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    Soluble serum Klotho levels in healthy subjects. Comparison of two different immunoassays. Pedersen Lise,Pedersen Susanne Møller,Brasen Claus Lohman,Rasmussen Lars Melholt Clinical biochemistry OBJECTIVE:Soluble serum Klotho is a new biomarker linked to chronic kidney disease, cardiovascular disease and diabetes. This study describes the evaluation and comparison of two different immunoassays and establishment of assay specific reference intervals in adults. DESIGN AND METHODS:Serum Klotho concentrations were determined in 120 healthy adults aged 19-66 years. Blood samples were collected, and stored sera were assayed for Klotho according to age and gender. In addition several other clinical and laboratory characteristics were determined in the cohort and compared to the levels of serum Klotho. RESULTS:Serum Klotho levels were significantly higher in time-resolved fluorescence immunoassay (TRF) compared to an ELISA (IBL) and no correlation was found between the assays. No signal was obtained in either assay when the standard curve was switched between the two different immunoassays. The median serum Klotho concentration using TRF was 61 ng/mL (2.5-97.5% reference limits; 11-181 ng/mL) for males and 99 ng/mL (2.5-97.5% reference limits; 19-316 ng/mL) for females while the ELISA gave a mean value of 472 pg/mL (2.5-97.5% reference limits; 204-741 pg/mL) with no difference between genders. Concentrations of serum Klotho were independently associated with estimated glomerular filtration rate (eGFR) and body weight using TRF whereas serum Klotho concentrations were associated with age using the ELISA. CONCLUSION:Comparison of two different immunoassays for serum Klotho indicate, that the protein exists in human beings in different forms which may function as independent factors and whose role and potential value as biomarkers needs to be evaluated separately. Reference intervals specific for the different forms recognized by the different assays were calculated in this study. 10.1016/j.clinbiochem.2013.05.046
    [Research Progress of Klotho]. Chang Jin-Rui,Sun Na,Nan Ying,Yu Wei,Qi Yong-Fen Sheng li ke xue jin zhan [Progress in physiology] Klotho, a newly identified anti-aging gene, can be regulated by many factors, such as calcitonin gene-related peptide, fibroblast growth factor 2 could up-regulate Klotho expression; whereas renin-angiotensin system, urinary toxins, inflammation and oxidative stress could reduce expression of Klotho. There are two forms of Klotho protein: membrane-bound Klotho and secreted Klotho. Existing studies showed that Klotho was involved in the development of many diseases, including vascular calcification, atherosclerosis, hypertension, kidney damage, hyperparathyroidism, diabetes and tumors. In this paper, the regulation of Klotho expression and its role in diseases are reviewed briefly.
    Soluble Klotho levels in diabetic nephropathy: relationship with arterial stiffness. Inci A,Sari F,Olmaz R,Coban M,Dolu S,Sarikaya M,Ellidag H Y European review for medical and pharmacological sciences OBJECTIVE:In this cross-sectional study, we investigate the relationship between soluble Klotho (s-Klotho) levels, markers of bone mineral metabolism and arterial stiffness in 109 diabetic nephropathy patients (median age 61.00± 9.77 years) and 32 healthy controls (median age 49.23 ± 7.32 years). PATIENTS AND METHODS:Blood samples were collected to measure the levels of s-Klotho, and FGF23, serum creatinine, Calcium (Ca), Phosphorus (P), 25-hydroxyvitamin D3 (25hD) and parathyroid hormone (PTH). Pulse wave velocity (PWV) and blood pressure were also measured using a combined monitor. RESULTS:s-Klotho, FGF23 and PTH levels were significantly higher and 25hD was significantly lower in the patients than in controls (p < 0.001). Systolic blood pressure, pulse pressure and PWV were also significantly higher in the patients (p < 0.001). s-Klotho, FGF23 and 25hD levels significantly varied between sub-groups according to CKD stages, defined according to the CKD epidemiology collaboration equation. A strong positive correlation was found between s-Klotho and FGF23 (r = 0.768, p = 0.001) levels, but not with other bone mineral metabolism, blood pressure or arterial stiffness parameters. Creatinine levels significantly differed (p = 0.009) between three s-Klotho-level sub-groups, with the high creatinine levels in the sub-group with the lowest s-Klotho levels and estimated glomerular filtration rate (eGFR). CONCLUSIONS:There was no correlation between eGFR and s-Klotho levels. Arterial stiffness increased in CKD but was not related to s-Klotho or FGF23 levels. Among all parameters, FGF23 levels had the greatest effect on s-Klotho levels.
