Ebook Clinical physiology of acid - base and electrolyte disorders (5th edition): Part 1

(BQ) Part 1 book Clinical physiology of acid - base and electrolyte disorders presents the following contents: Renal physiology, regulation of water and electroltye balance. Invite you to consult.

Editors: Rose, Burton David; Post, Theodore W Title: Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th Edition C opyright Š2001 McGraw-Hill > Front of Book > Editors Editors Burton David Rose MD C linical Professor of Medicine Harvard Medical School, Boston, Massachusetts; Editor-in-Chief, UpToDate, Wellesley, Massachusetts Theodore W Post MD Deputy Editor Nephrology, UpToDate, Wellesley, Massachusetts Secondary Editors This book was set in Times Roman by Keyword Publishing Services Marty Wonsiewicz Editor Kathleen McCullough Editor Karen Davis Editor Phil Galea Production Supervisor Mary McKeon C over Designer The index was prepared by Kathi Unger R R Donnelley & Sons was printer and binder Editors: Rose, Burton David; Post, Theodore W Title: Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th Edition C opyright Š2001 McGraw-Hill > Front of Book > DEDICATION DEDICATION To Gloria, Emily, Anne, and Daniel and To C laire, Garrett, and Ian Editors: Rose, Burton David; Post, Theodore W Title: Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th Edition C opyright Š2001 McGraw-Hill > Front of Book > PREFACE PREFACE The fifth edition of Clinical Physiology of Acid-Base and Electrolyte Disorders has been largely rewritten to include the many important advances that have been made and the controversies that have arisen in the past six years As with the previous four editions, this book attempts to integrate the essentials of renal and electrolyte physiology with the common clinical disorders of acid-base and electrolyte balance Its underlying premise is that these clinical disturbances can be best approached from an understanding of basic physiologic principles Thus, C hapters 1,2,3,4,5,6 review the physiology of normal renal function and the effects of hormones on the kidney This is followed by a discussion of the extrarenal and renal factors involved in the internal distribution of the body water and in the normal regulation of volume (sodium), water, acid-base, and potassium balance (C hapters 7,8,9,10,11,12) In addition to providing the foundation for understanding how disease states can overcome these regulatory processes, the initial chapters can also be used by first-year medical students studying renal physiology The material presented in these chapters presents the core of information that, in our opinion, the clinician should possess Although relatively complete, it is not meant to be an exhaustive review In those areas where controversy exists, we have chosen to note the presence of uncertainty and to refer the interested reader to appropriate references, rather than extensively reviewing each theory Since the primary purpose of this book is to teach the reader how to approach clinical problems, the physiological discussions are correlated with situations in clinical medicine wherever possible The last section of the book (C hapters 13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28) contains a separate chapter on each major acid-base and electrolyte disturbance In addition to discussing etiology, symptoms, diagnosis, and treatment, each chapter begins with a short summary of the pathophysiology of the specific disorder with cross-references to more complete discussions in the earlier chapters Although this leads to a certain amount of repetition, it has the advantage of allowing each clinical chapter to be read independently of the other parts of the book, making the book easier to use by a physician dealing with an acutely ill patient Problems are presented at the end of most of the chapters in both the physiology and clinical sections These problems are intended both to test understanding and to emphasize important concepts frequently misunderstood by physicians dealing with these disorders The answers to these problems are presented in C hapter 29, and C hapter 30 contains a summary of important equations and formulas that are useful in the clinical setting We are extremely grateful to C olin Sieff, Donald Kohan, Philip Marsden, Evan Loh, Bruce Runyon, and Jess Mandel for contributing material to selected chapters, particularly 6, 16, 20, and 21 Editors: Rose, Burton David; Post, Theodore W Title: Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th Edition C opyright Š2001 McGraw-Hill > Front of Book > NOTICE NOTICE Medicine is an ever-changing science As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work Readers are encouraged to confirm the information contained herein with other sources For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration This recommendation is of particular importance in connection with new or infrequently used drugs Editors: Rose, Burton David; Post, Theodore W Title: Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th Edition C opyright ©2001 McGraw-Hill > Table of Contents > Part One - Renal Physiology > Chapter one - Introduction to Renal Function Chapter one Introduction to Renal Function The kidney normally performs a number of essential functions: It participates in the maintenance of the constant extracellular environment that is required for adequate functioning of the cells This is achieved by excretion of some of the waste products of metabolism (such as urea, creatinine, and uric acid) and by specifically adjusting the urinary excretion of water and