HIGH HEPARANASE LEVEL IN SURVIVORS OF COVID-19 - INDICATOR OF VASCULAR AND PULMONARY RECOVERY?

ABSTRACT: Background: Severe progression of coronavirus disease 2019 (COVID-19) causes respiratory failure and critical illness. Recently, COVID-19 has been associated with heparanase (HPSE)-induced endothelial barrier dysfunction and inflammation, so called endothelitis, and therapeutic treatment with heparin or low-molecular-weight heparin (LMWH) targeting HPSE has been postulated. Because, up to this date, clinicians are unable to measure the severity of endothelitis, which can lead to multiorgan failure and concomitant death, we investigated plasma levels of HPSE and heparin-binding protein (HBP) in COVID-19 intensive care patients to render a possible link between endothelitis and these plasma parameters. Therefore, a prospective prolonged cohort study was conducted, including 47 COVID-19 patients from the intensive care unit. Plasma levels of HPSE, and HBP were measured daily by enzyme-linked immunosorbent assay in survivors (n = 35) and nonsurvivors (n = 12) of COVID-19 from admission until discharge or death. All patients were either treated with heparin or LMWH, aiming for an activated partial thromboplastin time of ≥60 seconds or an anti-Xa level of >0.8 IU/mL using enoxaparin, depending on the clinical status of the patient (patients with extracorporeal membrane oxygenation or >0.1 µg/kg/min noradrenaline received heparin, all others enoxaparin). Results: We found significantly higher plasma levels of HPSE and HBP in survivors and nonsurvivors of COVID-19, compared with healthy controls. Still, interestingly, plasma HPSE levels were significantly higher ( P < 0.001) in survivors compared with nonsurvivors of COVID-19. In contrast, plasma HBP levels were significantly reduced ( P < 0.001) in survivors compared with nonsurvivors of COVID-19. Furthermore, when patients received heparin, they had significantly lower HPSE ( P = 2.22 e - 16) and significantly higher HBP ( P = 0.00013) plasma levels as when they received LMWH. Conclusion: Our results demonstrated that patients, who recover from COVID-19-induced vascular and pulmonary damage and were discharged from the intensive care unit, have significantly higher plasma HPSE level than patients who succumb to COVID-19. Therefore, HPSE is not suitable as marker for disease severity in COVID-19 but maybe as marker for patient's recovery. In addition, patients receiving therapeutic heparin treatment displayed significantly lower heparanse plasma level than upon therapeutic treatment with LMWH.

Tumour necrosis factor alpha (TNFα) and alpha-Klotho (αKL) in children and adolescents with chronic kidney disease (CKD).

INTRODUCTION: Chronic kidney disease (CKD) in children, despite the progress in science and technology, is still a serious challenge. Early CKD detection gives a chance of early therapeutic intervention and lowering the progression of the disease. According to several publications indicating the possible use of alpha-Klotho (αKL) and tumour necrosis factor alpha (TNFα) for the early detection of the disease in adults, an attempt was made to evaluate their usefulness in the paediatric population. MATERIAL AND METHODS: The study group consisted of 42 patients with CKD with a mean age of 10.7 years (18 girls and 24 boys). The control group involved 21 healthy children with a mean age of 8.4 years (11 girls and 10 boys). Anthropometrical parameters and blood pressure were taken and routine biochemical tests were performed in the whole group. The concentrations of TNFα and αKL in serum and urine were determined by enzyme immunoassay. RESULTS: Children from the CKD group showed a statistically significant difference in serum TNFα and αKL in comparison to the control group. There was no significant relationship between the evaluated markers and sex, presence of hypertension, or proteinuria in the children. The mean αKL serum concentration was higher in patients on dialysis compared to the group of conservatively treated children, whereas the values of TNFα in serum and urine, as well as the αKL in urine, did not differ significantly in these groups. A significant positive correlation was found between serum αKL concentration and serum creatinine, but there was no other correlation between serum αKL or TNFα concentration and any of the measured anthropometric and laboratory parameters. CONCLUSIONS: Serum TNFα and αKL levels in children with chronic kidney disease, although being statistically different compared to the group of healthy children, except for the correlation of serum aKL and creatinine, showed no other correlations to the most parameters used for chronic kidney disease evaluation including, eGFR. Their usefulness in the early detection of kidney dysfunction in children was not proven.

