Renal Acid-Base Handling

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 = 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 ECF 2H+ 2 CO H2O 2 HCO3- Sulfur-AA SO42- 2 HCO3- Glutamine SO42- 2 NH4+ •H+ cannot be eliminated by metabolism of SO42- to neutral end products or by being excreted bound to SO42- in the urine 2 NH4+ Kidney Urine •Acid balance is achieved when SO42- are excreted in the urine with NH4+ because HCO3- is generated in the process

Buffering During Metabolism of Organic Phosphates
Diet ECF HCO3- CO2 + H2O H+ RNA-P- HCO3- HPO42- CO2 + H2O H+ Diet consists primarily of intracellular organic phosphates in nucleic acids (RNA, DNA) and phospholipids. Elimination of H+ produced during metabolism of organic phosphates does not require excretion of NH4+ H2PO4- Kidney Urine

Base Balance During Metabolism of Organic Anions
Diet ECF HCO3- CO2 H+ liver K+ + OA- Glucose liver OA- K+ OA- Diet provides an alkali load that is produced during the metabolism of organic anions in fruits and vegetables. Organic anions are first converted to HCO3 in the liver. Endogenous organic acids are produced in the liver, with subsequent binding of H+ to HCO3. The conjugate bases (i.e. citrate anions) are excreted with K+ in the urine, to prevent the synthesis of HCO3 at a later time. Kidney Urine

Acid-Base Balance Urine Production H+ Production HCO3- Removal HCO3-
Acid Balance Diet  2H+ + SO42- 2H+ + HCO3-  2CO H2O 2NH SO42- Base Balance Diet  3K+ + 3HCO3- Glucose  3H+ + Citrate3- 3K Citrate3- Production H+ Production HCO3- Removal HCO3- Removal H+ Add “new” HCO3- Urine Excrete OA

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 Despite effectiveness of respiratory compensation, pH is protected for only a few days Initial ∆ Pco2 alters renal HCO3 reabsorption

Sequential Response to H+ Load
Extracellular buffering by HCO3- Immediate Respiratory buffering by Pco2 Minutes-Hours Intracellular and bone buffering 2-4 hours renal H+ excretion Hours to Days -extracellular buffering of the excess H+ by HCO3 occurs almost immediately -within several minutes, respiratory compensation begins, resulting in hyperventilation, a decrease in Pco2 and increase in pH toward normal -within 2-4 hours, intracellular buffers (proteins and organic phosphates) and bone provide further buffering -adaptive renal response begins on the first day and is complete within 5-6 days

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

Acid load cannot be excreted unless virtually all of the filtered HCO3- has been reabsorbed Secreted H+ ions bind to: Filtered buffers (HPO42-, creatinine) NH3 to form NH4+ Rate of NH4+ generation in the proximal tubules varies according to physiologic needs

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 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 increased quantity not replenishable (HPO42-, Cr) titratable acid is a term used to express the amount of acid that has been added to urine. To determine titratable acid, urine is titrated from its collected pH up to plasma pH (7.4) with the strong alkali sodium hydroxide (NaOH). The amount of alkali used to bring the urine pH up to plasma pH is quantitatively titratable acid. 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 -primary step in proximal acidification is the secretion of H by the Na-H exchanger in the luminal membrane. This transporter also mediate most of HCO3 reabsorption in the thick ascending limb of loop of Henle. -H-ATPase pump is also present in the proximal tubule, similar to that in the distal nephron. -the energy for Na-H exchange is indirectly provided by the Na-K-ATPase pump in the basolateral membrane. -maintains a low intracellular Na concentration -creates a negative electrical potential in the cell interior due to loss of cation from the cell, because of the 3Na: 2K stoichiometry of the pump and the back-diffusion of the K out of the cell through the basolateral membrane. The low cell Na concentration creates a favorable gradient for the passive diffusion of luminal Na into the cell that is large enough to drive H secretion against a concentration gradient. -HCO3 is returned to the systemic circulation primarily via Na-3HCO3 cotransporter in the basolateral membrane. The Na-3HCO3 transporter results in the net movement of negative charge; the energy for this process is provided by the electronegative potential within the cell that is created by the Na-K ATPase. -carbonic anhydrase within the cell plays a central role in HCO3 reabsorption: -catalyzes formation of HCO3 from CO2 + OH- in the cell -catalyzes dehydration of H2CO3 into Co2 + H2O in the lumen by carbonic anhydrase in the brush border of the tubular cells, keeping a low H2CO3 concentration (which drives the reaction to the right, thereby keeping the free H concentration at a low level in the lumen. This minimizes the gradient against which H is secreted, thus enhancing the function of the Na-H exchange). H+ + HCO3- <> H2CO3 <> CO2 + H2O

