Guyton and Hall Textbook of Medical Physiology, 12th Ed

CHAPTER 31

Diuretics, Kidney Diseases

image Diuretics and Their Mechanisms of Action

A diuretic is a substance that increases the rate of urine volume output, as the name implies. Most diuretics also increase urinary excretion of solutes, especially sodium and chloride. In fact, most diuretics that are used clinically act by decreasing the rate of sodium reabsorption from the tubules, which causes natriuresis (increased sodium output), which in turn causes diuresis (increased water output). That is, in most cases, increased water output occurs secondary to inhibition of tubular sodium reabsorption because sodium remaining in the tubules acts osmotically to decrease water reabsorption. Because the renal tubular reabsorption of many solutes, such as potassium, chloride, magnesium, and calcium, is also influenced secondarily by sodium reabsorption, many diuretics raise renal output of these solutes as well.

The most common clinical use of diuretics is to reduce extracellular fluid volume, especially in diseases associated with edema and hypertension. As discussed in Chapter 25, loss of sodium from the body mainly decreases extracellular fluid volume; therefore, diuretics are most often administered in clinical conditions in which extracellular fluid volume is expanded.

Some diuretics can increase urine output more than 20-fold within a few minutes after they are administered. However, the effect of most diuretics on renal output of salt and water subsides within a few days (Figure 31-1). This is due to activation of other compensatory mechanisms initiated by decreased extracellular fluid volume. For example, a decrease in extracellular fluid volume may reduce arterial pressure and glomerular filtration rate (GFR) and increase renin secretion and angiotensin II formation; all these responses, together, eventually override the chronic effects of the diuretic on urine output. Thus, in the steady state, urine output becomes equal to intake, but only after reductions in arterial pressure and extracellular fluid volume have occurred, relieving the hypertension or edema that prompted the use of diuretics in the first place.

image

Figure 31-1 Sodium excretion and extracellular fluid volume during diuretic administration. The immediate increase in sodium excretion is accompanied by a decrease in extracellular fluid volume. If sodium intake is held constant, compensatory mechanisms will eventually return sodium excretion to equal sodium intake, thus re-establishing sodium balance.

The many diuretics available for clinical use have different mechanisms of action and, therefore, inhibit tubular reabsorption at different sites along the renal nephron. The general classes of diuretics and their mechanisms of action are shown in Table 31-1.

Table 31-1 Classes of Diuretics, Their Mechanisms of Action, and Tubular Sites of Action

Class of Diuretic

Mechanism of Action

Tubular Site of Action

Osmotic diuretics (mannitol)

Inhibit water and solute reabsorption by increasing osmolarity of tubular fluid

Mainly proximal tubules

Loop diuretics (furosemide, bumetanide)

Inhibit Na+-K+-Cl co-transport in luminal membrane

Thick ascending loop of Henle

Thiazide diuretics (hydrochlorothiazide, chlorthalidone)

Inhibit Na+-Cl co-transport in luminal membrane

Early distal tubules

Carbonic anhydrase inhibitors (acetazolamide)

Inhibit H+ secretion and HCO3 reabsorption, which reduces Na+ reabsorption

Proximal tubules

Aldosterone antagonists (spironolactone, eplerenone)

Inhibit action of aldosterone on tubular receptor, decrease Na+ reabsorption, and decrease K+ secretion

Collecting tubules

Sodium channel blockers (triamterene, amiloride)

Block entry of Na+ into Na+ channels of luminal membrane, decrease Na+ reabsorption, and decrease K+ secretion

Collecting tubules

Osmotic Diuretics Decrease Water Reabsorption by Increasing Osmotic Pressure of Tubular Fluid

Injection into the blood stream of substances that are not easily reabsorbed by the renal tubules, such as urea, mannitol, and sucrose, causes a marked increase in the concentration of osmotically active molecules in the tubules. The osmotic pressure of these solutes then reduces water reabsorption, flushing large amounts of tubular fluid into the urine.

Large volumes of urine are also formed in certain diseases associated with excess solutes that fail to be reabsorbed from the tubular fluid. For example, when the blood glucose concentration rises to high levels in diabetes mellitus, the increased filtered load of glucose into the tubules exceeds their capacity to reabsorb glucose (i.e., exceeds their transport maximum for glucose). Above a plasma glucose concentration of about 250 mg/dl, little of the extra glucose is reabsorbed by the tubules; instead, the excess glucose remains in the tubules, acts as an osmotic diuretic, and causes rapid loss of fluid into the urine. In patients with diabetes mellitus, the high urine output is balanced by a high level of fluid intake owing to activation of the thirst mechanism.

“Loop” Diuretics Decrease Active Sodium-Chloride-Potassium Reabsorption in the Thick Ascending Loop of Henle

Furosemide, ethacrynic acid, and bumetanide are powerful diuretics that decrease active reabsorption in the thick ascending limb of the loop of Henle by blocking the 1-sodium, 2-chloride, 1-potassium co-transporter located in the luminal membrane of the epithelial cells. These “loop” diuretics are among the most powerful of the clinically used diuretics.

By blocking active sodium-chloride-potassium co-transport in the luminal membrane of the loop of Henle, the loop diuretics raise urine output of sodium, chloride, potassium, and other electrolytes, as well as water, for two reasons: (1) they greatly increase the quantities of solutes delivered to the distal parts of the nephrons, and these act as osmotic agents to prevent water reabsorption as well; and (2) they disrupt the countercurrent multiplier system by decreasing absorption of ions from the loop of Henle into the medullary interstitium, thereby decreasing the osmolarity of the medullary interstitial fluid. Because of this effect, loop diuretics impair the ability of the kidneys to either concentrate or dilute the urine. Urinary dilution is impaired because the inhibition of sodium and chloride reabsorption in the loop of Henle causes more of these ions to be excreted along with increased water excretion. Urinary concentration is impaired because the renal medullary interstitial fluid concentration of these ions, and therefore renal medullary osmolarity, is reduced. Consequently, reabsorption of fluid from the collecting ducts is decreased, so the maximal concentrating ability of the kidneys is also greatly reduced. In addition, decreased renal medullary interstitial fluid osmolarity reduces absorption of water from the descending loop of Henle. Because of these multiple effects, 20 to 30 percent of the glomerular filtrate may be delivered into the urine, causing, under acute conditions, urine output to be as great as 25 times normal for at least a few minutes.

Thiazide Diuretics Inhibit Sodium-Chloride Reabsorption in the Early Distal Tubule

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. Under favorable conditions, these agents may cause a maximum of 5 to 10 percent of the glomerular filtrate to pass into the urine. This is about the same amount of sodium normally reabsorbed by the distal tubules.

Carbonic Anhydrase Inhibitors Block Sodium Bicarbonate Reabsorption in the Proximal Tubules

Acetazolamide inhibits the enzyme carbonic anhydrase, which is critical for the reabsorption of bicarbonate in the proximal tubule, as discussed in Chapter 30. Carbonic anhydrase is abundant in the proximal tubule, the primary site of action of carbonic anhydrase inhibitors. Some carbonic anhydrase is also present in other tubular cells, such as in the intercalated cells of the collecting tubule.

Because H+ secretion and image reabsorption in the proximal tubules are coupled to sodium reabsorption through the sodium-hydrogen ion counter-transport mechanism in the luminal membrane, decreasing imagereabsorption also reduces sodium reabsorption. The blockage of sodium and image reabsorption from the tubular fluid causes these ions to remain in the tubules and act as an osmotic diuretic. Predictably, a disadvantage of the carbonic anhydrase inhibitors is that they cause some degree of acidosis because of the excessive loss of image in the urine.

