Renal Tubular Acidosis: The Clinical Entity

Abstract

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 de