    Soluble Klotho Improves Hepatic Glucose and Lipid Homeostasis in Type 2 Diabetes. Gu Huiying,Jiang Wei,You Nan,Huang Xiaobing,Li Yuming,Peng Xuehui,Dong Rui,Wang Zheng,Zhu Yinan,Wu Ke,Li Jing,Zheng Lu Molecular therapy. Methods & clinical development Type 2 diabetes (T2D) is one of the most escalating global metabolic diseases, which is highly associated with insulin resistance (IR) and risk of combination with nonalcoholic fatty liver disease (NAFLD). Previous studies suggest that soluble klotho (sKL) could serve as a circulating hormone to mediate energy metabolism, but the detailed mechanism is poorly understood. In this study, we generated T2D models of wild-type (WT), heterozygous ( ), and transgenic (Tg) mice continuously fed a high-fat diet (HFD) and constructed L02 cell lines that stably overexpress to investigate the effect of sKL on hepatic glucose and lipid metabolism. Surprisingly, we discovered that sKL deficiency resulted in exacerbated diabetic phenotypes and hepatic glucolipid metabolism disorders in HFD-fed diabetic mice ( DM), whereas TgKL diabetic mice (TgKL DM) exhibited ameliorated diabetic phenotypes and decreased IR. Mechanistic studies and demonstrated that sKL could inhibit the PI3K/AKT/mTORC1 signaling to upregulate peroxisome proliferator-activated receptor α (PPARα) expression by directly interacting with type 1 insulin-like growth factor receptor (IGF1R) in HFD-fed T2D mice. Thus, sKL could improve hepatic glucolipid homeostasis to ameliorate diabetic phenotypes and lipid accumulation and may function as a potential therapeutic target for the treatment of T2D and reduce the risk of NAFLD. 10.1016/j.omtm.2020.08.002
    Increased oxidative stress in diabetic nephropathy and its relationship with soluble Klotho levels. Inci A,Olmaz R,Sarı F,Coban M,Ellidag H Y,Sarıkaya M Hippokratia BACKGROUND:In the present study, we aimed to assess the relationship between the levels of soluble Klotho (s-Klotho) and oxidative stress markers in diabetic nephropathy patients with different stages of chronic kidney disease (CKD) and albuminuria levels. METHODS:We enrolled 109 patients with type 2 diabetes (mean age, 61.63 ± 9.77 years) and 32 healthy controls (mean age, 49.53 ± 7.32 years) between January and June 2014.  Patients were classified into three groups based on their urinary albumin/creatinine ratio (UACR). Blood samples were collected to measure the levels of s-Klotho, serum creatinine, calcium, phosphorus, 25-hydroxyvitamin D3, and parathyroid hormone (PTH). We used the total oxidant status (TOS), total antioxidant status (TAS), ischemia-modified albumin (IMA), and ischemia-modified albumin ratio (IMAR) values to measure the oxidative status. Moreover, the oxidative stress index (OSI) was estimated as the percentage ratio of TOS/TAS values. RESULTS:The TOS, TAS, and OSI values were significantly greater in the diabetic nephropathy patients compared to controls (p <0.001). When patients were classified based on their UACR, we noted that the TOS, OSI, and IMA values did not significantly differ, although the TAS (p <0.001), and IMAR (p =0.002) values significantly differed between the groups. The s-Klotho levels also significantly differed (p =0.031) between the groups. These s-Klotho levels exhibited a significant positive correlation with TOS (r =0.186, p =0.034) and OSI (r =0.207 p =0.018), but showed no correlation with the estimated glomerular filtration rate; UACR; HbA1c, calcium, phosphorus, and PTH levels; and TAS, IMA, and IMAR values. CONCLUSION:Oxidative stress is greater in patients with diabetic nephropathy, and the TOS was positively correlated with s-Klotho levels in diabetic patients. The therapeutic reduction of oxidative stress in patients with diabetic nephropathy could improve the renal and cardiovascular outcomes. Hippokratia 2016, 20(3): 198-203.
