Klotho is an anti-aging protein produced primarily by tubular epithelial cells (TECs). Down-regulated expression of Klotho in injured TECs plays a key pathogenic role in promoting acute kidney injury (AKI) to chronic kidney disease (CKD) transition, yet therapeutic approaches targeting the restoration of renal Klotho levels remain challenging for clinical application. Here, we synthesize polydopamine-polyethylenimine-l-serine-Klotho plasmid nanoparticles (PPSK NPs), which can safely and selectively deliver the Klotho gene to the injured TECs through binding kidney injury molecule-1 and maintain the expression of Klotho protein. In vitro, PPSK NPs effectively reduce the hypoxia-reoxygenation-induced reactive oxygen species production and fibrotic gene expression. In the unilateral ischemia-reperfusion injury- and folic acid-induced AKI-CKD transition mouse models, a single low-dose injection of PPSK NPs is sufficient to preserve the normal kidney architecture and prevent renal fibrosis. Mechanismly, the protective effect of PPSK NPs relies on upregulating a key molecule peroxisome proliferator-activated receptor alpha (PPARα) via the inhibition of p38 and JNK phosphorylation, which in turn improves tubular fatty acid beta-oxidation and reduces renal lipid accumulation, thereby protecting against kidney fibrosis. In conclusion, our results highlight the translational potential of nanoparticle-based Klotho gene therapy in preventing the AKI-CKD transition.

Vascular calcification(VC) significantly increases the risk of cardiovascular events, leading to thickening of the myocardium and arteries, coronary heart disease, heart failure, and potentially triggering myocardial infarction and sudden cardiac death. Although VC is a reversible process, there are currently no methods or medications in clinical practice that can completely reverse or cure it. The current treatment strategies primarily focus on slowing the progression of VC and exploring new diagnostic and therapeutic approaches, making the identification of early diagnostic markers for VC particularly important. Alternative splicing(AS)has extensive potential in clinical applications as a biomarker, including in disease diagnosis and therapeutic targeting. This article provides an overview of the roles played by different isoforms of biomarkers in VC, with the aim of offering insights for early diagnosis and disease monitoring of VC.

As a microvascular complication, diabetic kidney disease is the leading cause of chronic kidney disease and end-stage renal disease worldwide. While the underlying pathophysiology driving transition of diabetic kidney disease to renal failure is yet to be fully understood, recent studies suggest that cellular senescence is central in disease development and progression. Consequently, understanding the molecular mechanisms which initiate and drive senescence in response to the diabetic milieu is crucial in developing targeted therapies that halt progression of renal disease.

To understand the mechanistic pathways underpinning cellular senescence in the context of diabetic kidney disease, we reviewed the literature using PubMed for English language articles that contained key words related to senescence, inflammation, fibrosis, senescence-associated secretory phenotype (SASP), autophagy, and diabetes.

Aberrant accumulation of metabolically active senescent cells is a notable event in the progression of diabetic kidney disease. Through autocrine- and paracrine-mediated mechanisms, resident senescent cells potentiate inflammation and fibrosis through increased expression and secretion of pro-inflammatory cytokines, chemoattractants, recruitment of immune cells, myofibroblast activation, and extracellular matrix remodelling. Compounds that eliminate senescent cells and/or target the SASP - including senolytic and senomorphics drugs - demonstrate promising results in reducing the senescent cell burden and associated pro-inflammatory effect.

Here we evidence the link between senescence and diabetic kidney disease and highlight underlying molecular mechanisms and potential therapeutic targets that could be exploited to delay disease progression and improve outcomes for individuals with the disease. Trials are now required to translate their therapeutic potential to a clinical setting.

Older individuals usually have greater arterial stiffness, lower serum Klotho levels and a greater incidence of chronic kidney disease (CKD). The current study aimed to evaluate the interaction effect of estimated pulse wave velocity (ePWV) and serum Klotho levels on CKD in Americans.

Data from the National Health and Nutrition Examination Survey database from 2007 to 2016 were used. Participants with data for the assessment of ePWV and serum Klotho and for the assessment of CKD were enrolled. The associations between ePWV and serum Klotho levels were analyzed via restricted cubic spline analysis and a linear regression model. The associations between exposure factors and CKD prevalence were assessed via a logistic regression model. Subgroup analysis was performed for each confounding factor to assess the robustness of the results.

This study enrolled 13,273 participants, 3859 of whom were CKD patients. CKD patients had higher ePWV (9.66 ± 1.75 m/s vs. 8.48 ± 1.64 m/s, p < 0.001) and lower levels of serum Klotho (816.35 ± 290.47 pg/mL vs. 869.87 ± 315.87 pg/mL, p < 0.001). A significant negative linear association was found between ePWV and serum Klotho. According to the fully adjusted model, a significant interaction effect between ePWV and serum Klotho was observed on the risk of CKD (p < 0.001). Compared with individuals with a lower ePWV and higher serum Klotho, individuals with an increased ePWV and lower serum Klotho had a significantly elevated risk of CKD (OR: 1.847, 95% confidence interval: 1.467-2.325; p < 0.001). The subgroup analysis revealed that the results were robust.

The study demonstrated significant interaction effect of ePWV and serum Klotho on the prevalence of CKD. Individuals with increased ePWV and decreased serum Klotho levels had the highest risk of CKD. The assessment of the combination of ePWV and serum Klotho for CKD management should be considered routine in clinical practice.

Microalbuminuria is the earliest clinical abnormality in diabetic kidney disease. High glucose (HG) concentrations are associated with the induction of oxidative stress in podocytes, leading to disruption of the glomerular filtration barrier. Our recent study revealed a significant decrease in the membrane-bound fraction of Klotho in podocytes that were cultured under HG conditions. Given that disintegrin and metalloproteinase 17 (ADAM17) is responsible for the shedding of Klotho from the cell membrane, the present study investigated the impact of HG on the interplay between ADAM17 and Klotho in human podocytes. We demonstrated that ADAM17 protein levels significantly increased in urine, renal tissue, and glomeruli from diabetic rats, with a concomitant increase in glomerular albumin permeability. High glucose increased ADAM17 extracellular activity, NADPH oxidase activity, and albumin permeability in podocytes. These effects were reversed after treatment with ADAM17 inhibitor, in cells with downregulated ADAM17 expression, or after the addition of Klotho. Additionally, elevations of extracellular ADAM17 activity were observed in podocytes with the downregulation of Klotho expression. Our data indicate a novel mechanism whereby hyperglycemia deteriorates podocyte function via ADAM17 activation. We also demonstrated the ability of Klotho to protect podocyte function under hyperglycemic conditions in an ADAM17-dependent manner.