electrolytes to match net intake and endogenous production As will be seen, the kidney is able to regulate individually the excretion of water and solutes such as sodium, potassium, and hydrogen largely by changes in tubular reabsorption or secretion It secretes hormones that participate in the regulation of systemic and renal hemodynamics (renin, angiotensin II, prostaglandins, nitric oxide, endothelin, and bradykinin), red blood cell production (erythropoietin), and calcium, phosphorus, and bone metabolism (1,25-dihydroxyvitamin D or calcitriol) It performs such miscellaneous functions as catabolism of peptide hormones1,2 and synthesis of glucose (gluconeogenesis) in fasting condition.3,4 This chapter will review briefly the morphology of the kidney and the basic processes of reabsorption and secretion The regulation of renal hemodynamics, the specific functions of the different nephron segments, and the relationships between hormones and the kidney will then be discussed in the ensuing chapters RENAL MORPHOLOGY The basic unit of the kidney is the nephron, with each kidney in humans containing approximately 1.0 to 1.3 million nephrons Each nephron consists of a glomerulus, which is a tuft of capillaries interposed between two arterioles (the afferent and efferent arterioles), and a series of tubules lined by a continuous layer of epithelial cells (Fig 1-1) The glomeruli are located in the outer part of the kidney, called the cortex, whereas the tubules are presented in both the cortex and the inner part of the kidney, the medulla (Figs 1-1 and 1-2) Figure 1-1 Anatomic relationships of the component parts of the nephron (Adapted from Vander R, Renal Physiology, 2d ed, McGraw-Hill, New York, 1980.) Figure 1-2 Section of a human kidney The outer portion (the cortex) contains all the glomeruli The tubules are located in both the cortex and the medulla, with the collecting tubules forming a large portion of the inner medulla (the papilla) Urine leaving the collecting tubules drains sequentially into the calyces, renal pelvis, ureter, and then the bladder (Adapted from Vander R, Renal Physiology, 2d ed, McGraw-Hill, New York, 1980.) The initial step in the excretory function of the nephron is the formation of an ultrafiltrate of plasma across the glomerulus This fluid then passes through the tubules and is modified in two ways: by reabsorption and by secretion Reabsorption refers to the removal of a substance from the filtrate, whereas secretion refers to the addition of a substance to the filtrate As will be seen, the different tubular segments make varying contributions to these processes Fluid filtered across the glomerulus enters Bowman's space and then the proximal tubule (Fig 1-1) The proximal tubule is composed anatomically of an initial convoluted segment and a later straight segment, the pars recta, which enters the outer medulla The loop of Henle begins abruptly at the end of the pars recta It generally includes a thin descending limb and thin and thick segments of the ascending limb The hairpin configuration of the loop of Henle plays a major role in the excretion of a hyperosmotic urine It is important to note that the length of the loops of Henle is not uniform (Fig 1-3) Approximately 40 percent of nephrons have short loops that penetrate only the outer medulla or may even turn around in the cortex; these short loops lack a thin ascending limb.5 The remaining 60 percent have long loops that course through the medulla and may extend down to the papilla (the innermost portion of the medulla) The length of the loops is largely determined by the cortical location of the glomerulus: Glomeruli in the outer cortex (about 30 percent) have only short loops; those in the juxtamedullary region (about 10 percent) have only long loops; and those in the midcortex may have either short or long loops (Fig 1-3) The thick ascending limb also has a cortical segment that returns to the region of the parent glomerulus It is in this area, where the tubule approaches the afferent glomerular arteriole, that the specialized tubular cells of the macula densa are located (Fig 1-4) The juxtaglomerular cells of the afferent arteriole and the macula densa compose the juxtaglomerular apparatus, which plays a central role in renin secretion (see C hap 2) Figure 1-3 Anatomic relationships of the different nephron segments according to location of the glomeruli in the outer cortex (OC ), midcortex (MC ), or juxtamedullary area (JM) The major nephron segments are labeled as follows: PC T=proximal convoluted tubule; PR=pars recta, which ends in the S segment at the junction of the outer and inner stripes in the outer medulla; DLH=descending limb of the loop of Henle; tAL=thin ascending limb, which is not present in outer cortical nephrons that have short loops of Henle; TAL=medullary thick ascending limb; C AL=cortical thick ascending limb, which ends in the macula densa adjacent to the parent glomerulus (see Fig 1-4); DC T=distal convoluted tubule; C S=connecting segment; C C T=cortical collecting tubule; MC T=medullary collecting tubule; and PC D=papillary collecting duct, at the end of the medullary collecting tubule (Adapted from Jacobson HR, Am J Physiol 241:F203, 1981 Used with permission.) After the macula densa, there are three cortical segments (Fig 1-3): The distal convoluted tubule, the connecting segment (previously considered part of the late distal tubule), and the cortical collecting tubule.6,7 The connecting segments of many nephrons drain into a single collecting tubule Fluid leaving the cortical collecting tubule flows