Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone secreted by the bone in response to dietary phosphate intake. High circulating FGF23 levels is an early sign of cardiovascular disease in individuals with obesity. This randomized controlled trial investigated the effects of replacing meat and fish with pulse intake on circulating FGF23 levels during a dietary weight-loss intervention. Sixteen middle-aged and older individuals with overweight and obesity (63.7 ± 5.1 years of age) were randomly assigned to control and plant groups. All participants attended a dietary weight-loss class once per week for 12 weeks. Participants in the plant group replaced meat and fish with pulse intake. Circulating FGF23 levels were measured before and after the intervention. Both groups showed reductions in body weight (control: 73.3 kg to 66.9 kg, plant: 78.8 kg to 73.1 kg, P < 0.001 for time effect). Plant-based protein intake was significantly higher in the plant group than in the control group (control: 7.3% of energy to 7.7% vs. plant: 7.0% of energy to 9.2%; P = 0.002 for group × time effect). However, the circulating FGF23 levels did not change in either group. Our results suggest that dietary weight-loss intervention promoting plant-based protein intake does not decrease circulating FGF23 levels. As this trial is one of the few to examine the effects of dietary weight-loss interventions on circulating FGF23 levels, additional intervention studies are needed. The protocol was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000048081; registered on 6/18/2022).

Chronic kidney disease (CKD) is a growing global public health concern, particularly in aging population. Despite the strong epidemiological evidence linking physical activity to improved kidney outcomes, interventional findings remain scarce and inconsistent. The primary purpose of the Aging Kidney and Exercise Training Study (AKETS) is to investigate whether a structured exercise program would attenuate the kidney function decline in middle–aged and older adults using a trial within cohorts (TwiCs) design. The AKETS is a 24–month, community–based, randomized controlled trial embedded in the prospective Aging Kidney Study cohort, which started in November 2018. A total of 141 participants aged 40–90 years are enrolled and allocated to one of the following three groups: (1) exercise intervention, (2) stretching intervention (active control), and (3) usual lifestyle (time control). The exercise program comprises individualized multicomponent training, including aerobic, resistance, and balance exercises, performed three times per week over 12 months. The primary outcome is the slope of the estimated glomerular filtration rate (eGFR) based on serum cystatin C. The secondary outcomes include renal hemodynamics, mineral metabolism, cardiovascular function, body composition, muscle strength, and physical performance. At baseline, the exercise, stretching, and usual lifestyle groups were well matched for key demographic and clinical characteristics, such as age, proportion of women, and eGFR. Findings from the AKETS will allow for a robust evaluation of exercise as a primary preventive strategy for CKD and are expected to inform future nonpharmacological interventions targeting kidney health in the aging population. This study is registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN000055825. Registered on the 13th of October 2024.

Duchenne muscular dystrophy (DMD) is a lethal, progressive skeletal and cardiac myopathy. Cardiomyopathy is the leading cause of death in patients with DMD, but the molecular basis for heart failure is incompletely understood. As with humans, in the mdx mouse model of DMD, cardiac function is impaired after the onset of skeletal muscle pathology. Dysregulation of Klotho gene regulation in dystrophic skeletal muscles occurs at disease onset, affecting pathogenesis. Whether Klotho is protective against dystrophin-deficient cardiomyopathy is unknown. This study found that expression of a Klotho transgene prevented deficits in left ventricular ejection fraction and fractional shortening in mdx mice. Improvements in cardiac performance were associated with reductions in adverse cardiac remodeling, cardiac myocyte hypertrophy, and fibrosis. In addition, mdx mice expressed high concentrations of plasma fibroblast growth factor 23 (FGF23), and expression was increased locally in hearts. The cardioprotective effects of Klotho were not associated with differences in renal function or serum biochemistries, but transgene expression prevented increased expression of plasma FGF23 and cardiac Fgf23 mRNA expression. Cardiac reactive oxygen species, oxidative damage, mitochondrial damage, and apoptosis were reduced in transgenic hearts. FGF23 stimulated hypertrophic growth in dystrophic neonatal mouse ventricular myocytes in vitro, which was inhibited by co-stimulation with soluble Klotho. Taken together, these results show that Klotho prevented dystrophic cardiac remodeling and improved function.

