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肾脏对钾平衡的调控及临床意义

谢琼虹^*, 郝传明

复旦大学附属华山医院肾病科，上海 200040

摘要

饮食摄入的K+在肠道中几乎全部被吸收，肾脏是机体排钾最重要的器官，占机体排出钾总量的90%以上。肾脏对钾的排泄主要取决于醛固酮敏感的远端小管主细胞对钾的分泌，该分泌过程与主细胞顶端膜上的上皮钠通道(epithelial sodium channel, ENaC)对Na+的重吸收相耦联。当ENaC将Na+从管腔中转入细胞内，管腔中负电荷相对增加，而K+外流、H+外流和Cl−内流是应对Na+内流的3条途径，即3条途径均与Na+内流耦联。一般情况下，Na+内流 = K+外流 + H+外流 + Cl−内流，Na+内流、H+外流和Cl−内流中任一因素发生变化，均可影响K+外流，从而影响肾脏对K+的排泄：(1) Na+内流受ENaC表达水平的影响，而ENaC的表达主要受醛固酮-盐皮质激素受体(mineralocorticoid receptor, MR)通路的调控，ENaC高功能突变(Liddle综合征，又称假性醛固酮增多症)、MR高功能突变(Geller综合征)、醛固酮水平增加(原发或继发性醛固酮增多症)和拟醛固酮激素增加(如皮质醇或去氧皮质酮增多症)均可导致ENaC表达上调，Na+重吸收增加，K+和H+排出也增加，临床表现为高血压、低血钾和碱中毒；反之，ENaC低功能突变(假性醛固酮减少症1b型)、MR低功能突变(假性醛固酮减少症1a型)或者醛固酮减少(醛固酮减少症)则可引起Na+重吸收减少，K+和H+排出减少，临床上表现为低血压、高血钾和酸中毒。利尿剂阿米洛利和氨苯蝶啶是ENaC抑制剂，引起类似假性醛固酮减少症1b型的表现；螺内酯是MR抑制剂，引起类似假性醛固酮减少症1a型的表现。(2) Na+内流还受水和Na+远端输送的调控，当髓袢升支粗段的Na+-K+-2Cl−同向转运体(Na+-K+-2Cl− cotransporter, NKCC)和远曲小管的Na+-Cl−同向转运体(Na+-Cl− cotransporter, NCC)发生低功能突变(分别为Bartter综合征和Gitelman综合征)时，水和Na+的远端输送增加，集合管处ENaC对Na+重吸收增加，K+和H+排出也增加，临床上也表现为低血钾和碱中毒。袢利尿剂和噻嗪类利尿剂分别是NKCC和NCC的抑制剂，可引起类似Bartter综合征和Gitelman综合征的表现。而当水和Na+的远端输送减少(如Gordon综合征，又称假性醛固酮减少症2型)，临床上则表现为高血压、高血钾和酸中毒。(3) 当非氯阴离子的远端输送增加(如近端小管酸中毒和先天性失氯性腹泻)，集合管处Cl−内流减少，或者集合管闰细胞泌氢障碍(如远端小管酸中毒)，H+外流减少，也可引起K+分泌增加，出现低钾血症。本文将对肾脏排钾的调控机制以及调控异常产生的相应疾病进行综述。

关键词： 钾平衡; 肾性失钾; 低钾血症; 高钾血症

Regulation of kidney on potassium balance and its clinical significance

XIE Qiong-Hong^*, HAO Chuan-Ming

Division of Nephrology, Huashan Hospital, Fudan University, Shanghai 200040, China

