The secretion of acid from the blood to the lumen—whether for reabsorption of filtered , formation of titratable acid, or excretion—shares three steps: (1) transport of H+ (derived from H2O) from tubule cell to lumen, which leaves behind intracellular OH−; (2) conversion of intracellular OH− to , catalyzed by CA; and (3) transport of newly formed from tubule cell to blood. In addition, because the buffering power of filtered buffers is not high enough for these buffers to accept sufficient luminal H+, the adequate formation of new requires that the kidney generate buffer de novo. This buffer is NH3.
H+ moves across the apical membrane from tubule cell to lumen by Na-H exchange, electrogenic H pumping, and K-H pumping
Although the kidney could, in principle, acidify the tubule fluid either by secreting H+ or by reabsorbing OH− or , the secretion of H+ appears to be solely responsible for acidifying tubule fluid. At least three mechanisms can extrude H+ across the apical membrane; not all of these are present in any one cell.
Of the known NHE isoforms (see p. 124), NHE3 is particularly relevant for the kidney because it moves more H+ from tubule cell to lumen than any other transporter. N39-4 NHE3 is present not only throughout the proximal tubule (Fig. 39-4A, B) but also in the TAL (see Fig. 39-4C) and DCT.
FIGURE 39-4 Cell models of H+ secretion.
Contributed by Peter Aronson, Emile Boulpaep, Walter Boron
As described on page 124 of the text, several related genes encode NHEs. N5-20
In the renal proximal tubule, Na-H exchange is blocked by the removal of Na+ from the lumen. Although all NHEs are far less sensitive to amiloride than the ENaC epithelial Na+ channels (see pp. 758–759 and Fig. 35-4D), the apical NHE3 isoform in the proximal tubule is even less amiloride sensitive than the ubiquitous or “housekeeping” NHE1. The NHE1 isoform is present in the basolateral membranes of several nephron segments. The role of basolateral NHEs in acid-secreting nephron segments, such as the proximal tubule, is unclear; they may help regulate pHi independently of transepithelial H+ secretion.
Given a 10 : 1 concentration gradient for Na+ from the proximal tubule lumen to the cell interior, a maximal pH gradient of 1 pH unit can be achieved by this gradient. Indeed, the late proximal tubule may have a luminal pH as low as ~6.4.
The NHE2 isoform is present at the apical membrane of the DCT, where it may participate in the apical step of H+ secretion.
The apical NHE3 secretes H+ in exchange for luminal Na+. Because a steep lumen-to-cell Na+ gradient drives this exchange process (see p. 115), apical H+ secretion ultimately depends on the activity of the basolateral Na-K pump.
The carboxyl termini of the NHEs have phosphorylation sites for various protein kinases. For example, protein kinase A (PKA) phosphorylates apical NHE in the proximal tubule, inhibiting it. Both parathyroid hormone and dopamine inhibit NHE3 via PKA.
Electrogenic H Pump
A second mechanism for apical H+ secretion by tubule cells is the electrogenic H pump, a vacuolar-type ATPase (see pp. 118–119). The ATP-driven H pump can establish steep transepithelial H+ concentration gradients, thus lowering the urine pH to ~4.0 to 5.0. In contrast, NHE3, which depends on the 10-fold Na+ gradient across the apical membrane, cannot generate an H+ gradient in excess of ~1 pH unit.
The apical electrogenic H pumps are located mainly in a subpopulation of intercalated cells (α cells) of the CNT, ICT, and cortical collecting tubule (CCT) and in cells of the IMCD and outer medullary collecting duct (OMCD; Fig. 39-4D). However, H pumps are also present in the apical membrane of the proximal tubule (see Fig. 39-4A, B), the TAL (see Fig. 39-4C), and the DCT. In addition, an electrogenic H pump is also present in the basolateral membrane of β-intercalated cells. N39-5 Mutations in genes encoding subunits of this H pump cause a metabolic acidosis (see p. 635) in the blood—a distal renal tubular acidosis (dRTA).
The β-Intercalated Cell
Contributed by Walter Boron, Peter Aronson, Emile Boulpaep
Electrogenic H pumps are present in β-intercalated cells (see Fig. 39-9B), which, to a first approximation, are backward α-intercalated cells (see Fig. 39-4D). We discuss β-intercalated cells (β-ICs) in the text on page 834.