The circulating fibroblast growth factor 23 (FGF23) is a potential therapeutic target for cardiorenal syndrome. However, current evidence on the determinants, particularly the modifiable factors of circulating FGF23 levels that increase independently of the kidney function, remains limited. In this study, we aimed to investigate the association between physical performance measures and circulating FGF23 levels in middle-aged and older adults with normal kidney function. This cross-sectional study assessed circulating FGF23 levels and physical performance parameters, including the handgrip strength, knee extension strength, maximal gait speed, the 30-second chair stand test (30s-CST), sit-and-reach test, and aerobic exercise capacity in 158 participants. Multiple regression analyses were performed to evaluate the independent associations between circulating FGF23 levels and physical performance measures after adjusting for potential confounders including age, sex, the presence of lifestyle-related disease, serum phosphate and phosphate-regulating hormone, estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio. Higher circulating FGF23 levels were associated with lower handgrip strength, knee extension strength, maximal gait speed, 30s-CST score, and aerobic exercise capacity. These associations remained significant after adjusting for confounders, except for the association with handgrip strength and aerobic exercise capacity, which was attenuated when renal function variables were included. However, when all physical performance parameters were included in a model, knee extension strength and aerobic exercise capacity were identified as independent determinants of circulating FGF23 levels. Physical performance, particularly knee extension strength, and to a lesser extent aerobic exercise capacity, was independently or partially associated with circulating FGF23 levels in individuals with normal kidney function. Maintaining physical performance may help regulate circulating FGF23 levels, highlighting a potential role in preventing its elevation.

Objective: An increase in proximal tubule fluid phosphate concentration is caused by increased serum fibroblast growth factor-23 (FGF23) levels, which resulted in renal tubular damage in a mouse model of chronic kidney disease (CKD). However, few human studies have supported this concept. This study aimed to explore the association among estimated proximal tubule fluid phosphate concentration (ePTFp), serum FGF23 levels, and renal tubular damage biomarkers in middle-aged and older populations with mild decline in renal function. Methods: This cross-sectional study included 218 participants aged >= 45 with CKD stages G2-G4. Anthropometric measurements, blood tests, spot urine biomarkers, renal ultrasonography, cardiovascular assessment, smoking status, and medication usage were obtained in the morning in fasted states. The ePTFp was calculated using serum creatinine, urine phosphate, and creatinine concentrations. Urinary (32-microglobulin ((32-MG) and liver-type fatty acid-binding protein (L-FABP) levels were evaluated to assess renal tubular damage. Results: PTFp, serum FGF23, urinary (32-MG, and urinary L-FABP levels increased with CKD stage progression (stages G2, G3, and G4). However, serum and urine phosphate concentrations were comparable across the CKD stages. Univariate analysis revealed a stronger correlation of ePTFp with serum FGF23, urinary (32-MG, and urinary L-FABP levels than with the corresponding serum and urine phosphate concentrations. Multivariate analyses demonstrated that increased ePTFp was independently associated with elevated serum FGF23 and urinary (32-MG levels, even after adjusting for potential covariates, including the estimated glomerular filtration rate and urinary albumin-to-creatinine ratio. Conclusions: Our results are consistent with the concept in mouse model and suggest that increased ePTFp are associated with increased serum FGF23 levels and renal tubular damage during the early stages of CKD.

