Acid Base 2 Kidneys

Question 1

Describe the process of ammoniagenesis.

Answer 1

In PCT cells glutamine –> 2NH₄⁺ + 2-oxoglutarate^2-

2-oxoglutarate^2- –> 2HCO₃^- + other stuff

2HCO₃^- exits basolateral membrane and enters the peritubular blood

2NH₄⁺exits apical membrane and enters the tubular fluid via Na+-H+ antiporter, with NH₄⁺ substituting for H+

TAL primary site of this NH₄⁺ reabsorption, with NH₄⁺ substituting for K+ on the Na+-K+-2Cl− symporter

NH₄⁺ accumulates in medullary interstitium and then secreted into urine of collecting duct via

1. Transport into intercalated cells by the Na+-K+-ATPase (NH₄⁺ substituting for K+) and exit from the cell across the apical membrane of intercalated cells by the H+-K+-ATPase (NH₄⁺ substituting for H+)
2. Nonionic diffusion and diffusion trapping. NH3 diffuses from the medullary interstitium into the lumen of the collecting duct. H+ secretion by the intercalated cells of the collecting duct protonates NH3 to NH₄⁺ by the acidic tubular fluid. CD is less permeable to NH₄⁺ than to NH3, NH₄⁺ is trapped in the tubule lumen (diffusion trapping) and eliminated from the body in the urine. NH3 diffusion occurs via Rh glycoproteins

Question 2

How is the production and excretion of NH4+ regulated?

Answer 2

Question 3

• The primary action of aldosterone on the […] and […] is to stimulate […] reabsorption by […].
• What effect does this have on intercalated cells?

Answer 3

• distal tubule; collecting duct; Na+; principal cells
• Directly stimulates alpha intercalated to secrete H+, also bBy stimulating Na+ reabsorption by principal cells, aldosterone hyperpolarizes the transepithelial voltage making the lumen more negative. This change in voltage then facilitates the secretion of H+ by the intercalated cells.

Question 4

Explain how “titratable acid” generates new HCO3-.

Answer 4

This occurs in the collecting duct.

CO2 + H2O in cell produces H+ and HCO3-. Need to remove H+ to prevent reversal of reaction. H+/ATPase pump in apical membrane pumps H+ against H+ gradient until pH of 4.0-4.5 at which point it is no longer able to function b/c it is pH sensitive. Thus, any H+ that is pumped into filtrate using this pump must be buffered. This is done with HPO42-. Once H+ removed, HCO3- is pumped across basolateral membrane by HCO3- / Cl- pump. Cl- then exits through Cl- channel.

Question 5

Explain the difference between volatile and non-volatile acid.

Answer 5

The major constituents of the diet are carbohydrates and fats. When tissue perfusion is adequate, O2 is available to tissues, and insulin is present at normal levels, carbohydrates and fats are metabolized to CO2 and H2O. Normally, this large quantity of CO2 is effectively eliminated from the body by the lungs. Therefore this metabolically derived CO2 has no impact on acid-base balance. CO2 usually is termed volatile acid, reflecting the fact that it has the potential to generate H+ after hydration with H2O. Acid not derived directly from the hydration of CO2 is termed nonvolatile acid (e.g., lactic acid).

Question 6

What is the relationship between the hormones/molecules that regulate H+ secretion and those that regulate BP?

Answer 6

All the hormones/molecules that increase H+ secretion also are secreted when someone’s BP is low due to decreased volume.

Question 7

What must renal net excretion be equal to?

Answer 7

Net endogenous acid production

Question 8

Explain how HCO3- is reabsorbed and secreted in the CD.

Answer 8

In ALPHA intercalated cells, ACID is secreted:

Within the cell, H+ and HCO−3 are produced by the hydration of CO2 (carbonic anhydrase). H+ is secreted into the tubular fluid either by apical membrane vacuolar H+-ATPase or secretion of H+with the reabsorption of K+ through an H+-K+-ATPase. The HCO3- exits the cell across the basolateral membrane in exchange for Cl− (antiporter) and enters the peritubular capillary blood. Cl− exit from the cell across the basolateral membrane occurs via a Cl− channel, and perhaps also via a K+-Cl− symporter (KCC4).

In BETA intercalated cells, BASE is secreted.

H+-ATPase is located in the basolateral membrane, and a Cl-/HCO3- antiporter is located in the apical membrane. The apical membrane Cl-/HCO3-antiporter is different from the one found in the basolateral membrane of the H+-secreting intercalated cell.

Question 9

Describe how HCO3- is reabsorbed in the PCT, TAL and DCT.

