Potassium, calcium and phosphate homeostasis; and regulation of acid-base balance (berne Ch. 35-36)

Question 1

IN THE CLINIC
The most frequent causes of hypokalemia include administration of diuretic drugs, surreptitious vomiting (e.g., bulimia), and severe diarrhea. Gitelman’s syndrome (a genetic defect in the Na+-Cl− symporter in the apical membrane of distal tubule cells) also causes hypokalemia. Hyperkalemia often occurs in patients with renal failure, in patients taking drugs, including angiotensin-converting enzyme (ACE) inhibitors and K+-sparing diuretics, in patients with hyperglycemia (i.e., high blood sugar), and in the elderly. Pseudohyperkalemia, falsely high plasma [K+], is caused by traumatic lysis of red blood cells during blood drawing. Red blood cells, like all cells, contain K+, and lysis of red blood cells releases K+ into plasma, thereby artificially elevating plasma [K+].

Answer 1

REMEMBER

Question 2

The rise in plasma [K+] that follows K+ absorption by the gastrointestinal tract stimulates secretion of:

Answer 2

(1) Insulin from the pancreas
(2) Aldosterone from the adrenal cortex
(3) Epinephrine from the adrenal medulla
* * Stimulates uptake of serum potassium into the cells

Question 3

Catecholamines affect the distribution of K+ across cell membranes by activating α- and β2-adrenergic receptors.
RELEASE of K from the cell:
Promotes K UPTAKE by the cells:

Answer 3

RELEASE of K from the cells: α-adrenoceptors

Promotes K UPTAKE by the cells: β2-adrenergic receptors

Question 4

The most important hormone that shifts K+ into cells after the ingestion of K+ in a meal
Insulin

True or false
Metabolic acidosis increases the plasma [K+] whereas metabolic alkalosis and respiratory alkalosis decreases it

Answer 4

True

• *In contrast, respiratory acidosis has little or no effect on the plasma [K+]
• *The reduced pH promotes the movement of H+ into cells and the reciprocal movement of K+ out of cells to maintain electroneutrality

Question 5

Excretion of K+ depends on the rate and direction of K+ transport on what segment of the nephron

Answer 5

The distal tubule and collecting duct

• *The distal tubule and collecting duct are able to reabsorb or secrete K+
• *Principal cells of the distal tubule and collecting duct secrete K via Na+,K+-ATPase while intercalated cells of distal tubule and collecting duct reabsorbs K via H/K-ATPase transport mechanism

Question 6

Secretion of potassium from blood into the tubule lumen is a two-step process:

Answer 6

(1) Uptake of K+ from blood across the basolateral membrane by Na+,K+-ATPase
(2) Diffusion of K+ from the cell into tubular fluid via K+ channels.
* *Na+,K+-ATPase creates a high intracellular [K+] that provides the chemical driving force for exit of K+ across the apical membrane through K+ channels

Question 7

Major factors and hormones influencing potassium secretion
Physiological:
Pathophysiological:

Answer 7

Physiological: Plasma, aldosterone and ADH
Pathophysiological: Flow rate of tubule fluid, Acid-base balance and glucocorticoids

Question 8

Increased tubular flow bends the primary cilium in principal cells, which activates the PKD1/PKD2 Ca+ + conducting channel complex.
This allows more Ca+ + to enter principal cells and increases intracellular [Ca+ +]. The increase in [Ca+ +] activates K+ channels in the apical plasma membrane, which enhances secretion of K+ from the cell into tubule fuid.

Answer 8

REMEMBER
Increased flow may also stimulate secretion of K+ by other mechanisms. As flow increases, such as after the administration of diuretics or as the result of an increase in ECF volume, so does the [Na+] of tubule fluid. This increase in [Na+] facilitates entry of Na+ across the apical membrane of distal tubule and collecting duct cells, thereby decreasing the cells’ interior negative membrane potential. This depolarization of the cell membrane potential increases the electrochemical driving force that promotes secretion of K+ across the apical cell membrane into tubule fluid.

Question 9

The primary channel in the apical membrane responsible for secretion of K+

Answer 9

ROMK (KCNJ1)

Question 10

ACUTE metabolic acidosis (a) increase (b) decrease potassium excretion

Answer 10

b. decrease

* *CHRONIC metabolic acidosis increases potassium excretion

Question 11

Elevated K+ intake increases secretion of K+ by several mechanisms, all related to increased serum [K+]. Hyperkalemia increases the activity of the ROMK channel in the apical plasma membrane of principal cells. Moreover, hyperkalemia inhibits reabsorption of NaCl and water by the proximal tubule, thereby increasing the distal tubule and collecting duct flow rate, a potent stimulus to secretion of K+.

