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192 Cards in this Set

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1. What is a diuretic?
A diuretic is a substance that increases the rate of urine volume output.

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, which in turn causes diuresis.
2. How do diuretics cause increased water output?
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.

B/c 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.
3. Length of time a diuretic works
Some diuretics can increase urine output more than 20x 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.

This is due to other compensatory mechanisms initiated by the decreased ECF volume.

For example, a decreased ECF often reduces arterial pressure and GFR and increases renin secretion and angiotensin II formation. All these responses, together, eventually override the chronic effects of the diuretic on urine output.
4. How do osmotic diuretics decrease water reabsorption?
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 greatly reduces water reabsorption, flushing large amounts of tubular fluid into the urine.
5. How do loop diuretics work?
Furosemide, ethacrynic acid, and bumetanide are powerful loop 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 diuretics are among the most powerful of the clinically used diuretics.
6. What are the two reasons for loop diuretics raising urine output of Cl, Na, K, and other electrolytes as well as water?
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.

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. B/c of this effect, loop diuretics impair the ability of the kidneys to either concentrate or dilute the urine.
7. Why is urinary dilution impaired with loop diuretics?
Urinary dilution is impaired b/c 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.
8. Why is urinary concentration impaired with loop diuretics?
Urinary concentration is impaired b/c 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 that the maximal concentrating ability of the kidneys is also greatly reduced.
9. Loop diuretic summary
B/c of these multiple effect, 20-30% of the glomerular filtrate may be delivered into the urine, causing, under acute conditions, urine output to be as great as 25x normal for at least a few minutes.
10. How do thiazide diuretics work?
Thiazide diuretics inhibit NaCl reabsorption in the early distal tubule.

The thiazide derivatives, such as chlorothiazide, act mainly on the early distal tubules to block the NaCl co-transporter in the luminal membrane of the tubular cells.

Under favorable conditions, these agents cause 5-10% of the glomerular filtrate to pass into the urine. This is about the same amount of sodium normally reabsorbed by the distal tubules.
11. How do carbonic anhydrase inhibitors work?
Carbonic anhydrase inhibitors block sodium-bicarbonate reabsorption in the proximal tubules.
12. Acetazolamide
Acetazolamide inhibits the enzyme carbonic anhydrase, which is critical for the reabsorption of bicarb int he proximal tubule.
13. Where is carbonic anhydrase located?
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 the intercalatated cells of the collecting tubule.
14. How and why is sodium reabsorption decreased with carbonic anhydrase inhibitors?
B/c hydrogen ion secretion and bicarb reabsorption in the proximal tubules are couples to sodium reabsorption through the sodium-hydrogen ion counter-transport mechanism in the luminal membrane, decreasing bicarb reabsorption also reduces sodium reabsorption.

The blockage of sodium and bicarb reabsorption from the tubular fluid causes these ions to remain int he tubules and act as an osmotic diuretic.
15. What is a disadvantage of the carbonic anhydrase inhibitors?
They cause some degree of acidosis b/c of the excessive loss of bicarb in the urine.
16. How do competitive inhibitors of aldosterone work?
Competitive inhibitors of aldosterone decrease sodium reabsorption from and potassium secretion into the cortical collecting tubule.
17. Spironolactone and eplerenone are....
Spironolactone and eplerenone are aldosterone antagonists that compete with aldosterone for receptor 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.
18. How are adosterone inhibitors potassium sparing diuretics?
B/c these drugs also block the effect of aldosterone to promote potassium secretion in the tubules, they decrease the excretion of potassium.

Aldosterone antagonists also cause movement of potassium from the cells to the ECF. In some instances, this causes the ECF potassium concentration to increase excessively.

For this reason, spironolactone and other aldosterone inhibitors are referred to as potassium sparing diuretics.
19. Amiloride and triamterene are...?
Amiloride and triamterene also inhibit sodium reabsorption and potassiium 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. B/c 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 ATP pump.
20. How are sodium channel blockers also potassium sparing diuretics?
The decreased activity of the sodium-potassium ATP pump reduces the transport of sodium 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.
21. What are the two main categories of severe kidney disease?
1. Acute renal failure, in which the kidneys abruptly stop working entirely or almost entirely but may eventually recover nearly normal function

2. Chronic renal failure, in which there is progressive loss of function of more and more nephrons that gradually decreases overall kidney function.
22. What are the three main categories of causes for acute renal failure?
1. Acute renal failure resulting from decreased blood supply to the kidneys; this condition is often referred to as prerenal acute renal failure - can be a consequence of heart failure with reduced cardiac output and low BP

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. Common causes are kidney stones.
23. Prerenal acute renal failure is caused by...?
Caused by decreased blood flow to the kidney.

The main purpose of 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 concentration.

Therefore, decreased renal blood flow is usually accompanied by decreased GFR and decreased urine output of water and solutes.
24. How can acute renal failure be reversed?
As long as renal blood flow does not fall below about 20-25% normal, acute renal failure can ususally 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.
25. Reason for kidney being able to endure a large reduction in blood flow
As renal blood flow is reduced, the GFR and the amount of sodium chloride filtered by the glomeruli are reduced.

This decreases the amt of sodium chloride that must be reabsorbed by the tubules, which uses 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.
26. What happens when blood flow is less than 20-25x the normal renal blood flow?
When blood flow is reduced below this basal requirement, 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 the prerenal acute renal failure is not corrected and ischemia persists longer than a few hours, it can lead to intrarenal acute renal failure.
27. Intrarenal acute renal railure
Abnormalities that originate within the kidney and that abruptly diminish urine output fall into the general category of intrarenal acute renal failure.
28. What are the three categories of acute renal failure?
1. Conditions that injure the glomerular capillaries or other small renal vessels

2. Conditions that damage the renal tubular epithelium

3. Conditions that cause damage to the renal interstitium.
29. Glomerulonephritis and acute renal failure
Acute glomerulonephritis is a type of intrarenal acute renal failure usually caused by an abnormal immune reaction that damages the glomeruli.

It is related to infections caused by a certain type of group A beta streptococci.

It is not the infection that damages the kidneys.

Instead, over a few weeks, as antibodies develop against the stretococcal antigen, the 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.
30. What happens 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 WBCs become entrapped in the glomeruli. Many of the glomeruli become blcoked by this inflammatory reaction, and those that are not blocked ususally become excessively permeable, allowing both protein and RBCs to leak from the blood of the glomerular capillaries into the glomerular filtrate.

In severe cases, either total or almost complete renal shutdown occurs.
31. How long does the acute inflammation of the glomeruli last?
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.
32. 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.
33. What are two common causes of tubular necrosis?
1. Severe ischemia and inadequate supply of oxygen and nutrients to the tubular epithelial cells

2. Poisons, toxins, or medications that destroy the tubular epithelial cells
34. Acute tubular necrosis caused by severe renal ischemia
Severe ischemia of the kidney can result from circulatory shock or another 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 lough off and plug many of the nephrons, so that there is not 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.
35. What are the most common causes of ischemic damage to the tubular epithelium?
The most common causes of ischemic damage to the tubular epithelium are the prerenal causes of acute renal failure associated with circulatory shock.
36. Acute tubular necrosis caused by toxins or medications
Some of these are carbon tetrachloride, heavy metals, ethylene glycol, various insecticides, various medications used as antibiotics, and cis-platinum.

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 that the tubule repairs itself within 10-20 days.
37. Postrenal acute renal failure caused by abnormalities of the lower urinary tract
Multiple abnormalities of the lower urinary tract can block or partially block urine flow and therefore lead to acute renal failure even when the kidney's blood supply and other functions are initially normal.

