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Myocardial Infarction and Renal Function

A 65-year-old man had a myocardial infarction 4 months ago, and now he complains of easy fatigability,
shortness of breath, and swelling of his ankles. On physical examination he is found to have distended
neck veins and pitting edema of the ankles. His breathing is rapid (20 respirations/min), and rales are
heard bilaterally at the bases of the lungs. He is afebrile, his pulse rate is 90 beats/min, and his blood
pressure is 110/70. Since his myocardial infarction, he has been taking a cardiac glycoside and a thiazide
diuretic. A blood sample is obtained, and the following abnormalities are noted:

1. Is the extracellular fluid (ECF) volume in this man above or below normal? What evidence in the
physical examination supports your conclusion?

2. Is the effective circulating volume (ECV) in this man above or below normal? What laboratory test
could you perform to support your conclusion?

3. How would you characterize renal Na+ handling in this man? What evidence in the physical
examination supports this conclusion?

4. What is the mechanism for the development of hyponatremia in this man?

5. What is the mechanism for the development of hypokalemia in this man?

6. What type of acid-base disturbance does this man have? What is the mechanism for the development
of this disorder?

7. What is the significance of the elevated serum [creatinine]?

8. The physician treating this man prescribes a loop diuretic in addition to the thiazide diuretic to further
reduce his Na+ retention and edema. What effect will this treatment have on the man's ECV? What is
the potential effect of this treatment on the man's serum Na+, K+, HCO3-, and creatinine

1. The ECF volume of this man is increased above normal. The presence of edema, distension of the neck
veins, and rales (sounds caused by fluid) in the lungs are evidence of this increased volume.
Additional evidence could be obtained by measuring weight gain, because accumulation of each liter
of extracellular fluid would increase body weight by 1 kg.

2. The ECV in this man would be decreased below normal. With damage to the myocardium, cardiac
output and therefore tissue perfusion would be reduced; this would be sensed by the body as a
decrease in the ECV. The ECV cannot be measured directly. Therefore to determine if the ECV is
reduced, measurements would have to be made of parameters that change in response to alterations
in the ECV. For example, the kidneys reduce Na+ excretion in response to a decrease in the ECV.
Measurement of fractional Na +excretion could confirm the existence of a reduced effective
circulating volume (fraction Na+ excretion < 1%). However, in this man fractional excretion may not
be very low because a thiazide diuretic was used. Alternatively, measurements would be made of
plasma renin activity because this would be stimulated by the decreased ECV.

3. The kidneys would be avidly retaining Na+. With a decrease in the effective circulating volume, sensors
in the low-pressure (cardiac atria and pulmonary vasculature) and high-pressure (juxtaglomerular
apparatus, aortic arch, and carotid sinus) sides of the circulation would be activated, and the signals
would be sent to the kidneys to retain Na+.

Sympathetic nerves that innervate the afferent and efferent arterioles of the glomeruli would cause
vasoconstriction. The net result would be to reduce the GFR; this in turn would reduce the filtered
load of Na+.

Sympathetic innervation of the proximal tubule and the thick ascending limb of Henle's loop will also
increase Na+ reabsorption at these sites.

Increased sympathetic nerve activity, together with decreased perfusion pressure at the afferent
arteriole, will result in the secretion of renin. This activation of the renin-angiotensin-aldosterone
system will further stimulate Na+ reabsorption, because angiotensin II stimulates proximal tubule
Na+ reabsorption, and aldosterone stimulates Na+ reabsorption in the distal tubule and collecting
duct. With the increase in the ECV, atrial natriuretic peptide (ANP) levels will be elevated. However,
the effect of ANP (inhibition of renin secretion and natriuresis) appears to be blunted by the effect of
the other factors, all of which act to reduce Na+ excretion.

The net effect of these responses is retention of Na + by the kidneys. As a result of this Na + retention
(positive Na+ balance), the ECF volume will increase and lead to the formation of edema, as seen in
the physical examination of this man.

4. The development of hyponatremia indicates that this man is in positive water balance. In this case the
ingestion of water has exceeded the capacity of the kidneys to excrete solute-free water. Solute-free
water excretion is impaired in this man for several reasons:

ADH secretion is stimulated because of the decreased ECV. As a consequence, solute-free water
is reabsorbed by the collecting duct.