Answer 11

REMEMBER
Hyperkalemia also enhances [aldosterone], which increases K+ secretion by three mechanisms. First, aldosterone increases the number of K+ channels in the apical plasma membrane. Second, aldosterone stimulates uptake of K+ across the basolateral membrane by increasing the number of Na+,K+-ATPase pumps, thereby enhancing the electrochemical gradient driving secretion of K+ across the apical membrane. Third, aldosterone increases movement of Na+ across the apical membrane, which depolarizes the apical plasma membrane voltage and thus increases the electrochemical gradient promoting secretion of K+.

Question 12

Three hormones regulate the distribution of Ca+ + between bone and ECF and thereby regulate plasma [Ca+ +].

Answer 12

Parathyroid hormone [PTH], calcitriol and calcitonin

Question 13

PTH, calcitriol and calcitonin (a) stimulate (b) inhibit calcium excretion in the urine

Answer 13

b. inhibit

Question 14

Calcitriol is to bone (a) formation (b) resorption; calcitonin is to (a) formation (b) resorption

Answer 14

b. resorption; a. formation

Question 15

PTH increases plasma [Ca+ +] by:

Answer 15

(1) Stimulating bone resorption
(2) Increasing Ca+ + reabsorption by the kidneys
(3) Stimulating the production of calcitriol, which in turn increases Ca+ + absorption by the gastrointestinal tract and facilitates PTH-mediated bone resorption

Question 16

The production of calcitriol, a metabolite of vitamin D3 is produced in what part of the kidney?

Answer 16

Proximal tubule

Question 17

Calcitonin is secreted from?

Answer 17

Thyroid C cells (Parafollicular cells)

Question 18

Reabsorption of Ca+ + by the proximal tubule occurs via transcellular and paracellular pathways.
In the transcellular pathway, by what mechanism does calcium enters the cells from the tubule fluid?

Answer 18

Passive diffusion through the electrochemichal gradient via calcium channels in the apical membrane
**Calcium is extruded out the cell into the blooc via Ca-ATPase in the basolateral membrane

Question 19

Reabsorption of Ca+ + by the proximal tubule occurs via transcellular and paracellular pathways.
In the paracellular pathway, by what mechanism does calcium enter the tight junction?

Answer 19

Passive diffusion that occurs via solvent drag along the entire length of the proximal tubule and is also driven by the positive luminal voltage in the second half of the proximal tubule
**Paracellular – 80%; transcellular – 20%

Question 20

Reabsorption of Ca+ + by the loop of Henle is restricted to the cortical portion of the thick ascending limb. Ca+ + is reabsorbed by the cellular and paracellular routes via mechanisms similar to the proximal tubule but with one difference:

Answer 20

Ca+ + is not reabsorbed by solvent drag in this segment

** The thick ascending limb is impermeable to water

Question 21

Loop diuretics inhibit reabsorption of Na+ in what part of the Henle’s loop?

Answer 21

THICK ascending limb (TAL)

• *loop diuretics inhibit reabsorption of sodium and calcium (INDIRECTLY) in TAL
• *The reabsorption of sodium reduces the magnitude of the positive transepithelial luminal voltage, which inhibit the reabsorption of calcium via the paracellular pathway

Question 22

In what part of the nephron does calcium reabsorption occur entirely via active transport?

Answer 22

Distal tubule
**The voltage in the tubule lumen of the distal lumen is negative with respect to blood thus reabsorption of calcium must occur against the electrochemical gradient

Question 23

In the cells of the distal tubule, after calcium has enter the apical membrane via Ca+ +-permeable epithelial ion channels (TRPV5/TRPV6), calcium binds to what protein?

Answer 23

Calbindin

Question 24

A receptor expressed in the plasma membrane of cells involved in regulating Ca+ + homeostasis

Answer 24

CaSR
**Ca+ + binds to CaSRs in PTH-secreting cells of the parathyroid gland, calcitonin-secreting parafollicular cells in the thyroid gland, and calcitriol-producing cells of the proximal tubule.

Question 25

Reabsorption of Pi by the proximal tubule occurs mainly, if not exclusively, by means of what pathway?

Answer 25

Transcellular

Question 26

What are the three kinds of Na-P symporter found in the apical membrane of the proximal tubule?

