Institute for Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.
Renal Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.
Front Endocrinol (Lausanne). 2023 Jan 17;13:1075809. doi: 10.3389/fendo.2022.1075809. eCollection 2022.
Chronic kidney disease (CKD) describes the long-term condition of impaired kidney function from any cause. CKD is common and associated with a wide array of complications including higher mortality, cardiovascular disease, hypertension, insulin resistance, dyslipidemia, sarcopenia, osteoporosis, aberrant immune function, cognitive impairment, mood disturbances and poor sleep quality. Glucocorticoids are endogenous pleiotropic steroid hormones and their excess produces a pattern of morbidity that possesses considerable overlap with CKD. Circulating levels of cortisol, the major active glucocorticoid in humans, are determined by a complex interplay between several processes. The hypothalamic-pituitary-adrenal axis (HPA) regulates cortisol synthesis and release, 11β-hydroxysteroid dehydrogenase enzymes mediate metabolic interconversion between active and inactive forms, and clearance from the circulation depends on irreversible metabolic inactivation in the liver followed by urinary excretion. Chronic stress, inflammatory states and other aspects of CKD can disturb these processes, enhancing cortisol secretion the HPA axis and inducing tissue-resident amplification of glucocorticoid signals. Progressive renal impairment can further impact on cortisol metabolism and urinary clearance of cortisol metabolites. Consequently, significant interest exists to precisely understand the dysregulation of cortisol in CKD and its significance for adverse clinical outcomes. In this review, we summarize the latest literature on alterations in endogenous glucocorticoid regulation in adults with CKD and evaluate the available evidence on cortisol as a mechanistic driver of excess mortality and morbidity. The emerging picture is one of subclinical hypercortisolism with blunted diurnal decline of cortisol levels, impaired negative feedback regulation and reduced cortisol clearance. An association between cortisol and adjusted all-cause mortality has been reported in observational studies for patients with end-stage renal failure, but further research is required to assess links between cortisol and clinical outcomes in CKD. We propose recommendations for future research, including therapeutic strategies that aim to reduce complications of CKD by correcting or reversing dysregulation of cortisol.
慢性肾脏病（CKD）描述了由任何原因引起的肾功能长期受损的状态。CKD 很常见，与多种并发症相关，包括更高的死亡率、心血管疾病、高血压、胰岛素抵抗、血脂异常、肌肉减少症、骨质疏松症、免疫功能异常、认知障碍、情绪障碍和睡眠质量差。糖皮质激素是内源性多效类固醇激素，其过量会产生一种与 CKD 有很大重叠的发病率模式。人类主要的活性糖皮质激素皮质醇的循环水平取决于几个过程之间的复杂相互作用。下丘脑-垂体-肾上腺轴（HPA）调节皮质醇的合成和释放，11β-羟类固醇脱氢酶介导活性和非活性形式之间的代谢转化，而循环清除取决于肝脏的不可逆代谢失活，然后通过尿液排泄。慢性应激、炎症状态和 CKD 的其他方面会干扰这些过程，增强 HPA 轴的皮质醇分泌，并诱导组织内糖皮质激素信号的放大。进行性肾功能损害还会进一步影响皮质醇代谢和皮质醇代谢物的尿液清除。因此，人们非常有兴趣精确了解 CKD 中皮质醇的失调及其对不良临床结局的意义。在这篇综述中，我们总结了关于 CKD 成人内源性糖皮质激素调节改变的最新文献，并评估了皮质醇作为过度死亡率和发病率的机制驱动因素的现有证据。新兴的情况是亚临床高皮质醇血症，皮质醇水平的昼夜下降减弱，负反馈调节受损，皮质醇清除减少。观察性研究报告了终末期肾衰竭患者皮质醇与调整后的全因死亡率之间的关联，但需要进一步研究来评估皮质醇与 CKD 临床结局之间的联系。我们提出了未来研究的建议，包括旨在通过纠正或逆转皮质醇失调来减少 CKD 并发症的治疗策略。