    Soluble Klotho and fibroblast growth factor 23 levels in diabetic nephropathy with different stages of albuminuria. Inci Ayca,Sari Funda,Coban Melahat,Olmaz Refik,Dolu Suleyman,Sarıkaya Metin,Yılmaz Necat Journal of investigative medicine : the official publication of the American Federation for Clinical Research The relationship between soluble Klotho (s-Klotho) levels, fibroblast growth factor 23 (FGF23) levels, and albuminuria in patients with diabetic chronic kidney disease (CKD) remains unclear. A total of 109 patients with type 2 diabetes (mean age 61.63±9.77 years), at the outpatient clinic of the Antalya Research and Training Hospital Nephrology Unit between January and June 2014, as well as 32 healthy controls (mean age 49.53±7.32 years) were enrolled for this cross-sectional study. Patients were classified into three groups according to their urinary albumin creatinine ratio (UACR), normoalbuminuria (UACR<30 mg/g), microalbuminuria (UACR 30-300 mg/g), and macroalbuminuria (UACR>300 mg/g). The blood was analyzed for FGF23, s-Klotho, parathyroid hormone (PTH), P, Ca, creatinine, and 25-hydroxyvitamin D3 (25hD) levels. Creatinine, s-Klotho, FGF23, and PTH levels were significantly higher and 25hD levels were significantly lower in the patient group than in the healthy controls (p<0.001). Between the groups according to UACR, 1-way analysis of variance revealed statistically significant differences for creatinine (p<0.001), 25hD (p<0.001), PTH (p=0.002), Ca (p=0.002), and albumin levels (p<0.001). A statistically significant positive correlation was found between s-Klotho and FGF23 (r=0.768; p=0.001), and between FGF23 levels and UACR (r=0.768; p=0.001). In conclusion, the results of the present study suggest that s-Klotho levels are significantly elevated in patients with diabetes and s-Klotho levels decreased with increasing albumin excretion in our patients despite a reduction in estimated glomerular filtration rate. 10.1136/jim-2016-000142
    Plasma klotho and cardiovascular disease in adults. Semba Richard D,Cappola Anne R,Sun Kai,Bandinelli Stefania,Dalal Mansi,Crasto Candace,Guralnik Jack M,Ferrucci Luigi Journal of the American Geriatrics Society OBJECTIVES:To determine whether plasma klotho, a recently discovered hormone that has been implicated in atherosclerosis, is related to prevalent cardiovascular disease (CVD) in adults. DESIGN:Cross-sectional. SETTING:Population-based sample of adults residing in Tuscany, Italy. PARTICIPANTS:One thousand twenty-three men and women aged 24 to 102 participating in the Invecchiare in Chianti (InCHIANTI) study. MEASUREMENTS:Anthropometric measures, plasma klotho, fasting plasma total, high-density lipoprotein cholesterol (HDL-C), triglycerides, glucose, creatinine, C-reactive protein (CRP). Clinical measures: medical assessment, diabetes mellitus, hypertension, coronary heart disease, heart failure, stroke, peripheral artery disease, cancer, chronic kidney disease. Logistic regression models were used to examine the relationship between plasma klotho and prevalent CVD. RESULTS:Of 1,023 participants, 259 (25.3%) had CVD. Median (25th, 75th percentile) plasma klotho concentrations were 676 pg/mL (530, 819 pg/mL). Plasma klotho was correlated with age (correlation coefficient (r) = -0.14, P < .001), HDL-C (r = 0.11, P<.001), and CRP (r = -0.10, P < .001) but not systolic blood pressure, fasting plasma glucose, or renal function. Plasma klotho age-adjusted geometric means were 626 pg/mL (95% confidence interval (CI) = 601-658 pg/mL) in participants with CVD and 671 pg/mL (95% CI = 652-692 pg/mL) in those without CVD (P = .001). Adjusting for traditional cardiovascular risk factors (age, sex, smoking, total cholesterol, HDL-C, systolic blood pressure, and diabetes mellitus), log plasma klotho was associated with prevalent CVD (odds ratio per 1 standard deviation increase = 0.85, 95% CI = 0.72-0.99). CONCLUSION:In community-dwelling adults, higher plasma klotho concentrations are independently associated with a lower likelihood of having CVD. 10.1111/j.1532-5415.2011.03558.x
    Rapid decline of kidney function in diabetic kidney disease is associated with high soluble Klotho levels. Bob Flaviu,Schiller Adalbert,Timar Romulus,Lighezan Daniel,Schiller Oana,Timar Bogdan,Bujor Cristiana Georgeta,Munteanu Mircea,Gadalean Florica,Mihaescu Adelina,Grosu Iulia,Hategan Andreea,Chisavu Lazar,Pusztai Agneta-Maria,Covic Adrian Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia BACKGROUND:Klotho is found in two forms: a transmembrane form and a soluble form (s-Klotho). In order to be excreted, s-Klotho, that is too large to be filtered, will probably reach the proximal convoluted tubule by a transcytosis process. The aim of our study was to show the relationship between the levels of s-Klotho and tubular injury in patients with diabetic kidney disease (DKD), using as tubular injury marker the kidney injury molecule-1 (KIM-1). METHODS:Our study included 63 DKD patients (stages 1-5, mean eGFR 65.15±32.45ml/min) with