Potential application of klotho in human chronic kidney disease

Abstract

The extracellular domain of transmembrane alpha-Klotho (αKlotho, hereinafter simply called Klotho) is cleaved by secretases and released into the circulation as soluble Klotho. Soluble Klotho in the circulation starts to decline early in chronic kidney disease (CKD) stage 2 and urinary Klotho possibly even earlier in CKD stage 1. Therefore soluble Klotho could serve as an early and sensitive marker of kidney function decline. Moreover, preclinical animal data support Klotho deficiency is not just merely a biomarker, but a pathogenic factor for CKD progression and extrarenal CKD complications including cardiovascular disease and disturbed mineral metabolism. Prevention of Klotho decline, re-activation of endogenous Klotho production or supplementation of exogenous Klotho are all associated with attenuation of renal fibrosis, retardation of CKD progression, improvement of mineral metabolism, amelioration of cardiomyopathy, and alleviation of vascular calcification in CKD. Therefore Klotho is not only a diagnostic and/or prognostic marker for CKD, but the treatment of Klotho deficiency may be a promising strategy to prevent, retard, and decrease the burden of comorbidity in CKD.

Plasma S-Klotho is Related to Kidney Function and Predicts Adverse Renal Outcomes in Patients with Advanced Chronic Kidney Disease

“…Consistent with these findings, we recently observed that s-Klotho inhibited endoplasmic reticulum stress-induced apoptosis in obstructive nephropathy7 and epithelial mesenchymal transition (EMT)-induced renal fibrosis in cyclosporin nephropathy 8. These results indicate that s-Klotho is involved in various kidney diseases, and it has been proposed as a novel renal protective protein with therapeutic potential 9. s-Klotho is located predominantly in the kidney, parathyroid gland, and choroid plexus.…”

The tripartite interaction of phosphate, autophagy, and αKlotho in health maintenance

“…25 The ectodomain of membrane-anchored αKlotho is shed by secretases [26][27][28] into the circulation, and exerts FGF23-independent actions including antiaging, antiapoptosis, anti-senescence, and blockade of vascular calcification. 29,30 Soluble αKlotho, a cleaved extracellular domain of membrane-anchored αKlotho protein was proposed to also function as a deliverable soluble receptor for FGF23 in very high concentrations in vitro. 31 The cellular and molecular mechanisms by which αKlotho deficiency initiates and/or promotes aging are not understood.…”

Treating Systemic Klotho Deficiency

“…While this has been enormously useful as proofof-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.…”

“…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?…”

“…Although only selective studies are cited, these methods have been used by multiple laboratories and Klotho expression and biologic effects were all verified. Pharmacologic means to increase endogenous Klotho levels include phosphate restriction, vitamin D, angiotensin-converting enzyme inhibitor, peroxisome proliferator-activated receptor-gamma agonists (thiazolidinediones), 3-hydroxy-3-methylglutaryl CoA reductase inhibitors; all currently approved for clinical use for other indications [4]. The increase in Klotho with these agents has not been uniformly proven in humans, may be limited in magnitude and consistency, and likely will not work in advanced CKD when the capacity of the kidney to increase Klotho output is limited.…”