Regulation of Potassium Balance

110

Practical Urology: EssEntial PrinciPlEs and PracticE

5. Exercise: During exercise skeletal muscle cells

2. Aldosterone: Aldosterone stimulates sodium

release potassium and produces variable deg-

reabsorption by the distal tubule and collect-

rees of hyperkalemia. Usually, these changes

ing duct, and enhances potassium secretion

produce no symptoms and are reversed after

by increasing activity of the Na, K-ATPase.

several minutes of rest.However,under certain

3. Flow rate of tubule fluid: An increase in

circumstances a significant increase in plasma

tubule fluid flow rate increases potassium

potassium concentration can occur such as the

secretion.

individuals who are using beta blockers during

4. Plasma flow rate: Flow rate influences potas-

exercise.

sium secretion by the distal tubule and col-

Excretion of potassium by the kidneys: App-

lecting duct.

roximately 92% of ingested potassium is excreted

5. Plasma pH: Alkalemia increases potassium

by the kidney. The remaining 8% is excreted by

secretion and acidemia decreases potassium

the gastrointestinal tract. Potassium is freely fil-

secretion.

tered by the glomerulus and normally the uri-

6. Sodium concentration of the tubule fluid: An

nary potassium excretion is 15% of the amount

increase in the sodium concentration in the

filtered. The proximal tubule reabsorbs about

distal tubule fluid stimulates potassium secre-

67% of the filtered load of potassium, whereas

tion, whereas a fall has the opposite effect.

the loop of Henle reabsorbs 20%. It is in the dis-

tal tubule and the collecting duct where regula-

tion of potassium secretion occurs. When

Regulation of Acid–Base Balance

dietary intake is normal, potassium is secreted

by these distal nephron segments, however,

when potassium intake is below normal potas-

The body maintains the systemic pH in a nar-

sium reabsorption occurs.

row range to permit normal metabolic func-

The mechanism by which potassium is

tions. The CO2/HCO3 buffer system is the most

secreted by the principal cells of the collecting

important buffer system in the body because it

duct is provided by an electrochemical gradi-

is under the regulation of both the lungs and the

ent. The

uptake of potassium via the Na,

kidney. The relationship is characterized by the

K-ATPase in the basolateral membrane increases

Henderson–Hasselbalch equation.

the potassium concentration within the cell,

6.1+1og

HCO

3 ]

and provides a (1) chemical gradient for potas-

pH =

[

0.03 PCO

2 )

sium to exit across the apical membrane through

(

potassium

channels. Sodium conductance at

In the normal individual, metabolism of carbo-

the apical

membrane depolarizes the apical

hydrates and fats produce large quantities of

membrane relative to the basolateral membrane

CO2. CO2 is in equilibrium with H2CO3, a volatile

and thus

provides an (2) electrical gradient

(lumen negative charge favoring potassium

acid. In addition to volatile acids, metabolism of

amino acids produces nonvolatile acids. The

excretion).

metabolism of cysteine and methionine yields

There are various factors which regulate

sulfuric acid, whereas lysine, arginine, and histi-

potassium secretion by the principal cells.

dine produce hydrochloric acid. A normal diet

1. Plasma potassium concentration: Plasma

produces about 70–100 mmol/day of nonvolatile

potassium concentration is an important

acid. These acids then consume bicarbonate

determinant of potassium secretion by the

from the ECF, and must be replenished in order

distal tubule and collecting duct. An increase

to maintain acid–base balance.

The kidney has a major role in replenishing

in the plasma potassium concentration stim-

bicarbonate loss. There are essentially two com-

ulates the Na, K-ATPase, thereby raising

ponents to renal bicarbonate generation. The

intracellular potassium concentration and

first involves the reabsorption of filtered bicar-

increasing the chemical gradient for potas-

bonate, and the second involves synthesis of new

sium secretion.

bicarbonate.