In β-ICs, the electrogenic H pump is present in the basolateral membrane, and the Cl-HCO3 exchanger is in the apical membrane. Thus, unlike the α-ICs, which engage in net reabsorption, the β-ICs engage in net secretion.
An interesting difference between the α-ICs and the β-ICs is that in the α cells, the Cl-HCO3 exchanger is a variant of AE1 (the Cl-HCO3 exchanger in red blood cells, and a member of the SLC4 family), whereas in the β cells the Cl-HCO3 exchanger is molecularly quite different, being a member of the SLC26 family.
In addition to the switch from α-IC to β-IC, secretion can also be stimulated by increased luminal delivery of Cl−, which promotes the exchange of luminal Cl− for intracellular via the apical Cl-HCO3 exchanger.
A molecule by the name of hensin controls the conversion from β- to α-intercalated cells. Genetic deletion of hensin in the tubule causes a distal renal tubular acidosis (dRTA) because the mice secrete inappropriately and therefore become deficient in the blood.
Al-Awqati Q. 2007 Homer W. Smith Award: Control of terminal differentiation in epithelia. J Am Soc Nephrol. 2008;19:443–449.
The regulation of the apical H pump involves several mechanisms. First, the transepithelial electrical potential may modulate the H pump rate. For instance, aldosterone induces increased apical Na+ uptake by the principal cells in the CCT (see pp. 765–766), thus causing an increase in the lumen-negative potential, which in turn stimulates the H pump. Second, aldosterone stimulates the H pump independently of changes in voltage. Third, acidosis increases the recruitment and targeting of pump molecules to the apical membranes of α-intercalated cells in the CNT, ICT and CCT, whereas alkalosis has the opposite effect.
H-K Exchange Pump
A third type of H+-secretory mechanism is present in the ICT, the CCT, and the OMCD (see Fig. 39-4D): an electroneutral H-K pump (see pp. 117–118) that is related to the Na-K pump. Several isoforms of the H-K pump are present in the kidney and exhibit differential sensitivities to inhibition by drugs such as omeprazole, SCH-28080, and ouabain. The H-K pump probably does not contribute significantly to acid secretion under normal conditions. However, K+ depletion (see p. 803) induces expression of the H-K pump, which retrieves luminal K+ and, as a side effect, enhances H+ secretion. This H+ secretion contributes to the metabolic alkalosis often observed in patients with hypokalemia—hypokalemic metabolic alkalosis.
CAs in the lumen and cytosol stimulate H+ secretion by accelerating the interconversion of CO2 and
The CAs N18-3 play an important role in renal acidification by catalyzing the interconversion of CO2 to . Inhibition of CAs by sulfonamides, such as acetazolamide, profoundly slows acid secretion. CAs may act at three distinct sites of acid-secreting tubule cells (see Fig. 39-4): the extracellular face of the apical membrane, the cytoplasm, and the extracellular face of the basolateral membrane. Two CAs are especially important for tubule cells. The soluble CA II is present in the cytoplasm, whereas CA IV is coupled via a GPI linkage (see p. 13) to the outside of the apical and basolateral membranes, predominantly in proximal-tubule cells.
Apical CA (CA IV)
In the absence of apical CA, the H+ secreted accumulates in the lumen, and Na-H exchange and H+ secretion are inhibited. By promoting the conversion of luminal to CO2 plus OH−, apical CA prevents the lumen from becoming overly acidic and thus substantially relieves this inhibition. Thus, CA promotes high rates of reabsorption along the early proximal tubule (see Fig. 39-4A).
In the distal nephron (see Fig. 39-4D), H+ secretion is less dependent on luminal CA than it is in the early proximal tubule for two reasons. First, the H+ secretion rate is lower than that in the proximal tubule. Thus, the uncatalyzed conversion of luminal H+ and to CO2 and H2O can more easily keep up with the lower H+ secretion rate. Second, in the collecting tubules and ducts the electrogenic H pump can extrude H+ against a very high gradient. Therefore, even in the absence of CA, the collecting ducts can raise luminal [H+] substantially, thereby accelerating the uncatalyzed reaction by mass action.
