No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Bone and mineral disorders in chronic kidney disease: Implications for cardiovascular health and ageing in the general population
Abstract
The patient with chronic kidney disease (CKD) represents an extreme model for arteriosclerosis, vascular calcification, and bone disorders, all of which are also associated with ageing in the general population. These pathological features are also relevant to other common chronic health disorders such as diabetes, and chronic inflammatory and cardiovascular diseases. Although management and interventions for these major risk factors are now incorporated into most public health guidelines (eg, smoking cessation and control of bodyweight and blood pressure, as well as glucose and cholesterol concentrations), some residual cardiovascular risk is not reduced by implementation of these interventions. CKD should be regarded as an atypical disease in which both traditional and novel cardiovascular risk factors have effects on outcomes. But CKD can also be viewed conceptually as an accelerator of traditional cardiovascular risk factors. Findings from research into mineral bone disorder associated with CKD (CKD-MBD) could help the medical community to better understand the vascular actions of certain molecules, such as phosphates, fibroblast growth factor 23, parathyroid hormone, sclerostin, or vitamin D and their relevance to the management of different pathologies in the general population. Importantly, these components, which are recognised in nephrology, could help to explain residual risk of cardiovascular events in the general population. Thus, achieving a better understanding of CKD-MBDs could provide substantial insight into future treatments for arteriosclerosis and osteoporosis, which are strongly associated with ageing and morbidity in the general population.
... One of the most common causes of death in patients with CKD is CVD. Uremic vascular calcification might be the primary reason for poor CVD outcomes in patients with CKD [12,13]. Vascular calcification was thought to be a passive and degenerative condition without any proposed efficient treatment solutions. ...
... Despite the great improvement in dialysis technologies, the life expectancy of patients with end-stage renal disease (ESRD) undergoing chronic hemodialysis (HD) is still rather poor when compared to the general population [12,13,16]. In patients with chronic renal failure, cardiovascular complications increase as renal function deteriorates, and the risk of reaching ESRD is as present as the risk for cardiovascular disease. ...
... In patients with chronic renal failure, cardiovascular complications increase as renal function deteriorates, and the risk of reaching ESRD is as present as the risk for cardiovascular disease. Once ESRD is reached, cardiovascular disease (CVD) is the leading cause of morbidity and mortality, and about half of the deaths of patients on dialysis are attributed to cardiovascular causes [12,13,16]. Several contributors to the complex puzzle of uremia-related cardiovascular disease have been identified so far, with oxidative stress being one of the most important players [17]. ...
Preclinical studies have shown that parathyroid hormone (PTH) loses its biological effects through oxidation. PTH can be oxidized at methionines 8 and 18. Three possible variations of oxidized PTH (oxPTH) exist: Met8(ox)PTH, Met18(ox)PTH, and Met8, Met18(di-ox)PTH. A recent study showed that Met18(ox)PTH retained biological activity and was able to upregulate Fgf23 gene expression, whereas Met8(ox)PTH and Met8, Met18(di-ox)PTH showed less or no biological activity. An earlier study likewise showed that the oxidation of Met18 has minor effects on the secondary structure of PTH, whereas the oxidation of Met8 causes substantial structural changes, consistent with another study showing that oxidization just at Met8 blocks the generation of the second messenger cAMP, whereas the effect of the oxidation of Met18 is much less potent in inhibiting cAMP formation. A considerable percentage of circulating PTH in chronic kidney disease (CKD) patients is oxidized. However, we do not know the relative amounts of the different forms of oxPTH with agonistic, partial agonistic, or even antagonistic biological actions in different CKD populations. This might explain different clinical findings in the different CKD populations analyzed so far. The currently available method that was used in these clinical studies just distinguishes between oxPTH and noxPTH without being able to differentiate between different forms of oxPTH. Only methods of PTH measurement that are able to differentiate between PTH forms (noxPTH, Met8(ox)PTH, Met18(ox)PTH, and Met8, Met18(di-ox)PTH) have the potential to improve patient care, because only these methods will definitively separate bioactive from non-bioactive PTH forms. Such methods need to be developed, validated, and used in prospective randomized clinical trials to define the potential value of bioactive PTH forms as a predictor of cardiovascular events, mortality, and bone turnover.
... Thus, impaired kidney function frequently develops a deficiency of mineral metabolism, and the condition becomes the worst at the end-stage of CKD. Mineral disorder is commonly seen in dialysis patients, who are also more prevalent with VC (31). Importantly, abnormal mineral metabolism has been demonstrated to contribute to the large burden of CVD in dialysis patients (32). ...
... Importantly, abnormal mineral metabolism has been demonstrated to contribute to the large burden of CVD in dialysis patients (32). The additional health risks imposed by abnormal mineral metabolism are greatly challenging the management of patients with CKD although the traditional risk factors have well been controlled, especially for dialysis patients (8,31). In this study, we observe that serum Ca, rather than traditional risk factors, plays a critical role in high ABI among PD patients. ...
