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Thenarrow physiologic window for H+ concentration demonstrates the necessity for tight control of pH at all times.Because acid balance is critical for controlling ECF pH, thedaily entry of H+ into the ECF must equal the losses. Net gainof H+ can occur from ingestion of acid contained infoods (acidic drinks, proteins), cell and protein metabolism,hypoventilation, and diarrhea (loss of HCO3− results in gainin H+, described later).
Net losses of acid can result fromhyperventilation, vomiting, and of course urinary acid excretion. Under normal conditions, the daily gain of acid fromnormal metabolism (sulfuric acid, phosphoric acid, keto acids,etc.) and diet (proteins) will be equaled by acid excreted inthe urine. CO2 is a volatile acid and can be excreted by thelungs, but when it is in the blood it is dissolved, and contributes to the overall acid pool. A general scheme is illustratedin Figure 20.1.In general, we ingest and produce ∼40 to 80 millimoles (mM)of acid each day.
This is a huge amount compared with the∼40 nanomolar level (at pH 7.4) that is maintained in the ECF.This excess acid must be:■■Buffered, to prevent a fall in pH to below physiologiclevels (e.g., below 7.35).Excreted in the urine, which is the job of the kidneys.Buffering of AcidThe body handles excess acid using intracellular and extracellular buffers, in a continuous regulatory “dance,” escortingacid in and out of cells and through the blood to the kidneysfor excretion.Extracellular BufferingBicarbonate (HCO3−) is the major ECF buffer, available forconsuming free H+ through the following reaction:←CAHCO3 H → H2CO3 ↔ CO2 H2OThe carbonic acid can be converted to CO2 and H2O, in thepresence of carbonic anhydrase (CA).
This occurs in ECF andtissues, allowing diffusion of CO2 and H2O into and out oftissues. CO2 does not normally contribute to the net gain inacid (because the H+ gained in the above reaction is utilized,as water is formed in the lungs when the CO2 is blown offduring respiration). However, CO2 does contribute to the netacid gain during hypoventilation.As described in Chapter 15, the Henderson-Hasselbalch equation describes the relation between acid–base status and pHas:pH = 6.1 + log[base/acid]where the base is plasma bicarbonate (normally ∼24 mM/Lof ECF), and acid is the PCO2 × 0.03 (solubility constant)(normally 40 mm Hg × 0.03 = 1.2 mM/L of ECF).
And thus,under normal conditions,pH = 6.1 + log[24/1.2]pH = 7.4The kidneys control the amount of base (free bicarbonate) inthe ECF. This is accomplished by generating new bicarbonate,or excreting excess bicarbonate (in alkalosis). Although theamount of acid is also controlled by urinary acid excretion, inacidosis and alkalosis respiration can also regulate ECF acid.ECF phosphates and proteins also contribute to the buffering,but to a very small extent.What makes a good buffer? Good buffers have a pK thatis close to the physiologic pH of 7.4. In the ECF, the bestbuffer would be phosphate (HPO42−), which has a pK of 6.8(which at a pH of 7.4 results in a base to acid ratio of 4 : 1[HPO42−: H2PO4−]). However, there is relatively little phosphatein the ECF (∼1 mM/L), so it is not an effective ECF buffer.Instead, bicarbonate (pK = 6.1 and base to acid ratio is 20 : 1[HCO3−: H2CO3] at pH of 7.4) is the main ECF buffer, becauseof its high ECF concentration (∼24 mEq/L).
The large amountof free bicarbonate allows ready buffering of additional acidload.232Renal PhysiologyLungs“Acid Load”AcidintakeCellH2O + CO2Nonvolatileacid (HA)Volatile acid+ NaHCO3NaAThe kidneys generate new HCO3– to replenishHCO3– lost during titration of acid loadKidneysNH4A + acidFigure 20.1 General Scheme for Eliminating Excess Acid New acid is added daily from dietand metabolism and must be buffered (primarily by ECF bicarbonate), and then excreted in the urine.Intracellular BufferingAlthough phosphates offer minor buffering in the ECF, whenneeded they provide major buffering capacity within the cells,because of their high concentration. In addition, cellular proteins contribute to the buffering process.
Movement of H+into and out of cells occurs through cation exchange (H+/K+and Na+/H+ antiporters). The buffering process minimizes theeffects of generated and ingested acid on pH of the ECF andallows shuttling of acid to the kidneys, where it can beexcreted.HCO3- AND H+ HANDLING THROUGH THERENAL TUBULEHCO3As previously described, the process of bicarbonate reabsorption occurs in the proximal tubule, thick ascending limb ofHenle (TALH), and collecting duct and is dependent on thesecretion of H+ into the tubular lumen (see Fig. 17.3). Thiscycle effectively reclaims 100% of the filtered bicarbonate backinto the ECF, and under normal conditions there is no urinaryexcretion of bicarbonate.upper right panel). These cells have lumenal H+ ATPase pumpsand actively secrete H+ into the tubular fluid.