Associations of serum soluble klotho and fibroblast growth factor 23 with carotid artery calcification in patients undergoing continuous ambulatory peritoneal dialysis: A retrospective study.

ABSTRACT: This study aimed to assess the associations of serum soluble klotho and fibroblast growth factor 23 (FGF-23) with the occurrence of carotid artery calcification. Peritoneal dialysis patients treated from June 2018 to June 2019 were retrospectively analyzed. They were divided into the carotid artery calcification and non-carotid artery calcification groups according to color Doppler ultrasound findings. Basic indicators in both groups were compared, and the influencing factors of carotid artery calcification were analyzed by logistic regression. Among the 73 continuous ambulatory peritoneal dialysis (CAPD) patients enrolled, 40 (54.8%) had carotid artery calcification. Significant differences were found in age (68.85 ±â€Š7.45 vs 46.62 ±â€Š5.51 years), dialysis time (8.15 ±â€Š1.42 vs 6.02 ±â€Š1.14 months), klotho amounts (325.56 ±â€Š41.15 vs 436.65 ±â€Š45.58 pg/mL) and FGF-23 levels (114.45 ±â€Š15.56 vs 70.15 ±â€Š12.23 pg/mL) between the carotid artery calcification and non-carotid artery calcification groups (all P < .001). The above factors were associated with carotid artery calcification occurrence in univariate analysis. Multivariate analysis showed that elevated age (odds ratio [OR] = 1.55, 95% confidence interval [CI] 1.13-1.74; P = .025) and FGF-23 (OR = 2.16, 95% CI 2.01-2.44; P = .042), and lower klotho (OR = 0.66, 95% CI 0.47-0.85; P = .036) were independent risk factors for carotid artery calcification in CAPD. Serum FGF-23 and age are risk factors for carotid artery calcification in patients with CAPD, whereas klotho is a protective factor.

Constitutive transgenic α-Klotho overexpression enhances resilience to and recovery from murine acute lung injury.

Normal lungs do not express α-Klotho (Klotho) protein but derive cytoprotection from circulating soluble Klotho. It is unclear whether chronic supranormal Klotho levels confer additional benefit. To address this, we tested the age-related effects of modest Klotho overexpression on acute lung injury (ALI) and recovery. Transgenic Klotho-overexpressing (Tg-Kl) and wild-type (WT) mice (2 and 6 mo old) were exposed to hyperoxia (95% O2; 72 h; injury; Hx) then returned to normoxia (21% O2; 24 h; recovery; Hx-R). Control mice were kept in normoxia. Renal and serum Klotho, lung histology, and bronchoalveolar lavage fluid oxidative damage markers were assessed. Effects of hyperoxia on Klotho release were tested in human embryonic kidney cells stably expressing Klotho. A549 lung epithelial cells transfected with Klotho cDNA or vector were exposed to cigarette smoke; lactate dehydrogenase and double-strand DNA breaks were measured. Serum Klotho decreased with age. Hyperoxia suppressed renal Klotho at both ages and serum Klotho at 2 mo of age. Tg-Kl mice at both ages and 2-mo-old WT mice survived Hx-R; 6-mo-old Tg-Kl mice showed lower lung damage than age-matched WT mice. Hyperoxia directly inhibited Klotho expression and release in vitro; Klotho transfection attenuated cigarette smoke-induced cytotoxicity and DNA double-strand breaks in lung epithelial cells. Young animals with chronic high baseline Klotho expression were more resistant to ALI. Chronic constitutive Klotho overexpression in older Tg-Kl animals attenuated hyperoxia-induced lung damage and improves survival and short-term recovery despite an acute reduction in serum Klotho during injury. We conclude that chronic enhancement of Klotho expression increases resilience to ALI.

Effect of Lipopolysaccharide-Induced Inflammatory Challenge on ß-Glucuronidase Activity and the Concentration of Quercetin and Its Metabolites in the Choroid Plexus, Blood Plasma and Cerebrospinal Fluid.

