Acid-Base Physiology

Question 1

Limits of compensation for a metabolic alkalosis

Answer 1

You can hypoventilate a little, but not past a certain point. You need to get enough oxygen! So, a consequence of this is that we can only retain so much bicarbonate and compensate a metabolic alkalosis so much.

This number isn’t really much above ~45.

Question 2

“serum or plasma bicarbonate”, “total CO2” and “CO2 content”

Answer 2

• “serum or plasma bicarbonate” = [HCO₃ ^-]plasma
• “total CO₂” = “CO₂ content” = [CO₂]_plasma + [HCO₃ ^-]plasma = 0.03 mEq L^-1 mmHg^-1 x P_CO2

Question 3

Two main ways to acquire a metabolic alkalosis

Answer 3

• Increased loss of acid (H+), vomitting for the GI tract, enhanced collecting duct function for the kidnies
• Increased bicarbonate production or administration of base equivalents (citrate, carbonate)

Question 4

Major roles of the kidney in acid-base physiology

Answer 4

• Proximal tubule: Reabsorption of bicarbonate
• Distal tubule/collecting duct:Secretion of protons. In the tubular lumen, they are trapped urinary buffers (ammonia, to form ammonium, NH4+ andphosphates, to form H2PO4 - ).

Question 5

Toxic acidosis etiologies

Answer 5

• Non-ethanol alcohol ingestions, such as methanol which is metabolized into formic acid
• Ethylene glycol is metabolized into oxalic and glycolic acid, with severe toxicity to the kidney. Renal failure can occur due to precipitation of calcium oxalate crystals.
• Aspirin overdose produces salicylate, which results in elevated anion gap and respiratory alkalosis

Question 6

Reabsorption of bicarbonate at the proximal tubule

Answer 6

85% of bicarbonate reabsorption occurs here. H⁺ brought into the lumen by Nhe3 is used to convert HCO₃^- to H₂CO₃, thus driving the carbon equilibrium to CO₂ with the help of carbonic anhydrase on the apical proximal cell membrane.

The CO₂ can then freely diffuse into the proximal tubule cell, where the pH is higher and the carbonic anhydrase equilibrium once again favors HCO₃^- production. But this time, the HCO₃^- is trapped, and must diffuse down its concentration gradient back into the blood.

Question 7

Regulation of acid base physiology by extracellular volume depletion, hypokalemia, and high P_CO2

Answer 7

• All increase proximal HCO3 - reabsorption.
• Hypokalemia also stimulates net acid excretion by increasing ammonium production.

Question 8

Bicarbonaturia

Answer 8

Loss of bicarbonate in the urine.

May be the result of carbonic anhydrase defiency when seen in isolation.

However, it is often part of Fanconi’s syndrome, where generalized proximal tubule dysfunction leads to bicarbonaturia, glucosuria, phosphaturia, aminoaciduria and hypokalemia. This may be the result of heritable mutations in Nhe3,or induced bymedicationssuch as acetazolamide, topiramate, ifosfamide, tenofovir disproxal fumarate, or caused byacquired disease like multiple myeloma.

Question 9

Acidification of the urine, which can reach a pH of ___

Answer 9

Acidification of the urine, which can reach a pH of 4.5

However, this is not adequate to eliminate the normally generated 70 mEq/day of H+ . (at a pH of 4.5, [H+] = 0.03 mEq/L!). This would require us to excrete over 2,000 gallons of urine per day.

That is why we also need high urine buffer capacity.

Question 10

Kussmaul’s respiration

Answer 10

Breathing pattern associated with acidosis. Deep breaths (hyperventilation) in order to reduce pCO₂

Question 11

When there is proximal tubular cell dysfunction, what would you expect the urine pH to be?

Answer 11

In this situation, initially urine pH is elevated (>7) because the kidney excretes large amounts of bicarbonate ions.

As the serum bicarbonate falls, however, a new steady state is reached at which the proximal tubule is able to reclaim the smaller filtered load. At that point, urine pH will fall as the urine bicarbonate disappears.

