ACIDBASE BALANCE URINE BLOOD AIR H 2 PO 4 NH 4 HCO 3 KIDNEY H H HCO 3 CELLS Hb H LUNG H 2 CO 3 HHb CO 2 H 2 O ph = 7.4 [HCO 3 ] = 24 meq/l PCO 2 = 40 mm Hg CO 2
PRIMARY RENAL MECHANISMS INVOLVED IN ACIDBASE CONTROL Transport mechanisms that secrete protons into tubular fluid. Reabsorption of HCO 3. Secretion of HCO 3 by the collecting tubule. The buffer systems in tubular fluid that react with secreted protons. The manufacture and transport of ammonium. Whatever the nature of an acidbase disturbance, the response of these mechanisms leads to the formation and extraction from the plasma of a fluid with an excess or a deficit of acid. The primary result is a return of the proton concentration (ph) of the blood toward the normal level.
PROTON SECRETORY MECHANISMS NaH EXCHANGER PROTON ATPASE HK EXCHANGER H 3HCO 3 Na HCO 3 H ATP ADP HCO H 3 Cl ATP ADP K 1Na Cl K PROXIMAL TUBULE INTERCALATED CELLS
CONTROL OF PROTON SECRETION TUBULAR FLUID BUFFER CONC. HCO 3 p BLOOD P CO2 VENTILATION H SECRETION HCO REABSORPTION 3 ACID EXCRETION
CONTROL OF THE NaH EXCHANGER The NaH exchanger is gradientlimited. When the proton conc. in the lumen rises, protons begin to compete with Na for transport back into the cell. The buffer concentration in the lumen (primarily HCO3) controls the proton conc. Thus an increase in filtered HCO3 increases net proton secretion. Proton secretion is inhibited by plasma HCO3 via a receptor in the basolateral membrane. Proton secretion is stimulated by CO2 via a receptor in the basolateral membrane. H 2 O CO 2 3HCO H 3 1Na CO 2 HCO 3 Na The NaH exchanger is stimulated by Angiotensin II.
BUFFER REACTIONS IN TUBULAR FLUID H 2 O CO 2 H 3HCO 3 1Na NH 3 CO 2 H 2 O H HCO 3 H 2 CO 3 H HPO 4 H 2 PO 4 H NH 3 NH 4 (1) (2) (3)
CONTROL OF HCO 3 REABSORPTION AND EXCRETION PLASMA HCO 3 CONCENTRATION TUBULAR FLUID [HCO 3 ] H SECRETION CO 2 HCO 3 SECRETION HCO 3 EXCRETION HCO 3 REABSORPTION
BICARBONATE REABSORPTION FILTERED REABSORBED 50 40 30 EXCRETED HCO3, meq / min 20 10 0 0 10 20 30 40 50 60 PLASMA HCO 3, meq / L
BICARBONATE REABSORPTION HCO 3, meq / min 50 40 30 20 10 FILTERED REABSORBED EXCRETED P CO2 60 mm Hg 40 40 60 0 0 10 20 30 40 50 60 PLASMA HCO 3, meq / L
CONTROL OF ACID EXCRETION PLASMA [HCO 3 ] _ BLOOD P CO2 TUBULAR FLUID [H ] TUBULAR FLUID NONHCO 3 BUFFERS ACID TITRATION ACID EXCRETION
BUFFER REACTIONS IN TUBULAR FLUID CO 2 CO 2 H 2 O H HCO 3 H 2 CO 3 (1) CO 2 H H HPO 4 H 2 PO 4 (2) HCO 3 H NH 3 NH 4 (3) NH 3 HCO 3
AMMONIUM PRODUCTION Glutamine is the major precursor of ammonium. It is deaminated to glutamate and the glutamate is deaminated to α ketoglutarate. Alinine and glycine are also precursors of ammonium. They can be transaminated to form glutamate. α NH 4 Na PDG = phosphate dependent glutaminase. GDH = glutamate dehydrogenase.
