Guyton Ch 32 PDF - Diuretics and Kidney Diseases

CHAPTER 32 UNIT V Diuretics and Kidney Diseases DIURETICS AND THEIR MECHANISMS...

CHAPTER 32 UNIT V Diuretics and Kidney Diseases DIURETICS AND THEIR MECHANISMS The general classes of diuretics, their mechanisms of OF ACTION action, and their tubular sites of action are shown in Diuretics increase the rate of urine volume output, as the Table 32-1. name implies. Most diuretics also increase the urinary excretion of solutes, especially sodium and chloride. In Osmotic Diuretics Decrease Water fact, most diuretics that are used clinically act by decreas- Reabsorption by Increasing Osmotic ing renal tubular sodium reabsorption, which causes Pressure of Tubular Fluid natriuresis (increased sodium output), in turn causing Injection of substances into the blood stream that are diuresis (increased water output). That is, in most cases, filtered by the glomerular capillaries but are not easily increased water excretion occurs secondary to inhibi- reabsorbed by the renal tubules, such as urea, mannitol, tion of tubular sodium reabsorption because sodium and sucrose, causes a marked increase in the concentra- remaining in the tubules acts osmotically to decrease tion of osmotically active molecules in the tubules. The water reabsorption. Because renal tubular reabsorption of osmotic pressure of these solutes then reduces water many solutes, such as potassium, chloride, magnesium, reabsorption, flushing large amounts of tubular fluid into and calcium, is also influenced secondarily by sodium the urine. reabsorption, many diuretics raise the renal excretion of Large volumes of urine are also formed in certain these solutes as well. diseases associated with excess solutes that fail to be The most common clinical use of diuretics is to reduce reabsorbed from the tubular fluid. For example, when extracellular fluid volume, especially in diseases associated blood glucose concentration rises to high levels in diabe- with edema and in hypertension. As discussed in Chap- tes mellitus, the increased filtered load of glucose into the ter 25, loss of sodium from the body mainly decreases tubules exceeds their capacity to reabsorb glucose (i.e., extracellular fluid volume; therefore, diuretics are usually exceeds their transport maximum for glucose). Above a administered in clinical conditions in which extracellular plasma glucose concentration of about 250 mg/dl, little of fluid volume is expanded. the extra glucose is reabsorbed by the tubules; instead, the Some diuretics can increase urine output more than excess glucose remains in the tubules, acts as an osmotic 20-fold within a few minutes after they are administered. diuretic, and increases urine flow rate. Therefore, one of However, the effect of most diuretics on renal output of the hallmarks of uncontrolled diabetes mellitus is poly- salt and water subsides within a few days due to activa- uria (frequent urination), which is balanced by a high tion of compensatory mechanisms initiated by decreased level of fluid intake (polydipsia) secondary to dehydration, extracellular fluid volume (Figure 32-1). For example, a increased extracellular fluid osmolarity, and activation of decrease in extracellular fluid volume may reduce arte- the thirst mechanism.! rial pressure and glomerular filtration rate (GFR) and increase renin secretion and angiotensin II (Ang II) for- Loop Diuretics Decrease Sodium-Chloride- mation; all these responses together eventually override Potassium Reabsorption in the Thick the chronic effects of the diuretic on urine output. Thus, in Ascending Loop of Henle the steady state, urine output becomes equal to intake, but Furosemide, ethacrynic acid, and bumetanide are powerful only after reductions in arterial pressure and extracellular diuretics that decrease reabsorption in the thick ascend- fluid volume have occurred, relieving the hypertension or ing limb of the loop of Henle by blocking the 1-sodium, edema that prompted the use of diuretics in the first place. 2-chloride, 1-potassium co-transporter located in the The many diuretics available for clinical use have dif- luminal membrane of the epithelial cells (see Figure 28- ferent mechanisms of action and, therefore, inhibit tubu- 9). These loop diuretics are among the most powerful of lar reabsorption at different sites along the renal nephron. the clinically used diuretics. 421 UNIT V The Body Fluids and Kidneys By blocking sodium-chloride-potassium co-transport the kidneys to concentrate or dilute the urine. Urinary in the luminal membrane of the loop of Henle, the loop dilution is impaired because the inhibition of sodium and diuretics increase urine output of sodium, chloride, chloride reabsorption in the loop of Henle causes more potassium, and other electrolytes, as well as water, for of these ions to be excreted, along with increased water two reasons: (1) they greatly increase the quantities of excretion. Urine concentrating ability is impaired because solutes delivered to the distal parts of the nephrons, and the renal medullary interstitial fluid concentration of these solutes act as osmotic agents to prevent water these ions, and therefore renal medullary osmolarity, is reabsorption; and (2) they disrupt the countercurrent reduced. Consequently, reabsorption of fluid from the col- multiplier system by decreasing absorption of ions lecting ducts is decreased, so the maximal concentrating from the loop of Henle into the medullary interstitium, ability of the kidneys is also greatly reduced. In addition, thereby decreasing the osmolarity of the medullary inter- decreased renal medullary interstitial fluid osmolarity stitial fluid. Therefore, loop diuretics impair the ability of reduces reabsorption of water from the descending loop of Henle. Because of these multiple effects, 20% to 30% Diuretic therapy of the glomerular filtrate may be delivered into the urine, causing urine output, under acute conditions, to be as great as 25 times normal for at least a few minutes.! sodium intake (mEq/day) 200 Excretion Sodium excretion or Thiazide Diuretics Inhibit Sodium- Chloride Reabsorption in the Early Distal 100 Tubule Intake The thiazide derivatives, such as chlorothiazide, act mainly on the early distal tubules to block the sodium- chloride co-transporter in the luminal membrane of the tubular cells (see Figure 28-10). Under favorable condi- 15.0 tions, these agents may cause a maximum of 5% to 10% Extracellular fluid volume (liters) of the glomerular filtrate to pass into the urine, which is about the same amount of sodium normally reabsorbed 14.0 by the distal tubules.! 13.0 Carbonic Anhydrase Inhibitors Block Sodium Bicarbonate Reabsorption Acetazolamide inhibits the enzyme carbonic anhy- −4 −2 0 2 4 6 8 drase, which is critical for reabsorption of bicarbonate Time (days) (HCO3−) in the renal tubules, as discussed in Chapter 31. Figure 32-1. Sodium excretion and extracellular fluid volume during Carbonic anhydrase is especially abundant in the proxi- diuretic administration. The immediate increase in sodium excretion mal tubule, the primary site of action of carbonic anhy- is accompanied by a decrease in extracellular fluid volume. If sodium intake is held constant, compensatory mechanisms will eventually re- drase inhibitors. Some carbonic anhydrase is also present turn sodium excretion to equal sodium intake, thus re-establishing in other tubular cells, such as in the intercalated cells of sodium balance. the collecting tubule. Table 32-1 Classes of Diuretics, Their Mechanisms of Action, and Tubular Sites of Action Class of Diuretic (examples) Mechanism of Action Tubular Site of Action Osmotic diuretics (mannitol) Inhibit water and solute reabsorption by Mainly proximal tubules increasing osmolarity of tubular fluid Loop diuretics (furosemide, Inhibit Na+-K+-Cl− co-transport in luminal Thick ascending loop of bumetanide) membrane Henle Thiazide diuretics (hydrochloro- Inhibit Na+-Cl− co-transport in luminal Early distal tubules thiazide, chlorthalidone) membrane Carbonic anhydrase inhibitors Inhibit H+ secretion and HCO3− reabsorption, Mainly proximal tubules (acetazolamide) which reduces Na+ reabsorption Aldosterone antagonists Inhibit action of aldosterone on tubular receptor, Collecting tubules (spironolactone, eplerenone) decrease Na+ reabsorption, decrease K+ secretion Sodium channel blockers Block entry of Na+ into Na+ channels of Collecting tubules (triamterene, amiloride) luminal membrane, decrease Na+ reabsorption, decrease K+ secretion 422  Chapter 32 Diuretics and Kidney Diseases Because hydrogen ion (H+) secretion and HCO3− KIDNEY DISEASES reabsorption in the proximal tubules are coupled to sodium reabsorption through the sodium-hydrogen ion Diseases of the kidneys are among the most important counter-transport mechanism in the luminal membrane, causes of death and disability in many countries