into the medullary collecting tubule and then drains sequentially into the calyces, the renal pelvis, the ureters, and the bladder (Fig 1-2) The segmental subdivision of the nephron is based upon different permeability and transport characteristics that translate into important differences in function.5 In general, the proximal tubule and loop of Henle reabsorb the bulk of the filtered solutes and water, while the collecting tubules make the final small changes in urinary composition that permit solute and water excretion to vary appropriately with alterations in dietary intake Figure 1-4 Diagram of the juxtaglomerular apparatus The juxtaglomerular cells in the wall of the afferent arteriole secrete renin into the lumen of the afferent arteriole and the renal lymph Stretch receptors in the afferent arteriole, the sympathetic nerves ending in the juxtaglomerular cells, and the composition of the tubular fluid reaching the macula densa all contribute to the regulation of renin secretion (Adapted from Davis JO, Am J Med 55:333, 1973 Used with permission.) There may also be significant heterogeneity within a given tubular segment, particularly in the proximal tubule and cortical collecting tubule In the latter segment, for example, there are two cell types with very different functions: The principal cells reabsorb sodium and chloride and secrete potassium, in part under the influence of aldosterone; and the intercalated cells secrete hydrogen or bicarbonate and reabsorb potassium, but play no role in sodium balance.6 REABSORPTION AND SECRETION The rate of glomerular filtration averages 135 to 180 L/day in a normal adult Since this represents a volume that is more than 10 times that of the extracellular fluid and approximately 60 times that of the plasma, it is evident that almost all of this fluid must be returned to the systemic circulation This process is called tubular reabsorption and can occur either across the cell or via the paracellular route between the cells With transcellular reabsorption, the substance to be reabsorbed is first transported from the tubular lumen into the cell, usually across the luminal aspect of the cell membrane; next, it moves across the basolateral (or peritubular) aspect of the cell membrane into the interstitium and then the capillaries that surround the tubules (Fig 1-5) With paracellular reabsorption, the substance to be reabsorbed moves from the tubular lumen across the tight junction at the luminal surface of adjacent cells (see below) into the interstitium and then into the peritubular capillaries Most reabsorbed solutes are returned to the systemic circulation intact However, some are metabolized within the cell, particularly lowmolecular-weight proteins in the proximal tubule Solutes can also move in the opposite direction, from the peritubular capillary through the cell and into the urine This process is called tubular secretion (Fig 1-5) Filtered solutes and water may be transported by one or both of these mechanisms For example, Na + , C l- , and H2O are reabsorbed; hydrogen ions are secreted; K + and uric acid are both reabsorbed and secreted; and filtered creatinine is excreted virtually unchanged, since it is not reabsorbed and only a small amount is normally added to the urine by secretion The transcellular reabsorption or secretion of almost all solutes is facilitated by protein carriers or ion-specific channels; these transport processes are essential, since free diffusion of ions is limited by the lipid bilayer of the cell membrane The spatial orientation of the cells is also important, because the luminal and basolateral aspects of the cell membrane, which are separated by the tight junction, have different functional characteristics As an example, filtered sodium enters the cell passively down a favorable electrochemical gradient, since the active Na + -K + -ATPase pump in the basolateral membrane maintains the cell Na + concentration at a low level and makes the cell interior electronegative Sodium entry occurs by a variety of mechanisms at different nephron sites, such as Na + -H+ exchange and Na + -glucose cotransport in the proximal tubule, a Na + -K + -2C l- carrier protein in the cortical collecting tubule and papillary collecting duct (Fig 1-6) The sodium that enters the cells is then returned to the systemic circulation by the Na + -K + -ATPase pump in the basolateral membrane.8 Removal of this Na + from the cell maintains the cell Na + concentration at a low level, thereby promoting further diffusion of luminal Na + into the cell and continued Na + reabsorption Figure 1-5 Schematic representation of reabsorption and secretion in the nephron Figure 1-6 Major mechanisms of passive Na + entry into the cells across the luminal (apical) membrane in the different nephron segments With the exception of the selective Na + channels in the collecting tubules, Na + reabsorption in the more proximal segments is linked to the reabsorption or secretion of other solutes (Adapted from Rose BD, Kidney Int 39:336, 1991 Used with permission from Kidney International.) This simple summary of the mechanism of Na + transport illustrates that reabsorption can involve both active and passive mechanisms This is also true for tubular secretion Potassium, for example, is secreted from the cortical collecting tubule cell into the lumen The Na + -K + -ATPase pump in the basolateral membrane actively transports K + from the peritubular capillary into the cell; the ensuing rise in the cell K + concentration then promotes secretion into the lumen via K + channels in the luminal