One of thepumps is the H+/K+ pump, discussed in Chapter 17, whichcontributes to net potassium reabsorption during potassiumdepletion. The H+/K+ ATPase is aldosterone-sensitive. Thebasolateral membranes have HCO3−/Cl− exchangers thattransport HCO3− into the interstitium, from which it is entersthe blood. Excess acid secreted along the nephron must bebuffered (to allow continued secretion of H+) and excreted.Factors that can regulate H+ secretion in the nephron are givenin Table 20.1.RENAL MECHANISMS CONTRIBUTING TO NETACID EXCRETIONThe ingested/generated acid load is always buffered in theplasma and is then dissociated from the buffers in the kidneysin the process of bicarbonate metabolism. The free H+ issecreted into the tubular lumen (in PT, TALH, CD), where itis incorporated into either phosphates (to become a titratableacid), or ammonia (to become ammonium).
This buffers theacid controlling urine pH.The exception to this occurs in alkalosis, when acid–basebalance depends on the removal of HCO3−. This is accomplished in the collecting ducts (CD), where the b-intercalatedcells have the ability to secrete HCO3− into the tubule forexcretion, via HCO3−/Cl− antiporters. Again, this transporteris only active during alkalosis, when its activation results inHCO3− loss and H+ accumulation.A key concept is that a new bicarbonate ion is generatedfor every H+ ion that is excreted, and this is always in a 1 : 1ratio (1 HCO3− reabsorbed to 1 H+ excreted).
This occursbecause both the secretion of H+ into the renal tubule andexcretion of ammonium (NH4+) result in HCO3− reabsorption(Fig. 20.2). If the secreted H+ ends up being excreted as atitratable acid or ammonium, the amount excreted is directlyequated with generation of new bicarbonate.H+Production of Titratable AcidsH+ is secreted into distal segments of the nephron in excess offiltered bicarbonate, with significant secretion occurring fromthe a-intercalated cells of the collecting ducts (see Fig.
17.3,The primary form of titratable acid is phosphoric acid(H2PO4−). Remember, phosphate is a strong buffer (pK 6.8)but is not readily available in the ECF, because of its lowRegulation of Acid–Base Balance by the KidneysTable 20.1Factors Influencing H+ Secretion bythe NephronFactorPrincipal Site of ActionINCREASED H+ SECRETION—PRIMARY↓HCO3− concentration (↓pH)Entire nephron↑Arterial PCO2Entire nephronINCREASED H+ SECRETION—SECONDARY↑Filtered load of HCO3−Proximal tubule↓ECF volumeProximal tubule↑Angiotensin IIProximal tubule↑AldosteroneCollecting ductHypokalemiaProximal tubuleDECREASED H+ SECRETION—PRIMARY↑HCO3− concentration (↑pH)Entire nephron↓Arterial PCO2Entire nephronDECREASED H+ SECRETION—SECONDARY↓Filtered load of HCO3−Proximal tubule↑ECF volumeProximal tubule↓AldosteroneCollecting ductHyperkalemiaProximal tubule(Reprinted with permission from Hansen J: Netter’s Atlas of HumanPhysiology, Philadelphia, Elsevier, 2002.)concentration (∼1 mM/L). However, in the tubular fluid, theamount of filtered phosphate (FLPi) is significant (FLPi =1 mM/L × ∼140 L/day (GFR) = ∼140 mM Pi/day), and part ofthis can be used for buffering and excreting H+ (bicarbonatecannot be used, because it is completely reabsorbed).
Theamount of phosphate available to form titratable acid dependson (1) the amount of basic phosphate (HPO42−) available tobind with H+, and (2) the renal handling of phosphate.■Phosphate buffering: According to the HendersonHasselbalch equation, at a blood pH of 7.4, there will be4 times the amount of base (HPO42−) to acid (H2PO4−),and this base is available for buffering excess H+. Thus,the ∼140 mM/day of filtered phosphate includes about116 mM/day of HPO42− that could be used as buffer—however, not all of this is available because of the tubularhandling of phosphate.■233Renal handling of phosphate: In the normal adult, ∼75%of the filtered phosphate is reabsorbed and thereforeunavailable for generating titratable acid.
Thus only 25%of the filtered HPO42− can be used, or ∼29 mM/day(116 mM/day × 0.25 = 29 mM/day).Formation of titratable acids occurs in the CDs at the αintercalated cells. At this point of the nephron, phosphatereabsorption is complete and the final reabsorption of HCO3−is occurring. Thus, the excess H+ that is actively secreted canbind to the HPO42−, creating the titratable acid H2PO4−, whichis then excreted. Under normal conditions, titratable acidswill be the main source of acid excretion, but their maximalrate of excretion is fixed because titratable acid formationdepends on the amount of phosphate reabsorption occurring,and this is not enough to eliminate the daily acid load. Theremaining acid is buffered by NH3, and when the acid loadincreases, ammoniagenesis will be further stimulated to handlethe load.AmmoniagenesisThe proximal tubule cells are capable of producing ammoniafrom glutamine, extracted from the tubular fluid as well as peritubular capillary blood.
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