Cytoplasmic CA (CA II)
Cytoplasmic CA accelerates the conversion of intracellular CO2 and OH− to (see Fig. 39-4). As a result, CA II increases the supply of H+ for apical H+ extrusion and the supply of for the basolateral exit step. In the CNT, ICT, and CCT, the intercalated cells (which engage in acid-base transport) contain CA II, whereas the principal cells do not.
Basolateral CA (CA IV and CA XII)
The role played by basolateral CA IV and CA XII (an integral membrane protein with an extracellular catalytic domain) is not yet understood. N39-6
Carbonic Anhydrase at the Basolateral Membrane
Contributed by Walter Boron
Although it has been known for years that carbonic anhydrases (CAs) are present at the basolateral membrane of the proximal tubule (CA IV, CA XII), only recently has research begun to shed light on the significance of this observation. Two distinct classes of CAs are present near or at the basolateral membrane: (1) the cytosolic or soluble CA II, and (2) one or more membrane-bound CAs (e.g., CA IV, CA XII) with the catalytic domain facing the interstitial fluid. Renal CA XIV is abundant in rodents but is virtually undetectable in human and rabbit kidneys. The role of CA XIV in rodents may be an adaptation to the relatively low activity of rodent CA IV, owing to a G63Q substitution.
According to several reports, the soluble CA II binds reversibly to a site on the cytosolic carboxyl termini of certain transporters in the SLC4 family. Among these is the electrogenic Na/HCO3cotransporter NBCe1, which is responsible for the vast majority of efflux across the basolateral membrane of the proximal tubule (see Fig. 39-4A). According to one viewpoint, the function of the bound CA II is to provide as a substrate for the NBCe1 to export to the basolateral side of the tubule cell according to the reaction
Published data are consistent with the hypothesis that bound—but not free—CA II increases transport.
According to an alternate view that is emerging from the laboratory of Walter Boron, the role of CA II is very different. Preliminary data suggest that NBCe1 transports . Thus, when operating with an apparent Na+: stoichiometry of 1 : 3, as it appears to do in the proximal tubule, NBCe1 might actually transport 1 Na+, 1 , and 1 out of the cell across the basolateral membrane. You might imagine that 1 Na+ and 3 ions approach the basolateral membrane from the bulk cytosol. NBCe1 directly extrudes the Na+ and 1 . The second dissociates to provide the that NBCe1 will export:
The third , in a reaction catalyzed by CA II, produces an OH−,
and this OH− neutralizes the newly formed H+:
As a result, NBCe1 would export 1 Na+, 1 , and 1 . Of the original 3 ions that approached the basolateral membrane, 1 carbon atom, 2 hydrogen atoms, and 3 oxygen atoms would be left behind in the cytosol in the form of CO2 + H2O. According to the alternate view proposed by the Boron laboratory, the CO2 and H2O would exit across the basolateral membrane via another route. Also according to the alternate view, the role of the bound CA II would be to buffer the H+ ions that accumulate on the intracellular side of the membrane as forms from . Preliminary data from the Boron laboratory indicate that the presence of CA II does not stimulate the electrical current carried by NBCe1, at least as expressed in Xenopus oocytes.
According to the classical view, the role of CAs that face the basolateral ECF would be to consume the exported by NBCe1 according to the following reaction:
According to this view, in consuming the newly exported , the CA would stimulate the NBCe1.
According to the alternate hypothesis put forward by the Boron laboratory, the role of these extracellular CAs is just the opposite of that of the cytoplasmic CA II. Recall that this hypothesis proposes that NBCe1 directly exports 1 Na+, 1 , and 1 , and that 1 CO2 and 1 H2O exit by a parallel route. The extracellular CA would assist in the reassembly of 1 CO2, 1 H2O, and 1 to form 2 ions, which would then diffuse away from the membrane into the bulk ECF. Indeed, preliminary data show that expressing CA IV on the surface of a Xenopus oocyte greatly reduces the magnitude of the alkalinization produced as NBCe1 exports “” from the cell. Moreover, blocking the CA IV with acetazolamide increases the magnitude of the alkalinization by more than twofold. Finally, preliminary data show that blockade of the CA IV has virtually no effect on the current carried by NBCe1. Thus, it may be that the role of the extracellular CA is not to stimulate NBCe1, but to minimize the size of pH changes on the extracellular surface of the cell.