Aging is a risk factor for several chronic conditions, including intervertebral disc degeneration and associated back pain. Disc pathologies include loss of reticular-shaped nucleus pulposus cells, disorganization of annulus fibrosus lamellae, reduced disc height, and increased disc bulging. Sonic hedgehog, cytokeratin 19, and extracellular matrix proteins are markers of healthy disc. Preclinical murine models help understand cellular and molecular mechanisms of disc pathologies and the associated neurological symptoms. Klotho (Kl) is a known anti-aging gene. Kl-deficient mice (KlKl/KlKl) have a reduced lifespan and display accelerated aging phenotypes in several tissues, including the kidney, pancreas, bone, and brain. To test the suitability of KlKl/KlKl mice for studying accelerated disc pathologies, we characterized the lumbar discs of eight-week-old KlKl/KlKl mice compared to wild-type controls. No structural, morphological, or molecular differences were observed in the discs of KlKl/KlKl mice compared to controls. Next, we tested the hypothesis that KlKl/KlKl mice do not display accelerated disc pathologies due to the absence of Kl expression or response by disc cells. Multiplex qPCR analysis did not detect any Kl isoforms in the disc cells, explaining the absence of disc phenotype in KlKl/KlKl mutants.

α-Klotho (KLA) is a type-1 membranous protein that can associate with fibroblast growth factor receptor (FGFR) to form co-receptor for FGF23. The ectodomain of unassociated KLA is shed as soluble KLA (sKLA) to exert FGFR/FGF23-independent pleiotropic functions. The previously determined X-ray crystal structure of the extracellular region of sKLA in complex with FGF23 and FGFR1c suggests that sKLA functions solely as an on-demand coreceptor for FGF23. To understand the FGFR/FGF23-independent pleiotropic functions of sKLA, we investigated biophysical properties and structure of apo-sKLA. Single particle cryogenic electron microscopy (cryo-EM) revealed a 3.3 Å resolution structure of apo-sKLA that overlays well with its counterpart in the ternary complex with several distinct features. Compared to the ternary complex, the KL2 domain of apo-sKLA is more flexible. Three-dimensional variability analysis revealed that apo-sKLA adopts conformations with different KL1-KL2 interdomain bending and rotational angles. Mass photometry revealed that sKLA can form a stable structure with FGFR and/or FGF23 as well as sKLA dimer in solution. Cryo-EM supported the dimeric structure of sKLA. Recent studies revealed that FGF23 contains two KLA-binding sites. Our computational studies revealed that each site binds separate KLA in the dimer. The potential multiple forms and shapes of sKLA support its role as FGFR-independent hormone with pleiotropic functions. The ability of FGF23 to engage two KLA's simultaneously raises a potential new mechanism of action for FGF23-mediated signaling by the membranous klotho.

Semaglutide (Smg), a GLP-1 receptor agonist (GLP-1RA), shows renal protective effects in patients with diabetic kidney disease (DKD). However, the exact underlying mechanism remains elusive. This study employs transcriptome sequencing and identifies β-Klotho (KLB) as the critical target responsible for the role of Smg in kidney protection. Smg treatment alleviates diabetic kidney injury by inhibiting ferroptosis in patients, animal models, and HK-2 cells. Notably, Smg treatment significantly increases the mRNA expression of KLB through the activation of the cyclic adenosine monophosphate (cAMP) signaling pathway, specifically through the phosphorylation of protein kinase A (PKA) and cAMP-response element-binding protein (CREB). Subsequently, the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway is activated, reprograming the key metabolic processes of ferroptosis such as iron metabolism, fatty acid synthesis, and the antioxidant response against lipid peroxidation. Suppression of ferroptosis by Smg further attenuates renal inflammation and fibrosis. This work highlights the potential of GLP-1RAs and KLB targeting as promising therapeutic approaches for DKD management.

Vascular calcification (VC) is common in patients with advanced chronic kidney disease (CKD).A series of factors, such as calcium and phosphorus metabolism disorders, uremic toxin accumulation, inflammation and oxidative stress and cellular senescence, cause osteoblast-like differentiation of vascular smooth muscle cells, secretion of extracellular vesicles, and imbalance of calcium regulatory factors, which together promote the development of VC in CKD. Recent advances in epigenetics have provided better tools for the investigation of VC etiology and new approaches for finding more accurate biomarkers. These advances have not only deepened our understanding of the pathophysiological mechanisms of VC in CKD, but also provided valuable clues for the optimization of clinical predictors and the exploration of potential therapeutic targets. The aim of this article is to provide a comprehensive overview of the pathogenesis of CKD VC, especially the new advances made in recent years, including the various key factors mentioned above. Through the comprehensive analysis, we expect to provide a solid theoretical foundation and research direction for future studies targeting the specific mechanisms of CKD VC, the establishment of clinical predictive indicators and the development of potential therapeutic strategies.

Cis-regulatory elements bridge enhancers and gene promoters to control gene expression via distal DNA interaction and three-dimensional chromosomal conformation organization. The aberrant changes of cis-acting regulatory systems as one type of the epigenetic regulative ways may be connected with human genetic diseases. Klotho, as an antiaging protein, is selectively expressed in kidney tissues and plays a crucial role in preventing chronic kidney disease (CKD) and renal fibrosis. However, the underlying transcription regulatory mechanism of Klotho in CKD is not fully understood. Herein, we analyzed the spatial organization of the chromatin region spanning 2 Mb upstream Klotho in human renal punctured CKD tissues using chromosome conformation capture (3C)-qPCR and identified the distal interaction of the Klotho promoter with certain specific chromatin regions characterized as the regulatory elements. Moreover, we determined that four DNase I hypersensitive sites (DHSs) involved in the regulation of Klotho gene expression lost their activities in CKD tissues compared to control accompanied by the reduction of H3K27ac. Finally, the CCCTC-binding factor (CTCF) sites were validated on the DHSs beyond the Klotho promoter by chromatin looping formation through the recruitment of CTCF.

Background: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for causing the Coronavirus disease 2019 (COVID-19) outbreak. While mutations cause the emergence of new variants, the ancestral SARS-CoV-2 strain is unique among other strains. Methods: Various clinical parameters, the activity of cathepsin proteases, and the concentration of various proteins were measured in urine samples from COVID-19-negative participants and COVID-19-positive participants. Urinary extracellular vesicles (uEVs) were isolated from urine samples from the two groups and used for proteomic analysis and subsequent pathway analyses. Results: Activity levels of cathepsin S and L were greater in the urine of COVID-19-positive participants. The concentration of C-reactive protein, transmembrane serine protease 2, and klotho protein were significantly greater in the urine of COVID-19-positive participants. There was a greater amount of uEVs in the COVID-19 group and klotho protein was found to be enriched in uEVs from the COVID-19 group. Pathway analyses of the proteomics data showed most of the identified proteins were involved in signal transduction, stress response, protein metabolism, and transport. The identified proteins were predominantly associated with cellular membranes and with function of the cytoskeleton, enzyme regulation, and signal transduction. Conclusions: Taken together, our data identify novel urinary biomarkers that could be used to further investigate the long-term effects of SARS-CoV-2 infection.