Abstract

Virtually all of the dietary potassium intake is absorbed in the intestine, over 90% of which is excreted by the kidneys regarded as the most important organ of potassium excretion in the body. The renal excretion of potassium results primarily from the secretion of potassium by the principal cells in the aldosterone-sensitive distal nephron (ASDN), which is coupled to the reabsorption of Na+ by the epithelial Na+ channel (ENaC) located at the apical membrane of principal cells. When Na+ is transferred from the lumen into the cell by ENaC, the negativity in the lumen is relatively increased. K+ efflux, H+ efflux, and Cl− influx are the 3 pathways that respond to Na+ influx, that is, all these 3 pathways are coupled to Na+ influx. In general, Na+ influx is equal to the sum of K+ efflux, H+ efflux, and Cl− influx. Therefore, any alteration in Na+ influx, H+ efflux, or Cl− influx can affect K+ efflux, thereby affecting the renal K+ excretion. Firstly, Na+ influx is affected by the expression level of ENaC, which is mainly regulated by the aldosterone-mineralocorticoid receptor (MR) pathway. ENaC gain-of-function mutations (Liddle syndrome, also known as pseudohyperaldosteronism), MR gain-of-function mutations (Geller syndrome), increased aldosterone levels (primary/secondary hyperaldosteronism), and increased cortisol (Cushing syndrome) or deoxycorticosterone (hypercortisolism) which also activate MR, can lead to up-regulation of ENaC expression, and increased Na+ reabsorption, K+ excretion, as well as H+ excretion, clinically manifested as hypertension, hypokalemia and alkalosis. Conversely, ENaC inactivating mutations (pseudohypoaldosteronism type 1b), MR inactivating mutations (pseudohypoaldosteronism type 1a), or decreased aldosterone levels (hypoaldosteronism) can cause decreased reabsorption of Na+ and decreased excretion of both K+ and H+, clinically manifested as hypotension, hyperkalemia, and acidosis. The ENaC inhibitors amiloride and Triamterene can cause manifestations resembling pseudohypoaldosteronism type 1b; MR antagonist spironolactone causes manifestations similar to pseudohypoaldosteronism type 1a. Secondly, Na+ influx is regulated by the distal delivery of water and sodium. Therefore, when loss-of-function mutations in Na+-K+-2Cl− cotransporter (NKCC) expressed in the thick ascending limb of the loop and in Na+-Cl− cotransporter (NCC) expressed in the distal convoluted tubule (Bartter syndrome and Gitelman syndrome, respectively) occur, the distal delivery of water and sodium increases, followed by an increase in the reabsorption of Na+ by ENaC at the collecting duct, as well as increased excretion of K+ and H+, clinically manifested as hypokalemia and alkalosis. Loop diuretics acting as NKCC inhibitors and thiazide diuretics acting as NCC inhibitors can cause manifestations resembling Bartter syndrome and Gitelman syndrome, respectively. Conversely, when the distal delivery of water and sodium is reduced (e.g., Gordon syndrome, also known as pseudohypoaldosteronism type 2), it is manifested as hypertension, hyperkalemia, and acidosis. Finally, when the distal delivery of non-chloride anions increases (e.g., proximal renal tubular acidosis and congenital chloride-losing diarrhea), the influx of Cl− in the collecting duct decreases; or when the excretion of hydrogen ions by collecting duct intercalated cells is impaired (e.g., distal renal tubular acidosis), the efflux of H+ decreases. Both above conditions can lead to increased K+ secretion and hypokalemia. In this review, we focus on the regulatory mechanisms of renal potassium excretion and the corresponding diseases arising from dysregulation.

Key words: potassium homeostasis; renal potassium loss; hypokalemia; hyperkalemia

收稿日期：　　录用日期：

通讯作者：谢琼虹　　E-mail: qionghongxie@fudan.edu.cn

DOI: 10.13294/j.aps.2023.0026

引用本文：

谢琼虹, 郝传明. 肾脏对钾平衡的调控及临床意义[J]. 生理学报 2023; 75 (2): 216-230.

XIE Qiong-Hong, HAO Chuan-Ming. Regulation of kidney on potassium balance and its clinical significance. Acta Physiol Sin 2023; 75 (2): 216-230 (in Chinese with English abstract).