Proximal Acidification
Major cellular and luminal events in bicarbonate reabsorption in the proximal tubule (left panel) and collecting tubules (right panel). Intracellular H2O breaks down into H+ and OH- ions. The latter combine with CO2 to form HCO3- via a reaction catalyzed by carbonic anhydrase (CA). In the proximal tubule, the H+ ions are secreted into the lumen by the Na+-H+ exchanger, whereas the HCO3- ions are returned to the systemic circulation primarily by a Na+-3HCO3- cotransporter. The same processes occur in the collecting tubules, although they are respectively mediated by an active H+-ATPase pump and a Cl- HCO3- exchanger in the basolateral membrane. The secreted H+ ions combined with filtered HCO3- to form carbonic acid (H2CO3) and then CO2 and H2O which are passively reabsorbed. The dissociation of carbonic acid is facilitated when luminal carbonic anhydrase (CA in box) is present, as occurs in the early proximal tubule (segments that lack luminal carbonic anhydrase-S3 segment of proximal tubule, cortical collecting tubule, medullary collecting tubule, pg 337). The net effect is HCO3- reabsorption even though the HCO3- ions returned to the systemic circulation are not the same as those that were filtered. Although not shown, the collecting tubules also have H+-K+-ATPase pumps in the luminal membrane that are involved in both acid secretion and, perhaps more important, K+ reabsorption. 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
Transport mechanisms involved in hydrogen secretion and HCO3 and K reabsorption in type A intercalated cells in the cortical collecting tubule and in the outer medullary collecting tubule cells. Water within the cell dissociates into H and OH ions. The former are secreted into the lumen by H-ATPase pumps in the luminal membrane, where they primarily combine with NH3 to from NH4+. The OH ions in the cell combine with CO2 to form HCO3 in a reaction catalyzed by carbonic anhydrase (CA). Bicarbonate is then returned to the systemic circulation via Cl-HCO3 exchangers in the basolateral membrane. The favorable inward concentration gradient for Cl (plasma and interstitial concentration greater than that in the cell) provides the energy for HCO3 reabsorption. H-K-ATPase pumps, which lead to both H secretion and K reabsorption, are also present in the luminal membrane. The number of these pumps increases with K depletion, suggesting that their main function may be to promote K conservation. UpToDate, 2009

Type B Intercalated Cell
Transport mechanisms involved in the secretion of HCO3 into the tubular lumen in the type B intercalated cells in the cortical collecting tubule. Water within the cell dissociates into H and OH ions. The former are secreted into the peritubular capillary by H-ATPase pumps in the basolateral membrane. The OH ions combine with carbon dioxide to form HCO3 in a reaction catalyzed by carbonic anhydrase (CA). HCO3 is then secreted into the tubular lumen via Cl-HCO3 exchangers in the luminal membrane. The favorable inward concentration gradient for Cl (lumen concentration greater than that in the cell) provides the energy for HCO3 secretion. UpToDate, 2009

Type A vs B Intercalated Cells

Ammonium Generation and Excretion
Glutamine 2-Oxoglutarate NH4+ Liver Glutamine in proximal tubular cells are metabolized to NH4 and 2-oxoglutarate; the latter is metabolized to new HCO3. The new HCO3 generation is maintained when NH4 is excreted in the urine. NH4 ions are lipid-insoluble and are therefore “trapped” in the lumen, since back-diffusion cannot occur. If NH4 is not excreted in the urine, it returns to the liver and is metabolized to urea, which consumes HCO3, thus negating the gain of HCO3 in the process. Each NH4 produced results in the equimolar generation of HCO3 from the metabolism of 2-oxoglutarate. 2 NH4+  Urea 2HCO3- to body 2 NH4+ in urine 2 HCO3-