Current evidence regarding the effects of serum Klotho among patients with metabolic syndrome (MetS) is scarce. This study explored the relationship between serum Klotho levels and the odds of chronic kidney disease (CKD) in middle-aged and older populations with MetS.

This cross-sectional study analyzed data from 4870 adults aged 40-79 years who participated in the National Health and Nutrition Survey (NHANES) from 2007 to 2016. CKD was identified at urinary albumin to creatinine ratio (UACR) of 30 mg/g or higher and/or an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2. Measurement of serum Klotho concentration was determined via enzyme-linked immunosorbent assay (ELISA) and subsequently divided into four quartiles (Q1-Q4). The NHANES criteria were followed in calculating the sampling weights. Multivariable logistic regression models were employed to assess the correlation between Klotho and CKD, while generalized linear models with cubic spline functions and smooth curve fitting were utilized to detect any nonlinear relationship. Additionally, subgroup analysis and a range of sensitivity analyzes were conducted.

Results showed that a nonlinear L-shaped relationship existed between serum Klotho levels and CKD risk, with the lowest prevalence observed at 9.63-9.94 pg/mL Klotho concentrations. With a two-segment linear regression model, an inflection point of 9.88 pg/mL was noted. Hypertension status was identified as an interaction mediator (P interaction = 0.006). Sensitivity analysis showed stable results.

A nonlinear L-shaped relationship exists between serum Klotho levels and risks of CKD among middle-aged and older adults with MetS, with the lowest prevalence observed at 9.63 to 9.94 pg/mL Klotho concentrations. Our findings, if replicated, underscore the need to estimate the optimal serum Klotho concentrations and the consequential inverse relationship, thus implying the potential of Klotho as both a serum biomarker and a possible preventive or therapeutic intervention.

Cardiovascular-kidney-metabolic (CKM) syndrome is characterized as a systemic disease resulting from the pathophysiological interplay among metabolic risk factors, chronic kidney disease (CKD), and cardiovascular disease (CVD). The Klotho protein may serve as a novel biomarker. However, the utility of serum Klotho levels as an indicator of severity and mortality risk in CKM syndrome remains uncertain.

This study involved 9,871 participants from the National Health and Nutrition Examination Survey (NHANES) conducted between 2007 and 2016. Serum Klotho levels were measured using an enzyme-linked immunosorbent assay kit. The optimal cutoff value was established through the maximum Youden's index. Multivariable weighted regression models were employed to calculate the odds ratio and hazard ratio, along with the 95% confidence interval, to evaluate the association between serum Klotho levels and the severity of CKM syndrome, as well as all-cause and cardiovascular mortality. Additionally, the receiver operating characteristic curve and restricted cubic spline curves were utilized to assess predictive efficacy and to explore nonlinear relationships.

After adjusting for potential confounding factors, a non-linear relationship was seen between the Klotho protein, and CKM syndrome. In the multivariable, piecewise logistic regression, when the Serum klotho was less than 801, the risk of CKM syndrome decreased with the increase in Serum klotho (OR = 0.82, 95%CI 0.70, 0.96; p < 0.001). Furthermore, we observed the association when the Serum klotho was greater than 801 (OR = 0.94, 95%CI 0.89, 0.99; p = 0.035). The relationship between serum Klotho levels and all-cause mortality was U-shaped, while the relationship with cardiovascular mortality was L-shaped. Specifically, low serum Klotho levels were associated with an increase in all-cause mortality by 21% and cardiovascular mortality by 76% among patients with CKM syndrome. Furthermore, serum Klotho levels demonstrated excellent predictive efficacy for both the severity and mortality associated with CKM syndrome.

This study indicates that low serum Klotho levels serve as reliable indicators of both the severity of CKM syndrome and the associated risk of mortality.

The relationship between serum klotho level and albuminuria is unknown in middle-aged and elderly participants without diabetes mellitus (DM). Therefore, we will investigate the association between serum klotho level and albuminuria in middle-aged and elderly participants without DM.

Participants (aged 40-79) were from the five continuous cycles (2007-2016) of the National Health and Nutrition Examination Survey (NHANES). Multiple logistic regression was performed to investigate the association between serum klotho level and albuminuria.

9217 participants were included in the present study. 47.6% of the participants were male. The average age of the overall participants was 56.3 years (40-79 years). Overall, 823 participants with albuminuria were identified. After adjusted confounders (age, gender, marital status, ethnicity, family income to poverty ratio, education, body mass index, smoke, charlson comorbidity index, hypertension, hyperlipidemia, angiotensin converting enzyme inhibitor/angiotonin receptor blocker, and estimated glomerular filtration rate), participants with a high serum klotho level had a decreased risk for albuminuria. Compared with the lowest serum klotho level (Tertile 1), participants in Tertile 2 (odds ratio [OR] 0.83, 95% CI 0.70-0.99, P = 0.044) and Tertile 3 (OR 0.76, 95% CI 0.63-0.91, P = 0.003) had a lower risk of albuminuria (P for trend = 0.002). The stratified analysis showed that serum klotho level was still negatively associated with albuminuria in the subgroups, and statistically significant interactions were not observed in the subgroups (all P values for interactions > 0.05, except for the hypertension subgroup).

In middle-aged and elderly participants without DM, a high serum klotho level is associated with a decreased risk of albuminuria. In the future, the mechanism of the interaction between klotho and albuminuria needs to be elucidated to find new treatment targets for individuals without DM who suffer from albuminuria.

Systemic Immune-Inflammation Index (SII) is a novel inflammatory biomarker closely associated with the inflammatory response and chronic kidney disease. Klotho is implicated as a pathogenic factor in the progression of kidney disease, and supplementation of Klotho may delay the progression of chronic kidney disease by inhibiting the inflammatory response. Our aim is to investigate the potential relationship between SII and Klotho in adult patients in the United States and explore the differences in the populations with and without albuminuria.

We conducted a cross-sectional study recruiting adult participants with complete data on SII, Klotho, and urine albumin-to-creatinine ratio (ACR) from the National Health and Nutrition Examination Survey from 2007 to 2016. SII was calculated as platelet count × neutrophil count/lymphocyte count, with abnormal elevation defined as values exceeding 330 × 10^9/L. Albuminuria was defined as ACR >30 mg/g. Weighted multivariable regression analysis and subgroup analysis were employed to explore the independent relationship between SII and Klotho.