Competitive Inhibitors of Aldosterone Decrease Sodium Reabsorption from and Potassium Secretion into the Cortical Collecting Tubule

Spironolactone and eplerenone are mineralocorticoid receptor antagonists that compete with aldosterone for receptor binding sites in the cortical collecting tubule epithelial cells and, therefore, can decrease the reabsorption of sodium and secretion of potassium in this tubular segment. As a consequence, sodium remains in the tubules and acts as an osmotic diuretic, causing increased excretion of water, as well as sodium. Because these drugs also block the effect of aldosterone to promote potassium secretion in the tubules, they decrease the excretion of potassium. Mineralocorticoid receptor antagonists also cause movement of potassium from the cells to the extracellular fluid. In some instances, this causes extracellular fluid potassium concentration to increase excessively. For this reason, spironolactone and other mineralocorticoid receptor antagonists are referred to as potassium-sparing diuretics. Many of the other diuretics cause loss of potassium in the urine, in contrast to the mineralocorticoid receptor antagonists, which “spare” the loss of potassium.

Diuretics That Block Sodium Channels in the Collecting Tubules Decrease Sodium Reabsorption

Amiloride and triamterene also inhibit sodium reabsorption and potassium secretion in the collecting tubules, similar to the effects of spironolactone. However, at the cellular level, these drugs act directly to block the entry of sodium into the sodium channels of the luminal membrane of the collecting tubule epithelial cells. Because of this decreased sodium entry into the epithelial cells, there is also decreased sodium transport across the cells’ basolateral membranes and, therefore, decreased activity of the sodium-potassium-adenosine triphosphatase pump. This decreased activity reduces the transport of potassium into the cells and ultimately decreases the secretion of potassium into the tubular fluid. For this reason, the sodium channel blockers are also potassium-sparing diuretics and decrease the urinary excretion rate of potassium.

Kidney Diseases

Diseases of the kidneys are among the most important causes of death and disability in many countries throughout the world. For example, in 2009, more than 26 million adults in the United States were estimated to have chronic kidney disease, and many more millions of people have acute renal failure or less severe forms of kidney dysfunction.

Severe kidney diseases can be divided into two main categories: (1) acute renal failure, in which the kidneys abruptly stop working entirely or almost entirely but may eventually recover nearly normal function, and (2) chronic renal failure, in which there is progressive loss of function of more and more nephrons that gradually decreases overall kidney function. Within these two general categories, there are many specific kidney diseases that can affect the kidney blood vessels, glomeruli, tubules, renal interstitium, and parts of the urinary tract outside the kidney, including the ureters and bladder. In this chapter, we discuss specific physiologic abnormalities that occur in a few of the more important types of kidney diseases.

Acute Renal Failure

The causes of acute renal failure can be divided into three main categories:

1. Acute renal failure resulting from decreased blood supply to the kidneys; this condition is often referred to as prerenal acute renal failure to reflect the fact that the abnormality occurs as a result of an abnormality originating outside the kidneys. For example, prerenal acute renal failure can be a consequence of heart failure with reduced cardiac output and low blood pressure or conditions associated with diminished blood volume and low blood pressure, such as severe hemorrhage.

2. Intrarenal acute renal failure resulting from abnormalities within the kidney itself, including those that affect the blood vessels, glomeruli, or tubules.

3. Postrenal acute renal failure, resulting from obstruction of the urinary collecting system anywhere from the calyces to the outflow from the bladder. The most common causes of obstruction of the urinary tract outside the kidney are kidney stones, caused by precipitation of calcium, urate, or cystine.

Prerenal Acute Renal Failure Caused by Decreased Blood Flow to the Kidney

The kidneys normally receive an abundant blood supply of about 1100 ml/min, or about 20 to 25 percent of the cardiac output. The main purpose of this high blood flow to the kidneys is to provide enough plasma for the high rates of glomerular filtration needed for effective regulation of body fluid volumes and solute concentrations. Therefore, decreased renal blood flow is usually accompanied by decreased GFR and decreased urine output of water and solutes. Consequently, conditions that acutely diminish blood flow to the kidneys usually cause oliguria, which refers to diminished urine output below the level of intake of water and solutes. This causes accumulation of water and solutes in the body fluids. If renal blood flow is markedly reduced, total cessation of urine output can occur, a condition referred to as anuria.

As long as renal blood flow does not fall below about 20 to 25 percent of normal, acute renal failure can usually be reversed if the cause of the ischemia is corrected before damage to the renal cells has occurred. Unlike some tissues, the kidney can endure a relatively large reduction in blood flow before actual damage to the renal cells occurs. The reason for this is that as renal blood flow is reduced, the GFR and the amount of sodium chloride filtered by the glomeruli (as well as the filtration rate of water and other electrolytes) are reduced. This decreases the amount of sodium chloride that must be reabsorbed by the tubules, which use most of the energy and oxygen consumed by the normal kidney. Therefore, as renal blood flow and GFR fall, the requirement for renal oxygen consumption is also reduced. As the GFR approaches zero, oxygen consumption of the kidney approaches the rate that is required to keep the renal tubular cells alive even when they are not reabsorbing sodium. When blood flow is reduced below this basal requirement, which is usually less than 20 to 25 percent of the normal renal blood flow, the renal cells start to become hypoxic, and further decreases in renal blood flow, if prolonged, will cause damage or even death of the renal cells, especially the tubular epithelial cells.

If the cause of prerenal acute renal failure is not corrected and ischemia of the kidney persists longer than a few hours, this type of renal failure can evolve into intrarenal acute renal failure, as discussed later. Acute reduction of renal blood flow is a common cause of acute renal failure in hospitalized patients, especially those who have suffered severe injuries. Table 31-2 shows some of the common causes of decreased renal blood flow and prerenal acute renal failure.

Table 31-2 Some Causes of Prerenal Acute Renal Failure

Intravascular Volume Depletion

Hemorrhage (trauma, surgery, postpartum, gastrointestinal)

Diarrhea or vomiting

Burns

Cardiac Failure

Myocardial infarction

Valvular damage

Peripheral Vasodilation and Resultant Hypotension

Anaphylactic shock

Anesthesia

Sepsis, severe infections

Primary renal hemodynamic abnormalities

Renal artery stenosis, embolism, or thrombosis of renal artery or vein

Intrarenal Acute Renal Failure Caused by Abnormalities Within the Kidney

Abnormalities that originate within the kidney and that abruptly diminish urine output fall into the general category of intrarenal acute renal failure. This category of acute renal failure can be further divided into (1) conditions that injure the glomerular capillaries or other small renal vessels, (2) conditions that damage the renal tubular epithelium, and (3) conditions that cause damage to the renal interstitium. This type of classification refers to the primary site of injury, but because the renal vasculature and tubular system are functionally interdependent, damage to the renal blood vessels can lead to tubular damage, and primary tubular damage can lead to damage of the renal blood vessels. Some causes of intrarenal acute renal failure are listed in Table 31-3.