Antecedentes y objetivo: En un fracaso renal agudo (FRA) se activa un fuerte componente inflamatorio como respuesta al daño renal, y uno de los principales mediadores de este proceso es la interleuquina pro-inflamatoria 6 o IL-6. A su vez, ligado a este fenómeno también se producen alteraciones en los distintos componentes del metabolismo mineral como son aquellos dependientes del factor de crecimiento de fibroblasto (FGF)23 y el cofactor anti-envejecimiento klotho. El objetivo de este trabajo fue explorar la asociación entre la función renal y los niveles sistémicos tanto de IL-6, así como de FGF23 y klotho, en las etapas tempranas de un FRA, analizando la capacidad predictora de IL-6 en la mortalidad temprana asociada al FRA.Materiales y métodos: Se analizaron los niveles plasmáticos de IL-6, klotho y FGF23 en muestras procedentes de 28 pacientes con FRA, y se relacionaron con la función renal en el momento del ingreso hospitalario, y después de 24 y 72 horas. Además, se analizó la capacidad predictora de IL-6 sobre la mortalidad asociada al FRA en los tres tiempos del estudio. En un modelo experimental de FRA nefrotóxico en ratón, se analizaron también los valores sistémicos de IL-6 y FGF23 tras las 24 y 72 horas desde la inducción del daño renal, así como en ratones que sobreexpresan la proteína anti-envejecimiento, klotho.Resultados: Los niveles de IL-6 aumentaron en los pacientes con FRA, especialmente en el momento del ingreso hospitalario, y fueron disminuyendo en paralelo a la mejora de la función renal. Al mismo tiempo que el aumento de IL-6, se produjo el incremento sistémico de FGF23 y el descenso de klotho, existiendo una correlación significativa y positiva entre los niveles de IL-6 y FGF23. Además, obtuvimos que los niveles sistémicos de IL-6 son un buen predictor de la mortalidad en los pacientes, con un área bajo la curva igual a uno tras las 72 horas desde el diagnóstico de FRA. En el modelo de FRA experimental en ratón, observamos también un incremento en los niveles plasmáticos tanto de IL-6 como de FGF23, tras las 24 horas del daño renal. Sin embargo, en los ratones transgénicos con sobreexpresión de klotho, no se produjo tal incremento en ninguna de ellas.Conclusiones: Existe una asociación entre el daño renal, el incremento de la IL-6 y de FGF23 en pacientes con FRA, especialmente en el momento del diagnóstico. Además, los niveles elevados de IL-6 predicen la mortalidad de estos pacientes a corto y medio plazo, considerándose un buen biomarcador pronóstico con una predicción total tras las 72 horas desde el diagnóstico del FRA. Mantener unos niveles adecuados de klotho podría prevenir la respuesta inflamatoria mediada por la IL-6 y por lo tanto también aminorar el grado y severidad del daño renal tras un FRA.

Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone secreted by osteocytes in response to dietary phosphate intake. An increase in FGF23 level is an indicator of excess phosphate intake relative to the residual nephron number. Therefore, avoiding excessive phosphate intake and inhibiting the elevation of serum FGF23 levels are important to preserve the number of functional nephrons. This randomized crossover trial aimed to determine the potential differences in the impacts on serum FGF23 levels between plant protein and animal protein-based meals in individuals with normal renal function. Nine young men were administered plant (no animal protein) or animal protein-based meals (70% of their protein was from animal sources) with the same phosphate content. The test meals consisted of breakfast, lunch, and dinner. Blood samples were collected in the morning, after overnight fasting, and before and after eating the test meals (for two consecutive days at the same hour each day). Furthermore, a 24-h urine sample was obtained on the day the test meal was consumed. No significant interactions were found among serum phosphate, calcium, and 1,25-dihydroxyvitamin D levels. However, after eating plant protein-based meals, serum FGF23 levels decreased and serum intact parathyroid hormone levels increased (interaction, p<0.05). Additionally, urine 24-h phosphate excretion tended to be lower in individuals consuming plant protein-based meals than in those consuming animal protein-based meals (p=0.06). In individuals with normal renal function, plant protein-based meals may prevent an increase in serum FGF23 levels and kidney damage caused by phosphate loading.

Abstract Background and Aims Extended-hours hemodialysis (HD) has better clinical outcomes than conventional HD. Previous studies have shown that a prolonged dialysis treatment time is associated with lower serum phosphorus levels, but the impact of extended-hours HD on calciprotein particles (CPP) is unknown. We investigated whether extended-hour HD and conventional HD have varying effects on blood levels of CPP and phosphorus, which have been identified as the main pathogenic molecules for vascular calcification. Method We performed a cross-sectional study of patients with extended-hours HD or conventional HD between January and March 2020. Blood CPP levels were measured in plasma and serum predialysis samples using a previously reported "gel filtration method". Linear and nonlinear associations between CPP and serum phosphorus levels were examined across dialysis modalities. Results A total of 382 participants (185 with extended-hours HD and 197 with conventional HD) were included in the analysis. The median age of participants was 71 years, 65% of the patients were men, and the mean phosphorus level was 5.4 mg/dL. Extended-hours HD was associated with lower plasma CPP levels (Extended-hours HD vs Conventional HD; 40,018 AU vs 75,728 AU) and serum CPP levels (Extended-hours HD vs Conventional HD; 66,524 AU vs 100,812 AU), regardless of similar serum phosphorus levels. Multivariable linear regression analysis showed that extended-hours HD was associated with lower natural logarithmic plasma CPP levels: -0.64 (95% CI: -0.74 to -0.55). Restricted cubic spline function indicated that extended-hours HD was associated with lower plasma CPP levels across levels of serum phosphorus, with significant differences observed between groups, especially in hyperphosphatemic conditions (P for interaction <0.01). Conclusion The patients with extended-hours HD had lower CPP levels than those with the conventional HD group despite no significant differences in serum phosphorus levels, which may contribute to better clinical outcomes in patients on extended-hours HD.