Chronic obstruction of the urinary tract, lasting for several days or weeks, can lead to irreversible kidney damage.
38. What are some causes of postrenal acute kidney failure?
1. Bilateral obstruction of the ureters or renal pelvises caused by large stones or blood clots
2. Bladder obstruction
3. Obstruction of the urethra
39. What are the major 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, b/c hyperkalemia can be fatal.

B/c 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.
40. Chronic renal failure
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 70-75% below normal.

In general, chronic renal failure can occur b/c of disorders of the blood vessels, glomeruli, tubules, renal interstitium, and lower urinary tract.

The end result is essentially the same - decrease in the number of functional nephrons.
41. End stage renal disease
In many cases, an inital 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.
42. What is the vicious circle of chronic renal failure?
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.
43. Sclerotic lesions in renal disease
These sclerotic lesions can eentually obliterate the glomerulus, leading to further reduction in kidney function, further adaptive changes in the remaining nephrons, and a slowly progressing vicious circle that eventually terminates in end-stage renal disease.
44. What is the only proven method of slowing down the progressive loss of kidney function in end-stage renal disease?
Only way is to lower arterial pressure and glomerular hydrostatic pressure, especially by using drugs such as angiotensin-converting enzyme inhibitors or angiotensin II antagonists.
45. What are the four most common causes of end stage renal disease?
Polycystic kidney disease
46. What types of vascular lesions can lead to ischemia and death of kidney tissue?
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

3. Nephrosclerosis caused by sclerotic lesions of the smaller arteries, arterioles, and glomeruli.
47. What is Benign nephrosclerosis?
Benign nephrosclerosis is the most common form of kidney disease and is seen at least some extent in about 70% of postmortem exams in people who die after teh 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 the 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.

Therefore, much of the kidney tissue becomes replaced by small amounts of fibrous tissue.
48. Prevalence of nephrosclerosis and glomerulosclerosis
Nephrosclerosis and glomerulosclerosis occur to some extent in most people after the foruth decade of life, causing about 10% decrease in the number of functional nephrons each 10 years after age 40.

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 40-50% by age 80.
49. What can increase the frequency and severity of nephrosclerosis and glomerulosclerosis?
The frequency and severity of nephrosclerosis and glomerulosclerosis are greatly increased by concurrent hypertension or diabetes.

In fact, DM and hypertension are the two most important causes of end-stage renal disease.
50. Malignant nephrosclerosis
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 sever ischemia occurring in the affected nephrons.
51. Chronic glomerulonephritis
In contrast to the acute form, chronic glomerulonephritis is a slowly progressive disease that often leads to irreversible renal failure. It may be primary kidney disease, following acute glomerulonephritis, or it may be secondary to systemic diseases, such as SLE.
52. How does chronic glomerulonephritis form?
In most cases, chronic glomerulonephritis begins with accumulation of precipitated antigen-antibody complexes in the glomerular membrane.

The results of the accumulation of antigen-antibody complex in the glomerular membranes are inflammation, progressive thickening of the membranes and eventual invasion of the glomeruli by fibrous tissue.

In later stages of the disease, the glomerular capillary filtration coefficient becomes greatly reduced b/c of decreased numbers of filtering capillaries in the glomerular tufts and b/c of thickened glomerular membranes.
53. What is 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.
54. What is pyelonephritis?
Renal interstitial injury caused by bacterial infection is called pyelonephritis. The infection can result from different types of bacteria but especially from E. 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.
55. What are the 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

2. The existence of obstruction of urine outflow. Can result form cystitis.
56. What is vesicoureteral reflux?
Once cystitis has occurred, it may remain localized w/o ascending to the kidney, or in some people, bacteria may reach the renal pelvis b/c of a pathological condition in which urine is propelled up on one or both of the ureters 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.
57. Progression of 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.

B/c one of the primary functions of the medulla is to provide the countercurrent mechanism for concentrating urine, patients with pyelonephritis freq have markedly impaired ability to concentrate the urine.
58. What is long standing pyelonephritis?
With long-standing pyelonephritis, invasion of the kidneys by bacteria not only causes damage to the renal tubules, glomeruli, and other structures throughout the kidney.

Consequently, large parts of functional renal tissue are lost, and chronic renal failure can develop.
59. What is nephrotic syndrome?
Nephrotic syndrome 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 w/some degree of renal failure.
60. What is the cause of the protein loss in the urine in nephrotic syndrome?
The cause is increased permeability of the glomerular membrane.

Therefore, any disease that increase the permeability of this membrane can cause the nephrotic syndrome.
61. What three conditions can cause nephrotic syndrome?
1. Chronic glomerulonephritis, which affect primarily the glomeruli and often causes greatly increase 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.

3. Minimal change nephrotic syndrome, which is associated w/no major abnormality in the glomerular capillary membrane that can be detected w/light microscopy.
62. What causes the minimal change nephropathy?
Minimal change nephropathy has been found to be associated w/loss of the negative charges that are normally present in the glomerular capillary basement membrane.

This loss of 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, esp albumin, to pass thru the glomerular membrane w/ease b/c the negative charges in the basement membrane normally repel the negatively charged plasma proteins.

Can lead to severe edema.
63. Loss of functional nephrons causes...
Causes the surviving nephrons to excrete more water and solutes.

However, metabolic waste products such as creatinine and urea accumulate in direct proportion to the number of nephrons destroyed.
64. Why do these other substances accumulate when water and electrolytes do not?
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 equal to the rate at which it is filtered.
65. Equation for creatinine filtration and excretion rate
Creatinine filtration rate =

= GFR x Plasma creatinine concentration

= Creatinine excretion rate
66. What happens when the GFR decreases?
If the 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.

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.
67. Phosphate, urate, and hydrogen ions and GFR
Some solutes, such as phosphate, urate, and hydrogen ions, are often maintained near the normal range until GFR fall below 20-30% of normal.

Thereafter, the plasma concentrations of these substances rise, but not in proportion to the fall in GFR.

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.
68. What about sodium and chloride ions?
Their plasma concentrations are maintained virtually constant even with severe decreases in GFR.

This is accomplished by greatly decreasing tubular reabsorption of these electrolytes.

For example, with a 75% loss of functional nephrons, each surviving nephron must excrete 4x as much Na and 4x as much volume as under normal conditions.
69. What causes this adaptation of the nephrons?
Part of this adaptation occurs b/c 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 vasodilate.

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.
70. What is isosthenuria?
Isosthenuria is the 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.
71. Why is the concentrating ability of the kidney impaired in diseased kidneys?

Two reasons...
1. The rapid flow of tubular fluid through the collecting ducts prevents adequate water reabsorption

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 max concentrating ability of the kidney declines, and urine osmolarity and specific gravity approach the osmolarity and specific gravity of the glomerular filtrate.
72. Why is the diluting mechanism in diseased kidneys also impaired?
The diluting mechanism in the kidney is also impaired when the number of nephrons decreases b/c 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 osmolarity and specific gravity approach those of the glomerular filtrate.
73. Which is more indicative of renal function when a person's water intake is restricted for 12+ hours - diluting or concentrating?
B/c the concentrating mechanisms 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.
74. The effect of complete renal failure on the body fluids depends on what two things?
1. Water and food intake
2. The degree of impairment of renal function.
75. What are the four effects of renal failure on the body fluids (AKA uremia)?
1. Generalized edema resultign from water and salt retention
2. Acidosis resulting from failure of the kidneys to rid the body of nromal acidic products
3. High concentration fo the nonprotein nitrogens - especially urea, creatinine, and uric acid- resulting from failure of teh body to excrete the metabolic end products of proteins
4. High concentrations of other substances excreted by the kidney, including phenols, sulfates, phosphates, potassium and guanidine bases.
76. Water retention and development of edema in renal failure
Edema usually does not become severe until kidney function falls to 25% of normal or lower.