Our study included a total of 10,592 individuals. In all populations, non-albuminuria population, and proteinuria population with ACR ≥ 30, participants with abnormally elevated SII levels, as compared to those with SII less than 330 × 10^9/L, showed a negative correlation between elevated SII levels and increased Klotho, which persisted after adjusting for covariates.

There is a negative correlation between SII and Klotho in adult patients in the United States. This finding complements previous research but requires further analysis through large prospective studies.

This study aimed to investigate the effect of the soluble Klotho (sKlotho)/Wnt/β-catenin signaling pathway on vascular calcification in rat models of chronic kidney disease (CKD) and the intervention effect of Shenyuan granules.

Rats with 5/6 nephrectomy and high phosphorus feeding were used to establish the vascular calcification model. The rats were given gradient doses of Shenyuan granules aqueous solution and calcitriol solution by gavage for 8 weeks, which were divided into experimental group and positive control group.

The 5/6 nephrectomy combined with high phosphorus feeding induced thoracic aortic calcification in rats. Shenyuan granules intervention increased the serum sKlotho level, inhibited the mRNA and protein expression of Wnt1, β-catenin, and Runx2 in the thoracic aorta, and alleviated thoracic aortic media calcification in rats.

Shenyuan granules may partially regulate the Wnt/β-catenin signaling pathway via serum sKl to interfere with the expression of Runx2, thereby improving vascular calcification in CKD.

Calcification of tissues involves the formation and deposition of calcium-containing crystals in the extracellular matrix (ECM). While this process is normal in bones, it becomes pathological when it occurs in cardiovascular and musculoskeletal soft tissues. Pathological calcification (PC) triggers detrimental pathways such as inflammation and oxidative stress, contributing to tissue damage and dysregulated tissue biomechanics, ultimately leading to severe complications and even death. The underlying mechanisms of PC remain elusive. Emerging evidence suggests a significant role of lysyl oxidases (LOX(L)) in PC. LOX(L) are a group of five enzymes involved in collagen cross-linking and ECM maturation. Beyond their classical role in bone mineralization, recent investigations propose new non-classical roles for LOX(L) that could be relevant in PC. In this review, we analyzed and summarized the functions of LOX(L) in cardiovascular and musculoskeletal PC, highlighting their deleterious roles in most studies. To date, specific inhibitors targeting LOX(L) isoforms are under development. New therapeutic tools targeting LOX(L) are warranted in PC and must avoid adverse effects on physiological bone mineralization.

Background and Objectives: Soluble alpha Klotho (s.Klotho) is an emerging marker for chronic kidney disease (CKD) prognosis. The objective was to study the association between s.Klotho and CKD-related decrease in glomerular filtration rate (GFR), bone and vascular damage. Method: A total of 118 patients with CKD stage 2-4 were enrolled and 107 patients continued in the study. Clinical and laboratory parameters were recorded at time of enrollment and 12 months. A double sandwich ELISA for s.Klotho was recorded in controls (n = 25) and patients' serum samples at 6 months (n = 107) and 12 months (n = 102). Primary endpoints like 40% or more fall in GFR, a requirement for renal replacement therapy (RRT), and death with different grades of s.Klotho deficiency were studied. Results: Of the 107 patients (80 male and 27 female), mean s.Klotho was 3.46 ng/mL (02.3-04.2). The GFR fall was significantly different (p value < 0.0001) in the different grades of s.Klotho deficiency with Grade 4 s.Klotho deficiency (0.1-2.99 ng/mL) having the maximum fall of GFR at 9.2 mL/min/1.73 m2 (04.8-12.0) and minimum in Grade 2 (3-5.99 ng/mL) at 1.35 mL/min/1.73 m2 (03.0-02.75). The Ankle Brachial Pressure Index positively correlated with s.Klotho and the correlation coefficient was 0.536 (0.382-0.662) (p < 0.001). The carotid intimal medial thickness negatively correlated with s.Klotho and the correlation coefficient was -0.712 (95% CI: -0.797--0.601, p < 0.001). All five deaths had s.Klotho Grade 4 (severe) deficiency. The event-free survival rate was maximum (100%) in Grade 2 Klotho deficiency and lowest (55%) in Grade 4 s.Klotho deficiency. Conclusions: s.Klotho levels decreased significantly in patients with progressive kidney failure. s.Klotho levels significantly correlated with the presence of vascular disease. Death and need for RRT were significantly more in patients with severe s.Klotho deficiency.

Pulmonary hypertension (PH) is common in patients with chronic kidney disease (CKD) or kidney failure, with an estimated prevalence of up to 78% in those referred for right-heart catheterization. PH is independently associated with adverse outcomes in CKD, raising the possibility that early detection and appropriate management of PH might improve outcomes in at-risk patients. Among patients with PH, the prevalence of CKD stages 3 and 4 is estimated to be as high as 36%, and CKD is also independently associated with adverse outcomes. However, the complex, heterogenous pathophysiology and clinical profile of CKD-PH requires further characterization. CKD is often associated with elevated left ventricular filling pressure and volume overload, which presumably leads to pulmonary vascular stiffening and post-capillary PH. By contrast, a distinct subgroup of patients at high risk is characterized by elevated pulmonary vascular resistance and right ventricular dysfunction in the absence of pulmonary venous hypertension, which may represent a right-sided cardiorenal syndrome defined in principle by hypervolaemia, salt avidity, low cardiac output and normal left ventricular function. Current understanding of CKD-PH is limited, despite its potentially important ramifications for clinical decision making. In particular, whether PH should be considered when determining the suitability and timing of kidney replacement therapy or kidney transplantation is unclear. More research is urgently needed to address these knowledge gaps and improve the outcomes of patients with or at risk of CKD-PH.

Chronic kidney disease (CKD) is a significant global health issue and often involves CKD-mineral and bone disorder (MBD) and sarcopenia. Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of fibrinolysis. PAI-1 has been implicated in the pathogenesis of osteoporosis and muscle wasting induced by inflammatory conditions. However, the roles of PAI-1 in CKD-MBD and sarcopenia remain unknown. Therefore, the present study investigated the roles of PAI-1 in bone loss and muscle wasting induced by adenine in PAI-1-deficient mice. CKD was induced in PAI-1+/+ and PAI-1-/- mice by administration of adenine for ten weeks. Muscle wasting was assessed by grip strength test, quantitative computed tomography (CT) analysis and muscle weight measurement. Osteoporosis was assessed by micro-CT analysis of femoral microstructural parameters. PAI-1 deficiency did not affect adenine-induced decreases in body weight and food intake or renal dysfunction in male or female mice. PAI-1 deficiency also did not affect adenine-induced decreases in grip strength, muscle mass in the lower limbs, or the tissue weights of the gastrocnemius, soleus, and tibialis anterior muscles in male or female mice. PAI-1 deficiency aggravated trabecular bone loss in CKD-induced male mice, but significantly increased trabecular bone in CKD-induced female mice. On the other hand, PAI-1 deficiency did not affect cortical bone loss in CKD-induced mice. In conclusion, PAI-1 is not critical for the pathophysiology of CKD-MBD or CKD-induced sarcopenia in mice. However, PAI-1 may be partly related to bone metabolism in trabecular bone in the CKD state with sex differences.

