Plasma Klotho is not related to kidney function and does not predict adverse outcome in patients with chronic kidney disease

Seiler, Sarah; Wen, Ming; Roth, Heinz Jürgen; Fehrenz, Michael; Flügge, Franziska; Herath, Esther; Weihrauch, Anja; Fliser, Danilo; Heine, Gunnar H.

doi:10.1038/ki.2012.288

Cited by 133 publications

(161 citation statements)

References 33 publications

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“…36,37 In this study, we observed that the decrease of serum Klotho was closely related with the decline of eGFR in patients with CKD, which is in accordance with previous reports. 38,39 However, a recent study performed by Seiler et al 40 showed that the plasma level of Klotho was not related to renal function in patients with CKD stages 2-4. We agree with the opinion that the discrepancy is probably caused by the study design and sampling strategies, including proportion of patients with different CKD stages, exclusion of specific intervention factors, and samples prepared from serum or plasma.…”

Section: Discussionmentioning

confidence: 96%

Klotho Protects Against Indoxyl Sulphate-Induced Myocardial Hypertrophy

Yang

Wang²,

Nie

et al. 2015

Journal of the American Society of Nephrology

161

156

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Left ventricular hypertrophy (LVH) is a common complication in patients with CKD and an independent risk factor for death. Changes in the levels of uremic solutes or Klotho have been reported to be related to CKD, whereas the relationships between these factors and CKD-associated LVH remain unclear. Here, we investigated the interaction between Klotho and indoxyl sulfate (IS), a typical uremic solute, in CKD-associated LVH. In a survey of 86 patients with CKD, a negative relationship was found between serum levels of IS and Klotho (r=20.59, P,0.001). Furthermore, serum levels of IS and Klotho were independently associated with LVH (for IS: r=0.69, P,0.001; for Klotho: r=20.49, P,0.001). In normal mice, intraperitoneal injection of IS for 8 weeks induced LVH accompanied by substantial downregulation of renal Klotho. Notably, IS-induced LVH was more severe in heterozygous Klotho-deficient (kl/+) mice. In vitro, treatment with Klotho strongly inhibited IS-induced cardiomyocyte hypertrophy by blocking oxidative stress and inhibiting p38 and extracellular signal-regulated protein kinase 1/2 signaling pathways. In a mouse model of CKD-associated LVH, the renal expression of Klotho was lower and the level of serum IS was higher than in healthy controls. Moreover, treatment of CKD mice with Klotho protein significantly restrained the development of LVH. Taken together, these results suggest that Klotho is an endogenous protector against IS-induced LVH, and the imbalance between Klotho and IS may contribute to the development of LVH in CKD.

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Section: Discussionmentioning

confidence: 96%

Klotho Protects Against Indoxyl Sulphate-Induced Myocardial Hypertrophy

Yang

Wang²,

Nie

et al. 2015

Journal of the American Society of Nephrology

161

156

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“…We previously reported the association between sKlotho and CKD progression in a subgroup of 321 patients recruited before February 2011 (24).…”

Section: (17)mentioning

confidence: 99%

“…Baseline blood samples were drawn under standardized conditions and processed as described previously (24). Plasma C-terminal FGF-23 levels and sKlotho were measured by ELISA (FGF-23: Immutopics, San Clemente, CA: low cutoff, 1.5 rU/ml; high cutoff, 1500 rU/ml; samples with FGF-23 levels .1500 rU/ml were measured after dilution; sKlotho: Immuno-Biologic Laboratories, Fujiokashi, Gunma, Japan).…”

Section: Laboratory Testsmentioning

confidence: 99%

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Associations of FGF-23 and sKlotho with Cardiovascular Outcomes among Patients with CKD Stages 2–4