a mean age 58.13±12 years. In all patients we determined serum levels of: KIM-1 and s-Klotho using ELISA, urinary albumin/creatinine ratio (UACR) and reduction in the estimated glomerular filtration rate (eGFR) per year. RESULTS:We found a strong statistically significant correlation of s-Klotho with the rate of reduction of eGFR/year (r=0.714, p=0.0004) and with the tubular injury marker KIM-1 (r=0.758, p=0.005) and strong correlations of UACR with the rate of reduction of eGFR/year (r=0.53, p<0.01), KIM-1 (r=0.49, p<0.05) and s-Klotho (r=0.52, p<0.01). CONCLUSION:Despite previous published data, that shows a decrease of s-Klotho in chronic kidney disease, in our study the rapid annual decline of kidney function but not the level of eGFR was associated with increased s-Klotho. A possible explanation could be a more severe proximal tubule injury that could lead to a reduction of tubular excretion of s-Klotho as suggested by the correlation of s-Klotho levels with the serum levels of KIM-1. 10.1016/j.nefro.2018.08.004
    Systemic Klotho therapy protects against insulitis and enhances beta-cell mass in NOD mice. Prud'homme Gérald J,Glinka Yelena,Kurt Merve,Liu Wenjuan,Wang Qinghua Biochemical and biophysical research communications The levels of the anti-aging protein α-Klotho, in its soluble form (s-Klotho), are depressed in the circulation of patients with type 1 diabetes (T1D) or type 2 diabetes (T2D). Gene transfer experiments have suggested a protective role for β-cell specific expression of α-Klotho in murine models of T1D and T1D, but these approaches are not easily translatable to clinical therapy. It is unknown whether systemic s-Klotho protein treatment ameliorates disease in T1D, which is characterized by autoimmune destruction of β cells. We previously reported from in vitro experiments with β cells that s-Klotho increases insulin secretion, reduces cells death and promotes β-cell replication. Here, we investigated s-Klotho protein therapy in NOD mice, which have autoimmune T1D. We observed that diabetic NOD mice have significantly lower plasma levels of s-Klotho, compared to their non-diabetic counterparts. To examine in vivo effects of Klotho, we treated NOD mice with s-Klotho protein, or with a Klotho blocking antibody. Systemic treatment with s-Klotho ameliorated diabetes; notably increasing β-cell replication and total β-cell mass. Klotho expression was increased locally in the islets. s-Klotho also markedly reduced immune-cell infiltration of islets (insulitis). In contrast, administration of the Klotho antibody was detrimental, and aggravated the loss of β-cell mass. Thus, s-Klotho has protective effects in this model of T1D, and this appears to depend on a combination of increased β-cell replication and reduced insulitis. These findings suggest that s-Klotho might be effective as a new therapeutic agent for T1D. 10.1016/j.bbrc.2020.02.123
    Roles of klotho and stem cells in mediating vascular calcification (Review). Yu Liangzhu,Li Mincai Experimental and therapeutic medicine Vascular calcification, characterized by the active deposition of calcium phosphate in the vascular walls, is commonly observed in aging, diabetes mellitus and chronic kidney disease. This process is mediated by different cell types, including vascular stem/progenitor cells. The anti-aging protein klotho may act as an inhibitor of vascular calcification through direct effects on vascular stem/progenitor cells with osteogenic differentiation potential. A better understanding of the possible effects of klotho on vascular stem/progenitor cells may provide novel insight into the cellular and molecular mechanisms of klotho deficiency-related vascular calcification and disease. The klotho protein may be considered as a promising therapeutic agent for treating vascular calcification and disease and calcification-related vascular diseases. 10.3892/etm.2020.9252
    Circulating Levels of Soluble Klotho and Fibroblast Growth Factor 23 in Diabetic Patients and Its Association with Early Nephropathy. Farías-Basulto Alfonso,Martínez-Ramírez Héctor Ramón,Gómez-García Erika Fabiola,Cueto-Manzano Alfonso Martín,Cortés-Sanabria Laura,Hernández-Ramos Luis Eduardo,Ramírez-López Guadalupe,Mendoza-Carrera Francisco Archives of medical research INTRODUCTION:Diabetic nephropathy is a leading cause of chronic kidney disease (CKD). In diabetes, changes in serum levels of both soluble alpha Klotho (sKL) and fibroblast growth factor 23 (FGF-23) have been associated with CKD progression. OBJECTIVE:To evaluate the associations of circulating levels of sKL and FGF-23 with the presence of early nephropathy (EN) in diabetic patients. METHODS:A cross-sectional study in 136 Mexicans with type 2 diabetes mellitus (T2DM). Early nephropathy was defined as an estimated glomerular filtration rate (≥60 ml/min) and urinary albumin excretion (≥30 mg/g). Serum concentrations of sKL and FGF-23 were measured using ELISA. Associations were evaluated with multiple logistic regression. RESULTS:Fifty-two