Answer 9

H+ secretion across the apical membrane of the cell occurs by both a Na+-H+ antiporter and H+-ATPase. The Na+-H+ antiporter is the predominant pathway for H+ secretion (2/3 HCO−3 reabsorption) and uses the Na+ gradient established by the action of the Na+/K+ ATPase pump on the basolateral membrane to drive this process. Within the cell, H+ and HCO3- are produced in a reaction catalyzed by carbonic anhydrase. In order to prevent their recombining and reversing the reaction, the H+is secreted into the tubular fluid through the H+/Na+ or H+/ATPase pumps whereas the HCO3- exits the cell across the basolateral membrane and returns to the peritubular blood. HCO3- movement out of the cell across the basolateral membrane is coupled to other ions. The majority of HCO3- exits through a symporter that couples the efflux of Na+ with 3HCO3- (sodium bicarbonate cotransporter, NBCe1). In addition, some of the HCO3- may exit in exchange for Cl− (via a Cl−-HCO−3 antiporter; AE1)

Question 10

How do the kidneys achieve making RNAE equal to NEAP? (3 things)

What equation defines RNAE?

Answer 10

Question 11

Explain the process of ammoniagenesis that occurs in the kidney.

Answer 11

In the PCT, ammonia (NH4+) can be made when stimulated by acidosis. For every NH4+, a new HCO3- is produced. Glutamine in cells of PCT is used to produce 2 HCO3- and 2 NH4+. The HCO3- are reabsorbed into the blood and the NH4+ is secreted into the urine. The body does not want the NH4+ to be reabsorbed becuase if that happened it would be metabolized in liver to urea which produces 2H+ which would then need to be buffered by the 2 HCO3- just produced so it would be futile cycle. Unfortunately, the NH4+ can be reabsorbed in the TAL as a substitute for K+ in the Na+/K+/2Cl- co-transporter or across the paracellular route due to the gradient that is established between urine and blood (urine more +). To ensure this doesn’t travel to blood, the kidney re-secretes the NH4+ in the CD.

Question 12

Why must NH4+ not be reabsorbed and allowed to enter systemic circulation?

Answer 12

NH4+ must be excreted and NOT enter the systemic circulation ⇒ liver would use to produce urea b/c generates H+, which is buffered by HCO3- , negating its formation in kidneys.

Question 13

In a volume contracted state, angiotensin 2 acts on the […] of the kidney. It increases the activity and the number of […] transporters. This results in increased secretion of […] and leads to metabolic […].

Answer 13

proximal tubule

Apical Na+-H+ antiporter and basolateral Na+-3HCO−3 symporter.

H+

Alkalosis

Question 14

How will the kidneys compensate when the body is in metabolic acidosis?

Answer 14

Question 15

What is renal tubule acidosis?

Answer 15

Renal tubule acidosis (RTA) refers to conditions in which RNAE is impaired, so NEAP > RNAE –> 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 16

What is a simple acronym to remember the potential causes of an anion gap in metabolic acidosis?

Which of these mechanisms result in increased anion gap vs. normal anion gap?

Answer 16

K = ketoacidosis (diabetic, alcoholic, starvation)

U =Uremia (renal failure)

L = Lactic acidosis

T = toxins/drugs

Question 17

What is renal tubular acidosis?

Answer 17

Defects in the ability of the kidneys to excrete acid and reabsorb bicarbonate.

Question 18

What is renal net acid excretion?

Answer 18

Kidneys have to secrete nonvolatile acid and generate new bicarb

Question 19

Why do we secrete H+?

What effect does this have on the urine?

Answer 19

Most of the secreted H+ serves to reabsorb the filtered load of HCO3-. As a result of this acid excretion, the urine is normally acidic.

Question 20

Where in the nephron does “titratable acid” occur?

Answer 20

Distal tubule and collecting duct

Question 21

Disturbances of acid-base balance that result from a change in the [HCO₃^-] are termed […], whereas those that result from a change in the PCO₂ are termed […]

Answer 21

metabolic acid-base disorders

respiratory acid-base disorders

Question 22

Why does excreting NH4+ in the urine result in increased reabsorption of HCO3-?

Answer 22

With regard to the renal regulation of acid-base balance, each NH+4 excreted in the urine results in the return of one HCO−3 to the systemic circulation, which replenishes the HCO−3 lost during neutralization of the nonvolatile acids. Thus the production and excretion of NH+4, like the excretion of titratable acid, are equivalent to the excretion of acid by the kidneys

Question 24

How will the kidneys compensate when we are in metabolic alkalosis?

Answer 24

Question 25

What hormones/molecules stimulate ammoniagenesis?

Answer 25

Cortisol

Angiotensin 2

Question 26

What factors in our diet affect acidity?

Answer 26

Consuming protein generates more acid than a vegetarian diet

Lose bicarb in feces (equivalent to gaining acid)

Question 27

The pH of the urine cannot be lower than 4.0. However if you converted the [H+] secreted by the kidney daily to pH it would be lower than 4.0. How does the kidney accomplish this?

