Renal Acid-Base Handling

Introduction

• [H+] is maintained within narrow limits• Normal extracellular [H+] ≈ 40 nanomol/L

(one-millionth the mmol/L concentrations of Na+, K+, Cl-, HCO3-)

• Regulation of [H+] at this low level is essential for normal cellular (protein) fxn– Increase in [H+] change charge, shape and

function of proteins

3 Basic Steps of H+ Regulation

• Chemical buffering by extracellular and intracellular buffers

• Control of partial pressure of CO2 in the blood by alterations in alveolar ventilation

• Control of plasma [HCO3-] by changes in renal H+ excretion

Buffers

• Take up or release H+ ions to maintain a stable [H+]

• HPO42- (base) + H+ ⇄ H2PO4

- (acid)

• HCO3- (base) + H+ ⇄

H2CO3 (acid)

Henderson-Hasselbalch Equation

• Ka (dissociation constant) = [H+] [A-]

• [H+] = Ka [HA]

• -log [H+] = -log Ka - log [HA]

• pH = pKa + log [A-]

• pH = 6.10 + log [HCO3-]/0.03 Pco2

• H+ + HCO3- ⇄ H2CO3 ⇄ H20 + CO2

[HA]

[A-]

[A-]

[HA]

Bicarbonate Buffer System

• The major physiologic buffer system• [HCO3

-] and Pco2 regulated independently– [HCO3

-] regulated by renal H+ excretion

– Pco2 regulated by changes in alveolar ventilation• As H+ are buffered by HCO3, elevation in Pco2 is prevented

by increase in alveolar ventilation, thus enhancing effectiveness of HCO3 buffering

• Capable of removing large quantity of H+ due to large amount of HCO3 in the body

Buffering During Metabolism of Sulfur-Containing Amino Acids

Diet

Sulfur-AA2 HCO3

- 2 CO2 + 2 H2O

2 HCO3-

Glutamine

2 NH4+

SO42-

SO42-

2 NH4+

Urine

•Acid balance is achieved when SO42- are excreted in the

urine with NH4+ because HCO3- is generated in the process

ECF

2H+

Kidney

Buffering During Metabolism of Organic Phosphates

Diet

RNA-P-

H+ HCO3- CO2 + H2O

HCO3-

CO2 + H2O

H+

HPO42-

H2PO4-

Urine

ECF

Kidney

Base Balance During Metabolism of Organic Anions

Diet

K+ + OA-

HCO3- CO2

Glucose

OA-

K+OA-

Urine

ECF

Kidney

H+

liver

liver

Acid-Base Balance

Excrete OA

Production H+

Production HCO3-

Removal H+ Removal HCO3-

Add “new” HCO3- Urine

Alveolar Ventilation

• Main physiologic stimuli to respiration– Pco2

• Chemoreceptors in respiratory center in brainstem respond to CO2-induced ∆ cerebral interstitial pH

– Po2

• Peripheral chemoreceptors in the carotid bodies

Sequential Response to H+ Load

Renal H+ Excretion: Basic Principles

• Achieved by H+ secretion– Na+/H+ exchange: proximal tubules and thick

ascending limb of the LOH– H+-ATPase: collecting tubules

• Acid load cannot be excreted as free H+ ions– Urinary [H+] is extremely low (< 0.05 mEq/L) in

the physiologic pH range

Renal H+ Excretion: Basic Principles

• Acid load cannot be excreted unless virtually all of the filtered HCO3

- has been reabsorbed

• Secreted H+ ions bind to:– Filtered buffers (HPO4

2-, creatinine)

– NH3 to form NH4+

• Rate of NH4+ generation in the proximal tubules varies

according to physiologic needs

Renal H+ Excretion: Basic Principles

• Extracellular pH is the primary physiologic regulator of net acid excretion– Other factors include:

• Effective circulating volume• Aldosterone• Plasma [K+]

2 Basic Steps of Renal H+ Excretion

• Reabsorption of the filtered HCO3-

• Excretion of 50-100 mEq of H+ produced per day (daily acid load on a typical Western diet)

Reabsorption of Filtered HCO3-

• Loss of filtered HCO3- = addition of H+

• Virtually all of the filtered HCO3- must be

reabsorbed– Normal person reabsorbs about 4300 mEq of

HCO3- per day (GFR 180 L/day x 24mEq/L HCO3

- )

Renal H+ Secretion

• Secreted H+ ions are generated within tubular cells from dissociation of H2O

• OH- ions combine with CO2 to form HCO3-,

catalyzed by intracellular carbonic anhydrase

– HCO3- is absorbed across basolateral membrane

• Secretion of one H+ ion in the urine = generation of one HCO3

- in the plasma

Renal H+ Secretion

• If secreted H+ combines with filtered HCO3- ,

the result is HCO3- reabsorption thus

preventing HCO3- loss in the urine

• If secreted H+ combines with HPO42- or NH3, a

new HCO3- is added to the plasma (replaces

the HCO3- lost in buffering the daily H+ load)

Net Acid Excretion

Net Acid Excretion (NAE) = titratable acid + NH4+ - urinary HCO3

-

excretion can be increasedquantity not

replenishable (HPO42-, Cr)

Titratable acid represents the amount of alkali that is required to titrate the urine pH back to the plasma pH (7.4)

Proximal Acidification

• Proximal tubules reabsorb 90% of filtered HCO3

-

• Primary step is secretion of H+ by Na+-H+ exchanger in luminal membrane– Energy indirectly provided by Na+/K+ ATPase in

basolateral membrane• HCO3

- returned to systemic circulation by

Na+/3 HCO3- cotransporter

• Carbonic anhydrase plays central role

Proximal Acidification

UpToDate, 2009

Distal Acidification

• H+ secretion in distal nephron occurs in type A intercalated cells in the cortical collecting tubule and in the cells of the medullary colllecting tubule