Quercetin-3-glucuronide (Q3GA), the main phase II metabolite of quercetin (Q) in human plasma, is considered to be a more stable form of Q for transport with the bloodstream to tissues, where it can be potentially deconjugated by ß-glucuronidase (ß-Gluc) to Q aglycone, which easily enters the brain. This study evaluates the effect of lipopolysaccharide (LPS)-induced acute inflammation on ß-Gluc gene expression in the choroid plexus (ChP) and its activity in blood plasma, ChP and cerebrospinal fluid (CSF), and the concentration of Q and its phase II metabolites in blood plasma and CSF. Studies were performed on saline- and LPS-treated adult ewes (n = 40) receiving Q3GA intravenously (n = 16) and on primary rat ChP epithelial cells and human ChP epithelial papilloma cells. We observed that acute inflammation stimulated ß-Gluc activity in the ChP and blood plasma, but not in ChP epithelial cells and CSF, and did not affect Q and its phase II metabolite concentrations in plasma and CSF, except Q3GA, for which the plasma concentration was higher 30 min after administration (p < 0.05) in LPS- compared to saline-treated ewes. The lack of Q3GA deconjugation in the ChP observed under physiological and acute inflammatory conditions, however, does not exclude its possible role in the course of neurodegenerative diseases.

Circulating α-klotho regulates metabolism via distinct central and peripheral mechanisms.

Emerging evidence implicates the circulating α-klotho protein as a prominent regulator of energy balance and substrate metabolism, with diverse, tissue-specific functions. Despite its well-documented ubiquitous role inhibiting insulin signaling, α-klotho elicits potent antidiabetic and anti-obesogenic effects. α-Klotho facilitates insulin release and promotes ß cell health in the pancreas, stimulates lipid oxidation in liver and adipose tissue, attenuates hepatic gluconeogenesis, and increases whole-body energy expenditure. The mechanisms underlying α-klotho's peripheral functions are multifaceted, including hydrolyzing transient receptor potential channels, stimulating integrin ß1➔focal adhesion kinase signaling, and activating PPARα via inhibition of insulin-like growth factor receptor 1. Moreover, until recently, potential metabolic roles of α-klotho in the central nervous system remained unexplored; however, a novel α-klotho➔fibroblast growth factor receptor➔PI3kinase signaling axis in the arcuate nucleus of the hypothalamus has been identified as a critical regulator of energy balance and glucose metabolism. Overall, the role of circulating α-klotho in the regulation of metabolism is a new focus of research, but accumulating evidence identifies this protein as an encouraging therapeutic target for Type 1 and 2 Diabetes and obesity. This review analyzes the new literature investigating α-klotho-mediated regulation of metabolism and proposes impactful future directions to progress our understanding of this complex metabolic protein.

Comparison of serum human Klotho levels and thiol/disulfide homeostasis in women with polycystic ovary syndrome and in healthy women.

OBJECTIVES: Women with polycystic ovary syndrome (PCOS) have an increased cardiometabolic risk. Similarly, it was previously shown that atherosclerotic and cardiovascular risk is increased in the general population with lower serum Klotho levels. The aim of this study was to investigate the lotho and thiol/disulfide levels in women with non-obese PCOS compared to healthy controls and also to investigate the relationship of serum Klotho and thiol/disulfide homeostasis with cardiometabolic risk factors. MATERIALS AND METHODS: In this prospective case control study, human serum alpha Klotho levels and thiol/disulfide homeostasis of women with PCOS aged between 19-33 were compared to their age and BMI matched non - PCOS healthy controls. In addition, the correlation of these molecules with other metabolic markers/measurements were also investigated. RESULTS: Metabolic parameters such as mean waist circumference, lipid accumulation product, visceral adiposity index, fasting insulin, homeostasis model assessment of insulin resistance and triglyceride values were higher in the PCOS group (p = 0.038, p = 0.008, p = 0.001, p = 0.001, p = 0.002 and p = 0.002, respectively) compared to controls. However, mean serum Klotho and native thiol levels (respectively p < 0.0001 and p = 0.038) were lower compared to controls. Correlation analysis revealed that serum Klotho levels were negatively correlated with BMI, waist circumference, disulphide/total thiol, disulphide/native thiol, HOMA-IR and LAP-index. CONCLUSIONS: Findings of decreased serum Klotho and native thiol values of the PCOS group compared to controls and the negative correlation of serum Klotho levels with metabolic markers supports the idea that decreased Klotho may be another mechanism by which cardiovascular risk is increased in women with PCOS.