Answer 27

To excrete sufficient acid, the kidneys excrete H+ with urinary buffers such as inorganic phosphate (Pi) –> titratable acids

Question 28

The elimination rate of HCO3- is ~5mL/min, while a normal GFR is ~125mL/min. What does this tell you in general about the renal handling of HCO3-?

Answer 28

Normally, almost the entire filtered load is reabsorbed

Question 29

Why does acidosis cause PTH secretion?

Answer 29

In the condition of acidosis, the body will need to increase secretion of H+. This H+ all needs to be buffered. PTH inhibits reabsorption of phosphate, so more phosphate will be available in filtrate to buffer increased H+ in urine.

Question 30

What happens if there is a problem with principal cells of the CD secreting H+?

Answer 30

If collecting duct H+ secretion is inhibited, the NH+4 reabsorbed by the thick ascending limb of Henle’s loop is not excreted in the urine. Instead, it is returned to the systemic circulation

Question 31

The kidneys secrete […] acid while the lungs handle removing […] acid

Answer 31

Non-volatile

Volatile

Question 32

[…]kalemia inhibits NH4+ production whereas […]kalemia stimulates it.

Answer 32

Hyperkalemia

Hypokalemia

Question 33

What are the ways in which the body can buffer changes in pH? (3)

Answer 33

Question 34

Describe what is meant by net endogenous acid production.

Answer 34

The diet of humans contains many constituents that are either acid or alkali. In addition, cellular metabolism produces acid and alkali. Finally, alkali is normally lost each day in the feces. The net effect of these processes is the addition of acid to the body fluids

Question 35

When a person is substantially volume contracted, they will develop metabolic alkalosis that cannot be corrected until euvolemia is restored. Why?

Answer 35

Body prioritizes volume restoration. Does this by increasing reabsorption of Na+. Angiotensin 2 increases reabsorption of Na+ in proximal segments of nephron by increasing activity and # of Na+/H+ antiporters and increasing activity and # of Na+/HCO3- symporters.

Additionally, in the distal segments of the nephron, aldosterone acts on principal cells to increase the activity and # of Na+/H+ antiporters and to also increase secretion of H+ directly from alpha intercalated cells.

Both of these measures increase Na+ in order to try and correct the volume loss, but they also increase secretion of H+ and HCO3-, which makes the alkalosis worse. Therefore, the acid-base disturbance can’t be corrected until the volume is restored to normal.

Question 36

Why can volume depletion lead to metabolic alkalosis?

Answer 36

When a person is volume depleted, their body will trigger the RAAS system to try and hold onto Na+ and water to increase volume. However, some of the signaling molecules generated in this system (Aldosterone and Angiotensin 2) also increase H+ secretion and thus HCO3- reabsorption. This leads to increased blood alkalosis and the kidneys cannot correct this by then secreting HCO3- unless the fluid volume is restored because the mechanism of secreting H+ and reabsorbing HCO3- will continue until volume is restored. So it is essential to restore volume quickly so the kidneys can secrete any excess bicarb.

Question 37

What is the anion gap?

How can it be used to differentiate between different causes of metabolic acidosis?

Answer 37

In body fluids, the total number of cations = the total number of anions. When clinicians want to measure this balance, we approximate this as [Na+] - ([Cl-] + [HCO3-]). However, this always leaves a small (+) gap because there are other unmeasured anions that we don’t account for. As such, a normal anion gap is 8-16 mEq/L.

Metabolic acidosis can occur either through a loss of HCO3- or a gain of non-volatile acid. In the case of loss of HCO3-, the body will try to produce more HCO3- and this will also result in the increase of Cl- in equal proportions. So even though there is a net decrease in HCO3- Cl- will increase resulting in a normal anion gap.

If we are increasing volatile acid, then there will be normal Na+, Normal Cl-, decreased HCO3- b/c its used to buffer acids, and increased unmeasured anions. This will cause an increase in the anion gap.

Question 38

Describe the relative amount of reabsorption of HCO3- at the following locations:

• PCT
• TAL
• DCT
• CD

Answer 38

Question 39

It may seem counter intuitive that the CD has cells that can both reabsorb and secrete HCO3- however this process is heavily regulated to avoid a futile cycle. Discuss the regulation of H+ secretion (and thereby HCO3- reabsorption) and the regulation of HCO3- secretion.

Answer 39

• The regulation of HCO3- secretion by beta intercalated cells is not well understood
• Reabsorption by alpha intercalated cells:
  
  • Cortisol, angiotensin 2, and endothelin increase the activity and amount of Na+/H+ antiporter in apical membrane
  • Aldosterone increases the activity and amount of H+ ATPase in apical membrane

Question 40

How does potassium balance influence H+ secretion?

Answer 40

H+ secretion is stimulated by hypokalemia and inhibited by hyperkalemia