Table 31-3 Some Causes of Intrarenal Acute Renal Failure

Small Vessel and /or Glomerular Injury

Vasculitis (polyarteritis nodosa)

Cholesterol emboli

Malignant hypertension

Acute glomerulonephritis

Tubular Epithelial Injury (Tubular Necrosis)

Acute tubular necrosis due to ischemia

Acute tubular necrosis due to toxins (heavy metals, ethylene glycol, insecticides, poison mushrooms, carbon tetrachloride)

Renal Interstitial Inury

Acute pyelonephritis

Acute allergic interstitial nephritis

Acute Renal Failure Caused by Glomerulonephritis

Acute glomerulonephritis is a type of intrarenal acute renal failure usually caused by an abnormal immune reaction that damages the glomeruli. In about 95 percent of the patients with this disease, damage to the glomeruli occurs 1 to 3 weeks after an infection elsewhere in the body, usually caused by certain types of group A beta streptococci. The infection may have been a streptococcal sore throat, streptococcal tonsillitis, or even streptococcal infection of the skin. It is not the infection itself that damages the kidneys. Instead, over a few weeks, as antibodies develop against the streptococcal antigen, the antibodies and antigen react with each other to form an insoluble immune complex that becomes entrapped in the glomeruli, especially in the basement membrane portion of the glomeruli.

Once the immune complex has deposited in the glomeruli, many of the cells of the glomeruli begin to proliferate, but mainly the mesangial cells that lie between the endothelium and the epithelium. In addition, large numbers of white blood cells become entrapped in the glomeruli. Many of the glomeruli become blocked by this inflammatory reaction, and those that are not blocked usually become excessively permeable, allowing both protein and red blood cells to leak from the blood of the glomerular capillaries into the glomerular filtrate. In severe cases, either total or almost complete renal shutdown occurs.

The acute inflammation of the glomeruli usually subsides in about 2 weeks and, in most patients, the kidneys return to almost normal function within the next few weeks to few months. Sometimes, however, many of the glomeruli are destroyed beyond repair, and in a small percentage of patients, progressive renal deterioration continues indefinitely, leading to chronic renal failure, as described in a subsequent section of this chapter.

Tubular Necrosis as a Cause of Acute Renal Failure

Another cause of intrarenal acute renal failure is tubular necrosis, which means destruction of epithelial cells in the tubules. Some common causes of tubular necrosis are (1) severe ischemia and inadequate supply of oxygen and nutrients to the tubular epithelial cells and (2) poisons, toxins, or medications that destroy the tubular epithelial cells.

Acute Tubular Necrosis Caused by Severe Renal Ischemia

Severe ischemia of the kidney can result from circulatory shock or any other disturbance that severely impairs the blood supply to the kidney. If the ischemia is severe enough to seriously impair the delivery of nutrients and oxygen to the renal tubular epithelial cells, and if the insult is prolonged, damage or eventual destruction of the epithelial cells can occur. When this happens, tubular cells “slough off” and plug many of the nephrons, so that there is no urine output from the blocked nephrons; the affected nephrons often fail to excrete urine even when renal blood flow is restored to normal, as long as the tubules remain plugged. The most common causes of ischemic damage to the tubular epithelium are the prerenal causes of acute renal failure associated with circulatory shock, as discussed earlier in this chapter.

Acute Tubular Necrosis Caused by Toxins or Medications

There is a long list of renal poisons and medications that can damage the tubular epithelium and cause acute renal failure. Some of these are carbon tetrachloride, heavy metals (such as mercury and lead), ethylene glycol (which is a major component in antifreeze), various insecticides, some medications (such as tetracyclines) used as antibiotics, and cis-platinum, which is used in treating certain cancers. Each of these substances has a specific toxic action on the renal tubular epithelial cells, causing death of many of them. As a result, the epithelial cells slough away from the basement membrane and plug the tubules. In some instances, the basement membrane also is destroyed. If the basement membrane remains intact, new tubular epithelial cells can grow along the surface of the membrane, so the tubule may repair itself within 10 to 20 days.

Postrenal Acute Renal Failure Caused by Abnormalities of the Lower Urinary Tract

Multiple abnormalities in the lower urinary tract can block or partially block urine flow and therefore lead to acute renal failure even when the kidneys’ blood supply and other functions are initially normal. If the urine output of only one kidney is diminished, no major change in body fluid composition will occur because the contralateral kidney can increase its urine output sufficiently to maintain relatively normal levels of extracellular electrolytes and solutes, as well as normal extracellular fluid volume. With this type of renal failure, normal kidney function can be restored if the basic cause of the problem is corrected within a few hours. But chronic obstruction of the urinary tract, lasting for several days or weeks, can lead to irreversible kidney damage. Some of the causes of postrenal acute failure include (1) bilateral obstruction of the ureters or renal pelvises caused by large stones or blood clots, (2) bladder obstruction, and (3) obstruction of the urethra.

Physiologic Effects of Acute Renal Failure

A major physiologic effect of acute renal failure is retention in the blood and extracellular fluid of water, waste products of metabolism, and electrolytes. This can lead to water and salt overload, which, in turn, can lead to edema and hypertension. Excessive retention of potassium, however, is often a more serious threat to patients with acute renal failure because increases in plasma potassium concentration (hyperkalemia) above 8 mEq/L (only twice normal) can be fatal. Because the kidneys are also unable to excrete sufficient hydrogen ions, patients with acute renal failure develop metabolic acidosis, which in itself can be lethal or can aggravate the hyperkalemia.

In the most severe cases of acute renal failure, complete anuria occurs. The patient will die in 8 to 14 days unless kidney function is restored or unless an artificial kidney is used to rid the body of the excessive retained water, electrolytes, and waste products of metabolism. Other effects of diminished urine output, as well as treatment with an artificial kidney, are discussed in the next section in relation to chronic renal failure.

Chronic Renal Failure: An Irreversible Decrease in the Number of Functional Nephrons

Chronic renal failure results from progressive and irreversible loss of large numbers of functioning nephrons. Serious clinical symptoms often do not occur until the number of functional nephrons falls to at least 70 to 75 percent below normal. In fact, relatively normal blood concentrations of most electrolytes and normal body fluid volumes can still be maintained until the number of functioning nephrons decreases below 20 to 25 percent of normal.

Table 31-4 gives some of the most important causes of chronic renal failure. In general, chronic renal failure, like acute renal failure, can occur because of disorders of the blood vessels, glomeruli, tubules, renal interstitium, and lower urinary tract. Despite the wide variety of diseases that can lead to chronic renal failure, the end result is essentially the same—a decrease in the number of functional nephrons.

Table 31-4 Some Causes of Chronic Renal Failure

Metablolic Disorders

Diabetes mellitus

Obesity

Amyloidosis

Hypertension

Renal Vascular Disorders

Atherosclerosis

Nephrosclerosis-hypertension

Immunologic Disorders

Glomerulonephritis

Polyarteritis nodosa

Lupus erythernatosus

Infections

Pyelonephritis

Tuberculosis

Primary Tubular Disorders

Nephrotoxins (analgesics, heavy metals)

Urinary Tract Obstruction

Renal calculi

Hypertrophy of prostate

Urethral constriction

Congenital Disorders

Polycystic disease

Congenital absence of kidney tissue (renal hypoplasia)

Vicious Cycle of Chronic Renal Failure Leading to End-Stage Renal Disease

In many cases, an initial insult to the kidney leads to progressive deterioration of kidney function and further loss of nephrons to the point where the person must be placed on dialysis treatment or transplanted with a functional kidney to survive. This condition is referred to as end-stage renal disease (ESRD).

