Renal Tubular Acidosis and Management Strategies: A Narrative Review

Abstract

Renal tubular acidosis (RTA) occurs when the kidneys are unable to maintain normal acid-base homeostasis because of tubular defects in acid excretion or bicarbonate ion reabsorption. Using illustrative clinical cases, this review describes the main types of RTA observed in clinical practice and provides an overview of their diagnosis and treatment. The three major forms of RTA are distal RTA (type 1; characterized by impaired acid excretion), proximal RTA (type 2; caused by defects in reabsorption of filtered bicarbonate), and hyperkalemic RTA (type 4; caused by abnormal excretion of acid and potassium in the collecting duct). Type 3 RTA is a rare form of the disease with features of both distal and proximal RTA. Accurate diagnosis of RTA plays an important role in optimal patient management. The diagnosis of distal versus proximal RTA involves assessment of urinary acid and bicarbonate secretion, while in hyperkalemic RTA, selective aldosterone deficiency or resistance to its effects is confirmed after exclusion of other causes of hyperkalemia. Treatment options include alkali therapy in patients with distal or proximal RTA and lowering of serum potassium concentrations through dietary modification and potential new pharmacotherapies in patients with hyperkalemic RTA including newer potassium binders.

Keywords: Alkali therapy; Distal renal tubular acidosis; Hyperkalemic renal tubular acidosis; Normal anion gap metabolic acidosis; Potassium binders; Proximal renal tubular acidosis.

Fig. 1

Schematic diagrams illustrating bicarbonate (HCO₃^–) reabsorption and regeneration in the kidney. a HCO₃^– reabsorption in the proximal tubule. Hydrogen ions (H⁺) are secreted into the lumen via apical sodium (Na⁺)/H⁺ exchanger 3 (NHE3) and H⁺-ATPase transporters. Apical carbonic anhydrase (CA) IV catalyzes the reaction between H⁺ and HCO₃^–, which forms H₂CO₃ that rapidly dissociates to water and carbon dioxide (CO₂). CO₂ diffuses back across the apical membrane, where CA-II catalyzes its reaction with intracellular hydroxide ions (OH^–) to form H⁺ and HCO₃^–. HCO₃^– is transported across the basolateral membrane by the Na⁺/HCO₃^–/CO₃^2– cotransporter (NBCe1). b HCO₃^– reabsorption in the thick ascending limb. As in the proximal tubule, H⁺ is secreted into the lumen via NHE3, where it reacts with HCO₃^– to release CO₂ that diffuses back across the apical membrane. HCO₃^– is transported across the basolateral membrane by NBCe1 and the kidney anion exchanger (AE1). c H⁺ secretion by α-intercalated cells in cortical collecting duct (CCD). H⁺ is secreted into the lumen by H⁺/K⁺-ATPase and vacuolar (v) H⁺-ATPase transporters on the apical membrane. Intracellular OH^– generated by H⁺ secretion reacts with CO₂ via CA-II to form HCO₃^–, which is removed by basolateral AE1. The resulting intracellular chloride (Cl^–) exits via conductance channels in the basolateral membrane. Luminal K⁺ transported into the cell via H⁺/K⁺-ATPase can exit via channels in the apical or basolateral membrane, depending on K⁺ balance. d HCO₃^– secretion by β-intercalated cells in CCD. H⁺-ATPase transports H⁺ across the basolateral membrane. Intracellular OH^– generated by H⁺ secretion reacts with CO₂ via CA-II to form HCO₃^–, which is transported into the lumen by the apical Cl^–/HCO₃^– exchanger pendrin. Intracellular Cl^– exits via conductance channels in the basolateral membrane (These figures were published in Comprehensive Clinical Nephrology: 5th Edition, Palmer BF, Normal acid–base balance, pp. 142–148, Copyright Elsevier (2014) [6])

Fig. 2

Schematic diagrams illustrating ammonia (NH₃) production and transport in the kidney. a NH₃ production in the proximal tubular cells. After glutamine uptake via sodium (Na⁺)-coupled neutral amino acid transporter 3 (SNAT3), mitochondrial glutamine metabolism results in production of ammonium (NH₄⁺). NH₃ passively diffuses across apical membrane and hydrogen (H⁺) is transported via apical Na⁺/H⁺ exchanger 3 (NHE3) and H⁺-ATPase; NH₃ and H⁺ combine in the lumen to form NH₄⁺. b NH₃ transport in the thick ascending limb. Lumen-positive voltage drives passive paracellular transport of NH₄⁺ from the lumen into the blood. By substituting for potassium (K⁺), NH₄⁺ is also transported into the cell via the Na⁺/K⁺/2Cl^– transporter and the apical membrane K⁺ channel (ROMK). The basolateral Na⁺/bicarbonate (HCO₃^–) cotransporter (NBCn2) may play a role in maintaining cellular pH. NH₄⁺ crosses the basolateral membrane into the blood via NHE4 (Adapted with permission from Palmer 2014 [6])

Fig. 3

A schematic diagram illustrating the underlying kidney tubule defects causing the different types of renal tubular acidosis (RTA). Distal (type 1) RTA is caused by either impaired hydrogen (H⁺) secretion by vacuolar (v) H⁺-ATPase or H⁺/K⁺-ATPase or increased H⁺ permeability of luminal membrane by α-intercalated cells of the collecting duct, which leads to a reduction in net H⁺ secretion. Proximal (type 2) RTA is caused by defects in bicarbonate (HCO₃^–) reabsorption in the proximal tubule, due to either impaired HCO₃^– transport across the basolateral membrane or inhibition of carbonic anhydrase (CA) activity. Hyperkalemic (type 4) RTA is caused by aldosterone deficiency or resistance, which leads to reduced Na⁺ (sodium) reabsorption by principal cells of the collecting duct and decreased transepithelial voltage, leading to diminished H⁺ secretion by α-intercalated cells and K⁺ secretion by principal cells. AE1 kidney anion exchanger, ENaC epithelial Na⁺ channel, MR mineralocorticoid receptor, NHE3 Na⁺/H⁺ exchanger 3, ROMK apical membrane K⁺ channel

Fig. 4

A suggested algorithm for diagnosing renal tubular acidosis. Reprinted by permission of Edizioni Minerva Medica from Minerva Endocrinologica 2019 December; 44(4):363–77 [7]