membrane The tubular cells perform these functions in an extremely efficient manner, reabsorbing almost all the filtrate to maintain the balance between intake and excretion In an individual on a normal diet, more than 98 to 99 percent of the filtered H2O, Na + , C l- , and HC O 3- is reabsorbed (Table 1-1) Although this process of filtration and almost complete reabsorption may seem inefficient, a high rate of filtration is required for the excretion of those waste products of metabolism (such as urea and creatinine) that enter the urine primarily by glomerular filtration Role of the Tight Junction The tight junction is composed primarily of the zona occludens, which is a strandlike structure on the luminal membrane that brings Any persistent increase in K + secretion must be accompanied by enhanced Na + -K + -ATPase activity; if this did not occur; there would be eventual depletion of cell K + stores It is of interest in this regard that the ratio of Na + reabsorption to K + secretion in the cortical collecting tubule is : 2, similar to the stoichiometry of the Na + -K + -ATPase pump.89 This observation suggests the following sequence: The Na + -K + -ATPase pump transports reabsorbed Na + out of the cell in exchange for extracellular K + ; most of this K + is then secreted into the lumen, rather than leaking back out across the basolateral membrane and being returned to the systemic circulation.89 The primacy of the Na + reabsorptive effect is also suggested by the response to the diuretic amiloride (see C hap 15) This agent closes the luminal Na + channels and at least transiently prevents the aldosterone-induced increases in K + secretion, luminal K + permeability, and Na + -K + -ATPase activity.88,90 Other hormones can also enhance distal K + secretion, including ADH, which appears to increase the number of luminal K + channels.91,92 Although ADH is not a primary regulator of K + excretion, the elevation in luminal K + permeability may be physiologically important It can counteract the associated reduction in distal flow due to ADH-induced water reabsorption, thereby preventing an undesired decrease in K + excretion.91 Plasma Potassium Concentration The plasma K + concentration can directly affect K + excretion, independent of other factors such as aldosterone.93 An example of this relationship is illustrated in Fig 12-10 Dogs were adrenalectomized, given aldosterone replacement at different doses, and then studied at different levels of K + intake As intake was increased, there was a gradual elevation in the plasma K + concentration When aldosterone replacement was at a normal level (50 µg/day, middle curve), urinary K + excretion remained at low levels until the plasma K + concentration exceeded 4.2 meq/L At this point, K + excretion increased markedly in an attempt to maintain K + balance This presumably reflected a direct effect of the plasma K + concentration, since aldosterone levels, Na + intake, and the urine output were relatively constant In intact animals, however, aldosterone secretion will rise after a K + load, resulting in even more rapid excretion of K + (left curve, Fig 12-10) The kidney is normally so efficient in excreting excess K + that chronic hyperkalemia cannot occur unless there is an associated defect in urinary K + excretion Studies in adrenalectomized animals have also elucidated the mechanism by which the plasma K + concentration affects distal K + secretion.94,95 Potassium alone replicates all of the changes in the principal cells that are induced by aldosterone: It increases Na + reabsorption and K + secretion, luminal membrane permeability to Na + and K + (by increasing the number of open channels),75 and the activity of the Na + -K + -ATPase pump.94 How these changes occur is not known They are, however, less prominent that those seen when a K + load is appropriately accompanied by a rise in aldosterone secretion.96 The experiments in Fig 12-10 also demonstrate the effect of chronic changes in aldosterone secretion on the steady-state plasma K + concentration.80 If K + intake and excretion are normal at 50 meq/day, the plasma K + concentration will be approximately 4.3 meq/L in dogs receiving physiologic levels of aldosterone (50 µg/day), 3.4 meq/L with hyperaldosteronism (250 µg/day), and 5.0 meq/L with hypoaldosteronism (20 µg/day) When less aldosterone is available, for example, urinary K + excretion becomes less efficient; as a result, a higher plasma K + concentration is required to establish a new steady state in which intake again equals excretion Thus, hypoaldosteronism is associated with hyperkalemia, whereas primary hyperaldosteronism enhances urinary K + loss, often leading to a fall in the plasma K + concentration (see C haps 27 and 28) Figure 12-10 Mean values for plasma potassium concentration and steady-state urinary potassium excretion in adrenalectomized dogs given different levels of aldosterone replacement and studied at increasing levels of K + intake The dashed line represents the effects seen when K + excretion is 50 meq/day (From Young DB, Paulsen AW, Am J Physiol 244:F28, 1983, with permission.) Distal Flow Rate Increasing distal flow rate is another potentially important stimulus of distal K + secretion (Fig 12-11).97,99 This response is most prominent in the presence of a high-K + diet, since the concurrent elevations in aldosterone release and the plasma K + concentration produce a high basal level of K + secretion In comparison, K + depletion can lead to net reabsorption, not secretion, in the distal nephron.66 It is not surprising, therefore, that