Studies in laboratory animals have shown that surgical removal of large portions of the kidney initially causes adaptive changes in the remaining nephrons that lead to increased blood flow, increased GFR, and increased urine output in the surviving nephrons. The exact mechanisms responsible for these changes are not well understood but involve hypertrophy (growth of the various structures of the surviving nephrons), as well as functional changes that decrease vascular resistance and tubular reabsorption in the surviving nephrons. These adaptive changes permit a person to excrete normal amounts of water and solutes even when kidney mass is reduced to 20 to 25 percent of normal. Over a period of several years, however, these renal adaptive changes may lead to further injury of the remaining nephrons, particularly to the glomeruli of these nephrons.

The cause of this additional injury is not known, but some investigators believe that it may be related in part to increased pressure or stretch of the remaining glomeruli, which occurs as a result of functional vasodilation or increased blood pressure; the chronic increase in pressure and stretch of the small arterioles and glomeruli are believed to cause injury and sclerosis of these vessels (replacement of normal tissue with connective tissue). These sclerotic lesions can eventually obliterate the glomerulus, leading to further reduction in kidney function, further adaptive changes in the remaining nephrons, and a slowly progressing vicious cycle that eventually terminates in ESRD (Figure 31-2). The only proven method of slowing down this progressive loss of kidney function is to lower arterial pressure and glomerular hydrostatic pressure, especially by using drugs such as angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists.

image

Figure 31-2 Vicious circle that can occur with primary kidney disease. Loss of nephrons because of disease may increase pressure and flow in the surviving glomerular capillaries, which in turn may eventually injure these “normal” capillaries as well, thus causing progressive sclerosis and eventual loss of these glomeruli.

Table 31-5 gives the most common causes of ESRD. In the early 1980s, glomerulonephritis in all its various forms was believed to be the most common initiating cause of ESRD. In recent years, diabetes mellitus and hypertensionhave become recognized as the leading causes of ESRD, together accounting for more than 70 percent of all chronic renal failure.

Table 31-5 Most Common Causes of End-Stage Renal Disease (ESRD)

Cause

Percentage of Total ESRD Patients

Diabetes mellitus

45

Hypertension

27

Glomerulonephritis

8

Polycystic kidney disease

2

Other/unknown

18

Excessive weight gain (obesity) appears to be the most important risk factor for the two main causes of ESRD—diabetes and hypertension. As discussed in Chapter 78, type II diabetes, which is closely linked to obesity, accounts for more than 90 percent of all diabetes mellitus. Excess weight gain is also a major cause of essential hypertension, accounting for as much as 65 to 75 percent of the risk for developing hypertension in adults. In addition to causing renal injury through diabetes and hypertension, obesity may have additive or synergistic effects to worsen renal function in patients with preexisting kidney disease.

Injury to the Renal Vasculature as a Cause of Chronic Renal Failure

Many types of vascular lesions can lead to renal ischemia and death of kidney tissue. The most common of these are (1) atherosclerosis of the larger renal arteries, with progressive sclerotic constriction of the vessels; (2) fibromuscular hyperplasia of one or more of the large arteries, which also causes occlusion of the vessels; and (3) nephrosclerosis, caused by sclerotic lesions of the smaller arteries, arterioles, and glomeruli.

Atherosclerotic or hyperplastic lesions of the large arteries frequently affect one kidney more than the other and, therefore, cause unilaterally diminished kidney function. As discussed in Chapter 19, hypertension often occurs when the artery of one kidney is constricted while the artery of the other kidney is still normal, a condition analogous to “two-kidney” Goldblatt hypertension.

Benign nephrosclerosis, the most common form of kidney disease, is seen to at least some extent in about 70 percent of postmortem examinations in people who die after the age of 60. This type of vascular lesion occurs in the smaller interlobular arteries and in the afferent arterioles of the kidney. It is believed to begin with leakage of plasma through the intimal membrane of these vessels. This causes fibrinoid deposits to develop in the medial layers of these vessels, followed by progressive thickening of the vessel wall that eventually constricts the vessels and, in some cases, occludes them. Because there is essentially no collateral circulation among the smaller renal arteries, occlusion of one or more of them causes destruction of a comparable number of nephrons. Therefore, much of the kidney tissue becomes replaced by small amounts of fibrous tissue. When sclerosis occurs in the glomeruli, the injury is referred to as glomerulosclerosis.

Nephrosclerosis and glomerulosclerosis occur to some extent in most people after the fourth decade of life, causing about a 10 percent decrease in the number of functional nephrons each 10 years after age 40 (Figure 31-3). This loss of glomeruli and overall nephron function is reflected by a progressive decrease in both renal blood flow and GFR. Even in “normal” people, kidney plasma flow and GFR decrease by 40 to 50 percent by age 80.

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Figure 31-3 Effect of aging on the number of functional glomeruli.

The frequency and severity of nephrosclerosis and glomerulosclerosis are greatly increased by concurrent hypertension or diabetes mellitus. In fact, diabetes mellitus and hypertension are the two most important causes of ESRD, as discussed previously. Thus, benign nephrosclerosis in association with severe hypertension can lead to a rapidly progressing malignant nephrosclerosis. The characteristic histological features of malignant nephrosclerosis include large amounts of fibrinoid deposits in the arterioles and progressive thickening of the vessels, with severe ischemia occurring in the affected nephrons. For unknown reasons, the incidence of malignant nephrosclerosis and severe glomerulosclerosis is significantly higher in blacks than in whites of similar ages who have similar degrees of severity of hypertension or diabetes.

Injury to the Glomeruli as a Cause of Chronic Renal Failure—Glomerulonephritis

Chronic glomerulonephritis can be caused by several diseases that cause inflammation and damage to the capillary loops in the glomeruli of the kidneys. In contrast to the acute form of this disease, chronic glomerulonephritis is a slowly progressive disease that often leads to irreversible renal failure. It may be a primary kidney disease, following acute glomerulonephritis, or it may be secondary to systemic diseases, such as lupus erythematosus.

In most cases, chronic glomerulonephritis begins with accumulation of precipitated antigen-antibody complexes in the glomerular membrane. In contrast to acute glomerulonephritis, streptococcal infections account for only a small percentage of patients with the chronic form of glomerulonephritis. Accumulation of antigen-antibody complex in the glomerular membranes causes inflammation, progressive thickening of the membranes, and eventual invasion of the glomeruli by fibrous tissue. In the later stages of the disease, the glomerular capillary filtration coefficient becomes greatly reduced because of decreased numbers of filtering capillaries in the glomerular tufts and because of thickened glomerular membranes. In the final stages of the disease, many glomeruli are replaced by fibrous tissue and are, therefore, unable to filter fluid.

Injury to the Renal Interstitium as a Cause of Chronic Renal Failure—Interstitial Nephritis

Primary or secondary disease of the renal interstitium is referred to as interstitial nephritis. In general, this can result from vascular, glomerular, or tubular damage that destroys individual nephrons, or it can involve primary damage to the renal interstitium by poisons, drugs, and bacterial infections.

Renal interstitial injury caused by bacterial infection is called pyelonephritis. The infection can result from different types of bacteria but especially from Escherichia coli that originate from fecal contamination of the urinary tract. These bacteria reach the kidneys either by way of the blood stream or, more commonly, by ascension from the lower urinary tract by way of the ureters to the kidneys.

