Control of Acid

Control of Acid-Base Balance

Introduction

The rate at which acid is removed from the body (acid ouput) = rate of production of acid (acid input)

Acid production: 2 types: Volatile and Non-volatile:

(1) Volatile Acids: CO₂ – produced from aerobic metabolism of carbohydrate, fat cells. Can combine with H₂O to form H₂CO₃, a weak acid. Eliminated via respiration.

(2) Non-volatile acids (fixed acids): endogenous metabolism of protein (some), hydrogen produced in association with anions other than bicarbonate, produced from oxidation of amino acids (predominantly sulfur-containing amino acids)

Sulfuric Acid (product of protein catabolism)
phosphoric acid (product of phospholipid metabolism)
Kidney only organ capable of excreting these

Plasma free hydrogen concentration: exceedingly small (average: 40x10^-9 mol/L)

Normal daily acid Load: 60-70 meq of acid/day – must be excreted daily to maintain acid-base balance.

Defending Against Excess Acid

2 mechanisms to defend against excess acid: Body buffers and Renal control

1. Body Buffers

Characteristics: immediate defense but limited in capacity

Intracellular:

Hemoglobin
protein
organic phosphates (AMP, ADP, ATP, 2,3-DPG)

Extracellular:

Carbonic acid-bicarbonate Buffer System - major

Phosphate - minor

Buffering capacity of both are equal and in rapid equilibrium such that a ß in one system will result in a proportional decrease in the other. Therefore, only major extracellular buffer system is clinically evaluated. How? Via 3 parameters: (1) blood pH, (2) PaCO₂, and (3) Plasma total CO₂ (mM/L)

Henderson-Hasslbach equation: (H⁺) = 24 pCO₂ / (HCO₃)

Carbonic acid-bicarbonate buffer system is effective because

(a) PaCO₂ is directly regulated by pulmonary ventilation
(b) Bicarbonate is directly regulated by the kidney

Acid-Base disturbances arise only if the lungs and/or the kidneys are unable to perform their homeostatic functions due to either damage or overload

2. Renal Control

Characteristics: slow process (3-5 days) but most important because it regenerates bicarbonate consumed in buffering acid

4 distinct mechanisms: (described more fully below)

(1) Reabsorption of filtered bicarbonate – proximal tubule
(2) Excretion of buffered anions other than bicarbonate in the form of titratable acid (mainly phosphate) – distal tubule
(3) Excretion of ammonia – distal tubule
(4) Excretion of free hydrogen (quantitatively insignificant contribution) – distal tubule
4 Processes mediated by 1 operation: exchange of reabsorbed Na (from lumen to interstitium) for secreted H⁺ (Na⁺/H⁺exchanger)
Secreted H⁺disposed of by either conversion to CO₂ and H₂O (proximal tubule) or by buffering by ammonia and phosphate (distal tubule)

(1) Reabsoprtion of filtered HCO₃^- – in proximal tubule

Function: RECLAIMS significant fraction of the filtered bicarbonate critical for maintenance of body buffer economy

Mechanism: Refer to figure 16 in the overview lecture

In the LUMEN: Filtered HCO₃- combines with secreted H⁺(via a Na⁺,H⁺exchanger) to form H₂CO₃ which dissociates into CO₂ and H₂O catalyzed by BRUSH BORDER Carbonic Anhydrase. CO₂ and H₂O diffuse into the cell freely.
IN the proximal tubule cell: CO₂ and H₂O combine to form H₂ CO₃, catalyzed by INTRACELLULAR Carbonic Anhydrase; H₂ CO₃dissociates into H⁺and HCO₃^-. H⁺is secreted into the lumen via the Na⁺-H⁺exchange mechanism in the luminal membrane. Filtered HCO₃- is reabsorbed.
In effect, H⁺secreted in the prox tubule via Na⁺absorption captures HCO₃- in the lumen and reabsorbs it as CO₂ and H₂O via carbonic anhydrase. Reclaims over 90% of the filtered bicarbonate

Key features:

Proximal tubule fluid pH: very close to that of plasma. Secreted hydrogen is not excreted as carbonic acid. Carbonic acid is dissociated to water and CO₂ by brush border carbonic anhydrase.
Process results in net reabsorption of filtered HCO₃^-. It DOES NOT result in net secretion of H⁺.
1 mole of secreted hydrogen (via Na+ exchange) = 1 mole of reabsorbed bicarbonate into the blood

Regulation:

Filtered load: Ý filtered load Ý HCO₃^-reabsorption

PCO₂: Ý CO₂ Þ Ý HCO₃^-reabsorption (because Ý intracellular H+ supply for secretion)

ECF Volume: Ý Volume Þ ß HCO₃^-reabsorption (ß Na⁺ resorption Þ ß H⁺secretion) Angiotensin II: stimulates Na⁺\H⁺exchange Þ Ý HCO₃^- reabsorption