Renal αKlotho along with fibroblast growth factor 23 regulates phosphate and vitamin D metabolism. Its cleavage yields soluble Klotho controlling intracellular processes. αKlotho has anti-inflammatory and antioxidant effects and is nephro- and cardioprotective. AMP-dependent kinase (AMPK) is a nephro- and cardioprotective energy sensor. Given that both αKlotho and AMPK have beneficial effects in similar organs, we studied whether AMPK regulates αKlotho gene expression in Madin-Darby canine kidney, normal rat kidney 52E, and human kidney 2 cells. Using quantitative real-time PCR and western blotting, we measured αKlotho expression upon pharmacological manipulation or siRNA-mediated knockdown of AMPKα. AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) enhanced αKlotho expression, an effect reduced in the presence of AMPK inhibitor compound C or siRNA targeting AMPK catalytic α-subunits (α1 and α2). Similarly, AMPK activators metformin and phenformin upregulated αKlotho transcripts. Taken together, our results suggest that AMPK is a powerful inducer of αKlotho and could thereby contribute to the development of future therapeutic interventions.

Traditional Chinese medicine (TCM) and Western Medicine both have shown efficacy in treating male sexual dysfunction (MSD). The aim of this perspective paper is to discuss a possible link between Western medicine and TCM in the MSD field as represented by the entity of Klotho. Klotho is a recently discovered protein, mainly expressed in the kidney, encoded by the anti-aging gene klotho. Not only is Klotho significantly correlated with the development and progression of kidney diseases and their complications, but increasing evidence indicates that it is also closely related to MSD. A comprehensive search within PubMed database was performed to retrieve available evidence on Klotho's roles, particularly in kidney and in MSD. Indeed, in the TCM theory, the concept of the "kidney" is entirely different from the Western medicine: it is closely related to metabolism and to the reproductive, nervous, endocrine systems, being more than just a urinary organ. According to the "Kidney storing essence (jīng) and governing reproduction" (KSEGR) theory, a cornerstone in TCM, the treatment of MSD mainly consists of restoring the kidney's function. Signs of decreasing kidney essence show a consistent similarity to deficiencies of Klotho, also for what regards the male sexual function. Based on the current evidence, Klotho may represent a potential biological indicator for sexual desire and sexual function and a kind of new scientific Silk Road between TCM and Western medicine for MSD; nevertheless, there is a need to conduct further high-quality research to prove this hypothesis.

Chronic kidney disease (CKD) is now an unquestionable progressive condition that affects more than 10% of the general population worldwide, and has emerged as one of the most important causes of global mortality. It is clear that the prevalence of CKD among the aging population is significantly elevated. It involves a broad range of complex and poorly understood concerns in older adults such as frailty, malnutrition, sarcopenia, and even cognitive and mental dysfunction. In kidneys, renal function such as glomerular filtration, urine concentration and dilution, and homeostasis of sodium and potassium, can be influenced by the aging process. In addition, it is worth noting that CKD and end-stage kidney disease patients often have accompanying activation of immune system and inflammation, involving both the innate and adaptive immune system. Based on this background, in this review article we attempt to summarize the epidemiological characteristics of CKD in the aging population, discuss the immunological mechanisms in aging-related CKD, and furnish the reader with processes for the therapy and management of elderly patients with CKD.

Cardiovascular disease (CVD) is a leading cause of death in chronic kidney disease (CKD). Hemodialysis is one of the main treatments for patients with end-stage kidney disease. Epidemiological data has shown that acute myocardial infarction (AMI) accounts for the main reason for death in patients with CKD under hemodialysis therapy. Immune dysfunction and changes in metabolism (including a high level of inflammatory cytokines, a disorder of lipid and mineral ion homeostasis, accumulation of uremic toxins et al.) during CKD can deteriorate stability of atherosclerotic plaque and promote vascular calcification, which are exactly the pathophysiological mechanisms underlying the occurrence of AMI. Meanwhile, the hemodialysis itself also has adverse effects on lipoprotein, the immune system and hemodynamics, which contribute to the high incidence of AMI in these patients. This review aims to summarize the mechanisms and further promising methods of prevention and treatment of AMI in CKD patients undergoing hemodialysis, which can provide an excellent paradigm for exploring the crosstalk between the kidney and cardiovascular system.

This study was to investigate the role of serum Klotho, fetuin-A, and Matrix Gla Protein (MGP) in Coronary Artery Calcification (CAC) in patients with Maintenance Hemodialysis (MHD) and their predictive value for CAC.

100 patients receiving MHD were selected. Serum Klotho, fetuin-A, and MGP levels were detected by ELISA. CAC scores were assessed by coronary CT scan. Multifactor analysis was used to evaluate the risk factors affecting CAC. The ability of serum Klotho, fetuin-A, and MGP levels to diagnose CAC was evaluated by receiver operating characteristic curves.

Serum Klotho, fetuin-A, and MGP were independent risk factors for CAC. Serum Klotho, fetuin-A, and MGP were valuable in the diagnosis of CAC in MHD patients.

There is a close relationship between Klotho, fetuin-A, and MGP levels in MHD patients and CAC.

For several years, alpha klotho has been considered as a candidate biomarker in chronic kidney disease (CKD), progression of CKD and CKD mineral bone disorders (CKD-MBD). The evidence on the relationship between klotho and kidney function is controversial in some areas. The aim of the study was to identify the influence of age, sex and breed on urinary alpha klotho, values in the early stages of CKD within the studied population and determine a reference interval in a group of healthy dogs. Significantly higher values were measured in older dogs over 6 years old (p = 0.026, p = 0.0007) and in the breed German Shepherd than Belgian Shepherd (p = 0.0401). On the basis of sex and in small breed dogs, no significant differences were noted. In dogs with CKD stage 2, alpha klotho values were significantly lower (p = 0.0135) than in healthy dogs. Within the studied population, a reference interval for urinary klotho to creatinine ratio (UrKl/Cr) was determined in the range of 3.94-23.55 pg/gCr. Since our findings show that alpha klotho is associated with older age, we assume that this may have influenced the results in the group of dogs with CKD stage 1 due to the presence of predominantly old dogs in this group. Future studies would be needed to consider age as a factor affecting urinary alpha klotho in dogs with CKD.