through- decreasing HCO3− reabsorption also reduces sodium out the world. For example, in 2018, more than 14% of reabsorption. The blockage of sodium and HCO3− reab- adults in the United States, or more than 30 million peo- UNIT V sorption from the tubular fluid causes these ions to remain ple, were estimated to have chronic kidney disease, and in the tubules and act as an osmotic diuretic. Predictably, many more millions have acute renal injury or less severe a disadvantage of the carbonic anhydrase inhibitors is that forms of kidney dysfunction. they cause some degree of acidosis because of the exces- Severe kidney diseases can be divided into two main sive loss of HCO3− in the urine.! categories: 1. Acute kidney injury (AKI), in which there is an Mineralocorticoid Receptor Antagonists abrupt loss of kidney function within a few days. Decrease Sodium Reabsorption From and The term acute renal failure is usually reserved for Potassium Secretion Into the Collecting severe acute kidney injury, in which the kidneys Tubules may abruptly stop working entirely or almost en- Spironolactone and eplerenone are mineralocorticoid tirely, necessitating renal replacement therapy such receptor antagonists that compete with aldosterone for as dialysis, as discussed later in this chapter. In some receptor-binding sites in the collecting tubule and col- cases, patients with AKI may eventually recover lecting duct epithelial cells and, therefore, can decrease nearly normal kidney function. the reabsorption of sodium and secretion of potassium 2. Chronic kidney disease (CKD), in which there is in these tubular segments (see Figure 28-12). As a con- progressive loss of function of more and more sequence, sodium remains in the tubules and acts as an nephrons that gradually decreases overall kidney osmotic diuretic, causing increased excretion of water, as function. well as sodium. Because these drugs also block the effect Within these two general categories, there are many of aldosterone to promote potassium secretion in the specific kidney diseases that can affect the kidney blood tubules, they decrease the excretion of potassium. vessels, glomeruli, tubules, renal interstitium, and parts of Mineralocorticoid receptor antagonists also cause the urinary tract outside the kidney, including the ureters movement of potassium from the cells to the extra- and bladder. In this chapter, we discuss specific physio- cellular fluid. In some cases, this movement causes logic abnormalities that occur in a few of the more impor- extracellular fluid potassium concentration to increase tant types of kidney diseases.! excessively. For this reason, spironolactone and other mineralocorticoid receptor antagonists are referred to as ACUTE KIDNEY INJURY potassium-sparing diuretics. Many of the other diuretics cause loss of potassium in the urine, in contrast to the The causes of AKI are often divided into three main mineralocorticoid receptor antagonists, which spare the categories: loss of potassium.! 1. AKI resulting from decreased blood supply to the kidneys. This condition is often referred to as pre- Sodium Channel Blockers Decrease renal AKI to reflect an abnormality originating out- Sodium Reabsorption in the Collecting side the kidneys. For example, prerenal AKI can be Tubules a consequence of heart failure with reduced cardiac Amiloride and triamterene also inhibit sodium reabsorp- output and low blood pressure or conditions as- tion and potassium secretion in the collecting tubules, sociated with diminished blood volume and low similar to the effects of spironolactone. However, at the blood pressure, such as severe hemorrhage. cellular level, these drugs act directly to block the entry 2. Intrarenal AKI resulting from abnormalities with- of sodium into the sodium channels of the luminal mem- in the kidney itself, including those that affect the brane of the collecting tubule epithelial cells (see Figure blood vessels, glomeruli, or tubules. 28-12). Because of this decreased sodium entry into the 3. Postrenal AKI, resulting from obstruction of the epithelial cells, there is also decreased sodium transport urinary collecting system anywhere from the caly- across the cells’ basolateral membranes and, therefore, ces to the outflow from the bladder. The most decreased activity of the sodium-potassium–adenos- common causes of obstruction of the urinary tract ine triphosphatase pump (Na+-K+ ATPase pump). This outside the kidney are kidney stones, caused by decreased activity reduces the transport of potassium into precipitation of calcium, urate, or cystine. the cells and ultimately decreases the secretion of potas- In some important causes of AKI, such as sepsis, sium into the tubular fluid. For this reason, the sodium prerenal (e.g., reduced blood pressure) and intrarenal channel blockers are also potassium-sparing diuretics and (endothelial and tubular injury) abnormalities may occur decrease the urinary excretion rate of potassium.! simultaneously. 423 UNIT V The Body Fluids and Kidneys PRERENAL ACUTE KIDNEY INJURY Table 32-2 Some Causes of Prerenal Acute Kidney CAUSED BY DECREASED BLOOD FLOW Injury TO THE KIDNEY Intravascular Volume Depletion The kidneys normally receive an abundant blood supply Hemorrhage (e.g., trauma, surgery, postpartum, gastrointestinal) of about 1100 ml/min, or about 20% to 25% of the car- Diarrhea or vomiting diac output. The main purpose of this high blood flow to the kidneys is to provide enough plasma for the high rates Burns of glomerular filtration needed for effective regulation of Cardiac Failure body fluid volumes and solute concentrations. Therefore, Myocardial infarction decreased renal blood flow is usually accompanied by Valvular damage decreased GFR and decreased urine output of water and Peripheral vasodilation and resultant hypotension solutes. Consequently, conditions that acutely diminish Anaphylactic shock blood flow to the kidneys usually cause oliguria, which Anesthesia refers to diminished urine output below the level of intake Sepsis, severe infections of water and solutes. This condition causes accumula- Primary renal hemodynamic abnormalities tion of water and solutes in the body fluids. If renal blood flow is markedly reduced, total cessation of urine output Renal artery stenosis, embolism, or thrombosis of renal artery or vein can occur, a condition referred to as anuria. As long as renal blood flow does not fall below about 20% to 25% of normal, AKI can usually be reversed if Table 32-3 Some Causes of Intrarenal Acute Kidney the cause of the ischemia is corrected before damage Injury to the renal cells has occurred. Unlike some tissues, the kidney can endure a relatively large reduction in blood Small vessel and/or glomerular injury flow before there is major damage to the renal cells. The Vasculitis (polyarteritis nodosa) reason for this phenomenon is that as renal blood flow Cholesterol emboli is reduced, the GFR and amount of sodium chloride fil- Malignant hypertension tered by the glomeruli (as well as the filtration rate of Acute glomerulonephritis water and other electrolytes) are reduced. This decreases Tubular epithelial injury (tubular necrosis) the amount of sodium chloride that must be reabsorbed Acute tubular necrosis due to ischemia by the tubules, which use most of the energy and oxy- Acute tubular necrosis due to toxins (e.g., heavy metals, gen consumed by the normal kidney. Therefore, as renal ethylene glycol, insecticides, poison mushrooms, blood flow and GFR fall, renal oxygen consumption is also carbon tetrachloride) reduced. As the GFR approaches zero, oxygen consump- Renal interstitial injury tion of the kidney approaches the rate that is required to Acute pyelonephritis keep the renal tubular cells alive when they are not reab- Acute allergic interstitial nephritis sorbing sodium. When blood flow is reduced below this basal requirement, which is usually less than 20% to 25% of the normal renal blood flow, the renal cells become further divided into the following: (1) conditions that hypoxic, and further decreases in renal blood flow, if pro- injure the glomerular capillaries or other small renal ves- longed, will cause damage or even death of the renal cells, sels; (2) conditions that damage the renal tubular epithe- especially the tubular epithelial cells. lium; and (3) conditions that cause damage to the renal If the cause of prerenal AKI is not corrected, and interstitium. This type of classification refers to the pri- ischemia of the kidney persists longer than a few hours, mary site of injury, but because the renal vasculature and this type of renal failure can evolve into intrarenal AKI, tubular system are functionally interdependent, damage as discussed later. Acute reduction of renal blood flow is to the renal blood vessels can lead to tubular damage, and a common cause of AKI in hospitalized patients, espe- primary tubular