Even the small fluid retention that does occur, along with increased secretion of renin and angiotensin II that usually occurs in ischemic kidney diseases, often causes severe hypertension in chronic renal failure.

Thus, dialysis is usually required to preserve life but it usually results in hypertension. In most of these patients, severe reduction of salt intake or removal of ECF by dialysis can control the hypertension.
77. Uremia and azotemia
The nonprotein nitrogens include urea, uric acid, creatinine, and others. These end products 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 10x normal during 1-2 weeks of total renal failure. With chronic renal failure, the concentrations rise appox in proportion to the degree of reduction in functional nephrons.

Thus, measures of urea and creatinine provide an important means for assessing the degree of renal failure.
78. What causes acidosis in renal failure?
When the kidneys fail to function, acid accumulates in the body fluids. The buffers of the body can be overwhelmed and the blood pH falls drastically.
79. What causes anemia in those with chronic renal failure?
Patients with severe chronic renal failure almost always develop anemia.

The most important cause of this is decreased renal secretion of erythropoietin, which leads to diminished RBC production.
80. What causes osteomalacia in chronic renal failure?
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 cause is the rise in serum phosphate concentration that occurs as a result of decreased GFR, which leads to increased in PTH secretion - thus causing secondary hyperparathyroidism.
81. How do renal lesions cause hypertension?
Renal lesions either decrease GFR -OR- increase tubular reabsorption usually lead to hypertension of varying degrees.
82. Three types of renal abnormalities that can cause hypertension
1. Increased renal vascular resistance (renal artery stenosis)
2. Decreased glomerular capillary filtration coefficient (glomerulonephritis)
3. Excessive tubular sodium reabsorption (hyperadosteronism)
83. What are the most likely sequence of events that cause hypertension in patchy renal damage?
1. Ischemic kidney tissue itself excretes less than normal amts 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 to also retain salt and water
3. Excess salt and water cause hypertension in the usual manner.
84. In what condition does a kidney disease cause loss of entire nephrons and leads to renal failure - but may not cause hypertension?
With minimal salt intake, this condition might not cause clinically significant hypertension, b/c even a slight rise in BP 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, the patient with this type of abnormality may develop hypertension if salt intake increases.
85. What is renal glycosuria?
Failure of the kidneys to reabsorb glucose.

The blood glucose concentration may be normal, but the transport mechanisms for tubular reabsorption of glucose is greatly limited or absent.

Consequently, large amts of glucose pass into the urine each day. Diabetes is associated with this as well, so renal glycosuria must be ruled out first.
86. What is aminoaciduria?
Failure of the kidneys to reabsorb AAs.

Rarely, a condition called generalized aminoaciduria results from deficient reabsorption of all AAs; more frequently, deficiencies of specific carrier systems may result in:

1. Essential cystinuria, in which large amts of cystine fail to be reabsorbed and often form kidney stones
2. Simple glycinuria, in which glycine fails to be absorbed
3. β-aminoisobutyricaciduria, which occurs in about 5% of all people but has not clinical significance.
87. What is renal hypophosphatemia?
Failure of the kidneys to reabsorb phosphate.

Usually not clinically significant in the short term but over a long period, a low phosphate level can cause diminished calcification of the bones, causing the person to develop vitamin D resistant rickets.
88. What causes renal tubular acidosis?
Failure of the tubules to secrete hydrogen ions. As a result, large amts of sodium bicarb are continually lost in the urine. This causes a continued state of metabolic acidosis.
89. What is nephrogenic diabetes insipidus?
Failure of the kidneys to respond to ADH.

This causes large quantities of dilute urine to be excreted. As long as the person is supplied with plenty of water, the person is OK. However, with dehydration, it can become problematic.
90. What is Fanconi's syndrome?
A generalized reabsorptive defect of the renal tubules.

Fanconi's syndrome is usually associated with increased urinary excretion of virtually all AAs, glucose, and phosphate. It can also cause:
1. failure to reabsorb bicarb, which causes metabolic acidosis
2. increased excretion of potassium and sometimes calcium
3. nephrogrenic diabetes insipidus
91. What are three causes of Fanconi's syndrome?

What part of the kidneys is especially affected in Fanconi's syndrome?
1. Hereditary defects in cells transport mechanisms
2. Toxins or drugs that injure the renal tubular epithelial cells
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, b/c these cells reabsorb and secrete many of the drugs and toxins that can cause damage.
92. The rate of movement of solute across the dialyzing membrane depends on what four things?
1. Concentration gradient of the solute between the two solutions
2. Permeability of the membrane to the solute
3. Surface area of the membrane
4. Length of time that the blood and fluid remain in contact w/the membrane
93. What is the juxtaglomerular apparatus?
Renin is an aspartyl protease produced and secreted by the juxtaglomerular apparatus, a specialized set of smooth muscle cells that line the afferent and efferent arterioles of the renal glomerulus.
94. What is the result of renal secretion?
The ultimate result of renin secretion is vasoconstriction and Na retention, actions that maintain tissue perfusion and increase ECF volume.
95. What three mechanisms control juxtaglomerular cell release of renin?
1. A direct pressure sensing mechanism of the afferent arteriole increases juxtaglomerular cell release of renin in response to decreased tension.

2. Sympathetic innervation of juxtaglomerular cells promotes renin release via β₁-adrenoceptor signaling.

3. An autoregulatory mechanism known as tubuloglomerular feedback senses distal nephron sodium delivery and modulates renin release.
96. What is the macula densa?
Macula densa cells of the cortical thick ascending limb respond to increased luminal NaCl delivery by increasing EC adenosine in the juxtoglomerular interstitium and thereby activating A₁ receptors on the juxtaglomerular mesangial cells.
97. What are the four physiologic actions of angiotensin II?
1. Stimulation of aldosterone secretion by zona glomerulosa cells of the adrenal glands.

2. Increased reabsorption of NaCl at the proximal tubule and other nephron segments

3. Stimulation of thirst and ADH secretion

4. Arteriolar vasoconstriction
98. What mediates the actions of angiotensin II?
All of the actions of AT II are mediated by its binding to the AT II receptor subtype 1 (AT₁ receptor), a G protein coupled receptor.
99. What modulates urine and plasma osmolality?
Regulation of renal water reabsorption in the collecting duct modulates urine and plasma osmalality, and serves as a reserve mechanism for increasing intravascular volume in situations of severe dehydration.
100. What occurs in the proximal tubule?
The proximal tubule is the first reabsorptive site in the nephron. It is responsible for approx 2/3's of sodium reabsorption, 85-90% of bicarbonate reabsorption, and 60% of chloride reabsorption.

Specific sodium coupled symporters in the proximal tubule apical membrane drive renal reabsorption of glucose, AAs, phosphate, and sulfate. The proximal tubule also mediates secretion and reabsorption of weak organic acids and bases coupled to sodium or proton symport or antiport, or to anion exchange mechanisms.
101. What does carbonic anhydrase IV do?
CAIV converts liminal HCO₃⁻ to CO₂ and OH⁻.

