Rivera Frederick Berro, Alfonso Pia, Golbin Jem Marie, Lo Kevin, Lerma Edgar, Volgman Annabelle Santos, Kazory Amir
Department of Medicine, Philippine General Hospital, University of the Philippines System, National Capital Region, Manila, Philippines.
University of the Philippines System, National Capital Region, Manila, Philippines.
Cardiorenal Med. 2021;11(2):87-98. doi: 10.1159/000515604. Epub 2021 Apr 19.
Clinical guidelines include diuretics for the treatment of heart failure (HF), not to decrease mortality but to decrease symptoms and hospitalizations. More attention has been paid to the worse outcomes, including mortality, associated with continual diuretic therapy due to hypochloremia. Studies have revealed a pivotal role for serum chloride in the pathophysiology of HF and is now a target of treatment to decrease mortality. The prognostic value of serum chloride in HF has been the subject of much attention. Mechanistically, the macula densa, a region in the renal juxtaglomerular apparatus, relies on chloride levels to sense salt and volume status. The recent discovery of with-no-lysine (K) (WNK) protein kinase as an intracellular chloride sensor sheds light on the possible reason of diuretic resistance in HF. The action of chloride on WNKs results in the upregulation of the sodium-potassium-chloride cotransporter and sodium-chloride cotransporter receptors, which could lead to increased electrolyte and fluid reabsorption. Genetic studies have revealed that a variant of a voltage-sensitive chloride channel (CLCNKA) gene leads to almost a 50% decrease in current amplitude and function of the renal chloride channel. This variant increases the risk of HF. Several trials exploring the prognostic value of chloride in both acute and chronic HF have shown mostly positive results, some even suggesting a stronger role than sodium. However, so far, interventional trials exploring serum chloride as a therapeutic target have been largely inconclusive. This study is a review of the pathophysiologic effects of hypochloremia in HF, the genetics of chloride channels, and clinical trials that are underway to investigate novel approaches to HF management.
临床指南将利尿剂纳入心力衰竭（HF）的治疗方案，目的不是降低死亡率，而是减轻症状和减少住院次数。由于低氯血症，持续使用利尿剂治疗所带来的包括死亡率在内的更差预后受到了更多关注。研究表明血清氯化物在HF的病理生理学中起关键作用，现已成为降低死亡率的治疗靶点。血清氯化物在HF中的预后价值一直备受关注。从机制上讲，致密斑是肾近球小体中的一个区域，它依靠氯化物水平来感知盐和容量状态。最近发现无赖氨酸（K）（WNK）蛋白激酶作为一种细胞内氯化物传感器，揭示了HF中利尿剂抵抗的可能原因。氯化物对WNK的作用导致钠-钾-氯化物协同转运体和钠-氯化物协同转运体受体上调，这可能导致电解质和液体重吸收增加。基因研究表明，电压敏感氯化物通道（CLCNKA）基因的一个变体导致肾氯化物通道的电流幅度和功能降低近50%。这种变体增加了患HF的风险。几项探索氯化物在急性和慢性HF中预后价值的试验大多显示出阳性结果，有些甚至表明其作用比钠更强。然而，到目前为止，探索将血清氯化物作为治疗靶点的干预试验在很大程度上尚无定论。本研究综述了低氯血症在HF中的病理生理效应、氯化物通道的遗传学以及正在进行的研究HF管理新方法的临床试验。