damage can lead to damage of the renal cially those who have sustained severe injuries. Table 32- blood vessels. Some causes of intrarenal acute kidney 2 shows some of the common causes of decreased renal injury are listed in Table 32-3. blood flow and prerenal AKI.! Acute Kidney Injury Caused by INTRARENAL ACUTE KIDNEY INJURY Glomerulonephritis CAUSED BY ABNORMALITIES IN THE Acute glomerulonephritis is a type of intrarenal AKI usu- KIDNEY ally caused by an abnormal immune reaction that dam- Abnormalities that originate in the kidney and that ages the glomeruli. In about 95% of patients with this abruptly diminish urine output fall into the general cat- disease, damage to the glomeruli occurs 1 to 3 weeks egory of intrarenal AKI. This category of AKI can be after an infection elsewhere in the body, often caused by 424  Chapter 32 Diuretics and Kidney Diseases certain types of group A beta streptococci. The infection Some of these substances are carbon tetrachloride, heavy may have been a streptococcal sore throat, streptococcal metals (e.g., mercury and lead), ethylene glycol (which is tonsillitis, or even streptococcal infection of the skin. It is a major component in antifreeze), various insecticides, not the infection itself that damages the kidneys. Instead, some medications (e.g., tetracyclines) used as antibiotics, over a few weeks, as antibodies develop against the strep- and cis-platinum, used in treating certain cancers. Each tococcal antigen, the antibodies and antigen react with of these substances has a specific toxic action on the renal UNIT V each other to form an insoluble immune complex that tubular epithelial cells, causing death of many of them. As becomes entrapped in the glomeruli, especially in the a result, the epithelial cells slough away from the base- basement membrane portion of the glomeruli. ment membrane and plug the tubules. In some cases, the Once the immune complex has been deposited in the basement membrane also is destroyed. If the basement glomeruli, many of the glomerular cells begin to prolifer- membrane remains intact, new tubular epithelial cells can ate, but mainly the mesangial cells that lie between the grow along the surface of the membrane, so the tubule endothelium and epithelium. In addition, large numbers may repair itself within 10 to 20 days.! of white blood cells become entrapped in the glomeruli. Many of the glomeruli become blocked by this inflam- POSTRENAL ACUTE KIDNEY INJURY matory reaction, and those that are not blocked usually CAUSED BY ABNORMALITIES OF THE become excessively permeable, allowing protein and red LOWER URINARY TRACT blood cells to leak from the blood of the glomerular capil- Multiple abnormalities in the lower urinary tract can laries into the glomerular filtrate. In severe cases, total or block or partially block urine flow and therefore lead to almost complete renal shutdown occurs. AKI, even when the kidneys’ blood supply and other func- The acute inflammation of the glomeruli usually sub- tions are initially normal. If the urine output of only one sides in about 2 weeks and, in most patients, the kidneys kidney is diminished, no major change in body fluid com- return to almost normal function within the next few position will occur because the contralateral kidney can weeks to few months. Sometimes, however, many of the increase its urine output sufficiently to maintain relatively glomeruli are destroyed beyond repair and, in a small normal levels of extracellular electrolytes and solutes, as percentage of patients, progressive renal deterioration well as normal extracellular fluid volume. With this type continues indefinitely, leading to CKD, as described in a of renal injury, normal kidney function can be restored if subsequent section of this chapter.! the basic cause of the problem is corrected within a few Tubular Necrosis as a Cause of Acute hours. However, chronic obstruction of the urinary tract Kidney Injury that lasts for several days or weeks can lead to irrevers- ible kidney damage. Some of the causes of postrenal AKI Another cause of intrarenal acute renal failure is tubular include the following: (1) bilateral obstruction of the ure- necrosis, which means destruction of epithelial cells in the ters or renal pelvises caused by large stones or blood clots; tubules. Some common causes of tubular necrosis are as fol- (2) bladder obstruction; and (3) obstruction of the urethra.! lows: (1) severe ischemia and inadequate supply of oxygen and nutrients to the tubular epithelial cells; and (2) poisons, PHYSIOLOGICAL EFFECTS OF ACUTE toxins, or medications that destroy the tubular epithelial cells. KIDNEY INJURY Acute Tubular Necrosis Caused by Severe Renal Is- A major physiological effect of AKI is the retention of chemia. Severe ischemia of the kidney can result from water, waste products of metabolism, and electrolytes in circulatory shock or other disturbances that severely im- the blood and extracellular fluid. This can lead to water pair the blood supply to the kidneys. If the ischemia is and salt overload, which, in turn, can lead to edema and severe enough to seriously impair the delivery of nutrients hypertension. Excessive retention of potassium, how- and oxygen to the renal tubular epithelial cells, and if the ever, is often a more serious threat to patients with AKI insult is prolonged, damage or eventual destruction of the because increases in the plasma potassium concentration epithelial cells can occur. When this damage occurs, tu- (hyperkalemia) above 8 mEq/L (only twice normal) can bular cells slough off and plug many of the nephrons so be fatal. Because the kidneys are also unable to excrete that there is no urine output from the blocked nephrons; sufficient hydrogen ions, patients with AKI may experi- the affected nephrons often fail to excrete urine, even ence metabolic acidosis, which in itself can be lethal or when renal blood flow is restored to normal, as long as can aggravate the hyperkalemia. the tubules remain plugged. The most common causes of In the most severe cases of AKI, complete anuria occurs. ischemic damage to the tubular epithelium are the pre- The patient will die in 8 to 14 days unless kidney function renal causes of AKI associated with circulatory shock, as is restored or unless an artificial kidney is used to rid the discussed earlier in this chapter.! body of the excessive retained water, electrolytes, and Acute Tubular Necrosis Caused by Toxins or Medica- waste products of metabolism. Other effects of diminished tions. There is a long list of renal poisons and medications urine output, as well as treatment with an artificial kidney, that can damage the tubular epithelium and cause AKI. are discussed in the next section in relation to CKD.! 425 UNIT V The Body Fluids and Kidneys Table 32-4 Some Causes of Chronic Kidney Disease Primary kidney disease Metabolic Disorders Diabetes mellitus Obesity + Nephron number Amyloidosis Hypertension Renal Vascular Disorders Atherosclerosis Nephrosclerosis-hypertension Immunological Disorders Hypertrophy Glomerulonephritis Glomerular and vasodilation sclerosis of surviving Polyarteritis nodosa nephrons Lupus erythematosus Infections Arterial Pyelonephritis pressure Tuberculosis Glomerular Primary Tubular Disorders pressure Nephrotoxins (analgesics, heavy metals) and/or filtration Urinary Tract Obstruction Renal calculi Figure 32-2. Shown is the vicious cycle that can occur with primary kidney disease. Loss of nephrons because of disease may increase Hypertrophy of prostate pressure and flow in the surviving glomerular capillaries, which in turn Urethral constriction may eventually injure these normal capillaries as well, thus causing Congenital Disorders progressive sclerosis and eventual loss of these glomeruli. Polycystic disease Congenital absence of kidney tissue (renal hypoplasia) undergo dialysis treatment or transplantation with a functional kidney to survive. This condition is referred to as end-stage renal disease (ESRD). CHRONIC KIDNEY DISEASE IS OFTEN Experimental studies have shown that surgical removal ASSOCIATED WITH IRREVERSIBLE of large portions of the kidney initially causes adap- LOSS OF FUNCTIONAL NEPHRONS tive changes in the remaining nephrons, which lead to increased blood flow, increased GFR, and increased urine CKD is usually defined as the presence of kidney dam- output in the surviving nephrons. The exact mechanisms age or decreased kidney function that persists for at least responsible for these changes are not well understood but 3 months. CKD is often associated with progressive and involve hypertrophy (growth of the various structures of irreversible loss of large numbers of functioning neph- the surviving nephrons), as well as functional changes that rons. Serious clinical symptoms usually do not occur until decrease vascular resistance and tubular reabsorption in the number of functional