Table 1.

Klotho and the Klotho/FGF-23 axis in CKD-associated cardiovascular disease. Summary of some of the studies analyzed in this review, concerning the role of Klotho and the Klotho/FGF-23 axis in cardiovascular disease, an important and common morbidity and cause of mortality in CKD patients.

Author/Year	Model Used	Study Design	Conclusion
Karalliedde, J., et al., 2013 [85]	Patients with diabetes type 2, presenting systolic hypertension and albuminuria	Single-Center, Double-Blind Randomized Controlled Trial	Inhibition of RAAS led to an increase in soluble Klotho levels.
Saito, Y., et al., 2000 [86]	Rats with atherosclerosis	Preclinical Study	Klotho adenoviral delivery resulted in the mitigation of vascular endothelial dysfunction and reduction of blood pressure values
Kuro-o, M., et al.,1997 [1]	Klotho-deficient mice	Preclinical Study	The animals presented artery calcification, cardiac fibrosis and hypertrophy. Klotho might participate in the signaling pathways involved in these processes.
Xie, J., et al., 2015 [87]	Klotho-deficient mice	Preclinical Study	The increase in soluble Klotho levels attenuated cardiac remodeling in CKD animals. Decrease in this protein level is proposed to be an independent factor for cardiomyopathy in CKD.
Ding, et al., 2019 [88]	Mice with angiotensin-II infusion	Preclinical Study	Klotho was related to the decrease of cardiac FGF-23 expression in vitro and in vivo; moreover, it prevented cardiac remodeling and dysfunction in this model.
Memmos, et al., 2019 [84]	79 patients on dialysis	Prospective Cohort Study	Low levels of Klotho are correlated with an increased risk of cardiovascular disease and reduced overall survival in these patients. It might contribute to cardiovascular disease in individuals with CKD.
Brandenburg, V.M., et al., 2015 [89]	2948 patients	Multicenter Longitudinal Study	In individuals with normal kidney function, Klotho does not act as a predictive marker of cardiovascular and mortality risk.
Pan, H.C., et al., 2018 [90]	168 patients with diabetes type 2	Prospective Study	Low levels of Klotho are associated with cardiovascular outcomes, such as coronary disease. In these patients, Klotho level is a predictor for vascular events.
Gutierrez, O.M., et al., 2009 [91]	162 patients with CKD	Cross-Sectional Study	FGF-23 is correlated with vascular dysfunction, such as left ventricular mass index and hypertrophy in these individuals.