subjects had EN. Median values of sKL and FGF-23 for all individuals were 244 pg/mL (interquartile range [IQR]: 201-402) and 92 pg/mL (IQR: 39-507), respectively. A positive correlation was found between levels of sKL and FGF-23 (r = 0.38; p <0.001). FGF-23 levels correlated negatively with angiotensin-II receptor blocker therapy (ARB, r = 0.24; p <0.01). Subjects without EN were younger (59 vs. 63 years old, p = 0.02). Elevated concentrations of FGF-23 were negatively associated with EN (Odds Ratio [OR] = 0.29, 95% Confidence Interval [95% CI] = 0.13, 0.65). CONCLUSIONS:In Mexican diabetic patients, serum levels of FGF-23 were positively correlated with sKL but negatively correlated with ARB therapy. In addition, a higher concentration of FGF-23 reduced the odds of early nephropathy in patients with T2DM. 10.1016/j.arcmed.2019.01.008
    Plasmatic Klotho and FGF23 Levels as Biomarkers of CKD-Associated Cardiac Disease in Type 2 Diabetic Patients. Silva Ana Paula,Mendes Filipa,Carias Eduarda,Gonçalves Rui Baptista,Fragoso André,Dias Carolina,Tavares Nelson,Café Hugo Mendonça,Santos Nélio,Rato Fátima,Leão Neves Pedro,Almeida Edgar International journal of molecular sciences BACKGROUND:Research over the past decade has focused on the role of Klotho as a cardio protective agent that prevents the effects of aging on the heart and reduces the burden of cardiovascular disease CVD. The role of the interaction between fibroblast growth factor 23-(FGF-23)/Klotho in Klotho-mediated actions is still under debate. The main objective was to ascertain the potential use of plasmatic Klotho and FGF23 as markers for CKD-associated cardiac disease and mortality. METHODS:This was a prospective analysis conducted in an outpatient diabetic nephropathy clinic, enrolling 107 diabetic patients with stage 2⁻3 CKD. Patients were divided into three groups according to their left ventricular mass index and relative wall thickness. RESULTS:Multinomial regression analysis demonstrated that low Klotho and higher FGF-23 levels were linked to a greater risk of concentric hypertrophy. In the generalized linear model (GLM), Klotho, FGF-23 and cardiac geometry groups were statistically significant as independent variables of cardiovascular hospitalization ( = 0.007). According to the Cox regression model, fatal cardiovascular events were associated with the following cardiac geometric classifications; eccentric hypertrophy ( = 0.050); concentric hypertrophy ( = 0.041), and serum phosphate ≥ 3.6 mg/dL ( = 0.025), FGF-23 ≥ 168 ( = 0.0149), α-klotho < 313 ( = 0.044). CONCLUSIONS:In our population, Klotho and FGF23 are associated with cardiovascular risk in the early stages of CKD. 10.3390/ijms20071536
    Decreased plasma α-Klotho predict progression of nephropathy with type 2 diabetic patients. Kim Sang Soo,Song Sang Heon,Kim In Joo,Lee Eun Young,Lee Su Mi,Chung Choon Hee,Kwak Ihm Soo,Lee Eun Kyung,Kim Yong Ki Journal of diabetes and its complications AIM:The potential role of soluble α-klotho in diabetic kidney disease has not yet been evaluated. The aim of this study was to evaluate the association of plasma and/or urine α-klotho with the progression of type 2 diabetic nephropathy. METHODS:The baseline values of plasma and urine α-klotho were measured in 147 patients with type 2 diabetes mellitus with an estimated glomerular filtration rate (eGFR) of ≥60mL/min/1.73m(2). In this prospective observational study, a total of 109 type 2 diabetic patients were followed up for 34months (8-50 months). RESULTS:Plasma α-klotho, but not urine α-klotho, was negatively correlated with the decline of eGFR (r=-0.304, P=0.001; r=0.042, P=0.068, respectively). After adjusting for several clinical parameters, baseline eGFR and urine ACR, plasma α-klotho was significantly associated with the decline of eGFR (r=-0.219, P=0.008). In the normoalbuminuria group (n=63), the plasma α-klotho remained significantly associated with a decline in eGFR (r=0.324, P=0.004) in the final model. CONCLUSIONS:It is suggested that plasma α-klotho may be an early biomarker for predicting renal impairment in type 2 diabetic patients. The disappearance of a compensatory increase of plasma α-klotho might be a predictive marker for the progression of type 2 diabetic nephropathy. 10.1016/j.jdiacomp.2016.03.006
    Association of plasma soluble α-klotho with pro-endothelin-1 in patients with type 2 diabetes. Liu Jian-Jun,Liu Sylvia,Morgenthaler Nils G,Wong Melvin D S,Tavintharan Subramaniam,Sum Chee Fang,Lim Su Chi Atherosclerosis OBJECTIVES:To study the relationship between plasma soluble klotho (sKlotho) and pro-endothelin-1 (proET-1) in patients with type 2 diabetes (T2DM). SUBJECTS AND METHODS:In this cross-sectional study, we recruited 175 T2DM subjects and 56 non-diabetic controls. Plasma sKlotho, proET-1 and extracellular superoxide dismutase (SOD) were measured by ELISA and ILMA, respectively. RESULTS:Plasma sKlotho level in patients with T2DM was lower compared to that in non-diabetic controls (416.8±148.1 vs. 494.6±134.3 pg/ml, p=0.001) and showed significant interaction with diabetes status in its association with proET-1. Plasma sKlotho was inversely correlated with proET-1 in T2DM (Rho=-0.410, p<0.0001) but not in non-diabetic controls (Rho=0.091, p=0.505). Multivariable linear regression models revealed that sKlotho was independently associated with proET-1 after adjustment for renal filtration function, albuminuria, diabetes duration, HbA1c, systolic and diastolic blood pressure. CONCLUSIONS:Plasma sKlotho was associated with proET-1 independent of renal function in patients with T2DM. 10.1016/j.atherosclerosis.2014.01.024