distal flow has little or no effect of K + secretion in this setting.97 The mechanism by which distal flow affects renal K + handling is incompletely understood, but changes in the tubular fluid K + concentration appear to play an important role.98 As described previously, almost all of the filtered K + is reabsorbed in the proximal tubule and loop of Henle; as a result, the K + concentration in the fluid entering the distal nephron may be less than meq/L Figure 12-11 C ombined effects of dietary intake and distal tubular flow rate on distal K + secretion (From Khuri RM, Wiederholt M, Strieder N, Giebisch G, Am J Physiol 228:1249, 1975, with permission.) The combination of K + secretion and, if ADH is present, water reabsorption in the cortical collecting tubule raises the tubular fluid K + concentration.98 Increasing distal flow washes the secreted K + away and replaces it with relatively K + -free fluid from the more proximal segments Thus, the K + concentration in the lumen is kept at a relatively low level, maintaining a favorable gradient for continued K + secretion.99 The net effect is that the tubular fluid K + concentration remains nearly constant within the physiologic range of flow rate; increasing flow results in more K + being secreted without any elevation in the luminal K + concentration.99 There may, however, be a rise in the tubular fluid K + concentration when distal flow is substantially diminished due, for example, to volume depletion.99 In this setting, the high luminal concentration (due to less washout of secreted K + ) and the low urine flow lead to a reduction in the absolute rate of K + secretion The flow dependence of K + secretion may also be related to changes in the delivery of Na + to the distal secretory site.99 Increased distal flow is generally associated with enhanced NA + delivery to and reabsorption in the cortical collecting tubule As noted above, this elevation in Na + transport has two effects that favor K + secretion: The entry of Na + into the cells through its channels in the luminal membrane makes the lumen relatively electronegative, creating an electrical gradient that favors the movement of K + from the cells into the lumen (see below), and the subsequent transport of this Na + out of the cell by the Na + -K + -ATPase pump in the basolateral membrane results in the entry of new K + into the cells, thereby providing more K + for continued secretion Thus, the flow dependence of K + secretion is probably mediated by the parallel changes in both water98,100 and Na + delivery.99 Physiologic role The relationship between K + secretion and distal flow rate plays an important role in allowing aldosterone to regulate Na + and K + balance independently 80 and, as mentioned above, in allowing ADH to regulate H2O balance without affecting the secretion of K + (see page 184).91,92 As an example, a Na + load expands the extracellular volume, resulting in a reduction in the secretion of renin and therefore that of aldosterone Although the latter change promotes the excretion of the excess Na + (by decreasing cortical collecting tubule Na + reabsorption), it should also lead to K + retention and hyperkalemia This does not happen, however, since volume expansion tends to increase the glomerular filtration rate (GFR) and to diminish proximal Na + reabsorption (see C hap 8), both of which augment the distal flow rate The enhanced flow counteracts the fall in aldosterone release, resulting in little or no change in K + excretion.80,101 The outcome will be different if a Na + load is administered in the presence of nonsuppressible aldosterone secretion, as occurs in patients with primary hyperaldosteronism.102 In this setting, the combination of increased distal flow and normal or elevated aldosterone levels leads to enhanced urinary K + excretion and a reduction in the plasma K + concentration.102,103 These changes are reversed with volume depletion, as the combination of increased aldosterone release and reduced distal flow allows Na + to be conserved without substantially affecting K + balance.80,104 These observations explain why untreated patients with heart failure or cirrhosis are typically normokalemic, despite the common presence of secondary hyperaldosteronism and high ADH levels If, however, distal flow is increased, then inappropriate K + wasting is likely to ensue This appears to be the major mechanism by which the loop and thiazide diuretics induce hypokalemia.105 These agents enhance distal delivery by diminishing Na + and water reabsorption in the loop of Henle and distal tubule, respectively (see C hap 15) They also tend to stimulate aldosterone secretion, because of the concomitant reduction in extracellular volume Sodium Reabsorption and the Transepithelial Potential Difference Since K + is a charged particle, its secretion is importantly affected by the transepithelial potential difference across the tubular cell The normal potential difference in the K + -secreting cells is approximately -15 to -50 mV (lumen negative).89,106,107 This potential is generated by the transport of Na + from the lumen into the peritubular capillary (Fig 12-12) Since Na + is positively charged, its reabsorption makes the lumen relatively electronegative C l- is passively reabsorbed via the paracellular route down this electrical gradient; there is, however, a finite time lag, and it is this delay that is responsible for the observed potential difference The importance of Na + in the generation of this potential can be illustrated by the response to replacing luminal Na + with a nonreabsorbable