... Likewise, we find that the Kt/V level of PD patients with high ABI tends to be <1.7 and PD adequacy is associated with a lower prevalence of high ABI. This might be because insufficient PD could lead to internal environmental disorders and mineral metabolism imbalance, which then initiates vascular lesions and VC (5,31). Indeed, further mediation analysis estimates that ∼84.4% of the relationship between Kt/V and ABI might be mediated by Ca in PD patients. ...
Cardiovascular disease (CVD) is the leading cause of death in peritoneal dialysis (PD) patients. But the relationship between regular PD and the risk of major adverse cardiovascular events (MACE) remains controversial. The possible risk factors are not fully elucidated. This study aims to investigate the possible factors affecting the risk of MACE estimated by high ankle-brachial index (ABI) in PD patients. A total of 243 patients were enrolled and divided into chronic kidney diseases (CKD) stage 1, non-dialyzed CKD stages 2–5, and PD groups. The prevalence of high ABI, indicating increased MACE, was elevated with CKD progression but not further increased in PD patients. Systolic blood pressure was closely correlated with high ABI in non-dialyzed CKD patients (β = 0.059, P = 0.001). But in PD patients, serum calcium had a crucial effect on high ABI (β = −9.853, P < 0.001). Additionally, PD patients with high ABI tended to dialyze inadequately (Kt/V <1.7) compared to those with normal ABI (29.0 vs. 13.3%, P = 0.031). Further mediation analysis revealed that ~86.2% of the relationship between Kt/V and high ABI was mediated by serum calcium in PD patients (mediation effect = 86.2%, ab = −0.220, 95% CI: −0.381 to −0.059, P = 0.008), especially in those starting PD before 55 years of age and with normal body mass index. This present study indicated that improvement of PD adequacy by maintaining calcium balance might be a promising method to reduce the risk of MACE estimated by high ABI for PD patients.
... In adult research, fibroblast growth factor-23 (FGF-23) and its co-receptor α-Klotho have attracted interest as promising biomarkers of cardiovascular disease. 23 High concentrations of FGF-23 are associated with hypertension, 24 left ventricular mass and hypertrophy, [25][26][27] incident coronary heart disease, heart failure and overall cardiovascular mortality. [28][29][30][31] Animal studies further suggest direct i.e. ...
... 35 This increasing body of evidence leads to the question whether FGF-23 and α-Klotho may be suitable markers of an increased cardiovascular risk or even causal contributory factors in cardiovascular disease. 23 Along similar lines, secretoneurin proved valuable in predicting mortality in patients with severe sepsis and septic shock, 36,37 cardiovascularrelated acute respiratory failure, 38 acute and chronic heart failure 39,40 and in patients undergoing heart surgery due to structural heart disease. 41,42 Animal models further indicate an effect of secretoneurin on endothelium-dependent vascular relaxation. ...
Background
Preterm birth is associated with long-term cardiovascular morbidity and mortality. In adults, fibroblast growth factor-23 (FGF-23), α-Klotho, and secretoneurin have all garnered attention as cardiovascular biomarkers, but their utility in pediatric populations has not yet been ascertained. The aim of this pilot study was to evaluate these novel cardiovascular biomarkers and their association with indicators of cardiovascular impairment in the highly vulnerable population of former very preterm infants.
Methods
Five- to seven-year-old children born at < 32 weeks’ gestation were eligible for the study. Healthy same-aged children born at term served as controls. Biomarkers were quantified in fasting blood samples, and echocardiographic measurements including assessment of aortic elastic properties were obtained.
Results
We included 26 former very preterm infants and 21 term-born children in the study. At kindergarten age, former very preterm infants exhibited significantly higher plasma concentrations of biologically active intact FGF-23 (iFGF-23; mean 43.2 pg/mL vs. 29.1 pg/mL, p = 0.003) and secretoneurin (median 93.8 pmol/L vs. 70.5 pmol/L, p = 0.046). iFGF-23 inversely correlated with distensibility of the descending aorta.
Conclusion
In preterm-born children, iFGF-23 and secretoneurin both offer prospects as valuable cardiovascular biomarkers, potentially allowing for risk stratification and timely implementation of preventive measures.
Impact
Former very preterm infants have increased plasma concentrations of the novel cardiovascular biomarkers intact fibroblast growth factor-23 (iFGF-23) and secretoneurin at kindergarten age.
Increases in iFGF-23 concentrations are associated with decreased distensibility of the descending aorta even at this early age.
Monitoring of cardiovascular risk factors is essential in individuals with a history of preterm birth. Both iFGF-23 and secretoneurin hold promise as clinically valuable biomarkers for risk stratification, enabling the implementation of early preventive measures.