    Validation of an immunoassay for soluble Klotho protein: decreased levels in diabetes and increased levels in chronic kidney disease. Devaraj Sridevi,Syed Basir,Chien Alexander,Jialal Ishwarlal American journal of clinical pathology The Klotho gene has been identified as an aging suppressor gene that encodes a transmembrane protein, which is expressed primarily in renal tubules. There are 2 forms of Klotho, membrane and secreted. However, there is a paucity of data on levels of soluble Klotho in diseases like diabetes and kidney disease. We validated an enzyme-linked immunosorbent assay for Klotho and quantitated Klotho levels separately in patients with diabetes and also in patients with chronic kidney disease (CKD). The Klotho assay showed good precision and was linear down to 19 ng/mL. There were no significant effects on Klotho levels with the addition of common interferents such as ascorbate, triglycerides, or hemolysis; only bilirubin (250 mg/L) significantly reduced Klotho levels (P < .05). There was a significant reduction in Klotho levels in samples with glycated hemoglobin (HbA(1c)) levels of 6.5% or more compared with control samples (HbA(1c) < 6.5%; P < .001). We also documented significantly higher levels of Klotho with CKD. Thus, we validated an assay for Klotho and made the novel observation that levels are decreased in diabetes and increased in CKD. 10.1309/AJCPGPMAF7SFRBO4
    Reduced Levels of Anti-Ageing Hormone Klotho Predict Renal Function Decline in Type 2 Diabetes. Fountoulakis Nikolaos,Maltese Giuseppe,Gnudi Luigi,Karalliedde Janaka The Journal of clinical endocrinology and metabolism Context and Objective:Soluble Klotho (sKlotho) is a circulating hormone with cardiovascular-renal protective effects. Whether sKlotho predicts estimated glomerular filtration rate (eGFR) decline in patients with type 2 diabetes mellitus (T2DM) with relatively preserved renal function is unknown. Design, Setting, Participants, and Measurements:Single-center observational follow-up study of 101 patients with T2DM and eGFR >45 mL/min [91% on renin angiotensin system (RAS) blockade] followed for a median of 9 years (range, 2 to 13 years). Main Outcome:Primary outcome was a >50% decline in eGFR. sKlotho, serum phosphorus, serum calcium, and fibroblast growth factor-23 levels were measured from stored samples collected at baseline. Patients were followed up with standardized clinical and biochemical measurements. Results:Patients with residual microalbuminuria (MA) despite RAS blockade (n = 53) had significantly lower levels of sKlotho [median, 184.7 pg/mL; interquartile range (IQR), 130.5 to 271.8 pg/mL) compared with patients without MA (n = 39; median, 235.2 pg/mL; IQR, 172.0 to 289.4 pg/mL; P = 0.03). Of the cohort, 21% reached the primary outcome. In a competing risk analysis, a 10% higher sKlotho level reduced the incidence of the primary outcome by 12% (hazard ratio, 0.27; 95% confidence interval, 0.15 to 0.52; P < 0.001] independent of traditional risk factors. Patients with sKlotho below the median of 204.4 pg/mL had nearly a fourfold higher cumulative incidence of the primary outcome compared with those above the median (24% vs 6.2%; P = 0.01). Conclusions:In patients with T2DM with relatively preserved eGFR, reduced levels of sKlotho predict renal function decline independent of traditional risk markers. sKlotho is a biomarker of renal dysfunction and a potential treatment target for renoprotection in T2DM. 10.1210/jc.2018-00004
    Circulating Klotho levels can predict long-term macrovascular outcomes in type 2 diabetic patients. Pan Heng-Chih,Chou Kuei-Mei,Lee Chin-Chan,Yang Ning-I,Sun Chiao-Yin Atherosclerosis BACKGROUND AND AIMS:Type 2 diabetes is a global health problem that is associated with a wide variety of vascular complications and associated morbidity and mortality. Klotho is an enzyme and transmembrane protein, and increasing evidence suggests that Klotho may contribute to reduced oxidative stress, improved endothelial function, and vasoprotection. To date, the physiological role of Klotho in vascular complications associated with diabetes is unclear. METHODS:We prospectively recruited 252 patients with type 2 diabetes, who visited an outpatient clinic at our hospital between 2009 and 2011. Patients in the top and bottom tertiles of circulating Klotho levels were enrolled for analysis. RESULTS:Of the 168 patients enrolled, 45.8% were male, the mean age was 57.2 years, and the average duration of diabetes was 7.58 years. In multiple regression analysis, a high Klotho level was associated with a reduced risk of developing coronary artery disease and cerebrovascular accidents. Klotho level was also an independent predictor for the development of macroangiopathies within the 7-year study period. CONCLUSIONS:Our results suggest that circulating Klotho level is a predictor of long-term macrovascular outcomes in patients with type 2 diabetes. 10.1016/j.atherosclerosis.2018.07.006