Reabsorption of Filtered Bicarbonate: Of the

calcium concentration in blood is dependent

filtered load of bicarbonate (4,500 mEq/day),

upon the plasma pH as hydrogen ions compete

approximately 85% is reabsorbed by the proxi-

with calcium ions for binding by plasma pro-

mal tubule and most of the rest is reabsorbed by

teins. In states of acidemia, hydrogen ions dis-

the loop of Henle and collecting duct less than

place calcium from proteins, thereby increasing

1% is lost in the urine.

the plasma concentration of free ionized cal-

Synthesis of New Bicarbonate: As discussed

cium. In contrast, in states of alkalemia, hydro-

above, because dietary intake involves the con-

gen ions are displaced from plasma protein

sumption of volatile acids, which amounts to

binding sites and replaced by calcium ions,

about 70–100 mmol/day, we must excrete this

thereby decreasing the plasma free ionized cal-

amount of acid daily to stay in acid–base bal-

cium concentration.

ance. This is achieved primarily by the secretion

Of the filtered load of calcium, approximately

of titratable acids (H PO

, and NH +). In states

99% of the free ionized calcium is reabsorbed by

2

4

4

the nephron,the majority of which is reabsorbed

of acidemia, the filtered load of phosphate is not

regulated and therefore has a limited capacity to

by the proximal tubule (70%). The thick ascend-

excrete extra acid (30–50 mmol/day). However,

ing limb is responsible for the reabsorption of

NH3

production in response to acidemia

20% of the filtered load of calcium, and the dis-

increases dramatically, therefore, becomes the

tal tubule and collecting ducts combine to reab-

dominant pathway for acid excretion (NH +).

sorb approximately 10% of the filtered load of

Urine

NH +

4

calcium. The net result is that approximately 1%

excretion begins with glutamine

4

of the filter load is excreted into the urine.

metabolism in the proximal tubule forming

NH . NH /NH + enters the lumen of the proxi-

Calcium reabsorption occurs through a trans-

3

3

4

cellular or a paracellular pathway. In the proxi-

mal tubule and, through a convoluted process,

enters the collecting duct as NH3

and traps H+

mal tubule and in the thick ascending limb,

secreted by the H+-ATPase in the collecting duct.

changes in sodium reabsorption alter calcium

It is the presence of NH

3

which permits the H+

reabsorption in parallel. In contrast, in the distal

to continue to be secreted by the collecting duct.

tubule and collecting duct it appears that cal-

Without NH3 the lumen PH would decrease to a

cium and sodium transport are independently

point where limiting gradient would exit and

regulated.Therefore,changes in urinary calcium

prevent further excretion of H+.

and sodium excretion do not always occur in

A defect in renal excretion of H+ or in recla-

parallel. For example, thiazide diuretics inhibit

mation of bicarbonate leads to a group of disor-

NaCl transport by the distal tubule increasing

ders termed renal tubular acidosis. These

sodium excretion but decreasing calcium excre-

disorders result in a metabolic acidosis as well as,

tion. Factors that are associated with an increase

in some cases, a propensity to nephrolithiasis.

in calcium excretion includes: A decrease in

parathyroid hormone (PTH) levels, ECF volume

Regulation of Calcium and

expansion, phosphate depletion, and metabolic

acidosis. Factors which are associated with a

Phosphate Balance

decrease in calcium excretion include: An

increase in PTH, ECF volume concentration,

phosphate loading metabolic alkalosis, and 1,25

Calcium: Calcium is importantly involved in

(OH)2 D3 (vitamin D).

bone formation, subdivision and growth, blood

Phosphate: The kidney is an important organ

coagulation, intracellular signaling, and excita-

in the maintenance of phosphate homeostasis.

tion concentration coupling. The following will

Phosphate is an important component in nucle-

be limited to the renal handling of calcium. In

otides, ATP, and it is an important component of

the blood, approximately 50% of the calcium in

bone. The proximal tubule reabsorbs approxi-

plasma is present in a free ionized form. The

mately 80% of the phosphate filtered load, and

majority of ionized calcium is bound to plasma

the distal tubule reabsorbs approximately 10%.

proteins, primarily albumin, and a very small

The loop of Henle and the collecting duct have

percent is complexed through several anions,

an insignificant contribution to phosphate reab-

including HCO3, PO4, and SO4. The free ionized

sorption. Phosphate reabsorption across the

112

Practical Urology: EssEntial PrinciPlEs and PracticE

apical membrane of the proximal tubule occurs

prevention has been the focus of much research.

by sodium phosphate cotransport mechanism.