Background Hemodialysis patients exhibit a reduced response to vaccination and have different vaccine dose regimens. Vaccines induce antibodies and affect the inflammatory balance through antibody glycosylation and effector functions. Therefore, we aimed to analyze the antibody glycosylation profiles in hemodialysis patients who were vaccinated against severe acute respiratory syndrome coronavirus 2, infected with the virus, or both, and compare them with those of dialysis patients in a control group. Methods Plasma samples from 112 hemodialysis patients were assigned to four groups: control, infected, vaccinated, and post-vaccine-infected. Paired plasma samples from 47 people with vaccination (vaccinees) were analyzed before and after the booster dose. The same analytical approach was applied to the four groups for a cross-sectional comparison. Results Our study found that both vaccination and infection groups showed decreased fucosylation of IgG1, which is associated with a proinflammatory biosignature. However, vaccination also leads to increased galactosylation and bisection of IgG antibodies, which are associated with anti-inflammatory effects and the additional regulation of immune responses. In contrast, infection led to an additional decrease in the fucosylation of IgG2 and IgA, demonstrating a more intense proinflammatory biosignature than vaccination. Conclusions Our findings emphasize the proinflammatory biosignature of afucosylation in both vaccination and infection groups. Additionally, we uncovered further regulated profiles related to galactosylation in vaccinees. These findings suggest that antibody investigation for vaccination or infection should not solely focus on neutralization but should also consider effector function-related glycosylation profiling. This comprehensive information can be valuable for fine-tuning vaccine development in the future.

Background and hypothesis:Extended-hours haemodialysis (HD) is associated with better clinical outcomes than conventional HD. We investigated whether extended-hours HD and conventional HD have varying effects on blood levels of calciprotein particles (CPPs) and phosphorus, which have been identified as major pathogenic molecules for vascular calcification. Methods:Patients who underwent conventional or extended in-centre daytime HD between January and March 2020 were included. Plasma CPP levels, representing only secondary CPPs (CPP-II), were measured in pre-dialysis samples. Linear and non-linear associations between CPPs and serum phosphorus levels were examined across dialysis modalities. Results:A total of 382 participants (185 undergoing extended-hours HD and 197 undergoing conventional HD) were included in the analysis. The median age of participants was 71 years, 65% of the patients were men and the mean phosphorus level was 5.4 mg/dl. Plasma CPP (CPP-II) levels were lower in the extended-hours HD group than in the conventional HD group [40 018 (arbitrary units) AU versus 75 728 AU; P < .01]. Multivariable linear regression analysis showed that extended-hours HD was associated with lower natural logarithmic plasma CPP (CPP-II) levels: -0.64 (95% confidence interval -0.74 to -0.55). A restricted cubic spline function indicated that extended-hours HD was associated with lower plasma CPP (CPP-II) levels across levels of serum phosphorus, with significant differences observed between groups, especially in hyperphosphataemic conditions (P for interaction <.01). Conclusions:The extended-hours HD group had lower CPP levels than the conventional HD group despite no significant differences in serum phosphorus levels, which may contribute to better clinical outcomes in patients on extended-hours HD.

Calciprotein particles (CPP), found in the blood, are composite nanoparticles consisting of the protein fetuin-A and solid-phase calcium phosphate. Among these, amorphous CPP (a-CPP), composed of fetuin-A/amorphous calcium phosphate nanoparticles, are non-pathogenic. In contrast, crystalline CPP (c-CPP), which contain calcium phosphate crystals and result from the agglomeration of a-CPP, are known to cause inflammation and vascular calcification. We have developed an in vitro synthesis method for CPP and studied the phase transition process from a-CPP to c-CPP. This study evaluates the influence of atmospheric carbon dioxide on this transition by examining microscopic structures using fi eld emission scanning electron microscopy, transmission electron microscopy, X-ray diffraction analysis, and infrared spectroscopy. We found that the transition from a-CPP to cCPP was significantly accelerated by atmospheric carbon dioxide. This phenomenon can be attributed to the formation of carbonate-containing hydroxyapatite, which is expected to have a highly symmetric hexagonal structure conducive to crystal growth.