Although the normal bladder is able to clear bacteria readily, there are two general clinical conditions that may interfere with the normal flushing of bacteria from the bladder: (1) the inability of the bladder to empty completely, leaving residual urine in the bladder, and (2) the existence of obstruction of urine outflow. With impaired ability to flush bacteria from the bladder, the bacteria multiply and the bladder becomes inflamed, a condition termed cystitis.Once cystitis has occurred, it may remain localized without ascending to the kidney, or in some people, bacteria may reach the renal pelvis because of a pathological condition in which urine is propelled up one or both of the ureters during micturition. This condition is called vesicoureteral reflux and is due to the failure of the bladder wall to occlude the ureter during micturition; as a result, some of the urine is propelled upward toward the kidney, carrying with it bacteria that can reach the renal pelvis and renal medulla, where they can initiate the infection and inflammation associated with pyelonephritis.

Pyelonephritis begins in the renal medulla and therefore usually affects the function of the medulla more than it affects the cortex, at least in the initial stages. Because one of the primary functions of the medulla is to provide the countercurrent mechanism for concentrating urine, patients with pyelonephritis frequently have markedly impaired ability to concentrate the urine.

With long-standing pyelonephritis, invasion of the kidneys by bacteria not only causes damage to the renal medulla interstitium but also results in progressive damage of renal tubules, glomeruli, and other structures throughout the kidney. Consequently, large parts of functional renal tissue are lost and chronic renal failure can develop.

Nephrotic Syndrome—Excretion of Protein in the Urine Because of Increased Glomerular Permeability

Many patients with kidney disease develop the nephrotic syndrome, which is characterized by loss of large quantities of plasma proteins into the urine. In some instances, this occurs without evidence of other major abnormalities of kidney function, but more often it is associated with some degree of renal failure.

The cause of the protein loss in the urine is increased permeability of the glomerular membrane. Therefore, any disease that increases the permeability of this membrane can cause the nephrotic syndrome. Such diseases include (1) chronic glomerulonephritis, which affects primarily the glomeruli and often causes greatly increased permeability of the glomerular membrane; (2) amyloidosis, which results from deposition of an abnormal proteinoid substance in the walls of the blood vessels and seriously damages the basement membrane of the glomeruli; and (3) minimal change nephrotic syndrome, which is associated with no major abnormality in the glomerular capillary membrane that can be detected with light microscopy. As discussed in Chapter 26, minimal change nephropathy has been found to be associated with loss of the negative charges that are normally present in the glomerular capillary basement membrane. Immunologic studies have also shown abnormal immune reactions in some cases, suggesting that the loss of the negative charges may have resulted from antibody attack on the membrane. Loss of normal negative charges in the basement membrane of the glomerular capillaries allows proteins, especially albumin, to pass through the glomerular membrane with ease because the negative charges in the basement membrane normally repel the negatively charged plasma proteins.

Minimal-change nephropathy can occur in adults, but more frequently it occurs in children between the ages of 2 and 6 years. Increased permeability of the glomerular capillary membrane occasionally allows as much as 40 grams of plasma protein loss into the urine each day, which is an extreme amount for a young child. Therefore, the child’s plasma protein concentration often falls below 2 g/dl and the colloid osmotic pressure falls from a normal value of 28 to less than 10 mm Hg. As a consequence of this low colloid osmotic pressure in the plasma, large amounts of fluid leak from the capillaries all over the body into most of the tissues, causing severe edema, as discussed in Chapter 25.

Nephron Function in Chronic Renal Failure

Loss of Functional Nephrons Requires the Surviving Nephrons to Excrete More Water and Solutes

It would be reasonable to suspect that decreasing the number of functional nephrons, which reduces the GFR, would also cause major decreases in renal excretion of water and solutes. Yet patients who have lost up to 75 to 80 percent of their nephrons are able to excrete normal amounts of water and electrolytes without serious accumulation of any of these in the body fluids. Further reduction in the number of nephrons, however, leads to electrolyte and fluid retention, and death usually ensues when the number of nephrons falls below 5 to 10 percent of normal.

In contrast to the electrolytes, many of the waste products of metabolism, such as urea and creatinine, accumulate almost in proportion to the number of nephrons that have been destroyed. The reason for this is that substances such as creatinine and urea depend largely on glomerular filtration for their excretion, and they are not reabsorbed as avidly as the electrolytes. Creatinine, for example, is not reabsorbed at all, and the excretion rate is approximately equal to the rate at which it is filtered.

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Therefore, if GFR decreases, the creatinine excretion rate also transiently decreases, causing accumulation of creatinine in the body fluids and raising plasma concentration until the excretion rate of creatinine returns to normal—the same rate at which creatinine is produced in the body (Figure 31-4). Thus, under steady-state conditions the creatinine excretion rate equals the rate of creatinine production, despite reductions in GFR; however, this normal rate of creatinine excretion occurs at the expense of elevated plasma creatinine concentration, as shown in curve A of Figure 31-5.

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Figure 31-4 Effect of reducing glomerular filtration rate (GFR) by 50 percent on serum creatinine concentration and on creatinine excretion rate when the production rate of creatinine remains constant.

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Figure 31-5 Representative patterns of adaptation for different types of solutes in chronic renal failure. Curve A shows the approximate changes in the plasma concentrations of solutes such as creatinine and urea that are filtered and poorly reabsorbed. Curve B shows 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.

Some solutes, such as phosphate, urate, and hydrogen ions, are often maintained near the normal range until GFR falls below 20 to 30 percent of normal. Thereafter, the plasma concentrations of these substances rise, but not in proportion to the fall in GFR, as shown in curve B of Figure 31-5. Maintenance of relatively constant plasma concentrations of these solutes as GFR declines is accomplished by excreting progressively larger fractions of the amounts of these solutes that are filtered at the glomerular capillaries; this occurs by decreasing the rate of tubular reabsorption or, in some instances, by increasing tubular secretion rates.

In the case of sodium and chloride ions, their plasma concentrations are maintained virtually constant even with severe decreases in GFR (see curve C of Figure 31-5). This is accomplished by greatly decreasing tubular reabsorption of these electrolytes.

For example, with a 75 percent loss of functional nephrons, each surviving nephron must excrete four times as much sodium and four times as much volume as under normal conditions (Table 31-6).

Table 31-6 Total Kidney Excretion and Excretion per Nephron in Renal Failure

 

Normal

75% Loss of Nephrons

Number of nephrons

2,000,000

500,000

Total GFR (ml/min)

125

40

Single nephron GFR (nl/min)

62.5

80

Volume excreted for all nephrons (ml/min)

1.5

1.5

Volume excreted per nephron (nl/min)

0.75

3.0

GFR, glomerular filtration rate.

Part of this adaptation occurs because of increased blood flow and increased GFR in each of the surviving nephrons, owing to hypertrophy of the blood vessels and glomeruli, as well as functional changes that cause the blood vessels to dilate. Even with large decreases in the total GFR, normal rates of renal excretion can still be maintained by decreasing the rate at which the tubules reabsorb water and solutes.

