Inhibition of the Mammalian Target of Rapamycin May Augment the Increase in Soluble Klotho Levels in Renal Transplantation Recipients

Mizusaki, Kosuke; Hasuike, Yukiko; Kimura, Tomoko; Nagasawa, Yasuyuki; Kuragano, Takahiro; Yamada, Yusuke; Nojima, Masanori; Yamamoto, Shingo; Nakanishi, Takeshi; Ishihara, Masaharu

doi:10.1159/000496630

Cited by 13 publications

(14 citation statements)

References 20 publications

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“…Eighteen of these were excluded from the full-length review as they did not report the outcome of interest, while six articles were excluded because they were not observational studies. Thus, 15 studies (10 cohort studies [ 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ] with a total of 431 KTx recipients and 5 cohort studies [ 68 , 69 , 70 , 71 , 72 ] with a total of 108 living kidney donors) were included. The literature retrieval, review, and selection process are demonstrated in Figure 1 .…”

Section: Resultsmentioning

confidence: 99%

“…In addition, living donor KTx provides greater allograft longevity than those transplanted from a deceased donor [ 57 ]. However, changes in serum klotho levels and the impact of klotho on outcomes among KTx recipients and kidney donors remain unclear [ 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ]. Thus, we conducted this systematic review and meta-analysis to assess serum klotho levels and the impact of klotho on outcomes among KTx recipients and kidney donors…”

Section: Introductionmentioning

confidence: 99%

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Serum Klotho in Living Kidney Donors and Kidney Transplant Recipients: A Meta-Analysis

Neyra

Hansrivijit

Medaura

et al. 2020

JCM

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α-Klotho is a known anti-aging protein that exerts diverse physiological effects, including phosphate homeostasis. Klotho expression occurs predominantly in the kidney and is significantly decreased in patients with chronic kidney disease. However, changes in serum klotho levels and impacts of klotho on outcomes among kidney transplant (KTx) recipients and kidney donors remain unclear. A literature search was conducted using MEDLINE, EMBASE, and Cochrane Database from inception through October 2019 to identify studies evaluating serum klotho levels and impacts of klotho on outcomes among KTx recipients and kidney donors. Study results were pooled and analyzed utilizing a random-effects model. Ten cohort studies with a total of 431 KTx recipients and 5 cohort studies with a total of 108 living kidney donors and were identified. After KTx, recipients had a significant increase in serum klotho levels (at 4 to 13 months post-KTx) with a mean difference (MD) of 243.11 pg/mL (three studies; 95% CI 67.41 to 418.81 pg/mL). Although KTx recipients had a lower serum klotho level with a MD of = −234.50 pg/mL (five studies; 95% CI −444.84 to −24.16 pg/mL) compared to healthy unmatched volunteers, one study demonstrated comparable klotho levels between KTx recipients and eGFR-matched controls. Among kidney donors, there was a significant decrease in serum klotho levels post-nephrectomy (day 3 to day 5) with a mean difference (MD) of −232.24 pg/mL (three studies; 95% CI –299.41 to −165.07 pg/mL). At one year following kidney donation, serum klotho levels remained lower than baseline before nephrectomy with a MD of = −110.80 pg/mL (two studies; 95% CI 166.35 to 55.24 pg/mL). Compared to healthy volunteers, living kidney donors had lower serum klotho levels with a MD of = −92.41 pg/mL (two studies; 95% CI −180.53 to −4.29 pg/mL). There is a significant reduction in serum klotho levels after living kidney donation and an increase in serum klotho levels after KTx. Future prospective studies are needed to assess the impact of changes in klotho on clinical outcomes in KTx recipients and living kidney donors.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Serum Klotho in Living Kidney Donors and Kidney Transplant Recipients: A Meta-Analysis

Neyra

Hansrivijit

Medaura

et al. 2020

JCM

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“…The authors proposed that Klotho was mediating the rapamycin-related clinical alterations. In a renal transplantation clinical trial, everolimus significantly increased Klotho serum levels ( Mizusaki et al, 2019 ). These investigators measured Klotho levels before transplantation and 1 year after.…”

Section: Approaches To Klotho-based Therapymentioning

confidence: 99%

“…Statins: Adeli et al, 2017 ; Janic et al, 2019 ; Kuwahara et al, 2008 ; Narumiya et al, 2004 ; Yoon et al, 2012 . PPAR-γ agonists: Chen LJ, et al, 2014 ; Cheng et al, 2017 ; Huang KC, et al, 2014 ; Maquigussa et al, 2018 ; Shen et al, 2018 ; Zhang H, et al, 2008. mTOR inhibitors: Mizusaki et al, 2019 ; Tabibzadeh, 2021 ; Tataranni et al, 2011 ; Zhao Y, et al, 2015. Vitamin D: Haussler et al, 2020 ; Kuro-o, 2019 ; Lerch et al, 2018 ; Tsujikawa al., 2003.…”

Section: Approaches To Klotho-based Therapymentioning

confidence: 99%

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Prud’homme

Kurt²,

Wang

2022

Front. Aging

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The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.

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“…Finally, Klotho can be inducible by other substances and then acts as an induced protective factor to inhibit VC. Upregulation of Klotho expression by inhibiting mTOR signaling via oral rapamycin ameliorates VC and protects against vascular disease in CKD [60]. Another study showed that intermedin 1-53 attenuates VC in rats with CKD by upregulating membrane-bound Klotho expression in the vessel wall [61].…”

Section: The Role Of Klotho In Vcmentioning

confidence: 99%

The Protective Role of Klotho in CKD-Associated Cardiovascular Disease

Yang

Zhang

et al. 2020

Kidney Dis

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Background: Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in advanced CKD. The major pathological changes of CKD-associated CVD are severe vascular media calcification, aberrant cardiac remodeling such as hypertrophy and fibrosis, as well as accelerated atherosclerosis. α-Klotho is proposed as an anti-aging gene, which is primarily expressed in the kidney. Recent studies reveal that α-Klotho deficiency is associated with profound cardiovascular dysfunction. Of note, CKD represents extremely declined α-Klotho levels, hinting that α-Klotho deficiency may be implicated in the pathogenesis of CKD-associated CVD. Summary: Based on the pathogenic mechanism of α-Klotho deficiency and decreased Klotho levels in the circulation even early in stage 1 of CKD, α-Klotho serves as a sensitive biomarker for renal insufficiency and also a novel predictor of risk of overall mortality of CVD events in CKD. Meanwhile, loss of Klotho resulted from kidney dysfunction markedly contributes to the progressive development of CKD and CVD. By contrast, prevention of Klotho decline using exogenous supplementation or genetically activated ways by several mechanisms can dramatically mitigate cardiac dysfunction, prevent vascular calcification, and retard the progression of CKD-accelerated atherosclerosis. Key Messages: Klotho deficiency is proposed as a novel predictive biomarker as well as a pathogenic contributor to CVD events in CKD. In the future, Klotho may be a crucial potential therapeutic strategy to decrease the burden of CVD comorbidity with CKD in clinics.

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Inhibition of the Mammalian Target of Rapamycin May Augment the Increase in Soluble Klotho Levels in Renal Transplantation Recipients

Cited by 13 publications

References 20 publications

Serum Klotho in Living Kidney Donors and Kidney Transplant Recipients: A Meta-Analysis

Serum Klotho in Living Kidney Donors and Kidney Transplant Recipients: A Meta-Analysis

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

The Protective Role of Klotho in CKD-Associated Cardiovascular Disease

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