Then, the OH⁻ is rapidly hydrated to water by the abundance of local protons, and the CO₂ freely diffuses into the cytoplasm of the proximal tubular epithelial cell.
102. What does carbonic anhydrase II do?
CAII rapidly rehydrates the intracellular CO₂ to HCO₃⁻.

The HCO₃⁻ produced by the CAII reaction is then cotransported with sodium across the basolateral membrane of the epithelial cell using the Na⁺/HCO₃⁻ cotransporter (NBC1).
103. What is the importance of aquaporins?
Data from mice genetically modified to lack the aquaporin water channel (AQP1) demonstrate that most proximal tubular water reabsorption is transcellular.

The important role of aquaporins in transepithelial water permeability seems to hold true for all water-permeable nephron segments.
104. What occurs in the thick ascending limb of the loop of Henle (TAL)?
The tubular fluid emerging from the thin ascending limb is hypertonic and has an elevated NaCl concentration. The TAL reabsorbs NaCl without accompanying water, diluting the tubular fluid.

The TAL reabsorbs between 25-35% of the filtered sodium load by means of the membrane Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2)
105. What is the energy requirement of the TAL?
The TAL, working at maximal capacity, can consume up to 25% of the body's total ATP production, ~65 moles/day at rest.
106. What occurs in the distal convoluted tubule?
This continuation of the diluting segment actively reabsorbs between 2-100% of the filtered NaCl load, while remaining impermeable to luminal water.
107. What occurs in the collecting ducts?
The terminal portion of the nephron is divided into cortical, outer medullary, and inner medullary collecting duct segments.

These collecting ducts account for 4-5% of the kidney's reabsorption of sodium and 5% of the kidney's reabsorption of water. At times of extreme dehydration, over 24% of the filtered water may be reabsorbed in the collecting duct system.

*They are extremely sensitive to ADH.

The collecting duct system participates in the regulation of other electrolytes, including chloride, potassium, hydrogen ions, and bicarbonate.
108. How does ADH affect the collecting duct system?
In the absence of ADH, water in the renal filtrate is left alone to enter the urine, promoting diuresis.

When ADH is present, aquaporins allow for the reabsorption of this water, thereby inhibiting diuresis.
109. What are the three pharmacologic strategies for interruption of the renin-angiotensin system?
1. ACE inhibitors interrupt the conversion of angiotensin I to angiotensin II

2. Angiotensin receptor antagonists are competitive antagonists of the AT₁ receptor, and thus inhibit the target-organ effects of angiotensin II.

3. Antagonists of the mineralocorticoid receptor block aldosterone action at the nephron collecting duct.
110. What are ACE inhibitors?
B/c angiotensin II is the primary mediator of the activity of the renin-angtiotensin-aldosterone system, decreased conversion of ATI to ATII inhibits arteriolar vasoconstriction, decreases aldosterone synthesis, inhibits renal proximal tubule NaCl reabsorption, and decreases ADH release.

All of these actions result in decreased BP and increased natriuresis. In addition, b/c ACE proteolytically cleaves bradykinin, ACE inhibitors increase bradykinin levels, leading to vascular smooth muscle relaxation and increased NO production.
111. What are the names of the ACE inhibitors?
1. Captopril
2. Enalopril
3. Ramipril
4. Benazepril
5. Fosinopril
6. Moexipril
7. Perindopril
8. Quinapril
9. Trandolapril
10. Lisinopril
112. ACE inhibitors MOA and PURPOSE
ADVERSE: Angioedema (more frequent in Black patients), agranulocytosis, neutropenia, cough, edema, hypertension, rash, gynecomastia, hyperkalemia, proteinuria

CONTRA: History of angioedema, bilateral renal artery stenosis, renal failure, and *pregnancy.

*Causes major fetal malformations
113. What are the three patterns of metabolism in ACE inhibitors?
1. The first pattern is exemplified by the prototypical ACE inhibitor, captopril - it is active as administered, but is also processed to an active metabolite.

2. The most common pattern, exemplified by enalapril and ramipril, is that of an ester prodrug converted in the plasma to an active metabolite.

3. Lisinopril is the sole example of the third pattern, in which the drug is administered in active form and excreted unchanged by the kidneys.
114. What causes the cough and angioedema in ACE inhibitors?
Cough and angioedema are caused by bradykinin action; angioedema occurs within the first week of therapy in 0.1-0.2% of patients and can be potentially life threatening.
115. ACE inhibitor therapeutic considerations
NOTES: First does hypotension and/or acute renal failure are more common in patients with bilateral renal artery stenosis; *hyperkalemia is more common when ACE inhibitors are used in combo with potassium sparing diuretics

ACE inhibitors delay progression of cardiac contractile dysfunction in heart failure and after MI, and delay progression of diabetic nephropathy.

A few case reports suggest that coadministration of allopurinol may predispose to hypersensitivity reactions, including Stevens-Johnson syndrome and anaphylaxis.
116. What are angiotensin II receptor antagonists?

How do they compare to ACE inhibitors?
AT₁ receptor antagonists, such as losartan and valsartan, inhibit the action of AT II at its receptor.

Compared to ACE inhibitors, AT₁ receptor antagonists may allow more complete inhibition of ATII's actions, b/c ACE is not the only enzyme that can generate ATII.

In addition, b/c AT₁ receptor antagonists have not effect on bradykinin metabolism, their use may minimize the incidence of drug induced cough and angioedema.

However, they may be less effective vasodilation than ACE inhibitors.
117. What are the angiotensin II receptor antagonists?
1. Candesartan
2. Irbesartan
3. Losartan
4. Telmisartan
5. Valsartan
118. Angiotensin II receptor antagonists
MOA: Antagonize action of ATII at AT₁ receptor, may also indirectly increase vasorelaxant AT2 receptor activity

PURPOSE: hypertension, diabetic nephropathy, heart failure, MI, prevention of stroke

ADVERSE: Rare thrombocytopenia, rhabdomyolysis, rare angioedema, hypotension, diarrhea, asthenia, dizziness

CONTRA: Bilateral artery stenosis and pregnancy.

NOTES: Also called ARBs. In combo with ACE inhibitors, may provide survival benefit in severe heart failure; AT₁ receptor antagonists may also protect against stroke.

Initially only prescribed for patients with intolerable reaction to ACE inhibitors, but are now considered potential first-line treatments for hypertension.
119. What is B-type natriuretic peptide?
Nesiritide, a recombinant human-sequence B-type natriuretic peptide (BNP), has recently been approved for short term managemetn of decompensated HF.

IN clinincal trials, it results in decreased pumonary capillary wedge pressure, decreased systemic vascular resistance, and improved cardiac stroke volume.

B/c it is a peptide, it is ineffective when given orally.
120. Nesiritide
MOA: Increases intracellular concentration of cGMP by binding to the particulate guanylyl cyclase receptor of vascular smooth muscle and endothelial cells, resulting in smooth muscle relaxation

PURPOSE: Acutely decompensated heart failure

ADVERSE: Hypotension, cardiac arrhythmia, renal dysfunction, headache, confusion, somnolence, tremor, pruritus, nausea.

CONTRA: Cardiogenic shock or systolic BP less than 90 mm Hg.

NOTES: May be associated with a lower incidence of arrhythmias than dobutamine. The risk of hypotension is increased by coadministration with ACE inhibitors. Nesiritide treatment is also associated with an increased risk of renal dysfunction.
121. What are vasopressin receptor 2 (V2) antagonists?
These antidiuretic hormone antagonists prevent vasopressin-stimulated water reabsorption via V2 coupled aquaporin channels in apical membranes of collecting duct cells.