Isosthenuria—Inability of the Kidney to Concentrate or Dilute the Urine

One important effect of the rapid rate of tubular flow that occurs in the remaining nephrons of diseased kidneys is that the renal tubules lose their ability to fully concentrate or dilute the urine. The concentrating ability of the kidney is impaired mainly because (1) the rapid flow of tubular fluid through the collecting ducts prevents adequate water reabsorption, and (2) the rapid flow through both the loop of Henle and the collecting ducts prevents the countercurrent mechanism from operating effectively to concentrate the medullary interstitial fluid solutes. Therefore, as progressively more nephrons are destroyed, the maximum concentrating ability of the kidney declines and urine osmolarity and specific gravity (a measure of the total solute concentration) approach the osmolarity and specific gravity of the glomerular filtrate, as shown in Figure 31-6.

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Figure 31-6 Development of isosthenuria in a patient with decreased numbers of functional nephrons.

The diluting mechanism in the kidney is also impaired when the number of nephrons decreases because the rapid flushing of fluid through the loops of Henle and the high load of solutes such as urea cause a relatively high solute concentration in the tubular fluid of this part of the nephron. As a consequence, the diluting capacity of the kidney is impaired and the minimal urine osmolality and specific gravity approach those of the glomerular filtrate. Because the concentrating mechanism becomes impaired to a greater extent than does the diluting mechanism in chronic renal failure, an important clinical test of renal function is to determine how well the kidneys can concentrate urine when a person’s water intake is restricted for 12 or more hours.

Effects of Renal Failure on the Body Fluids—Uremia

The effect of renal failure on the body fluids depends on (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 amounts of water and food, the concentrations of different substances in the extracellular fluid are approximately those shown in Figure 31-7. Important effects include (1) generalized edema resulting from water and salt retention; (2) acidosisresulting from failure of the kidneys to rid the body of normal acidic products; (3) high concentration of the nonprotein nitrogens—especially urea, creatinine, and uric acid—resulting from failure of the body to excrete the metabolic end products of proteins; and (4) high concentrations of other substances excreted by the kidney, including phenols, sulfates, phosphates, potassium, and guanidine bases. This total condition is called uremia because of the high concentration of urea in the body fluids.

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Figure 31-7 Effect of kidney failure on extracellular fluid constituents. NPN, nonprotein nitrogens.

Water Retention and Development of Edema in Renal Failure

If water intake is restricted immediately after acute renal failure begins, the total body fluid content may become only slightly increased. If fluid intake is not limited and the patient drinks in response to the normal thirst mechanisms, the body fluids begin to increase immediately and rapidly.

With chronic partial kidney failure, accumulation of fluid may not be severe, as long as salt and fluid intake are not excessive, until kidney function falls to 25 percent of normal or lower. The reason for this, as discussed previously, is that the surviving nephrons excrete larger amounts of salt and water. Even the small fluid retention that does occur, along with increased secretion of renin and angiotensin II that usually occurs in ischemic kidney disease, often causes severe hypertension in chronic renal failure. Almost all patients with kidney function so reduced as to require dialysis to preserve life develop hypertension. In many of these patients, severe reduction of salt intake or removal of extracellular fluid by dialysis can control the hypertension. The remaining patients continue to have hypertension even after excess sodium has been removed by dialysis. In this group, removal of the ischemic kidneys usually corrects the hypertension (as long as fluid retention is prevented by dialysis) because it removes the source of excessive renin secretion and subsequent increased angiotensin II formation.

Uremia—Increase in Urea and Other Nonprotein Nitrogens (Azotemia)

The nonprotein nitrogens include urea, uric acid, creatinine, and a few less important compounds. These, in general, are the end products of protein metabolism and must be removed from the body to ensure continued normal protein metabolism in the cells. The concentrations of these, particularly of urea, can rise to as high as 10 times normal during 1 to 2 weeks of total renal failure. With chronic renal failure, the concentrations rise approximately in proportion to the degree of reduction in functional nephrons. For this reason, measuring the concentrations of these substances, especially of urea and creatinine, provides an important means for assessing the degree of renal failure.

Acidosis in Renal Failure

Each day the body normally produces about 50 to 80 millimoles more metabolic acid than metabolic alkali. Therefore, when the kidneys fail to function, acid accumulates in the body fluids. The buffers of the body fluids normally can buffer 500 to 1000 millimoles of acid without lethal increases in extracellular fluid H+ concentration, and the phosphate compounds in the bones can buffer an additional few thousand millimoles of H+. However, when this buffering power is used up, the blood pH falls drastically and the patient will become comatose and die if the pH falls below about 6.8.

Anemia in Chronic Renal Failure Caused by Decreased Erythropoietin Secretion

Patients with severe chronic renal failure almost always develop anemia. The most important cause of this is decreased renal secretion of erythropoietin, which stimulates the bone marrow to produce red blood cells. If the kidneys are seriously damaged, they are unable to form adequate quantities of erythropoietin, which leads to diminished red blood cell production and consequent anemia.

The availability since 1989 of recombinant erythropoietin, however, has provided a means of treating anemia in patients with chronic renal failure.

Osteomalacia in Chronic Renal Failure Caused by Decreased Production of Active Vitamin D and by Phosphate Retention by the Kidneys

Prolonged renal failure also causes osteomalacia, a condition in which the bones are partially absorbed and, therefore, become greatly weakened. An important cause of this condition is the following: Vitamin D must be converted by a two-stage process, first in the liver and then in the kidneys, into 1,25-dihydroxycholecalciferol before it is able to promote calcium absorption from the intestine. Therefore, serious damage to the kidney greatly reduces the blood concentration of active vitamin D, which in turn decreases intestinal absorption of calcium and the availability of calcium to the bones.

Another important cause of demineralization of the skeleton in chronic renal failure is the rise in serum phosphate concentration that occurs as a result of decreased GFR. This rise in serum phosphate increases binding of phosphate with calcium in the plasma, thus decreasing the plasma serum ionized calcium concentration, which, in turn, stimulates parathyroid hormone secretion. This secondary hyperparathyroidism then stimulates the release of calcium from bones, causing further demineralization of the bones.

Hypertension and Kidney Disease

As discussed earlier in this chapter, hypertension can exacerbate injury to the glomeruli and blood vessels of the kidneys and is a major cause of end-stage renal disease. Abnormalities of kidney function can also cause hypertension, as discussed in detail in Chapter 19. Thus, the relation between hypertension and kidney disease can, in some instances, propagate a vicious cycle: primary kidney damage leads to increased blood pressure, which causes further damage to the kidneys, further increases in blood pressure, and so forth, until end-stage renal disease develops.

Not all types of kidney disease cause hypertension because damage to certain portions of the kidney causes uremia without hypertension. Nevertheless, some types of renal damage are particularly prone to cause hypertension. A classification of kidney disease relative to hypertensive or nonhypertensive effects is the following.

Renal Lesions That Reduce the Ability of the Kidneys to Excrete Sodium and Water Promote Hypertension

Renal lesions that decrease the ability of the kidneys to excrete sodium and water almost invariably cause hypertension. Therefore, lesions that either decrease GFR or increase tubular reabsorption usually lead to hypertension of varying degrees. Some specific types of renal abnormalities that can cause hypertension are as follows:

1. Increased renal vascular resistance, which reduces renal blood flow and GFR. An example is hypertension caused by renal artery stenosis.

2. Decreased glomerular capillary filtration coefficient, which reduces GFR. An example of this is chronic glomerulonephritis, which causes inflammation and thickening of the glomerular capillary membranes, thereby reducing the glomerular capillary filtration coefficient.

3. Excessive tubular sodium reabsorption. An example is hypertension caused by excessive aldosterone secretion, which increases sodium reabsorption mainly in the cortical collecting tubules.