Distal Tubule:Function: EXCRETION of the Fixed Non-volatile H⁺or REPLACING the bicarbonate utilized in buffering the Fixed H⁺

Distal tubule pH: drops as low as 4.2 because no brush border carbonic anhydrase present, no HCO₃ to buffer secreted H⁺

(2) Titratable Acid: buffering by phosphate

Mechanism: H⁺and HCO₃- are produced in the cell from CO₂ and H₂O . The H⁺is secreted into the lumen by an H⁺-ATPase, and the HCO₃^-is reabsorbed into the blood ("new" HCO₃^-) In the urine, the secreted H⁺combines with filtered HPO₄^-2 to form H₂PO₄., which is excreted as Titratable Acid refer to figure 17

Result: net secretion of H⁺and net reabsorption of newly synthesized HCO₃^-.

Key features:

pH of urine becomes progressively lower (because of H⁺secretion) – minimum urinary pH=4.4
The amount of H⁺excreted as titratable acid depends on the amount of urinary buffer and the pK of the buffer

Other weak acids in the urine (creatinine) become important buffers as the urine pH approaches their pK

(3) Ammoniagenesis: buffering by ammonia

Mechanism: H⁺ and HCO₃^- are produced in the cell from CO₂ and H₂O (via CA). Glutamine (produced in the liver) is double deaminated (loses NH₄+) to a -ketoglutarate. a -ketoglutarate accepts 2H+ prior to its further metabolism to glucose (gluconeogenesis) or to CO₂ + H₂O (Kreb’s cycle). 2 "new" HCO₃- are reabsorbed into the blood.

So, each urinary NH₄⁺ serves as a marker for one regenerated bicarbonate and net acid excretion (1:1 ratio).

Note: it was originally believed that NH₃, derived from glutamine, was secreted by the distal tubular cell and combined with secreted H⁺ in the urinary lumen, "trapping" it and allowing excretion of H⁺ as NH₄⁺. This is not possible because pK of NH₃ >8 and pH in the distal cell is 7 (so NH₃ must exist in its protonated form)

Result: Net reabsorption of newly synthesized HCO₃-.

Key features:

Net acid excretion = urinary NH₃ + urinary titratable acid – urinary bicarbonate (was not reabsorbed)

Excretion of NH₄⁺ is important for acid-base and volume homeostasis because

(1) prevents NH₄⁺from being metabolized in the liver to urea – which generates a H⁺
(2) NH₄⁺ prevents Na⁺depletion (serum) by facilitating Na⁺reabsorption in the distal tubule via its effect on the electrochemical gradient

In metabolic acidosis: hepatic production of glutamine Ý Þ Ý urinary NH₄⁺excretion Þ Ý Bicarb production

Fate of a -ketoglutarate: whether it is metabolized to glucose or to CO₂ and H₂O depends upon the energy state of the distal tubule cell: Kreb’s cycle requires 27 ADP as substrate, if the cell has been metabolically active Þ Ý ADP Þ CO₂ and H₂O Production is favored.

(4) Free H⁺excretion

Mechanism: H⁺ATPase (intercalated cell) stimulated by aldosterone.

Result: H⁺secretion into the lumen

Key features: contributes to a Ý urine/plasma [H⁺] which enables the kidney to excrete acid at a rate equal to that of endogenously produced H⁺

Urinary buffers

Composition: 2/3 ammonia

1/3 titratable acid (phosphate)

weak acids (creatanine): becomes important with ß pH

In DKA, b hydroxybuturate and acetoacetic acids become important urinary buffers.

Importance: vital to the excretion of acid. 6000Liters of urine would be required to excrete the 60mEq of non-volatile acid produced daily. Fortunately, 99.99% of urinary H⁺ is excreted in a buffered form allowing economy of volume and pH.

Chronic Renal Failure: limitation in buffer production Þ inability to excrete acid to match reduction (even though urine pH may be normal)

Disturbances in Acid-Base Balance

Definition: 4 primary disturbances defined based on changes in either PaCO₂ or plasma bicarbonate

Disorder	Primary Event	Effect on [H⁺]	Compensation
Metabolic Acidosis	ß HCO₃-	Ý (ß pH)	ß pCO₂
Metabolic Alkalosis	Ý HCO₃-	ß (Ý pH)	Ý pCO₂
Respiratory Acidosis	Ý pCO₂	Ý (ß pH)	Ý HCO₃-
Respiratory Alkalosis	ß pCO₂	ß (Ý pH)	ß HCO₃-

Principles:

2/3 of the variables of the equilibrium equation must be known. The third can be calculated. All the variables must be evaluated before the nature of the acid-base problem can be defined
Single acid base problem: the directional changes in [HCO₃^-] and PaCO₂ are the same but the magnitude of change is different.
The primary event is always a larger change than the compensatory event such that the compensation is never sufficient enough to correct the underlying acid-base disorder