Exogenous Endogenous Proteins 2HCO3- Methionine + Glutamine 2NH4+ Sulfur-containing amino acids (ie methionine) are converted to H+ and SO4 anions. A deficit of HCO3 is created when these new H+ react with HCO3. Glutamine is converted to NH4 and HCO3 in cells of the proximal tubular cells. The new HCO3 are added to the body to replace the deficit of HCO3. NH4 is excreted in the urine in equivalent amounts to SO4. 2H+ + SO42- 2 CO2 + 2H2O H+ NH4+ + NH3 2HCO3- 2NH4+ + SO42-

In the proximal tubule, glutamine is taken up by the cells and metabolized into NH4+ and alpha-ketoglutarate. Utilization of the latter results in the generation of HCO3-, whereas NH4+ substitutes for H+ on the Na+-H+ exchanger and is then secreted directly into the lumen. The mechanism is different in the collecting tubules; nonpolar, lipid-soluble NH3 diffuses from the interstitial fluid into the lumen, where it combines with secreted H+ to form NH4+. Ammonium is lipid-insoluble and is therefore unable to back-diffuse out of the lumen. Note that each NH4+ ion that is excreted is associated with the generation of a new HC03- ion that is returned to the peritubular capillary. UpToDate, 2009

Medullary Ammonium Recycling
Generation of a high NH 4 + concentration in the medullary interstitial compartment. The U-shaped structure is the loop of Henle. The first step in the process that raises the concentration of NH 4 + in the medullary interstitial compartment is NH 4 + production in the proximal convoluted tubule; NH 4 + enter the lumen on the Na + /H + exchanger ( site 1 ). The second step is the reabsorption of NH 4 + via the Na + , K + , 2Cl − -cotransporter (NKCC-2) in the medullary thick ascending limb ( site 2 ). The third step is the entry of NH 4 + ultimately into the descending limb of the loop of Henle, completing a countercurrent exchange of NH 4 + ( site 3 ). -the high concentration of NH4 in the interstitial compartment causes movement of NH4 into the lumen of the thin descending limb of the loop of Henle where the concentration of NH4 is low. Net effect of this countercurrent exchange is to raise the concentrations of NH4 and NH3 deep in the medullary interstitial compartment, promoting secretion into the medullary collecting tubule Fluid, Electrolyte and Acid-Base Physiology, 2010

Schematic representation of ammonia recycling within the renal medulla. Although NH4+ production occurs primarily in the proximal tubule, most of the NH4+ is then reabsorbed in the thick ascending limb, apparently by substitution for K+ on the Na+-K+-2Cl- carrier in the luminal membrane. Partial dissociation into NH3 and H+ then occurs in the less acid tubular cell. The NH3 diffuses into the medullary interstitium where it achieves relatively high concentrations; it then diffuses back into those segments that have the lowest pH and therefore the favorable gradient: the S3 segment of the late proximal tubule and, more importantly, the medullary collecting tubule, where the secreted NH3 is trapped as NH4+ and then excreted. 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
Hypokalemia Changes in K+ balance lead to transcellular cation shifts that affect intracellular [H+] Hypokalemia leads to low intracellular pH Cell ECF K+ H+ Na+