These include:
1. Conivaptan
2. Lixivaptan
3. Tolvaptan
122. Vasopressin receptor 2 (V2) antagonists
MOA: Potent antagonists activity at V2 and weaker antagonist activity at V1, preventing vasopressin-stimulated water reabsorption via V2 coupled aquaporin channels in apical membranes of collecting duct cells.

PURPOSE: Euvolemic hyponatremia, SIADH, heart failure, cirrhotic ascites, autosomal dominant polycystic kidney disease

ADVERSE: Atrial fibrillation, orthostatic hypotension, hypertension, peripheral edema, injection-site reaction, hypokalemia, thirst, dyspepsia, headache, polyuria

CONTRA: Concurrent use of potent P450 3A4 inhibitors, and hypovolemic hyponatremia

NOTES: Approval of the orally bioavailable, V2-selective agents tolvaptan and lixivaptan is anticipated. V2 receptor antagonists are under eval as agents to retard vasopressin driven renal cyst growth in polycystic kidney disease
123. Specific notes about conivaptan
Conivaptan is the first specific non-peptide vasopressin receptor antagonist approved for treatment of euvolemic hyponatremias (SIADH).

Conivaptan is relatively nonselective for V2 and V1 receptors and MUST be administered via IV.
124. What are carbonic anhydrase inhibitors?
Carbonic anhydrase inhibitors, specifically acetazolamide, inhibit sodium reabsorption by noncompetitively and reversibly inhibiting proximal-tubule cytoplasmic carbonic anhydrase II and luminal carbonic anhydrase IV.

Inhibition of carbonic anhydrase leads to increased delivery of sodium bicarbonate to more distal segments of the nephron. Much of this sodium bicarbonate is initially excreted, however, over the course of several days of therapy, the diuretic effect of the drug is diminished by compensatory up-regulation of NaHCO₃ reabsorption, and by increased NaCl reabsorption across more distal nephron segments.
125. Acetazolamide
MOA: Inhibits sodium reabsorption by noncompetitively and reversibly inhibiting proximal-tubule cytoplasmic carbonic anhydrase II and luminal carbonic anhydrase IV, leading to increased delivery of sodium bicarbonate to more distal segments of the nephron.

PURPOSE: High altitude sickness, heart failure, epilepsy, glaucoma

ADVERSE: Metabolic acidosis, sulfonamide adverse reaction, diarrhea, weight and appetite loss, tinnitus, nausea, vomiting, paresthesia, somnolence, polyuria.

CONTRA: Adrenal gland failure, chronic angle-closure glaucoma, cirrhosis, hyponatremia, hypokalemia, hyperchloremic acidosis, and severe hepatic or renal disease.
126. Acetazolamide therapeutic considerations
NOTES on acetazolamide:
1. Clinical use is associated w/mild-to-moderate metabolic acidosis
2. Used occasionally in heart failure to restore acid-base balance
3. Carbonic anhydrase inhibition of ciliary process of the eye reduces secretion of aqueous humor and may thereby reduce elevated intraocular pressure in glaucoma
4. Can be used prophylactically against acute mountain sickness, presumably owing to the drug's effects on choroid plexus and ependyma, respiratory centers of the brain, and blood-brain barrier
5. These agents alkalinize urine (especially iwth oral bicarbonate) and increase urinary excretion of endogenous (uric acid) and exogenous (aspirin) organic acid anions; can be used in the treatment of hyperuricemia or gout
6. Aspirin increases plasma concentrations of acetazolamide, potentially leading to CNS toxicity.
127. What are osmotic diuretics?
Osmotic diuretics, such as mannitol, are small molecules that are filtered at the glomerulus but not subsequently reabsorbed in the nephron. Thus, they constitute an intraluminal osmotic force limiting reabsorption of water across water permeable nephron segments.

The effect of osmotic agents is greatest in the proximal tubule, where most iso-osmotic reabsorption of water takes place.
128. Mannitol
MOA: Act as an osmole, filtered at the glomerulus but not subsequently reabsorbed in the nephron; exert an intraluminal osmotic force limiting reabsorption of water across water permeable nephron segments.

PURPOSE: Cerebral edema, increased intraocular pressure, prophylaxis of oliguria in acute renal failure

ADVERSE: Thrombophlebitis, acidosis, seizure, urinary retention, pulmonary edema, hypotension, palpitations, fluid and/or electrolyte imbalance, diarrhea, nausea, rhinitis.

CONTRA: anuria, severe dehydration, heart failure, pulmonary congestion, or renal dysfunction after initiation of mannitol
129. Mannitol therapeutic considerations
Mannitol notes:

1. Promotes vigorous natriuresis; requires careful monitoring of volume status

2. Water loss in excess of sodium excretion can lead to unintended hypernatremia

3. Used primarily for rapid reduction of intracranial pressure in the setting of head trauma, brain hemorrhage, or symptomatic cerebral mass; also used rarely in treatment of compartment syndrome.
130. Radiocontrast agents as osmotic diuretics
Radiocontrast agents are filtered at the glomerulus but not reabsorbed by the tubular epithelium. Thus, the dyes constitute an osmotic load and can produce osmotic diuresis.

In patients with borderline cardiovascular status, the consequent reduction in intravascular volume can lead to hypotension or to renal and/or cardiac insufficiency secondary to reduced organ perfusion.
131. What are loop diuretics?
MOA: Loop diuretics at the TAL of the loop of Henle. These agents reversible and competitively inhibit the Na⁺-K⁺-2Cl⁻ cotransporter NKCC2 in the apical (luminal) membrane of TAL epithelial cells.

They also inhibit transcellular transport of NaCl which also reduces or abolishes the lumen-positive transeptihelial potential difference across the TAL.
132. What is the prototypical loop diuretic?
The prototypical loop diuretic is furosemide.

Other drugs in this class include bumetanide, torsemide, and ethacrynic acid.
133. Loop diuretics (PURPOSE, ADVERSE)
PURPOSE: hypertension, acute pulmonary edema, edema associated with congestive heart failure, hepatic cirrhosis, or renal dysfunction, hypercalcemia, hyperkalemia.

ADVERSE: hypotension, erythema multiforme, Stevens-Johnson syndrome, pancreatitis, aplastic or hemolytic anemia, leukopenia, thrombocytopenia, volume contraction, alkalosis, ototoxicity (dose related), hypokalemia, hyperuricemia, hypomagnesmia, hyperglycemia, rash, cramps, spactivity, headache, blurred vision, dyspepsia, glycosuria
134. Loop diuretics (CONTRA)
CONTRA: Hypersensitivity to sulfonamides (contraindication for furosemide, bumetanide, and torsemide), anuria, coadministration with aminoglycosides increases ototoxicity and nephrotoxicity
135. Loop diuretics therapeutic considerations

Bumetanide is approx 40x more potent than the other loop diuretics; furosemide, bumetanide, and torsemide are all sulfonamide derivatives, while ethacrynic acid is not.

Front line therapy for acute relief of pulmonary and peripheral edema in heart failure. Edematous states can be treated with low-dose loop diuretics.

Also used to counteract hypercalcemic and hyperkalemic states.
136. What are thiazides?
Thiazide diuretics inhibit sodium chloride reabsorption in the distal convoluted tubule.

These agents cause a modest reduction in intravascular volume, and decreases systemic BP.

