumen-positive transepithelial potential Apical cell difference that favors the passive reabsorption of Na . membrane Tight Lateral Basolateral Figure 23.16 shows that the [K ] hardly changes along junction intercellular cell space the proximal convoluted tubule. If K were not reabsorbed, membrane its concentration would increase as much as that of inulin. FIGURE 23.17 A cell model for transport in the proximal The fact that the concentration ratio for K remains about tubule. The luminal (apical) cell membrane in 1 in this nephron segment indicates that 70% of filtered K this nephron segment has a large surface area for transport be- is reabsorbed along with 70% of the filtered water. cause of the numerous microvilli that form the brush border (not The concentrations of glucose and amino acids fall shown). Glucose, amino acids, phosphate, and numerous other steeply in the proximal convoluted tubule. This nephron seg- substances are transported by separate carriers. ment and the proximal straight tubule are responsible for complete reabsorption of these substances. Separate, specific rounding the tubules, and filtered Na salts and water are mechanisms reabsorb glucose and various amino acids. returned to the circulation. The concentration ratio for urea rises along the proximal At the luminal cell membrane (brush border) of the tubule, but not as much as the inulin concentration ratio be- proximal tubule cell, Na enters the cell down combined cause about 50% of the filtered urea is reabsorbed. The electrical and chemical potential gradients. The inside of concentration ratio for PAH in proximal tubular fluid in- the cell is about 70 mV compared to tubular fluid, and in- creases more steeply than the inulin concentration ratio be- tracellular [Na ] is about 30 to 40 mEq/L compared with a cause of PAH secretion. tubular fluid concentration of about 140 mEq/L. Na entry In summary, though the osmolality (total solute concen- into the cell occurs via several cotransporter and antiport tration) does not detectably change along the proximal mechanisms. Na is reabsorbed together with glucose, convoluted tubule, it is clear that the concentrations of in- amino acids, phosphate, and other solutes by way of sepa- dividual solutes vary widely. The concentrations of some rate, specific cotransporters. The downhill (energetically substances fall (glucose, amino acids, HCO 3 ), others rise speaking) movement of Na into the cell drives the uphill (inulin, urea, Cl , PAH), and still others do not change transport of these solutes. In other words, glucose, amino (Na , K ). By the end of the proximal convoluted tubule, acids, phosphate, and so on are reabsorbed by secondary only about one-third of the filtered Na , water, and K re- active transport. Na is also reabsorbed across the luminal main; almost all of the filtered glucose, amino acids, and cell membrane in exchange for H . The Na /H ex- HCO 3 have been reabsorbed, and several solutes destined changer, an antiporter, is also a secondary active transport for excretion (PAH, inulin, urea) have been concentrated in mechanism; the downhill movement of Na into the cell the tubular fluid. energizes the uphill secretion of H into the lumen. This mechanism is important in the acidification of urine (see Na Reabsorption Is the Major Driving Force Chapter 25). Cl may enter the cells by way of a luminal for Reabsorption of Solutes and Water in the cell membrane Cl -base (formate or oxalate) exchanger. Once inside the cell, Na is pumped out the basolateral Proximal Tubule side by a vigorous Na /K -ATPase that keeps intracellular Figure 23.17 is a model of a proximal tubule cell. Na en- [Na ] low. This membrane ATPase pumps three Na out ters the cell from the lumen across the apical cell mem- of the cell and two K into the cell and splits one ATP mol- brane and is pumped out across the basolateral cell mem- ecule for each cycle of the pump. K pumped into the cell brane by Na /K -ATPase. The Na and accompanying diffuses out the basolateral cell membrane mostly through anions and water are then taken up by the blood sur- a K channel. Glucose, amino acids, and phosphate, accu-
CHAPTER 23 Kidney Function 393 mulated in the cell because of active transport across the ies was previously filtered in the glomeruli. Because a pro- luminal cell membrane, exit across the basolateral cell tein-free filtrate was filtered out of the glomeruli, the [pro- membrane by way of separate, Na -independent facilitated tein] (hence, colloid osmotic pressure) of blood in the per- diffusion mechanisms. HCO 3 exits together with Na by itubular capillaries is high, providing an important driving an electrogenic mechanism; the carrier transports three force for the uptake of reabsorbed fluid. The hydrostatic HCO 3 for each Na . Cl may leave the cell by way of an pressure in the peritubular capillaries (a pressure that op- electrically neutral K-Cl cotransporter. poses the capillary uptake of fluid) is low because the blood The reabsorption of Na and accompanying solutes es- has passed through upstream resistance vessels. The bal- tablishes an osmotic gradient across the proximal tubule ance of pressures acting across peritubular capillaries favors epithelium that is the driving force for water reabsorption. the uptake of reabsorbed fluid from the interstitial spaces Because the water permeability of the proximal tubule ep- surrounding the tubules. ithelium is extremely high, only a small gradient (a few mOsm/kg H 2 O) is needed to account for the observed rate of water reabsorption. Some experimental evidence indi- The Proximal Tubule Secretes Organic Ions cates that proximal tubular fluid is slightly hypoosmotic to The proximal tubule, both convoluted and straight por- plasma; since the osmolality difference is so small, it is still tions, secretes a large variety of organic anions and organic proper to consider the fluid as essentially isosmotic to cations (Table 23.2). Many of these substances are endoge- plasma. Water crosses the proximal tubule epithelium nous compounds, drugs, or toxins. The organic anions are through the cells via water channels (aquaporin-1) in the mainly carboxylates and sulfonates (carboxylic and sulfonic cell membranes and between the cells (tight junctions and acids in their protonated forms). A negative charge on the lateral intercellular spaces). molecule appears to be important for secretion of these The final step in the overall reabsorption of solutes and compounds. Examples of organic anions actively secreted water is uptake by the peritubular capillaries. This mecha- in the proximal tubule include penicillin and PAH. Organic nism involves the usual Starling forces that operate across anion transport becomes saturated at high plasma organic capillary walls. Recall that blood in the peritubular capillar- anion concentrations (see Fig. 23.9), and the organic anions compete with each other for secretion. Figure 23.18 shows a cell model for active secretion. Proximal tubule cells actively take up PAH from the blood Some Organic Compounds Secreted by TABLE 23.2 Proximal Tubules a Compound Use Tubular Proximal tubule cell Blood urine Organic anions Phenol red pH indicator dye 2K + 3Na + (phenolsulfonphthalein) p-Aminohippurate (PAH) Measurement of renal plasma flow - - and proximal tubule secretory mass Anion PAH 2- αKG Na + Penicillin Antibiotic Probenecid (Benemid) Inhibitor of penicillin secretion and uric acid reabsorption Furosemide (Lasix) Loop diuretic drug 2- Acetazolamide (Diamox) Carbonic anhydrase inhibitor + Metabolism αKG Creatinine b Normal end-product of muscle Na OAT1 metabolism - Organic cations H + PAH Histamine Vasodilator, stimulator of gastric acid H + OC + secretion OCT Cimetidine Drug for treatment of gastric and duodenal ulcers OC + Cisplatin Cancer chemotherapeutic agent -70 mV 0 mV Norepinephrine Neurotransmitter Quinine Antimalarial drug A cell model for the secretion of organic FIGURE 23.18 Tetraethylammonium (TEA) Ganglion blocking drug anions (PAH) and organic cations in the Creatinine b Normal end-product of muscle proximal tubule. Upward pointing arrows indicate transport metabolism against an electrochemical gradient (energetically uphill trans- port) and downward pointing arrows indicate downhill transport. a This list includes only a few of the large variety of organic anions and cations secreted by kidney proximal tubules. There are two steps in the transcellular secretion of an organic an- b Creatinine is an unusual compound because it is secreted by both or- ion or organic cation (OC ): the active (uphill) transport step oc- ganic anion and cation mechanisms. The creatinine molecule bears curs in the basolateral membrane for PAH and in the luminal negatively charged and positively charged groups at physiological pH (brush border) membrane for the OC . There are actually more (it is a zwitterion), and this property may enable it to interact with transporters for these molecules than are depicted in this figure. 2– both secretory mechanisms. -KG , -ketoglutarate; OAT1, organic anion transporter 1; OCT, organic cation transporter.
394 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS side by exchange for cell -ketoglutarate. This exchange is Descending and Ascending Limbs Differ mediated by an organic anion transporter (OAT) called in Water Permeability OAT1. The cells accumulate -ketoglutarate from metabo- lism and because of cell membrane Na -dependent dicar- Tubular fluid entering the loop of Henle is isosmotic to boxylate transporters. PAH accumulates in the cells at a plasma, but fluid leaving the loop is distinctly hypoos- high concentration and then moves downhill into the tu- motic. Fluid collected from the earliest part of the distal bular urine in an electrically neutral fashion, by exchanging convoluted tubule has an osmolality of about 100 for an inorganic anion (e.g., Cl ) or an organic anion. mOsm/kg H 2 O, compared with 285 mOsm/kg H 2 O in The organic cations are mainly amine and ammonium plasma because more solute than water is reabsorbed by the compounds and are secreted by other transporters. Entry loop of Henle. The loop of Henle reabsorbs about 20% of 2 into the cell across the basolateral membrane is favored by filtered Na , 25% of filtered K , 30% of filtered Ca , 2 the inside negative membrane potential and occurs via fa- 65% of filtered Mg , and 10% of filtered water. The de- cilitated diffusion, mediated by an organic cation trans- scending limb of the loop of Henle (except for its terminal porter (OCT). The exit of organic cations across the lumi- portion) is highly water-permeable. The ascending limb is nal membrane is accomplished by an organic cation/H water-impermeable. Because solutes are reabsorbed along antiporter (exchanger) and is driven by the lumen-to-cell the ascending limb and water cannot follow, fluid along the [H ] gradient established by Na /H exchange. The ascending limb becomes more and more dilute. Deposition transporters for organic anions and organic cations show of these solutes (mainly Na salts) in the interstitial space broad substrate specificity and accomplish the secretion of of the kidney medulla is critical in the operation of the uri- a large variety of chemically diverse compounds. nary concentrating mechanism. In addition to being actively secreted, some organic compounds passively diffuse across the tubular epithelium. The Luminal Cell Membrane of the Organic anions can accept H and organic cations can re- lease H , so their charge is influenced by pH. The non- Thick Ascending Limb Contains a ionized (uncharged) form, if it is lipid-soluble, can diffuse Na-K-2Cl Cotransporter through the lipid bilayer of cell membranes down concen- Figure 23.19 is a model of a thick ascending limb cell. Na tration gradients. The ionized (charged) form passively enters the cell across the luminal cell membrane by an elec- penetrates cell membranes with difficulty. trically neutral Na-K-2Cl cotransporter that is specifically Consider, for example, the carboxylic acid probenecid inhibited by the “loop” diuretic drugs bumetanide and (pK a 3.4). This compound is filtered by the glomeruli and furosemide. The downhill movement of Na into the cell secreted by the proximal tubule. When H is secreted into results in secondary active transport of one K and two the tubular urine (see Chapter 25), the anionic form (A ) is Cl . Na is pumped out the basolateral cell membrane by converted to the nonionized acid (HA). The concentration a vigorous Na /K -ATPase. K recycles back into the lu- of nonionized acid is also increased because of water reab- men via a luminal cell membrane K channel. Cl leaves sorption. A concentration gradient for passive reabsorption through the basolateral side by a K-Cl cotransporter or Cl across the tubule wall is created, and appreciable quantities channel. The luminal cell membrane is predominantly per- of probenecid are passively reabsorbed. This occurs in most meable to K , and the basolateral cell membrane is pre- parts of the nephron, but particularly in those where pH gradients are largest and where water reabsorption has re- sulted in the greatest concentration (i.e., the collecting ducts). The excretion of probenecid is enhanced by making Tubular urine Thick ascending limb cell Blood the urine more alkaline (by administering NaHCO 3 ) and by +6 mV -72 mV -72 mV 0 mV increasing urine output (by drinking water). Na , K , Ca , + + 2+ Finally, a few organic anions and cations are also actively Mg , NH 4 + 2+ reabsorbed. For example, uric acid is both secreted and re- absorbed in the proximal tubule. Normally, the amount of Blocked by + uric acid excreted is equal to about 10% of the filtered uric furosemide ATP Na acid, so reabsorption predominates. In gout, plasma levels Na + ADP + P i K + of uric acid are increased. One treatment for gout is to pro- - mote urinary excretion of uric acid by administering drugs Cl Cl - K + that inhibit its tubular reabsorption. K + Cl - K + TUBULAR TRANSPORT IN THE LOOP OF HENLE The loop of Henle includes several distinct segments with Na + K + different structural and functional properties. As noted ear- Cl - lier, the proximal straight tubule has transport properties similar to those of the proximal convoluted tubule. The H + thin descending, thin ascending, and thick ascending limbs of the loop of Henle all display different permeability and A cell model for ion transport in the thick transport properties. FIGURE 23.19 ascending limb.
CHAPTER 23 Kidney Function 395 dominantly permeable to Cl . Diffusion of these ions out Tubular Distal convoluted Blood of the cell produces a transepithelial potential difference, urine tubule cell with the lumen about 6 mV compared with interstitial space around the tubules. This potential difference drives Blocked by ATP Na + 2 2 small cations (Na , K , Ca , Mg , and NH 4 ) out of thiazides the lumen, between the cells. The tubular epithelium is ex- ADP + P i K + tremely impermeable to water; there is no measurable wa- Na + ter reabsorption along the ascending limb despite a large K + transepithelial gradient of osmotic pressure. Cl - Cl - TUBULAR TRANSPORT IN THE DISTAL NEPHRON The so-called distal nephron includes several distinct seg- ments: distal convoluted tubule; connecting tubule; and FIGURE 23.20 A cell model for ion transport in the distal cortical, outer medullary, and inner medullary collecting convoluted tubule. ducts (see Fig. 23.2). Note that the distal nephron includes the collecting duct system, which, strictly speaking, is not part of the nephron, but from a functional perspective, this the lumen into the cell by a Na-Cl cotransporter that is in- is justified. Transport in the distal nephron differs from that hibited by thiazide diuretics. Na is pumped out the baso- in the proximal tubule in several ways: lateral side by the Na /K -ATPase. Water permeability of 1) The distal nephron reabsorbs much smaller amounts the distal convoluted tubule is low and is not changed by of salt and water. Typically, the distal nephron reabsorbs arginine vasopressin. 9% of the filtered Na and 19% of the filtered water, com- pared with 70% for both substances in the proximal con- voluted tubule. The Cortical Collecting Duct Is an Important 2) The distal nephron can establish steep gradients for Site Regulating K Excretion salt and water. For example, the [Na ] in the final urine may be as low as 1 mEq/L (versus 140 mEq/L in plasma) and Under normal circumstances, most of the excreted K the urine osmolality can be almost one-tenth that of comes from K secreted by the cortical collecting ducts. plasma. By contrast, the proximal tubule reabsorbs Na and With great K excess (e.g., a high-K diet), the cortical water along small gradients, and the [Na ] and osmolality collecting ducts may secrete so much K that more K is of its tubule fluid are normally close to that of plasma. excreted than was filtered. With severe K depletion, the 3) The distal nephron has a “tight” epithelium, whereas cortical collecting ducts reabsorb K . the proximal tubule has a “leaky” epithelium (see Chapter K secretion appears to be a function primarily of the 2). This explains why the distal nephron can establish steep collecting duct principal cell (Fig. 23.21). K secretion in- gradients for small ions and water, whereas the proximal volves active uptake by a Na /K -ATPase in the basolat- tubule cannot. eral cell membrane, followed by diffusion of K through 4) Na and water reabsorption in the proximal tubule luminal membrane K channels. Outward diffusion of K are normally closely coupled because epithelial water per- from the cell is favored by concentration gradients and op- meability is always high. By contrast, Na and water reab- posed by electrical gradients. Note that the electrical gra- sorption can be uncoupled in the distal nephron because dient opposing exit from the cell is smaller across the lumi- water permeability may be low and variable. nal cell membrane than across the basolateral cell Proximal reabsorption overall can be characterized as a membrane, favoring movement of K into the lumen rather coarse operation that reabsorbs large quantities of salt and than back into the blood. The luminal cell membrane po- water along small gradients. By contrast, distal reabsorption tential difference is low (e.g., 20 mV, cell inside negative) is a finer process. because this membrane has a high Na permeability and is The collecting ducts are at the end of the nephron sys- depolarized by Na diffusing into the cell. Recall that the tem, and what happens there largely determines the excre- entry of Na into a cell causes membrane depolarization tion of Na , K , H , and water. Transport in the collect- (see Chapter 3). ing ducts is finely tuned by hormones. Specifically, The magnitude of K secretion is affected by several aldosterone increases Na reabsorption and K and H se- factors (see Fig. 23.21): cretion, and arginine vasopressin increases water reabsorp- 1) The activity of the basolateral membrane Na /K - tion at this site. ATPase is a key factor affecting secretion; the greater the pump activity, the higher the rate of secretion. A high plasma [K ] promotes K secretion. Increased amounts of The Luminal Cell Membrane of the Distal Na in the collecting duct lumen (e.g., a result of inhibition Convoluted Tubule Contains a Na-Cl of Na reabsorption by a loop diuretic drug) result in in- Cotransporter creased entry of Na into principal cells, increased activity of the Na /K -ATPase, and increased K secretion. Figure 23.20 is a model of a distal convoluted tubule cell. In 2) The lumen-negative transepithelial electrical poten- this nephron segment, Na and Cl are transported from tial promotes K secretion.
