Renal Tubular Acidosis

The term renal tubular acidosis (RTA) is applied to a group of transport defects in the reabsorption of bicarbonate (HCO3−), the excretion of hydrogen ion (H+), or both. This condition was first described in 1935 (1), confirmed as a renal tubular disorder in 1946 (2), and designated “renal tubular acidosis” in 1951 (3). The RTA syndromes are characterized by a relatively normal GFR and a metabolic acidosis accompanied by hyperchloremia and a normal plasma anion gap. In contrast, the term uremic acidosis is applied to patients with low GFR in whom metabolic acidosis is accompanied by normo- or hypochloremia and an increased plasma anion gap. Physiology of Renal Acidification The renal acid-base homeostasis may be broadly divided into two processes: (1) reabsorption of filtered HCO3−, which occurs fundamentally in the proximal convoluted tubule; and (2) excretion of fixed acids through the titration of urinary buffers and the excretion of ammonium, which takes place primarily in the distal nephron. Proximal HCO−3 Reabsorption The mechanisms for proximal reabsorption of approximately 80 to 90% of filtered HCO3− are displayed in Figure 1. The foremost processes occurring in this segment are H+ secretion at the luminal membrane via a specific Na+- H+ exchanger (NHE-3) and HCO3− transport at the basolateral membrane via a Na+- HCO3− cotransporter (NBC-1). In the proximal tubules, carbonic acid (H2CO3) is formed within the cell by the hydration of CO2, a reaction catalyzed by a soluble cytoplasmic carbonic anhydrase (CA II). The H2CO3 ionizes and the H+ is secreted in exchange for luminal Na+. This mechanism is electroneutral, driven by a lumen-to-cell Na+ gradient, stimulated by intracellular acidosis, and inhibited by high concentrations of amiloride. Bicarbonate generated within the cell leaves it across the basolateral membrane by passive 1 Na+- 3 HCO3− cotransport. The secreted H+ reacts with filtered bicarbonate to form luminal H2CO3, which quickly dissociates into CO2 and water by the luminal action of membrane-bound carbonic anhydrase (CA IV). Luminal CO2 can freely diffuse back into the cell to complete the reabsorption cycle. Both CA II and CA IV are markedly stimulated during chronic metabolic acidosis. A substantial fraction of proximal HCO3− reabsorption is mediated by vacuolar H+-ATPase. Also, about 20% of filtered HCO3− is reabsorbed by passive back-diffusion along the paracellular pathway.Figure 1.: Schematic model of HCO3 − reabsorption in proximal convoluted tubule. The processes occurring are H+ secretion at the luminal membrane via a specific Na+- H+ exchanger (NHE-3) and HCO3 − transport at the basolateral membrane via a 1 Na+-3 HCO3 − cotransporter (NBC-1). Cytoplasmic carbonic anhydrase II (CA II) and membrane-bound carbonic anhydrase IV (CA IV) are necessary to reabsorb HCO3 −.Proximal HCO3− reabsorption is influenced by luminal HCO3− concentration and flow rate, extracellular fluid volume, peritubular HCO3− concentration, and PCO2, Cl−, K+, Ca2+, phosphate, parathyroid hormome, glucocorticoids, α-adrenergic tone, and angiotensin II (4). Distal Urinary Acidification Urinary acidification takes place in the distal nephron by three related processes: (1) reclamation of the small fraction of filtered HCO3− that escapes reabsorption proximally (10 to 20%); (2) titration of divalent basic phosphate (HPO4=), which is converted to the monovalent acid form (H2PO4−) or titrable acid; and (3) accumulation of ammonia (NH3) intraluminally, which buffers H+ to form nondiffusible ammonium (NH4+). The thick ascending limb of Henle’s loop reabsorbs about 15% of the filtered HCO3− load by a mechanism similar to that present in the proximal tubule, i.e., through Na+-H+ apical exchange. It also participates in NH3 transport. Absorption of NH4+ in the apical membrane of the Henle’s loop occurs by substitution for K+ both in the Na+ K+ 2Cl− cotransport system and in the K+-H+ antiport system. The medullary thick ascending limb has a low permeability to NH3, limiting back-diffusion. A NH4+ medullary concentration gradient is generated and amplified by countercurrent multiplication through NH4+ secretion into the proximal tubule and possibly into the thin descending limb of the loop of Henle. The accumulation of NH3 in the medullary interstitium increases the driving force for diffusional entry of NH3 into the collecting tubule, a process facilitated by the high acidity of the tubular fluid at this level (5). Distal urinary acidification occurs mainly in the collecting tubules (6). In the cortical collecting tubule, the intercalated cells are involved in both H+ and HCO3− secretion, whereas the principal cells are in charge of Na+ reabsorption and K+ secretion. There are two populations of intercalated cells, which differ both