As such, they are first line agents for treatment of hypertension
137. What are the names of the thiazides?
1. Hydrochlorothiazide
2. Bendroflumethiazide
3. Hydroflumethizide
4. Polythiazide
5. Chlorthalidone
6. Metolazone
7. Indapamide
138. Hydrochlorthiazide
Hydrochlorthiazide is the prototypical thiazide diuretic. In addition to its effects on renal electrolyte handling, Hydrochlorthiazide decreases glucose tolerance and may unmask diabetes in patients at risk for impaired glucose metabolism.
139. Thiazides
MOA: These agents act from the apical (luminal) side as competitive antagonists of the NCC1 Na⁺-Cl⁻ cotransporter in the luminal membrane of distal convoluted tubule cells.

PURPOSE: Hypertension, adjunct in edema states associated with congestive heart failure, hepatic cirrhosis, renal dysfunction, corticosteroid and estrogen therapy

ADVERSE: cardiac arrhythmias, Stevens-Johnson syndrome, toxic epidermal necrolysis, pancreatitis, hepatotocitiy, SLE, hypotension, vasculitis, photosensitivity, electrolyte abnormalities, hypokalemic metabolic alkalosis, hyperglycemia, hyperuricemia, dyspepsia, headache, blurred vision, impotence, restlessness.

CONTRA: Anuria, hypersensitivity to sulfonamides, coadministration with agents that prolong QT interval
140. Thiazide therapeutic considerations
Thiazide NOTES:

1. First line agents for treatment of hypertension

2. Used to diminish hypercalciuria in patients at risk for kidney stones and rarely to decrease urinary calcium wasting in osteoporosis

3. Should not be administered concurrently with antiarrhythmic agents that prolong the QT interval

4. In patients with nephrogenic diabetes insipidus, thiazide diuretics can paradoxically produce a modest decrease in urine flow.
141. What are the collecting duct (potassium sparing) diuretics?
In contrast to all other diuretic classes, potassium sparing diuretics increase nephron reabsorption of potassium.

Agents in this class interrupt collecting-duct principal cell Na reabsorption.
142. Spironolactone and epleronone
MOA: Inhibits aldosterone action by binding to and preventing nuclear translocation of the mineralocorticoid receptor.
Inhibits the biosynthesis of new Na channels in the principal cells.

PURPOSE: Hypertension, edema associated with congestive heart failure, liver cirrhosis (w/ or w/o ascites), or nephrotic syndrome, hypokalemia, primary aldostgeronism, acne vulgaris (spironoloactone), female hirsutism (spironoloactone)

ADVERSE: Hyperkalemic metabolic acidsosis, GI hemorrhage, agranulocytosis, SLE, breast cancer, gynecomastia, dyspepsia, lethargy, abnormal menstruation, impotence, rash

CONTRA: Anuria, hyperkalemia, acute renal insufficiency
143. Spironolactone and epleronone therapeutic considerations
Spironolactone and epleronone NOTES:

1. Potassium sparing diuretics are mild diuretics when used in isolation, but can potentiate the action or more proximally acting loop diuretics
2. Occasionally used in combo with thiazides to counteract potassium wasting effect of thiazide
3. Spironolactone also antagonizes the androgen receptor, can cuase importence and gynecomastia in men but confers therapeutic advantage in women with acne and hirsutism; eplerenone has less anti-androgenic activity
4. Used to treat hypokalemic alkalotic states secondary to mineralocorticoid excess in heart failure, hepatic failure, and other disease states associated with diminished aldosterone metabolism.
5. Both spironolactone and epleronone reduce mortality in patients with heart failure; the mechanism may be related to inhibition of cardiac fibrosis resulting from a paracrine aldosterone-signaling pathway.
144. Amiloride and triamterene
MOA: Competitive inhibitors of the principal cell apical membrane ENaC sodium channel

PURPOSE: Hypertension and Liddle syndrome

ADVERSE: disease of the hematopoietic system, nephrotoxicity (triamterene), hyperkalemic metabolic acidosis, orthostatic hypotension, hyperkalemia, dyspepsia, headache

CONTRA: anuria, hyperkalemia, acute renal insufficiency

NOTES: Amiloride and triameterene are drugs of choice for treatment of Liddle syndrome, a rare, Mendelian form of hypertension resulting from gain-of-function mutations in the β or γ subunit of the ENaC sodium channel.
145. What are three main implications of the anatomy of renal vessels?
1. B/c the arteries are largely end-arteries, occlusion of any branch usually results in infarction of the specific area it supplies.
2. All tubular capillary beds are derived from the efferent arterioles and thus glomerular disease that interferes w/blood flow thru the glomerular capillaries has profound effects on the tubules
3. The peculiarities of the blood supply to the renal medulla render them especially vulnerable to ischemia; the medulla does not have its own arterial blood supply but is dependent on the blood emanating from the glomerular efferent arterioles. Thus, minor interference w/the blood supply of the medulla may result in medullary necrosis from ischemia.
146. What are glomeruli and what are the major characteristics of their filtration?
The glomerulus consists of an anastomosing network of capillaries lined by fenestrated endothelium invested by two layers of epithelium.

The major characteristics of normal glomerular filtration are an extraordinarily high permeability to water and small solutes, b/c of the highly fenestrated nature of the endothelium, and impermeability to proteins, such as molecules the size of albumin or larger.
147. What is the glomerular barrier function?
This function discriminates among various protein molecules depending on their size (the larger, the less permeable) and charge (the more cationic, the more permeable).

This size and charge dependent barrier function is accounted for by the complex structure of the capillary wall, the collagenous porous and charged structure of the BGM, and the many anionic moieties present within the wall, including the acidic proteoglycans of the GBM and the sialoglycoproteins of epithelial and epithelial cell coats.

The charge-dependent restriction is important in the virtually complete exclusion of albumin from the filtrate, b/c albumin in an anionic molecule of pI 4.5.
148. What is the visceral epithelial cell AKA podocyte important for?
The podocyte is important for the maintenance of glomerular barrier function; its slit diaphragm presents a size selective distal diffusion barrier to the filtration of proteins, and it is the cell type that is largely responsible for synthesis of GBM components.

Proteins located in the slit diaphragm control glomerular permeability.
149. What are the important proteins have been identified in the slit diaphragm?
Nephrin; a transmembrane protein w/a large EC portion made up of Ig like domains.

Nephrin then forms molecular connections w/podocin, CD2-associated protein, and ultimately the actin skeleton.

Mutations in the genes that encode for these proteins give rise to nephrotic syndrome.
150. What is the structure and function of the tubules?
The structure of the tubule is correlated with its function; for ex: the highly developed structure of the proximal tubular cells, with their abundant long microvilli, numerous mitochondria, apical canaliculi, and extensive intercellular interdigitations is correlated w/their major functions: reabsorption of 2/3's of filtered sodium and water as well as glucose, potassium, phosphate, AAs, and proteins.

The proximal tubule is particularly vulnerable to ischemic damage. Furthermore, toxins are freq reabsorbed by the proximal tubule, rendering it also susceptible to chemical injury.
151. What is the juxtaglomerular apparatus?
It lies against the glomerulus where the afferent arteriole enters it. It consists of:
1. The JG cells, modified granulated smooth muscle cells that contain renin
2. The macula densa
3. The lacis cells or nongranular cells.

The JG apparatus is a small endocrine organ, and the JG cells are the principal sources of renin production in the kidney.
152. What are the four categories of renal diseases?
Renal diseases are divided into four categories based on the four basic anatomic compartments affected:

1. Glomeruli
2. Tubules
3. Intersitium
4. Blood vessels

Whatever the origin, there is a tendency for all forms of chronic renal disease ultimately to destroy all four components of the kidney, culminating in chronic renal failure.
153. What is azotemia?
Azotemia is a biochemical abnormality that refers to an elevation of the blood urea nitrogen (BUN) and creatinine levels and is related largely to a decreased glomerular filtration rate (GFR).

