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The ammonia can buffer H+ byforming ammonium (NH4+) that can ultimately be excreted inthe urine. A key aspect of this reaction is that the excretion ofNH4+ produces new HCO3− that is reabsorbed into the plasma.In the proximal tubular cells, the glutamine is hydrolyzedto produce glutamate and one NH3.
The glutamate is furthermetabolized to α-ketoglutarate, producing another NH3. Thetwo NH3 are immediately combined with two H+, formingtwo NH4+. Additional α-ketoglutarate metabolism yields twoHCO3−. Thus, a single glutamine generates two HCO3−, whichare reabsorbed as new HCO3−, and two NH4+, which aresecreted into the tubular fluid (see Fig. 20.2, upper right).The NH4+ produced in the proximal tubule is not directlyexcreted. Instead it is reabsorbed in place of K+ by the Na+K+-2Cl− transporters. The NH3 stays in the interstitial fluid,increasing the medullary interstitial concentration of NH3.The dissociated H+ is secreted into Henle’s loop in exchangefor Na+. The NH3 gradient promotes secretion of NH3 into thetubular lumen of the collecting ducts; NH3 immediately bindsfree H+ in the collecting ducts, re-forming NH4+ that is excretedin the urine (see Fig.
20.2, lower right).Net Acid ExcretionAcid balance is determined by the difference between acidintake and urinary excretion of acid. Under normal conditions, intake will equal excretion. Net acid excretion (NAE)describes the total amount of acid that is excreted in theurine:NAE = TA + NH4+ − HCO3−234Renal PhysiologyNet Acid Excretion (NAE) = (UTA x V) + (UNH4+ x V) + (UHCO3– x V)Titration of Urine BuffersProduction and Excretion of AmmoniumBloodLumenNormally 0(no net excretion)LumenBloodNa+Buffer+H+GlutamineH+HCO3–H+NH3H+-bufferCACO2 + H2O2NH4+NH3NH4+NH4+NH4+NH4+NH3Na+A–2HCO3–NH3NH3NH3NH4+NH3NH3+H+NH4+H+HCO3–H+CANH4+CO2 + H2ONH4+Figure 20.2 Renal Handling of Acid Excretion H+ is excreted as titratable acids (mainly phosphoricacids) and ammonium (NH4+).
With either mechanism, excretion of an H+ results in generation of a newHCO3− that enters into the blood.where TA is titratable acids. Under most conditions,urinary HCO3− is zero (all HCO3− is normally reabsorbed).However, when HCO3− appears in the urine, it impliesthat H+ was added to the ECF (recall the 1 : 1 relationshipbetween bicarbonate reabsorbed or excreted and H+ transported in the opposite direction). In the equation above,the HCO3− is subtracted from the TA and NH4+ to accountfor the newly accumulated acid.
HCO3− excretion isindicative of alkalosis or renal tubular acidosis, and in bothconditions, there is an equimolar gain of acid for theHCO3− excreted.Urine pHNormal urine pH varies between 4.4 and 8 according tothe acid–base status, with average values around 5.5 to 6.5.The minimal attainable urine pH is 4.4, which represents1000-fold greater concentration of H+ than the blood pH of7.4. This is the greatest concentration difference against whichthe H+ pumps can effectively secrete H+.
This maximal levelof urine acidity is only attained with severe metabolicacidosis.ACIDOSIS AND ALKALOSISWhen pH falls outside of the normal physiologic range, acidosis (pH less than 7.35) or alkalosis (pH greater than 7.45)results. A disturbance is designated as:■■Respiratory (acidosis or alkalosis) if it is caused byabnormal CO2, orMetabolic (acidosis or alkalosis), if the pH change isconsistent with the alteration in HCO3−.Regulation of Acid–Base Balance by the KidneysTable 20.2Sample Values for UncompensatedAcid–Base Imbalances■■pHPCO2 (mm Hg)HCO3- (mMor mEq/L)Primary respiratoryacidosis7.325024Primary metabolicacidosis7.324018Primary respiratoryalkalosis7.54Primary metabolicalkalosis7.542824■■34■■The acid–base status is assessed by examining the plasmavalues of pH, PCO2, and HCO3− (the arterial blood gases),which are the key components of the Henderson-Hasselbalchequation.