Association of bone biomarkers with advanced atherosclerotic disease in people with overweight/obesity.

BACKGROUND: A growing body of evidence suggests a potential link between bone metabolism and cardiovascular disease. Aim of this study was to investigate the relationship between levels of circulating bone turnover biomarkers and advanced atherosclerosis. METHODS: Klotho (KL), sclerostin (SOST), osteopontin (OPN) and osteoprotegerin (OPG) were measured in patients undergoing elective coronary angiography and carotid Doppler ultrasound. The primary outcome was the difference in bone biomarkers levels between participants with and without advanced atherosclerosis, defined as the presence of a critical coronary (≥70%) and/or carotid (≥50%) stenosis. RESULTS: A total of 80 subjects (32.5% females) with a mean age of 68 ± 10 years were included. Advanced atherosclerosis was detected in 55 (68.8%) patients. Subjects with advanced atherosclerosis showed higher serum levels of OPG (p = 0.0015) and SOST (p = 0.017) and similar levels of KL (p = 0.62) and OPN (p = 0.06) compared to patients without. After adjustment for age and sex, only elevated levels of OPG remained significantly associated with advanced atherosclerosis (p = 0.011). CONCLUSIONS: Higher serum levels of OPG are independently associated with advanced atherosclerosis confirming a common bond between bone metabolism and vascular disease. Further investigations on the role of selected bone biomarkers in the pathogenesis of cardiovascular disease are needed.

Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home residents.

Serum alpha-klotho (s-klotho) protein has been linked with lifespan, and low concentrations of s-klotho have been associated with worse physical and cognitive outcomes. Although its significance in aging remains unclear, s-klotho has been proposed as a molecular biomarker of frailty and dependence. This study is a secondary analysis of data from a clinical trial performed in a population of 103 older individuals living in 10 nursing homes in Gipuzkoa (Spain). We aimed to elucidate associations between s-klotho (as measured by enzyme-linked immunosorbent assay) and body composition, physical fitness, and cognition, as well as frailty and dependence (determined using validated tests and scales). In addition, we investigated the association of s-klotho concentration with falls in the six months following the initial assessment. Low s-klotho levels were associated with a lower score in the psychological component of the Tilburg Frailty Indicator, a worse score in the Coding Wechsler Adult Intelligence Scale, and a greater dependence in activities of daily living. Moreover, participants with lower s-klotho concentrations suffered more falls during the 6 months after the assessment. Future translational research should aim to validate klotho's putative role as a biomarker that could identify the risk of aging-related adverse events in clinical practice.

Soluble Alpha Klotho in Acromegaly: Comparison With Traditional Markers of Disease Activity.

CONTEXT: Soluble alpha klotho (sαKL) has been linked to growth hormone (GH) action, but systematic evaluation and comparisons with traditional biomarkers in acromegaly are lacking. OBJECTIVE: To evaluate the potential of sαKL to aid classification of disease activity. METHODS: This retrospective study at 2 academic centers included acromegaly patients before surgery (A, n = 29); after surgery (controlled, discordant, or uncontrolled) without (B1, B2, B3, n = 28, 11, 8); or with somatostatin analogue treatment (C1, C2, C3, n = 17, 11, 5); nonfunctioning pituitary adenomas (n = 20); and healthy controls (n = 31). sαKL was measured by immunoassay and compared with traditional biomarkers (random and nadir GH, insulin-like growth factor I [IGF-I], IGF binding protein 3). Associations with disease activity were assessed. RESULTS: sαKL was correlated to traditional biomarkers, particularly IGF-I (rs=0.80, P <0.0001). High concentrations before treatment (A, median, interquartile range: 4.04 × upper limit of normal [2.26-8.08]) dropped to normal after treatment in controlled and in most discordant patients. A cutoff of 1548 pg/mL for sαKL discriminated controlled (B1, C1) and uncontrolled (B3, C3) patients with 97.8% (88.4%-99.9%) sensitivity and 100% (77.1%-100%) specificity. sαKL was below the cutoff in 84% of the discordant subjects. In the remaining 16%, elevated sαKL and IGF-I persisted, despite normal random GH. Sex, age, body mass index, and markers of bone and calcium metabolism did not significantly affect sαKL concentrations. CONCLUSION: Our data support sαKL as a biomarker to assess disease activity in acromegaly. sαKL exhibits close association with GH secretory status, large dynamic range, and robustness toward biological confounders. Its measurement could be helpful particularly when GH and IGF-I provide discrepant information.