functionally and structurally. The α cell is responsible for H+ secretion, and the β cell is responsible for HCO3− secretion. The cellular mechanisms involved in distal acidification are depicted in Figure 2. The main pump for luminal H+ secretion in the α type-intercalated cell is a vacuolar H+-ATPase but is also highly influenced by the luminal electronegativity caused by active Na+ transport taking place in the principal cells. A second ATPase, the H+K+-ATPase, is also involved in H+ secretion, but its physiologic role is probably more related to potassium than to acid-base homeostasis. Intracellularly formed HCO3− leaves the cell by an electroneutral mechanism involving Cl−-HCO3− exchange, facilitated by an anion exchanger (AE1 or band 3 protein).Figure 2.: Schematic model of H+ secretion in cortical collecting tubule. The main pump for luminal H+ secretion in the α type-intercalated cell is a vacuolar H+-ATPase. A H+,K+-ATPase is also involved in H+ secretion. Intracellularly formed HCO3 − leaves the cell via Cl−-HCO−3 exchange, facilitated by an anion exchanger (AE1). Cytoplasmic carbonic anhydrase II (CA II) is necessary to secrete H+.H+ secretion proceeds in the outer medullary collecting tubule, which is a unique segment that does not reabsorb Na+ or secrete K+ and the only function of which is the transport of H+. The medullary collecting tubule is lumen-positive, and H+ must be secreted against the electrochemical gradient via an electrogenic, Na+-independent process modulated by the vacuolar H+-ATPase. H+ secretion is not inhibited by agents that block Na+ transport, but it is influenced by aldosterone through a mechanism that is independent of Na+ delivery or reabsorption. The terminal part, the inner medullary collecting duct, also plays an important role in distal acidification. The cellular process involved in mediating H+ secretion appears to be similar to the process described in α-intercalated cells, but its quantitative importance in overall renal H+ secretion remains to be determined. All segments of the collecting tubule are very rich in cytosolic carbonic anhydrase II, but membrane-bound, luminal carbonic anhydrase IV is also present in both outer and inner segments of the medullary collecting duct. The luminal CA IV seems to play an important role for HCO3− absorption in this segment. Distal urinary acidification is influenced by blood pH and PCO2, distal Na+ transport and transepithelial potential difference, aldosterone, and K+. Aldosterone influences distal acidification through several mechanisms. First, it enhances Na+ transport in late distal and cortical collecting tubules and thereby increases the lumen-negative potential difference across epithelium, so favoring both H+ and K+ secretion. This action is first mediated by activation of preexisting epithelial Na+ channels (ENaC) and pumps (Na+,K+-ATPase) and subsequently mediated by increasing the overall transport capacity of the renal tubular cells. Aldosterone seems to be responsible of the specific localization of the ENaC in the apical membrane of principal cells of distal and cortical collecting tubules. Both early regulatory and late anabolic-type actions depend on the transcriptional regulation exerted by hormone-activated mineralocorticoid receptors (MR). However, the regulatory pathways that link the transcriptional action of aldosterone to these Na+ transport proteins is mediated by sgk (serum and glucocorticoid-regulated kinase) and other regulatory proteins (7). Aldosterone also enhances H+-ATPase activity in cortical and medullary collecting tubules, an effect that is independent of plasma K+ levels. However, the stimulation of H+,K+-ATPase also observed in states of aldosterone excess depends predominantly on the stimulus exerted by accompanying hypokalemia. Aldosterone also has an effect on NH4+ excretion by increasing NH3 synthesis, both as a direct action and as a consequence of simultaneous changes in K+ homeostasis. Classification of Renal Acidification Defects On clinical and pathophysiologic grounds, RTA has been separated into three main categories: proximal RTA or type 2; distal RTA or type 1; and hyperkalemic RTA or type 4. Each may occur in a varied number of hereditary or acquired etiologies (8). Recent advances in molecular biology of acid-base transporters have allowed a better knowledge of the hereditary syndromes (9–11). Proximal RTA (Type 2) Proximal RTA may occur as a primary and isolated entity (12–15) or be accompanied by other proximal tubular defects (Fanconi syndrome). It may also have a hereditary origin, be secondary to administration of drugs and toxins, or be associated with a number of varied diseases (Tables 1 and 2). Stunted growth is a prominent clinical feature in children. Rickets and osteomalacia are never observed