Institute of Physiology, University of Zurich, Zurich, Switzerland; National Center for Competence in Research Kidney, Switzerland.
Institute of Physiology, University of Zurich, Zurich, Switzerland; National Center for Competence in Research Kidney, Switzerland.
Semin Nephrol. 2019 Jul;39(4):340-352. doi: 10.1016/j.semnephrol.2019.04.004.
Acid-base balance is critical for normal life. Acute and chronic disturbances impact cellular energy metabolism, endocrine signaling, ion channel activity, neuronal activity, and cardiovascular functions such as cardiac contractility and vascular blood flow. Maintenance and adaptation of acid-base homeostasis are mostly controlled by respiration and kidney. The kidney contributes to acid-base balance by reabsorbing filtered bicarbonate, regenerating bicarbonate through ammoniagenesis and generation of protons, and by excreting acid. This review focuses on acid-base disorders caused by renal processes, both inherited and acquired. Distinct rare inherited monogenic diseases affecting acid-base handling in the proximal tubule and collecting duct have been identified. In the proximal tubule, mutations of solute carrier 4A4 (SLC4A4) (electrogenic Na/HCO-cotransporter Na/bicarbonate cotransporter e1 [NBCe1]) and other genes such as CLCN5 (Cl/H-antiporter), SLC2A2 (GLUT2 glucose transporter), or EHHADH (enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase) causing more generalized proximal tubule dysfunction can cause proximal renal tubular acidosis resulting from bicarbonate wasting and reduced ammoniagenesis. Mutations in adenosine triphosphate ATP6V1 (B1 H-ATPase subunit), ATPV0A4 (a4 H-ATPase subunit), SLC4A1 (anion exchanger 1), and FOXI1 (forkhead transcription factor) cause distal renal tubular acidosis type I. Carbonic anhydrase II mutations affect several nephron segments and give rise to a mixed proximal and distal phenotype. Finally, mutations in genes affecting aldosterone synthesis, signaling, or downstream targets can lead to hyperkalemic variants of renal tubular acidosis (type IV). More common forms of renal acidosis are found in patients with advanced stages of chronic kidney disease and are owing, at least in part, to a reduced capacity for ammoniagenesis.
酸碱平衡对正常生命至关重要。急性和慢性紊乱会影响细胞能量代谢、内分泌信号、离子通道活性、神经元活动以及心血管功能，如心肌收缩力和血管血流。酸碱平衡的维持和适应主要由呼吸和肾脏控制。肾脏通过重吸收滤过的碳酸氢盐、通过氨生成和质子生成再生碳酸氢盐以及排泄酸来为酸碱平衡做出贡献。本综述重点介绍了由肾脏过程引起的酸碱平衡紊乱，包括遗传性和获得性疾病。已经确定了一些影响近端肾小管和集合管酸碱处理的遗传性单基因疾病。在近端肾小管中，溶质载体 4A4 (SLC4A4)（电中性的 Na/HCO3共转运蛋白 Na/碳酸氢盐共转运蛋白 e1 [NBCe1]）和其他基因（如 CLCN5 [Cl/H-反向转运蛋白]、SLC2A2 [GLUT2 葡萄糖转运蛋白] 或 EHHADH [烯酰 CoA、水合酶/3-羟基酰 CoA 脱氢酶]）的突变会导致更广泛的近端肾小管功能障碍，从而导致碳酸氢盐流失和氨生成减少的近端肾小管酸中毒。三磷酸腺苷 ATP6V1 (B1 H-ATPase 亚基)、ATPV0A4 (a4 H-ATPase 亚基)、SLC4A1 (阴离子交换蛋白 1) 和 FOXI1 (叉头转录因子) 的突变会导致 I 型远端肾小管酸中毒。碳酸酐酶 II 突变影响几个肾单位段并导致混合的近端和远端表型。最后，影响醛固酮合成、信号传导或下游靶标的基因突变可导致肾小管酸中毒的高钾血症变异型 (IV 型)。在慢性肾脏病晚期患者中发现了更常见的肾性酸中毒形式，至少部分原因是氨生成能力降低。