nephrons falls to at least 70% to the surviving nephrons. These adaptive changes permit a 75% below normal. In fact, relatively normal blood con- person to excrete normal amounts of water and solutes, centrations of most electrolytes and normal body fluid even when kidney mass is reduced to 20% to 25% of normal. volumes can still be maintained until the number of func- Over a period of several years, however, these renal adap- tioning nephrons decreases below 20% to 25% of normal. tive changes may lead to further injury of the remaining Table 32-4 lists some of the most important causes nephrons, particularly to the glomeruli of these nephrons. of CKD. In general, CKD, like AKI, can occur because of This progressive injury may be related in part to increased disorders of the blood vessels, glomeruli, tubules, renal pressure or stretch of the remaining glomeruli, which occurs interstitium, and lower urinary tract. Despite the wide as a result of functional vasodilation of afferent arterioles or variety of diseases that can lead to CKD, the end result is increased blood pressure. The chronic increase in pressure essentially the same—a decrease in the number of func- and stretch of the small arterioles and glomeruli are believed tional nephrons. to cause injury and sclerosis of these vessels (replacement of normal tissue with connective tissue). These sclerotic lesions VICIOUS CYCLE OF CHRONIC KIDNEY can eventually obliterate the glomerulus, leading to further DISEASE LEADING TO END-STAGE RENAL reduction in kidney function, further adaptive changes in the DISEASE remaining nephrons, and a slowly progressing vicious cycle In some cases, an initial insult to the kidney leads to that eventually terminates in ESRD (Figure 32-2). The most progressive deterioration of kidney function and further effective method of slowing down this progressive loss of loss of nephrons to the point where the person must kidney function is to lower arterial pressure and glomerular 426  Chapter 32 Diuretics and Kidney Diseases Table 32-5 Most Common Causes of End-Stage Renal 2.5 Disease (ESRD) 2.0 Total No. of Patients Glomeruli (×106) Cause With ESRD (%) 1.5 Diabetes mellitus 45 UNIT V Hypertension 27 1.0 Glomerulonephritis 8 Polycystic kidney disease 2 0.5 Other, unknown 18 0.0 0 20 40 60 80 hydrostatic pressure, especially by using drugs such as Age (years) angiotensin-converting enzyme (ACE) inhibitors or Ang II Figure 32-3. Effect of aging on the number of functional glomeruli. receptor antagonists. Table 32-5 lists the most common causes of ESRD. In the early 1980s, glomerulonephritis in all its various forms through the intimal membrane of these vessels. This leak- was believed to be the most common initiating cause of age causes fibrinoid deposits to develop in the medial lay- ESRD. More recently, diabetes mellitus and hypertension ers of these vessels, followed by progressive thickening of have become recognized as the leading causes of ESRD, the vessel wall that eventually constricts the vessels and, together accounting for more than 70% of all ESRD. in some cases, occludes them. Because there is essentially Excessive weight gain (obesity) appears to be the most no collateral circulation among the smaller renal arteries, important risk factor for the two main causes of ESRD— occlusion of one or more of them causes destruction of diabetes and hypertension. As discussed in Chapter 79, a comparable number of nephrons. Therefore, much of type 2 diabetes, which is closely linked to obesity, accounts the kidney tissue becomes replaced by small amounts of for more than 90% of all cases of diabetes mellitus. Excess fibrous tissue. When sclerosis occurs in the glomeruli, the weight gain is also a major cause of essential hyperten- injury is referred to as glomerulosclerosis. sion, accounting for 65% to 75% of the risk for developing Nephrosclerosis and glomerulosclerosis occur to some hypertension in adults. In addition to causing renal injury extent in most people after the fourth decade of life, caus- through diabetes and hypertension, obesity may have ing about a 10% decrease in the number of functional additive or synergistic effects to worsen renal function in nephrons for every 10 years after the age of 40 years (Fig- patients with pre-existing kidney disease.! ure 32-3). This loss of glomeruli and overall nephron func- tion is reflected by a progressive decrease in renal blood INJURY TO RENAL BLOOD VESSELS AS A flow and GFR. Even in healthy people without underlying CAUSE OF CHRONIC KIDNEY DISEASE hypertension or diabetes, renal plasma flow and GFR may decrease by 40% to 50% by the age of 80 years. Many types of vascular lesions can lead to renal ischemia The frequency and severity of nephrosclerosis and and death of kidney tissue. The most common of these glomerulosclerosis are greatly increased by concurrent lesions are the following: (1) atherosclerosis of the larger hypertension or diabetes mellitus. Thus, benign nephro- renal arteries, with progressive sclerotic constriction of sclerosis in association with severe hypertension can lead the vessels; (2) fibromuscular hyperplasia of one or more to a rapidly progressing malignant nephrosclerosis. The of the large arteries, which also causes occlusion of the characteristic histological features of malignant nephro- vessels; and (3) nephrosclerosis, caused by sclerotic lesions sclerosis include large amounts of fibrinoid deposits in of the smaller arteries, arterioles, and glomeruli. the arterioles and progressive thickening of the vessels, Atherosclerotic or hyperplastic lesions of the large with severe ischemia occurring in the affected nephrons. arteries frequently affect one kidney more than the For unknown reasons, the incidence of malignant neph- other and, therefore, cause unilaterally diminished kid- rosclerosis and severe glomerulosclerosis is significantly ney function. As discussed in Chapter 19, hypertension higher in blacks than in whites of similar ages who have often occurs when the artery of one kidney is constricted similar degrees of severity of hypertension or diabetes.! while the artery of the other kidney is still normal, a condition analogous to so-called two-kidney Goldblatt INJURY TO THE GLOMERULI AS hypertension. A CAUSE OF CHRONIC KIDNEY Benign nephrosclerosis, the most common form of kid- DISEASE—GLOMERULONEPHRITIS ney disease, is seen to at least some extent in about 70% of postmortem examinations in people who die after the Chronic glomerulonephritis can be caused by several age of 60 years. This type of vascular lesion occurs in the diseases that cause inflammation and damage to the glo- smaller interlobular arteries and in the afferent arterioles merular capillary loops of the kidneys. In contrast to the of the kidney. It is believed to begin with leakage of plasma acute form of this disease, chronic glomerulonephritis is a 427 UNIT V The Body Fluids and Kidneys slowly progressive disease that often leads to irreversible one of the primary functions of the medulla is to provide renal failure. It may be a primary kidney disease, follow- the countercurrent mechanism for concentrating urine, ing acute glomerulonephritis, or it may be secondary to patients with pyelonephritis frequently have markedly a systemic disease, such as systemic lupus erythematosus. impaired ability to concentrate the urine. In most cases, chronic glomerulonephritis begins with With long-standing pyelonephritis, invasion of the accumulation of precipitated antigen-antibody com- kidneys by bacteria not only causes damage to the renal plexes in the glomerular membrane. In contrast to acute medulla interstitium but also progressive damage of renal glomerulonephritis, streptococcal infections account tubules, glomeruli, and other structures throughout the for only a small percentage of patients with the chronic kidney. Consequently, large parts of functional renal tis- form of glomerulonephritis. Accumulation of antigen- sue are lost, and CKD can develop.! antibody complex in the glomerular membranes causes inflammation, progressive thickening of the membranes, NEPHROTIC SYNDROME—EXCRETION OF and eventual invasion of the glomeruli by fibrous tissue. PROTEIN IN THE URINE In later stages of the disease, the glomerular capillary Nephrotic syndrome, characterized by the loss of large filtration coefficient becomes greatly reduced because quantities of plasma proteins into the urine, develops in of decreased numbers of filtering capillaries in the glo- many patients with kidney disease. In some cases, this merular tufts and because of thickened glomerular mem- syndrome occurs without evidence of other major abnor- branes. In the final stages of the disease, many glomeruli malities of kidney function, but it is usually associated are replaced by fibrous tissue and are unable to filter fluid.! with some degree of CKD. INJURY TO THE RENAL INTERSTITIUM