No significant association of serum klotho concentration with blood pressure and pulse wave velocity in a Chinese population.

Klotho, an important anti-aging protein, may be related to elevated blood pressure (BP) and arterial stiffness. We aimed to investigate associations between the serum klotho concentration and peripheral/central BP and arterial stiffness based on the carotid-femoral pulse wave velocity (cfPWV) in a Chinese population. We invited all inhabitants aged ≥ 18 years in two Dali communities for participation. The SphygmoCor system was used to record radial arterial waveforms. Aortic waveforms were derived using a generalized transfer function. The central BP was assessed by calibrating the brachial BP, which was measured using an oscillometric device. The serum klotho concentration was measured using an enzyme-linked immunosorbent assay and logarithmically transformed. Of the 716 participants (mean age: 51.9 ± 12.6 years), 467 (65.2%) were women. The median serum klotho concentration was 381.8 pg/mL. The serum klotho concentration did not significantly differ between patients with and without hypertension (P > 0.05) and between those with and without arterial stiffness (cfPWV ≥ 10 m/s) (P > 0.05). After adjusting for confounders, the serum klotho concentration was not significantly associated with the peripheral or central BP (P > 0.05) and cfPWV (P > 0.05). Our data indicated that the serum klotho concentration was not associated with BP or cfPWV in the general Chinese population.

Exercise intensity regulates cytokine and klotho responses in men.

BACKGROUND: Short-term exercise training programs that consist of moderate intensity endurance training or high intensity interval training have become popular choices for healthy lifestyle modifications, with as little as two weeks of training being shown to improve cardiorespiratory fitness and whole-body glucose metabolism. An emerging concept in exercise biology is that exercise stimulates the release of cytokines and other factors into the blood that contribute to the beneficial effects of exercise on metabolism, but whether these factors behave similarly in response to moderate and high intensity short term training is not known. Here, we determined the effects of two short-term exercise training programs on the concentrations of select secreted cytokines and Klotho, a protein involved in anti-aging. METHODS: Healthy, sedentary men (n = 22) were randomized to moderate intensity training (MIT) or sprint intensity training (SIT) treatment groups. SIT consisted of 6 sessions over 2 weeks of 6 × 30 s all out cycle ergometer sprints with 4 min of recovery between sprints. MIT consisted of 6 sessions over 2 weeks of cycle ergometer exercise at 60% VO2peak, gradually increasing in duration from 40 to 60 min. Blood was taken before the intervention and 48 h after the last training session, and glucose uptake was measured using [18F]FDG-PET/CT scanning. Cytokines were measured by multiplex and Klotho concentrations by ELISA. RESULTS: Both training protocols similarly increased VO2peak and decreased fat percentage and visceral fat (P < 0.05). MIT and SIT training programs both reduced the concentrations of IL-6, Hepatocyte Growth Factor (HGF) and Leptin. Interestingly, MIT, but not SIT increased monocyte chemoattractant protein-1 (MCP-1) concentrations, an exercise-induced cytokine, as well as Klotho concentrations. CONCLUSION: Short-term exercise training at markedly different intensities similarly improves cardiovascular fitness but results in intensity-specific changes in cytokine responses to exercise.

Relationship between dietary factors and S-Klotho plasma levels in young sedentary healthy adults.

OBJECTIVE: To study the associations of dietary factors with S-Klotho plasma levels in young adults. We also aimed to study whether body composition and cardiometabolic risk factors affected the association between dietary factors and S-Klotho plasma levels. METHODS: A total of 139 young adults took part in this study. Dietary factors were measured using a food frequency questionnaire and three non-consecutive 24 h recalls. S-Klotho plasma levels were measured by immunosorbent assay. Body composition was measured by DXA. RESULTS: We observed a direct association of ethanol intake and S-Klotho plasma levels in women. An inverse association was also observed between the dietary inflammatory index (DII) with S-Klotho plasma levels in all sample. No mediation effects of body composition or cardiometabolic risk factors were observed in the relationship between alcohol and S-Klotho plasma levels. Lean mass index (LMI) and uric acid levels mediated the relationship between DII and S-Klotho plasma levels. CONCLUSION: A pro-inflammatory dietary pattern was inversely associated with S-Klotho plasma levels in young adults, which was partially mediated by LMI and uric acid levels.