unless hypophosphatemia is present as occurs in the Fanconi syndrome. Nephrocalcinosis and urolithiasis are also infrequent, even in situations in which hypercalciuria is present (16). Hypokalemia and related symptoms are also restricted to cases with the Fanconi syndrome.Table 1: Genetics of primary renal tubular acidosis (RTA)aTable 2: Causes of proximal RTA (type 2)Proximal RTA (type 2) is caused by an impairment of HCO3− reabsorption in the proximal tubule and is characterized by a decreased renal HCO3− threshold, which is normally situated between 22 mmol/L in infants and 26 mmol/L in older children and aduts. Distal acidification mechanisms are intact; when plasma HCO3− concentration diminishes to sufficiently low levels, these patients may lower urine pH below 5.5 and excrete adequate amounts of NH4+. However, when plasma HCO3− concentration is normalized by administration of alkali, the distal nephron is not capable of handling the large delivery of HCO3−. As a consequence, the urine is highly alkaline and contains a great fraction of the filtered load (>10 to 15%). This HCO3− wasting is a transient phenomenon, and a steady state is again maintained when plasma HCO3− concentration stabilizes in the acidemic range. It may occur as an isolated defect (e.g., mutations in the gene SLC4A4, encoding the cotransporter or more in with proximal tubular transport defects (e.g., in the of a Distal RTA (Type This type is caused by distal acidification and is characterized by the to lower urinary pH the stimulus of The secretion of NH4+ is secondary to this In HCO3− reabsorption is as a consequence of the urine a of may be present of the filtered The term distal RTA has been to patients with or urolithiasis but metabolic acidosis. these patients the a high of NH4+ excretion for excretion of titrable cases have been as a of for in of a with complete distal RTA In distal RTA is observed as a primary clinical impairment of and K+ of may to of chronic renal early in of the acidosis by administration may of normal of and of renal function distal RTA may be observed or with or (Tables 1 and distal RTA has been to be associated in several with mutations in the gene encoding the Cl−-HCO3− exchanger or band 3 important fraction of cases of or distal RTA There is great in the of to late have that patients with distal RTA and present mutations in the gene encoding the of H+-ATPase. or distal RTA is the primary also that this form may be caused by mutations in the gene encoding the of H+ In these patients may also the second of Causes of distal RTA (type distal RTA as a consequence of and with renal as and syndrome. chronic active and primary and chronic renal have also been to be associated with distal RTA distal RTA can when is a of the distal nephron to secrete H+ defect or distal or when capacity is but As mutations in encoding renal acid-base transporters have been as of The of acquired cases of distal RTA is but of renal patients with have the of H+-ATPase in the intercalated cells of the collecting However, in two patients with and hyperkalemic distal intercalated cells normally with H+-ATPase A function at the apical of intercalated cells has been also as a potential mechanism of but this remains highly this is more in K+ than in H+ homeostasis function secondary to has been to be the of the distal RTA present in The defects are caused by an to a lumen-to-cell H+ gradient to increased of secreted H+ as observed or an to or a distal lumen-negative transepithelial difference as observed in patients with distal Na+ transport cell or administration of and with distal RTA present with normo- or but when is a defect the associated impairment of K+ secretion to distal defect is caused by urinary NH4+ not caused by high distal nephron luminal pH but by low NH4+ delivery proximal tubule to medullary It may be observed in patients with or chronic of The of distal RTA has been to patients in whom urine pH is low during but present a low urine during alkaline as of a low of H+ secretion. this defect is described in with or with it may also be observed in children with primary distal RTA It is not patients have a and type of distal RTA or a Proximal and Distal RTA (Type In the between proximal and distal RTA is to of both In these is a in tubular reclamation of filtered HCO3−, in to a of proximal is also an to the urine of This type 3 may be observed as a transient in infants and children with primary distal RTA and does not a entity cases observed during the and probably in with as high It be that this of hereditary distal RTA has the two proximal and distal RTA is also observed as the of carbonic anhydrase II in the gene encoding this to an of renal tubular acidosis, and more than cases have been However, the of patients and the with of All clinical may be as