Question 12

H+ATPase defects

Answer 12

Very uncommon form of distal tubule defect that can result in acidosis.

Question 13

Four mechanisms of metabolic acidosis due to non-volatile acid

Answer 13

• Tissue hypo-perfusion leading to anaerobic metabolism and lactemia.
• Ketoacidosis, as seen in diabetes mellitus, ethanol toxicity, or nutrient deprivation (starving/fasting). Acetoacetic acid and β-hydroxybuteric acid.
• Advanced renal disease, where the body’s ability to excrete phosphates and sulfates is impaired
• Ingestion of a compound that either is acidic or is metabolized into an acid

Question 14

Most meat-based Western diets produce ___ H⁺ per day.

Answer 14

Most meat-based Western diets produce ~70 mEq H⁺ per day.

Question 15

Mechanism of furosemide and its effects on urine pH

Answer 15

Loop diuretics inhibit the Na⁺K⁺2Cl^- co-transporter of the thick ascending limb of the loop of Henle. This prevents dilution of the tubular fluid in this segment. Consequently, there is greater salt delivery to the collecting duct.

Since there is more Na⁺ delivery to the collecting duct, there is more Na⁺ to exchange for H⁺ via the H⁺-ATPase and ENaC circuit, thus urine pH drops.

Question 16

Ingestion of isopropyl alcohol

Answer 16

Unlike methanol and ethylene glycol which are terminal alcohols, isopropyl alcohol cannot be metabolized by alcohol dehydrogenase into an acid. Instead, it is oxidized to acetone.

As a result, intake of isopropyl alcohol will produce elevated serum ketone levels not metabolic acidosis!

Question 17

Most diets that contain animal protein have a net ___ quantity of non-volatile acids.

Answer 17

Most diets that contain animal protein have a net positive quantity of non-volatile acids.

This is predominantly due to sulfur-containing amino acids (cysteine and methionine). High protein diets increase the acid metabolic load.

Question 18

Decreased renal ammoniagenesis

Answer 18

Chronic decline in renal function is usually associated with a loss of nephron mass, and reduction of proximal tubular capacity. Before bicarbonate reabsorption is affected, production of ammonium and new bicarbonate equivalents declines.

This decreases net acid excretion because there is insufficient ammonia in the urine to trap the requisite amount of H+ .

Question 19

When the diet results in more non-volatile acids, the kidneys ___. When the diet has more alkaline substances, the kidney ___.

Answer 19

When the diet results in more non-volatile acids, the kidneys excrete more H+ and the urine becomes more acidic. When the diet has more alkaline substances, the kidney will not reabsorb as much filtered HCO3 - and the urine pH may approach 8.0.

Question 20

Anion gap in acidosis

Answer 20

When metabolic acidoses are the result of an acid that is not routinely measured (e.g. lactate, ketoacids, other ingestions producing organic acid), then the anion gap is greater than the normal amount (~ 10-12 mEq/l) because of the presence of these organic acid anions.

Question 21

Estimated renal compensation for chronic CO₂ retention and respiratory acidosis

Answer 21

Δ[Bicarb] = 0.35 x (current pCO₂ - 40 mmHg)

This can be used to determine if renal compensation for a metabolic acidosis is appropriate or not

Question 22

Collecting duct and distal tubule bicarbonate regulation

Answer 22

• Alpha intercalated cells: Pump protons into the lumen and reabsorb bicarbonate by a similar mechanism to proximal tubule cells, utilizing cellular carbonic anhydrase, but no luminal carbonic anhydrase.
• Beta intercalated cells: Perform the same process in reverse and can be used to excrete more bicarbonate in situations where the diet is net alkaline (like vegetarian diets).

Question 23

Chloride depletion as a mechanism of persistant alkalosis

Answer 23

• Low Cl- levels seen in alkaloses are sensed by the macula densa and lead to renin release, promoting secondary hyperaldosteronism.
• Beta-intercalated cells in the collecting duct rely on Cl- / HCO3 - exchange and so, if tubular Cl^- is low, HCO3^- cannot be secreted.