A novel antibody for the detection of alternatively spliced secreted KLOTHO isoform in human plasma.

αKlotho is primarily known to express as a transmembrane protein. Proteolytic cleavage results in shedding of the extracellular domain which enters systemic circulation. A truncated form of αKlotho resulting from alternative splicing of the αKLOTHO transcript exists and is believed to be secreted, thereby also entering systemic circulation. Existing ELISA methods fail to distinguish between the two circulating isoforms resulting in inconsistencies in assessing circulating αKlotho levels. We have exploited a unique 15aa peptide sequence present in the alternatively spliced secreted isoform to generate an antibody and show that it is able to specifically detect only the secreted Klotho isoform in human plasma. This finding will facilitate in distinguishing the levels of different circulating Klotho isoforms in health and disease and enhance their potential to serve as a biomarker for CKD and other conditions.

Alpha-Klotho is a novel predictor of treatment responsiveness in patients with heart failure.

Heart failure is a major cause of death with an increasing population of elderly individuals. Several studies have demonstrated the involvement of soluble alpha-Klotho (sαKl) in various diseases. However, the correlation between sαKl and heart failure remains to be understood. The aim of this study is to investigate the levels and role of sαKl in patients with heart failure. Twenty-eight consecutive patients with acute heart failure (19 male, 9 female), admitted to the Osaka University Hospital from 2010 to 2018, were enrolled in this study. Mean NYHA score, left ventricular ejection fraction and BNP were 3.3, 17.0% and 588 pg/mL, respectively. SαKl significantly increased in heart failure patients. SαKl on admission were significantly higher in patients with heart failure who showed improvement after intensive treatment than that in patients who did not show improvement after the treatment. SαKl levels decreased significantly in patients who showed improvement. Interestingly, sαKl levels increased in male patients with heart failure, but not in female patients. Our data suggest that soluble αKl may be a novel biomarker for the responsiveness against treatment in patients with heart failure with reduced ejection fraction. Our findings may help developing a personalized therapy for different patients with heart failure.

Lower soluble Klotho levels in the pretransplant period are associated with an increased risk of renal function decline in renal transplant patients.

Serum soluble Klotho levels are associated with renal function in predialysis patients with chronic kidney disease. However, few reports exist regarding the association between soluble Klotho levels and renal function in kidney transplant (KTx) recipients. This was a retrospective observational study of 41 living KTx recipients. The serum soluble Klotho levels were classed as "high" (>456 pg/mL [i.e., high-Klotho group]) or "low" (≤456 pg/mL [i.e., low-Klotho group]). Renal function decline was defined as a decrease in the estimated glomerular filtration rate (eGFR) of 30% or more from the baseline value within 3 months after KTx. A multivariable time-to-event analysis between the groups was conducted. Among the KTx recipients, the incidence of a 30% decrease in the eGFR was significantly higher in the low-Klotho group than in the high-Klotho group (P = .036). After adjusting for donor age, donor sex, the presence of rejection, and the number of cytomegalovirus infections, multivariable Cox models revealed that low soluble Klotho levels remained associated with a higher risk of a 30% decrease in the eGFR (hazard ratio, 2.38; 95% confidence interval, 1.02-6.41). These findings suggested that lower soluble Klotho levels in the pre-KTx period are associated with an increased risk of renal function decline in KTx recipients.

New Insights into the Role of FGF-23 and Klotho in Cardiovascular Disease in Chronic Kidney Disease Patients.

Alterations of fibroblast growth factor 23 (FGF-23) and Klotho levels are considered to be the earliest biochemical abnormality of chronic kidney disease - mineral and bone disease (CKDMBD) syndrome. Moreover, emerging data suggests that the dysregulated FGF-23 and Klotho axis has many effects on the cardiovascular (CV) system and contributes significantly to the increased CV morbidity and mortality rates of CKD patients. This review examines recent evidence on the role of FGF-23 and Klotho in the development and progression of CV complications of uremia namely cardiac hypertrophy, uremic cardiomyopathy, and atherosclerotic and arteriosclerotic vascular lesions. Moreover, the available evidence on their associations with adverse clinical outcomes are summarized. Undoubtedly, more studies are needed to further elucidate the effects of FGF-23 and Klotho on the heart and vessels and to gain insights into their prognostic value as CV risk factors. Finally, large prospective studies are required to test the hypothesis that modification of their levels would have a favourable impact on the unacceptably high mortality rates of these patient populations.

