University of Tennessee Health Science Center, Memphis, TN, USA.
Nephrol Dial Transplant. 2013 Sep;28(9):2228-36. doi: 10.1093/ndt/gft065. Epub 2013 Apr 25.
Traditional risk factors of cardiovascular morbidity and mortality such as hypertension, hypercholesterolemia and obesity are paradoxically associated with better outcomes in dialysis patients, and the few trials of interventions targeting modifiable traditional risk factors have yielded disappointing results in this patient population. Non-traditional risk factors such as inflammation, anemia and abnormalities in bone and mineral metabolism have been proposed as potential explanations for the excess mortality seen in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), but without clear understanding of what the most important pathophysiologic mechanisms of these risk factors are, which ones might be ideal treatment targets and which therapeutic interventions may be effective and safe in targeting them. Among the novel risk factors, fibroblast growth factor-23 (FGF23) has recently emerged as one of the most powerful predictors of adverse outcomes in patients with CKD and ESRD. FGF23 is a hormone produced by osteoblasts/osteocytes in bone that acts on the kidney to regulate phosphate and vitamin D metabolism through activation of FGF receptor/α-Klotho co-receptor complexes. It is possible that elevated FGF23 may exert its negative impact through distinct mechanisms of action independent from its role as a regulator of phosphorus homeostasis. Elevated circulating FGF23 concentrations have been associated with left ventricular hypertrophy (LVH), and it has been suggested that FGF23 exerts a direct effect on the myocardium. While it is possible that 'off target' effects of FGF23 present in very high concentrations could induce LVH, this possibility is controversial, since α-klotho is not expressed in the myocardium. Another possibility is that FGF23's effect on the heart is mediated indirectly, via 'on target' activation of other humoral pathways. We will review the physiology and pathophysiology of FGF23, the outcomes associated with elevated FGF23 levels, and describe putative mechanisms of action responsible for its negative effects and potential therapeutic strategies to treat these.
传统的心血管发病率和死亡率风险因素，如高血压、高胆固醇血症和肥胖症，与透析患者的更好结果呈矛盾关系，针对可改变的传统风险因素的少数干预试验在该患者人群中产生了令人失望的结果。非传统风险因素，如炎症、贫血和骨与矿物质代谢异常，被提出作为慢性肾脏病 (CKD) 和终末期肾病 (ESRD) 患者中过度死亡率的潜在解释，但对于这些风险因素的最重要病理生理机制是什么，哪些可能是理想的治疗靶点，以及哪些治疗干预可能有效且安全地针对这些靶点，仍缺乏明确的认识。在新型风险因素中，成纤维细胞生长因子 23 (FGF23) 最近成为 CKD 和 ESRD 患者不良结局的最强预测因子之一。FGF23 是骨中成骨细胞/成骨细胞产生的一种激素，通过激活 FGF 受体/α-Klotho 共受体复合物，作用于肾脏来调节磷酸盐和维生素 D 代谢。升高的 FGF23 可能通过独立于其作为磷稳态调节剂的作用的不同作用机制发挥其负面影响。循环中升高的 FGF23 浓度与左心室肥厚 (LVH) 相关，并且有人提出 FGF23 对心肌有直接作用。虽然在非常高的浓度下，FGF23 的“脱靶”效应可能导致 LVH，但这种可能性存在争议，因为 α-Klotho 不在心肌中表达。另一种可能性是 FGF23 通过其他体液途径的“靶标”激活间接作用于心脏。我们将回顾 FGF23 的生理学和病理生理学、与升高的 FGF23 水平相关的结局，并描述其负性效应的潜在作用机制和潜在的治疗策略。