Azotemia is produced by many renal disorders but also arises from extrarenal disorders.
154. What is prerenal azotemia?
This is encountered when there is hypoperfusion of the kidneys (e.g. in hemorrhage or shock) that impairs renal function in the absence of parenchymal damage.
155. What is postrenal azotemia?
This is seen whenever urine flow is obstructed below the level of the kidney. Relief of the obstruction is followed by correction of the azotemia.
156. What is uremia?
When azotemia becomes associated w/a constellation of clinical signs and symptoms and biochemical abnormalities, it is termed uremia.

Uremia is characterized no only by failure of renal excretory function but also by a host of metabolic and endocrine alterations resulting from renal damage. There is, in addition, secondary involvement of the GI system, peripheral nerves, and heart, which is usually necessary for the Dx of uremia.
157. What is acute nephrotic syndrome?
ANS is a glomerular syndrome dominated by the acute onset of usually grossly visible hematuria, mild to moderate proteinuria, and hypertension; it is the classic presentation of acute poststreptococcal glomerulonephritis.
158. What is nephrotic syndrome?
Nephrotic syndrome is characterized by heavy proteinuria, hypoalbuminemia, severe edema, hyperlipidemia, and lipiduria (lipids in the urine).
159. What is acute renal failure?

What is chronic renal failure?
Acute renal failure is dominated by oliguria or anuria, with recent onset of azotemia. It can result from glomerular, interstitial, or vascular injury or tubular necrosis.

Chronic renal failure is characterized by prolonged symptoms and signs of uremia, and is the end result of all chronic renal parenchymal diseases.
160. What are renal tubular defects?
Renal tubular defects are dominated by polyuria, nocturia, and electrolyte disorders. They are the result of either diseases that directly affect tubular structure (e.g. medullary cystic disease) or defects in specific tubular functions. The latter can be inherited (e.g. familial nephrogenic diabetes, cystinuria, renal tubular acidosis) or acquired (e.g. lead nephropathy).
161. What are the characteristics of UTIs?
UTI is characterized by bacteriuria and pyuria (bacteria and leukocytes in the urine). The infection may be symptomatic or asymptomatic, and it may affect the kidney or the bladder.
162. What are the four stages of chronic renal failure?
1. Diminished renal reserve (GFR = 50% of normal)
2. Renal insufficiency (GFR = 20-50% of normal with azotemia, anemia, and hypertension)
3. Renal failure (GFR < 20-25% of normal; with edema, metabolic acidosis, and hypocelcemia)
4. End-stage renal disease (GFR < 5% of normal; this is the terminal stage of uremia)
163. What is renal agenesis?
Total bilateral agenesis of the kidney is incompatible w/life and is usually encountered in stillborn infants. It is often associated w/many other congenital disorders (e.g. limb defects, hypoplastic lungs) and leads to early death.

Unilateral agenesis is an uncommon anomaly that is compatible w/normal life if no other abnormalities exist. The opposite kidney is usually enlarged as a result of compensatory hypertrophy. Progressive glomerular sclerosis sometimes develops in the remaining kidney.
164. What is renal hypoplasia?
Refers to failure of the kidneys to develop to a normal size. This may occur bilaterally, resulting in renal failure in early childhood, but it is more commonly encountered as a unilateral defect.

True renal hypoplasia is extremely rare. ***A truly hypoplastic kidney shows no scars and has a reduced number of renal lobes and pyramids, usually 6 or less.

In one form of hypoplastic kidney, oligomeganephronia, the kidney is small but the nephrons are markedly hypertrophied.
165. What is an ectopic kidney?
Ectopic kidneys lie either just above the pelvic brim or sometimes within the pelvis.

Because of their abnormal position, kinking or tortuosity of the ureters may cause urinary obstruction, predisposing to bacterial infection.
166. What are horseshoe kidneys?
Fusion of the upper (10%) or lower (90%) poles produces a horseshoe-shaped structure continuous across the midline anterior to the aorta and inferior vena cava.

This anomaly is quite common and is found in about 1 in 500-1,000 autopsies.
167. Why are cystic diseases of the kidney important?

Three reasons...
1. They are reasonably common and often represent diagnostic problems for clinicians, radiologists, and pathologists
2. Some forms, such as AKPD, are major causes of chronic renal failure
3. They can occasionally be confused w/malignant tumors.
168. What are the classifications of renal cysts?
1. Cystic renal dysplasia
2. Polycystic kidney disease
3. Medullary cystic disease
4. Acquired cystic disease
5. Simple renal cysts
6. Glomerulocytic disease
7. Extraparenchymal renal cysts
8. Renal cysts in hereditary malformation syndromes
169. What is cystic renal dysplasia?
Cystic renal dysplasia refers to sporadic, nonfamilial disease resulting from abnormal metanephric differentiation. It is frequently associated w/obstructive abnormalities of the ureter and lower urinary tract and may be uni- or bilateral.

Histologically, it is characterized by the persistence in the kidney of abnormal structures- cartilage, undifferentiated mesenchyme, and immature collecting ductules, and by abnormal lobar organization.
170. What are the gross and morphological characteristics of cystic renal dysplasia?
Dysplasia can be unilateral or bilateral and is almost always cystic. In gross appearance, the kidney is usually enlarged, extremely irregular, and multicystic. The cysts vary in size from microscopic structures to some that are several cm in diameter.

On histologic exam, they are lined by flattened epithelium. Although normal nephrons are present, many have immature ducts.

*The characteristic histologic feature is the present of islands of undifferentiated mesenchyme, often w/cartilage, and immature collecting ducts.
171. What are the clinical features of cystic renal dysplasia?
When unilateral, the dysplasia is discovered by the appearance of a flank mass that leads to surgical exploration and nephrectomy.

The function of the opposite kidney is normal, and such patients have an excellent prognosis after surgical removal of the affected kidney. In bilateral renal dysplasia, renal failure may ultimately result.
172. What is autosomal dominant adult polycystic kidney disease?
ADPKD is a hereditary disorder characterized by multiple expanding cysts of both kidneys that ultimately destroy the renal parenchyma and cause renal failure.

It is a common condition affecting roughly 1/400 - 1,000 live births and accounting for about 5-10% of cases of chronic renal failure requiring transplantation or dialysis.

The disease is universally bilateral; reported unilateral cases probably represent multicystic dysplasia. The cysts initially involve only portions of the nephrons, so renal function is retained until the 4th or 5th decade of life.
173. What are the genetic causes of ADPKD?
ADPKD is autosomal dominant, with high penetrance. Family studies show that the disease is caused by mutations in genes located on chromosome 16p13.3 (PKD1) and 4q21 (PKD2).

Mutations of PKD1 account for about 85% of cases and are associated w/a more severe disease, ESRD or death occurring at an average of 53 years, compared to 69 years for PKD2.
174. What is the role of the PKD1 gene?
The PKD1 gene accounts for 85% of cases.

It encodes a large protein named polycystin1. Although the precise function is unknown, polycystin 1 normally localizes to tubular epithelial cells and has homology to proteins involved in cell-cell and cell-matrix interactions.