• H+ secretion is mediated by active luminal secretory pumps – H+-ATPase– H+/K+ ATPase

Distal Acidification

• H+ secretion by intercalated cells is indirectly influenced by Na+ reabsorption in the adjacent principal cells– Na+ absorption makes the lumen relatively

electronegative, thus promoting H+ secretion

• HCO3- reabsorption across basolateral

membrane is mediated by Cl-/ HCO3- exchanger

Type A Intercalated Cell

UpToDate, 2009

Type B Intercalated Cell

UpToDate, 2009

Type A vs B Intercalated Cells

Ammonium Generation and Excretion

Glutamine 2-Oxoglutarate2- + 2 NH4+

2HCO3- to body

2 NH4+ in

urine

2 NH4+ Urea

2 HCO3-

Liver

Ammonium Generation and Excretion

Exogenous Endogenous

Proteins

Methionine + Glutamine

NH4+

H+

+

NH3

2NH4+ + SO4

2-

2NH4+

2HCO3-

2HCO3-

2 CO2 +2H2O

2H+ + SO42-

Ammonium Generation and Excretion

UpToDate, 2009

Medullary Ammonium Recycling

Fluid, Electrolyte and Acid-Base Physiology, 2010

Ammonium Generation and Excretion

Comprehensive Pediatric Nephrology, 2008

Regulation of Renal H+ Excretion

• Extracellular pH• Effective circulating volume

– Renin-angiotensin-aldosterone system– Chloride depletion

• Plasma potassium

Extracellular pH Is Major Regulator of Renal H+ Excretion

• NAE varies inversely with extracellular pH• Acidemia⇑prox and distal acidification

– Proximal tubule• ⇑luminal Na+/H+ exchange• ⇑luminal H+-ATPase activity• ⇑Na+/3HCO3

- activity in basolateral membrane• ⇑NH4 production from glutamine

– Collecting tubule• ⇑luminal H+-ATPase activity in intercalated cells

• Alkalemia⇓prox HCO3- reabsorption and ⇑HCO3

- secretion in CCD

Effective Circulating Volume

• Hypovolemia activates RAAS system, causing HCO3

- reabsorption– Angiotensin II

• ⇑luminal Na+/H+ exchange in proximal tubule• ⇑basolateral Na+/3HCO3

- activity in proximal tubule– Aldosterone

• ⇑luminal H+-ATPase activity in collecting tubule• ⇑basolateral Cl-HCO3

- activity in collecting tubule• ⇑Na+ absorption in principal cells in cortical collecting

tubule, resulting in net H+ secretion

Effective Circulating Volume

• Hypochloremia commonly occurs in metabolic alkalosis– Low filtered [Cl-] increases H+ secretion

• Cl- is passively cosecreted with H+ secretion via H+-ATPase to maintain electroneutrality thus ability to secrete H+ is enhanced with low tubular fluid [Cl-]

• In setting of low tubular fluid [Cl-], Na+ reabsorption must be accompanied by H+ or K+ secretion in CCD

Hypochloremia Decreases HCO3-

Secretion Type B Intercalated Cell • Energy for luminal

Cl-/HCO3- exchange is

provided by favorable inward gradient for Cl-

• Low tubular [Cl-] ⇓gradient thus less HCO3

- secreted

UpToDate, 2009

Plasma K+ Influences Renal H+ Secretion

K+

H+

Na+

Cell ECF

Hypokalemia

Changes in K+ balance lead to transcellular cation shifts that affect intracellular [H+]

Hypokalemia leads to low intracellular pH

Intratubular Acidosis Increases H+ Excretion in Hypokalemia

• ⇑H+ secretion in proximal tubule– ⇑luminal Na+/H+ exchange– ⇑basolateral Na+/3HCO3

- activity

• ⇑NH4 generation from glutamine in proximal tubule

• ⇑H+ secretion in distal nephron– ⇑luminal H+/K+ ATPase, resulting in H+ secretion

and K+ absorption

Renal Acification: Summary

Molecular and Genetic Basis of Renal Disease, 2007

References

• Rose BD, Post TW: Clinical Physiology of Acid-Base and Electrolyte Disorders. New York, McGraw-Hill, 2001, pp 299-371.

• Bidani A, Tuazon DM, Heming TA: Regulation of Whole Body Acid-Base Balance. In DuBose TD, Hamm LL (eds): Acid-Base and Electrolyte Disorders. Philadelphia, Saunders, 2002, pp 1-21.

References

• Alpern RJ, Hamm LL: Urinary Acidification. In DuBose TD, Hamm LL (eds): Acid-Base and Electrolyte Disorders. Philadelphia, Saunders, 2002, pp 23-40.

• Halperin ML, Goldstein MB, Kamel KS: Fluid, Electrolyte and Acid-Base Physiology. Saunders, 2010, pp 3-29.

References

• UpToDate, 2009• Mount DB, Pollak MR: Molecular and Genetic

Basis of Renal Disease: A Companion to Brenner and Rector’s The Kidney. Saunders, 2007.

• Geary D, Schaefer F: Comprehensive Pediatric Nephrology. Mosby, 2008.

Distal Acidification

Comprehensive Pediatric Nephrology, 2008

Chronic Metabolic Acidosis and Respiratory Compensation

Clinical state Arterial pH [HCO3-], mEq/L Pco2, mmHg

Baseline 7.40 24 40

Metabolic acidosis

No compensation 7.29 19 40

Compensation

Acute 7.37 19 34

Chronic 7.29 16 34

Medullary Transfer of Ammonium

Fluid, Electrolyte and Acid-Base Physiology, 2010