Soluble klotho may be a marker of phosphate reabsorption

Tan, Sven‐Jean; Smith, Edwin R.; Holt, Stephen; Hewitson, Tim D.; Toussaint, Nigel D

doi:10.1093/ckj/sfw146

Cited by 15 publications

(10 citation statements)

References 51 publications

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“…This could be attributed to the fact that phosphaturia characterizes more advanced CKD stages which are also characterized by lower sKlotho plasma levels. The significant difference of sKlotho plasma levels among CKD stages, as well the independent correlation of sKlotho with mGFR and phosphate in multiple regression analysis, confirmed the already recognized relationship of sKlotho with renal function and phosphate [48]. In contrast with other studies, patients with DM had lower sKlotho plasma levels [49].…”

Section: Cfgf-23 and Sklotho Associations With Cardiovascular Risk Fasupporting

confidence: 82%

Fibroblast Growth factor 23 and α-Klotho protein are associated with adverse clinical outcomes in non dialysis chronic kidney disease stage 1-5 patients

Manou

Thodis

Arsos

et al. 2019

Preprint

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Background: Fibroblast Growth Factor 23 (FGF-23) and α-Klotho contribute to the patho-genesis of chronic kidney disease - mineral and bone disorders (CKD-MBD). The aim of our study was to evaluate the association of FGF-23 and α-Klotho levels with CKD-MBD parameters, as well as with renal prognosis and mortality, in CKD patients stage 1-5, not in renal replacement therapy (RRT). Methods: 128 patients were included. At enrollment GFR was measured (mGFR) and plasma levels of carboxyl terminal FGF-23 (cFGF-23) and soluble α-Klotho (sKlotho) were determined by ELISA. Abdominal aorta calcification (AAC) score was assessed in lateral abdominal X ray. The composite end point (event) was initiation of RRT or death. Follow-up was five years (median 36, range 2-60 months). Results: mGFR significantly correlated with cFGF-23 and sKlotho negatively and posi-tievely respectively (p<0.0001 for both). Multiple regression analysis showed an inde-pendent correlation of cFGF-23 with mGFR, 25-OH vitamin D, presence of diabetes melli-tus and AAC score, of sKlotho with mGFR and phosphate and of AAC score with sKlotho and cFGF-23. Multivariate regression tree analysis, led to the formation of three regression groups (A, B, C) based on two “cut off” values: mGFR levels of 60.85 ml/min/1.73m2 and serum phosphate levels of 3.7 mg/dl. These groups significantly correlated with the five CKD stages and additionally cFGF-23 and sKlotho plasma levels (p<0.0001 for both). During follow-up, 40 out of the 128 patients, (31.2%) either initiated RRT or died (31 and 9 respectively). Kaplan Meier survival analysis showed that groups of patients with cFGF-23 levels less than median and those with sKlotho more than median value showing a more favorable course, regarding outcome (p=0.0003 for cFGF-23, p=0.004 for s-Klotho). In Cox regression analysis the association of cFGF-23 (p=0.04), sKlotho (p=0.008) and AAC score (p=0.01) with the presence of “event” remained significant after adjustment for traditional and CKD- related covariates. Conclusions: In CKD patients stage 1-5, cFGF-23 and sKlotho levels are associated with adverse clinical outcomes. mGFR and serum phosphate, in association with sKlotho lev-els, may provide a “new classification” of CKD patients, which appears to be predictive of outcome.

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Section: Cfgf-23 and Sklotho Associations With Cardiovascular Risk Fasupporting

confidence: 82%

Fibroblast Growth factor 23 and α-Klotho protein are associated with adverse clinical outcomes in non dialysis chronic kidney disease stage 1-5 patients

Manou

Thodis

Arsos

et al. 2019

Preprint

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“…Clinical studies in patients with CKD have shown that soluble klotho is lower than normal (519 ± 183 versus 845 ± 330 pg/mL, P < .0001) in renal patients, and soluble klotho is positively correlated with serum calcium and negatively correlated with serum phosphate, PTH, and FGF23, suggesting that soluble klotho might reflect the ensuing tubular resistance to FGF23, which could be an early marker of CKD-MBD [ 143 , 144 ]. Recently, another clinical study suggested that soluble klotho is significantly associated with phosphate reabsorption independently of FGF-23, which may be a marker of phosphate reabsorption [ 145 ]. Therefore, soluble klotho seems to be a marker for disorders of phosphate and bone metabolism in CKD.…”