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
Schematic model of renal acidifying mechanisms: HCO3− reabsorption in proximal tubular cells and H+ secretion in α-intercalated cells of the collecting duct. In the proximal tubule, H+ is secreted at the apical membrane by the NHE3 Na+/H+ exchanger and by the vacuolar H+-ATPase. Membrane-bound carbonic anhydrase (CA) IV catalyzes the accelerated formation of CO2 from H2CO3 generated by protonation of filtered HCO3−. CO2 enters the tubular cell by diffusion and probably also via aquaporin 1. H2CO3 is formed in the presence of cytosolic CA II, and HCO3− is transported out of the cell at the basolateral surface by Na+/HCO3− cotransporter NBCe1. In type A α-intercalated cells of the cortical collecting duct, H+ is transported out of the cell into the lumen by vacuolar H+-ATPase, and, in K+-depleted conditions, perhaps also by H+/K+-ATPase. HCO3− generated inside the cells leaves via anion exchanger 1 (kAE1) in exchange for Cl− entry across the basolateral membrane. Basolateral Cl− recycling is depicted with KCC4 K+/Cl− cotransporter but may require Cl− channel(s) in humans. Type B β-intercalated cells secrete HCO3− in exchange for Cl− via their apical anion exchanger pendrin. In contrast to α-intercalated cells, they can express a basolateral vH+-ATPase. 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 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 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
Figure 31-2 Model of cortical collecting duct hydrogen ion secretion. illustrates the mechanism and transporters involved in H+ secretion in the CCD. Just like in the proximal tubule, H+ and HCO3− are generated inside the cell from CO2 and H2O. This is facilitated by carbonic anhydrase type II. Most of the H+ is secreted into the lumen via H+-ATPase.[8] This secretion is enhanced and the back diffusion of H+ lowered by the electronegativity of the lumen, because H+ is a positive ion. The electronegative potential of the lumen is created as a result of electrogenic Na+ reabsorption by the adjacent principal cells. Thus, if for some reason the electronegative potential in the lumen is reduced such that it is relatively more positive, H+ secretion will be impaired. In low effective circulating volume states, the amount of Na+ delivered to the principal cell is so low that, even if most of it is reabsorbed, the electronegative potential generated is not adequate to facilitate H+ secretion. H+K+-ATPase is another pump that is involved in H+ secretion into the lumen and that exchanges H+ for K+. This appears to play an active role in K+ homeostasis (i.e., in hypokalemic states) but not in acid–base homeostasis.[10] After H+ enters the lumen, it is very quickly buffered by ammonia (NH3) and monohydrogen phosphate (HPO42−) to form ammonium (NH4+) and titratable acid (H2PO4−). Net acid excretion is the sum of NH4+ and H2PO4−, which results in the removal of H+, thereby promoting further H+ secretion into the lumen. Some of the secreted H+ binds to the small fraction of filtered HCO3− (<5%) that was not reabsorbed by the upstream nephron segments. The HCO3− formed within the cell exits via the Cl−-HCO3− exchanger.[2,][8,][11] Thus, H+ secretion in this segment results in the following two changes: 1. The reabsorption of the final quantity of the filtered HCO3−, which, in body terms, is neutral in that there is no net addition or loss of HCO3− 2. The excretion of H+ in the form of NH4+ and H2PO4−, which results in a net gain of HCO3− so that the HCO3− concentration in the body is returned to its baseline Formation of titratable acidity, which is primarily due to buffering of filtered HPO4(2-) and, to a lesser degree, other buffers such as creatinine. Note that a new HCO3- ion is returned to the peritubular capillary for every H+ ion that is secreted. H+ secretion occurs primarily by Na+-H+ exchange in the proximal tubule and by an active H+-ATPase pump in the collecting tubules. CA: carbonic anhydrase. 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 Compensation Acute 7.37 34 Chronic 16 1. in chronic metabolic acidosis, the compensatory fall in Pco2 decreases HCo3 reabsorption and therefore the plasma HCo3 concentration; net effect is after several days, the pH is the same as it would have been if no respiratory compensation had occurred, since the decline in Pco2 is balanced by a further reduction in the HCO3 concentration (fortunately, most forms of severe metabolic acidosis are acute) 2. In chronic metabolic alkalosis, there is a similar limitation of respiratory compensation; compensatory rise in Pco2 leads to increased H+ secretion, a further elevation in the plasma HCo3 concentration and no net improvement in metabolic alkalosis.

Medullary Transfer of Ammonium
Transfer of NH 4 + from the loop of Henle to the medullary collecting duct (MCD). The medullary thick ascending limb (mTAL) of the loop of Henle is shown to the far left and the MCD is shown to the far right . The funnel-shaped structure in the MCD represents a NH 3 channel. The added NH 3 from the mTAL is converted to NH 4 + by H + arriving from site 3 . Recycling of NH 4 + in the loop of Henle raises the concentration of NH 4 + in the medullary interstitium ( site 1 ) to aid its diffusion ( site 2 ). NH 4 + enters the hydrophobic mouth of the NH 3 channel, where it is converted to H + and NH 3 ( site 3 ). This raises the local concentration of NH 3 close to 1000-fold and permits NH 3 to diffuse into the lumen of the MCD if this channel is open. The gradient of NH3 secretion is enhanced by the low urine pH in the medullary collecting duct, caused by distal H secretion. Fluid, Electrolyte and Acid-Base Physiology, 2010

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