Once hypertension has developed, renal excretion of sodium and water returns to normal because the high arterial pressure causes pressure natriuresis and pressure diuresis, so intake and output of sodium and water become balanced once again. Even when there are large increases in renal vascular resistance or decreases in the glomerular capillary coefficient, the GFR may still return to nearly normal levels after the arterial blood pressure rises. Likewise, when tubular reabsorption is increased, as occurs with excessive aldosterone secretion, the urinary excretion rate is initially reduced but then returns to normal as arterial pressure rises. Thus, after hypertension develops, there may be no obvious sign of impaired excretion of sodium and water other than the hypertension. As explained in Chapter 19, normal excretion of sodium and water at an elevated arterial pressure means that pressure natriuresis and pressure diuresis have been reset to a higher arterial pressure.

Hypertension Caused by Patchy Renal Damage and Increased Renal Secretion of Renin

If one part of the kidney is ischemic and the remainder is not ischemic, such as occurs when one renal artery is severely constricted, the ischemic renal tissue secretes large quantities of renin. This secretion leads to increased formation of angiotensin II, which can cause hypertension. The most likely sequence of events in causing this hypertension, as discussed in Chapter 19, is (1) the ischemic kidney tissue itself excretes less than normal amounts of water and salt; (2) the renin secreted by the ischemic kidney, as well as the subsequent increased angiotensin II formation, affects the nonischemic kidney tissue, causing it also to retain salt and water; and (3) excess salt and water cause hypertension in the usual manner.

A similar type of hypertension can result when patchy areas of one or both kidneys become ischemic as a result of arteriosclerosis or vascular injury in specific portions of the kidneys. When this occurs, the ischemic nephrons excrete less salt and water but secrete greater amounts of renin, which causes increased angiotensin II formation. The high levels of angiotensin II then impair the ability of the surrounding otherwise normal nephrons to excrete sodium and water. As a result, hypertension develops, which restores the overall excretion of sodium and water by the kidney, so balance between intake and output of salt and water is maintained, but at the expense of high blood pressure.

Kidney Diseases That Cause Loss of Entire Nephrons Lead to Renal Failure but May Not Cause Hypertension

Loss of large numbers of whole nephrons, such as occurs with the loss of one kidney and part of another kidney, almost always leads to renal failure if the amount of kidney tissue lost is great enough. If the remaining nephrons are normal and the salt intake is not excessive, this condition might not cause clinically significant hypertension because even a slight rise in blood pressure will raise the GFR and decrease tubular sodium reabsorption sufficiently to promote enough water and salt excretion in the urine, even with the few nephrons that remain intact. However, a patient with this type of abnormality may become severely hypertensive if additional stresses are imposed, such as eating a large amount of salt. In this case, the kidneys simply cannot clear adequate quantities of salt at a normal blood pressure with the small number of functioning nephrons that remain. Increased blood pressure restores excretion of salt and water to match intake of salt and water under steady-state conditions.

Effective treatment of hypertension requires that the kidneys’ capability to excrete salt and water is increased, either by increasing GFR or by decreasing tubular reabsorption, so that balance between intake and renal excretion of salt and water excretion can be maintained at lower blood pressures. This can be achieved by drugs that block the effects of nervous and hormonal signals that cause the kidneys to retain salt and water (e.g., with β-adrenergic blockers, angiotensin receptor antagonists, or angiotensin-converting enzyme inhibitors) or with diuretic drugs that directly inhibit renal tubular reabsorption of salt and water.

Specific Tubular Disorders

In Chapter 27, we point out that several mechanisms are responsible for transporting different individual substances across the tubular epithelial membranes. In Chapter 3, we also point out that each cellular enzyme and each carrier protein is formed in response to a respective gene in the nucleus. If any required gene happens to be absent or abnormal, the tubules may be deficient in one of the appropriate carrier proteins or one of the enzymes needed for solute transport by the renal tubular epithelial cells. In other instances, too much of the enzyme or carrier protein is produced. Thus, many hereditary tubular disorders occur because of abnormal transport of individual substances or groups of substances through the tubular membrane. In addition, damage to the tubular epithelial membrane by toxins or ischemia can cause important renal tubular disorders.

Renal Glycosuria—Failure of the Kidneys to Reabsorb Glucose

In this condition the blood glucose concentration may be normal, but the transport mechanism for tubular reabsorption of glucose is greatly limited or absent. Consequently, despite a normal blood glucose level, large amounts of glucose pass into the urine each day. Because diabetes mellitus is also associated with the presence of glucose in the urine, renal glycosuria, which is a relatively benign condition, must be ruled out before making the diagnosis of diabetes mellitus.

Aminoaciduria—Failure of the Kidneys to Reabsorb Amino Acids

Some amino acids share mutual transport systems for reabsorption, whereas other amino acids have their own distinct transport systems. Rarely, a condition called generalized aminoaciduria results from deficient reabsorption of all amino acids; more frequently, deficiencies of specific carrier systems may result in (1) essential cystinuria, in which large amounts of cystine fail to be reabsorbed and often crystallize in the urine to form renal stones; (2) simple glycinuria, in which glycine fails to be reabsorbed; or (3) beta-aminoisobutyricaciduria, which occurs in about 5 percent of all people but apparently has no major clinical significance.

Renal Hypophosphatemia—Failure of the Kidneys to Reabsorb Phosphate

In renal hypophosphatemia, the renal tubules fail to reabsorb large enough quantities of phosphate ions when the phosphate concentration of the body fluids falls very low. This condition usually does not cause serious immediate abnormalities because the phosphate concentration of the extracellular fluid can vary widely without causing major cellular dysfunction. Over a long period, a low phosphate level causes diminished calcification of the bones, causing the person to develop rickets. This type of rickets is refractory to vitamin D therapy, in contrast to the rapid response of the usual type of rickets, as discussed in Chapter 79.

Renal Tubular Acidosis—Failure of the Tubules to Secrete Hydrogen Ions

In this condition, the renal tubules are unable to secrete adequate amounts of hydrogen ions. As a result, large amounts of sodium bicarbonate are continually lost in the urine. This causes a continued state of metabolic acidosis, as discussed in Chapter 30. This type of renal abnormality can be caused by hereditary disorders, or it can occur as a result of widespread injury to the renal tubules.

Nephrogenic Diabetes Insipidus—Failure of the Kidneys to Respond to Antidiuretic Hormone

Occasionally, the renal tubules do not respond to antidiuretic hormone, causing large quantities of dilute urine to be excreted. As long as the person is supplied with plenty of water, this condition seldom causes severe difficulty. However, when adequate quantities of water are not available, the person rapidly becomes dehydrated.

Fanconi’s Syndrome—A Generalized Reabsorptive Defect of the Renal Tubules

Fanconi’s syndrome is usually associated with increased urinary excretion of virtually all amino acids, glucose, and phosphate. In severe cases, other manifestations are also observed, such as (1) failure to reabsorb sodium bicarbonate, which results in metabolic acidosis; (2) increased excretion of potassium and sometimes calcium; and (3) nephrogenic diabetes insipidus.

There are multiple causes of Fanconi’s syndrome, which results from a generalized inability of the renal tubular cells to transport various substances. Some of these causes include (1) hereditary defects in cell transport mechanisms, (2) toxins or drugs that injure the renal tubular epithelial cells, and (3) injury to the renal tubular cells as a result of ischemia. The proximal tubular cells are especially affected in Fanconi’s syndrome caused by tubular injury because these cells reabsorb and secrete many of the drugs and toxins that can cause damage.