Section: Main Textmentioning

confidence: 99%

The role of klotho in chronic kidney disease

et al. 2018

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Chronic kidney disease (CKD) is an inherently systemic disease that refers to a long-term loss of kidney function. The progression of CKD has repercussions for other organs, leading to many kinds of extrarenal complications. Intensive studies are now being undertaken to reveal the risk factors and pathophysiological mechanism of this disease. During the past 20 years, increasing evidence from clinical and basic studies has indicated that klotho, which was initially known as an anti-aging gene and is mainly expressed in the kidney, is significantly correlated with the development and progression of CKD and its complications. Here, we discuss in detail the role and pathophysiological implications of klotho in ion disorders, the inflammation response, vascular calcification, mineral bone disorders, and renal fibrosis in CKD. Based on the pathogenic mechanism of klotho deficiency and klotho decline in urine early in CKD stage 2 and even earlier in CKD stage 1, it is not difficult to understand that soluble klotho can serve as an early and sensitive marker of CKD. Moreover, the prevention of klotho decline by several mechanisms can attenuate renal injuries, retard CKD progression, ameliorate extrarenal complications, and improve renal function. In this review, we focus on the functions and pathophysiological implications of klotho in CKD and its extrarenal complications as well as its potential applications as a diagnostic and/or prognostic biomarker for CKD and as a novel treatment strategy to improve and decrease the burden of comorbidity in CKD.

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“…The advances in Klotho biology described above may have major implications for the pathophysiology of renal disease. There is good evidence from clinical and experimental studies that both acute and chronic renal failure are associated with reduced expression of Klotho in the kidney, and with reduced sKlotho levels in the blood [ 43 ▪▪ , 44 – 47 ]. In agreement with these data, kidney transplantation in CKD patients results in a rapid rise in circulating sKlotho, and a decline in circulating FGF23 levels [ 48 ▪ , 49 ▪ ].…”

Section: Pathophysiological Role Of Klotho In Acute and Chronic Renalmentioning

confidence: 99%

α-Klothoʼs effects on mineral homeostasis are fibroblast growth factor-23 dependent

Erben

2018

Current Opinion in Nephrology and Hypertension

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Purpose of reviewα-Klotho (Klotho) occurs in three isoforms, a membrane-bound form acting as a coreceptor for fibroblast growth factor-23 (FGF23) signalling, a shed soluble form consisting of Klotho's large ectodomain thought to act as an enzyme or a hormone, and a secreted truncated form generated by alternative splicing of the Klotho mRNA with unknown function. The purpose of this review is to highlight the recent advances in our understanding of Klotho's function in mineral homeostasis.Recent findingsA number of seminal discoveries have recently been made in this area, shifting existing paradigms. The crystal structure of the ternary FGF receptor (FGFR)-1c/Klotho/FGF23 complex has been uncovered, revealing how the ligand FGF23 interacts with FGFR1c and the coreceptor Klotho at atomic resolution. Furthermore, it was shown that soluble Klotho lacks any glycosidase activity and serves as a bona fide coreceptor for FGF23 signalling. Experiments with a combination of Klotho and Fgf23-deficient mouse models demonstrated that all isoforms of Klotho lack any physiologically relevant, FGF23-independent functions in mineral homeostasis or ageing. Finally, it was demonstrated that the alternatively spliced Klotho mRNA is degraded and is not translated into a secreted Klotho protein isoform in humans.SummaryTaken together, there is now overwhelming evidence that the main physiological function of transmembrane and soluble Klotho for mineral homeostasis is their role as coreceptors mediating FGF23 actions. In light of these findings, the main pathophysiological consequence of the downregulation of Klotho observed in acute and chronic renal failure may be the induction of renal FGF23 resistance.

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Soluble klotho may be a marker of phosphate reabsorption

Cited by 15 publications

References 51 publications

Fibroblast Growth factor 23 and α-Klotho protein are associated with adverse clinical outcomes in non dialysis chronic kidney disease stage 1-5 patients

Fibroblast Growth factor 23 and α-Klotho protein are associated with adverse clinical outcomes in non dialysis chronic kidney disease stage 1-5 patients

The role of klotho in chronic kidney disease

α-Klothoʼs effects on mineral homeostasis are fibroblast growth factor-23 dependent

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