The emerging role of Klotho in clinical nephrology

Abstract

Klotho is highly expressed in the kidney and a soluble form of Klotho functions as an endocrine substance that exerts multiple actions including the modulation of renal solute transport and the protection of the kidney from a variety of insults in experimental models. At present, the Klotho database is still largely preclinical, but the anticipated forthcoming impact on clinical nephrology can be immense. This manuscript puts these potentials into perspective for the clinician. There is renal and systemic Klotho deficiency in both acute kidney injury (AKI) and chronic kidney disease (CKD). Klotho plummets very early and severely in AKI and represents a pathogenic factor that exacerbates acute kidney damage. In CKD, Klotho deficiency exerts a significant impact on progression of renal disease and extra renal complications. In AKI, soluble Klotho levels in plasma and/or urine may serve as an early biomarker for kidney parenchymal injury. Restoration by exogenous supplementation or stimulation of endogenous Klotho may prevent and/or ameliorate kidney injury and mitigate CKD development. In CKD, Klotho levels may be an indicator of early disease and predict the rate of progression, and presence and severity of soft tissue calcification. The correction of Klotho deficiency may delay progression and forestall development of extra renal complications in CKD. Rarely does one find a molecule with such broad potential applications in nephrology. Klotho can possibly emerge on the horizon as a candidate for an unprecedented sole biomarker and intervention. Nephrologists should monitor the progress of the preclinical studies and the imminently emerging human database.

Fig. 1.

Schema for Klotho gene, transcripts and proteins. Rodent and human Klotho spans 50 kb and consists of five exons. Two transcripts, secreted and membrane forms of Klotho, are generated through alternative RNA splicing. The internal splice donor site is in exon 3. The resultant alternatively spliced transcript after exon 3 (grey) with an in-frame translation stop codon is introduced. The short protein product, secreted Klotho, contains only Kl1 and is released from the cell. The longer Klotho encoded by the membrane form of the Klotho transcript is a single-pass transmembrane protein anchored in the cell surface. The extracellular domain of membrane Klotho containing Kl1 and Kl2 repeats is shed and cleaved by ADAM10/17, and released into bloodstream. Thus, the circulation harbors two forms of Klotho—one is the ectodomain derived from cleavage of the extracellular domain of membrane Klotho and another is the secreted protein derived from an alternatively spliced Klotho transcript. Transmembrane Klotho works with FGFRs as co-receptor for FGF23 signal transduction.

Fig. 2.

Proposed model of beneficial roles of Klotho in AKI: after acute exposure to insults such as ischemia, nephrotoxin or obstruction, Klotho is reduced in the kidney, plasma and urine. Oxidative stress and cytokine production also directly suppress renal Klotho expression. The low Klotho level may be a pathological intermediate for exacerbation of kidney damage. If kidney damage is mild, the kidney undergoes normal tissue regeneration to restore normal kidney morphology. In more serious injury, reparative regeneration is replaced by fibrosis, which further worsens renal Klotho deficiency. Administrations of exogenous Klotho protein can effectively prevent and limit kidney injury, promote normal healing and prevent-fibrosis.

Fig. 3.

Proposed time profile of disturbances in mineral metabolism and phosphate-regulating hormones and therapeutic strategies in CKD. (A) Changes in parameters of mineral metabolism with CKD progression. Normal range is shown in the grey box. The x-axis represents a decline in renal function from normal to Stage 1–5 of CKD. Decreased plasma Klotho is proposed as an early event, followed by an increase in FGF23 and a decrease in vitamin D levels in that order. The elevation of plasma PTH occurs later with hyperphosphatemia appearing only in advanced CKD. (B) Potential therapeutic strategies targeting Klotho. Five principal mineral disturbances in CKD: Klotho deficiency, excess FGF23, secondary hyperparathyroidism, vitamin D deficiency and phosphate toxicity, and over-stimulation of Ang II are shown as an interacting and self-amplifying vicious downhill spiral. Hyperphosphatemia further reduces Klotho expression and increases plasma FGF23 and PTH. The final outcome is the severe downregulation of Klotho in the kidney and plasma. Shown in italics are potential means to interrupt these pathways at specific target points. Each maneuver has the potential of arresting the spiral with a direct or indirect impact on endogenous Klotho expression in the kidney. For a given CKD patient, a particular combination of prescriptions can be tailored to best suit that individual.