AS The cause of the protein loss in the urine is usually A CAUSE OF CHRONIC KIDNEY DISEASE— increased permeability of the glomerular membrane. INTERSTITIAL NEPHRITIS Therefore, any disease that increases the permeability of this membrane can cause the nephrotic syndrome. Such Primary or secondary disease of the renal interstitium is diseases include the following: (1) chronic glomerulonephri- referred to as interstitial nephritis. In general, this condi- tis, which affects primarily the glomeruli and often causes tion can result from vascular, glomerular, or tubular dam- greatly increased permeability of the glomerular mem- age that destroys individual nephrons, or it can involve brane; (2) amyloidosis, which results from deposition of primary damage to the renal interstitium by poisons, an abnormal proteinoid substance in the walls of the blood drugs, and bacterial infections. vessels and seriously damages the basement membrane of Renal interstitial injury caused by bacterial infection is the glomeruli; and (3) minimal-change nephrotic syndrome, called pyelonephritis. The infection can result from differ- which is associated with no major abnormality in the glo- ent types of bacteria but especially from Escherichia coli, merular capillary membrane that can be detected with which originate from fecal contamination of the urinary light microscopy. As discussed in Chapter 27, minimal- tract. These bacteria reach the kidneys either by way of change nephropathy has been associated with an abnormal the blood stream or, more commonly, by ascension from immune response and increased T-cell secretion of cyto- the lower urinary tract via the ureters to the kidneys. kines that cause podocyte injury and increased permeabil- Although the normal bladder is able to clear bacteria ity to lower molecular weight proteins, such as albumin. readily, there are two general clinical conditions that may Minimal-change nephropathy can occur in adults, but interfere with the normal flushing of bacteria from the more frequently it occurs in children between the ages bladder: (1) the inability of the bladder to empty completely, of 2 and 6 years. Increased permeability of the glomeru- leaving residual urine in the bladder; and (2) obstruction of lar capillary membrane occasionally allows as much as urine outflow. With impaired ability to flush bacteria from 40 grams of plasma protein loss into the urine each day, the bladder, the bacteria multiply, and the bladder becomes which is an extreme amount for a young child. There- inflamed, a condition termed cystitis. Once cystitis occurs, fore, the child’s plasma protein concentration often falls it may remain localized without ascending to the kidney or, below 2 g/dl, and the colloid osmotic pressure falls from in some people, bacteria may reach the renal pelvis because a normal value of 28 mm Hg to less than 10 mm Hg. As of a pathological condition in which urine is propelled up a consequence of this low colloid osmotic pressure in the one or both of the ureters during micturition. This condi- plasma, large amounts of fluid leak from the capillaries tion is called vesicoureteral reflux and is due to failure of the all over the body into most of the tissues, causing severe bladder wall to occlude the ureter during micturition; as a edema, as discussed in Chapter 25.! result, some of the urine is propelled upward toward the kidney, carrying with it bacteria that can reach the renal NEPHRON FUNCTION IN CHRONIC KIDNEY pelvis and renal medulla, where they can initiate infection DISEASE and inflammation associated with pyelonephritis. Pyelonephritis begins in the renal medulla and there- Loss of Functional Nephrons Requires Surviving fore usually affects the function of the medulla more than Nephrons to Excrete More Water and Solutes. It would it affects the cortex, at least in the initial stages. Because be reasonable to suspect that decreasing the number of 428  Chapter 32 Diuretics and Kidney Diseases 100 GFR (ml/min) 50 Plasma concentration A Creatinine UNIT V Urea 0 concentration (mg/dl) 2 B Plasma creatinine PO4 H+ 1 C Na+, Cl– 0 0 25 50 75 100 Glomerular filtration rate (percentage of normal) Creatinine production and Positive balance Production renal excretion (g/day) 2 Figure 32-5. Representative patterns of adaptation for different types of solutes in chronic renal failure. Curve A shows the approxi- mate changes in the plasma concentrations of solutes such as creati- Excretion GFR × PCreatinine nine and urea that are filtered and poorly reabsorbed. Curve B shows 1 the approximate concentrations for solutes such as phosphate, urate, and hydrogen ion. Curve C shows the approximate concentrations for solutes such as sodium and chloride. 0 0 1 2 3 4 Days until excretion rate of creatinine returns to normal— Figure 32-4. Effect of reducing the glomerular filtration rate (GFR) the same rate at which creatinine is produced in the by 50% on the serum creatinine concentration and creatinine excre- body (Figure 32-4). Thus, under steady-state conditions, tion rate when the production rate of creatinine remains constant. creatinine excretion rate equals the rate of creatinine pro- duction, despite reductions in GFR; however, this normal functional nephrons, which reduces the GFR, would also rate of creatinine excretion occurs at the expense of an cause major decreases in renal excretion of water and sol- elevated plasma creatinine concentration, as shown in utes. Yet, patients who have lost up to 75% to 80% of their curve A of Figure 32-4. nephrons are able to excrete normal amounts of water Some solutes, such as phosphate, urate, and hydro- and electrolytes without serious accumulation of fluid or gen ions, are often maintained near the normal range most electrolytes in the body fluids. Further reduction in until GFR falls below 20% to 30% of normal. Thereafter, the number of nephrons, however, leads to electrolyte and the plasma concentrations of these substances rise, but fluid retention, and death usually ensues when the num- not in proportion to the fall in GFR, as shown in curve ber of nephrons falls below 5% to 10% of normal. B of Figure 32-5. Maintenance of relatively constant In contrast to the electrolytes, many of the waste prod- plasma concentrations of these solutes as GFR declines ucts of metabolism, such as urea and creatinine, accumu- is accomplished by excreting progressively larger frac- late almost in proportion to the number of nephrons that tions of the amounts of these solutes that are filtered at have been destroyed. The reason for this is that substances the glomerular capillaries; this occurs by decreasing the such as creatinine and urea depend largely on glomerular rate of tubular reabsorption or, in some cases, by increas- filtration for their excretion, and they are not reabsorbed ing tubular secretion rates. as avidly as the electrolytes. Creatinine, for example, is In the case of sodium and chloride ions, their plasma not reabsorbed at all, and the excretion rate is approxi- concentrations are maintained virtually constant, even mately equal to the rate at which it is filtered (neglecting with severe decreases in GFR (see curve C of Fig- the small amount that is secreted): ure 32-5). This maintenance is accomplished by greatly decreasing tubular reabsorption of these electrolytes. Creatinine filtration rate For example, with a 75% loss of functional nephrons, = GFR × Plasma creatinine concentration each surviving nephron must excrete four times as much = Creatinine excretion rate sodium and four times as much volume as under normal Therefore, if GFR decreases, creatinine excretion rate conditions (Table 32-6). Part of this adaptation occurs also transiently decreases, causing accumulation of creati- because of increased blood flow and increased GFR in nine in the body fluids and raising plasma concentration each of the surviving nephrons due to hypertrophy of the 429 UNIT V The Body Fluids and Kidneys Table 32-6 Total Kidney Excretion and Excretion per Nephron in Kidney Disease 75% Loss of ter N Wa + Increase Normal Nephrons NP K+ Na Number of nephrons 2,000,000 500,000 H+ Total glomerular filtration 125 40 Phenols rate (GFR; ml/min) Normal SO4= HPO4= Single-nephron GFR (nl/min) 62.5 80 HCO Decrease − 3 Volume excreted for all 1.5 1.5 nephrons (ml/min) Volume excreted per nephron 0.75 3.0 Kidney shutdown (nl/min) 0 3 6 9 12 Days 1.050 Figure 32-7. Effect of kidney failure on extracellular fluid constitu- Maximal ents. NPN, Nonprotein nitrogens. Specific gravity of urine 1.040 kidney is impaired, and the minimal urine osmolality and 1.030 Isosthenuria specific gravity approach those of the glomerular filtrate. Because the concentrating mechanism becomes impaired 1.020 to a greater extent than the diluting mechanism in CKD, an important clinical test of renal function is to determine Glomerular filtrate specific gravity 1.010 how well the kidneys can concentrate urine when a per- Minimal son’s water intake is restricted for 12 or more hours. 