Although mannitol has been tested in animal

PTH is an important regulator of phosphate

models of acute renal failure, its efficacy in

excretion. PTH increases cyclic AMP production

human acute renal failure is controversial and it

and inhibits phosphate reabsorption by the

cannot be recommended for this purpose.

proximal tubule. Other factors which increase

Infusions of mannitol are used to lower the ele-

phosphate excretion include phosphate loading,

vated intracranial pressure of cerebral edema

ECF volume expansion, glucocorticoids, and

associated with tumors, neurosurgical proce-

acidosis. Other factors which are important in

dures, or other conditions. Osmotic agents cause

decreasing phosphate excretion include phos-

the redistribution of body fluid, increase urine

phate depletion, ECF volume contraction, and

flow rate, and accelerate the renal elimination of

alkalosis.

filtered solutes.

Carbonic Anhydrase Inhibitors: Carbonic

Diuretics

anhydrase facilitates the reabsorption of sodium

bicarbonate. This enzyme is located primarily in

the proximal tubule and represents the major

Diuretics produce an increase in urine output

site of action. The degree of natriuresis is not as

by increasing sodium excretion (natriuresis).

great as expected for the same reason as dis-

Various classes of diuretics affect specific

cussed with osmotic diuretics (i.e., distal reab-

nephron segments.The site of action determines

sorption of sodium delivered). Acetazolamide is

the magnitude of natriuresis. For example, in

used effectively to treat chronic open-angle

general, proximal acting diuretics such as car-

glaucoma. Since the aqueous humor has a high

bonic anhydrase inhibitors, or osmotic diuretics

bicarbonate concentration, these drugs can be

are weak diuretics because the more distal

used to reduce aqueous humor formation.

nephron segments reabsorb the increase in

Acetazolamide is also used to prevent and treat

sodium and chloride delivered to it.On the other

acute mountain sickness, to alkalinize the urine,

hand, the more distal acting diuretics like loop

and to treat metabolic alkalosis.

diuretics are potent diuretics. Diuretics gain

Loop Diuretics: Loop diuretics primarily

access to the tubule fluid by glomerular filtra-

inhibits sodium reabsorption by the thick

tion, secretion by organic anions and cationic

ascending limb by blocking the Na-2Cl-1K

secretory mechanism located in the proximal

cotransport mechanism located in the apical

tubule. By gaining access through the tubule

membrane of these cells. This class of diuretics

fluid they can exert their action by interacting

exert a potent inhibition of sodium reabsorp-

with transport mechanism located in the apical

tion by the thick ascending limb because it not

membrane of nephron segments.

only inhibits sodium transport by the thick

Osmotic Diuretics: Osmotic diuretics such as

ascending limb, but it also impairs dilution and

mannitol or glucose inhibit reabsorption of sol-

concentrating ability (one function of the thick

ute and water by altering osmotic forces along

ascending limb is to produce a hypertonic med-

the nephron. In addition, inhibition of sodium

ullary interstitium). Inhibition of transport by

reabsorption by the more proximal nephron,

furosemide decreases tonicity of the intersti-

allows more sodium to be delivered to and

tium. Furosemide, torasemide ethacrynic acid

absorbed by the thick ascending limb. This reab-

may increase renal blood flow for brief intervals

sorptive response by the distal segments limits

during which urinary excretion of prostaglan-

the degree of natriuresis seen with osmotic

din E is elevated. Intravenous injections of furo-

diuretics. Mannitol is usually the drug of choice

semide reduce pulmonary arterial pressure and

among osmotic agents. It is a common clinical

peripheral venous compliance. Indomethacin,

impression that mannitol improves renal hemo-

an inhibitor of prostaglandin synthesis, inter-

dynamics in a variety of situations of impend-

feres with all these actions.Vascular phenomena

ing or incipient acute renal failure (rapid

of this sort occurring in the kidney and else-

reduction in glomerular filtration rate). The

where precede the onset of diuresis. The thera-

incidence of acute renal failure in hospitalized

peutic value of loop diuretics in pulmonary

patients is significant and associated with an

edema may be attributable in part to stimula-

increase in morbidity and mortality. Thus its

tion of prostaglandin synthesis in the lung. The

greater efficacy of loop agents often enables

calcium excretion,they are used in the treatment

their successful use in evoking diuresis in edem-

of calcium nephrolithiaisis and osteoporosis.