396 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS Tubular Collecting duct Blood body. The ability to concentrate the urine decreases the urine principal cell amount of water we are obliged to find and drink each day. Na + ATP Na + Arginine Vasopressin Promotes the Excretion of an Osmotically Concentrated Urine ADP + P i K + Changes in urine osmolality are normally brought about largely by changes in plasma levels of arginine vasopressin K + K + (AVP), also known as antidiuretic hormone (ADH) (see Chapter 32). In the absence of AVP, the kidney collecting ducts are relatively water-impermeable. Reabsorption of -50 mV -70 mV -70 mV 0 mV solute across a water-impermeable epithelium leads to os- motically dilute urine. In the presence of AVP, collecting A model for ion transport by a collecting duct water permeability is increased. Because the medullary FIGURE 23.21 duct principal cell. interstitial fluid is hyperosmotic, water reabsorption in the medullary collecting ducts can lead to the production of an osmotically concentrated urine. 3) An increase in permeability of the luminal cell mem- A model for the action of AVP on cells of the collecting brane to K favors secretion. duct is shown in Figure 23.22. When plasma osmolality is 4) A high fluid flow rate through the collecting duct lu- increased, plasma AVP levels increase. The hormone binds men maintains the cell-to-lumen concentration gradient, to a specific vasopressin (V 2 ) receptor in the basolateral cell which favors K secretion. membrane. By way of a guanine nucleotide stimulatory pro- The hormone aldosterone promotes K secretion by tein (G s ), the membrane-bound enzyme adenylyl cyclase is several actions (see Chapter 24). activated. This enzyme catalyzes the formation of cyclic Na entry into the collecting duct cell is by diffusion AMP (cAMP) from ATP. Cyclic AMP then activates a through a Na channel (see Fig. 23.21). This channel has cAMP-dependent protein kinase (protein kinase A [PKA]) been cloned and sequenced and is known as ENaC, for ep- that phosphorylates other proteins. This leads to the inser- ithelial sodium (Na) channel. The entry of Na through tion, by exocytosis, of intracellular vesicles that contain wa- this channel is rate-limiting for overall Na reabsorption ter channels (aquaporin-2) into the luminal cell membrane. and is increased by aldosterone. The resulting increase in number of luminal membrane wa- Intercalated cells are scattered among collecting duct ter channels leads to an increase in water permeability. Wa- principal cells; they are important in acid-base transport (see ter can then move out of the duct lumen through the cells, Chapter 25). A H /K -ATPase is present in the luminal cell and the urinary solutes become concentrated. This response membrane of -intercalated cells and contributes to renal to AVP occurs in minutes. AVP also has delayed effects on K conservation when dietary intake of K is deficient. collecting ducts; it increases the transcription of aquaporin- URINARY CONCENTRATION AND DILUTION Tubular Collecting duct Blood The human kidney can form urine with a total solute con- urine epithelium centration greater or lower than that of plasma. Maximum and minimum urine osmolalities in humans are about 1,200 V receptor to 1,400 mOsm/kg H 2O and 30 to 40 mOsm/kg H 2O. We Aquaporin-2 Vesicle with 2 next consider the mechanisms involved in producing os- aquaporin-2 motically concentrated or dilute urine. AVP PKA G s The Ability to Concentrate Urine Osmotically Is cAMP an Important Adaptation to Life on Land Adenylyl ATP cyclase When the kidneys form osmotically concentrated urine, Nucleus they save water for the body. The kidneys have the task of ( gene transcription) getting rid of excess solutes (e.g., urea, various salts), which requires the excretion of solvent (water). Suppose, for ex- ample, we excrete 600 mOsm of solutes per day. If we were aquaporin-2 synthesis only capable of excreting urine that is isosmotic to plasma (approximately 300 mOsm/kg H 2O), we would need to ex- A model for the action of AVP on the ep- crete 2.0 L H 2O/day. If we can excrete the solutes in urine FIGURE 23.22 ithelium of the collecting duct. The second that is 4 times more concentrated than plasma (1,200 messenger for AVP is cyclic AMP (cAMP). AVP has both prompt mOsm/kg H 2 O), only 0.5 L H 2 O/day would be required. effects on luminal membrane water permeability (the movement By excreting solutes in osmotically concentrated urine, the of aquaporin-2-containing vesicles to the luminal cell membrane) kidneys, in effect, saved 2.0 0.5 1.5 L H 2 O for the and delayed effects (increased aquaporin-2 synthesis).
CHAPTER 23 Kidney Function 397 2 genes and produces an increase in the total number of recta help maintain the gradient in the medulla. The col- aquaporin-2 molecules per cell. lecting ducts act as osmotic equilibrating devices; depend- ing on the plasma level of AVP, the collecting duct urine is allowed to equilibrate more or less with the hyperosmotic The Loops of Henle Are Countercurrent medullary interstitial fluid. Multipliers, and the Vasa Recta Are Countercurrent multiplication is the process in which a Countercurrent Exchangers small gradient established at any level of the loop of Henle is It has been known for longer than 50 years that there is a increased (multiplied) into a much larger gradient along the gradient of osmolality in the kidney medulla, with the high- axis of the loop. The osmotic gradient established at any level est osmolality present at the tips of the renal papillae. This is called the single effect. The single effect involves move- gradient is explained by the countercurrent hypothesis. ment of solute out of the water-impermeable ascending limb, Two countercurrent processes occur in the kidney solute deposition in the medullary interstitial fluid, and with- medulla—countercurrent multiplication and countercurrent drawal of water from the descending limb. Because the fluid exchange. The term countercurrent indicates a flow of fluid in entering the next, deeper level of the loop is now more con- opposite directions in adjacent structures (Fig. 23.23). The centrated, repetition of the same process leads to an axial gra- loops of Henle are countercurrent multipliers. Fluid flows dient of osmolality along the loop. The extent to which coun- toward the tip of the papilla along the descending limb of tercurrent multiplication can establish a large gradient along the loop and toward the cortex along the ascending limb of the axis of the loop depends on several factors, including the the loop. The loops of Henle set up the osmotic gradient in magnitude of the single effect, the rate of fluid flow, and the the medulla. Establishing a gradient requires work; the en- length of the loop of Henle. The larger the single effect, the ergy source is metabolism, which powers the active trans- larger the axial gradient. Impaired solute removal, as from the port of Na out of the thick ascending limb. The vasa recta inhibition of active transport by thick ascending limb cells, are countercurrent exchangers. Blood flows in opposite di- leads to a reduced axial gradient. If flow rate through the loop rections along juxtaposed descending (arterial) and ascend- is too high, not enough time is allowed for establishing a sig- ing (venous) vasa recta, and solutes and water are exchanged nificant single effect, and consequently, the axial gradient is passively between these capillary blood vessels. The vasa reduced. Finally, if the loops are long, there is more opportu- nity for multiplication and a larger axial gradient can be es- tablished. Countercurrent exchange is a common process in the Vasa Loop of Collecting vascular system. In many vascular beds, arterial and venous recta Henle duct vessels lie close to each other, and exchanges of heat or ma- terials can occur between these vessels. For example, be- cause of the countercurrent exchange of heat between blood flowing toward and away from its feet, a penguin can stand on ice and yet maintain a warm body (core) temper- Outer ature. Countercurrent exchange between descending and medulla ascending vasa recta in the kidney reduces dissipation of the solute gradient in the medulla. The descending vasa recta tend to give up water to the more concentrated inter- stitial fluid; this water is taken up by the ascending vasa recta, which come from more concentrated regions of the medulla. In effect, much of the water in the blood short-cir- cuits across the tops of the vasa recta and does not flow Inner medulla deep into the medulla, where it would tend to dilute the ac- cumulated solute. The ascending vasa recta tend to give up solute as the blood moves toward the cortex. Solute enters the descending vasa recta and, therefore, tends to be trapped in the medulla. Countercurrent exchange is a purely passive process; it helps maintain a gradient estab- lished by some other means. Operation of the Urinary Concentrating Mechanism Requires an Integrated Functioning of the Loops of Henle, Vasa Recta, and Elements of the urinary concentrating mech- Collecting Ducts FIGURE 23.23 anism. The vasa recta are countercurrent ex- changers, the loops of Henle are countercurrent multipliers, and Figure 23.24 summarizes the mechanisms involved in pro- the collecting ducts are osmotic equilibrating devices. Note that ducing osmotically concentrated urine. Maximally concen- most loops of Henle and vasa recta do not reach the tip of the trated urine, with an osmolality of 1,200 mOsm/kg H 2O papilla, but turn at higher levels in the outer and inner medulla. and a low urine volume (1% of the original filtered water), Also, there are no thick ascending limbs in the inner medulla. is being excreted.
398 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS H O passive. It occurs because the [NaCl] in the tubular fluid is 2 100 NaCl H 2 O higher than in the interstitial fluid and because the passive 30 15-20 permeability of the thin ascending limb to Na is high. 285 285 100 200 There is also some evidence for a weak active Na pump in NaCl the thin ascending limb. The net addition of solute to the O K + Na + H 2 medulla by the loops is essential for the osmotic concen- Cortex 5 315 285 285 285 100 285 tration of urine in the collecting ducts. Fluid entering the distal convoluted tubule is hypoos- Outer H O motic compared to plasma (see Fig. 23.24) because of the 2 medulla removal of solute along the ascending limb. In the presence NaCl of AVP, the cortical collecting ducts become water-perme- O H O H 2 2 400 able and water is passively reabsorbed into the cortical in- NaCl terstitial fluid. The high blood flow to the cortex rapidly 400 400 200 NaCl Urea NaCl carries away this water, so there is no detectable dilution of Urea cortical tissue osmolality. Before the tubular fluid reenters 600 600 400 600 Inner the medulla, it is isosmotic and reduced to about 5% of the medulla H O original filtered volume. The reabsorption of water in the 2 NaCl cortical collecting ducts is important for the overall opera- Urea NaCl Urea 800 tion of the urinary concentrating mechanism. If this water 800 800 600 were not reabsorbed in the cortex, an excessive amount H O H 2 O 2 NaCl would enter the medulla. It would tend to wash out the gra- 1,000 1,000 800 1,000 NaCl Urea H O 1,200 1,200 2 1,200 1,200 1 Vasa Loop of Collecting recta Henle duct Osmolality Osmotically concentrated urine. This dia- 285 315 285 100 285 mOsm/kg H O 2 FIGURE 23.24 gram summarizes movements of ions, urea, and Flow water in the kidney during production of maximally concentrated 100 117 36 24 6 mL H O/min 2 urine (1,200 mOsm/kg H 2O). Numbers in ovals represent osmo- lality in mOsm/kg H 2O. Numbers in boxes represent relative amounts of water present at each level of the nephron. Solid ar- rows indicate active transport; dashed arrows indicate passive transport. The heavy outlining along the ascending limb of the Outer loop of Henle indicates relative water-impermeability. medulla About 70% of filtered water is reabsorbed along the prox- imal convoluted tubule, so 30% of the original filtered vol- ume enters the loop of Henle. As discussed earlier, proximal Inner reabsorption of water is essentially an isosmotic process, so medulla fluid entering the loop is isosmotic. As the fluid moves along the descending limb of the loop Henle in the medulla, it be- comes increasingly concentrated. This rise in osmolality, in principle, could be due to one of two processes: 1) The movement of water out of the descending limb because of the hyperosmolality of the medullary in- terstitial fluid. 2) The entry of solute from the medullary interstitial fluid. The relative importance of these processes may depend on the species of animal. For most efficient operation of the Osmolality concentrating mechanism, water removal should be pre- 1,200 mOsm/kg H O 2 dominant, so only this process is depicted in Figure 23.24. Flow The removal of water along the descending limb leads to a 1 mL H O/min 2 rise in [NaCl] in the loop fluid to a value higher than in the interstitial fluid. FIGURE 23.25 Mass balance considerations for the medulla as a whole. In the steady state, the When the fluid enters the ascending limb, it enters wa- inputs of water and solutes must equal their respective outputs. ter-impermeable segments. NaCl is transported out of the Water input into the medulla from the cortex (100 36 6 ascending limb and deposited in the medullary interstitial 142 mL/min) equals water output from the medulla (117 24 fluid. In the thick ascending limb, Na transport is active 1 142 mL/min). Solute input (28.5 10.3 1.7 40.5 and is powered by a vigorous Na /K -ATPase. In the thin mOsm/min) is likewise equal to solute output (36.9 2.4 1.2 ascending limb, NaCl reabsorption appears to be mainly 40.5 mOsm/min).
CHAPTER 23 Kidney Function 399 dient in the medulla, leading to an impaired ability to con- 50 centrate the urine maximally. All nephrons drain into collecting ducts that pass 30 through the medulla. In the presence of AVP, the medullary 100 50 100 collecting ducts are permeable to water. Water moves out of the collecting ducts into the more concentrated interstitial fluid. In high levels of AVP, the fluid equilibrates with the Cortex interstitial fluid, and the final urine becomes as concentrated as the tissue fluid at the tip of the papilla. Outer Many different models for the countercurrent mechanism medulla have been proposed; each must take into account the princi- ple of conservation of matter (mass balance). In the steady state, the inputs of water and every nonmetabolized solute must equal their respective outputs. This principle must be obeyed at every level of the medulla. Figure 23.25 presents a simplified scheme that applies the mass balance principle to the medulla as a whole. It provides some additional insight Inner into the countercurrent mechanism. Notice that fluids enter- medulla ing the medulla (from the proximal tubule, descending vasa recta, and cortical collecting ducts) are isosmotic; they all have an osmolality of about 285 mOsm/kg H 2 O. Fluid leav- ing the medulla in the urine is hyperosmotic. It follows from mass balance considerations that somewhere a hypoosmotic 50 fluid has to leave the medulla; this occurs in the ascending limb of the loop of Henle. The input of water into the medulla must equal its out- 20 put. Because water is added to the medulla along the de- scending limbs of the loops of Henle and the collecting 30 ducts, this water must be removed at an equal rate. The as- cending limbs of the loops of Henle cannot remove the FIGURE 23.26 Movements of urea along the nephron. The numbers indicate relative amounts (100 fil- added water, since they are water-impermeable. The water tered urea), not concentrations. The heavy outline from the thick is removed by the vasa recta; this is why ascending exceeds ascending limb to the outer medullary collecting duct indicates descending vasa recta blood flow (see Fig. 23.25). The relatively urea-impermeable segments. Urea is added to the inner blood leaving the medulla is hyperosmotic because it drains medulla by its collecting ducts; most of this urea reenters the loop a region of high osmolality and does not instantaneously of Henle, and some is removed by the vasa recta. equilibrate with the medullary interstitial fluid. may reenter the loop of Henle and be recycled (see Fig. Urea Plays a Special Role in the 23.26), building up its concentration in the inner medulla. Concentrating Mechanism Urea is also added to the inner medulla by diffusion from the It has long been known that animals or humans on low-pro- urine surrounding the papillae (calyceal urine). Urea ac- tein diets have an impaired ability to maximally concen- counts for about half of the osmolality in the inner medulla. trate the urine. A low-protein diet is associated with a de- The urea in the interstitial fluid of the inner medulla coun- creased [urea] in the kidney medulla. terbalances urea in the collecting duct urine, allowing the Figure 23.26 shows how urea is handled along the other solutes (e.g., NaCl) in the interstitial fluid to counter- nephron. The proximal convoluted tubule is fairly perme- balance osmotically the other solutes (e.g., creatinine, vari- able to urea and reabsorbs about 50% of the filtered urea. ous salts) that need to be concentrated in the urine. Fluid collected from the distal convoluted tubule, however, has as much urea as the amount filtered. Therefore, urea is A Dilute Urine Is Excreted When secreted in the loop of Henle. The thick ascending limb, distal convoluted tubule, con- Plasma AVP Levels Are Low necting tubule, cortical collecting duct, and outer Figure 23.27 depicts kidney osmolalities during excretion of medullary collecting duct are relatively urea-impermeable. a dilute urine, as occurs when plasma AVP levels are low. As water is reabsorbed along cortical and outer medullary Tubular fluid is diluted along the ascending limb and be- collecting ducts, the [urea] rises. The result is the delivery comes more dilute as solute is reabsorbed across the rela- to the inner medulla of a concentrated urea solution. A con- tively water-impermeable distal portions of the nephron and centrated solution has chemical potential energy and can collecting ducts. Since as much as 15% of filtered water is do work. not reabsorbed, a high urine flow rate results. In these cir- The inner medullary collecting duct has a facilitated urea cumstances, the osmotic gradient in the medulla is reduced transporter, which is activated by AVP and favors urea dif- but not abolished. The decreased gradient results from sev- fusion into the interstitial fluid of the inner medulla. Urea eral factors, including an increased medullary blood flow,
