The urine anion gap concept in metabolic acidosis assumes that the major cations in urine are Na+, K+, and NH4+, and the major anion is Cl− (with urine pH < 6.5, virtually no HCO3− is present). Therefore, the urine anion gap will yield a negative value when NH4+ is being excreted. The absence of a urine anion gap or the existence of a positive value indicates a renal defect in NH4+ production and excretion.

Both RhBG and RhCG transport NH3. There is evidence that RhBG may also transport some NH4+.

The production, transport, and excretion of NH4+ by the nephron are illustrated in Figure 37.7. Glutamine is metabolized to NH4+ and HCO3− in the proximal tubule. The NH4+ is secreted into the lumen, and the HCO3− enters the blood. The secreted NH4+ is reabsorbed in Henle's loop, primarily by the thick ascending limb, and accumulates in the medullary interstitium. NH3 is secreted by the collecting duct via rhesus glycoproteins, and H+ secretion traps NH4+ in the lumen. For each molecule of NH4+ excreted in the urine, a molecule of "new" HCO3− is added back to the ECF. Carbonic anhydrase (CA) is involved in this process.

In the net, one new HCO3− is returned to the systemic circulation for each NH4+ excreted in the urine.

An important feature of the renal NH4+ system is that it is regulated by systemic acid-base balance. Cortisol levels increase with acidosis, as does angiotensin II secretion into the lumen of the proximal tubule. Both cortisol and angiotensin II stimulate ammoniagenesis (i.e., NH4+ production from glutamine). During systemic acidosis, the enzymes in the proximal tubule cell responsible for the metabolism of glutamine are stimulated. This involves the synthesis of new enzymes and requires several days for complete adaptation. With increased levels of these enzymes, NH4+ production is increased, allowing enhanced production of new HCO3−. On the other hand, glutamine metabolism is reduced with alkalosis. Acidosis also increases the abundance of RhBG and RhCG in the collecting duct, enhancing the ability to secrete NH4+.

The pH of the extracellular fluid (ECF) is maintained within a narrow range of 7.35–7.45.
TheconceptofurineaniongapduringametabolicacidosisassumesthatthemajorcationsinurineareNa+ ,K+ ,andNH4+ andthatthemajoranionisCl− (withurinepH< 6.5,virtuallynoHCO3− ispresent).AsaresulttheurineaniongapwillyieldanegativevaluewhenNH4+ isbeingexcreted.Indeed,theabsenceofaurineaniongaportheexistenceofapositivevalueindicatesarenaldefectinNH4+ productionandexcretion.
gBoth RhBG and RhCG transport NH3. There is some evidence that RhBG may also transport some NH4 + .
•Fig. 37.7 Production,transport,andexcretionofNH4+bythenephron.GlutamineismetabolizedtoNH4+andHCO3−intheproximaltubule.TheNH4+issecretedintothelumen,andtheHCO3−enterstheblood.ThesecretedNH4+isreabsorbedinHenle’sloop,primarilybythethickascendinglimb,andaccumulatesinthemedullaryinterstitium.NH3issecretedbythecollectingductviarhesusglycoproteins,andH+secretiontrapsNH4+inthelumen.ForeachmoleculeofNH4+excretedintheurine,amoleculeof“new”HCO3−isaddedbacktotheECF.CA,carbonicanhydrase.Tubular fluid Tubular fluid CO2 + H2O NH4 + NH4 + 2NH4 + NH4 + NH3 NH3 NH4 + NH4 + NH3 + H+ NH4 + NH4 + NH4 + NH4 + H˜NH3HCO3 – Blood Blood Na+ Na+ H+H+ Glutamine A= 2HCO3 – CA
In the net, one new HCO3 − is returned to the systemic circulation for each NH4 + excreted in the urine.
An important feature of the renal NH4 + system is that it is regulated by systemic acid-base balance. As already described, cortisol levels increase with acidosis, as does angiotensin II secretion into the lumen of the proximal tubule. Both cortisol and angiotensin II stimulate ammoniagenesis (i.e., NH4 + production from glutamine). During systemic acidosis, the enzymes in the proximal tubule cell responsible for metabolism of glutamine are stimulated. This involves synthesis of new enzyme and requires several days for complete adaptation. With increased levels of these enzymes, NH4 + production is increased, allowing enhanced production of new HCO3 − . Conversely, glutamine metabolism is reduced with alkalosis. Acidosis also increases the abundance of RhBG and RhCG in the collecting duct. Thus the ability to secrete NH4 + is also enhanced.
Response to Acid-Base Disorders
The pH of the ECF is maintained within a very narrow range (7.35–7.45).
Inspection of
Eq. 37.3 shows that the pH of hFor simplicity of presentation in this chapter, the value of 7.40 for body fluid pH is used as normal, even though the normal range is from 7.35 to 7.45. Similarly the normal range for PCO2 is 35 to 45 mm Hg. However, a PCO2 of 40 mm Hg is used as the normal value. Finally, a value of 24 mEq/L is considered a normal ECF [HCO3 −], even though the normal range is 22 to 28 mEq/L.