Question 24

Hypokalemic conditions in regulation of kidney physiology

Answer 24

• Increases the endocytotic movement of H+ATPases from cellular sites to the plasma membrane, improving H+ secretion
• Increases the K+ /H+ ATPase, allowing both increased K+ reabsorption and H+ secretion.
• Stimulates ammoniagenesis. This is important, as more H⁺ (in the form of NH₄⁺) needs to be utilized for charge balance since Na⁺ and K⁺ are being conserved.

Question 25

Renal compensation for respiratory alkalosis

Answer 25

Alkalosis results in decreased proton secretion into the lumen of the nephron, and thus less bicarbonate reabsorption.

Question 26

The buffers present in urine

Answer 26

Question 27

The overall balance for net acid production and net acid excretion for urine

Answer 27

* **Net acid production = net acid excretion** * Net acid excretion = “free” H+ + urine NH4 + + urine phosphates – urine bicarbonate * **​**This can be simplified, as **free H+ and urine bicarbonate \<\<\< NH4 and phosphate-bound H+** * **Net acid excretion =** **urine NH4⁺ + urine HPhos​** * For most meat-eaters in America, net acid production = **70 mEq H⁺ / day**

Question 28

What kind of acidosis would ingestion of HCl produce, elevated or normal anion gap? What about ammonium chloride (NH4Cl)?

Answer 28

Both produce normal anion gap acidoses, as the body can readily metabolize or excrete the conjugate bases.

Question 29

Where foods fall on acid/base physiology

Answer 29

Question 30

Renal tubule acidoses

Answer 30

Note that for type II, urine pH will initially be high, but then reach equilibrium at a low pH

Question 31

Hyperkalemic distal renal tubular acidosis

Answer 31

Caused by defect in the production or **response to aldosterone in principal and alpha-intercalated cells.** It this tubular segment, **aldosterone promotes sodium reabsorption**, which **potentiates a lumen-negative electrochemical gradient**. That gradient **promotes H+ and K+ secretion.** This mechanism is **very important clinically** because so many medicines we use disrupt the normal functioning of these cells.

Question 32

Aldosterone in acid base physiology

Answer 32

* **Increases the H+ -ATPase** in the distal collecting duct cell, **acidifying the lumen** * **Stimulating Na+ reabsorption** (through its increase in the epithelial sodium channel **(ENaC)** activity). * Both these effects result in **increased proton secretion.**

Question 33

In order to excrete large amounts of acid in urine, you must also secrete \_\_\_.

Answer 33

In order to excrete large amounts of acid in urine, you must also secrete **chloride**. Remember that protons are **primarily secreted in the nephron as NH4⁺,** which must be **counterbalanced with Cl^-** to create a neutral charge.

Question 34

Hyperaldosteronism (physiologic or SIADH) resulting in persistant alkalosis

Answer 34

Aldosterone, whether produced from a tumor (primary hyperaldosteronism), produced in response to volume depletion (secondary hyperaldosteronism) or potentiated in its action (ENaC defects) will lead to **enhanced H+ secretion in alpha intercalated cells via ENaC activation in the principal cells of collecting duct, even in the presence of an alkalosis**

Question 35

Low circulating volume as a mechanism for maintaining alkalosis

Answer 35

1. When effective circulating volume is low, **GFR decreases** and **flow rate through the proximal tubule is reduced**. This **increases the** **efficiency of bicarbonate reabsorption.** 2. **RAAS activation** results in **A2**-mediated activation of **Nhe3** and **aldosterone**-mediated activation of **ENaC**, both contributing to **increased acid secretion** 3. **Distal Na⁺ delivery is also reduced** due to extensive **reabsorption,** **limiting ability of beta-intercalated cells** in the collecting duct to **secrete HCO₃^-**