    Soluble α-klotho as a novel biomarker in the early stage of nephropathy in patients with type 2 diabetes. Lee Eun Young,Kim Sang Soo,Lee Ji-Sung,Kim In Joo,Song Sang Heon,Cha Seung-Kuy,Park Kyu-Sang,Kang Jeong Suk,Chung Choon Hee PloS one OBJECTIVE:Although α-klotho is known as an anti-aging, antioxidant, and cardio-renal protective protein, the clinical implications of soluble α-klotho levels in patients with diabetes have not been evaluated. Therefore, this study evaluated whether plasma and urinary α-klotho levels are associated with albuminuria in kidney disease in diabetes. RESEARCH DESIGN AND METHODS:A total of 147 patients with type 2 diabetes and 25 healthy control subjects were enrolled. The plasma and urine concentrations of α-klotho were analyzed by enzyme-linked immunosorbent assay. RESULTS:Plasma α-klotho (572.4 pg/mL [95% CI, 541.9-604.6 pg/mL] vs. 476.9 pg/mL [95% CI, 416.9-545.5 pg/mL]) and urinary α-klotho levels (59.8 pg/mg creatinine [95% CI, 43.6-82.0 pg/mg creatinine] vs. 21.0 pg/mg creatinine [95% CI, 9.7-45.6 pg/mg creatinine]) were significantly higher in diabetic patients than non-diabetic controls. Among diabetic patients, plasma α-klotho concentration was inversely associated with albuminuria stages (normoalbuminuria, 612.6 pg/mL [95% CI, 568.9-659.6 pg/mL], microalbuminuria, 551.8 pg/mL [95% CI, 500.5-608.3 pg/mL], and macroalbuminuria, 505.7 pg/mL [95% CI, 439.7-581.7 pg/mL] (p for trend  = 0.0081), while urinary α-klotho levels were remained constantly high with increasing urinary albumin excretion. CONCLUSIONS:Soluble α-klotho levels in plasma and urine may be novel and useful early markers of diabetic renal injury. 10.1371/journal.pone.0102984
    The changes of serum sKlotho and NGAL levels and their correlation in type 2 diabetes mellitus patients with different stages of urinary albumin. Wu Can,Wang Qiuyue,Lv Chuan,Qin Ningning,Lei Sha,Yuan Qin,Wang Guan Diabetes research and clinical practice OBJECTIVE:To investigate the changes of serum anti-aging protein Klotho and neutrophil gelatinase-associated lipocalin (NGAL) levels and their correlation in type 2 diabetes mellitus (T2DM) patients at different stages of diabetic kidney disease (DKD) determined by urinary albuminuria. METHODS:462 cases with T2DM were divided into three groups: normoalbuminuric [N-UAlb; urinary albumin to creatinine ratio (UACR) < 30 mg/g, n=180], microalbuminuric [M-UAlb; UACR 30-300 mg/g, n = 158], macroalbuminuric [L-UAlb; UACR > 300 mg/g, n = 124]. The levels of serum soluble-Klotho (sKlotho), NGAL, 8-isoprostane prostaglandin F2α (8-iso-PGF2α), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) were determined by enzyme-linked immunosorbent assay (ELISA) in all cases and 160 control subjects. RESULTS:Compared with control, serum sKlotho levels were significantly decreased (P < 0.001), and serum NGAL levels increased significantly (P < 0.001) in T2DM patients. Furthermore, serum sKlotho and NGAL levels were significantly negatively correlated (P < 0.001). Serum sKlotho levels negatively correlated with UACR, TG, CHO, LDL, 8-Iso-PGF2α, MCP-1, TNF-α, TGF-β1 (P < 0.001), but positively correlated with LDL (P < 0.001). Serum NGAL levels positively correlated with UACR, 8-Iso-PGF2α, MCP-1, TNF-α, TGF-β1 (P < 0.001). In addition, serum NGAL levels and LDL were significantly positively correlated (P = 0.005), and HDL was significantly negatively correlated (P < 0.001). CONCLUSION:Serum Klotho and NGAL levels may become new biomarkers of the early diagnosis of DKD in T2DM. Klotho may participate in the development of DKD pathological mechanism such as oxidative stress related to inflammation, renal fibrosis, lipid metabolic disorders, modulating the pathological process of diabetic kidney tissue. NGAL may play a part in these mechanisms. 10.1016/j.diabres.2014.08.026