secondary to carbonic anhydrase II in and may be by the of to secrete acid to Renal the of renal reabsorption of HCO3−, to low urine decreased NH4+ low difference in alkaline and high urinary of the of proximal and distal RTA RTA (Type The acidification defect is mainly caused by and is characterized by a normal to the urine an acid load associated to a acid excretion to very low of NH4+ Renal HCO3− reabsorption is at normal plasma HCO3− concentration, but is not of to an associated proximal RTA has to distal the of this the to lower urinary pH in to acidosis is the in NH3 is mainly caused by aldosterone or may also play important RTA a large number of hyperkalemic states and is observed in states of or isolated or in the of chronic renal (Tables 1 and Nephrocalcinosis and urolithiasis are in this and are only in uremic Causes of hyperkalemic RTA (type RTA of hereditary is observed in children with primary type 1. This entity is characterized by and metabolic acidosis in the of markedly plasma activity and aldosterone In the aldosterone is to the and is to mutations in the gene encoding the mineralocorticoid In the aldosterone is to and and is caused by mutations in the encoding of the three and of the epithelial Na+ A transient of and metabolic acidosis, clinical has been described in activity and aldosterone excretion normal or This entity has been and a of the renal form of type probably to a disorder in the number or function of mineralocorticoid This remains highly it does not the of type is an of metabolic acidosis, and plasma The of has been also to the of a tubular of in thick ascending Henle’s loop and early distal tubule, to K+ and H+ secretion. it has been that the basic is to mutations in the encoding the and which probably play important in homeostasis by increasing the and paracellular to In hyperkalemic RTA an acquired disorder that is observed in the of mineralocorticoid as a primary disorder or as secondary to in patients with to renal to and It is also in a number of renal diseases that are associated with to aldosterone and tubular K+ secretion. a great number of drugs may hyperkalemic of RTA In RTA be when metabolic acidosis is accompanied by hyperchloremia and a normal plasma anion − to in a of HCO3− and is not taking or of Proximal HCO3− Reabsorption HCO3− The basic for tubular reabsorption of HCO3− is the of of reabsorption and excretion at filtered This is by to of plasma HCO3− concentration and by concentrations of HCO3− and in blood and of reabsorption and excretion are against the of plasma HCO3−. The of the reabsorption is it a by The of the renal HCO3− necessary for the of a defect in tubular reabsorption of HCO3−. pH A for tubular handling of HCO3− of the of urine pH during the of or administration of the of urine pH to of plasma HCO3− an of patients in whom renal HCO3− is HCO3− at HCO3− The of a large for to of plasma HCO3− concentration at about 22 mmol/L and of a excretion at this plasma concentration or more than 15% of the filtered load is as for a proximal defect in tubular reabsorption of HCO3−. However, have that this the of a proximal defect even is HCO3− reabsorption may in the functionally distal tubule In a defect in proximal HCO3− reabsorption is better by HCO3− excretion when plasma HCO3− concentration is below normal levels. of Distal Urinary Acidification and pH and NH4+ The of urine pH is a basic in the of the mechanisms of distal urinary acidification. It be that urine pH only the activity in the urine of which is than of the of in the distal nephron. The pH be in a urinary A normally low urine pH does not a normal distal urinary acidification mechanism excretion of is NH4+ is a with stimulated may have a urine pH as high as a defect in acidification. The urine pH must be in with the urinary NH4+ to the distal acidification process The urinary Na+ concentration also be an urine pH may be associated with low Na+ excretion the of an defect in distal urinary acidification It be also that a high urine pH may be secondary to urinary with The urine anion an of urinary NH4+ excretion in patients with metabolic acidosis The is by the concentration of in the Na+ K+ − On a normal the amounts of and in the urine are small and the excretion of The is to the concentration of NH4+ the concentration of The excretion of these remains in the excretion of NH4+ during a state of metabolic acidosis must be accompanied by a in the excretion of the more as NH4+ excretion urine pH the of the in NH4+ excretion as HCO3− a It is important to that this is only when applied to situations of metabolic acidosis. this against it be The of the is when other (e.g., are present in the urine in increased amounts or when it contains (e.g., In these the of the urine may be − with of and also in the urine is the is not the urine is A of