AMMONIUM TRANSPORT PROXIMAL TUBULE The pk of the reaction, NH 3 H NH 4, is 9.0. Thus, if cell ph is 7, the ratio NH 3 /NH 4 approximates 1/100. The cation is lipid insoluble and cannot diffuse across the cell membrane. However it is secreted into the tubular fluid by the Na H exchanger. The base form is uncharged and is lipidsoluble and can diffuse into the tubular fluid. There it is titrated by secreted protons to form NH 4. Na NH 4 NH 3 or H
AMMONIUM TRANSPORT THICK ASCENDING LIMB: NH 4, secreted by the proximal tubule, is reabsorbed by the talh into the medullary interstitial fluid. It can substitute for K for transport into the cell by the NaK2Cl cotransporter and then exit the cell via a basolateral K channel. Once in the medullary ISF it can be concentrated by the countercurrent mechanism in a fashion similar to Na. Na 2Cl Na K K or or NH 4 NH 4
COLLECTING TUBULE AMMONIUM TRANSPORT The NaK2Cl cotransporter, in the basolateral membrane of principal cells, can transport NH 4 into the cell from the medullary ISF. The cation will then move through K channels into the tubular fluid. NH 3 will diffuse down a large chemical gradient from the medullary ISF into the tubular fluid where it is titrated by H to NH 4. Thus ammonium, produced and secreted by the proximal tubule, leaves the tubule in the talh and moves back into the tubular fluid in the collecting tubule. NH 3 K or NH 4 K NH 3 Na 2Cl K or NH 4 Na
CONTRIBUTION OF TUBULAR SEGMENTS TO URINE ACIDIFICATION PROXIMAL TUBULE: The NaH exchanger secretes protons at a fast rate but the gradientlimitation prevents it from reducing tubular fluid ph below 6.7. 80% of the filtered HCO 3 is reabsorbed here. Ammonium is secreted. Little titratable acid is formed. THICK ALH: Proton secretion by the NaH exchanger accounts for reabsorption of 15% of the filtered HCO 3. NH 4, secreted by the proximal tubule, is reabsorbed here into the medullary ISF and concentrated by the countercurrent mechanism. DISTAL AND COLLECTING TUBULES: The proton ATPases secrete at a slow rate but can lower tubular fluid ph to 4.5. Ammonium is secreted into the tubular fluid. Most of the excreted titratable acid is formed here.
ROLE OF CARBONIC ANHYDRASE CA catalyzes the reaction H 2 O CO 2 H 2 CO 3 in either direction, increasing the reaction rate by a factor of 10 4. Within tubular cells CA promotes dehydration of H 2 CO 3, providing protons for secretion. Inhibition of cellular CA may cause cell ph to rise and retard the secretion of protons. CA is also attached to the brush border of proximal tubular cells and is in contact with tubular fluid. There it promotes the dehydration of carbonic acid to H 2 O and CO 2. This removes protons from tubular fluid, promotes HCO 3 reabsorption and maintains a favorable gradient for proton secretion. Indirectly it promotes the reabsorption of Na and H 2 O. Inhibition of CA reduces HCO 3 reabsorption causing a form of metabolic acidosis. It causes diuresis because it inhibits not only HCO 3 reabsorption but also Na and H 2 O reabsorption. Inhibition of CA also stimulates K excretion. Chronic inhibition of CA may cause hypokalemia.
ROLE OF CARBONIC ANHYDRASE CO 2 CO 2 H 2 O H 2 CO 3 CA HCO 3 H CO 2 H 2 O CA H HCO 3 H 2 CO 3
RESPIRATORY ACIDOSIS URINE BLOOD AIR H 2 PO 4 NH 4 HCO 3 KIDNEY H H H HCO 3 CELLS Hb LUNG H 2 CO 3 HHb CO 2 H 2 O ph = 7.28 [HCO 3 ] = 27 meq/l PCO 2 = 60 mm Hg CO 2
RESPIRATORY ACIDOSIS 60 7.6 7.5 7.4 HCO3 meq/l 50 40 30 7.3 7.2 Renal compensation 7.1 20 Hypoventilation 10 20 30 40 50 60 70 80 90 pco2 mmhg
BICARBONATE REABSORPTION HCO 3, meq / min 50 40 30 20 10 FILTERED REABSORBED EXCRETED P CO2 60 mm Hg 40 40 60 0 0 10 20 30 40 50 60 PLASMA HCO 3, meq / L
RENAL COMPENSATION FOR RESPIRATORY ACIDOSIS The rise in PCO 2 stimulates proton secretion, causing the excretion of titratable acid and ammonium. Chronic respiratory acidosis stimulates ammonium production and additional excretion. The extraction of acid from the blood, or, in other words, the addition of alkali to the blood, causes the blood ph and [HCO 3 ] p to rise. Until the respiratory disorder is corrected, the [HCO 3 ] p will remain high, but the blood ph will be near normal.