Blood Flow Restriction Training Blunts Chronic Kidney Disease Progression in Humans.

PURPOSE: This study aimed to verify the effect of 6 months of periodized resistance training (RT) with and without blood flow restriction (BFR) in patients with stage 2 chronic kidney disease (CKD) on glomerular filtration rate (GFR), uremic parameters, cytokines, and klotho-fibroblast growth factor 23 (FGF23) axis. METHODS: A total of 105 subjects were randomized in three groups of 35 each: control (CTL), RT, and RT + BFR. A first visit was required for an anamnesis to evaluate the number of medications and anthropometric measurements (body weight, height, and body mass index). Muscle strength (one-repetition maximum) was assessed. Venous blood samples were collected at baseline and after 6 months of training in all patients for the analysis of markers of renal function and integrity, as well as for the determination of the inflammatory profile. Statistical significances were adopted with P < 0.05. RESULTS: Both training therapies attenuated the decline of GFR (P < 0.05). The majority of CTL patients declined to stage 3 CKD (88.5%), whereas fewer incidents were noted with RT (25.7%) and RT + BFR (17.1%). Improved uremic parameters as well as inflammation (IL-6, IL-10, IL-15, IL-17a, IL-18, and TNF-α) and klotho-FGF23 axis in RT and RT + BFR (P < 0.05) were observed. Monocyte chemoattractant protein 1 was not changed (P > 0.05) but presented a large effect size (Cohen's d), demonstrating a propensity for improvement. CONCLUSION: Six months of periodized RT with and without BFR in patients with stage 2 CKD attenuated the progression of the disease by maintaining GFR, improving uremic parameters, cytokine profile regulation, and klotho-FGF23 axis.

Higher Serum-Soluble α-Klotho Level Does Not Predict Longer Survival after Stroke.

RESULTS: There were 5 recurrent strokes and 89 deaths during the 36-month follow-up. Even though no significant differences in OS and SFS between soluble α-Klotho level tertile groups were recorded, unexpectedly, OS and SFS were highest in patients with the lowest soluble α-Klotho concentrations. Moreover, the Cox proportional models adjusted for established risk factors, kidney function, and the severity of stroke revealed that each 100 pg/mL increase in soluble α-Klotho levels was associated with decreased OS (HR = 0.951 (0.908-0.995), p < 0.05) and SFS (HR = 0.949 (0.908-0.993), p < 0.05). In addition, the α-Klotho to iFGF23 index was predicting neither OS nor SFS. CONCLUSION: Soluble α-Klotho levels in serum were not related to the severity of neurological deficits and long-term outcomes in patients with IS. No neuroprotective effect of soluble α-Klotho levels in patients with IS was demonstrated.

Low KLOTHO level related to aging is associated with diminished ovarian reserve.

OBJECTIVE: To explore the relationship between KLOTHO expression and diminished ovarian reserve (DOR). DESIGN: A case-control study. SETTING: Reproductive medicine center. PATIENT(S): A total of 157 patients with DOR and 159 control women were recruited from the Centre of Reproductive Medicine, Peking University Third Hospital. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The granulosa cells were isolated from follicular fluid after oocyte retrieval, and the KLOTHO level of granulosa cell was measured using a modified quantitative polymerase chain reaction technique. The serum KLOTHO level was measured by solid-phase sandwich enzyme-linked immunosorbent assay. RESULT(S): In both granulosa cells and serum derived from women with DOR, KLOTHO expressions were significantly lower compared with normal ovarian reserve controls. Moreover, KLOTHO expression diminished with advancing age. CONCLUSION(S): Diminished KLOTHO expression was associated with DOR. Further longitudinal studies in a similar population accompanying disease progression and mechanism exploration are needed to substantiate the rules of KLOTHO in reproductive aging.