    FGF23 and Klotho Levels are Independently Associated with Diabetic Foot Syndrome in Type 2 Diabetes Mellitus. Donate-Correa Javier,Martín-Núñez Ernesto,Ferri Carla,Hernández-Carballo Carolina,Tagua Víctor G,Delgado-Molinos Alejandro,López-Castillo Ángel,Rodríguez-Ramos Sergio,Cerro-López Purificación,López-Tarruella Victoria Castro,Arévalo-González Miguel Angel,Pérez-Delgado Nayra,Mora-Fernández Carmen,Navarro-González Juan F Journal of clinical medicine BACKGROUND:Diabetic foot syndrome (DFS) is a prevalent complication in the diabetic population and a major cause of hospitalizations. Diverse clinical studies have related alterations in the system formed by fibroblast growth factor (FGF)-23 and Klotho (KL) with vascular damage. In this proof-of-concept study, we hypothesize that the levels of FGF23 and Klotho are altered in DFS patients. METHODS:Twenty patients with limb amputation due to DFS, 37 diabetic patients without DFS, and 12 non-diabetic cadaveric organ donors were included in the study. Serum FGF23/Klotho and inflammatory markers were measured by enzyme-linked immunosorbent assay (ELISA). Protein and gene expression levels in the vascular samples were determined by immunohistochemistry and quantitative real-time PCR, respectively. RESULTS:Serum Klotho is significantly reduced and FGF23 is significantly increased in patients with DFS ( < 0.01). Vascular immunoreactivity and gene expression levels for Klotho were decreased in patients with DFS ( < 0.01). Soluble Klotho was inversely related to serum C-reactive protein ( = -0.30, < 0.05). Vascular immunoreactivities for Klotho and IL6 showed an inverse association ( = -0.29, < 0.04). Similarly, vascular gene expression of and were inversely associated ( = -0.31, < 0.05). Logistic regression analysis showed that higher Klotho serum concentrations and vascular gene expression levels were related to a lower risk of DFS, while higher serum FGF23 was associated with a higher risk for this complication. CONCLUSION:FGF23/Klotho system is associated with DFS, pointing to a new pathophysiological pathway involved in the development and progression of this complication. 10.3390/jcm8040448
    Clinical implication of alterations in serum Klotho levels in patients with type 2 diabetes mellitus and its associated complications. Zhang Lingling,Liu Tianming Journal of diabetes and its complications AIM:To investigate the clinical significance of serum α-Klotho and β-Klotho levels in patients with type 2 diabetes mellitus (T2DM) and its associated complications. METHODS:Serum α-Klotho and β-Klotho levels were measured using an ELISA kit in 817 individuals, including 127 with T2DM, 106 with diabetic nephropathy, 99 with diabetic retinopathy, 108 with diabetic neuropathy, 102 with diabetic foot disease, 135 with T2DM and more than one complication and 140 healthy controls. RESULTS:Both α-Klotho and β-Klotho levels were significantly decreased in the T2DM group and the groups with associated complications compared with the levels in control group. The differences between the T2DM group and the T2DM with complications groups were not significant, except between the diabetic nephropathy group and the other diabetic complications groups. In addition, α-Klotho and β-Klotho levels were negatively correlated with serum fructosamine and HbA1c but were not associated with serum glucose in the model including all participants. Moreover, decreases in α-Klotho and β-Klotho levels in the high glucose-exposed cell culture model, which was dependent on glucose exposure time, were confirmed. CONCLUSIONS:Levels of α-Klotho and β-Klotho were downregulated in patients in the T2DM and complications groups. Our findings indicate that serum Klotho levels were associated with the development of T2DM, and long-term control of blood glucose will be beneficial in ameliorating changes to α-Klotho and β-Klotho levels in patients with T2DM and complications. 10.1016/j.jdiacomp.2018.06.002
    Serum klotho protein levels and their correlations with the progression of type 2 diabetes mellitus. Nie Fang,Wu Dongming,Du Hongfei,Yang Xianggui,Yang Min,Pang Xueli,Xu Ying Journal of diabetes and its complications AIM:To investigate the associations of serum α-Klotho and β-Klotho levels with type 2 diabetes mellitus (T2DM) progression. METHODS:We evaluated 106 healthy controls and 261 cases of T2DM with or without diabetic complications (range: 45-84years). Serum α-Klotho and β-Klotho levels were analyzed using enzyme-linked immunosorbent assays. RESULTS:Compared to the healthy controls, α-Klotho and β-Klotho levels were significantly lower among patients with T2DM and with or without diabetic complications (P<0.05). Furthermore, α-Klotho levels were lower in the microalbuminuric and macroalbuminuric groups, compared to the normoalbuminuric group. However, β-Klotho levels were only lower in the macroalbuminuric group (P<0.05). Multiple linear regression analyses revealed that α-Klotho and β-Klotho levels were positively correlated with the creatinine clearance rate, and negatively correlated with the urinary albumin to creatinine ratio and randomly sampled serum levels of creatinine, blood urea nitrogen, and blood glucose. Moreover, α-Klotho and β-Klotho levels were positively correlated among patients with T2DM (r=0.693, P<0.001). CONCLUSIONS:Serum levels of α-Klotho and β-Klotho are down-regulated in patients with T2DM. Thus, these proteins may participate in the pathological mechanism of diabetes, and the positive correlation of α-Klotho and β-Klotho levels indicates that they might have similar mechanisms in T2DM. 10.1016/j.jdiacomp.2016.11.008