INTRODUCTION:Recent studies have identified increased blood calciprotein particle (CPP) levels as risk factors for vascular calcification and cardiovascular events in patients undergoing maintenance hemodialysis. Although positively correlated with serum phosphate levels, serum CPP levels vary considerably among patients with similar serum phosphate levels. We investigated the capacity of the ratio of serum CPP levels to serum phosphate levels (CPP/Pi ratio) to predict cardiovascular events in incident hemodialysis patients compared to the serum calcification propensity test (T50). METHODS AND RESULTS:The association between the CPP/Pi ratio and major adverse cardiac and cerebrovascular events (MACCE) was investigated in 174 incident hemodialysis patients. Multivariate analysis revealed that the CPP/Pi ratio was independently associated with MACCE [hazard ratio 1.60, 95% confidence interval (1.15-2.23), p = 0.006] but serum T50 levels were not. CONCLUSIONS:The CPP/Pi ratio is a useful, novel biomarker for predicting the risk of cardiovascular events in patients undergoing incident hemodialysis.

Background and objective In acute kidney injury (AKI), a strong inflammatory component is activated in response to the renal damage, and one of the main mediators behind this process is the pro-inflammatory interleukin 6 or IL-6. Beside to this phenomenon, there are also alterations in different components of mineral metabolism, such as those dependent on fibroblast growth factor (FGF)23 and the anti-ageing cofactor klotho. The aim of this work was to explore the association between renal function and systemic levels of IL-6, as well as FGF23 and klotho in the early stages of AKI, analysing the predictive capacity of IL-6 in early mortality associated with AKI. Material and methods Plasma levels of IL-6, klotho and FGF23 were analysed in samples from 28 patients with AKI and related to renal function on hospital admission, and after 24 and 72 h. In addition, the predictive capacity of IL-6 on AKI-associated mortality was analysed at the three study time points. In an experimental nephrotoxic -AKI mouse model, systemic IL-6 and FGF23 values were also analysed 24 and 72 h after induction of kidney damage, as well as in mice overexpressing the anti-ageing protein, klotho. Results Systemic IL-6 levels increased in AKI patients, especially in hospital admission time, and decreased in parallel with improving renal function. At the same time as IL-6 values increased, there was an increase in FGF23 and a decrease in klotho levels, with a significant and positive correlation between IL-6 and FGF23 levels. In addition, we obtained that systemic IL-6 levels were a good predictor of mortality in these patients, with an area under the curve equal to one at 72 h after AKI. In the experimental mouse AKI model, we also observed an increase in plasma levels in both IL-6 and FGF23 after 24 h of kidney damage. Nevertheless, in transgenic mice overexpressing klotho, there was no such increase in any of them. Conclusions There is an association between renal damage and increased levels of IL-6 and FGF23 in patients with AKI, especially on hospital admission time. Moreover, IL-6 levels are able to predict mortality in these patients, being a promising prognostic biomarker at any study time with a strong prediction at 72 h after patient admission. Maintaining adequate klotho levels could prevent the IL-6 mediated inflammatory response and therefore also reduce the degree and severity of renal damage after AKI.

Background/Objectives: Levels of circulating soluble thrombomodulin (sTM), an anticoagulant factor, are associated with the severity and progression of arteriosclerotic diseases. However, the role of elevated sTM levels remains to be clarified in patients on dialysis. As the calcification propensity time T50 is a novel marker of arterial calcification, we aimed to determine the association between sTM and T50 in patients on hemodialysis (HD). Methods: This cross-sectional study included 49 adult patients on maintenance HD. Correlation analysis was performed to test the association between T50 and patient characteristics. Linear regression was used to evaluate the association between T50 and sTM. Results: Partial correlation analysis showed a strong association between T50 and glycated albumin, phosphorous, and sTM levels (partial correlation coefficient: r [partial] = −0.359, p = 0.023; r [partial] = −0.579, p < 0.001; and r [partial] = 0.346, p = 0.029, respectively). Multivariate linear regression analysis revealed that only sTM level was significantly and positively associated with T50 (β = 0.288; t = 2.27; p = 0.029; 95% confidence interval, 0.082–1.403). Conclusions: sTM is independently and positively associated with the propensity time for calcification, suggesting that sTM could be a good marker of arterial calcification progression in patients on HD.