1.000 2,000,000 1,500,000 1,000,000 500,000 0 Effects of Renal Failure on the Body Fluids—Uremia Number of nephrons in both kidneys The effect of CKD on the body fluids depends on the fol- Figure 32-6. Development of isosthenuria in a patient with de- creased numbers of functional nephrons. lowing: (1) water and food intake; and (2) the degree of impairment of renal function. Assuming that a person with complete renal failure continues to ingest the same blood vessels and glomeruli, as well as functional changes amounts of water and food, the concentrations of differ- that cause the blood vessels to dilate. Even with large ent substances in the extracellular fluid would change, decreases in the total GFR, normal rates of renal excretion as shown in Figure 32-7. Important effects include: can still be maintained by decreasing the rate at which the (1) generalized edema resulting from water and salt reten- tubules reabsorb water and solutes.! tion; (2) acidosis resulting from failure of the kidneys to rid Isosthenuria—Inability of the Kidney to Concen- the body of normal acidic products; (3) high concentration trate or Dilute the Urine. One important effect of the of the nonprotein nitrogens—especially urea, creatinine, and rapid rate of tubular flow that occurs in the remaining uric acid—resulting from failure of the body to excrete the nephrons of diseased kidneys is that the renal tubules lose metabolic end products of proteins; and (4) high concen- trations of other substances excreted by the kidney, includ- their ability to concentrate or dilute the urine fully. The con- ing phenols, sulfates, phosphates, potassium, and guanidine centrating ability of the kidney is impaired mainly because bases. This total condition is called uremia because of the of the following: (1) the rapid flow of tubular fluid through high concentration of urea in the body fluids. the collecting ducts prevents adequate water reabsorption; Water Retention and Development of Edema in Chronic and (2) the rapid flow through both the loop of Henle and Kidney Disease. If water intake is restricted immediately af- collecting ducts prevents the countercurrent mechanism ter acute kidney injury begins, the total body fluid content from operating effectively to concentrate the medullary may become only slightly increased. If fluid intake is not lim- interstitial fluid solutes. Therefore, as progressively more ited, and the patient drinks in response to the normal thirst nephrons are destroyed, the maximum concentrating abil- mechanisms, the body fluids begin to increase rapidly. ity of the kidney declines, and urine osmolarity and specific As long as salt and fluid intake are not excessive, accu- gravity approach the osmolarity and specific gravity of the mulation of fluid in CKD may not be severe until kidney glomerular filtrate, as shown in Figure 32-6. function falls to 25% of normal or lower. The reason for this, as discussed previously, is that the surviving nephrons The diluting mechanism in the kidney is also impaired excrete larger amounts of salt and water. Even the small when the number of nephrons decreases markedly because fluid retention that does occur, along with increased secre- the rapid flushing of fluid through the loops of Henle and tion of renin and Ang II formation that usually occurs in high load of solutes such as urea cause a relatively high ischemic kidney disease, often causes severe hypertension. solute concentration in the tubular fluid of this part of the When kidney function so reduced that dialysis is required nephron. As a consequence, the diluting capacity of the to preserve life, hypertension almost invariably develops. 430  Chapter 32 Diuretics and Kidney Diseases In many of these patients, severe reduction of salt intake or ionized calcium concentration, which, in turn, stimulates removal of extracellular fluid by dialysis can control the hy- parathyroid hormone secretion. This secondary hyperpar- pertension. Some patients continue to have hypertension, athyroidism then stimulates the release of calcium from even after excess sodium has been removed by dialysis. In bones, causing further bone demineralization. this group, removal of the ischemic kidneys usually corrects the hypertension (as long as fluid retention is prevented by Hypertension and Kidney Disease UNIT V dialysis) because it removes the source of excessive renin As discussed earlier in this chapter, hypertension can exacer- secretion and subsequent increased Ang II formation. bate injury to the glomeruli and blood vessels of the kidneys Increase in Urea and Other Nonprotein Nitrogens and is a major cause of ESRD. Abnormalities of kidney func- (Azotemia). The nonprotein nitrogens include urea, uric tion can also cause hypertension, as discussed in Chapter 19. acid, creatinine, and a few less important compounds. These Thus, the relationship between hypertension and kidney dis- nonprotein nitrogens, in general, are the end products of pro- ease can, in some cases, propagate a vicious cycle—primary tein metabolism and must be removed from the body to en- kidney damage leads to increased blood pressure, which sure continued normal protein metabolism in the cells. The causes further damage to the kidneys and further increases concentrations of these nonprotein nitrogens, particularly of in blood pressure, until ESRD develops. urea, can rise to as high as 10 times normal during 1 to 2 Not all types of kidney disease cause hypertension be- weeks of total renal failure. With CKD, the concentrations cause damage to certain portions of the kidney causes ure- rise approximately in proportion to the degree of reduction mia without hypertension. Nevertheless, some types of renal of GFR. For this reason, measuring the concentrations of damage are particularly prone to cause hypertension. A clas- these substances, especially of urea and creatinine, provides sification of kidney disease relative to hypertensive or non- an important means for assessing the severity of CKD. hypertensive effects is provided in the following sections. Acidosis in CKD. Each day, the body normally produces Renal Lesions That Reduce the Ability of the Kidneys to about 50 to 80 millimoles more metabolic acid than meta- Excrete Sodium and Water Promote Hypertension. Renal bolic alkali. Therefore, when the kidneys fail to function, lesions that decrease the ability of the kidneys to excrete acid accumulates in the body fluids. The buffers of the body sodium and water almost invariably cause hypertension. fluids normally can buffer 500 to 1000 millimoles of acid Therefore, lesions that decrease GFR or increase tubular without lethal increases in extracellular fluid H+ concentra- reabsorption usually lead to hypertension of varying de- tion, and the phosphate compounds in the bones can buff- grees. Some specific types of renal abnormalities that can er an additional few thousand millimoles of H+. However, cause hypertension are as follows: when this buffering power is exhausted, the blood pH falls 1. Increased renal vascular resistance, which reduces drastically, and the patient will become comatose and die if renal blood flow and GFR. An example is hyperten- the pH falls below about 6.8. sion caused by renal artery stenosis. Anemia in Chronic Kidney Disease Caused by De- 2. Decreased glomerular capillary filtration coefficient, creased Erythropoietin Secretion. Anemia almost always which reduces GFR. An example is chronic glomer- develops in patients with severe CKD. The most important ulonephritis, which causes inflammation and thicken- cause of this anemia is decreased renal secretion of eryth- ing of the glomerular capillary membranes, thereby ropoietin, which stimulates the bone marrow to produce reducing the glomerular capillary filtration coefficient. red blood cells. If the kidneys are seriously damaged, they 3. Excessive tubular sodium reabsorption. An example are unable to form adequate quantities of erythropoietin, is hypertension caused by excessive aldosterone se- which leads to diminished red blood cell production and cretion, which increases sodium reabsorption main- consequent anemia. ly in the cortical collecting tubules. The availability since 1989 of recombinant erythropoi- Once hypertension has developed, renal excretion of etin, however, has provided a means of treating anemia in sodium and water returns to normal because the high arte- patients with chronic renal failure. rial pressure causes pressure natriuresis and pressure diu- Osteomalacia in Chronic Kidney Disease Caused by De- resis, so intake and output of sodium and water become creased Production of Active Vitamin D and by Phosphate balanced once again. Even when there are large increases Retention by the Kidneys. Prolonged CKD also causes in renal vascular