Inhibition of CA
The administration of drugs that block CAs, such as acetazolamide, strongly inhibits reabsorption along the nephron, leading to the excretion of an alkaline urine. Because acetazolamide reduces the reabsorption of Na+, , and water, this drug is also a diuretic (i.e., it promotes urine output). N39-7 However, a small amount of H+ secretion and reabsorption remains despite the complete inhibition of CA. This remaining transport is related in part to the slow uncatalyzed hydration-dehydration reactions and in part to a buildup of luminal H2CO3, which may diffuse into the cell across the apical membrane (mimicking the uptake of CO2 and H2O).
Diuretic Action of the CA Inhibitor Acetazolamide
Contributed by Gerhard Giebisch, Erich Windhager
As described in Box 40-3 and in Table 40-3, the drug acetazolamide (a potent inhibitor of CAs) produces diuresis by inhibiting the component of proximal-tubule Na+ reabsorption that is coupled to reabsorption.
For further discussion of CAs, consult N18-3.
efflux across the basolateral membrane takes place by electrogenic Na/HCO3 cotransport and Cl-HCO3 exchange
The regulation of the intracellular pH of acid-secreting tubule cells requires that H+ secretion across the apical membrane be tightly linked to, and matched by, the extrusion of across the basolateral membrane. Two mechanisms are responsible for transport from the cell into the peritubular fluid: electrogenic Na/HCO3 cotransport and Cl-HCO3 exchange.
Electrogenic Na/HCO3 Cotransport
In proximal-tubule cells, the electrogenic Na/HCO3 cotransporter NBCe1 (see p. 122) is responsible for much of the transport across the basolateral membrane. NBCe1 (SLC4A4) is expressed at highest levels in the S1 portion of the proximal tubule (see Fig. 39-4A) and gradually becomes less abundant in the more distal proximal-tubule segments (see Fig. 39-4B). NBCe1 is a 1035–amino-acid protein with a molecular weight of ~130 kDa. 4,4′-Diisothiocyanostilbene-2,2′-disulfonate (DIDS), an inhibitor of most transporters, also inhibits NBCe1. Because, in proximal-tubule cells, this transporter usually transports three ions for each Na+ ion, the electrochemical driving forces cause it to carry these ions from cell to blood. Renal NBCe1 carries two net negative charges and is thus electrogenic. Human mutations that reduce either NBCe1 activity or NBCe1 targeting to the basolateral membrane cause a severe metabolic acidosis—proximal renal tubular acidosis (pRTA). N39-8
The Electrogenic Na/HCO3 Cotransporter NBCe1
Contributed by Walter Boron
NBCe1 is a member of the SLC4 family of solute transporters. It is believed that all of the family members have the same topology: (1) a large cytoplasmic N terminus (Nt) that comprises about 40% of the protein, (2) a large transmembrane domain (TMD) that includes 10 to 14 transmembrane segments (TMs) and comprises ~50% of the protein, and (3) a short cytoplasmic C terminus (Ct) that comprises ~10% of the protein.
The gene SLC4A4 encodes three known variants of NBCe1, which differ from one another at their extreme Nt and Ct. The proximal tubule expresses the variant NBCe1-A, which has a very high functional activity. The other variants—the more ubiquitous NBCe1-B and the “brain” form NBCe1-C—have a different Nt. This difference endows these transporters with a low functional activity—due to either reduced trafficking to the membrane or reduced intrinsic activity. However, a soluble protein called IRBIT appear to reverse this inhibition. The NBCe1-A variant in the proximal tubule, however, is the fast variant.
In the proximal tubule, NBCe1-A appears to operate with a stoichiometry of 1 Na+ for 3 ions. Thus, each transport event moves two negative charges out of the cell and thereby makes the basolateral membrane potential (Vbl) more positive. The reversal potential for NBCe1-A is very close to Vbl. Accordingly, cell depolarization inhibits Na/HCO3 efflux or can even reverse the direction of transport and cause basolateral Na/HCO3 uptake.