Answer 26

One transports 2Na+ with each Pi (NPT1), whereas the other two transport 3Na+ with each Pi (NPT2 and NPT3)
** NPT2 is the most important symporter involved in reabsorption of Pi by the proximal tubule

Question 27

IN THE CLINIC
In patients with chronic renal failure, the kidneys cannot excrete Pi. Because of continued Pi absorption by the gastrointestinal tract, Pi accumulates in the body and plasma [Pi] rises. The excess Pi complexes with Ca+ + and reduces plasma [Ca+ +]. Accumulation of Pi also decreases the production of calcitriol. This response reduces absorption of Ca+ + by the intestine, an effect that further reduces plasma [Ca+ +]. This reduction in plasma [Ca+ +] increases PTH secretion and Ca+ + release from bone. These actions result in osteitis fibrosa
cystica (i.e., increased bone resorption with replacement by fibrous tissue, which renders bone more susceptible to fracture).

Answer 27

**REMEMBER**
Chronic hyperparathyroidism (i.e., elevated PTH levels because of the fall in plasma [Ca+ +]) during chronic renal failure can lead to metastatic calcifications in which Ca+ + and Pi precipitate in arteries, soft tissues, and viscera. Deposition of Ca+ + and Pi in heart and lung tissue may cause myocardial failure and pulmonary insuffi ciency, respectively. Prevention and treatment of hyperparathyroidism and Pi retention include a low-Pi diet or the administration of a “phosphate binder” (i.e., an agent that forms insoluble Pi salts and thereby renders Pi unavailable for absorption by the gastrointestinal tract). Supplemental Ca+ + and calcitriol are also prescribed.

Question 28

True or false
PTH, calcitonin and calcitrial inhibits CALCIUM excretion; whereas PTH and calcitonin stiumalte PHOSPHATE excretion and calcitriol inhibits PHOSPHATE excretion

Answer 28

True
**PTH reduces Pi reabsorption by stimulating the endocytic removal of NPT2 from the brush border membrane of the proximal tubule

Question 29

This buffer system is regulated by the lungs and kidney

Answer 29

Bicarbonate buffer system

Question 30

cysteine and methionine = Sulfuric Acid; lysine, arginine, and histidine = _____

Answer 30

HCl

Question 31

IN THE CLINIC
When insulin levels are normal, carbohydrates and fats are completely metabolized to CO2 + H2O. However, if insulin levels are abnormally low (e.g., diabetes mellitus), metabolism of carbohydrates leads to the production of several organic keto acids (e.g., β-hydroxybutyric acid).
In the absence of adequate levels of O2 (hypoxia), anaerobic metabolism by cells can also lead to the production of organic acids (e.g., lactic acid) rather than CO2 + H2O. This frequently occurs in normal individuals during vigorous exercise. Poor tissue perfusion, such as that occurring with reduced cardiac output, can also lead to anaerobic metabolism by cells and thus to acidosis. In these conditions organic acids accumulate, and the pH of body fluids decreases (acidosis).

Answer 31

REMEMBER
Treatment (e.g., administration of insulin in the case of diabetes) or improved delivery of adequate levels of O2 to tissues (e.g., in the case of poor tissue perfusion) results in the metabolism of these organic acids to CO2 + H2O, which consumes H+ and thereby helps correct the acid-base disorder.

Question 32

Excretion of H+ as a titratable acid is insuffi cient to balance the daily nonvolatile acid load. An additional and important mechanism by which the kidneys contribute to the maintenance of acid-base balance is through the synthesis and excretion of _____

Answer 32

Ammonium NH4
** With regard to the renal regulation of acid-base balance, each NH4 excreted in urine results in the return of one HCO3 to the systemic circulation, which replenishes the HCO3 lost during neutralization of the nonvolatile acids.

Question 33

Maintenance of acid-base balance means that net acid excretion must equal production of what?

Answer 33

NONVOLATILE acid production

Question 34

NET ACID EXCRETION (NAE)

Answer 34

Rates of excretion of titratable acid and ammonium minus the amount of bicarbonate loss in urine

• • Quantitatively, titratable acid accounts for approximately a third and NH4 for two thirds of net acid excretion.
• • Under most conditions, very little HCO3 is excreted in urine. Thus, net acid excretion essentially reflects titratable acid and NH4 excretion

Question 35

Within the cell of the proximal tubule, H and HCO3 are produced by the action of carbonic anhydrase, H and HCO3 leave the cell by what mechanism?

Answer 35

(1) H leaves the cell and is excreted to the tubule lumen via Na/H-ATPase (NHE3) and H-ATPase.
(2) Exits the cell across the basolateral membrane and returns to the peritubular blood. Movement of HCO3 out of the cell across the basolateral membrane is coupled to other ions. The majority of HCO3 exits via a symporter that couples the efflux of 1Na+ with 3 HCO3 (NBC1). In addition, some of the HCO3 may exit in exchange for Cl (via Na+ independent and/or Na+-dependent Cl/HCO3 antiporters)

Question 36

The distal tubule and collecting duct reabsorb the small amount of HCO3 that escapes reabsorption by the proximal tubule and loop of Henle. What type of cell of the distal tubule and collecting duct is responsible for the reabsorption?