METABOLIC ALKALOSIS URINE BLOOD AIR H H 2 PO 4 KIDNEY H H LUNG NH 4 HCO 3 HCO 3 CELLS Hb H 2 CO 3 HHb CO 2 H 2 O ph = 7.5 [HCO 3 ] = 34 meq/l PCO 2 = 47 mm Hg CO 2
METABOLIC ALKALOSIS 60 7.6 7.5 7.4 50 HCO3 meq/l 40 30 Respiratory compensation Renal correction 7.3 7.2 7.1 20 10 20 30 40 50 60 70 80 90 pco2 mmhg
BICARBONATE REABSORPTION FILTERED REABSORBED 50 40 30 EXCRETED HCO3, meq / min 20 10 0 0 10 20 30 40 50 60 PLASMA HCO 3, meq / L
METABOLIC ALKALOSIS The loss of acid or the addition of alkali drives blood ph and HCO 3 up. Respiratory compensation. The rise in blood ph causes hypoventilation, which raises the PCO2 causing the blood ph to drop and the blood HCO 3 to increase slightly. Renal correction. The rise in blood HCO 3 increases the excretion of alkali. The extraction of fluid with an excess of alkali from the blood reduces blood ph, removing the cause of the hypoventilation. The blood acidbase composition returns to normal.
MEASUREMENT OF RENAL REACTION TO ACIDBASE IMBALANCE HCO 3 reabsorption, T HCO3 = P HCO3 GFR U HCO3 V Titratable acid excretion, U TA V = amount of OH added/ml urine x V Ammonium excretion. U NH4 V: Since the pk of ammonium is so high, little of it is titrated in the measurement of TA. Its concentration in the urine must be measured separately. Acid excretion rate = U TA V U NH4 V. Net acid excretion rate = U TA V U NH4 V U HCO3 V
RELATIONSHIP TO SALT AND WATER REABSORPTION A close interdependence exists between the regulation of acidbase balance and the regulation of salt and water balance. Changes in GFR and tubular reabsorption of salt and water affect HCO 3 reabsorption and acid excretion. Angiotensin II stimulates the NaH exchanger in the proximal tubule. Aldosterone stimulates proton secretion in the collecting tubule. ECF volume expansion reduces salt, water and HCO 3 reabsorption retarding the response to acidosis. ECF volume contraction increases salt, water and HCO 3 reabsorption, retarding the response to alkalosis. Examples: Vomiting causes ECF volume contraction and alkalosis. The kidney s ability to respond to the alkalosis is retarded until ECF volume is restored. Diarrhea causes metabolic acidosis and ECF volume contraction. The renal response to the volume contraction may enhance the response to the acidosis.
RENAL TUBULAR ACIDOSIS RTA is characterized by hyperchloremic metabolic acidosis that occurs as a result of a defect in urinary acidification. Proximal tubular RTAs: Fanconi syndrome is a result of a generalized disorder in proximal tubular function. The RTA is accompanied by glycosuria, aminoaciduria, phosphaturia and hypercitraturia. It may be due to depletion of intracellular ATP causing inhibition of the primary pump, NaKATPase. A second type of proximal RTA may be the result of depolarization of tubular cells inhibiting the bicarbonate extrusion mechanism in the basolateral membrane. An autosomal recessive proximal RTA has been identified and this is caused by mutation of the gene encoding the Na3HCO3 transporter.
RENAL TUBULAR ACIDOSIS Distal tubular RTAs: Failure of the distal nephron to lower urine ph below 5.5 in the presence of acidemia is due to the inability of the tubule to generate or maintain a normal ph gradient. Ammonium excretion rates are also low. Mutations in the acidbase transporters, HATPase, HKATPase and the ClHCO3 exchanger are among the causes of distal RTA.