At least 10 naturally occurring human mutations of NBCe1 are known. From a molecular perspective, these mutations cause poor function or poor targeting to the appropriate plasma membrane (i.e., the basolateral membrane in the case of NBCe1-A in the proximal-tubule cell). From a clinical perspective, these naturally occurring mutations have a devastating effect on the patient, causing a severe pRTA and other problems that may—depending on the mutation—lead to short stature, mental retardation, and ocular deficits.
Boron WF, Boulpaep EL. Intracellular pH regulation in the renal proximal tubule of the salamander. Basolateral transport. J Gen Physiol. 1983;81:53–94.
Parker MD, Boron WF. The divergence, actions, roles, and relatives of sodium-coupled bicarbonate transporters. Physiol Rev. 2013;93:803–959.
Parker MD, Boron WF. Sodium-coupled bicarbonate transporters. Alpern RJ, Hebert SC. The Kidney. Academic Press: Burlington, MA; 2007:1481–1497.
Romero MF, Fulton CM, Boron WF. The SLC4 family of transporters. Pflugers Arch. 2004;477:495–509.
Romero MF, Hediger MA, Boulpaep EL, Boron WF. Expression cloning of the renal electrogenic Na/HCO3 cotransporter. Nature. 1997;387:409–413.
Toye AM, Parker MD, Daly CM, et al. The Human NBCe1-A mutant R881C, associated with proximal renal tubular acidosis, retains function but is mistargeted in polarized renal epithelia. Am J Physiol Cell Physiol. 2006;291:788–801.
Chronic metabolic and respiratory acidosis, hypokalemia, and hyperfiltration all increase NBCe1 activity. As would be expected, several factors cause parallel changes in the activities of the apical NHE3 and basolateral Na/HCO3 cotransporter, minimizing changes in cell pH and [Na+]. Thus, angiotensin II (ANG II) and protein kinase C (PKC) stimulate both transporters, whereas parathyroid hormone and PKA markedly inhibit both.
In the S3 segment of the proximal tubule, as well as in the TAL and collecting tubules and ducts, Cl-HCO3 exchangers participate in transepithelial acid-base transport. The AE1 anion exchanger (see pp. 124–125) is found in the basolateral membranes of α-intercalated cells of the CNT, the ICT, and the CCT (see Fig. 39-4D). Basolateral AE2 is present in the TAL (see Fig. 39-4C) and the DCT.
is synthesized by proximal tubules, partly reabsorbed in the loop of Henle, and secreted passively into papillary collecting ducts
As we saw in our discussion of the segmental handling of (see pp. 826–827 and Fig. 39-3B), the proximal tubule is the main site of renal synthesis, although almost all other tubule segments have the capacity to form . The proximal tubule forms largely from glutamine (Fig. 39-5A), which enters tubule cells both from luminal and peritubular fluid via Na+-coupled cotransporters. Inside the mitochondria, glutaminase splits glutamine into and glutamate, and then glutamate dehydrogenase splits the glutamate into α-KG and a second . Ammonium is a weak acid that can dissociate to form H+ and NH3. Because the pK of the equilibrium is ~9.2, the ratio is 1 : 100 at a pH of 7.2. Whereas the cationic does not rapidly cross most cell membranes, the neutral NH3readily diffuses through most, but not all, cell membranes via gas channels. N39-3 When NH3 diffuses from a relatively alkaline proximal-tubule or collecting-duct cell into the more acidic lumen, the NH3becomes “trapped” in the lumen after buffering the newly secreted H+ to form the relatively impermeant (see Fig. 39-5A). Not only does NH3 diffuse across the apical membrane, but the apical NHE3 directly secretes some into the proximal tubule lumen (with taking the place of H+).
FIGURE 39-5 Ammonium handling. B, In juxtamedullary nephrons, the secretion of into the tubule lumen of the tDLH occurs mainly in the outer portion of the medulla. In D, the three numbered boxes indicate the three fates of the reabsorbed by the TAL. GLUT, glucose transporter; NBC, Na/HCO3 cotransporter; PEP, phosphoenolpyruvate.
A second consequence of synthesis is that the byproduct α-KG participates in gluconeogenesis, which indirectly generates ions. As shown in Figure 39-5A, the metabolism of two glutamines generates four NH3 and two α-KG. Gluconeogenesis of these two α-KG, along with four H+, forms one glucose and four ions. Accordingly, for each secreted into the tubule lumen, the cell secretes one new into the peritubular fluid.