Answer 36

Intercalated cells

Question 37

What are the two types of intercalated cells?

Answer 37

(1) a-intercalated cells that secrete H
(2) b-intercalated cells that secrete HCO3
Under metabolic alkalosis, b-intercalated cells activity increases

Question 38

In the a-intercalated cells, what are the two transport mechanisms found in the apical membrane responsible for the secretion of H

Answer 38

H-ATPase and H,K-ATPase
**In b-intercalated cells H-ATPase is located in the basolateral membrane, and the Cl/HCO3 antiporter is located in the apical membrane (pendrin)

Question 39

What segement of the nephron is the most acidic?

Answer 39

Collecting duct

** The apical membrane of collecting duct cells is not very permeable to H

Question 40

Endothelin-1 is produced in what cells?

Answer 40

Endothelial and proximal tubule cells

Question 41

Two important mediators of the renal response to acidosis

Answer 41

Endothelin-1 and cortisol
** ET-1 stimulates the phosphorylation and subsequent insertion of the Na+-H+ antiporter into the apical membrane and insertion of the 1Na+-3HCO3 symporter into the basolateral membrane

Question 42

Acidosis stimulates secretion of the glucocorticoid hormone cortisol by the adrenal cortex. Cortisol in turn acts on the kidneys to increase transcription of what transporter?

Answer 42

Na+-H+ antiporter and 1Na+-3HCO3− symporter genes in the proximal tubule, as well as increase translation of the mRNA of these transporters

Question 43

NH4 is produced in the kidneys via the metabolism of _____

Answer 43

Glutamine

** NH4 is produced from glutamine in the cells of the proximal tubule, a process termed ammoniagenesis

Question 44

Each glutamine molecule produces two molecules of NH4 and a divalent anion. Metabolism of this anion ultimately provides two molecules of HCO3. What is the anion?

Answer 44

2-oxoglutarate

Question 45

A significant proportion of the NH4 secreted by the proximal tubule is reabsorbed by what segement of the Henle’s loop?

Answer 45

Thick ascending limb

Question 46

True or false

Both angiotensin II and PTH stimulate ammoniagenesis, whereas ammoniagenesis is inhibited by prostaglandins

Answer 46

True
** Because PTH levels are increased with acidosis, it may play a role in mediating the renal response, which includes increased production and excretion of NH4.

Question 47

True or false
When hyperkalemia exists, NH4 production is inhibited, whereas hypokalemia stimulates
NH4production

Answer 47

True
**Alterations in plasma [K] may change the intracellular pH of the proximal tubule cells, and the change in intracellular pH may then control glutamine metabolism

Question 48

IN THE CLINIC

Refers to conditions in which net acid excretion by the kidneys is impaired

Answer 48

Renal tubule acidosis (RTA)
** Under these conditions the kidneys are unable to excrete a sufficient amount of net acid to balance nonvolatile acid production, and acidosis results. RTA can be caused by a defect in Hsecretion in the proximal tubule (proximal RTA) or distal tubule (distal RTA) or by inadequate production and excretion of NH4

Question 49

The body has three general mechanisms to compensate for or defend against changes in body fluid pH produced by acid-base disturbances:

Answer 49

(1) Extracellular and intracellular buffering
(2) Adjustments in blood PCO2 via alterations in the ventilatory rate of the lungs
(3) Adjustments in renal net acid excretion

Question 50

Virtually all Buffering in the RESPIRATORY acid-base imbalance occurs in what compartment of the body (ECF or ICF)

Answer 50

ICF
**When PCO2 rises (respiratory acidosis), CO2 moves into the cell, where it combines with H2O to form H2CO3, which then dissociates to H+ and HCO3. Some of the H+ is buffered by cellular protein, and HCO3 exits the cell and raises ECF [HCO3]

Question 51

IN THE CLINIC
Metabolic acidosis can develop in insulin-dependent diabetic patients secondary to the production of ketoacids if insulin dosages are not adequate. As a compensatory response to this acidosis, deep and rapid breathing develops. This breathing pattern is termed Kussmaul respiration. With prolonged Kussmaul respiration, the muscles involved can become fatigued.
When fatigue occurs, respiratory compensation is impaired and the acidosis can become more severe

Answer 51

REMEMBER

Question 52

True or false
In all acid-base disorders the compensatory response does not correct the underlying disorder but simply reduces the magnitude of the change in pH

Answer 52

True

** Correction of the acid-base disorder requires treatment of its cause