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Review
. 2020 Dec 31;16(1):162-176.
doi: 10.2215/CJN.02840320. Epub 2020 Jul 22.

Klotho in Clinical Nephrology: Diagnostic and Therapeutic Implications

Javier A Neyra  1   2   3 , Ming Chang Hu  1   2 , Orson W Moe  1   2   4
Affiliations
Review

Klotho in Clinical Nephrology: Diagnostic and Therapeutic Implications

Javier A Neyra et al. Clin J Am Soc Nephrol. .

Abstract

αKlotho (called Klotho here) is a membrane protein that serves as the coreceptor for the circulating hormone fibroblast growth factor 23 (FGF23). Klotho is also cleaved and released as a circulating substance originating primarily from the kidney and exerts a myriad of housekeeping functions in just about every organ. The vital role of Klotho is shown by the multiorgan failure with genetic deletion in rodents, with certain features reminiscent of human disease. The most common causes of systemic Klotho deficiency are AKI and CKD. Preclinical data on Klotho biology have advanced considerably and demonstrated its potential diagnostic and therapeutic value; however, multiple knowledge gaps exist in the regulation of Klotho expression, release, and metabolism; its target organs; and mechanisms of action. In the translational and clinical fronts, progress has been more modest. Nonetheless, Klotho has potential clinical applications in the diagnosis of AKI and CKD, in prognosis of progression and extrarenal complications, and finally, as replacement therapy for systemic Klotho deficiency. The overall effect of Klotho in clinical nephrology requires further technical advances and additional large prospective human studies.

Keywords: Klotho;; diagnosis;; kidney;; nephrology;; therapy.

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Figures

Figure 1.
Figure 1.
Overview of Klotho protein. (A) Fibroblast growth factor 23 (FGF23) engages the fibroblast growth factor receptor (FGFR)-Klotho coreceptor complex that triggers cellular signaling. (B) Transmembrane Klotho with its Kl1 and Kl2 domains and the generation of soluble circulating Klotho by secretases (ADAM10 and ADAM17). (C) Structure of FGFR1c, Klotho, and FGF23 (one molecule each) as determined by Chen et al. (12). RXXR motif, proteolytic cleavage motif.
Figure 2.
Figure 2.
Physiologic and pathophysiologic role of Klotho in mineral metabolism with preserved and decreased kidney function. The dashed line indicates putative action on the basis of experimental or clinical data; no evidence supports direct effect yet. PTH, parathyroid hormone.
Figure 3.
Figure 3.
Changes in circulating soluble Klotho according to eGFR decline and its relationship to other mineral metabolism parameters. 1,25(OH)2D3, 1,25-dihydroxyvitamin D.
Figure 4.
Figure 4.
Role of Klotho in kidney and cardiovascular protection. AKI occurs after exposure to kidney insults. If the insult is strong or long enough, kidney recovery is impaired, and AKI progresses to CKD. With CKD progression, kidney Klotho is decreased followed by increase in circulating FGF23 levels, low 1,25-dihydroxyvitamin D3, high blood phosphate, and increase in PTH. Abnormal mineral hormones individually and synergistically exacerbate each other in the manner of a vortex of downhill spiral (dashed line: putative action) and contribute to end organ complications, including CKD-MBD, uremic cardiomyopathy, and vascular calcification. Klotho replacement provides beneficial effects from protection of kidney against acute injury, promotion of kidney regeneration, retardation of CKD progression, and amelioration of extrarenal complications. Klotho also improves mineral metabolism disturbances and directly or indirectly lessens end organ dysfunction or abnormalities of advanced CKD. CKD-MBD, CKD-mineral and bone disorder; Ca, calcium; 1,25-D3, 1,25-dihydroxyvitamin D; Pi, phosphate.
Figure 5.
Figure 5.
Klotho-centric therapies in kidney disease, including increase in endogenous production or administration of exogenous Klotho protein or cDNA. miRNA, microRNA; PPAR-r, peroxisome proliferator-activated receptor gamma.
Figure 6.
Figure 6.
Potential diagnostic, prognostic, and therapeutic applications of Klotho in clinical nephrology. Dx, diagnosis.
See this image and copyright information in PMC

References

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