Seiler

Rogačev

Roth

et al. 2014

Clinical Journal of the American Society of Nephrology

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130

100

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Background and objectives CKD-mineral and bone disorders (CKD-MBD) measures contribute to cardiovascular morbidity in patients with CKD. Among these, fibroblast growth factor (FGF)-23 and its coreceptor Klotho may exert direct effects on vascular and myocardial tissues. Klotho exists in a membrane-bound and a soluble form (sKlotho). Recent experimental evidence suggests sKlotho has vasculoprotective functions.Design, settings, participants, & measurements Traditional and novel CKD-MBD variables were measured among 444 patients with CKD stages 2-4 recruited between September 2008 and November 2012 into the ongoing CARE FOR HOMe study. Across tertiles of baseline sKlotho and FGF-23, the incidence of two distinct combined end points was analyzed: (1) the first occurrence of an atherosclerotic event or death from any cause and (2) the time until hospital admission for decompensated heart failure or death from any cause.Results Patients were followed for 2.6 (interquartile range, 1.4-3.6) years. sKlotho tertiles predicted neither atherosclerotic events/death (fully adjusted Cox regression analysis: hazard ratio [HR] for third versus first sKlotho tertile, 0.75 [95% confidence interval (95% CI), 0.43-1.30]; P=0.30) nor the occurrence of decompensated heart failure/death (HR for third versus first sKlotho tertile, 0.81 [95% CI, 0.39-1.66]; P=0.56). In contrast, patients in the highest FGF-23 tertile had higher risk for both end points in univariate analysis. Adjustment for kidney function attenuated the association between FGF-23 and atherosclerotic events/death (HR for third versus first FGF-23 tertile, 1.23 [95% CI, 0.58-2.61]; P=0.59), whereas the association between FGF-23 and decompensated heart failure/death remained significant after adjustment for confounders (HR for third versus first FGF-23 tertile, 4.51 [95% CI, 1.33-15.21]; P=0.02).Conclusions In this prospective observational study of limited sample size, sKlotho was not significantly related to cardiovascular outcomes. FGF-23 was significantly associated with future decompensated heart failure but not incident atherosclerotic events.

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“…26,29 The kidney has the highest level of expression of aKlotho, but it is important to know whether aKlotho circulating in serum is derived from the kidney. Serum aKlotho levels in patients with CKD are extremely variable [30][31][32][33][34][35][36][37][38][39] probably due to assay-related variance. In contrast, renal aKlotho levels are uniformly reduced in CKD.…”

mentioning

confidence: 99%

Renal Production, Uptake, and Handling of Circulating αKlotho

Shi

Zhang³

et al. 2016

Journal of the American Society of Nephrology

221

254

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ABSTRACTaKlotho is a multifunctional protein highly expressed in the kidney. Soluble aKlotho is released through cleavage of the extracellular domain from membrane aKlotho by secretases to function as an endocrine/paracrine substance. The role of the kidney in circulating aKlotho production and handling is incompletely understood, however. Here, we found higher aKlotho concentration in suprarenal compared with infrarenal inferior vena cava in both rats and humans. In rats, serum aKlotho concentration dropped precipitously after bilateral nephrectomy or upon treatment with inhibitors of aKlotho extracellular domain shedding. Furthermore, the serum half-life of exogenous aKlotho in anephric rats was four-to five-fold longer than that in normal rats, and exogenously injected labeled recombinant aKlotho was detected in the kidney and in urine of rats. Both in vivo (micropuncture) and in vitro (proximal tubule cell line) studies showed that aKlotho traffics from the basal to the apical side of the proximal tubule via transcytosis. Thus, we conclude that the kidney has dual roles in aKlotho homeostasis, producing and releasing aKlotho into the circulation and clearing aKlotho from the blood into the urinary lumen.

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Plasma Klotho is not related to kidney function and does not predict adverse outcome in patients with chronic kidney disease

Cited by 133 publications

References 33 publications

Klotho Protects Against Indoxyl Sulphate-Induced Myocardial Hypertrophy

Klotho Protects Against Indoxyl Sulphate-Induced Myocardial Hypertrophy

Associations of FGF-23 and sKlotho with Cardiovascular Outcomes among Patients with CKD Stages 2–4

Renal Production, Uptake, and Handling of Circulating αKlotho

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