Chronic kidney disease (CKD) is linked to greater prevalence and rapid progression of calcific aortic valve disease (CAVD) characterized by valvular leaflet fibrosis and calcification. Fibroblast growth factor 23 (FGF23) level is elevated, and anti-aging protein Klotho is reduced in CKD patients. However, the roles of FGF23 and Klotho in the mechanism of aortic valve fibrosis and calcification remain unclear. We hypothesized that FGF23 mediates CKD-induced CAVD by enhancing aortic valve interstitial cell (AVIC) fibrosis and calcification, while soluble Klotho inhibits FGF23 effect. Methods and Results: In an old mouse model of CKD, kidney damages were accompanied by aortic valve thickening and calcification. FGF23 levels in plasma and aortic valve were increased, while Klotho levels were decreased. Recombinant FGF23 elevated the inflammatory, fibrogenic, and osteogenic activities in AVICs. Neutralizing antibody or shRNA targeting FGF23 suppressed the pathobiological activities in AVICs from valves affected by CAVD. FGF23 exerts its effects on AVICs via FGF receptor (FGFR)/Yes-associated protein (YAP) signaling, and inhibition of FGFR/YAP reduced FGF23's potency in AVICs. Recombinant Klotho downregulated the pathobiological activities in AVICs exposed to FGF23. Incubation of FGF23 with Klotho formed complexes and decreased FGF23's potency. Further, treatment of CKD mice with recombinant Klotho attenuated aortic valve lesions. Conclusion: This study demonstrates that CKD induces FGF23 accumulation, Klotho insufficiency and aortic valve lesions in old mice. FGF23 upregulates the inflammatory, fibrogenic and osteogenic activities in AVICs via the FGFR/YAP signaling pathway. Soluble Klotho suppresses FGF23 effect through molecular interaction and is capable of mitigating CKD-induced CAVD.

Cardiovascular disease (CVD) frequently occurs in patients with chronic kidney disease (CKD), particularly those undergoing dialysis. The mechanisms behind this may be related to traditional risk factors and CKD-specific factors that accelerate atherosclerosis and vascular calcification in CKD patients. The accumulation of uremic toxins is a significant factor in CKD-related systemic disorders. Basic research suggests that indoxyl sulfate (IS), a small protein-bound uremic toxin, is associated with macrophage dysfunctions, including increased oxidative stress, exacerbation of chronic inflammation, and abnormalities in lipid metabolism. Strategies to mitigate the toxicity of IS include optimizing gut microbiota, intervening against the abnormality of intracellular signal transduction, and using blood purification therapy with higher efficiency. Further research is needed to examine whether lowering protein-bound uremic toxins through intervention leads to a reduction in CVD in patients with CKD.

Chronic kidney disease (CKD) is associated with significant reductions in lean body mass and in the mass of various tissues, including skeletal muscle, which causes fatigue and contributes to high mortality rates. In CKD, the cellular protein turnover is imbalanced, with protein degradation outweighing protein synthesis, leading to a loss of protein and cell mass, which impairs tissue function. As CKD itself, skeletal muscle wasting, or sarcopenia, can have various origins and causes, and both CKD and sarcopenia share common risk factors, such as diabetes, obesity, and age. While these pathologies together with reduced physical performance and malnutrition contribute to muscle loss, they cannot explain all features of CKD-associated sarcopenia. Metabolic acidosis, systemic inflammation, insulin resistance and the accumulation of uremic toxins have been identified as additional factors that occur in CKD and that can contribute to sarcopenia. Here, we discuss the elevation of systemic phosphate levels, also called hyperphosphatemia, and the imbalance in the endocrine regulators of phosphate metabolism as another CKD-associated pathology that can directly and indirectly harm skeletal muscle tissue. To identify causes, affected cell types, and the mechanisms of sarcopenia and thereby novel targets for therapeutic interventions, it is important to first characterize the precise pathologic changes on molecular, cellular, and histologic levels, and to do so in CKD patients as well as in animal models of CKD, which we describe here in detail. We also discuss the currently known pathomechanisms and therapeutic approaches of CKD-associated sarcopenia, as well as the effects of hyperphosphatemia and the novel drug targets it could provide to protect skeletal muscle in CKD.

Compelling evidence suggests that calcium/phosphorus homeostasis-related parameters may be linked to diabetes mellitus and cardiovascular events. However, few studies have investigated the association of fibroblast growth factor 23 (FGF23), α-klotho and FGF23/α-klotho ratio with atherosclerosis in patients with type 2 diabetes mellitus (T2DM).

This study was designed to evaluate whether FGF23, α-klotho and FGF23/α-klotho ratio are associated with T2DM and further to explore the relationships between these three factors and atherosclerosis in Chinese patients with T2DM.

Serum FGF23 and α-klotho levels were measured via an enzyme-linked immunosorbent assay (ELISA) kit, and the carotid intima-media thickness (CIMT) was assessed via high-resolution color Doppler ultrasonography. The associations of serum FGF23, α-klotho and FGF23/α-klotho ratio with atherosclerosis in T2DM patients were evaluated using multivariable logistic regression models.

This cross-sectional study involved 403 subjects (207 with T2DM and 196 without T2DM), 41.7% of the patients had atherosclerosis, and 67.2% of the carotid intima were thickened to a thickness greater than 0.9 mm. Compared with those in the lowest tertile, higher tertiles of FGF23 levels and FGF23/α-klotho ratio were positively associated with T2DM after adjusting for covariates, and serum α-klotho concentration was inversely correlated with T2DM (all P values < 0.01). Moreover, elevated serum FGF23 levels and FGF23/α-klotho ratio were positively associated with CIMT and carotid atherosclerosis in T2DM patients (all P values < 0.01). Further spline analysis similarly revealed linear dose‒response relationship (all P values < 0.01). And there was still significant differences in CIMT and carotid atherosclerosis between the highest group of α-klotho and the reference group in T2DM patients (P values = 0.05).

T2DM was positively linearly related to serum FGF23 concentration and FGF23/α-klotho ratio, and negatively correlated with serum α-klotho concentration. Furthermore, both FGF23 and FGF23/α-klotho ratio were positively correlated with CIMT and atherosclerosis in T2DM patients, while α-klotho was inversely correlated with both CIMT and atherosclerosis, although the associations were not completely significant. Prospective exploration and potential mechanisms underlying these associations remain to be further elucidated.

The anti-aging protein Klotho plays a protective role in kidney disease, but its potential as a biomarker for chronic kidney disease (CKD) is controversial. Additionally, the main pathways through which Klotho exerts its effects on CKD remain unclear. Therefore, we used bioinformatics and clinical data analysis to determine its role in CKD.