Bartter’s Syndrome—Decreased Sodium, Chloride, and Potassium Reabsorption in the Loops of Henle

Bartter’s syndrome is an autosomal recessive disorder caused by impaired function of the 1-sodium, 2-chloride, 1-potassium co-transporter, or by defects in potassium channels in the luminal membrane or chloride channels in the basolateral membrane of the thick ascending loop of Henle. These disorders result in increased excretion of water, sodium, chloride, potassium, and calcium by the kidneys. The salt and water loss leads to mild volume depletion, resulting in activation of the renin-angiotensin-aldosterone system. The increased aldosterone and high distal tubular flow, due to impaired loop of Henle reabsorption, stimulate potassium and hydrogen secretion in the collecting tubules, leading to hypokalemia and metabolic alkalosis.

Gitelman’s Syndrome—Decreased Sodium Chloride Reabsorption in the Distal Tubules

Gitelman’s syndrome is an autosomal recessive disorder of the thiazide-sensitive sodium-chloride co-transporter in the distal tubules. Patients with Gitelman’s syndrome have some of the same characteristics as patients with Bartter’s syndrome—salt and water loss, mild water volume depletion, and activation of the renin-angiotensin-aldosterone system—although these abnormalities are usually less severe in Gitelman’s syndrome.

Because the tubular defects in Bartter’s or Gitelman’s syndrome cannot be corrected, treatment is usually focused on replacing the losses of sodium chloride and potassium. Some studies suggest that blockade of prostaglandin synthesis with nonsteroidal anti-inflammatory drugs and administration of aldosterone antagonists, such as spironolactone, may be useful in correcting the hypokalemia.

Liddle’s Syndrome—Increased Sodium Reabsorption

Liddle’s syndrome is a rare autosomal dominant disorder resulting from various mutations in the amiloride-sensitive epithelial sodium channel (ENaC) in the distal and collecting tubules. These mutations cause excessive activity of ENaC, resulting in increased reabsorption of sodium and water, hypertension, and metabolic alkalosis similar to the changes that occur with oversecretion of aldosterone (primary aldosteronism).

Patients with Liddle’s syndrome, however, have decreased levels of aldosterone due to sodium retention and compensatory decreases in renin secretion and angiotensin II levels, which, in turn, decrease adrenal secretion of aldosterone. Fortunately, Liddle’s syndrome can be treated with the diuretic amiloride, which blocks the excessive ENaC activity.

Treatment of Renal Failure by Transplantation or by Dialysis with an Artificial Kidney

Severe loss of kidney function, either acutely or chronically, is a threat to life and requires removal of toxic waste products and restoration of body fluid volume and composition toward normal. This can be accomplished by kidney transplantation or by dialysis with an artificial kidney. More than 500,000 patients in the United States are currently receiving some form of ESRD therapy.

Successful transplantation of a single donor kidney to a patient with ESRD can restore kidney function to a level that is sufficient to maintain essentially normal homeostasis of body fluids and electrolytes. Approximately 16,000 kidney transplants are performed each year in the United States. Patients who receive kidney transplants typically live longer and have fewer health problems than those who are maintained on dialysis. Maintenance of immunosuppressive therapy is required for almost all patients to help prevent acute rejection and loss of the transplanted kidney. The side effects of drugs that suppress the immune system include increased risk for infections and for some cancers, although the amount of immunosuppressive therapy can usually be reduced over time to greatly reduce these risks.

More than 350,000 people in the United States with irreversible renal failure or total kidney removal are being maintained chronically by dialysis with artificial kidneys. Dialysis is also used in certain types of acute renal failure to tide the patient over until the kidneys resume their function. If the loss of kidney function is irreversible, it is necessary to perform dialysis chronically to maintain life. Because dialysis cannot maintain completely normal body fluid composition and cannot replace all the multiple functions performed by the kidneys, the health of patients maintained on artificial kidneys usually remains significantly impaired.

Basic Principles of Dialysis

The basic principle of the artificial kidney is to pass blood through minute blood channels bounded by a thin membrane. On the other side of the membrane is a dialyzing fluid into which unwanted substances in the blood pass by diffusion.

Figure 31-8 shows the components of one type of artificial kidney in which blood flows continually between two thin membranes of cellophane; outside the membrane is a dialyzing fluid. The cellophane is porous enough to allow the constituents of the plasma, except the plasma proteins, to diffuse in both directions—from plasma into the dialyzing fluid or from the dialyzing fluid back into the plasma. If the concentration of a substance is greater in the plasma than in the dialyzing fluid, there will be a net transfer of the substance from the plasma into the dialyzing fluid.

image

Figure 31-8 Principles of dialysis with an artificial kidney.

The rate of movement of solute across the dialyzing membrane depends on (1) the concentration gradient of the solute between the two solutions, (2) the permeability of the membrane to the solute, (3) the surface area of the membrane, and (4) the length of time that the blood and fluid remain in contact with the membrane.

Thus, the maximum rate of solute transfer occurs initially 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 through the artificial kidney, the dissipation of the concentration gradient can be reduced and diffusion of solute across the membrane can be optimized by increasing the flow rate of the blood, the dialyzing fluid, or both.

In normal operation of the artificial kidney, blood flows continually or intermittently back into the vein. The total amount of blood in the artificial kidney at any one time is usually less than 500 milliliters, the rate of flow may be several hundred milliliters per minute, and the total diffusion surface area is between 0.6 and 2.5 square meters. To prevent coagulation of the blood in the artificial kidney, a small amount of heparin is infused into the blood as it enters the artificial kidney. In addition to diffusion of solutes, mass transfer of solutes and water can be produced by applying a hydrostatic pressure to force the fluid and solutes across the membranes of the dialyzer; such filtration is called bulk flow.

Dialyzing Fluid

Table 31-7 compares the constituents in a typical dialyzing fluid with those in normal plasma and uremic plasma. Note that the concentrations of ions and other substances in dialyzing fluid are not the same as the concentrations in normal plasma or in uremic plasma. Instead, they are adjusted to levels that are needed to cause appropriate movement of water and solutes through the membrane during dialysis.

Table 31-7 Comparison of Dialyzing Fluid with Normal and Uremic Plasma

image

Note that there is no phosphate, urea, urate, sulfate, or creatinine in the dialyzing fluid; however, these are present in high concentrations in the uremic blood. Therefore, when a uremic patient is dialyzed, these substances are lost in large quantities into the dialyzing fluid.

The effectiveness of the artificial kidney can be expressed in terms of the amount of plasma that is cleared of different substances each minute, which, as discussed in Chapter 27, is the primary means for expressing the functional effectiveness of the kidneys themselves to rid the body of unwanted substances. Most artificial kidneys can clear urea from the plasma at a rate of 100 to 225 ml/min, which shows that at least for the excretion of urea, the artificial kidney can function about twice as rapidly as two normal kidneys together, whose urea clearance is only 70 ml/min. Yet the artificial kidney is used for only 4 to 6 hours per day, three times a week. Therefore, the overall plasma clearance is still considerably limited when the artificial kidney replaces the normal kidneys. Also, it is important to keep in mind that the artificial kidney cannot replace some of the other functions of the kidneys, such as secretion of erythropoietin, which is necessary for red blood cell production.

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