cation, such as choline + 106 In this setting, the potential difference falls to zero (Fig 12-12) On the other hand, replacing luminal C l- with a poorly reabsorbed anion, such as SO 42- increases the anion delay and augments the potential difference The central role of the Na + -generated potential difference on K + secretion can be illustrated by the response to the diuretic amiloride.79,105 This agent impairs the entry of luminal Na + into the cells of the distal nephron by closing the Na + channels in the luminal membrane.108 The net effect is diminished Na + reabsorption and a reduction in the transepithelial potential difference, even in the presence of aldosterone.79,88,105 There is also a marked fall in K + secretion; it is likely that this effect is due to the decrease in potential difference, since amiloride has no known direct influence on K + handling.108 Figure 12-12 Schematic repre-sentation of the electrical events in a typical principal cell in the cortical collecting tubule (a) Na + is actively transported from the lumen into the capillary C l- follows via the paracellular route after a finite time lag; this delay is responsible for the trans-epithelial potential difference of -35 to -50 mV, lumen negative (b) Replacing Na + in the lumen with the nonreabsorbable cation choline essentially eliminates the potential difference, illustrating the central role of Na + transport (c) Replacing C l- in the lumen with the non-reabsorbable anion SO 2- increases the anion delay and enhances the potential difference, thereby favoring the secretion of K + into the lumen (Data from Giebisch G, Malnic G, Klose RM, Windhager EE, Am J Physiol 211:560, 1966, with permission.) The stimulatory effect of Na + transport on K + secretion is more prominent if Na + is delivered with an anion other than Cl- that is nonreabsorbable In this setting, there will be less C l- available for reabsorption to dissipate the lumen-negative electrical gradient created by Na + entry into the cell As an example, a volume-depleted subject has a strong stimulus to Na + reabsorption in the cortical collecting tubule that is mediated by aldosterone In this situation, the administration of Na 2SO results in Na + reabsorption without SO 42- and, consequently, increases in the potential difference (Fig 12-12) and K + secretion.107,109,110 In contrast, if Na + balance and therefore both C l- delivery and aldosterone secretion are normal, there is no stimulus to retain the excess Na + , and Na 2SO is excreted with only a small elevation in K + secretion.109,110 A clinical example of this phenomenon may follow the intravenous administration of the antibiotic carbenicillin, which contains 4.7 meq of Na + per gram Thirty grams of this compound contains approximately 140 meq of the carbenicillin anion; the presence of this nonreabsorbable anion in the tubular fluid can, in some patients, lead to enhanced urinary K + loss and hypokalemia.111,112 Studies in humans suggest that, in addition to volume status, the nonreabsorbable anion itself may be a determinant of the effect on K + secretion.110 Although the ability of sulfate to enhance K + loss is minimized by euvolemia, HC O - is still able to promote K + secretion in this setting How this might occur is not known Extracellular pH As noted above, changes in the extracellular pH produce reciprocal H+ and K + shifts between the cells and the EC F As a result, K + tends to move into cells with alkalemia and out of cells with acidemia These changes in the cell K + concentration will tend to reduce K + secretion in acidemia and to increase K + secretion in alkalemia.113,114 and 115 These pH-induced effects, however, are transient and are frequently overridden by concurrent variations in other factors that affect K + handling.116,117 In type renal tubular acidosis, for example, proximal HC O - reabsorption is impaired (see C hap 19) As a result, there is increased delivery of Na + , the poorly reabsorbable anion HC O - 3, and water to the distal secretory site These changes overcome the direct effect of acidosis, and K + loss ensues.118,119 A similar sequence occurs in diabetic ketoacidosis, where Na + and water are delivered to the distal nephron with the ketoacid anions, β -hydroxybutyrate and acetoacetate Renal Response to Potassium Depletion and Potassium Loading The regulation of K + excretion can be summarized by reviewing the renal responses to changes in K + balance Potassium depletion K + excretion, for example, appropriately falls with K + depletion.63,66,120 This response is initially mediated by diminished release of aldosterone,120 which represents a direct effect of K + on the adrenal zona glomerulosa cells.121 Within several days, however, a decrease in the cell K + concentration in the distal nephron probably assumes primary importance.120 At this time, neither the administration of aldosterone 120,122 nor increasing distal flow rate (Fig 12-11) substantially enhances urinary K + loss The fall in K + excretion in this setting is due both to reduced secretion and to active K + reabsorption.61,66 The latter process occurs in the intercalated cells in the cortex and outer medulla 66,67 and appears to be mediated by a luminal H+ -K + -ATPase pump.69,71 The activity of this pump, which reabsorbs K + and secretes H+ , increases with K + depletion.70,71 This change is associated with an elevation in luminal membrane area in the intercalated cells,66,67 due at least in part to insertion of new H+ -K + -ATPase pumps in the luminal membrane.61 The net effect is that K + excretion can be