Lefrère Antoine, Burtey Stéphane, Bobot Stanislas, Belzeaux Raoul, Bobot Mickaël
Pôle de Psychiatrie, Assistance Publique Hôpitaux de Marseille, Marseille, France; Institut de Neurosciences de la Timone, Aix-Marseille Univ, UMR CNRS, France.
Centre de Néphrologie et Transplantation Rénale, Hôpital de la Conception, AP-HM, Marseille, France; Aix Marseille Univ, INSERM 1263, INRAE 1260, C2VN, Marseille, France.
Behav Brain Res. 2025 Apr 12;483:115467. doi: 10.1016/j.bbr.2025.115467. Epub 2025 Feb 7.
Depression is highly prevalent during chronic kidney disease (CKD) with studies suggesting prevalence rates ranging from approximately one-quarter to half of CKD patients. CKD and depression have a bidirectional relationship, each disorder aggravating the other, leading to more complex and challenging patient management. Depression during CKD is multifactorial and is associated with increased risk of adverse events and hospitalization.
We conducted a narrative review of experimental and observational studies in animals and humans, as well as meta-analyses, to explore specific mechanisms of depression in CKD and its treatment.
In depression the gut-brain axis is central. CKD leads to an accumulation of gut-derived uremic toxins. One key factor is the accumulation of tryptophan-derived uremic toxins like kynurenines or indoxyl sulfate, whose serum concentration increases progressively with the stage of CKD (up to 100-fold in stage 5), and which plays an important role in depression mechanisms, by activating aryl hydrocarbon receptor, decreasing brain concentrations of serotonin by approximately 40 %, increasing brain inflammation, via activation of microglia and astrocytes and release of TNFα, IL-6 and NO. Randomized controlled studies found limited or no benefits of antidepressants for depressive symptoms in CKD and hemodialysis patients.
Chronic inflammation, in relation to uremic toxin accumulation during CKD, seems to be a complex but important mechanism for treatment resistance in depression. Future research should consider inhibitors of uremic toxins inhibitors and anti-inflammatory molecules as potential therapeutic agents, to improve the prognosis of depression in CKD patients.
抑郁症在慢性肾脏病（CKD）患者中极为普遍，研究表明其患病率约为CKD患者的四分之一至一半。CKD与抑郁症存在双向关系，两种病症相互加重，导致患者管理更加复杂且具有挑战性。CKD期间的抑郁症是多因素的，与不良事件和住院风险增加相关。
我们对动物和人类的实验及观察性研究以及荟萃分析进行了叙述性综述，以探讨CKD中抑郁症的具体机制及其治疗方法。
在抑郁症中，肠-脑轴起着核心作用。CKD会导致肠道来源的尿毒症毒素蓄积。一个关键因素是色氨酸衍生的尿毒症毒素如犬尿氨酸或硫酸吲哚酚的蓄积，其血清浓度会随着CKD分期的进展而逐渐升高（在5期时高达100倍），并且通过激活芳烃受体、使大脑中血清素浓度降低约40%、通过激活小胶质细胞和星形胶质细胞以及释放肿瘤坏死因子α、白细胞介素-6和一氧化氮来增加脑部炎症，从而在抑郁症机制中发挥重要作用。随机对照研究发现，抗抑郁药对CKD和血液透析患者的抑郁症状疗效有限或无疗效。
与CKD期间尿毒症毒素蓄积相关的慢性炎症似乎是抑郁症治疗抵抗的一个复杂但重要的机制。未来的研究应考虑将尿毒症毒素抑制剂和抗炎分子作为潜在的治疗药物，以改善CKD患者抑郁症的预后。