It also servers a suppressor function; its loss leads to hyperplasia of epithelial cells.
175. What is the role of the PKD2 gene?
The PKD2 gene product polycystin-2 is an integral membrane protein. Polycystin-2 may act as a calcium-permeable cation channel and that a basic defect in ADPKD is a disruption in the regulation of intracellular calcium levels.
176. What is the general theory as to how these mutations cause the pathogenesis of ADPKD?
*These mutations alter cell-cell and cell-matrix interactions that are important for tubular epithelial growth and differentiation.

Epithelial cells lining the cysts of ADPKD have a high proliferation rate. Cysts are freq detached from adjacent tubules and enlarge by active fluid secretion from the lining epithelial cells. In addition, the ECM produced by cyst-lining cells is abnormal. These findings have led to the scenario that cysts develop as a result of abnormality in cell differentiation, associated w/sustained cellular proliferation and some degree of apoptosis, transeptihelial fluid secretion, and remodeling of the ECM.
177. What is the morphology of ADPKD?

In gross appearance, the kidneys are usually bilaterally enlarged and may achieve enormous sizes. The external surface appears to be composed solely of a mass of cysts, up to 304 cm in diameter, w/no intervening parenchyma. However, microscopic exam reveals functioning nephrons dispersed between the cysts.

The cysts may be filled w/a clear, serous fluid or, more usually w/turbid, red to brown, sometimes hemorrhagic fluid.
178. What is the morphology of ADPKD?

As these cysts enlarge, they may encroach on the calyces and pelvis to produce pressure defects. The cysts arise from the tubules throughout the nephron and therefore have variable lining epithelia.

On occasion, papillary epithelial formations and polyps project into the lumen. Bowman capsules are occasionally involved in cyst formation, and glomerular tufts may be seen w/in the cystic space.
179. What are the clinical features of ADPKD?
Patients have flank pain from hemorrhage into cysts, hematuria, hypertension, proteinuria, progressive renal failure, and bilateral abdominal masses inducing a dragging sensation.

Progression is accentuated in the presence of hypertension, in blacks (w/sickle cell trait), and in males.

Patients w/PKD2 mutations tend to have an older age at onset and later development of renal failure.
180. What are the extrarenal anomalies associated with ADPKD?
1. About 40% have one to several cysts in the livers (polycystic liver disease) that are usually asymptomatic
2. Intracranial berry aneurysms, presumably from altered expression of polycystin in vascular smooth muscle, arise in the Circle of Willis, and subarachnoid hemorrhages from these account for death in about 4-10% of those with ADPKD
3. Mitral valve prolapse and other cardiac valvular anomalies occur in 20-25% of patients, but most are asymptomatic.
181. What is autosomal-recessive (childhood) polycystic kidney disease?
ARPKD is a rare developmental anomaly presenting from the perinatal through juvenile periods. Infants often succumb rapidly to renal failure.

Kidneys are enlarged by multiple, cylindrically dilated collecting ducts, oriented at right angels to the cortex and filling both the cortex and medulla.
182. What are the genetic causes of ARPKD?
The disease appears to be genetically homogenous, with a gene, PKHD1. The PKHD1 gene encodes a large novel protein, fibrocystin. This gene is highly expressed in adult and fetal kidney and also in liver and pancreas.

Fibrocystin is a protein that may function in cell surface receptors with a role in collecting-duct and biliary differentiation.
183. What is the morphology of ARPKD?
The kidneys are enlarged and have a smooth external appearance. On cut section, numerous small cysts in the cortex and medulla give the kidney a spongelike appearance.

Dilated elongated channels are present at right angles to the cortical surface, completely replacing the medulla and cortex.

On microscopic exam, there is cylindrical, or less commonly, saccular dilation of all collecting tubules. The cysts have a uniform lining of cuboidal cells, reflecting their origin from the collecting tubules.

The disease is bilateral; in almost all cases, the liver has cysts with portal fibrosis as well as proliferation of portal bile ducts.
184. What is the clinical course in ARPKD?
Patients who survive infancy may develop a peculiar type of hepatic fibrosis characterized by bland periportal fibrosis and proliferation of well-differentiated biliary ductules, a condition now termed congenital hepatic fibrosis. In older children, the hepatic picture in fact predominates.

Such patients may develop portal hypertension with splenomegaly.
185. What is medullary sponge kidney?
This disease should be restricted to lesions consisting of multiple cystic dilations of the collecting ducts in the medulla, usually presenting in adults.

Although it is typically an innocuous lesion discovered incidentally by radiographic studies, it can predispose to renal calculi, hematuria, infection, and dilated ducts.

On gross inspection, the papillary ducts in the medulla are dilated, and small cysts may be present. The cysts are lined by cuboidal epithelium or occasionally be transitional epithelium.
186. What with nephronophthisis-medullary cystic disease complex?
This complex is actually a family of progressive renal disorders, usually w/onset in childhood.

*The common characteristic is the presence of a variable number of cysts in the medulla, usually concentrated at the corticomedullary junction.

Although the presence of medullary cysts is important, the cortical tubulointerstitial damage is the cause of the eventual renal insufficiency.
187. What are the four variants of nephronophthisis-medullary cystic disease complex?
1. Sporadic; non-familial (20%)
2. *Familial juvenile nephronophthisis (50%)
3. *Renal-retinal dysplasia (15%)
4. **Adult onset medullary cystic disease (15%)

*Autosomal recessive
**Autosomal dominant
188. What are the clinical features of nephronophthisis-medullary cystic disease complex?
Affected children present first with polyuria and polydipsia, which reflect a marked defect in the concentrating ability of renal tubules. Sodium wasting and tubular acidosis are also prominent.

Some variants of juvenile nephronophthisis can have extrarenal associations, including ocular motor abnormalities, retinitis pigmentosa, liver fibrosis, and cerebellar abnormalities.

The expected course is progression to terminal renal failure in 5-10 years.
189. What are the genes involved in the pathogenesis of nephronophthisis-medullary cystic disease complex?
Thee genes, NPH1, NPH2, and NPH3, define the juvenile forms of the nephronophthisis and cause autosomal recessive disease.

The protein product of NPH1 is nephrocystin but its function is unknown.

Two genes (MCKD1 and MCKD2) with autosomal dominant transmission, have been identified as causing medullary cystic disease that is characterized by progression to endstage kidney disease in adult life.
190. What is the morphology of nephronophthisis-medullary cystic disease complex?
In gross appearance, the kidneys are small, have contracted granular surfaces, and show cysts in the medulla, most prominently at the corticomedullary junction. Small cysts are also seen in the cortex.

The cysts are lined by flattened or cuboidal epithelium and are usually surrounded by either inflammatory cells or fibrous tissues. In the cortex, there is widespread atrophy and thickening of the basement membranes of the proximal and distal tubules, together w/interstitial fibrosis.
191. What is acquired (dialysis-associated) cystic disease?
End-stage kidneys of patients undergoing dialysis can develop multiple cortical and medullary cysts.

They are often lined by atypical, hyperplastic epithelium that can undergo malignant transformation to renal cell carcinoma.

These cysts often contain calcium oxalate crystals.
192. What are simple renal cysts?

How do they differ radiologically from renal tumors?
These occur as multiple, single, usually cortical cystic spaces that vary widely. They are lined by low cuboidal epithelium and usually are 2-5 cm in diameter but can measure up to 10 cm. They have smooth walls and are filled w/clear serous fluid.

On occasion, they hemorrhage and calcification of the hemorrhage can cause flank pain and irregular contours, thus mimicking renal carcinoma.

Radiologic studies show that in contrast to renal tumors, renal cysts have smooth contours, are almost always avascular, and give fluid rather that solid signals on ultrasonography.