The filtered load of solute (NaCl) and water is reduced, and fractional reabsorption by the
proximal tubule is enhanced. As a result, delivery of solute and water to the thick ascending limb
(the primary site where solute-free water is generated) is decreased.

The thiazide diuretic inhibits NaCl reabsorption in the distal tubule. This portion of the nephron
also participates in the generation of solute-free water. With impaired NaCl reabsorption less
solute-free water can be generated.

5. Hypokalemia in this man is the result of increased renal K+ excretion. Two factors contribute to
stimulating K+ excretion. The first is related to the administration of the thiazide diuretic. Thiazide
diuretics act on the early portion of the distal tubule to inhibit NaCl reabsorption. Inhibition of NaCl
reabsorption in the distal tubule results in the delivery of increased quantities of Na+ and fluid to the
portion of the nephron responsible for K + secretion (cortical portion of the collecting duct). This
increased delivery stimulates K+ secretion by the principal cells in this part of the nephron. Second,
the ECV is decreased in this man, which in turn stimulates the renin-angiotensin-aldosterone system.
Aldosterone then acts on the collecting duct to stimulate K+ secretion. The enhanced secretion of K+
by the collecting duct will result in increased K+ excretion and the development of hypokalemia.
Extrarenal factors will also contribute to the development of hypokalemia because both alkalosis and
aldosterone cause K+ to move into cells.

6. Although an arterial blood sample was not obtained, the plasma [HCO3-] is elevated, suggesting the
presence of a metabolic alkalosis. The development of a metabolic alkalosis could reflect enhanced
renal HCO3- reabsorption and H+ excretion. HCO3- reabsorption by the proximal tubule would be
stimulated because proximal tubule reabsorption is enhanced when the ECV is decreased (see the
answer to question 3). Virtually all of the filtered load of HCO3- will be reabsorbed by the time the
tubular fluid reaches the distal tubule and collecting duct. H+ secretion at these sites will titrate
urinary buffers and lead to the generation of "new HCO3-" Because of the decreased ECV, aldosterone
levels are elevated. Because aldosterone stimulates H+ secretion in the distal tubule and collecting
duct, "new HCO3-" generation will be increased, and metabolic alkalosis will develop.

7. Creatinine is excreted from the body mainly by glomerular filtration (10% is excreted as a result of
secretion by the proximal tubule). Therefore the amount of creatinine excreted is determined mainly
by its filtered load. With a reduction in the ECV, the glomerular filtration rate is reduced (see the
answer to question 3). The reduced filtration rate will decrease the filtered load of creatinine, and
thus its excretion. As a result, the serum [creatinine] will increase. The serum [creatinine] should
return to normal when the ECV is restored to its normal value.

8. A loop diuretic will act on the thick ascending limb of Henle's loop to inhibit NaCI reabsorption and
increase Na+ excretion. This enhanced excretion of Na+ will further decrease the ECV. The loop

diuretic can further reduce the serum Na+ and K+ concentrations, make the metabolic alkalosis worse,
and further increase the serum [creatinine].

The thick ascending limb of Henle's loop is the primary site where tubular fluid is diluted. The loop
diuretic will inhibit the separation of solute (NaCl) and water at this site and further impair the
generation of solute-free water (see the answer to question 4). If water ingestion is not reduced,
hyponatremia could become more severe.

The thick ascending limb of Henle's loop reabsorbs approximately 20% of the filtered load of K+. This
process is inhibited by loop diuretics. Also, the loop diuretic will cause increased delivery of Na + and
fluid to the K+ secretory site. Together, these effects will further enhance K+ secretion and thus renal
K+ excretion, leading to a worsening of the hypokalemia.

Because the loop diuretic leads to a further reduction in the ECV, the stimuli for enhancing both
proximal tubule HCO3- reabsorption and distal tubule and collecting duct H + secretion will be
increased. As a result, the metabolic alkalosis may become more severe.

With the added decrement in the ECV caused by the loop diuretic, the glomerular filtration rate will
fall further and thereby cause the serum [creatinine] to increase.

The abnormalities in serum electrolytes seen in this man are caused mainly by the decreased ECV,
which was a result of his myocardial infarction. The diuretic therapy is directed at preventing the
kidneys from responding to the decreased ECV. Although the diuretics reduce Na+ retention by the
kidneys and help alleviate edema formation, they decrease further the ECV and thus may produce
the water, Na+, K+ and acid-base abnormalities seen in this patient.