Question 36

Acidemic conditions in regulation of kidney physiology

Answer 36

* Both metabolic and respiratory, increase the **endocytotic** **movement of H+ATPases from cellular sites to the plasma membrane**, **improving H+ secretion** * Hypokalemia does the same

Question 37

Gastrointestinal bicarbonate loss

Answer 37

Most cases of **diarrhea are rich in NaHCO₃**, and can amount to substantial **bicarbonate loss.** The notable exception to this is **chloride diarrhea**, such as in **congenital chloride diarrhea syndrome.** In these cases, **acid excretion in the kidney** (i.e. renal ammoniagenesis, new bicarbonate production) is **normal or even enhanced, to compensate** for the stool bicarbonate losses.

Question 38

Renal acidoses by nephron location

Answer 38

Type II: Loss of bicarbonate reabsorption at proximal cell Type I: Loss of alpha-intercalated cell acid secretion Type IV: Loss of principal cell sodium absorption (no generation of negative electrochemical gradient in the collecting duct lumen)

Question 39

Electrogenicity of the collecting duct

Answer 39

**Nhe3** in the proximal tubule is **electroneutral** (1 Na+ ion for 1 proton, so no net charge is carried by the exchange). In contrast the **distal tubule H⁺ATPase** carries a **positive charge and is electrogenic**. Because of this property, distal tubule alpha-intercalated cell electrogenic H⁺ secretion may be **increased by Na+ reabsorption in the neighboring principal cells** (through epithelial Na+ channels which leave the lumen more electronegative).

Question 40

Renal compensation for respiratory acidosis

Answer 40

Acidosis leads to increased secretion of protons into the lumen of the nephron. This, in turn, causes greater sodium bicarbonate reabsorption, resulting in an increased buffering of the blood.

Question 41

Things you need at the distal renal tubule and CD in order to excrete acid

Answer 41

1. Functioning ENaC 2. Functioning H+ ATPase and/or H+/K+ ATPase 3. Delivery of sodium to distal tubules 4. Intract mineralocorticoid signaling

Question 42

Resorptive threshold

Answer 42

The amount of bicarbonate that the kidney can reabsorb before it will no longer retain additional bicarbonate and any excess is excreted as urine.

Question 43

Hypokalemia as a mechanism for persistant alkalosis

Answer 43

Hypokalemia promotes **increased ammoniagenesis** to provide more NH3 to **favor NH4 + loss over K+ loss in the distal nephron.**

Question 44

If the maintenance of a metabolic alkalosis is due to the action of antidiuretics, then. . .

Answer 44

. . . **correcting volume depletion will turn the antidiuretics (RAAS and ADH) off and correct the alkalosis.** For this reason, they are also called **"saline responsive"** or **"chloride responsive"** alkaloses.

Question 45

In cases of *severe* hypovolemia, ___ prevents excretion of acid.

Answer 45

In cases of *severe* hypovolemia, **low collecting duct sodium delivery** prevents excretion of acid.

Question 46

Compensation for simple acid-base disorders

Answer 46

Question 47

Winter's equation is for. . .

Answer 47

. . . **metabolic acidosis only** It predicts the expected change in pCO₂ from respiratory compensation given a primary metabolic acidosis

Question 48

There are three main mechanisms of metabolic acidosis

Answer 48

1. **Increased body bicarbonate losses** (from the GI as in diarrhea or the kidney, anion gap will be normal) 2. **Decreased acid (H+ ) secretion** (from renal failure, distal renal tubular defects, anion gap will be normal) 3. **Increased acid production/ingestion** (anion gap will be elevated)

Question 49

Ion response to diarrhea

Answer 49

Diarrhea results in **stool loss of Na+ \> Cl-** (most diarrhea is rich in **NaHCO3**). The difference between Na+ and Cl- in the ECF, therefore, diminishes and **serum [HCO3 -] must fall.**