resistance or decreases in the glomerular osteomalacia, a condition in which the bones are partially capillary coefficient, GFR may still return to nearly nor- absorbed and, therefore, become greatly weakened. An im- mal levels after the arterial blood pressure rises. Likewise, portant cause of osteomalacia is that vitamin D must be when tubular reabsorption is increased, as occurs with ex- converted by a two-stage process, first in the liver and then cessive aldosterone secretion, the urinary excretion rate is in the kidneys, into 1,25-dihydroxycholecalciferol before it initially reduced but then returns to normal as arterial pres- is able to promote calcium absorption from the intestine. sure rises. Thus, after hypertension develops, there may be Therefore, serious damage to the kidney greatly reduces the no obvious sign of impaired excretion of sodium and water blood concentration of active vitamin D, which in turn de- other than the hypertension. As explained in Chapter 19, creases intestinal absorption of calcium and availability of normal excretion of sodium and water at an elevated arte- calcium to the bones. rial pressure means that pressure natriuresis and pressure Another important cause of demineralization of the diuresis have been reset to a higher arterial pressure. skeleton in CKD is the rise in serum phosphate concen- Hypertension Caused by Patchy Renal Damage and tration that occurs as a result of decreased GFR. This rise Increased Renal Secretion of Renin. If one part of the kid- in serum phosphate level increases binding of phosphate ney is ischemic, and the remainder is not ischemic, such as with calcium in the plasma, thus decreasing plasma serum when one renal artery is severely constricted, the ischemic 431 UNIT V The Body Fluids and Kidneys renal tissue secretes large quantities of renin. This secretion protein is formed in response to a respective gene in the leads to increased formation of Ang II, which can cause hy- nucleus. If any required gene happens to be absent or ab- pertension. The most likely sequence of events in causing normal, the tubules may be deficient in one of the appropri- this hypertension, as discussed in Chapter 19, is as follows: ate carrier proteins or one of the enzymes needed for solute (1) the ischemic kidney tissue excretes less than normal transport by the renal tubular epithelial cells. In other cas- amounts of water and salt; (2) the renin secreted by the is- es, too much of the enzyme or carrier protein is produced. chemic kidney, as well as the subsequent increased Ang II Thus, many hereditary tubular disorders occur because of formation, affects the nonischemic kidney tissue, causing it abnormal transport of individual substances or groups of also to retain salt and water; and (3) excess salt and water substances through the tubular membrane. In addition, cause hypertension in the usual manner. damage to the tubular epithelial membrane by toxins or is- A similar type of hypertension can result when patchy chemia can cause important renal tubular disorders. areas of one or both kidneys become ischemic as a result of Renal Glycosuria—Failure of the Kidneys to Reabsorb arteriosclerosis or vascular injury in specific portions of the Glucose. In renal glycosuria, the blood glucose concentra- kidneys. When this occurs, the ischemic nephrons excrete tion may be normal, but the transport mechanism for tu- less salt and water but secrete greater amounts of renin, bular reabsorption of glucose is greatly limited or absent. which causes increased Ang II formation. The high levels of Consequently, despite a normal blood glucose level, large Ang II then impair the ability of the surrounding, otherwise amounts of glucose pass into the urine each day. Because normal nephrons to excrete sodium and water. As a result, diabetes mellitus is also associated with the presence of hypertension develops, which restores the overall excretion glucose in the urine, renal glycosuria, which is a relatively of sodium and water by the kidney, so balance between in- benign condition, must be ruled out before making the di- take and output of salt and water is maintained, but at the agnosis of diabetes mellitus. expense of high blood pressure. Aminoaciduria—Failure of the Kidneys to Reabsorb Amino Acids. Some amino acids share mutual transport sys- Kidney Diseases That Cause Loss of Entire Nephrons tems for reabsorption, whereas other amino acids have their Lead to Chronic Kidney Disease but May Not Cause own distinct transport systems. Rarely, a condition called Hypertension generalized aminoaciduria results from deficient reabsorp- Loss of large numbers of whole nephrons, such as occurs tion of all amino acids. More frequently, deficiencies of spe- with the loss of one kidney and part of another kidney, al- cific carrier systems may result in the following: (1) essential most always leads to CKD if the loss of kidney tissue is great cystinuria, in which large amounts of cystine fail to be reab- enough. If the remaining nephrons are normal, and salt in- sorbed and often crystallize in the urine to form renal stones; take is not excessive, this condition might not cause clini- (2) simple glycinuria, in which glycine fails to be reabsorbed; cally significant hypertension. This is because even a slight or (3) beta-aminoisobutyricaciduria, which occurs in about rise in blood pressure will raise GFR and decrease tubular 5% of the population but apparently has no major clinical sig- sodium reabsorption in the surviving nephrons sufficiently nificance. to promote enough water and salt excretion in the urine, Renal Hypophosphatemia—Failure of the Kidneys to even with the few nephrons that remain intact. However, a Reabsorb Phosphate. In renal hypophosphatemia, the renal patient with this type of abnormality may become severely tubules fail to reabsorb large enough phosphate ions when hypertensive if additional stresses are imposed, such as eat- the phosphate concentration of the body fluids falls very ing a large amount of salt. In this case, the kidneys simply low. This condition usually does not cause serious immedi- cannot clear adequate quantities of salt at a normal blood ate abnormalities because the phosphate concentration of pressure with the small number of functioning nephrons the extracellular fluid can vary widely without causing ma- that remain. Increased blood pressure restores excretion jor cellular dysfunction. Over a long period, however, a low of salt and water to match intake of salt and water under phosphate level causes diminished calcification of the bones, steady-state conditions. causing rickets to develop. This type of rickets is refractory Effective treatment of hypertension requires enhancing to vitamin D therapy, in contrast to the rapid response of the the kidneys’ capability to excrete salt and water by increas- usual type of rickets, as discussed in Chapter 80. ing GFR or by decreasing tubular reabsorption, so that bal- Renal Tubular Acidosis—Reduced Tubular Secretion of ance between intake and renal excretion of salt and water Hydrogen Ions. In renal tubular acidosis, the renal tubules excretion can be maintained at a lower blood pressure. are unable to secrete adequate amounts of hydrogen ions. As This effect can be achieved by drugs that block the effects a result, large amounts of sodium bicarbonate are continually of nervous and hormonal signals that cause the kidneys lost in the urine. This loss causes a continued state of meta- to retain salt and water (e.g., with β-adrenergic blockers, bolic acidosis, as discussed in Chapter 31. This type of renal Ang II receptor antagonists, or ACE inhibitors), with drugs abnormality can be caused by hereditary disorders or can oc- that vasodilate the kidneys and increase GFR (e.g., calcium cur as a result of widespread injury to the renal tubules. channel blockers), or with diuretic drugs that directly in- Nephrogenic Diabetes Insipidus—Failure of the Kid- hibit renal tubular reabsorption of salt and water. neys to Respond to Antidiuretic Hormone. Occasionally, Specific Tubular Disorders the renal tubules do not respond to antidiuretic hormone, causing large quantities of dilute urine to be excreted. As In Chapter 28, we discussed several mechanisms responsi- long as the person is supplied with plenty of water, this ble for transporting different individual substances across condition seldom causes severe difficulty. However, when the tubular epithelial membranes. In Chapter 3, we also adequate quantities of water are not available, the person pointed out that each cellular enzyme and each carrier rapidly becomes dehydrated. 