In juxtamedullary nephrons, which have long loops of Henle, the tDLH may both reabsorb and secrete NH3, with the secretion dominating. Tubule fluid may become alkaline along the tDLH, titrating to NH3 and promoting NH3 reabsorption. On the other hand, reabsorption of by the TAL (see following paragraph) creates a gradient favoring NH3 diffusion from the interstitium into the lumen of the tDLH. Modeling of these processes predicts net secretion of NH3 into the tDLH in the outer medulla (see Fig. 39-5D). In the thin ascending limb, reabsorption may occur by diffusion of into the interstitium.
In contrast to the earlier segments, the TAL reabsorbs (see Fig. 39-5C). Thus, much of the secreted by the proximal tubule and tDLH does not reach the DCT. Because the apical membrane of the TAL is unusual in having a very low NH3 permeability, the TAL takes up across the apical membrane by using two transport mechanisms, the Na/K/Cl cotransporter and the K+ channels. Indeed, inhibiting the Na/K/Cl cotransporter blocks a significant fraction of reabsorption, which suggests that can replace K+ on the cotransporter. Ammonium leaves the cell across the basolateral membrane—probably as NH3, via a gas channel, and as carried by the NHE—which leads to accumulation of in the renal medulla.
The that has accumulated in the interstitium of the medulla has three possible fates (see Fig. 39-5D). First, some dissociates into H+ and NH3, which then enters the lumen of the late proximal tubule and the early tDLH (see Fig. 39-5D). This NH3 probably diffuses across the aquaporin 1 (AQP1) water channel (see Chapter 5) that is present in both the basolateral and apical membranes of these tubules. Luminal H+then traps the NH3 as (see Fig. 39-5B). Thus, recycles between the proximal tubule/tDLH and the TAL.
Second, some of the interstitial dissociates into H+ and NH3, which then enters the lumen of the medullary collecting ducts (see Fig. 39-5D). NH3 diffuses into the cell across the basolateral membrane via the gas channels RhBG and RhCG, and then enters the lumen via RhCG, where the NH3 combines with secreted H+ to form (see Fig. 39-5E). In addition, the Na-K pump may carry (in place of K+) into cells of the medullary collecting ducts. To the extent that moves directly from the TAL to the medullary collecting duct, it engages in a bypass of the cortical portions of the distal nephron. This bypass prevents cortical portions of the distal nephron from losing NH3 by diffusion from the lumen into the cortical interstitium, and thus minimizes the entry of the toxic NH3 into the circulation.
Third, a small fraction of medullary enters the vasa recta. This washout returns the nitrogen to the systemic circulation for eventual detoxification by the liver. In the steady state, the buildup of in the medulla leads to a sharp increase in  along the corticomedullary axis.
Because the liver synthesizes glutamine (see p. 965), the main starting material for production in the kidney, hepatorenal interactions are important in the overall process of excretion (Fig. 39-6). The liver disposes of ~1000 mmol/day of amino groups during the catabolism of amino acids. Some of these amino groups become via deamination reactions, and some end up as amino groups on either glutamate or aspartate via transamination reactions.
FIGURE 39-6 Cooperation between the liver and kidney in excreting nitrogen derived from amino-acid breakdown. In this example, we assume a release of 940 mmol/day of amino groups, resulting in the urinary excretion of 450 mmol/day of urea (900 mmol/day of amino nitrogen) and 40 mmol/day of . The values in the boxes are approximations.
Of the ~1000 mmol/day of catabolized amino groups, the liver detoxifies ~95% by producing urea (see p. 965), which the kidneys excrete (see p. 770). One −NH2 in urea comes from an that had dissociated to form NH3 and H+, the other −NH2 comes from aspartate, and the C=O comes from (see Fig. 39-6). The net result is the generation of urea and—considering that the generated H+ consumes another —the consumption of two .
The liver detoxifies the remaining ~5% of catabolized amino groups by converting and glutamate to glutamine (see Fig. 39-6). This reaction does not generate acid-base equivalents. The proximal-tubule cells take up this hepatic glutamine and use it as the source of the that they secrete into the tubule lumen as they generate one new (see Fig. 39-5A).
