Physiology Of Isosthenuria

GFR, glomerular filtration rate.

GFR, glomerular filtration rate.

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 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.

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 complete 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

Curva Drinker
Figure 31-6

Development of isosthenuria in a patient with decreased numbers of functional nephrons.

Isoathenuria
Figure 31-7

Effect of kidney failure on extracellular fluid constituents. NPN, nonprotein nitrogens.

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) acidosis resulting 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.

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 per cent 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 most 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 hydrogen ion concentration, and the phosphate compounds in the bones can buffer an additional few thousand millimoles of hydrogen ion. 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 Erythro-poietin 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.

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 causes increased 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 hyperparathy-roidism 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. Conversely, abnormalities of kidney function can cause hypertension, as discussed in detail in Chapter 19. Thus, the relation between hypertension and kidney disease can, in some instances, propagate a vicious circle: primary kidney damage leads to increased blood pressure, which in turn 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 cause 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 that 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 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 natriure-sis 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 the 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, and 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 that 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 with the small number of functioning nephrons that remain.

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. For this reason, many hereditary tubular disorders occur because of the 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 a 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 per cent 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.

Treatment of Renal Failure 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 dialysis with an artificial kidney. In certain types of acute renal failure, an artificial kidney may be used 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. In the United States alone, nearly 300,000 people with irreversible renal failure or even total kidney removal are being maintained by dialysis with artificial kidneys. 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. A better treatment for permanent loss of kidney function is to restore functional kidney tissue by means of a kidney transplant.

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

solution temperature solution bath

Figure 31-8

solution temperature solution bath

Figure 31-8

Principles of dialysis with an artificial kidney.

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.

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

Table 31-7

Comparison of Dialyzing Fluid with Normal and Uremic Plasma

Table 31-7

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Essentials of Human Physiology

Essentials of Human Physiology

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