lowered to 15 to 25 meq/day with a total K + deficit of 50 to 150 meq, and to to 15 meq/day with more marked K + loss.123 The inability to conserve K + more efficiently may be related to passive leakage down a favorable concentration gradient of cellular K + into the tubular lumen through a relatively nonselective cation channel in the terminal nephron segment, the inner medullary collecting duct.124 Potassium loading Urinary K + excretion increases after a K + load.60 This response is so efficient that normal subjects can maintain K + balance even if K + intake is slowly increased from the normal level of 60 to 80 meq/day up to 500 meq/day or more.125,126 This response is mediated both by aldosterone and by a rise in the plasma K + concentration.80,126 The ability to handle what might be a lethal K + load if given acutely is called K + adaptation and is due primarily to more rapid K + excretion in the urine.127 Early adaptation can be induced by a single normal meal As an example, rats fed a meal containing K + were better able to excrete an intravenous K + load several hours later than fasted rats; more rapid urinary excretion meant that there was a smaller elevation in the plasma K + concentration.128 In addition to increased urinary excretion, two other factors, both of which are promoted by aldosterone, also may contribute to more chronic adaptation: enhanced K + entry into extrarenal cells,129,130 the importance of which is uncertain,131 and increased gastrointestinal losses due to colonic secretion of K + 132,133 The increase in urinary K + excretion during adaptation is due to enhanced K + secretion throughout the late distal nephron, including the short connecting segment, and the principal cells in the cortical and outer medullary collecting tubules.66,84,95,96,134 The efficacy of this response is illustrated in Fig 12-13, which shows that distal K + secretion at a given plasma K + concentration is two to four times higher in K + -adapted rats.61 In addition to increased secretion, decreased reabsorption in the intercalated cells (mediated by a decrease in activity of the K + -ATPase pump) also may contribute to the kaliuresis.72 Figure 12-13 Relationship between plasma K + concentration (which is elevated by KC l infusion) and distal K + secretion in control animals (circles) and adapted animals (squares) given a high-K + diet for weeks At any plasma K + concentration, K + secretion is two to four times higher in the adapted animals (From Stanton BA, Am J Physiol 257:R989, 1989, with permission.) Both increased secretion of aldosterone and a small elevation in the plasma K + concentration are required for the complete expression of this response.84,96 They act in part by enhancing Na + -K + -ATPase activity in these distal segments,95,135 either directly or by increasing the entry of luminal Na + into the cell.87,90,94 The morphologic correlate of this increase in Na + -K + -ATPase activity is a marked increase in the area of the basolateral membrane, the site at which the Na + -K + -ATPase pumps are inserted.61 This morphologic change begins within the first day of a high K + intake and does not reach a plateau until weeks The role of these parameters in humans can be illustrated by the response to chronic K + loading (400 meq/day) in normal subjects (Fig 12-14).126 The plasma K + concentration rose from 3.8 to 4.8 meq/L and the plasma aldosterone concentration increased 2.5-fold in the first days By 20 days, however, both the plasma K + concentration (4.2 meq/L) and the plasma aldosterone concentration had partially returned toward baseline levels, even though urinary K + excretion remained very high The increased efficiency of K + secretion at this time was probably related to the hyperkalemia-induced rise in Na + -K + -ATPase activity.126 Indirect evidence in support of this hypothesis was the observation that discontinuing the K + load led to transient Na + retention, which could have reflected the time required for distal Na + -K + -ATPase activity to fall back to normal Figure 12-14 Response to increasing K + intake to 400 meq/day in normal subjects Urinary K + excretion rises to this level within days and is then maintained This response is initially driven by elevations in the plasma K + and aldosterone concentrations By day 20, the efficiency of K + secretion has increased, resulting in a lesser elevation in the plasma K + concentration (to 4.2 meq/L) and normalization of the plasma aldosterone concentration (Adapted from Rabelink TJ, Koomans HA, Hené RJ, Dorhout Mees EJ, Kidney Int 38:942, 1990 Reprinted by permission from Kidney International.) The major clinical example of K + adaptation occurs in chronic renal failure, in which the combination of a constant K + intake and fewer functioning nephrons requires an increase in K + excretion per nephron.136,137 This allows K + balance to be maintained even in advanced disease as long as intake is not excessive, the urine output and therefore the distal flow rate are adequate, and aldosterone secretion can be appropriately increased.138,139 Studies in experimental animals with renal failure have shown that Na + -K + -ATPase activity in the distal nephron is elevated, an expected correlate of enhanced K + secretion per nephron.140 However, this elevation in pump activity is seen only when K + intake is normal, not when intake is restricted in proportion to the fall in GFR, a setting in which increased K + excretion per nephron is not required.140 This finding suggests that the rise in Na + -K + -ATPase activity is appropriate and specific, not