Under normal conditions in arterial blood, thesevalues will be:NormalpH7.4PCO2 (mm Hg)40HCO3− (mM)24When pH is altered, the primary disturbance can be identifiedby determining which component (PCO2 or HCO3−) is alteredin the direction consistent with the change in pH. IncreasedPCO2 or decreased HCO3− will produce respiratory and metabolic acidosis, respectively; decreased PCO2 or increasedHCO3− will produce respiratory and metabolic alkalosis,respectively (Table 20.2 and Fig. 20.3).In general, compensation for metabolic disturbances willinclude altered respiratory rate: hyperventilation to blow offexcess CO2 in acidosis, or hypoventilation to retain CO2 inalkalosis (discussed in Chapter 15).
Compensation for respiratory disturbances will include altered renal bicarbonate andacid handling. Metabolic compensation occurs over severalhours through the renal excretion of acid (in acidosis), orbicarbonate (in alkalosis), to return the pH toward normal.The examples in Table 20.2 represent uncompensated disturbances. The following paragraphs will focus mainly on metabolic disturbances.AcidosisAcidosis can result from either gain of acid or loss of bicarbonate.
Net acid gain can arise from either decreased respiration (increasing CO2), or from the accumulation of acids frommetabolic sources (metabolic acidosis) outlined in the following text:Keto acids, from β-oxidation of fatty acids, which occursduring starvation and poorly controlled diabetes.Phosphoric acid, in renal failure, as a result of the inability to excrete the acids due to low GFR.Lactic acid, which is released from damaged tissuesduring hypoxia or heart failure.Ingestion of substances such as antifreeze (ethyleneglycol) and Sterno® (containing methanol).Bicarbonate losses are always caused by metabolic disturbances and mainly occur as a result of:■40235Increased fecal elimination with prolonged diarrhea,because HCO3− is secreted as a buffer and is lost withother constituents of the chyme (including the HCO3−that is also secreted into the ileum and colon).Increased urinary excretion because of insufficientHCO3− reabsorption in the proximal tubule.Elevated H+ secretion into the collecting ducts—thiscauses HCO3− secretion from the β-intercalated cells ofthe collecting ducts to buffer the urine (distal renaltubular acidosis).Whether due to addition of acid or loss of bicarbonate, theresulting acid load must be buffered systemically and thenexcreted by the kidneys.
To compensate for acid gain, theplasma level of free bicarbonate falls as it forms H2CO3 tobuffer the free acid. When pH is under 7.35, respiration willincrease to “blow off” CO2 and reduce acid load. Chronically,the main compensation will occur in the kidneys—increasedacid secreted into the renal tubules will combine with phosphates and ammonia to form titratable acids and ammoniumfor excretion (see Fig. 20.2).Although there can be an immediate increase in titratableacids because some excess HPO42− is present, the ability toexcrete titratable acids is limited by the amount of phosphatereabsorbed.
The main urinary buffering of H+ is by ammonia(forming NH4+). Ammoniagenesis increases during acidosisover a period of hours to days, allowing a great increase inammonium excretion. The increase in NAE will increase pHtoward normal values, although in severe cases of diabeticketoacidosis, the kidneys may not be able to attain normal pHvalues until blood glucose is restored.ANION GAPThe anion gap is used to differentiate between acidosis resulting from acid gain and acidosis caused by bicarbonate loss.This diagnostic tool utilizes the fact that the only way to losebicarbonate is through HCO3−/Cl− exchangers located in theβ-intercalated cells of the collecting ducts and in the lowerGI tract.
Thus, if HCO3− is lost, Cl− is gained, and this isreflected in the plasma concentrations of these anions. Theanion gap (AG) is the difference in concentration between the236Renal PhysiologyRole of Lungs and Kidneys in Regulation of Acid–Base BalanceTissuesLungCO2Acid–basebalanceKidneyHCO⫺3HRespiratoryLung diseaseSedativesNeuromusculardisordersBrain damageAcidosisMetabolicAdds acid:DiabetesUremiaLacticacidosis⫺HCO 3CO2⫺HCO 3CO2Loses base:DiarrheaRespiratoryHyperventilationFeverAnxietyBrain disordersAlkalosisMetabolicAdds base:AlkaliingestionCO2HCO⫺3HCO3AlkalosisCO2Loses acid:DiureticsVomitingGastric suctionHCO⫺3Figure 20.3 Role of the Lungs and Kidneys in the Regulation of Acid–Base Balance Thisscheme illustrates the changes in acid and base status in primary respiratory and metabolic disturbances.Under normal conditions (upper panel), the acid–base status is in balance, with kidneys absorbing all filteredHCO3−, and the daily gain of acid excreted by the kidneys.
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