The serendipitous disruption of the klotho gene promoter in 1997 by a cardiologist in Japan begot a phenotype of early multiorgan failure mimicking premature aging [1]. The gene was aptly named after the Greek Goddess who spins the threads of life. In 2005, the same investigator did the opposite experiment and showed that transgenic overexpression of klotho in mice extends life, placing Klotho once again in the spotlight and generated volumes of antiaging research [2]. Several findings that followed changed the landscape. Klotho is a single-pass transmembrane protein, primarily expressed in the kidney, but its extracellular domain is secreted into circulation as a soluble protein after being cleaved by proteases [3]; thus, the kidney supplies the body with soluble Klotho [3]. In multiple preclinical studies with diverse models, both acute and chronic kidney diseases are states of renal and systemic klotho deficiency [3], including human CKD. The relationship between Klotho and kidney disease is more than just a biomarker because restoration of Klotho ameliorated renal dysfunction and extrarenal complications in both acute [4] and chronic settings bringing Klotho supplementation into the therapeutic realm. However, how should Klotho be given?

In rodents, several methods have been used successfully to raise systemic Klotho levels (Fig. 1). The transgenic insertion of klotho into the genome of a mouse was the first attempt [2]. While this has been enormously useful as proof-of-concept in experimental animals, this technique is not applicable to patients currently. Recombinant Klotho protein was used successfully in the laboratory in both acute and chronic [5] settings that prevented AKI, accelerated AKI recovery, presented and retarded AKI-to-CKD transition, and ameliorated extrarenal complications [4]. Recombinant Klotho protein administration is a method where translation to human therapeutics is much more practical and proximal.