atous patients with disturbances of cardiovas-

Thiazide diuretics are also used to in the treat-

cular, renal, or hepatic origin. For example, an

ment of patients with nephrogenic diabetes

oliguric patient whose GFR is only 10% of nor-

insipidus. In this disorder, the tubules are unre-

mal derives no benefit from a thiazide but may

sponsive to vasopressin and therefore these

respond well to a large dose of a loop diuretic. In

patients undergo a water diuresis. Often the vol-

addition, furosemide is an important adjunct in

ume of dilute urine excreted is large enough to

the treatment of acute pulmonary edema. The

lead to intravascular volume depletion if the

drug increases pulmonary and peripheral

excreted volume is not matched by adequate

venous compliance, thereby affording rapid

intake of fluid. Chronic administration of thiaz-

relief,and then maintains these beneficial effects

ides increases the urine osmolality and reduces

by reducing the plasma volume. The initial vas-

urine flow in this condition. The mechanism

cular effects are not linked to actions on the

hinges on the excretion of sodium and hence

renal tubule (venodilatation occurs in anephric

removal of sodium from the ECF, an action that

patients). Because of the effect of loop diuretics

inevitably contracts ECF volume. The proximal

in inducing an increase in calcium excretion,

tubule then avidly reabsorbs sodium. Urine flow

they are used to lower serum calcium concen-

rate diminishes and urine osmolality rises when

trations in patients with hypercalcemia. Isoto-

sodium transport in the distal convoluted tubule

nic saline is often coadministered to maintain

is inhibited by the diuretic. Drug therapy in this

the glomerular filtration rate. Loop diuretics

instance is most effective in combination with

increase K+ excretion and thus are useful in the

dietary salt restriction.

treatment of acute and chronic hyperkalemia.

Potassium-Sparing Diuretics: In this group are

Thiazide Diuretics: Thiazide diuretics are

two types of diuretics which inhibit potassium

organic anions which are filtered and secreted

secretion. Spironolactone acts by antagonizing

by the proximal tubule. They inhibit sodium

aldosterone action on the principal cell of the

transport by the distal convoluted tubule, or that

collecting duct. Aldosterone increases sodium

portion of the distal tubule just beyond the thick

absorption and potassium secretion by increas-

ascending limb. These diuretics block a sodium

ing the number of functional sodium and potas-

chloride cotransport mechanism located in the

sium channels in the apical membrane, as well

apical or luminal membranes of these cells. All

as increasing the number of basolateral Na,

of the thiazides act in the same way, with the dif-

K-ATPase pumps. Aldosterone blocks this effect

ferences among them attributable largely to

and prevents sodium absorption and potassium

pharmacokinetic

characteristics and inherent

secretion. Amiloride and triamterene are com-

carbonic anhydrase inhibitory activity. In gen-

pounds which represent a second class of diuret-

eral, these agents are used in the treatment of

ics which antagonize potassium secretion. The

hypertension, CHF and in other conditions

mechanism by which these diuretics inhibit

when reduction of ECF volume is beneficial.

potassium secretion is through inhibition of

Reduction of blood pressure in patients with

sodium channels located in the apical mem-

hypertension results, in part, from contraction

branes of principal cells. By blocking these

of ECF volume. This occurs acutely, leading to a

channels they block the electrical gradient for

decrease in cardiac output with compensatory

potassium secretion. Depletion of body potas-

elevation of peripheral resistance. Vasocon-

sium with or without significant lowering of

striction then subsides enabling cardiac output

serum potassium concentration (only 2% of

to return to normal values. Augmented synthe-

total body potassium is present in ECF) is prob-

sis of vasodilator prostaglandins is reported and

ably the most common side effect of diuretic

may be a crucial factor for long-term main-

therapy. Hypokalemia of sufficient magnitude

tenance of a lower pressure, even though ECF

creates many problems and may be life threat-

volume tends to return toward normal. In addi-

ening. These problems may include impairment

tion to treatment of edematous disorders and

of neuromuscular function, cardiac arrhythmia,

hypertension,thiazide diuretics have been found

intestinal disturbances, and partial loss of the

effective in the treatment of other disorders.

ability to concentrate urine. Predisposition of

Because thiazide

diuretics decrease renal

diuretics to potassium wasting is especially