Thus, the two hepatorenal mechanisms for disposing of catabolized amino groups have opposite effects on . For each catabolized amino group excreted as urea, the liver consumes the equivalent of one . For each catabolized amino group excreted as via the glutamine pathway, the proximal tubule produces one new (see Fig. 39-6). To the extent that the kidney excretes , the liver consumes less as it synthesizes urea (Box 39-1). N39-9
Renal Tubular Acidosis
Contributed by Mark D. Parker
Renal tubular acidosis (RTA) is a broad label applied to a group of disorders that compromise renal acid-base handling. RTA is characterized by a reduced ability to eliminate H+ in the urine or by wasting, both of which can result in a lowered plasma pH (i.e., metabolic acidosis) and, in children, severe impairment of physical and intellectual development. RTA can follow a more generalized disruption of renal function (e.g., as a side effect of medication, autoimmune disease, multiple myeloma) or can result from mutations in genes that encode renal acid-base–handling proteins. RTA is classified into four types, each of which has a different set of causes and clinical manifestations. In addition, we can define a fifth type of RTA that is associated with end-stage renal disease.
Type 1 or Distal RTA
Distal RTA (dRTA) results from defective H+ excretion by distal segments of the nephron. Consequently, dRTA patients cannot appropriately acidify their urine and may exhibit a metabolic acidosis. Genetic causes of dRTA include mutations in the Cl-HCO3 exchanger AE1 and in subunits of the H pump, both of which are key components of the H+-secretory machinery in α-intercalated cells (see Fig. 39-4D). In patients with incomplete dRTA, blood pH is unaffected because compensatory mechanisms (e.g., proximal-tubule function) remain intact; in these individuals, metabolic acidosis occurs only following an acid load. Manifestations of dRTA can include hypokalemia, kidney stones, hemolytic anemia (due to loss of AE1 function in red cells), and hearing loss (due to loss of H pump function in the cochlea).
Type 2 or Proximal RTA
Proximal RTA (pRTA) results from the inability of proximal-tubule cells to reabsorb filtered or to generate new . Consequently, pRTA patients exhibit a severe metabolic acidosis and a wasting of into the urine. Genetic defects in the Na/HCO3 cotransporter NBCe1 cause pRTA because of the key role of that protein in mediating movement into the bloodstream (see Fig. 39-4A). Other causes include Fanconi syndrome (e.g., due to multiple myeloma, lead poisoning) and acetazolamide toxicity. Manifestations of pRTA can include hypokalemia and—in children—developmental defects, including ocular problems and poor dentition (considered in part to be due to loss of NBCe1 function in the eye and enamel organ).
Type 3 RTA
Type 3 RTA is a rare combination of type 1 and type 2 RTAs and is associated with defects in CA II, a shared component of the acid-base–handling mechanisms in the distal and proximal tubules. Clinical manifestations include osteopetrosis due to loss of CA II function in osteoclasts (see p. 1056).
Type 4 or Hyperkalemic RTA (Hypoaldosteronism)
Hyperkalemic RTA is a mild form of acidosis caused by aldosterone insufficiency or renal insensitivity to aldosterone. Insufficient stimulation of mineralocorticoid receptors in α-intercalated cells reduces H+directly (see p. 835); insufficient stimulation of these receptors in principal cells reduces K+ secretion, leading to hyperkalemia, which causes metabolic acidosis by several mechanisms (see p. 835).
In end-stage renal disease, a loss of functional renal mass compromises total ammoniagenesis. N39-1
Treatments for RTA vary depending on the clinical signs in each case but generally focus on correcting the metabolic acidosis by administration of or citrate salts (oral base therapy). Additional therapies include administration of diuretics (e.g., hydrochlorothiazide) to stimulate renal H+ secretion.
Net Renal Ammonium Excretion
Contributed by Peter Aronson, Gerhard Giebisch
As noted in the text, one component of the “new ” created by the proximal tubule parallels the generation of in the proximal-tubule lumen. However, this generation of new is reversed to the extent that the reabsorbed by the TAL into the medullary interstitium is then picked up by the vasa recta and carried back to the liver for urea production (see Fig. 39-6). Thus, the resecretion of from the medullary interstitium into the collecting-duct lumen (for excretion into the urine) is crucial to optimize the efficiency of generation by the kidney and thus to balance net acid production.