432  Chapter 32 Diuretics and Kidney Diseases Fanconi Syndrome—Generalized Reabsorptive Defect which, in turn, decrease adrenal secretion of aldosterone. of the Renal Tubules. Fanconi syndrome is usually associ- Fortunately, Liddle syndrome can be treated with the diu- ated with increased urinary excretion of virtually all amino retic amiloride, which blocks the excessive ENaC activity. acids, glucose, and phosphate. In severe cases, other mani- Treatment of Renal Failure by Transplantation or festations are also observed, such as (1) failure to reabsorb Dialysis With an Artificial Kidney sodium bicarbonate, which results in metabolic acidosis; Severe loss of kidney function, acutely or chronically, is UNIT V (2) increased excretion of potassium and sometimes cal- cium; and (3) nephrogenic diabetes insipidus. life-threatening and requires removal of toxic waste prod- There are multiple causes of Fanconi syndrome, which re- ucts and restoration of body fluid volume and composi- sults from a generalized inability of the renal tubular cells to tion toward normal. This can be accomplished by kidney transport various substances. Some of these include the follow- transplantation or by dialysis with an artificial kidney. Over ing: (1) hereditary defects in cell transport mechanisms; (2) tox- 700,000 patients in the United States are currently receiv- ins or drugs that injure the renal tubular epithelial cells; and (3) ing some form of ESRD therapy. injury to the renal tubular cells as a result of ischemia. The prox- Successful transplantation of a single donor kidney to imal tubular cells are especially affected in Fanconi syndrome a patient with ESRD can restore kidney function to a level caused by tubular injury because these cells reabsorb and se- sufficient to maintain essentially normal homeostasis of crete many of the drugs and toxins that can cause damage. body fluids and electrolytes. Approximately 19,000 kidney Bartter Syndrome—Decreased Sodium, Chloride, and transplantations are performed each year in the United Potassium Reabsorption in the Loops of Henle. Bartter States, but over 100,000 patients await kidney transplan- syndrome is a rare group of kidney disorders caused by mu- tation. Patients who receive kidney transplants typically tations that impair function of the 1-sodium, 2-chloride, live longer and have fewer health problems than those who 1-potassium co-transporter or by defects in potassium are maintained with dialysis. Maintenance of immunosup- channels in the luminal membrane or chloride channels in pressive therapy is required for almost all patients to help the basolateral membrane of the thick ascending loop of prevent acute rejection and loss of the transplanted kidney. Henle. At least five mutations, usually inherited in an auto- The side effects of drugs that suppress the immune system somal recessive manner, have been found to cause Bartter include increased risk for infections and some cancers, syndrome. These disorders result in increased excretion of although the amount of immunosuppressive therapy can water, sodium, chloride, potassium, and calcium by the kid- usually be reduced over time to reduce these risks greatly. neys. The salt and water loss leads to mild volume depletion, Over 475,000 people in the United States who have ir- resulting in activation of the renin-angiotensin-aldosterone reversible renal failure or total kidney removal are being system (RAAS). The increased aldosterone and high distal maintained chronically by dialysis with artificial kidneys. tubular flow, due to impaired loop of Henle reabsorption, Dialysis is also used in certain types of AKI to tide the stimulate potassium and hydrogen secretion in the collect- patient over until the kidneys resume their function. If ing tubules, leading to hypokalemia and metabolic alkalosis. the loss of kidney function is irreversible, it is necessary Gitelman Syndrome—Decreased Sodium Chloride Re- to perform dialysis chronically to maintain life. Because absorption in the Distal Tubules. Gitelman syndrome is an dialysis cannot maintain completely normal body fluid autosomal-recessive disorder of the thiazide-sensitive sodium- composition and cannot replace all the multiple functions chloride co-transporter in the distal tubules. Patients with performed by the kidneys, the health of patients main- Gitelman syndrome have some of the same characteristics as tained with the use of artificial kidneys usually remains patients with Bartter syndrome—salt and water loss, mild wa- significantly impaired. ter volume depletion, and activation of the renin-angiotensin- Basic Principles of Dialysis aldosterone system—although these abnormalities are usually less severe in persons with Gitelman syndrome. The basic principle of the artificial kidney is to pass blood Because the tubular defects in Bartter or Gitelman syn- through minute blood channels bounded by a thin membrane. drome cannot currently be corrected, treatment is usually On the other side of the membrane is a dialyzing fluid into focused on replacing the losses of sodium chloride and which unwanted substances in the blood pass by diffusion. potassium. Some studies have suggested that blockade of Figure 32-8 shows the components of one type of arti- prostaglandin synthesis with nonsteroidal antiinflamma- ficial kidney in which blood flows continually between two tory drugs (NSAIDs) and administration of aldosterone thin membranes of cellophane; outside the membrane is a antagonists, such as spironolactone, may be useful in cor- dialyzing fluid. The cellophane is porous enough to allow recting the hypokalemia. the constituents of the plasma, except the plasma proteins, Liddle Syndrome—Increased Sodium Reabsorption. to diffuse in both directions—from plasma into the dialyz- ing fluid or from the dialyzing fluid back into the plasma. Liddle syndrome is a rare autosomal-dominant disorder re- If the concentration of a substance is higher in the plasma sulting from various mutations in the amiloride-sensitive than in the dialyzing fluid, there will be a net transfer of the epithelial sodium channel (ENaC) in the distal and collect- substance from the plasma into the dialyzing fluid. ing tubules. These mutations cause excessive activity of The rate of movement of solute across the dialyzing ENaC, resulting in increased reabsorption of sodium and membrane depends on the following: (1) the concentration water, hypertension, and metabolic alkalosis similar to the gradient of the solute between the two solutions; (2) the changes that occur with oversecretion of aldosterone (pri- permeability of the membrane to the solute; (3) the surface mary aldosteronism). area of the membrane; and (4) the length of time that the Patients with Liddle syndrome, however, have sodium blood and fluid remain in contact with the membrane. retention and decreased renin secretion and Ang II levels, 433 UNIT V The Body Fluids and Kidneys Table 32-7 Comparison of Dialyzing Fluid With Normal and Uremic Plasma Normal Dialyzing Uremic Constituent Plasma Fluid Plasma Semipermeable Flowing Electrolytes (mEq/L) membrane blood Na+ 142 133 142 K+ 5 1.0 7 Ca2+ 3 3.0 2 Waste Water Flowing Mg2+ 1.5 1.5 1.5 products dialysate Cl− 107 105 107 HCO3 − 24 35.7 14 Lactate− 1.2 1.2 1.2 Bubble Blood out HPO42− 3 0 9 trap Urate− 0.3 0 2 Dialyzer Sulfate= 0.5 0 3 Nonelectrolytes Blood in Glucose 100 125 100 Dialysate Dialysate Urea 26 0 200 in out Creatinine 1 0 6 Thus, the maximum rate of solute transfer occurs ini- tially when the concentration gradient is greatest (when dialysis is begun) and slows down as the concentration gradient is dissipated. In a flowing system, as is the case with hemodialysis, in which blood and dialysate fluid flow Fresh dialyzing Constant Used dialyzing through the artificial kidney, the dissipation of the concen- solution temperature solution tration gradient can be reduced, and diffusion of solute bath across the membrane can be optimized, by increasing the Figure 32-8. Principles of dialysis with an artificial kidney. flow rate of the blood, dialyzing fluid, or both. In normal operation of the artificial kidney, blood flows The effectiveness of the artificial kidney can be ex- continually or intermittently back into the vein. The total pressed in terms of the amount of plasma that is cleared amount of blood in the artificial kidney at any one time is of different substances each minute, which, as discussed in usually less than 500 milliliters, the rate of flow may be sev- Chapter 28, is the primary means for expressing the func- eral hundred milliliters per minute, and the total diffusion tional effectiveness of the kidneys themselves to rid the surface area is between 0.6 and 2.5 m2. To prevent coagula- body of unwanted substances. Most artificial kidneys can tion of the blood in the artificial kidney, a small amount of clear urea from the plasma at a rate of 100 to 225 ml/min, heparin is infused into the blood as it enters the artificial which shows that at least for the excretion of urea, the arti- kidney. In addition to the diffusion of solutes, mass trans- ficial kidney can function about twice as rapid