incidentally induced by renal insufficiency Enhanced colonic secretion of K + also may play an important role in advanced renal disease.132,141 It has been estimated that increased stool losses may account for the excretion of as much as 30 to 50 percent of dietary K + in patients with end-stage renal failure on chronic dialysis.5,142 SUMMARY The maintenance of a normal plasma K + concentration is dependent upon the ability of K + to enter the cells, where it achieves high concentrations, and upon the urinary excretion of net dietary intake After a K + load, most of the extra K + is initially taken up by the cells, a response that is facilitated by basal levels of catecholamines and insulin This cell uptake minimizes the increase in the plasma K + concentration, pending the excretion of the excess K + in the urine Urinary K + excretion is largely a function of secretion in the distal nephron, primarily in the principal cells in the cortical collecting tubule The main factors modulating this process are aldosterone and the plasma K + concentration itself Distal flow rate and the transepithelial potential difference (which is generated primarily by Na + reabsorption) play a more permissive role: They not change directly with K + balance, but relatively normal values are required for adequate K + secretion Understanding these principles can simplify the approach to patients with disorders of K + balance C hronic hyperkalemia, for example, must be associated with a defect in distal K + secretion, since the adaptation response would normally permit excretion of the excess K + (Fig 12-14) From the preceding discussion, the two major mechanisms by which K + secretion might be impaired are hypoaldosteronism and decreased distal flow (due to a marked volume depletion or advanced renal failure) These conditions therefore constitute most of the differential diagnosis of persistent hyperkalemia (see C hap 28) Urinary K + wasting and hypokalemia, on the other hand, are due to activation of the distal secretory process This most often occurs with hyperaldosteronism (as long as distal flow is maintained), increased distal flow (as long as aldosterone secretion is normal or elevated, as with diuretic therapy), or the delivery of Na + to the distal nephron with a nonreabsorbable anion (as is seen in ketoacidosis or type renal tubular acidosis).118,119 PROBLEMS 12-1 What effect should aldosterone deficiency have on urinary K+ excretion? What factor ultimately limits the changes that occur? 12-2 In a patient with primary hyperaldosteronism due to an adrenal adenoma, what effect will increased Na + intake have on urinary K+ excretion? How does this differ from the response in normal subjects? 12-3 K+ depletion is most often due to urinary or gastrointestinal losses of K+ What test would be helpful in differentiating between these disorders? 12-4 Untreated patients with effective circulating volume depletion due to heart failure or cirrhosis (see Chap 10) are generally normokalemic even though the activity of the renin-angiotensin-aldosterone system is frequently increased Why doesn't aldosterone promote excess urinary K+ loss in this setting? What would happen to K+ excretion if a diuretic such as furosemide were then given to increase Na + and water excretion? 12-5 Which of the following drugs can raise the plasma K+ concentration? a A converting enzyme inhibitor, which limits the formation of angiotensin II b A thiazide diuretic c A β -adrenergic blocker d An α-adrenergic blocker e An intravenous infusion of glucose 12-6 ADH increases water reabsorption in the collecting tubules In patients with central diabetes insipidus, the urine output can exceed 10 L/day, because of decreased collecting tubule water reabsorption What effect will this highoutput state have on K+ excretion? 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significance of aldosterone deficiency in hyperkalemic patients with chronic renal insufficiency Kidney Int 17:89, 1980 140 Schon DA, Silva P, Hayslett JP Mechanism of potassium excretion in renal insufficiency Am J Physiol 227:1323, 1974 141 Bastl C , Hayslett JP, Binder HJ Increased large intestinal secretion of potassium in renal insufficiency Kidney Int 12:9, 1977 142 Hayes C P Jr, Robinson RR Fecal potassium excretion in patients on chronic intermittent hemodialysis Trans Am Soc Artif Inter Organs 11:242, 1965 Footnotes * Hyperkalemia is a common finding in ketoacidosis and lactic acidosis, but factors other than acidemia are probably of primary importance In ketoacidosis, for example, both insulin deficiency and hyperosmolality (see below) promote K + movement from the cells into the EC F Thus, the incidence of hyperkalemia is similar in diabetic ketoacidosis and in nonketotic hyperglycemia, where the systemic pH is relatively normal.50 † This process is similar to NH+ recycling between the loop of Henle and the medullary collecting tubule that promotes net NH+ excretion (see page 341) ... (Table 1- 4 ) Table 1- 4 Normal plasma electrolyte concentrations Electrolyte meq/L mmol/L Cations Na+ 14 2.0 14 2.0 K+ 4.3 4.3 Ca2+a 2.5 1. 25 Mg2+a 1. 1 0.55 Total 14 9.9 14 8 .1 Cl- 10 4.0 10 4.0 HCO-3 24.0... the cortex and the inner part of the kidney, the medulla (Figs 1- 1 and 1- 2 ) Figure 1- 1 Anatomic relationships of the component parts of the nephron (Adapted from Vander R, Renal Physiology, ... (Table 2 -1 ) .10 9 ,11 0 and 11 1 Although almost all of the filtered electrolytes and water are reabsorbed, the higher GFR is required to allow the filtration and subsequent excretion of a variety of metabolic