400 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS H O Inherited Defects in Kidney Tubule Ep- 2 100 NaCl TABLE 23.3 30 15-20 ithelial Cells 285 285 100 Condition Molecular Defect Clinical Features NaCl O K + Na + Renal glucosuria Na -dependent Glucosuria, polyuria, H 2 Cortex glucose cotransporter polydipsia, 285 285 100 90 polyphagia Cystinuria Amino acid Kidney stone disease Outer transporter medulla Bartter’s syndrome Na-K-2Cl Salt wasting, NaCl cotransporter, K hypokalemic H O channel or Cl metabolic alkalosis 2 channel in thick NaCl ascending limb Gitelman’s syndrome Thiazide-sensitive Salt wasting, 400 400 200 70 Na-Cl cotransporter hypokalemic Inner in distal convoluted metabolic alkalosis, medulla tubule hypocalciuria Liddle’s syndrome Increased open time Hypertension, (pseudohyperal- and number of hypokalemic O dosteronism) principal cell metabolic alkalosis H 2 epithelial sodium NaCl channels Pseudohypoal- Decreased activity of Salt wasting, 425 NaCl dosteronism type 1 epithelial sodium hyperkalemic 425 channels metabolic 425 40 15 Distal renal tubular -Intercalated cell Metabolic acidosis, acidosis type 1 Cl /HCO 3 osteomalacia Osmotic gradients during excretion of os- FIGURE 23.27 exchanger, H - motically very dilute urine. The collecting ATPase ducts are relatively water-impermeable (heavy outlining) because Nephrogenic Vasopressin-2 (V 2) Polyuria, polydipsia AVP is absent. Note that the medulla is still hyperosmotic, but less diabetes insipidus receptor or so than in a kidney producing osmotically concentrated urine. aquaporin-2 reduced addition of urea, and the addition of too much wa- Table 23.3 lists some of these inherited disorders. ter to the inner medulla by the collecting ducts. Specific molecular defects have been identified in the proximal tubule (renal glucosuria, cystinuria), thick as- cending limb (Bartter’s syndrome), distal convoluted INHERITED DEFECTS IN KIDNEY TUBULE tubule (Gitelman’s syndrome), and collecting duct (Lid- EPITHELIAL CELLS dle’s syndrome, pseudohypoaldosteronism type 1, distal renal tubular acidosis, nephrogenic diabetes insipidus). Recent studies have elucidated the molecular basis of several Although these disorders are rare, they shed light on inherited kidney disorders. In many cases, the normal and mu- the pathophysiology of disease in general. For example, tated molecules have been cloned and sequenced. It appears the finding that increased epithelial Na channel activ- that inherited defects in kidney tubule receptors (e.g., the va- ity in Liddle’s syndrome leads to hypertension strength- sopressin-2 receptor), ion channels, or carriers may explain the ens the view that excessive dietary salt leads to high disturbed physiological processes of these conditions. blood pressure. REVIEW QUESTIONS DIRECTIONS: Each of the numbered (C) mL plasma/min (E) Collecting duct intercalated cells items of incomplete statements in this (D) mL urine/min 3. A man needs to excrete 570 mOsm of section is followed by answers or by (E) mL urine/mL plasma solute per day in his urine and his completions of the statement. Select the 2. A luminal cell membrane Na channel maximum urine osmolality is 1,140 ONE lettered answer or completion that is is the main pathway for Na mOsm/kg H2O. What is the minimum BEST in each case. reabsorption in urine volume per day that he needs to (A) Proximal tubule cells excrete in order to stay in solute 1. The dimensions of renal clearance are (B) Thick ascending limb cells balance? (A) mg/mL (C) Distal convoluted tubule cells (A) 0.25 L/day (B) mg/min (D) Collecting duct principal cells (B) 0.5 L/day (continued)
CHAPTER 23 Kidney Function 401 (C) 2.0 L/day (C) 600 mOsm/kg H 2 O freely filterable substance is 2 mg/mL, (D) 4.0 L/day (D) 900 mOsm/kg H 2 O GFR is 100 mL/min, urine (E) 180 L/day (E) 1,200 mOsm/kg H 2 O concentration of the substance is 10 4. Which of the following results in an 10.An older woman with diabetes arrives mg/mL, and urine flow rate is 5 increased osmotic gradient in the at the hospital in a severely dehydrated mL/min, we can conclude that the medulla of the kidney? condition, and she is breathing rapidly. kidney tubules (A) Administration of a diuretic drug Blood plasma [glucose] is 500 mg/dL (A) reabsorbed 150 mg/min that inhibits Na reabsorption by thick (normal, 100 mg/dL) and the urine (B) reabsorbed 200 mg/min ascending limb cells [glucose] is zero (dipstick test). What (C) secreted 50 mg/min (B) A low GFR (e.g., 20 mL/min in an is the most likely explanation for the (D) secreted 150 mg/min adult) absence of glucose in the urine? (E) secreted 200 mg/min (C) Drinking a liter of water (A) The amount of splay in the glucose 17.A clearance study was done on a young (D) Long loops of Henle reabsorption curve is abnormally woman with suspected renal disease: (E) Low dietary protein intake increased Arterial [PAH] 0.02 mg/mL 5. Dilation of efferent arterioles results in (B) GFR is abnormally low Renal vein [PAH] 0.01 mg/mL an increase in (C) The glucose Tm is abnormally Urine [PAH] 0.60 mg/mL (A) Glomerular blood flow high Urine flow rate 5.0 mL/min (B) Glomerular capillary pressure (D) The glucose Tm is abnormally low Hematocrit, % cells 40 (C) GFR (E) The renal plasma glucose threshold What is her true renal blood flow? (D) Filtration fraction is abnormally low (A) 150 mL/min (E) Hydrostatic pressure in the space 11.In a suicide attempt, a nurse took an (B) 300 mL/min of Bowman’s capsule overdose of the sedative phenobarbital. (C) 500 mL/min 6. The main driving force for water This substance is a weak, lipid-soluble (D) 750 mL/min reabsorption by the proximal tubule organic acid that is reabsorbed by (E) 1,200 mL/min epithelium is nonionic diffusion in the kidneys. 18.A man has progressive, chronic kidney (A) Active reabsorption of amino acids Which of the following would disease. Which of the following and glucose promote urinary excretion of this indicates the greatest absolute decrease (B) Active reabsorption of Na substance? in GFR? (C) Active reabsorption of water (A) Abstain from all fluids (A) A fall in plasma creatinine from 4 (D) Pinocytosis (B) Acidify the urine by ingesting mg/dL to 2 mg/dL (E) The high colloid osmotic pressure NH 4Cl tablets (B) A fall in plasma creatinine from 2 in the peritubular capillaries (C) Administer a drug that inhibits mg/dL to 1 mg/dL 7. The following clearance measurements tubular secretion of organic anions (C) A rise in plasma creatinine from 1 were made in a man after he took a (D) Alkalinize the urine by infusing a mg/dL to 2 mg/dL diuretic drug. What percentage of NaHCO 3 solution intravenously (D) A rise in plasma creatinine from 2 filtered Na did he excrete? 12.Which of the following provides the mg/dL to 4 mg/dL Plasma [inulin] 1 mg/mL most accurate measure of GFR? (E) A rise in plasma creatinine from 4 Urine [inulin] 10 mg/mL (A) Blood urea nitrogen (BUN) mg/dL to 8 mg/dL Plasma [Na ] 140 mEq/L (B) Endogenous creatinine clearance 19.Renin in synthesized by Urine [Na ] 70 mEq/L (C) Inulin clearance (A) Granular cells Urine flow rate 10 mL/min (D) PAH clearance (B) Intercalated cells (A) 1% (E) Plasma (creatinine) (C) Interstitial cells (B) 5% 13.Hypertension was observed in a young (D) Macula densa cells (C) 10% boy since birth. Which of the (E) Mesangial cells (D) 50% following disorders may be present? 20.The following determinations were (E) 99% (A) Bartter’s syndrome made on a single glomerulus of a rat 8. Renal autoregulation (B) Gitelman’s syndrome kidney: GFR, 42 nL/min; glomerular (A) Is associated with increased renal (C) Liddle’s syndrome capillary hydrostatic pressure, 50 mm vascular resistance when arterial blood (D) Nephrogenic diabetes insipidus Hg; hydrostatic pressure in Bowman’s pressure is lowered from 100 to 80 mm (E) Renal glucosuria space, 12 mm Hg; average glomerular Hg 14.In a person with severe central diabetes capillary colloid osmotic pressure, 24 (B) Mainly involves changes in the insipidus (deficient production or mm Hg. What is the glomerular caliber of efferent arterioles release of AVP), urine osmolality and ultrafiltration coefficient? (C) Maintains a normal renal blood flow rate is typically about (A) 0.33 mm Hg per nL/min flow during severe hypotension (blood (A) 50 mOsm/kg H 2O, 18 L/day (B) 0.49 nL/min per mm Hg pressure, 50 mm Hg) (B) 50 mOsm/kg H 2O, 1.5 L/day (C) 0.68 nL/min per mm Hg (D) Minimizes the impact of changes (C) 300 mOsm/kg H 2O, 1.5 L/day (D) 1.48 mm Hg per nL/min in arterial blood pressure on renal Na (D) 300 mOsm/kg H 2O, 18 L/day (E) 3.0 nL/min per mm Hg excretion (E) 1,200 mOsm/kg H 2O, 0.5 L/day (E) Requires intact renal nerves 15.Which of the following substances has SUGGESTED READING 9. In a kidney producing urine with an the highest renal clearance? Brooks VL, Vander AJ, eds. Refresher osmolality of 1,200 mOsm/kg H 2O, (A) Creatinine course for teaching renal physiology. the osmolality of fluid collected from (B) Inulin Adv Physiol Educ 1998;20:S114–S245. the end of the cortical collecting duct (C) PAH Burckhardt G, Bahn A, Wolff NA. Molecu- is about (D) Na lar physiology of renal p-aminohippu- (A) 100 mOsm/kg H 2O (E) Urea rate secretion. News Physiol Sci (B) 300 mOsm/kg H 2 O 16.If the plasma concentration of a 2001;16:113–118. (continued)
402 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS Koeppen BM, Stanton BA. Renal Phy- and Electrolyte Disorders. 4th Ed. New Physiology and Pathophysiology. 3rd siology. 3rd Ed. St. Louis: Mosby, York: McGraw-Hill, 1994. Ed. Philadelphia: Lippincott Williams & 2001. Scheinman SJ, Guay-Woodford LM, Wilkins, 2000. Kriz W, Bankir L. A standard nomencla- Thakker RV, Warnock DG. Genetic Valtin H, Schafer JA. Renal Function. 3rd ture for structures of the kidney. Am J disorders of renal electrolyte transport. Ed. Boston: Little, Brown, 1995. Physiol 1988;254:F1–F8. N Engl J Med 1999;340:1177–1187. Vander AJ. Renal Physiology. 5th Ed. New Rose BD. Clinical Physiology of Acid-Base Seldin DW, Giebisch G, eds. The Kidney: York: McGraw-Hill, 1995.
CHAPTER The Regulation of Fluid 24 and Electrolyte Balance 24 George A. Tanner, Ph.D. CHAPTER OUTLINE ■ FLUID COMPARTMENTS OF THE BODY ■ CALCIUM BALANCE ■ WATER BALANCE ■ MAGNESIUM BALANCE ■ SODIUM BALANCE ■ PHOSPHATE BALANCE ■ POTASSIUM BALANCE ■ URINARY TRACT KEY CONCEPTS 1. Total body water is distributed in two major compart- filtration rate, angiotensin II and aldosterone, intrarenal ments: intracellular water and extracellular water. In an av- physical forces, natriuretic hormones and factors such as erage young adult man, total body water, intracellular wa- atrial natriuretic peptide, and renal sympathetic nerves. ter, and extracellular water amount to 60%, 40%, and 20% Changes in these factors may account for altered Na ex- of body weight, respectively. The corresponding figures for cretion in response to excess Na or Na depletion. Estro- an average young adult woman are 50%, 30%, and 20% of gens, glucocorticoids, osmotic diuretics, poorly reabsorbed body weight. anions in the urine, and diuretic drugs also affect renal Na 2. The volumes of body fluid compartments are determined excretion. by using the indicator dilution method and this equation is: 9. The effective arterial blood volume (EABV) depends on the Volume Amount of indicatorConcentration of indicator degree of filling of the arterial system and determines the at equilibrium. perfusion of the body’s tissues. A decrease in EABV leads 3. Electrical neutrality is present in solutions of electrolytes; to Na retention by the kidneys and contributes to the de- that is, the sum of the cations is equal to the sum of the an- velopment of generalized edema in pathophysiological ions (both expressed in milliequivalents). conditions, such as congestive heart failure. 4. Sodium (Na ) is the major osmotically active solute in ex- 10. The kidneys play a major role in the control of K balance. tracellular fluid (ECF), and potassium (K ) has the same K is reabsorbed by the proximal convoluted tubule and role in the intracellular fluid (ICF) compartment. Cells are the loop of Henle and is secreted by cortical collecting duct typically in osmotic equilibrium with their external environ- principal cells. Inadequate renal K excretion produces hy- ment. The amount of water in (and, hence, the volume of) perkalemia and excessive K excretion produces hy- cells depends on the amount of K they contain and, simi- pokalemia. larly, the amount of water in (and, hence, the volume of) 11. Calcium balance is regulated on both input and output the ECF is determined by its Na content. sides. The absorption of Ca 2 from the small intestine is 5. Plasma osmolality is closely regulated by arginine vaso- controlled by 1,25(OH) 2 vitamin D 3 , and the excretion of pressin (AVP), which governs renal excretion of water, and Ca 2 by the kidneys is controlled by parathyroid hormone by habit and thirst, which govern water intake. (PTH). 6. AVP is synthesized in the hypothalamus, released from the 12. Magnesium in the body is mostly in bone, but it is also an posterior pituitary gland, and acts on the collecting ducts important intracellular ion. The kidneys regulate the of the kidney to increase their water permeability. The ma- plasma [Mg 2 ]. jor stimuli for the release of AVP are an increase in effec- 13. Filtered phosphate usually exceeds the maximal reabsorp- tive plasma osmolality (detected by osmoreceptors in the tive capacity of the kidney tubules for phosphate (TmPO 4 ), anterior hypothalamus) and a decrease in blood volume and about 5 to 20% of filtered phosphate is usually ex- (detected by stretch receptors in the left atrium, carotid si- creted. Phosphate reabsorption occurs mainly in the proxi- nuses, and aortic arch). mal tubules and is inhibited by PTH. Phosphate is an im- 7. The kidneys are the primary site of control of Na excre- portant pH buffer in the urine. Hyperphosphatemia is a tion. Only a small percentage (usually about 1%) of the fil- significant problem in chronic renal failure. tered Na is excreted in the urine, but this amount is of 14. The urinary bladder stores urine until it can be conve- critical importance in overall Na balance. niently emptied. Micturition is a complex act involving 8. Multiple factors affect Na excretion, including glomerular both autonomic and somatic nerves. 403
404 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS major function of the kidneys is to regulate the volume, Interstitial fluid Acomposition, and osmolality of the body fluids. The and lymph water (15% body fluid surrounding our body cells (the ECF) is constantly re- Intracellular water weight; 10.5 L) Plasma water newed and replenished by the circulating blood plasma. (40% body weight; 28 L) (5% body The kidneys constantly process the plasma; they filter, re- weight; 3.5 L) absorb, and secrete substances and, in health, maintain the internal environment within narrow limits. In this chapter, we begin with a discussion of the fluid compartments of the body—their location, magnitude, and composition. Then we consider water, sodium, potassium, calcium, magne- sium, and phosphate balance, with special emphasis on the role of the kidneys in maintaining our fluid and electrolyte balance. Finally, we consider the role of the ureters, urinary bladder, and urethra in the transport, storage, and elimina- tion of urine. Extracellular water (20% body weight; 14 L) FLUID COMPARTMENTS OF THE BODY Total body water (60% body weight; 42 L) Water is the major constituent of all body fluid compart- Water distribution in the body. This dia- ments. Total body water averages about 60% of body FIGURE 24.1 gram is for an average young adult man weigh- weight in young adult men and about 50% of body weight ing 70 kg. In an average young adult woman, total body water is in young adult women (Table 24.1). The percentage of 50% of body weight, intracellular water is 30% of body weight, body weight water occupies depends on the amount of adi- and extracellular water is 20% of body weight. pose tissue (fat) a person has. A lean person has a high per- centage and an obese individual a low percentage of body weight that is water because adipose tissue contains a low percentage of water (about 10%), whereas most other tis- ter is in the ICF, and one third is in the ECF (Fig. 24.1). sues have a much higher percentage of water. For example, These two fluids differ strikingly in terms of their electrolyte muscle is about 75% water. Newborns have a low percent- composition. However, their total solute concentrations age of body weight as water because of a relatively large (osmolalities) are normally equal, because of the high water ECF volume and little fat (see Table 24.1). Adult women permeability of most cell membranes, so that an osmotic dif- have relatively less water than men because, on average, ference between cells and ECF rapidly disappears. they have more subcutaneous fat and less muscle mass. As The ECF can be further subdivided into two major sub- people age, they tend to lose muscle and add adipose tissue; compartments, which are separated from each other by the hence, water content declines with age. endothelium of blood vessels. The blood plasma is the ECF found within the vascular system; it is the fluid portion of the blood in which blood cells and platelets are suspended. Body Water Is Distributed in The blood plasma water comprises about one fourth of the Several Fluid Compartments ECF or about 3.5 L for an average 70-kg man (see Fig. 24.1). The interstitial fluid and lymph are considered together be- Total body water can be divided into two compartments or cause they cannot be easily separated. The water of the in- spaces: intracellular fluid (ICF) and extracellular fluid terstitial fluid and lymph comprises three fourths of the (ECF). The ICF is comprised of the fluid within the trillions ECF. The interstitial fluid directly bathes most body cells, of cells in our body. The ECF is comprised of fluid outside and the lymph is the fluid within lymphatic vessels. The of the cells. In a young adult man, two thirds of the body wa- blood plasma, interstitial fluid, and lymph are nearly iden- tical in composition, except for the higher protein concen- tration in the plasma. An additional ECF compartment (not shown in Fig. 24.1), Average Total Body Water as a Percent- TABLE 24.1 the transcellular fluid, is small but physiologically important. age of Body Weight Transcellular fluid amounts to about 1 to 3% of body weight. Age Men Both Sexes Women Transcellular fluids include cerebrospinal fluid, aqueous hu- mor of the eye, secretions of the digestive tract and associated 0–1 month 76 organs (saliva, bile, pancreatic juice), renal tubular fluid and 1–12 months 65 bladder urine, synovial fluid, and sweat. In these cases, the 1–10 years 62 10–16 years 59 57 fluid is separated from the blood plasma by an epithelial cell 17–39 years 61 50 layer in addition to a capillary endothelium. The epithelial 40–59 years 55 52 layer modifies the electrolyte composition of the fluid, so that 60 years and older 52 46 transcellular fluids are not plasma ultrafiltrates (as is intersti- tial fluid and lymph); they have a distinct ionic composition. From Edelman IS, Leibman J. Anatomy of body water and electrolytes. Am J Med 1959;27:256–277. There is a constant turnover of transcellular fluids; they are continuously formed and absorbed or removed. Impaired for-
CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 405 mation, abnormal loss from the body, or blockage of fluid re- Cellular water cannot be determined directly with any moval can have serious consequences. indicator. It can, however, be calculated from the differ- ence between measurements of total body water and extra- cellular water. The Indicator Dilution Method Measures Plasma water is determined by using Evans blue dye, Fluid Compartment Size which avidly binds serum albumin or radioiodinated serum The indicator dilution method can be used to determine albumin (RISA), and by collecting and analyzing a blood the size of body fluid compartments (see Chapter 14). A plasma sample. In effect, the plasma volume is measured known amount of a substance (the indicator), which should from the distribution volume of serum albumin. The as- be confined to the compartment of interest, is adminis- sumption is that serum albumin is completely confined to tered. After allowing sufficient time for uniform distribu- the vascular compartment, but this is not entirely true. In- tion of the indicator throughout the compartment, a plasma deed, serum albumin is slowly (3 to 4% per hour) lost from sample is collected. The concentration of the indicator in the blood by diffusive and convective transport through the plasma at equilibrium is measured, and the distribution capillary walls. To correct for this loss, repeated blood sam- volume is calculated from this formula ples can be collected at timed intervals, and the concentra- tion of albumin at time zero (the time at which no loss Volume Amount of indicator/ would have occurred) can be determined by extrapolation. Concentration of indicator (1) Alternatively, the plasma concentration of indicator 10 minutes after injection can be used; this value is usually If there was loss of indicator from the fluid compart- ment, the amount lost is subtracted from the amount ad- close to the extrapolated value. If plasma volume and hema- ministered. tocrit are known, total circulating blood volume can be cal- To measure total body water, heavy water (deuterium culated (see Chapter 11). oxide), tritiated water (HTO), or antipyrene (a drug that Interstitial fluid and lymph volume cannot be deter- distributes throughout all of the body water) is used as an mined directly. It can be calculated as the difference be- indicator. For example, suppose we want to measure total tween ECF and plasma volumes. body water in a 60-kg woman. We inject 30 mL of deu- terium oxide (D 2 O) as an isotonic saline solution into an arm vein. After a 2-hr equilibration period, a blood sample Body Fluids Differ in Electrolyte Composition is withdrawn, and the plasma is separated and analyzed for Body fluids contain many uncharged molecules (e.g., glu- D 2 O. A concentration of 0.001 mL D 2 O/mL plasma water cose and urea), but quantitatively speaking, electrolytes is found. Suppose during the equilibration period, urinary, (ionized substances) contribute most to the total solute respiratory, and cutaneous losses of D 2 O are 0.12 mL. Sub- concentration (or osmolality) of body fluids. Osmolality is stituting these values into the indicator dilution equation, of prime importance in determining the distribution of wa- we get ter between intracellular and ECF compartments. Total body water (30 0.12 mL D 2 O) The importance of ions (particularly Na ) in determin- 0.001 mL D 2 O/mL water ing the plasma osmolality (P osm ) is exemplified by an equa- 29,880 mL or 30 L (2) tion that is of value in the clinic: Therefore, total body water as a percentage of body P osm 2 [Na ] weight equals 50% in this woman. [glucose] in mg/dL To measure extracellular water volume, the ideal indica- 18 [blood urea nitrogen] in mg/dL tor should distribute rapidly and uniformly outside the cells (3) and should not enter the cell compartment. Unfortunately, 2.8 there is no such ideal indicator, so the exact volume of the If the plasma [Na ] is 140 mmol/L, blood glucose is 100 ECF cannot be measured. A reasonable estimate, however, mg/dL (5.6 mmol/L), and blood urea nitrogen is 10 mg/dL can be obtained using two different classes of substances: (3.6 mmol/L), the calculated osmolality is 289 mOsm/kg impermeant ions and inert sugars. ECF volume has been de- H 2 O. The equation indicates that Na and its accompany- termined from the volume of distribution of these ions: ra- ing anions (mainly Cl and HCO 3 ) normally account for dioactive Na , radioactive Cl , radioactive sulfate, thio- more than 95% of the plasma osmolality. In some special 2– cyanate (SCN ), and thiosulfate (S 2 O 3 ); radioactive circumstances (e.g., alcohol intoxication), plasma osmolal- 35 2– sulfate ( SO 4 ) is probably the most accurate. However, ity calculated from the above equation may be much lower ions are not completely impermeant; they slowly enter the than the true, measured osmolality as a result of the presence cell compartment, so measurements tend to lead to an over- of unmeasured osmotically active solutes (e.g., ethanol). estimate of ECF volume. Measurements with inert sugars The concentrations of various electrolytes in plasma, in- (such as mannitol, sucrose, and inulin) tend to lead to an terstitial fluid, and ICF are summarized in Table 24.2. The underestimate of ECF volume because they are excluded ICF values are based on determinations made in skeletal from some of the extracellular water—for example, the wa- muscle cells. These cells account for about two thirds of the ter in dense connective tissue and cartilage. Special tech- cell mass in the human body. Concentrations are expressed niques are required when using these sugars because they in terms of milliequivalents per liter or per kg H 2O. are rapidly filtered and excreted by the kidneys after their An equivalent contains one mole of univalent ions, and a intravenous injection. milliequivalent (mEq) is 1/1,000th of an equivalent. Equiv-
406 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS TABLE 24.2 Electrolyte Composition of the Body Fluids Plasma Electrolyte Plasma Water Interstitial Fluid Intracellular Fluid a (mEq/L) (mEq/kg H 2 O) (mEq/kg H 2 O) (mEq/kg H 2 O) Cations Na 42 153 145 10 K 4 4.3 4 159 Ca 2 55.43 1 Mg 2 22.22 40 Total 153 165 154 210 Anions Cl 103 111 117 3 HCO 3 25 27 28 7 Protein 17 18 — 45 Others 8 9 9 155 Total 153 165 154 210 a Skeletal muscle cells. alents are calculated as the product of moles times valence stitial fluid than in plasma and the concentrations of dif- and represent the concentration of charged species. For fusible anions (such as Cl ) are higher in interstitial fluid singly charged (univalent) ions, such as Na , K , Cl , or than in plasma. Second, Ca 2 and Mg 2 are bound to some HCO 3 , 1 mmol is equal to 1 mEq. For doubly charged (di- extent (about 40% and 30%, respectively) by plasma pro- 2 2 2– valent) ions, such as Ca , Mg , or SO 4 , 1 mmol is equal teins, and it is only the unbound ions that can diffuse to 2 mEq. Some electrolytes, such as proteins, are polyva- through capillary walls. Hence, the total plasma Ca 2 and lent, so there are several mEq/mmol. The usefulness of ex- Mg 2 concentrations are higher than in interstitial fluid. pressing concentrations in terms of mEq/L is based on the ICF composition (Table 24.2, Column 4) is different 2 fact that in solutions, we have electrical neutrality; that is from ECF composition. The cells have a higher K , Mg , and protein concentration than in the surrounding intersti- 3 cations 3 anions (4) 2 tial fluid. The intracellular Na , Ca , Cl , and HCO 3 If we know the total concentration (mEq/L) of all cations levels are lower than outside the cell. The anions in skele- in a solution and know only some of the anions, we can eas- tal muscle cells labeled “Others” are mainly organic phos- ily calculate the concentration of the remaining anions. phate compounds important in cell energy metabolism, This was done in Table 24.2 for the anions labeled “Oth- such as creatine phosphate, ATP, and ADP. As described in ers.” Plasma concentrations are listed in the first column of Chapter 2, the high intracellular [K ] and low intracellular Table 24.2. Na is the major cation in plasma, and Cl and [Na ] are a consequence of plasma membrane Na /K - HCO 3 are the major anions. The plasma proteins (mainly ATPase activity; this enzyme extrudes Na from the cell serum albumin) bear net negative charges at physiological and takes up K . The low intracellular [Cl ] and [HCO 3 ] pH. The electrolytes are actually dissolved in the plasma in skeletal muscle cells are primarily a consequence of the water, so the second column in Table 24.2 expresses con- inside negative membrane potential (90 mV), which fa- centrations per kg H 2 O. The water content of plasma is vors the outward movement of these small, negatively 2 usually about 93%; about 7% of plasma volume is occupied charged ions. The intracellular [Mg ] is high; most is not 2 by solutes, mainly the plasma proteins. To convert concen- free, but is bound to cell proteins. Intracellular [Ca ] is 2 tration in plasma to concentration in plasma water, we di- low; as discussed in Chapter 1, the cytosolic [Ca ] in rest- vided the plasma concentration by the plasma water con- ing cells is about 10 7 M (0.0002 mEq/L). Most of the cell tent (0.93 L H 2 O/L plasma). Therefore, 142 mEq Na /L Ca 2 is sequestered in organelles, such as the sarcoplasmic plasma becomes 153 mEq/L H 2 O or 153 mEq/kg H 2 O reticulum in skeletal muscle. (since 1 L of water weighs 1 kg). Interstitial fluid (Column 3 of Table 24.2) is an ultrafil- trate of plasma. It contains all of the small electrolytes in es- Intracellular and Extracellular Fluids Are sentially the same concentration as in plasma, but little pro- Normally in Osmotic Equilibrium tein. The proteins are largely confined to the plasma Despite the different compositions of ICF and ECF, the to- because of their large molecular size. Differences in small tal solute concentration (osmolality) of these two fluid ion concentrations between plasma and interstitial fluid compartments is normally the same. ICF and ECF are in os- (compare Columns 2 and 3) occur because of the different motic equilibrium because of the high water permeability protein concentrations in these two compartments. Two of cell membranes, which does not permit an osmolality factors are involved. The first is an electrostatic effect: Be- difference to be sustained. If the osmolality changes in one cause the plasma proteins are negatively charged, they compartment, water moves to restore a new osmotic equi- cause a redistribution of small ions, so that the concentra- librium (see Chapter 2). tions of diffusible cations (such as Na ) are lower in inter- The volumes of ICF and ECF depend primarily on the
CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 407 volume of water present in these compartments. But the lat- added to an original total body water volume of 42 L, the ter depends on the amount of solute present and the osmo- new total body water volume is 44 L. No solute was added, lality. This fact follows from the definition of the term con- so the new osmolality at equilibrium is (7,980 3,990 centration: concentration amount/volume; hence, volume mOsm)/44 kg 272 mOsm/kg H 2 O. The volume of the amount/concentration. The main osmotically active ICF at equilibrium, calculated by solving the equation, 272 solute in cells is K ; therefore, a loss of cell K will cause mOsm/kg H 2 O volume 7,980 mOsm, is 29.3 L The cells to lose water and shrink (see Chapter 2). The main os- volume of the ECF at equilibrium is 14.7 L. From these cal- motically active solute in the ECF is Na ; therefore, a gain culations, we conclude that two thirds of the added water or loss of Na from the body will cause the ECF volume to ends up in the cell compartment and one third stays in the swell or shrink, respectively. ECF. This description of events is artificial because, in real- The distribution of water between intracellular and ex- ity, the kidneys would excrete the added water over the tracellular compartments changes in a variety of circum- course of a few hours, minimizing the fall in plasma osmo- stances. Figure 24.2 provides some examples. Total body lality and cell swelling. water is divided into the two major compartments, ICF and In Figure 24.2C, 2.0 L of isotonic saline (0.9% NaCl so- ECF. The y-axis represents total solute concentration and lution) were added to the ECF. Isotonic saline is isosmotic the x-axis the volume; the area of a box (concentration to plasma or ECF and, by definition, causes no change in times volume) gives the amount of solute present in a com- cell volume. Therefore, all of the isotonic saline is retained partment. Note that the height of the boxes is always equal, in the ECF and there is no change in osmolality. since osmotic equilibrium (equal osmolalities) is achieved. Figure 24.2D shows the effect of infusing intravenously In the normal situation (shown in Figure 24.2A), two 1.0 L of a 5% NaCl solution (osmolality about 1,580 thirds (28 L for a 70-kg man) of total body water is in the mOsm/kg H 2 O). All the salt stays in the ECF. The cells are ICF, and one third (14 L) is in the ECF. The osmolality of exposed to a hypertonic environment, and water leaves the both fluids is 285 mOsm/kg H 2 O. Hence, the cell com- cells. Solutes left behind in the cells become more concen- partment contains 7,980 mOsm and the ECF contains trated as water leaves. A new equilibrium will be established, 3,990 mOsm. with the final osmolality higher than normal but equal in- In Figure 24.2B, 2.0 L of pure water were added to the side and outside the cells. The final osmolality can be calcu- ECF (e.g., by drinking water). Plasma osmolality is low- lated from the amount of solute present (7,980 3,990 ered, and water moves into the cell compartment along the 1,580 mOsm) divided by the final volume (28 14 1 L); osmotic gradient. The entry of water into the cells causes it is equal to 315 mOsm/kg H 2 O. The final volume of the them to swell, and intracellular osmolality falls until a new ICF equals 7,980 mOsm divided by 315 mOsm/kg H 2 O or equilibrium (solid lines) is achieved. Since 2 L of water were 25.3 L, which is 2.7 L less than the initial volume. The final Osmolality (mOsm/kg H 2 O)285 ICF ECF Osmolality (mOsm/kg H 2 O) 272 ICF ECF 0 0 044 02842 29.3 Volume (L) Volume (L) A Normal B Add 2.0 L pure H 2 O 315 Osmolality (mOsm/kg H 2 O)285 ICF ECF Osmolality (mOsm/kg H 2 O) ICF ECF bances on the osmolalities and Effects of vari- FIGURE 24.2 ous distur- volumes of intracellular fluid (ECF). The dashed lines indicate the normal condition; the solid 0 0 (ICF) and extracellular fluid 02844 25.3 43 lines, the situation after a new os- 0 Volume (L) Volume (L) motic equilibrium has been at- C Add 2.0 L isotonic saline D Add 1.0 L 5% NaCl solution tained. (See text for details.)
408 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS volume of the ECF is 17.7 L, which is 3.7 L more than its ini- and higher metabolic rate. They are much more susceptible tial value. The addition of hypertonic saline to the ECF, to volume depletion. therefore, led to its considerable expansion mostly because of loss of water from the cell compartment. Arginine Vasopressin Is Critical in the Control of Renal Water Output and Plasma Osmolality WATER BALANCE Arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), is a nonapeptide synthesized in the body People normally stay in a stable water balance; that is, wa- ter input and output are equal. There are three major as- of nerve cells located in the supraoptic and paraventricular pects to the control of water balance: arginine vasopressin, nuclei of the anterior hypothalamus (Fig. 24.3) (see Chap- excretion of water by the kidneys, and habit and thirst. ter 32). The hormone travels by axoplasmic flow down the hypothalamic-neurohypophyseal tract and is stored in vesi- cles in nerve terminals in the median eminence and, mostly, Water Input and Output Are Equal the posterior pituitary. When the cells are brought to threshold, they rapidly fire action potentials, Ca 2 enters A balance chart for water for an average 70-kg man is pre- the nerve terminals, the AVP-containing vesicles release sented in Table 24.3. The person is in a stable balance (or their contents into the interstitial fluid surrounding the steady state) because the total input and total output of wa- nerve terminals, and AVP diffuses into nearby capillaries. ter from the body are equal (2,500 mL/day). On the input The hormone is carried by the blood stream to its target tis- side, water is found in the beverages we drink and in the sue, the collecting ducts of the kidneys, where it increases foods we eat. Solid foods, which consist of animal or veg- water reabsorption (see Chapter 23). etable matter, are, like our own bodies, mostly water. Wa- ter of oxidation is produced during metabolism; for exam- Factors Affecting AVP Release. Many factors influence ple, when 1 mol of glucose is oxidized, 6 mol of water are the release of AVP, including pain, trauma, emotional produced. In a hospital setting, the input of water as a result stress, nausea, fainting, most anesthetics, nicotine, mor- of intravenous infusions would also need to be considered. phine, and angiotensin II. These conditions or agents pro- On the output side, losses of water occur via the skin, lungs, duce a decline in urine output and more concentrated urine. gastrointestinal tract, and kidneys. We always lose water by Ethanol and atrial natriuretic peptide inhibit AVP release, simple evaporation from the skin and lungs; this is called in- leading to the excretion of a large volume of dilute urine. sensible water loss. The main factor controlling AVP release under ordinary Appreciable water loss from the skin, in the form of circumstances is a change in plasma osmolality. Figure 24.4 sweat, occurs at high temperatures or with heavy exercise. shows how plasma AVP concentrations vary as a function As much as 4 L of water per hour can be lost in sweat. of plasma osmolality. When plasma osmolality rises, neu- Sweat, which is a hypoosmotic fluid, contains NaCl; exces- rons called osmoreceptor cells, located in the anterior hy- sive sweating can lead to significant losses of salt. Gas- pothalamus, shrink. This stimulates the nearby neurons in trointestinal losses of water are normally small (see Table 24.3), but with diarrhea, vomiting, or drainage of gastroin- testinal secretions, massive quantities of water and elec- Paraventricular nucleus trolytes may be lost from the body. The kidneys are the sites of adjustment of water output Supraoptic nucleus from the body. Renal water excretion changes to maintain Posterior balance. If there is a water deficiency, the kidneys diminish Anterior hypothalamus hypothalamus the excretion of water and urine output falls. If there is wa- Hypothalamic ter excess, the kidneys increase water excretion and urine Optic neurohypophyseal tract flow to remove the extra water. The renal excretion of wa- chiasm Hypophyseal ter is controlled by arginine vasopressin. stalk The water needs of an infant or young child, per kg body weight, are several times higher than that of an adult. Chil- Median Mammillary dren have, for their body weight, a larger body surface area eminence body Pars tuberalis Pars Central intermedia Daily Water Balance in an Average cavity TABLE 24.3 Pars 70-kg Man Pars nervosa anterior Input Output The pituitary and hypothalamus. AVP is syn- Water in beverages 1,000 mL Skin and lungs 900 mL FIGURE 24.3 thesized primarily in the supraoptic nucleus and Water in food 1,200 mL Gastrointestinal 100 mL to a lesser extent in the paraventricular nuclei in the anterior hypo- Water of oxidation 300 mL tract (feces) thalamus. It is then transported down the hypothalamic neurohy- Kidneys (urine) 1,500 mL Total 2,500 mL Total 2,500 mL pophyseal tract and stored in vesicles in the median eminence and posterior pituitary, where it can be released into the blood.
CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 409 Thirst volume. An increased blood volume inhibits AVP release, whereas a decreased blood volume (hypovolemia) stimu- lates AVP release. Intuitively, this makes sense, since with 12 excess volume, a low plasma AVP level would promote the excretion of water by the kidneys. With hypovolemia, a high plasma AVP level would promote conservation of wa- ter by the kidneys. The receptors for blood volume include stretch recep- tors in the left atrium of the heart and in the pulmonary Plasma AVP (pg/mL) impulses transmitted to the brain via vagal afferents and in- 8 veins within the pericardium. More stretch results in more hibition of AVP release. The common experiences of pro- ducing a large volume of dilute urine, a water diuresis— when lying down in bed at night, when exposed to cold weather, or when immersed in a pool during the summer— 4 may be related to activation of this pathway. In all of these situations, the atria are stretched by an increased central blood volume. Arterial baroreceptors in the carotid sinuses and aortic arch also reflexly change AVP release; a fall in pressure at these sites stimulates AVP release. Finally, a de- crease in renal blood flow stimulates renin release, which leads to increased angiotensin II production. Angiotensin II stimulates AVP release by acting on the brain. 270 280 290 300 310 Relatively large blood losses (more than 10% of blood Plasma osmolality (mOsm/kg H 2 O) volume) are required to increase AVP release (Fig. 24.6). The relationship between plasma AVP level With a loss of 15 to 20% of blood volume, however, large FIGURE 24.4 and plasma osmolality in healthy people. increases in plasma AVP are observed. Plasma levels of AVP Decreases in plasma osmolality were produced by drinking water may rise to levels much higher (e.g., 50 pg/mL) than are and increases by fluid restriction. Plasma AVP levels were meas- needed to concentrate the urine maximally (e.g., 5 pg/mL). ured by radioimmunoassay. At plasma osmolalities below 280 (Compare Figures 24.5 and 24.6.) With severe hemorrhage, mOsm/kg H 2 O, plasma AVP is decreased to low or undetectable high circulating levels of AVP exert a significant vasocon- levels. Above this threshold, plasma AVP increases linearly with strictor effect, which helps compensate by raising the plasma osmolality. Normal plasma osmolality is about 285 to 287 mOsm/kg H 2 O, so we live above the threshold for AVP release. blood pressure. The thirst threshold is attained at a plasma osmolality of 290 mOsm/kg H 2 O, so the thirst mechanism “kicks in” only when there is an appreciable water deficit. Changes in plasma AVP and consequent changes in renal water excretion are normally capable 1,400 of maintaining a normal plasma osmolality below the thirst threshold. (From Robertson GL, Aycinena P, Zerbe RL. Neuro- 1,200 genic disorders of osmoregulation. Am J Med 1982;72:339–353.) 1,000 the paraventricular and supraoptic nuclei to release AVP, Urine osmolaity (mOsm/kg H 2 O) 800 and plasma AVP concentration rises. The result is the for- mation of osmotically concentrated urine. Not all solutes 600 are equally effective in stimulating the osmoreceptor cells; for example, urea, which can enter these cells and, there- 400 fore, does not cause the osmotic withdrawal of water, is in- effective. Extracellular NaCl, however, is an effective stim- 200 ulus for AVP release. When plasma osmolality falls in response to the addition of excess water, the osmoreceptor 0 cells swell, AVP release is inhibited, and plasma AVP levels 0 1 2 3 4 5 10 15 fall. In this situation, the collecting ducts express their in- Plasma AVP (pg/mL) trinsically low water permeability, less water is reabsorbed, a dilute urine is excreted, and plasma osmolality can be re- FIGURE 24.5 The relationship between urine osmolality stored to normal by elimination of the excess water. Figure and plasma AVP levels. With low plasma 24.5 shows that the entire range of urine osmolalities, from AVP levels, a hypoosmotic (compared to plasma) urine is ex- creted and, with high plasma AVP levels, a hyperosmotic urine is dilute to concentrated urines, is a linear function of plasma excreted. Note that maximally concentrated urine (1,200 to 1,400 AVP in healthy people. mOsm/kg H 2O) is produced when the plasma AVP level is about A second important factor controlling AVP release is the 5 pg/mL. (From Robertson GL, Aycinena P, Zerbe RL. Neuro- blood volume—more precisely, the effective arterial blood genic disorders of osmoregulation. Am J Med 1982;72:339–353.)
410 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS AVP levels are low, and a large volume of dilute urine (up 50 to 20 L/day) is excreted. In nephrogenic diabetes in- 45 sipidus, the collecting ducts are partially or completely un- responsive to AVP. Urine output is increased, but the 40 plasma AVP level is usually higher than normal (secondary to excessive loss of dilute fluid from the body). Nephro- 35 Plasma AVP (pg/mL) 30 such as lithium) or inherited. Mutations in the collecting genic diabetes insipidus may be acquired (e.g., via drugs duct AVP receptor gene or in the water channel (aqua- 25 porin-2) gene have now been identified in some families. In 20 the syndrome of inappropriate secretion of ADH 15 the existing osmolality. Plasma osmolality is low because 10 (SIADH), plasma AVP levels are inappropriately high for the kidneys form concentrated urine and save water. This 5 condition is sometimes caused by a bronchogenic tumor 0 that produces AVP in an uncontrolled fashion. 0 5 10 15 20 Habit and Thirst Govern Water Intake Blood volume depletion (%) People drink water largely from habit, and this water intake The relationship between plasma AVP and FIGURE 24.6 normally covers an individual’s water needs. Most of the blood volume depletion in the rat. Note that severe hemorrhage (a loss of 20% of blood volume) causes a time, we operate below the threshold for thirst. Thirst, a striking increase in plasma AVP. In this situation, the vasocon- conscious desire to drink water, is mainly an emergency strictor effect of AVP becomes significant and counteracts the mechanism that comes into play when there is a perceived low blood pressure. (From Dunn FL, Brennan TJ, Nelson AE, water deficit. Its function is obviously to encourage water Robertson GL. The role of blood osmolality and volume in regu- intake to repair the water deficit. The thirst center is lo- lating vasopressin secretion in the rat. J Clin Invest cated in the anterior hypothalamus, close to the neurons 1973;52:3212–3219) that produce and control AVP release. This center relays impulses to the cerebral cortex, so that thirst becomes a conscious sensation. Interaction Between Stimuli Affecting AVP Release. Several factors affect the thirst sensation (Fig. 24.7). The The two stimuli, plasma osmolality and blood volume, most major stimulus is an increase in osmolality of the blood, often work synergistically to increase or decrease AVP re- which is detected by osmoreceptor cells in the hypothala- lease. For example, a great excess of water intake in a mus. These cells are distinct from those that affect AVP re- healthy person will inhibit AVP release because of both the lease. Ethanol and urea are not effective stimuli for the os- fall in plasma osmolality and increase in blood volume. In moreceptors because they readily penetrate these cells and certain important clinical circumstances, however, there is do not cause them to shrink. NaCl is an effective stimulus. a conflict between these two inputs. For example, severe An increase in plasma osmolality of 1 to 2% (i.e., about 3 to congestive heart failure is characterized by a decrease in the 6 mOsm/kg H 2 O) is needed to reach the thirst threshold. effective arterial blood volume, even though total blood Hypovolemia or a decrease in the effective arterial volume is greater than normal. This condition results be- blood volume stimulates thirst. Blood volume loss must be cause the heart does not pump sufficient blood into the ar- considerable for the thirst threshold to be reached; most terial system to maintain adequate tissue perfusion. The ar- blood donors do not become thirsty after donating 500 mL terial baroreceptors signal less volume, and AVP release is of blood (10% of blood volume). A larger blood loss (15 to stimulated. The patient will produce osmotically concen- 20% of blood volume), however, evokes intense thirst. A trated urine and will also be thirsty from the decreased ef- decrease in effective arterial blood volume as a result of se- fective arterial blood volume, with consequent increased vere diarrhea, vomiting, or congestive heart failure may water intake. The combination of decreased renal water ex- also provoke thirst. cretion and increased water intake leads to hypoosmolality The receptors for blood volume that stimulate thirst in- of the body fluids, which is reflected in a low plasma [Na ] clude the arterial baroreceptors in the carotid sinuses and or hyponatremia. Despite the hypoosmolality, plasma AVP aortic arch and stretch receptors in the cardiac atria and levels remain elevated and thirst persists. It appears that great veins in the thorax. The kidneys may also act as vol- maintaining an effective arterial blood volume is of over- ume receptors. When blood volume is decreased, the kid- riding importance, so osmolality may be sacrificed in this neys release renin into the circulation. This results in pro- condition. The hypoosmolality creates new problems, such duction of angiotensin II, which acts on neurons near the as the swelling of brain cells. Hyponatremia is discussed in third ventricle of the brain to stimulate thirst. Clinical Focus Box 24.1. The thirst sensation is reinforced by dryness of the mouth and throat, which is caused by a reflex decrease in se- Clinical AVP Disorders. Neurogenic diabetes insipidus cretion by salivary and buccal glands in a water-deprived (central, hypothalamic, pituitary) is a condition character- person. The gastrointestinal tract also monitors water in- ized by a deficient production or release of AVP. Plasma take. Moistening of the mouth or distension of the stomach,
CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 411 CLINICAL FOCUS BOX 24.1 Hyponatremia effective arterial blood volume stimulates thirst and AVP Hyponatremia, defined as a plasma [Na ] 135 mEq/L, release. Excretion of a dilute urine may also be impaired is the most common disorder of body fluid and electrolyte because of decreased delivery of fluid to diluting sites balance in hospitalized patients. Most often it reflects too along the nephron and collecting ducts. Although Na and much water, not too little Na , in the plasma. Since Na is water are retained by the kidneys in the edematous states, the major solute in the plasma, it is not surprising that hy- relatively more water is conserved, leading to a dilutional ponatremia is usually associated with hypoosmolality. Hy- hyponatremia. ponatremia, however, may also occur with a normal or Hyponatremia and hypoosmolality can cause a variety even elevated plasma osmolality. of symptoms, including muscle cramps, lethargy, fatigue, Drinking large quantities of water (20 L/day) rarely disorientation, headache, anorexia, nausea, agitation, hy- causes frank hyponatremia because of the large capacity pothermia, seizures, and coma. These symptoms, mainly of the kidneys to excrete dilute urine. If, however, plasma neurological, are a consequence of the swelling of brain AVP is not decreased when plasma osmolality is de- cells as plasma osmolality falls. Excessive brain swelling creased or if the ability of the kidneys to dilute the urine is may be fatal or may cause permanent damage. Treatment impaired, hyponatremia may develop even with a normal requires identifying and treating the underlying cause. If water intake. Na loss is responsible for the hyponatremia, isotonic or Hyponatremia with hypoosmolality can occur in the hypertonic saline or NaCl by mouth is usually given. If the presence of a decreased, normal, or even increased total blood volume is normal or the patient is edematous, water body Na . Hyponatremia and decreased body Na content restriction is recommended. Hyponatremia should be cor- may be seen with increased Na loss, such as with vomit- rected slowly and with constant monitoring because too ing, diarrhea, and diuretic therapy. In these instances, the rapid correction can be harmful. decrease in ECF volume stimulates thirst and AVP release. Hyponatremia in the presence of increased plasma os- More water is ingested, but the kidneys form osmotically molality is seen in hyperglycemic patients with uncon- concentrated urine and plasma hypoosmolality and hy- trolled diabetes mellitus. In this condition, the high plasma ponatremia result. Hyponatremia and a normal body Na [glucose] causes the osmotic withdrawal of water from content are seen in hypothyroidism, cortisol deficiency, cells, and the extra water in the ECF space leads to hy- and the syndrome of inappropriate secretion of antidi- ponatremia. Plasma [Na ] falls by 1.6 mEq/L for each 100 uretic hormone (SIADH). SIADH occurs with neurological mg/dL rise in plasma glucose. disease, severe pain, certain drugs (such as hypoglycemic Hyponatremia and a normal plasma osmolality are seen agents), and with some tumors. For example, a bron- with so-called pseudohyponatremia. This occurs when chogenic tumor may secrete AVP without control by plasma lipids or proteins are greatly elevated. These mole- plasma osmolality. The result is renal conservation of wa- cules do not significantly elevate plasma osmolality. They ter. Hyponatremia and increased total body Na are seen do, however, occupy a significant volume of the plasma, in edematous states, such as congestive heart failure, he- and because the Na is dissolved only in the plasma water, patic cirrhosis, and nephrotic syndrome. The decrease in the [Na ] measured in the entire plasma is low. for example, inhibit thirst, preventing excessive water in- the mouth and stomach in this situation limits water intake, take. For example, if a dog is deprived of water for some time preventing a dip in plasma osmolality below normal. and is then presented with water, it will commence drinking but will stop before all of the ingested water has been ab- sorbed by the small intestine. Monitoring of water intake by SODIUM BALANCE Na is the most abundant cation in the ECF and, with its accompanying anions Cl and HCO 3 , largely determines Plasma Blood the osmolality of the ECF. Because the osmolality of the osmolality volume ECF is closely regulated by AVP, the kidneys, and thirst, the amount of water in (and, hence, the volume of) the ECF Osmoreceptors Baroreceptors compartment is mainly determined by its Na content. ++ The kidneys are primarily involved in the regulation of Thirst + Renin Na balance. We consider first the renal mechanisms in- + volved in Na excretion and then overall Na balance. Angiotensin II Dryness of Monitoring of The Kidneys Excrete Only a Small Percentage mouth and throat water intake of the Filtered Na Load by GI tract Table 24.4 shows the magnitude of filtration, reabsorption, Factors affecting the thirst sensation. A plus and excretion of ions and water for a healthy adult man on FIGURE 24.7 sign indicates stimulation of thirst, the minus an average American diet. The amount of Na filtered was sign indicates an inhibitory influence. calculated from the product of the plasma [Na ] and
412 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS Magnitude of Daily Filtration, Reabsorption, and Excretion of Ions and Water in a Healthy Young Man TABLE 24.4 on a Typical American Diet [Plasma] GFR Filtered Excreted Reabsorbed % (mEq/L) (L/day) (mEq/day) (mEq/day) (mEq/day) Reabsorbed Sodium 140 180 25,200 100 25,100 99.6 Chloride 105 180 18,900 100 18,800 99.5 Bicarbonate 24 180 4,320 2 4318 99.9 Potassium 4 180 720 L/day 100 L/day 620 L/day 86.1 Water 0.93 a 180 167 1.5 165.5 99.1 a Plasma contains about 0.93 L H 2O per L. glomerular filtration rate (GFR). The quantity of Na reab- filtered Na , together with the same percentage of filtered sorbed was calculated from the difference between filtered water, is reabsorbed in the proximal convoluted tubule. and excreted amounts. Note that 99.6% (25,10025,200) The loop of Henle reabsorbs about 20% of filtered Na , of the filtered Na was reabsorbed or, in other words, per- but only 10% of filtered water. The distal convoluted centage excretion of Na was only 0.4% of the filtered load. tubule reabsorbs about 6% of filtered Na (and no water), In terms of overall Na balance for the body, the quantity and the collecting ducts reabsorb about 3% of the filtered of Na excreted by the kidneys is of key importance be- Na (and 19% of the filtered water). Only about 1% of the cause ordinarily about 95% of the Na we consume is ex- filtered Na (and water) is usually excreted. The distal creted by way of the kidneys. Tubular reabsorption of Na nephron (distal convoluted tubule, connecting tubule, and must be finely regulated to keep us in Na balance. collecting duct) has a lower capacity for Na transport Figure 24.8 shows the percentage of filtered Na reab- than more proximal segments and can be overwhelmed if sorbed in different parts of the nephron. Seventy percent of too much Na fails to be reabsorbed in proximal segments. The distal nephron is of critical importance in determining the final excretion of Na . Distal Proximal convoluted convoluted 70% tubule 6% Many Factors Affect Renal Na Excretion tubule Multiple factors affect renal Na excretion; these are dis- 100% cussed below. A factor may promote Na excretion either by increasing the amount of Na filtered by the glomeruli or by decreasing the amount of Na reabsorbed by the kid- ney tubules or, in some cases, by affecting both processes. Glomerular Filtration Rate. Na excretion tends to Space of Collecting change in the same direction as GFR. If GFR rises—for ex- Bowman's duct capsule 20% ample, from an expanded ECF volume—the tubules reabsorb the increased filtered load less completely, and Na excre- tion increases. If GFR falls—for example, as a result of blood loss—the tubules can reabsorb the reduced filtered Na load more completely, and Na excretion falls. These changes are 3% of obvious benefit in restoring a normal ECF volume. Small changes in GFR could potentially lead to massive changes in Na excretion, if it were not for a phenomenon called glomerulotubular balance (Table 24.5). There is a balance between the amount of Na filtered and the amount of Na reabsorbed by the tubules, so the tubules Loop of Henle increase the rate of Na reabsorption when GFR is in- creased and decrease the rate of Na reabsorption when GFR is decreased. This adjustment is a function of the prox- imal convoluted tubule and the loop of Henle, and it re- duces the impact of changes in GFR on Na excretion. 1% Urine The Renin-Angiotensin-Aldosterone System. Renin is a The percentage of the filtered load of Na proteolytic enzyme produced by granular cells, which are FIGURE 24.8 reabsorbed along the nephron. About 1% of located in afferent arterioles in the kidneys (see Fig. 23.4). the filtered Na is usually excreted. There are three main stimuli for renin release:
CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 413 Angiotensin II is also a potent vasoconstrictor of both TABLE 24.5 Glomerulotubular Balance a resistance and capacitance vessels; increased plasma levels following hemorrhage, for example, help sustain blood Filtered Na Reabsorbed Na pressure. Inhibiting angiotensin II production by giving an Excreted Na ACE inhibitor lowers blood pressure and is used in the treatment of hypertension. Period (mEq/min) (mEq/min) (mEq/min) The RAAS plays an important role in the day-to-day 1 6.00 5.95 0.05 control of Na excretion. It favors Na conservation by Increase GFR by one third the kidneys when there is a Na or volume deficit in the 2 8.00 7.90 0.10 body. When there is an excess of Na or volume, dimin- a Results from an experiment performed on a 10-kg dog. Note that in ished RAAS activity permits enhanced Na excretion. In response to an increase in GFR (produced by infusing a drug that di- the absence of aldosterone (e.g., in an adrenalectomized lated afferent arterioles), tubular reabsorption of Na increased, so that individual) or in a person with adrenal cortical insuffi- only a modest increase in Na excretion occurred. If there had been no glomerulotubular balance and if tubular Na reabsorption had ciency—Addison’s disease—excessive amounts of Na are stayed at 5.95 mEq/min, the kidneys would have excreted 2.05 lost in the urine. Percentage reabsorption of Na may de- mEq/min in period 2. If we assume that the ECF volume in the dog is 2 crease from a normal value of about 99.6% to a value of L (20% of body weight) and if plasma [Na ] is 140 mEq/L, an excre- 98%. This change (1.6% of the filtered Na load) may not tion rate of 2.05 mEq/min would result in excretion of the entire ECF seem like much, but if the kidneys filter 25,200 mEq/day Na (280 mEq) in a little more than 2 hours. The dog would have been dead long before this could happen, which underscores the im- (see Table 24.4) and excrete an extra 0.016 25,200 portance of glomerulotubular balance. 403 mEq/day, this is the amount of Na in almost 3 L of ECF (assuming a [Na ] of 140 mEq/L). Such a loss of Na would lead to a decrease in plasma and blood volume, cir- 1) A decrease in pressure in the afferent arteriole, with culatory collapse, and even death. the granular cells being sensitive to stretch and function as When there is an extra need for Na , people and many an intrarenal baroreceptor animals display a sodium appetite, an urge for salt intake, 2) Stimulation of sympathetic nerve fibers to the kid- which can be viewed as a brain mechanism, much like neys via 2-adrenergic receptors on the granular cells thirst, that helps compensate for a deficit. Patients with Ad- 3) A decrease in fluid delivery to the macula densa re- dison’s disease often show a well-developed sodium ap- gion of the nephron, resulting, for example, from a decrease petite, which helps keep them alive. in GFR Large doses of a potent mineralocorticoid will cause a All three of these pathways are activated and reinforce person to retain about 200 to 300 mEq Na (equivalent to each other when there is a decrease in the effective arterial about 1.4 to 2 L of ECF), and the person will “escape” from blood volume—for example, following hemorrhage, tran- the salt-retaining action of the steroid. Retention of this sudation of fluid out of the vascular system, diarrhea, severe amount of fluid is not sufficient to produce obvious edema. sweating, or a low salt intake. Conversely, an increase in The fact that the person will not continue to accumulate the effective arterial blood volume inhibits renin release. Na and water is due to the existence of numerous factors Long-term stimulation causes vascular smooth muscle cells that are called into play when ECF volume is expanded; in the afferent arteriole to differentiate into granular cells these factors promote renal Na excretion and overpower and leads to further increases in renin supply. Renin in the the salt-retaining action of aldosterone. This phenomenon blood plasma acts on a plasma 2-globulin produced by the is called mineralocorticoid escape. liver, called angiotensinogen (or renin substrate) and splits off the decapeptide angiotensin I (Fig. 24.9). Angiotensin I Intrarenal Physical Forces (Peritubular Capillary Starling is converted to the octapeptide angiotensin II as the blood Forces). An increase in the hydrostatic pressure or a de- courses through the lungs. This reaction is catalyzed by the crease in the colloid osmotic pressure in peritubular capil- angiotensin-converting enzyme (ACE), which is present laries (the so-called “physical” or Starling forces) results in on the surface of endothelial cells. All the components of reduced fluid uptake by the capillaries. In turn, an accumu- this system (renin, angiotensinogen, angiotensin-convert- lation of the reabsorbed fluid in the kidney interstitial ing enzyme) are present in some organs (e.g., the kidneys spaces results. The increased interstitial pressure causes a and brain), so that angiotensin II may also be formed and widening of the tight junctions between proximal tubule act locally. cells, and the epithelium becomes even more leaky than The renin-angiotensin-aldosterone system (RAAS) is a normal. The result is increased back-leak of salt and water salt-conserving system. Angiotensin II has several actions into the tubule lumen and an overall reduction in net reab- related to Na and water balance: sorption. These changes occur, for example, if a large vol- 1) It stimulates the production and secretion of the al- ume of isotonic saline is infused intravenously. They also dosterone from the zona glomerulosa of the adrenal cortex occur if the filtration fraction (GFR/RPF) is lowered from (see Chapter 36). This mineralocorticoid hormone then the dilation of efferent arterioles, for example. In this case, acts on the distal nephron to increase Na reabsorption. the protein concentration (or colloid osmotic pressure) in 2) Angiotensin II directly stimulates tubular Na reab- efferent arteriolar blood and peritubular capillary blood is sorption. lower than normal because a smaller proportion of the 3) Angiotensin stimulates thirst and the release of AVP plasma is filtered in the glomeruli. Also, with upstream va- by the posterior pituitary. sodilation of efferent arterioles, hydrostatic pressure in the
414 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS Angiotensinogen Liver Renin Kidney Angiotensin I Decreased effective arterial blood volume Converting enzyme Lungs Angiotensin II Normal effective arterial blood volume Thirst Blood vessels Adrenal Brain cortex H 2 O Vasoconstriction Aldosterone AVP intake Blood pressure Sodium H O 2 reabsorption reabsorption Components of the renin-angiotensin-aldos- hemorrhage) and results in compensatory changes that help re- FIGURE 24.9 terone system. This system is activated by a store arterial blood pressure and blood volume to normal. decrease in the effective arterial blood volume (e.g., following peritubular capillaries is increased, leading to a pressure na- cGMP. ANP directly inhibits aldosterone secretion by the triuresis and pressure diuresis. The term natriuresis means adrenal cortex; it also indirectly inhibits aldosterone secre- an increase in Na excretion. tion by diminishing renal renin release. ANP is a vasodila- tor and, therefore, lowers blood pressure. Some evidence Natriuretic Hormones and Factors. Atrial natriuretic suggests that ANP inhibits AVP secretion. The actions of peptide (ANP) is a 28 amino acid polypeptide synthesized ANP are, in many respects, just the opposite of those of the and stored in myocytes of the cardiac atria (Fig. 24.10). It RAAS; ANP promotes salt and water loss by the kidneys is released upon stretch of the atria—for example, follow- and lowers blood pressure. ing volume expansion. This hormone has several actions Several other natriuretic hormones and factors have been that increase Na excretion. ANP acts on the kidneys to in- described. Urodilatin (kidney natriuretic peptide) is a 32- crease glomerular blood flow and filtration rate and inhibits amino acid polypeptide derived from the same prohormone Na reabsorption by the inner medullary collecting ducts. as ANP. It is synthesized primarily by intercalated cells in The second messenger for ANP in the collecting duct is the cortical collecting duct and secreted into the tubule lu-
CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 415 tory drugs (NSAIDs), such as aspirin, may lead to a fall in Atrial renal blood flow and to Na retention. stretch Volume expansion Renal Sympathetic Nerves. The stimulation of renal sympathetic nerves reduces renal Na excretion in at least Heart three ways: 1) It produces a decline in GFR and renal blood flow, + leading to a decreased filtered Na load and peritubular capillary hydrostatic pressure, both of which favor dimin- Atrial natriuretic peptide ished Na excretion. 2) It has a direct stimulatory effect on Na reabsorp- tion by the renal tubules. 3) It causes renin release, which results in increased plasma angiotensin II and aldosterone levels, both of which Blood vessels Kidney increase tubular Na reabsorption. Adrenal Activation of the sympathetic nervous system occurs in cortex several stressful circumstances (such as hemorrhage) in which the conservation of salt and water by the kidneys is of clear benefit. Vasodilation Aldosterone Natriuresis Diuresis Estrogens. Estrogens decrease Na excretion, probably Angiotensin II Renin by the direct stimulation of tubular Na reabsorption. Most women tend to retain salt and water during pregnancy, Atrial natriuretic peptide and its actions. FIGURE 24.10 which may be partially related to the high plasma estrogen ANP release from the cardiac atria is stimulated levels during this time. by blood volume expansion, which stretches the atria. ANP pro- duces effects that bring blood volume back toward normal, such Glucocorticoids. Glucocorticoids, such as cortisol (see as increased Na excretion. Chapter 34), increase tubular Na reabsorption and also cause an increase in GFR, which may mask the tubular ef- men, inhibiting Na reabsorption by inner medullary col- fect. Usually a decrease in Na excretion is seen. lecting ducts via cGMP. There is also a brain natriuretic peptide. Guanylin and uroguanylin are polypeptide hor- Osmotic Diuretics. Osmotic diuretics are solutes that are mones produced by the small intestine in response to salt in- excreted in the urine and increase urinary excretion of Na gestion. Like ANP and urodilatin, they activate guanylyl cy- and K salts and water. Examples are urea, glucose (when clase and produce cGMP as a second messenger, as their the reabsorptive capacity of the tubules for glucose has names suggest. Adrenomedullin is a polypeptide produced been exceeded), and mannitol (a six-carbon sugar alcohol by the adrenal medulla; its physiological significance is still used in the clinic to promote Na excretion or cell shrink- not certain. Endoxin is an endogenous digitalis-like sub- age). Osmotic diuretics decrease the reabsorption of Na stance produced by the adrenal gland. It inhibits Na /K - in the proximal tubule. This response results from the de- ATPase activity and, therefore, inhibits Na transport by velopment of a Na concentration gradient (lumen [Na ] the kidney tubules. Bradykinin is produced locally in the plasma Na ]) across the proximal tubular epithelium in kidneys and inhibits Na reabsorption. the presence of a high concentration of unreabsorbed Prostaglandins E 2 and I 2 (prostacyclin) increase Na solute in the tubule lumen. When this occurs, there is sig- excretion by the kidneys. These locally produced hor- nificant back-leak of Na into the tubule lumen, down the mones are formed from arachidonic acid, which is liberated concentration gradient. This back-leak results in decreased from phospholipids in cell membranes by the enzyme net Na reabsorption. Because the proximal tubule is where phospholipase A 2. Further processing is mediated by a cy- most of the filtered Na is normally reabsorbed, osmotic clooxygenase (COX) enzyme that has two isoforms, COX- diuretics, by interfering with this process, can potentially 1 and COX-2. In most tissues, COX-1 is constitutively ex- cause the excretion of large amounts of Na . Osmotic di- pressed, while COX-2 is generally induced by uretics may also increase Na excretion by inhibiting distal inflammation. In the kidney, COX-1 and COX-2 are both Na reabsorption (similar to the proximal inhibition) and constitutively expressed in cortex and medulla. In the cor- by increasing medullary blood flow. tex, COX-2 may be involved in macula densa-mediated renin release. COX-1 and COX-2 are present in high Poorly Reabsorbed Anions. Poorly reabsorbed anions amounts in the renal medulla, where the main role of the result in increased Na excretion. Solutions are electrically prostaglandins is to inhibit Na reabsorption. Because the neutral; whenever there are more anions in the urine, there prostaglandins (PGE 2, PGI 2) are vasodilators, the inhibi- must also be more cations. If there is increased excretion of tion of Na reabsorption occurs via direct effects on the phosphate, ketone body acids (as occurs in uncontrolled di- 2– tubules and collecting ducts and via hemodynamic effects abetes mellitus), HCO 3 , or SO 4 , more Na is also ex- (see Chapter 23). Inhibition of the formation of creted. To some extent, the Na in the urine can be re- prostaglandins with common nonsteroidal anti-inflamma- placed by other cations, such as K , NH 4 , and H .
416 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS Diuretic Drugs. Most of the diuretic drugs used today are Regulated variable specific Na transport inhibitors. For example, the loop di- Extracellular fluid volume uretic drugs (furosemide, bumetanide) inhibit the Na-K- or EABV 2Cl cotransporter in the thick ascending limb, the thiazide diuretics inhibit the Na-Cl cotransporter in the distal con- + voluted tubule, and amiloride blocks the epithelial Na Renal Sensor channel in the collecting ducts (see Chapter 23). Spirono- Na + Cardiovascular lactone promotes Na excretion by competitively inhibit- excretion stretch receptors, kidneys ing the binding of aldosterone to the mineralocorticoid re- + ceptor. The diuretic drugs are really natriuretic drugs; they produce an increased urine output (diuresis) because water Effector + reabsorption is diminished whenever Na reabsorption is Kidneys decreased. Diuretics are commonly prescribed for treating 1. GFR hypertension and edema. 2. Aldosterone 3. Intrarenal physical forces 4. Natriuretic hormones and factors 5. Sympathetic nerve activity The Kidneys Play a Dominant Role in Regulating Na1 Balance The regulation of ECF volume or effective FIGURE 24.12 Figure 24.11 summarizes Na balance throughout the arterial blood volume (EABV) by a nega- body. Dietary intake of Na varies and, in a typical Amer- tive-feedback control system. Arterial baroreceptors and the kidneys sense the degree of fullness of the arterial system. The ican diet, amounts to about 100 to 300 mEq/day, mostly in kidneys are the effectors, and they change Na excretion to re- the form of NaCl. Ingested Na is mainly absorbed in the store EABV to normal. small intestine and is added to the ECF, where it is the ma- jor determinant of the osmolality and the amount of water in (or volume of) this fluid compartment. About 50% of the In a healthy individual, one can think of the ECF volume body’s Na is in the ECF, about 40% in bone, and about as the regulated variable in a negative-feedback control sys- 10% within cells. tem (Fig. 24.12). The kidneys are the effectors, and they Losses of Na occur via the skin, gastrointestinal tract, change Na excretion in an appropriate manner. An in- and kidneys. Skin losses are usually small, but can be con- crease in ECF volume promotes renal Na loss, which re- siderable with sweating, burns, or hemorrhage. Likewise, stores a normal volume. A decrease in ECF volume leads to gastrointestinal losses are usually small, but they can be decreased renal Na excretion, and this Na retention large and serious with vomiting, diarrhea, or iatrogenic suc- (with continued dietary Na intake) leads to the restora- tion or drainage of gastrointestinal secretions. The kidneys tion of a normal ECF volume. Closer examination of this are ordinarily the major routes of Na loss from the body, concept, particularly when considering pathophysiological excreting about 95% of the ingested Na in a healthy per- states, however, suggests that it is of limited usefulness. A son. Thus, the kidneys play a dominant role in the control more considered view suggests that the effective arterial of Na balance. The kidneys can adjust Na excretion over blood volume (EABV) is actually the regulated variable. In a wide range, reducing it to low levels when there is a Na a healthy individual, ECF volume and EABV usually change deficit and excreting more Na when there is Na excess together in the same direction. In an abnormal condition in the body. Adjustments in Na excretion occur by en- such as congestive heart failure, however, EABV is low gaging many of the factors previously discussed. when the ECF volume is abnormally increased. In this con- dition, there is a potent stimulus for renal Na retention that clearly cannot be the ECF volume. When EABV is diminished, the degree of fullness of the arterial system is less than normal and tissue blood flow is Ingested Na + inadequate. Arterial baroreceptors in the carotid sinuses 100 300 mEq/day and aortic arch sense the decreased arterial stretch. This Input will produce reflex activation of sympathetic nerve fibers to the kidneys, with consequently decreased GFR and renal blood flow and increased renin release. These changes fa- Bone Na + Extracellular Intracellular vor renal Na retention. Reduced EABV is also “sensed” in + 1,800 mEq fluid Na fluid Na + the kidneys in three ways: 2,000 mEq 400 mEq 1) A low pressure at the level of the afferent arteriole stimulates renin release via the intrarenal baroreceptor Output mechanism. 2) Decreases in renal perfusion pressure lead to a re- Skin Gastrointestinal losses Kidneys (sweat, burns, (diarrhea, vomiting) duced GFR and, hence, diminished Na excretion. hemorrhage) 3) Decreases in renal perfusion pressure will also re- duce peritubular capillary hydrostatic pressure, increas- Na balance. Most of the Na consumed in ing the uptake of reabsorbed fluid and diminishing Na FIGURE 24.11 our diets is excreted by the kidneys. excretion.
CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 417 When kidney perfusion is threatened, the kidneys re- The distribution of K across plasma membranes—that tain salt and water, a response that tends to improve their is, the ratio of intracellular to extracellular K concentra- perfusion. tions—is the major determinant of the resting membrane po- In several important diseases, including heart and liver tential of cells and, hence, their excitability (see Chapter 3). and some kidney diseases, abnormal renal retention of Na Disturbances of K balance often produce altered excitabil- contributes to the development of generalized edema, a ity of nerves and muscles. Low plasma [K ] leads to mem- widespread accumulation of salt and water in the interstitial brane hyperpolarization and reduced excitability; muscle spaces of the body. The condition is often not clinically ev- weakness is a common symptom. Excessive plasma K levels ident until a person has accumulated more than 2.5 to 3 L lead to membrane depolarization and increased excitability. of ECF in the interstitial space. Expansion of the interstitial High plasma K levels cause cardiac arrhythmias and, even- space has two components: (1) an altered balance of Star- tually, ventricular fibrillation, usually a lethal event. ling forces exerted across capillaries, and (2) the retention K balance is linked to acid-base balance in complex of extra salt and water by the kidneys. Total plasma volume ways (see Chapter 25). K depletion, for example, can lead is only about 3.5 L; if edema fluid were derived solely from to metabolic alkalosis, and K excess to metabolic acidosis. the plasma, hemoconcentration and circulatory shock A primary disturbance in acid-base balance can also lead to would ensue. Conservation of salt and water by the kidneys abnormal K balance. is clearly an important part of the development of general- K affects the activity of enzymes involved in carbohy- ized edema. drate metabolism and electron transport. K is needed for Patients with congestive heart failure may accumulate tissue growth and repair. Tissue breakdown or increased many liters of edema fluid, which is easily detected as protein catabolism result in a loss of K from cells. weight gain (since 1 L of fluid weighs 1 kg). Because of the effect of gravity, the ankles become swollen and pitting edema develops. As a result of heart failure, venous pressure Most of the Body’s K Is in Cells is elevated, causing fluid to leak out of the capillaries be- Total body content of K in a healthy, young adult, 70-kg cause of their elevated hydrostatic pressure. Inadequate man is about 3,700 mEq. About 2% of this, about 60 mEq, pumping of blood by the heart leads to a decrease in EABV, is in the functional ECF (blood plasma, interstitial fluid, and so the kidneys retain salt and water. Alterations in many of lymph); this number was calculated by multiplying the the factors discussed above—decreased GFR, increased plasma [K ] of 4 mEq/L times the ECF volume (20% of RAAS activity, changes in intrarenal physical forces, and body weight or 14 L). About 8% of the body’s K is in increased sympathetic nervous system activity—contribute bone, dense connective tissue, and cartilage, and another to the renal salt and water retention. To minimize the ac- 1% is in transcellular fluids. Ninety percent of the body’s cumulation of edema fluid, patients are often placed on a K is in the cell compartment. reduced Na intake and given diuretic drugs. A normal plasma [K ] is 3.5 to 5.0 mEq/L. By definition, Hypertension may often be a result of a disturbance in plasma [K ] below 3.5 mEq/L is hypokalemia and plasma NaCl (salt) balance. Excessive dietary intake of NaCl or in- [K ] above 5.0 mEq/L is hyperkalemia. The [K ] in skele- adequate renal excretion of salt tends to increase intravas- tal muscle cells is about 150 mEq/L cell water. Skeletal mus- cular volume; this change translates into an increase in cle cells constitute the largest fraction of the cell mass in blood pressure. A reduced salt intake, ACE inhibitors, di- the human body and contain about two thirds of the body’s uretic drugs, or drugs that more directly affect the cardio- K . One can easily appreciate that abnormal leakage of K vascular system (e.g., Ca 2 channel blockers or -adrener- from muscle cells, for example, as a result of trauma, may gic blockers) are useful therapies in controlling lead to dangerous hyperkalemia. hypertension in many people. A variety of factors influence the distribution of K be- tween cells and ECF (Fig. 24.13): 1) A key factor is the Na /K -ATPase, which pumps POTASSIUM BALANCE K into cells. If this enzyme is inhibited—as a result of in- adequate tissue oxygen supply or digitalis overdose, for ex- Potassium (K ) is the most abundant ion in the ICF com- ample—hyperkalemia may result. partment. It has many important effects in the body, and its 2) A decrease in ECF pH (an increase in ECF [H ]) tends plasma concentration is closely regulated. The kidneys play to produce a rise in ECF [K ]. This results from an exchange a dominant role in regulating K balance. of extracellular H for intracellular K . When a mineral acid such as HCl is added to the ECF, a fall in blood pH of 0.1 K Influences Cell Volume, Excitability, unit leads to about a 0.6 mEq/L rise in plasma [K ]. When an Acid-Base Balance, and Metabolism organic acid (which can penetrate plasma membranes) is added, the rise in plasma K for a given fall in blood pH is As the major osmotically active solute in cells, the amount considerably less. The fact that blood pH influences plasma of cellular K is the major determinant of the amount of [K ] is sometimes used in the emergency treatment of hy- water in (and, therefore, the volume of) the ICF compart- perkalemia; intravenous infusion of a NaHCO 3 solution ment, in the same way that extracellular Na is a major de- (which makes the blood more alkaline) will cause H to terminant of ECF volume. When cells lose K (and accom- move out of cells and K , in exchange, to move into cells. panying anions), they also lose water and shrink; the 3) Insulin promotes the uptake of K by skeletal mus- converse is also true. cle and liver cells. This effect appears to be a result of stim-
418 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS + Shift K to Shift K + Ingested K + outside of cells into cells 100 mEq/day Body cell Input ECF pH, ECF pH, digitalis, K + insulin, O lack, ATP epinephrine Bone, dense 2 hyperosmolality, connective tissue, hemolysis, ADP + P i cartilage K + Extracellular Intracellular infection, 300 mEq fluid K + fluid K + ischemia, Na + 60 mEq 3,300 mEq trauma Transcellular + fluid K K + + - H + HCO 3 CO + H O 40 mEq 2 2 H + + K Output Urinary K + K in feces + excretion 10 mEq/day Factors influencing the distribution of K FIGURE 24.13 90 mEq/day between intracellular and extracellular fluids. K balance for a healthy adult. Most K in the FIGURE 24.14 body is in the cell compartment. Renal K ex- ulation of plasma membrane Na /K -ATPase pumps. In- cretion is normally adjusted to keep a person in balance. sulin (administered with glucose) is also used in the emer- gency treatment of hyperkalemia. 4) Epinephrine increases K uptake by cells, an effect mediated by 2 -receptors. quate renal excretion is often compounded by tissue 5) Hyperosmolality (e.g., a result of hyperglycemia) trauma, infection, and acidosis, all of which raise plasma tends to raise plasma [K ]; hyperosmolality causes cells to [K ]. In chronic renal failure, hyperkalemia usually does shrink and raises intracellular [K ], which then favors out- not develop until GFR falls below 15 to 20 mL/min because ward diffusion of K into the ECF. of the remarkable ability of the kidney collecting ducts to 6) Tissue trauma, infection, ischemia, hemolysis, or se- adapt and increase K secretion. vere exercise release K from cells and can cause significant Excessive loss of K by the kidneys leads to hy- hyperkalemia. An artifactual increase in plasma [K ], pokalemia. The major cause of renal K wasting is iatro- pseudohyperkalemia, results if blood has been mishandled genic, an unwanted side effect of diuretic drug therapy. and red cells have been injured and allowed to leak K . Hyperaldosteronism causes excessive K excretion. In un- The plasma [K ] is sometimes taken as an approximate controlled diabetes mellitus, K loss is increased because of guide to total body K stores. For example, if a condition the osmotic diuresis caused by glucosuria and an elevated is known to produce an excessive loss of K (such as taking rate of fluid flow in the cortical collecting ducts. Several a diuretic drug), a decrease in plasma [K ] of 1 mEq/L may rare inherited defects in tubular transport, including Bart- correspond to a loss of 200 to 300 mEq K . Clearly, how- ter, Gitelman, and Liddle syndromes also lead to excessive ever, many factors affect the distribution of K between renal K excretion and hypokalemia (see Table 23.3). cells and ECF; in many circumstances, the plasma [K ] is not a good index of the amount of K in the body. Changes in Diet and K Excretion. As was discussed in Chapter 23, K is filtered, reabsorbed, and secreted in the The Kidneys Normally Maintain K Balance kidneys. Most of the filtered K is reabsorbed in the prox- imal convoluted tubule (70%) and the loop of Henle Figure 24.14 depicts K balance for a healthy adult man. (25%), and the majority of K excreted in the urine is usu- Most of the food we eat contains K . K intake (50 to 150 ally the result of secretion by cortical collecting duct prin- mEq/day) and absorption by the small intestine are unreg- cipal cells. The percentage of filtered K excreted in the ulated. On the output side, gastrointestinal losses are nor- urine is typically about 15% (Fig. 24.15). With prolonged mally small, but they can be large, especially with diarrhea. K depletion, the kidneys may excrete only 1% of the fil- Diarrheal fluid may contain as much as 80 mEq K /L. K tered load. However, excessive K intake may result in the loss in sweat is clinically unimportant. Normally, 90% of excretion of an amount of K that exceeds the amount fil- the ingested K is excreted by the kidneys. The kidneys are tered; in this case, there is greatly increased K secretion the major sites of control of K balance; they increase K by cortical collecting ducts. excretion when there is too much K in the body and con- When the dietary intake of K is changed, renal excre- serve K when there is too little. tion changes in the same direction. An important site for this adaptive change is the cortical collecting duct. Figure Abnormal Renal K Excretion. The major cause of K 24.16 shows the response to an increase in dietary K in- imbalances is abnormal renal K excretion. The kidneys take. Two pathways are involved. First, an elevated plasma may excrete too little K ; if the dietary intake of K con- [K ] leads to increased K uptake by the basolateral tinues, hyperkalemia can result. For example, in Addison’s plasma membrane Na /K -ATPase in collecting duct prin- disease, a low plasma aldosterone level leads to deficient cipal cells, resulting in increased intracellular [K ], K se- K excretion. Inadequate renal K excretion also occurs cretion and K excretion. Second, elevated plasma [K ] with acute renal failure; the hyperkalemia caused by inade- has a direct effect (i.e., not mediated by renin and an-
CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 419 Distal Increased K intake + Proximal convoluted convoluted tubule tubule + 100% Plasma [K ] 30% 5 20% Aldosterone secretion Uptake of K + by collecting duct principal cells Space of Bowman's 4 150% Plasma aldosterone capsule Luminal membrane permeability to + + Na and K and in basolateral + + membrane Na /K -ATPase activity in collecting duct principal cells Collecting duct + Increased K secretion + Increased K excretion Loop of Henle Effect of increased dietary K intake on K FIGURE 24.16 excretion. K directly stimulates aldosterone secretion and leads to an increase in cell [K ] in collecting duct principal cells. Both of these lead to enhanced secretion and, hence, excretion, of K . 1 150% Urine (usually about 15%) rate in the cortical collecting ducts, which diminishes K The percentage of the filtered load of K FIGURE 24.15 secretion and counterbalances the stimulatory effect of al- remaining in tubular fluid as it flows down the nephron. K is usually secreted in the cortical collecting duct. dosterone. Consequently, K excretion is unaltered. With K loading, this secretion is so vigorous that the amount of Another puzzling question is: Why is it that K ex- K excreted may actually exceed the filtered load. With K de- cretion does not increase during water diuresis? In Chap- pletion, K is reabsorbed by the collecting ducts. ter 23, we mentioned that an increase in fluid flow through the cortical collecting ducts increases K secre- tion. AVP, in addition to its effects on water permeabil- ity, stimulates K secretion by increasing the activity of giotensin) on the adrenal cortex to stimulate the synthesis luminal membrane K channels in cortical collecting and release of aldosterone. Aldosterone acts on collecting duct principal cells. Since plasma AVP levels are low dur- duct principal cells to (1) increase the Na permeability of ing water diuresis, this will reduce K secretion, oppos- the luminal plasma membrane, (2) increase the number and activity of basolateral plasma membrane Na /K -ATPase pumps, (3) increase the luminal plasma membrane K per- meability, and (4) increase cell metabolism. All of these Na deprivation + changes result in increased K secretion. In cases of decreased dietary K intake or K depletion, the activity of the luminal plasma membrane H /K -AT- GFR and proximal Pase found in -intercalated cells is increased. This pro- Aldosterone secretion Na reabsorption + motes K reabsorption by the collecting ducts. The col- lecting ducts can greatly diminish K excretion, but it takes a couple of weeks for K loss to reach minimal levels. Plasma aldosterone Fluid delivery to cortical collecting ducts Counterbalancing Influences on K Excretion. Consid- + ering that aldosterone stimulates both Na reabsorption K secretion K secretion + and K secretion, why is it that Na deprivation, a stimu- lus that raises plasma aldosterone levels, does not lead to enhanced K excretion? The explanation is related to the Unchanged K excretion + fact that Na deprivation tends to lower GFR and increase proximal Na reabsorption (Fig. 24.17). This response FIGURE 24.17 Why Na depletion does not lead to enhanced leads to a fall in Na delivery and a decreased fluid flow K excretion.
420 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS ing the effects of increased flow, with the result that K Distal excretion hardly changes. Proximal convoluted convoluted tubule tubule 100% 40% CALCIUM BALANCE 10% The kidneys play an important role in the maintenance of Ca 2 balance. Ca 2 intake is about 1,000 mg/day and mainly comes from dairy products in the diet. About 300 mg/day are absorbed by the small intestine, a process con- Space of 2 trolled by 1,25(OH) 2 vitamin D 3. About 150 mg Ca /day Bowman's 5% are secreted into the gastrointestinal tract (via saliva, gastric capsule juice, pancreatic juice, bile, and intestinal secretions), so that net absorption is only about 150 mg/day. Fecal Ca 2 excretion is about 850 mg/day and urinary excretion about 150 mg/day. 2 A normal plasma [Ca ] is about 10 mg/dL, which is Collecting equal to 2.5 mmol/L (since the atomic weight of calcium is duct 40) or 5 mEq/L. About 40% of plasma Ca 2 is bound to plasma proteins (mainly serum albumin), 10% is bound to small diffusible anions (such as citrate, bicarbonate, phos- phate, and sulfate) and 50% is free or ionized. It is the ion- Loop of Henle ized Ca 2 in the blood that is physiologically important and closely regulated (see Chapter 36). Most of the Ca 2 in the body is in bone (99%), which constantly turns over. In a healthy adult, the rate of release of Ca 2 from old bone exactly matches the rate of deposition of Ca 2 in newly formed bone (500 mg/day). Ca 2 that is not bound to plasma proteins (i.e., 60% of 0.5 2% 2 the plasma Ca ) is freely filterable in the glomeruli. About Urine 60% of the filtered Ca 2 is reabsorbed in the proximal con- FIGURE 24.18 The percentage of the filtered load of Ca 2 voluted tubule (Fig. 24.18). Two thirds is reabsorbed via a remaining in tubular fluid as it flows down the paracellular route in response to solvent drag and the small nephron. The kidneys filter about 10,800 mg/day (0.6 100 lumen positive potential (3 mV) found in the late proxi- mg/L 180 L/day) and excrete only about 0.5 to 2% of the fil- mal convoluted tubule. One third is reabsorbed via a tran- tered load, that is, about 50 to 200 mg/day. Thiazides increase 2 scellular route that includes Ca 2 channels in the apical Ca reabsorption by the distal convoluted tubule, and PTH in- 2 2 plasma membrane and a primary Ca -ATPase or 3 Na /1 creases Ca reabsorption by the connecting tubule and cortical collecting duct. Ca 2 exchanger in the basolateral plasma membrane. About 30% of filtered Ca 2 is reabsorbed along the loop of Henle. Most of the Ca 2 reabsorbed in the thick ascending is usually excreted. (Chapter 34 discusses Ca 2 balance and limb is by passive transport through the tight junctions, its control by several hormones in more detail.) propelled by the lumen positive potential. Reabsorption continues along the distal convoluted tubule. Reabsorption here is increased by thiazide diuretics, which may be prescribed in cases of excessive Ca 2 in the MAGNESIUM BALANCE 2 urine, hypercalciuria, and kidney stone disease (see Clini- An adult body contains about 2,000 mEq of Mg , of which cal Focus Box 24.2). Thiazides inhibit the luminal mem- about 60% is present in bone, about 39% in cells, and about brane Na-Cl cotransporter in distal convoluted tubule cells, 1% in the ECF. Mg 2 is the second most abundant cation in which leads to a fall in intracellular [Na ]. This, in turn, cells, after K (see Table 24.2). The bulk of intracellular promotes Na -Ca 2 exchange and increased basolateral Mg 2 is not free, but is bound to a variety of organic com- extrusion of Ca 2 and increased Ca 2 reabsorption. pounds, such as ATP. Mg 2 is present in the plasma at a con- The late distal tubule (connecting tubule and initial part centration of about 1 mmol/L (2 mEq/L). About 20% of of the cortical collecting duct) is an important site of control plasma Mg 2 is bound to plasma proteins, 20% is complexed of Ca 2 excretion because this is where parathyroid hor- with various anions, and 60% is free or ionized. mone (PTH) increases Ca 2 reabsorption. Ca 2 diffuses into About 25% of the Mg 2 filtered by the glomeruli is re- the cells, primarily through an epithelial Ca 2 channel absorbed in the proximal convoluted tubule (Fig. 24.19); 2 (ECaC) in the apical membrane, is transported through the this is a lower percentage than for Na , K , Ca , or wa- cytoplasm by a 1,25(OH) 2 vitamin D 3 -dependent calcium- ter. The proximal tubule epithelium is rather impermeable binding protein, called calbindin, and is extruded by a to Mg 2 under normal conditions, so there is little passive Na /Ca 2 exchange or Ca 2 -ATPase in the basolateral Mg 2 reabsorption. The major site of Mg 2 reabsorption is plasma membrane. Only about 0.5 to 2% of the filtered Ca 2 the loop of Henle (mainly the thick ascending limb), which
CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 421 CLINICAL FOCUS BOX 24.2 Kidney Stone Disease (Nephrolithiasis) down the urinary tract and spontaneously eliminated. Mi- A kidney stone is a hard mass that forms in the urinary croscopic and chemical examination of the eliminated tract. At least 1% of Americans develop kidney stones at stones is used to determine the nature of the stone and some time during their lives. Nephrolithiasis or kidney help guide treatment. Sometimes a change in diet is rec- stone disease occurs more commonly in men than in ommended to reduce the amount of potential stone-form- women and usually strikes men between the ages of 30 ing material (e.g., Ca 2 , oxalate, or uric acid) in the urine. and 60. A stone lodged in the ureter will cause bleeding Thiazide diuretics are useful in reducing Ca 2 excretion if and intense pain. Kidney stone disease causes consider- excessive urinary Ca 2 excretion (hypercalciuria) is the able suffering and loss of time from work, and it may lead problem. Potassium citrate is useful in treating most stone to kidney damage. Once a stone forms in a person, stone disease because citrate complexes Ca 2 in the urine and formation often recurs. inhibits the crystallization of Ca 2 salts. It also makes the Stones form when poorly soluble substances in the urine more alkaline (since citrate is oxidized to HCO 3 in urine precipitate out of solution, causing crystals to form, the body). This is helpful in reducing the risk of uric acid aggregate, and grow. Most kidney stones (75 to 85%) are stones because urates (favored in an alkaline urine) are made up of insoluble Ca 2 salts of oxalate and phosphate. more soluble than uric acid (the form favored in an acidic There may be excessive amounts of Ca 2 or oxalate in the urine). Administering an inhibitor of uric acid synthesis, urine as a result of diet, a genetic defect, or unknown such as allopurinol, can help reduce the amount of uric causes. Stones may also form from precipitated ammo- acid in the urine. nium magnesium phosphate (struvite), uric acid, and cys- If the stone is not passed, several options are available. tine. Struvite stones (10 to 15% of all stones) are the result Surgery to remove the stone can be done, but extracor- of infection with bacteria, usually Proteus species. Uric poreal shock wave lithotripsy is more common, using acid stones (5 to 8% of all stones) may form in patients with a device called a lithotriptor. The patient is placed in a excessive uric acid production and excretion, as occurs in tub of water, and the stone is localized by X-ray imaging. some patients with gout. Defective tubular reabsorption of Shock waves are generated in the water by high-voltage cystine (in patients with cystinuria) leads to cystine stone electric discharges and are focused on the stone through (1% of stones). The rather insoluble amino acid cystine the body wall. The shock waves fragment the stone so that was first isolated from a urinary bladder stone by Wollas- it can be passed down the urinary tract and eliminated. As ton in 1810, hence, its name. Because low urine flow rate some renal injury is produced by this procedure, it may raises the concentration of all poorly soluble substances in not be entirely innocuous. Other procedures include pass- the urine, favoring precipitation, a key to prevention of kid- ing a tube with an ultrasound transducer through the skin ney stones is to drink plenty of water and maintain a high into the renal pelvis; stone fragments can be removed di- urine output day and night. rectly. A ureteroscope with a laser can also be used to Fortunately, most stones are small enough to be passed break up stones. 2 reabsorbs about 65% of filtered Mg . Reabsorption here is H 2PO 4 . Phosphate plays a variety of roles in the body: It mainly passive and occurs through the tight junctions, is an important constituent of bone; it plays a critical role in driven by the lumen positive potential. Recent studies have cell metabolism, structure, and regulation (as organic phos- identified a tight junction protein that is a channel that fa- phates); and it is a pH buffer. cilitates Mg 2 movement. Changes in Mg 2 excretion re- Phosphate is mainly unbound in the plasma and freely sult mainly from changes in loop transport. More distal filtered by the glomeruli. About 60 to 70% of filtered phos- portions of the nephron reabsorb only a small fraction of phate is actively reabsorbed in the proximal convoluted filtered Mg 2 and, under normal circumstances, appear to tubule and another 15% is reabsorbed by the proximal play a minor role in controlling Mg 2 excretion. straight tubule via a Na -phosphate cotransporter in the 2 An abnormally low plasma [Mg ] is characterized by luminal plasma membrane (Fig. 24.20). The remaining por- neuromuscular and CNS hyperirritability. Abnormally high tions of the nephron and collecting ducts reabsorb little, if plasma Mg 2 levels have a sedative effect and may cause car- any, phosphate. The proximal tubule is the major site of diac arrest. Dietary intake of Mg 2 is usually 20 to 50 phosphate reabsorption. Only about 5 to 20% of filtered mEq/day; two thirds is excreted in the feces, and one third is phosphate is usually excreted. Phosphate in the urine is an excreted in the urine. The kidneys are mainly responsible for important pH buffer and contributes to titratable acid ex- 2 regulating the plasma [Mg ]. Excess amounts of Mg 2 are cretion (see Chapter 25). Phosphate reabsorption is Tm- 2 rapidly excreted by the kidneys. In Mg -deficient states, limited (see Chapter 23), and the amounts of phosphate fil- Mg 2 virtually disappears from the urine. tered usually exceed the maximum reabsorptive capacity of the tubules for phosphate. This is different from the situa- tion for glucose, in which normally less glucose is filtered than can be reabsorbed. If more phosphate is ingested and PHOSPHATE BALANCE absorbed by the intestine, plasma [phosphate] rises, more A normal plasma concentration of inorganic phosphate is phosphate is filtered, and the filtered load exceeds the Tm about 1 mmol/L. At a normal blood pH of 7.4, 80% of the more than usual and the extra phosphate is excreted. Thus, 2– phosphate is present as HPO 4 and 20% is present as the kidneys participate in regulating the plasma phosphate
422 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS Distal Distal Proximal convoluted Proximal convoluted convoluted tubule convoluted tubule tubule tubule 100% 100% 75% 30 40% 12% 5 20% Space of 10% Space of Bowman's Bowman's capsule capsule Collecting Collecting duct duct Loop of Henle Loop of Henle 10% 5 20% Urine Urine FIGURE 24.19 The percentage of the filtered load of Mg 2 FIGURE 24.20 The percentage of the filtered load of phos- remaining in tubular fluid as it flows down the phate remaining in tubular fluid as it flows nephron. The loop of Henle, specifically the thick ascending down the nephron. The proximal tubule is the major site of 2 limb, is the major site of reabsorption of filtered Mg . phosphate reabsorption, and downstream nephron segments reab- sorb little, if any, phosphate. by an “overflow” type mechanism. When there is an excess a complex with Ca 2 . Second, hyperphosphatemia de- of phosphate in the body, they automatically increase creases production of 1,25(OH) 2 vitamin D 3 in the kidneys phosphate excretion. In cases of phosphate depletion, the by inhibiting the 1-hydroxylase enzyme that forms this kidneys filter less phosphate and the tubules reabsorb a hormone. With decreased plasma levels of 1,25(OH) 2 vita- larger percentage of the filtered phosphate. min D 3 , there is less Ca 2 absorption by the small intestine Phosphate reabsorption in the proximal tubule is con- and a tendency for hypocalcemia. 2 trolled by a variety of factors. PTH is of particular im- Low plasma ionized [Ca ] stimulates hyperplasia of the portance; it decreases the phosphate Tm, increasing parathyroid glands and increased secretion of PTH. High phosphate excretion. plasma [phosphate] also stimulates PTH secretion directly. Patients with chronic renal disease often develop an el- PTH then inhibits phosphate reabsorption by the proximal evated plasma [phosphate] or hyperphosphatemia, de- tubules, promotes phosphate excretion, and helps return pending on the severity of the disease. When GFR falls, plasma [phosphate] back to normal. Elevated PTH levels, the filtered phosphate load is diminished, and the tubules however, also cause mobilization of Ca 2 and phosphate reabsorb phosphate more completely. Phosphate excre- from bone. Increased bone reabsorption results, and the tion is inadequate in the face of continued intake of phos- bone minerals are replaced with fibrous tissue that renders phate in the diet. Hyperphosphatemia is dangerous be- the bone more susceptible to fracture. cause of the precipitation of calcium phosphate in soft Patients with advanced chronic renal failure are often ad- tissue. For example, when calcium phosphate precipitates vised to restrict phosphate intake and consume substances in the walls of blood vessels, blood flow will be impaired. (such as Ca 2 salts) that bind phosphate in the intestines, so as Hyperphosphatemia can lead to myocardial failure and to avoid the many problems caused by hyperphosphatemia. pulmonary insufficiency. Administration of synthetic 1,25(OH) 2 vitamin D 3 may com- When plasma [phosphate] rises, the plasma ionized pensate for deficient renal production of this hormone. This 2 [Ca ] tends to fall, for two reasons. First, phosphate forms hormone opposes hypocalcemia and inhibits PTH synthesis
CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 423 and secretion. Parathyroidectomy is sometimes necessary in Micturition Involves Autonomic patients with advanced chronic renal failure. and Somatic Nerves Micturition (urination), the periodic emptying of the blad- der, is a complex act involving both autonomic and somatic URINARY TRACT nerve pathways and several reflexes that can be either in- The kidneys form urine all of the time. The urine is trans- hibited or facilitated by higher centers in the brain. The ba- ported by the ureters to the urinary bladder. The bladder is sic reflexes occur at the level of the sacral spinal cord and specialized to fill with urine at a low pressure and to empty are modified by centers in the midbrain and cerebral cor- its contents when appropriate. Contractions of the bladder tex. Distension of the bladder is sensed by stretch receptors and its sphincters are controlled by the nervous system. in the bladder wall; these induce reflex contraction of the detrusor and relaxation of the internal and external sphinc- ters. This reflex is released by removing inhibitory influ- The Ureters Convey Urine to the Bladder ences from the cerebral cortex. Fluid flow through the ure- thra reflexively causes further contraction of the detrusor The ureters are muscular tubes that propel the urine from the pelvis of each kidney to the urinary bladder. Peristaltic and relaxation of the external sphincter. Increased movements originate in the region of the calyces, which parasympathetic nerve activity stimulates contraction of contain specialized smooth muscle cells that generate the detrusor and relaxation of the internal sphincter. Sym- spontaneous pacemaker potentials. These pacemaker po- pathetic innervation is not essential for micturition. During tentials trigger action potentials and contractions in the micturition, the perineal and levator ani muscles relax, muscular regions of the renal pelvis that propagate distally shortening the urethra and decreasing urethral resistance. to the ureter. Peristaltic waves sweep down the ureters at a Descent of the diaphragm and contraction of abdominal frequency of one every 10 seconds to one every 2 to 3 min- muscles raises intra-abdominal pressure, and aids in the ex- utes. The ureters enter the base of the bladder obliquely, pulsion of urine from the bladder. forming a valvular flap that passively prevents the reflux of Micturition is fortunately under voluntary control in urine during contractions of the bladder. The ureters are in- healthy adults. In the young child, however, it is purely re- nervated by sympathetic and parasympathetic nerve fibers. Sensory fibers mediate the intense pain that is felt when a stone distends or blocks a ureter. Descending aorta L1 Inferior vena cava The Bladder Stores Urine Until It Can Be L2 Sympathetic trunk Conveniently Emptied L3 The urinary bladder is a distensible hollow vessel contain- ing smooth muscle in its wall (Fig. 24.21). The muscle is called the detrusor (from Latin for “that which pushes down”). The neck of the bladder, the involuntary internal sphincter, also contains smooth muscle. The bladder body and neck are innervated by parasympathetic pelvic nerves and sympathetic hypogastric nerves. The external sphinc- S2 ter, the compressor urethrae, is composed of skeletal mus- Right ureter S3 cle and innervated by somatic nerve fibers that travel in the Hypogastric S4 pudendal nerves. Pelvic, hypogastric, and pudendal nerves nerve Pelvic nerve contain both motor and sensory fibers. Bladder The bladder has two functions: to serve as a distensible reservoir for urine and to empty its contents at appropriate Pudendal nerve intervals. When the bladder fills, it adjusts its tone to its ca- Internal (involuntary) pacity, so that minimal increases in bladder pressure occur. sphincter The external sphincter is kept closed by discharges along Urethra the pudendal nerves. The first sensation of bladder filling is External (voluntary) sphincter experienced at a volume of 100 to 150 mL in an adult, and the first desire to void is elicited when the bladder contains FIGURE 24.21 The innervation of the urinary bladder. The about 150 to 250 mL of urine. A person becomes uncom- parasympathetic pelvic nerves arise from spinal fortably aware of a full bladder when the volume is 350 to cord segments S2 to S4 and supply motor fibers to the bladder 400 mL; at this volume, hydrostatic pressure in the bladder musculature and internal (involuntary) sphincter. Sympathetic is about 10 cm H 2 O. With further volume increases, blad- motor fibers supply the bladder via the hypogastric nerves, which der pressure rises steeply, partly as a result of reflex con- arise from lumbar segments of the spinal cord. The pudendal nerves supply somatic motor innervation to the external (volun- tractions of the detrusor. An increase in volume to 700 mL tary) sphincter. Sensory afferents (dashed lines) from the bladder creates pain and often loss of control. The sensations of travel mainly in the pelvic nerves but also to some extent in the bladder filling, of conscious desire to void, and painful dis- hypogastric nerves. (Modified from Anderson JE. Grant’s Atlas of tension are mediated by afferents in the pelvic nerves. Anatomy. 8th Ed. Baltimore: Williams & Wilkins, 1983.)
424 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS flex and occurs whenever the bladder is sufficiently dis- the upper urethra commonly occurs in older men and is a tended. At about 2 /2 years of age, it begins to come under result of enlargement of the surrounding prostate gland. 1 cortical control and, in most children, complete control is This condition is called benign prostatic hyperplasia, and achieved by age 3. Damage to the nerves that supply the it results in decreased urine stream, overdistension of the bladder and its sphincters can produce abnormalities of bladder as a result of incomplete emptying, and increased micturition and incontinence. An increased resistance of urgency and frequency of urination. REVIEW QUESTIONS DIRECTIONS: Each of the numbered 6.The nephron segment that reabsorbs 12.A 60-year-old woman is always thirsty items of incomplete statements in this the largest percentage of filtered Mg 2 and wakes up several times during the section is followed by answers or is the night to empty her bladder. Plasma completions of the statement. Select the (A) Proximal convoluted tubule osmolality is 295 mOsm/kg H 2 O ONE lettered answer or completion that is (B) Thick ascending limb (normal range, 281 to 297 mOsm/kg BEST in each case. (C) Distal convoluted tubule H 2 O), urine osmolality is 100 (D) Cortical collecting duct mOsm/kg H 2 O, and plasma AVP levels 1.Which of the following body fluid (E) Medullary collecting duct are higher than normal. The urine is volumes cannot be directly determined 7.Which of the following causes negative for glucose. The most likely with a single indicator? decreased renin release by the kidneys? diagnosis is (A) Extracellular fluid volume (A) Decreased fluid and solute delivery (A) Diabetes mellitus (B) Intracellular fluid volume to the macula densa (B) Diuretic drug abuse (C) Plasma volume (B) Hemorrhage (C) Nephrogenic diabetes insipidus (D) Total body water (C) Intravenous infusion of isotonic (D) Neurogenic diabetes insipidus 2.Which of the following results in saline (E) Primary polydipsia thirst? (D) Narrowing (stenosis) of the renal 13.The volume of the extracellular fluid is (A) Cardiac failure artery most closely related to the amount of (B) Decreased plasma levels of (E) Stimulation of renal sympathetic which solute in this compartment? angiotensin II nerves (A) HCO 3 (C) Distension of the cardiac atria 8.Which of the following may cause (B) Glucose (D) Distension of the stomach hyperkalemia? (C) K (E) Hypotonic volume expansion (A) Epinephrine injection (D) Serum albumin 3.Arginine vasopressin (AVP) is (B) Hyperaldosteronism (E) Na synthesized in the (C) Insulin administration 14.A homeless man was found comatose, (A) Adrenal cortex (D) Intravenous infusion of a NaHCO 3 lying in the doorway of a downtown (B) Anterior hypothalamus solution department store at night. His plasma (C) Anterior pituitary (E) Skeletal muscle injury osmolality was 370 mOsm/kg H 2O (D) Collecting ducts of the kidneys 9.Parathyroid hormone (PTH) (normal, 281 to 297 mOsm/kg H 2O), (E) Posterior pituitary (A) Decreases tubular reabsorption of plasma [Na ] was 140 mEq/L (normal, 4.A 60-kg woman is given 10 Ca 2 136 to 145 mEq/L), plasma [glucose] microcuries (CI) (370 kilobecquerels) (B) Decreases tubular reabsorption of 100 mg/dL (normal fasting level, 70 to of radioiodinated serum albumin phosphate 110 mg/dL), and BUN 15 mg/dL (RISA) intravenously. Ten minutes (C) Inhibits bone resorption. (normal, 7 to 18 mg/dL). His most later, a venous blood sample is (D) Secretion is decreased in patients likely problem is collected, and the plasma RISA activity with chronic renal failure (A) Alcohol intoxication is 4 CI/L. Her hematocrit ratio is (E) Secretion is stimulated by a rise in (B) Dehydration 0.40. What is her blood volume? plasma ionized Ca 2 (C) Diabetes insipidus (A) 417 mL 10.Aldosterone acts on cortical collecting (D) Diabetes mellitus (B) 625 mL ducts to (E) Renal failure (C) 2.5 L (A) Decrease K secretion 15.A hypertensive patient is given an (D) 4.17 L (B) Decrease Na reabsorption angiotensin-converting enzyme (ACE) (E) 6.25 L (C) Decrease water permeability inhibitor. Which of the following 5.Which of the following leads to (D) Increase K secretion changes would be expected? decreased Na reabsorption by the (E) Increase water permeability (A) Plasma aldosterone level will rise kidneys? 11.In response to an increase in GFR, the (B) Plasma angiotensin I level will rise (A) An increase in central blood proximal tubule and the loop of Henle (C) Plasma angiotensin II level will rise volume demonstrate an increase in the rate of (D) Plasma bradykinin level will fall (B) An increase in colloid osmotic Na reabsorption. This phenomenon is (E) Plasma renin level will fall pressure in the peritubular capillaries called 16.If a person consumes a high-K diet, (C) An increase in GFR (A) Autoregulation the majority of K excreted in the (D) An increase in plasma aldosterone (B) Glomerulotubular balance urine is derived from level (C) Mineralocorticoid escape (A) Glomerular filtrate (E) An increase in renal sympathetic (D) Saturation of tubular transport (B) K that is not reabsorbed in the nerve activity (E) Tubuloglomerular feedback proximal tubule (continued)
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