Overexpression of the longevity gene Klotho prolongs lifespan, while its knockout shortens lifespan and impairs cognition via perturbation of myelination and synapse formation. However, comprehensive analysis of Klotho knockout effects on mammalian brain transcriptomics is lacking. Here, we report that Klotho knockout alters the levels of aging- and cognition related mRNAs, long non-coding RNAs, microRNAs and tRNA fragments. These include altered neuronal and glial regulators in murine models of aging and Alzheimer's disease and in human Alzheimer's disease post-mortem brains. We further demonstrate interaction of the knockout-elevated tRNA fragments with the spliceosome, possibly affecting RNA processing. Last, we present cell type-specific short RNA-seq datasets from FACS-sorted neurons and microglia of live human brain tissue demonstrating in-depth cell-type association of Klotho knockout-perturbed microRNAs. Together, our findings reveal multiple RNA transcripts in both neurons and glia from murine and human brain that are perturbed in Klotho deficiency and are aging- and neurodegeneration-related. Transcriptomic profiling shows that Klotho knockout perturbs brain short non-coding RNAs, such as microRNA and tRNA fragments, in both neurons and glia, that mimics the changes associated with Alzheimer's disease and aging in humans and murine models.

Background:Fetuin-A inhibits precipitation of calcium-phosphate crystals by forming calciprotein particles (CPP). A novel T50 test, which measures transformation time from primary to secondary CPP, is an index for calcification propensity. Both lower fetuin-A and shorter T50 levels were associated with cardiovascular disease (CVD) risk in patients with chronic kidney disease (CKD). Extremely high risk for CVD death in advanced CKD patients consists of high-incidental CVD event and high mortality after CVD event. To date, it is unclear whether fetuin-A and/or T50 can equally predict each CVD outcome. Methods:This prospective cohort study examined patients undergoing maintenance hemodialysis. The exposures were fetuin-A and T50. The outcomes of interests were new CVD events and subsequent deaths. The patients were categorized into tertiles of fetuin-A or T50 (T1 to T3). Results:We identified 190 new CVD events during the 5-year follow-up of the 513 patients and 59 deaths subsequent to the CVD events during 2.5-year follow-up. A lower fetuin-A but not T50 was significantly associated with new CVD events [subdistribution hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.15-2.61, P = .009 for T1 vs T3]. In contrast, a shorter T50 but not fetuin-A was a significant predictor of deaths after CVD events (HR 3.31, 95% CI 1.42-7.74, P = .006 for T1 + T2 vs T3). A lower fetuin-A was predictive of new CVD events, whereas a shorter T50 was more preferentially associated with subsequent death. Conclusion:These results indicate that fetuin-A and T50 are involved in cardiovascular risk in different manners.

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.

Introduction Klotho, a key aging regulator, is predominantly expressed in the kidney. Various methods now enable the measurement of soluble αKlotho blood levels in humans. Limited studies have explored the renal origin of circulating αKlotho in humans.Methods Soluble αKlotho in the inferior vena cava blood was measured using an enzyme-linked immunosorbent assay kit using blood samples from patients undergoing adrenal venous catheterization for close examination of primary aldosteronism.Results The concentration at the suprarenal inferior vena cava (476 ± 68.2) was significantly higher than that at the infrarenal inferior vena cava (434 ± 74.8) (p = 0.018), with a rate of change of 8.12 (2.3)%.Conclusions We demonstrate a step-up in αKlotho concentration from the infrarenal to suprarenal vena cava in humans, supporting the kidney’s origin of soluble αKlotho in the bloodstream.

Acute kidney injury (AKI) is associated with an elevated risk of cardiovascular major events and mortality. The pathophysiological mechanisms underlying the complex cardiorenal network interaction remain unresolved. It is known that the presence of AKI and its evolution are significantly associated with an alteration in the anti-aging factor klotho expression. However, it is unknown whether a klotho deficiency might aggravate cardiac damage after AKI. We examined intracellular calcium (Ca2+) handling in native ventricular isolated cardiomyocytes from wild-type (+/+) and heterozygous hypomorphic mice for the klotho gene (+/kl) in which an overdose of folic acid was administered to induce AKI. Twenty-four hours after AKI induction, cardiomyocyte contraction was decreased in mice with the partial deletion of klotho expression (heterozygous hypomorphic klotho named +/kl). This was accompanied by alterations in Ca2+ transients during systole and an impairment of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) function in +/kl mice after AKI induction. Moreover, Ca2+ spark frequency and the incidence of Ca2+ pro-arrhythmic events were greater in cardiomyocytes from heterozygous hypomorphic klotho compared to wild-type mice after AKI. A decrease in klotho expression plays a role in cardiorenal damage aggravating cardiac Ca2+ mishandling after an AKI, providing the basis for future targeted approaches directed to control klotho expression as novel therapeutic strategies to reduce the cardiac burden that affects AKI patients.