Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain; RICORS2040, Madrid, Spain; Departamento de Medicina, Facultad de Medicina, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain; RICORS2040, Madrid, Spain; Departamento de Medicina, Facultad de Medicina, Universidad Autónoma de Madrid, 28049 Madrid, Spain; Consejo Nacional de Ciencia y Tecnología (CONACyT), Spain.
Biomed Pharmacother. 2023 Feb;158:114197. doi: 10.1016/j.biopha.2022.114197. Epub 2023 Jan 4.
Metabolic acidosis is frequent in chronic kidney disease (CKD) and is associated with accelerated progression of CKD, hypercatabolism, bone disease, hyperkalemia, and mortality. Clinical guidelines recommend a target serum bicarbonate ≥ 22 mmol/L, but metabolic acidosis frequently remains undiagnosed and untreated. Sodium zirconium cyclosilicate (SZC) binds potassium in the gut and is approved to treat hyperkalemia. In clinical trials with a primary endpoint of serum potassium, SZC increased serum bicarbonate, thus treating CKD-associated metabolic acidosis. The increase in serum bicarbonate was larger in patients with more severe pre-existent metabolic acidosis, was associated to decreased serum urea and was maintained for over a year of SZC therapy. SZC also decreased serum urea and increased serum bicarbonate after switching from a potassium-binding resin in normokalemic individuals. Mechanistically, these findings are consistent with SZC binding the ammonium ion (NH) generated from urea by gut microbial urease, preventing its absorption and, thus, preventing the liver regeneration of urea and promoting the fecal excretion of H. This mechanism of action may potentially result in benefits dependent on corrected metabolic acidosis (e.g., improved well-being, decreased catabolism, improved CKD mineral bone disorder, better control of serum phosphate, slower progression of CKD) and dependent on lower urea levels, such as decreased protein carbamylation. A roadmap is provided to guide research into the mechanisms and clinical consequences of the impact of SZC on serum bicarbonate and urate.
代谢性酸中毒在慢性肾脏病（CKD）中很常见，与 CKD 的加速进展、高代谢、骨病、高钾血症和死亡率有关。临床指南建议将目标血清碳酸氢盐≥22mmol/L，但代谢性酸中毒经常未被诊断和治疗。硅酸锆酸钠（SZC）在肠道中结合钾，被批准用于治疗高钾血症。在以血清钾为主要终点的临床试验中，SZC 增加了血清碳酸氢盐，从而治疗了 CKD 相关的代谢性酸中毒。在预先存在的代谢性酸中毒更严重的患者中，血清碳酸氢盐的增加更大，与血清尿素降低有关，并且在 SZC 治疗超过一年后仍能维持。在正常血钾个体中从钾结合树脂转换为 SZC 后，血清尿素也降低，血清碳酸氢盐增加。从机制上讲，这些发现与 SZC 结合肠道微生物脲酶产生的铵离子（NH）一致，防止其吸收，从而防止尿素的肝再生并促进 H 的粪便排泄。这种作用机制可能会带来与纠正代谢性酸中毒相关的益处（例如，改善健康状况、降低代谢率、改善 CKD 矿物质骨病、更好地控制血清磷酸盐、减缓 CKD 进展）和与较低的尿素水平相关的益处，例如减少蛋白质氨甲酰化。提供了一张路线图，以指导对 SZC 对血清碳酸氢盐和尿酸的影响的机制和临床后果的研究。