Question 50

What decreased renal acid excretion looks like on blood labs

Answer 50

When acid is retained in the blood, it will combine with bicarbonate and be neutralized by carbonic anhydrase and blowing off CO₂. The result will be **depression of serum bicarbonate/metabolic acidosis,** with a **normal anion gap.**

Question 51

Henderson-Hasselbalch adapted for bicarbonate physiology

Answer 51

**pH = pK + log [HCO3 ^-] / 0.03 x pCO₂** **pK is 6.1** and **0.03** refers to the **solubility factor** for CO2 in solution

Question 52

Winter’s Equation

Answer 52

P_CO2 = 1.5 [HCO3 ^-] + 8 +/- 2

Question 53

The two fundamental parts of any metabolic alkalosis

Answer 53

1. How the alkalosis was produced 2. The defect with renal regulatory mechanisms that allows it to persist

Question 54

Anion gap

Answer 54

**The difference between Na⁺ and (HCO3 ^- + Cl^- )** **Usually 10-12 mEq/lL**

Question 55

Typical urine pH

Answer 55

**~5.5-5.7** on a **Western diet** with lots of sulfur-containing meat On a **vegetarian or vegan diet,** slightly more alkaline at **~6.1-6.3** (low sulfiric acid level) This is assuming normal blood pH, as, of course, acidosis and alkalosis have totally different kidney physiology

Question 56

Renal loss of acid

Answer 56

Can result from **enhanced activity of ENaC**, which may occur in the setting of **increased distal sodium delivery** and distal flow (think **diuretics**), and **high aldosterone states** Increased activity of the ENaC and resulting sodium reabsorption will produce an electrochemical gradient (lumen negative) that **promotes H+ secretion by the A-type (alpha) intercalated cells** in the same tubular segment

Question 57

Ammonia production in the proximal tubule

Answer 57

Question 58

SNAT3

Answer 58

Glutamine transporter involved in renal ammoniagenesis Level of transcription responds to blood pH and is increased in any acidosis. Harvests ~3% of delivered glutamine under normal circumstances and ~6% under acidotic conditions.

Question 59

Examples of chloride-resistant metabolic alkaloses

Answer 59

* **Mineralocorticoid excess** (primary hyperaldosteronism, Cushing's syndrome, renin-secreting tumor) * **NaHCO₃ infusion** * "Apparent mineralocorticoid excess syndromes" * Licorice gluttony * Liddle's syndrome

Question 60

Angiotensin II in acid base physiology

Answer 60

* Stimulates Na+ reabsorption in the proximal tubule by **increasing Na+ -H+ exchange**, thus **acidifying the lumen**. By this mechanism, it also **increases bicarbonate reabsorption** (carbonic anhydrase mechanism) * Works on **Nhe3** * **Catecholamines** have the same effect

Question 61

GI loss of acid

Answer 61

When **emesis** occurs, HCl is the primary source of acid loss. Recall that the **proton in this HCl comes from bicarbonate** in the parietal cell, and that an **alkaline tide** is produced on the basolateral side as acid is released from the apical side, resulting in raised blood pH. When **chloride diarrhea** occurs, **sodium chloride and fluid are substantially lost, but bicarbonate is not**. Thus, the moles of bicarbonate contained within the body are diluted in less total volume, resulting in **metabolic alkalosis.**

Question 62

Ion response to emesis

Answer 62

Vomiting results in **loss of Cl- \> Na+** (vomitus contains a high concentration of HCl) resulting in **low serum Cl- concentration relative to Na+**. Serum **HCO3 - will therefore increase relatively to maintain electroneutrality.**

Question 63

A hemophilia patient presents to the emergency department with substantial blood loss. They are rapidly transfused with 3 units of red cells. Subsequently, their blood labs are checked and they are found to have alkalemia. What is its likely etiology?

Answer 63

Recall the additives to stock red cells - **citrate, phosphate, dextrose, and adenosine.** **Sodium citrate** is rapidly broken down into bicarbonate, and may result in a metabolic alkalosis if given rapidly.