We analyzed the transcriptomic and clinical data from the Nephroseq v5 database and found that the Klotho gene was mainly expressed in the tubulointerstitium, and its expression was significantly positively correlated with estimated glomerular filtration rate (eGFR) and negatively correlated with blood urea nitrogen (BUN) in CKD. We further found that Klotho gene expression was mainly negatively associated with inflammatory response and positively associated with lipid metabolism in CKD tubulointerstitium by analyzing two large sample-size CKD tubulointerstitial transcriptome datasets. By analyzing 10-year clinical data from the National Health and Nutrition Examination Survey (NHANES) 2007-2016, we also found that Klotho negatively correlated with inflammatory biomarkers and triglyceride and positively correlated with eGFR in the CKD population. Mediation analysis showed that Klotho could improve renal function in the general population by modulating the inflammatory response and lipid metabolism, while in the CKD population, it primarily manifested by mediating the inflammatory response. Restricted cubic spline (RCS) analysis showed that the optimal concentration range for Klotho to exert its biological function was around 1000 pg/ml. Kaplan-Meier curves showed that lower cumulative hazards of all-cause mortality in participants with higher levels of Klotho. We also demonstrated that Klotho could reduce cellular inflammatory response and improve cellular lipid metabolism by establishing an in vitro model similar to CKD.

Our results suggest that Klotho exerts protection in CKD, which may be mainly related to the regulation of inflammatory response and lipid metabolism, and it can serve as a potential biomarker for CKD.

The study aimed to determine the variability in the stages of diabetic nephropathy by examining specific biochemical functions associated with the target organ. As a result, various biochemical parameters were assessed in all of the groups under investigation.

These parameters encompassed soluble α-Klotho and serum insulin, which were determined through ELISA. Additionally, spectrophotometric methods were employed to assess other parameters such as blood levels of urea in all groups. Instead of using HPLC method, HbA1c levels were determined. Blood and urine samples were obtained from a total of 90 participants, who were aged between 37 and 70 years. A total of 70 patients were categorized into three groups according to their ACR. The first group consisted of patients with an ACR value of less than 30 mg/g. The second group included patients with an ACR value ranging from 30 to 300 mg/g. The third group comprised patients with an ACR value greater than 300 mg. Additionally, the study also involved 20 healthy individuals.

The serum soluble α-Klotho in the patient group was significantly lower than that of the healthy subjects. There were strong negative correlations between serum soluble α-Klotho and both ACR and HOMA-IR. The AUC value was excellent, measuring at 0.93 with a p < 0.0001.

Soluble α-Klotho levels in the sera of diabetic patients were shown to be lower and significantly linked to patients with diabetic nephropathy. This implies that klotho levels may be influenced by ACR in addition to playing a significant role in insulin resistance.

Cardiovascular disease (CVD) is the major cause of death in chronic kidney disease (CKD) and is associated with high circulating fibroblast growth factor (FGF)23 levels. It is unresolved whether high circulating FGF23 is a mere biomarker or pathogenically contributes to cardiomyopathy. It is also unknown whether the C-terminal FGF23 peptide (cFGF23), a natural FGF23 antagonist proteolyzed from intact FGF23 (iFGF23), retards CKD progression and improves cardiomyopathy. We addressed these questions in three murine models with high endogenous FGF23 and cardiomyopathy. First, we examined wild-type (WT) mice with CKD induced by unilateral ischemia-reperfusion and contralateral nephrectomy followed by a high-phosphate diet. These mice were continuously treated with intraperitoneal implanted osmotic minipumps containing either iFGF23 protein to further escalate FGF23 bioactivity, cFGF23 peptide to block FGF23 signaling, vehicle, or scrambled peptide as negative controls. Exogenous iFGF23 protein given to CKD mice exacerbated pathological cardiac remodeling and CKD progression, whereas cFGF23 treatment improved heart and kidney function, attenuated fibrosis, and increased circulating soluble Klotho. WT mice without renal insult placed on a high-phosphate diet and homozygous Klotho hypomorphic mice, both of whom develop moderate CKD and clear cardiomyopathy, were treated with cFGF23 or vehicle. Mice treated with cFGF23 in both models had improved heart and kidney function and histopathology. Taken together, these data indicate high endogenous iFGF23 is not just a mere biomarker but pathogenically deleterious in CKD and cardiomyopathy. Furthermore, attenuation of FGF23 bioactivity by cFGF23 peptide is a promising therapeutic strategy to protect the kidney and heart from high FGF23 activity.NEW & NOTEWORTHY There is a strong correlation between cardiovascular morbidity and high circulating fibroblast growth factor 23 (FGF23) levels, but causality was never proven. We used a murine chronic kidney disease (CKD) model to show that intact FGF23 (iFGF23) is pathogenic and contributes to both CKD progression and cardiomyopathy. Blockade of FGF23 signaling with a natural proteolytic product of iFGF23, C-terminal FGF23, alleviated kidney and cardiac histology, and function in three separate murine models of high endogenous FGF23.

Worldwide, the burden of chronic kidney disease (CKD) has increased rapidly and is a lethal disease. The klotho protein plays a vital role in the regulatory mechanism in the progression of CKD. Particularly the decreased expression of klothoand its genetic variations might affect the potency of drugs. This study aims to identify a new drug molecule, which works equipotential in all types of klotholike wild and mutant variants. All non-synonymous SNPs were predicted by several SNP tools. Where, two missense variants were examined as vulnerable, significantly damaging, and also involved in the structural conformational changes of the protein. Based on structure-based screening, E-pharmacophore screening, binding mode analysis, binding free energy analysis, QM/MM, and molecular dynamics analysis a lead compound (Lifechemical_F2493-2038) was identified as an effective agonistic molecule hence the identified Lifechemical_F2493-2038 compound is well bound to the wild and mutant proteins which found to increase the expression of klotho.Communicated by Ramaswamy H. Sarma.

Background: This study sought to assess the effect of statin therapy on myocardial inflammation in a White New Zealand rabbit model of atherogenesis. Methods: The mRNA expression levels of pro-inflammatory, pluripotency, and aging-related markers were quantified following a controlled feeding protocol and statin treatments. Results: Following high-cholesterol diet induction, we observed significant upregulation in the myocardial mRNA levels of MYD88, NF-κB, chemokines (CCL4, CCL20, and CCR2), IFN-γ, interleukins (IL-1β, IL-2, IL-4, IL-8, IL-10, and IL-18), and novel markers (klotho, KFL4, NANOG, and HIF1α). In contrast, HOXA5 expression was diminished following a hyperlipidemic diet. Both statin treatments significantly influenced the markers studied. Nevertheless, rosuvastatin administration resulted in a greater reduction in MYD88, NF-kB, chemokines (CCL4, CCL20, and CCR2), and interleukins IL-1β, IL-8, KLF4, NANOG, and HIF1α than fluvastatin. Fluvastatin, on the other hand, led to a stronger decrease in IL-4. Downregulation of IL-2 and IL-18 and upregulation of IFNβ and HOXA5 were comparable between the two statins. Notably, rosuvastatin had a stronger effect on the upregulation of klotho and IL-10. Conclusion: Overall, statin therapy significantly attenuated inflammatory, pluripotency, and klotho expression in myocardial tissue under atherogenic conditions. Our findings also highlight the differential efficacy of rosuvastatin over fluvastatin in curtailing proatherogenic inflammation, which could have profound implications for the clinical management of cardiovascular disease.