be of and ion the urine is highly as occurs a load of urine increases as a direct of distal H+ secretion. H+ reacts with luminal HCO3− to form carbonic acid acid in the medullary collecting to form CO2, which is in this of the of H2CO3 is also in the renal and to an that urine pH and HCO3− concentration and 80 the gradient be than in normal also markedly phosphate that urine pH is to the of the phosphate system a urine phosphate concentration normal a gradient K+ the action of aldosterone at the level of late distal and cortical collecting tubules it is the of the potassium concentration in the urine and and urine and plasma is situated in a hyperkalemic a that that the collecting is not to the and that potassium secretion is Urinary Urinary concentration the of the filtered load of not reabsorbed in the proximal tubule. As luminal pH acid reabsorption is a more alkaline urine increases the pH of the proximal tubular cell reabsorption is also urinary excretion is normal or high in proximal RTA and hyperkalemic but it is in distal in distal In the for urine excretion is to pH and NH4+ excretion are during metabolic acidosis or the administration of an but can also be during the of more the administration of Both and H+ and K+ secretion in the cortical collecting tubule by increasing distal Na+ delivery and a high luminal electronegativity in the distal nephron the simultaneous of distal H+ and K+ secretion The is very in clinical but it not be a for the a to the urine administration does not the of an acidification may be a of administration It be that the acidification effect of is taking place about to administration of the of the the is that it also in stimulation of the which is of importance in the of a with hyperkalemic RTA to a to RTA A for the of patients with RTA is in to clinical and in cases to the of the Also, the of the to between the of distal As between proximal and distal RTA can be quickly by the of the urine anion or a urine a with metabolic acidosis has a anion or an a or renal of HCO3− or a of an acid are the of proximal RTA is when the other have been of be in but is in children. A low urinary Na+ this of proximal RTA is by the of a low urine pH at low plasma HCO3− concentration and by the of a normal urine and a high urine HCO3− excretion at normal plasma HCO3− This a complete of other proximal tubular of a with metabolic acidosis and a urine anion gap. renal tubular urine excretion of PCO2, of of a urine a with metabolic acidosis has a anion or an below a defect in distal urinary acidification be The in the is to plasma K+ the plasma K+ is normal or the of an to lower urine pH below or the of distal This is by the of a low gradient or phosphate In primary distal RTA caused by an excretion of HCO3− at normal plasma HCO3− concentration not of the filtered A excretion the of an associated defect in HCO3− reabsorption. the for by and the of urinary excretion of and of a with metabolic acidosis and a urine anion gap. renal tubular urine excretion of PCO2, the of plasma K+ is even to the of the urine The of a urine pH than 5.5 the of a small group of patients with hyperkalemic distal RTA caused by a The for a distal in Na+ transport is in the urine pH is lower than the of hyperkalemic (type RTA is The of a of HCO3− wasting not the of proximal which is in these cases by the very low of NH4+ The of the of plasma of and aldosterone and of a and The of for RTA are not only to as as the but to fundamentally growth in children and to the of and the of chronic renal at The of is the administration of amounts of in the form of bicarbonate or The of for the urinary of HCO3− the of acid generated by the of proteins and the proximal the of is very large to to to the urinary of HCO3−, which takes place at normal HCO3− A of Na+ and K+ is It is important to the in along and is and so is relatively administration of a may be in the of but it may the hypokalemia. of proximal RTA depends on the in cases observed in the of the Fanconi syndrome. However, in children with isolated proximal RTA the tubular defect and can be at about 3 to of distal the is to adequate to H+ This is in children than in to H+ during the process of a of Na+ and K+ is The of of to In as as to of may be whereas amounts of about 3 to and 1 to are in children and can also be in an of is of the urinary of the hypercalciuria is urinary excretion remains and an urinary of phosphate of urinary and of are to the adequate of It is important to of the acidosis this of extracellular fluid and of the urinary distal RTA is a and be maintained is has been early in and amounts of are growth in children and the of at However, is to late or to renal may not be hyperkalemic and depends on the drugs be to may to of may also be in in with a loop as to the of extracellular fluid In to are also