We speculated that epigenetic modification of Klotho is a more sensitive biomarker for renal fibrosis prediction and prognosis because the extent of Klotho promoter hypermethylation closely correlated with the severity of CKD in renal patients16 and in animal studies18, and also because Klotho repression was detected early at 24 h (Fig. 2B), comparing to 72 h for Rasal1 in a similar cell-based assay28. Here, KL is linked to chronic kidney disease.