α-Klotho (KLA) is a type-1 membranous protein that can associate with fibroblast growth factor receptor (FGFR) to form co-receptor for FGF23. The ectodomain of unassociated KLA is shed as soluble KLA (sKLA) to exert FGFR/FGF23-independent pleiotropic functions. The previously determined X-ray crystal structure of the extracellular region of sKLA in complex with FGF23 and FGFR1c suggests that sKLA functions solely as an on-demand coreceptor for FGF23. To understand the FGFR/FGF23-independent pleiotropic functions of sKLA, we investigated biophysical properties and structure of apo-sKLA. Mass photometry revealed that sKLA can form a stable structure with FGFR and/or FGF23 as well as sKLA dimer in solution. Single particle cryogenic electron microscopy (cryo-EM) supported the dimeric structure of sKLA. Cryo-EM further revealed a 3.3Å resolution structure of apo-sKLA that overlays well with its counterpart in the ternary complex with several distinct features. Compared to the ternary complex, the KL2 domain of apo-sKLA is more flexible. 3D variability analysis revealed that apo-sKLA adopts conformations with different KL1-KL2 interdomain bending and rotational angles. The potential multiple forms and shapes of sKLA support its role as FGFR-independent hormone with pleiotropic functions. A comprehensive understanding of the sKLA conformational landscape will provide the foundation for developing klotho-related therapies for diseases.

Metabolic syndrome is a cluster of metabolic abnormalities that significantly increase the risk of cardiovascular disease and mortality. The identification of novel biomarkers associated with mortality in patients with metabolic syndrome could facilitate early risk stratification and targeted interventions.

We conducted a large prospective cohort study using data from five cycles (2009-2016) of the National Health and Nutrition Examination Survey (NHANES) database, including a total of 40,439 participants. Logistic regression analysis was used to assess the association between serum klotho protein levels and metabolic syndrome, while Cox regression analysis was employed to examine the correlation between serum klotho levels and all-cause mortality. Mortality data were updated until December 31, 2019.

After adjusting for demographic and socioeconomic confounders, the logistic regression model demonstrated that higher serum klotho levels were significantly associated with a decreased prevalence of metabolic syndrome (OR [95% CI] Highest vs. lowest quartile: 0.84 [0.70-0.99], P=0.038). In the Cox regression model, elevated klotho levels were found to significantly reduce the risk of all-cause mortality among individuals with metabolic syndrome (HR [95% CI] Highest vs. lowest quartile: 0.68 [0.51-0.90], P=0.006).

Serum klotho levels were found to be inversely associated with the prevalence of metabolic syndrome, independent of potential confounding factors such as demographics, socioeconomic status, and lifestyle factors. Furthermore, higher klotho levels strongly indicated a lower risk of all-cause mortality in individuals with metabolic syndrome.

Although Klotho-related research has seen a significant upsurge, the field lacks comprehensive analytical representation and in-depth exploration of pertinent areas such as prevailing research trends and key focus areas.

This review presents a bibliometric analysis of literature data gathered from the Web of Science Core Collection databases from January 1, 2000, to April 30, 2023. Parameters such as co-authorship, co-citation, co-occurrence, and the emergence of publications, countries, categories, references, and keywords were scrutinized predominantly using Citespace software.

Our investigation amassed a total of 3548 papers, with the United States leading in the quantity of publications (1175, accounting for 33.12%), followed by China (867, representing 24.44%), and Japan (439, accounting for 12.37%). While the United States is preeminent in the overall volume of publications, Scotland holds prominence in terms of centrality. Out of a total of 96 subject categories, urology and nephrology (573), and endocrinology and metabolism (542) were the two leading domains of Klotho-related publications. The 2011 paper titled "FGF23 induces left ventricular hypertrophy" by Faul C et al. holds the distinction of being the most frequently cited. The keywords "fibroblast growth factor 23," "phosphate homeostasis," and "functional variants" demonstrated the highest intensity, underscoring the potential of these research areas.

As the volume of literature grows, the role of Klotho in disease management and its applicability as a marker in disease progression warrant vigilant tracking and study.

Hyperphosphatemia is a common feature in patients with impaired kidney function and is associated with increased risk of cardiovascular disease. This phenomenon extends to the general population, whereby elevations of serum phosphate within the normal range increase risk; however, the mechanism by which this occurs is multifaceted, and many aspects are poorly understood. Less than 1% of total body phosphate is found in the circulation and extracellular space, and its regulation involves multiple organ cross talk and hormones to coordinate absorption from the small intestine and excretion by the kidneys. For phosphate to be regulated, it must be sensed. While mostly enigmatic, various phosphate sensors have been elucidated in recent years. Phosphate in the circulation can be buffered, either through regulated exchange between extracellular and cellular spaces or through chelation by circulating proteins (ie, fetuin-A) to form calciprotein particles, which in themselves serve a function for bulk mineral transport and signaling. Either through direct signaling or through mediators like hormones, calciprotein particles, or calcifying extracellular vesicles, phosphate can induce various cardiovascular disease pathologies: most notably, ectopic cardiovascular calcification but also left ventricular hypertrophy, as well as bone and kidney diseases, which then propagate phosphate dysregulation further. Therapies targeting phosphate have mostly focused on intestinal binding, of which appreciation and understanding of paracellular transport has greatly advanced the field. However, pharmacotherapies that target cardiovascular consequences of phosphate directly, such as vascular calcification, are still an area of great unmet medical need.

The crosstalk of the heart with distant organs such as the lung, liver, gut, and kidney has been intensively approached lately. The kidney is involved in (1) the production of systemic relevant products, such as renin, as part of the most essential vasoregulatory system of the human body, and (2) in the clearance of metabolites with systemic and organ effects. Metabolic residue accumulation during kidney dysfunction is known to determine cardiovascular pathologies such as endothelial activation/dysfunction, atherosclerosis, cardiomyocyte apoptosis, cardiac fibrosis, and vascular and valvular calcification, leading to hypertension, arrhythmias, myocardial infarction, and cardiomyopathies. However, this review offers an overview of the uremic metabolites and details their signaling pathways involved in cardiorenal syndrome and the development of heart failure. A holistic view of the metabolites, but more importantly, an exhaustive crosstalk of their known signaling pathways, is important for depicting new therapeutic strategies in the cardiovascular field.