... However, the kidneys are critical in maintaining magnesium homeostasis as they reabsorb over 80% of serum magnesium [15]. Therefore, impaired kidney function often results in diminished magnesium resorption [16,17]. This situation creates a vicious cycle, further accelerating the progression of DKD and increasing the mortality risk. ...
Background
The prognostic value of Magnesium Depletion Score (MDS) in Diabetic Kidney Disease (DKD) patients is still unclear. This study aimed to determine the associations between MDS and long-term mortality in DKD population.
Methods
Data were obtained from the National Health and Nutrition Examination Survey (NHANES III). MDS is calculated from four specific scoring items: estimated glomerular filtration rate (eGFR), heavy drinking, use of proton pump inhibitors (PPI), and use of diuretics. Multivariate Cox proportional hazards regression models was employed to explore the association between MDS and all-cause and cause specific mortality, with emphasis on age-specific analysis.Mediation analysis explored if metabolic indices mediate the relation between MDS and mortality. Sensitive analyses were performed to check the robustness of the main findings.
Results
3,179 patients with DKD were included in this study, with 1,698 females and 1,481 males. The multivariate Cox regression analyses showed higher MDS were significantly associated with the all-cause mortality of DKD population [MDS ≥ 3: adjusted hazard ratio (HR):1.932, 95% confidence interval (CI): 1.339–2.787,p < 0.001]. Meanwhile, the trend was also significant in cardiovascular mortality of the DKD population (MDS ≥ 3: HR = 3.688, 95%CI: 1.702–8.577,p < 0.001). Heavy drinking was the most influential factor among the four MDS scoring items that affects mortality outcomes. Mediation analysis showed increased MDS could slightly improve metabolic levels, but the improvement was insufficient to reverse the mortality outcome in DKD patients. Subgroup analysis manifested that the result was more applicable for patients over 60. The result of the sensitive analysis confirmed the robustness of the main conclusion.
Conclusions
Our study highlights the clinical prognostic value of MDS in predicting the survival of the DKD population, especially among patients over 60. The findings imply that reducing alcohol consumption and performing routine cardiovascular health assessments for DKD patients with MDS > 2 are important for prolonging DKD patients’ survival time.
... In 2019, 13.7 million CVD-related deaths globally were attributed to metabolic risk factors, accounting for 73.7% of all CVD-related deaths (18.6 million total). As societal development continues, understanding the impact of metabolic risk factors on the CVD burden has become increasingly important [11][12][13][14]. Kidney dysfunction (KD) is a key metabolic risk factor for CVD, characterized by impaired kidney function leading to the accumulation of metabolic waste products, including urea, creatinine, and blood urea nitrogen, as well as water, electrolyte, and acid-base imbalances. ...
Background
Cardiovascular diseases (CVD) remain a significant global health burden, particularly in China, where kidney dysfunction (KD) is a key risk factor. This study analyzed trends in the burden of KD-induced CVD and subtypes among the working-age population (25–64 years) in China over the past 30 years and explored its association with age, period, and birth cohort.
Methods
This study extracted data from the Global Burden of Disease (GBD) 2021, focusing on deaths and disability-adjusted life years (DALYs) caused by KD-induced CVD and subtypes, including ischemic heart disease (IHD), stroke, and lower extremity peripheral artery disease (LEPAD) among 25–64 years globally and in China from 1992 to 2021. Trends in disease burden were described by calculating age-standardized mortality rates (ASMR) and age-standardized DALYs rates (ASDR). Additionally, an age-period-cohort (APC) model was employed to estimate the overall annual percentage change in mortality (net drift), the annual percentage change for specific age groups (local drift), the relative risks of period and cohort effects, and the age-specific rates adjusted for period bias (age effect).
Results
From 1992 to 2021, the number of deaths and DALYs caused by KD-induced IHD and LEPAD among 25–64 years globally and in China showed an upward trend, while the number caused by stroke decreased. However, the ASMR and ASDR demonstrated a declining trend, with the disease burden in China being lower than the global level. Notably, the ASMR for IHD and LEPAD in Chinese males showed an upward trend. The declines in ASMR and ASDR were more pronounced in females than in males. The net drift for CVD and subtypes showed a downward trend, with differing patterns between males and females. Mortality rates from stroke in males was increasingly affecting younger populations, while LEPAD was more prevalent in older individuals. Aside from male IHD, the relative risks for CVD and subtypes across cohort and period analyses showed a slight decline. Females exhibited higher relative risks in earlier periods, but their decline in both period and cohort analyses was faster than that of males. Mortality rates for IHD and stroke increased with age, with males exhibiting higher mortality rates across all age groups compared to females.
Conclusion
Our findings provide strong evidence that from 1992 to 2021, KD-induced CVD and subtypes still require attention among the working population in China. There were notable differences across subtypes, genders, and age groups, with males experiencing higher mortality rates and cohort-period risks than females. Our study highlights the need for China’s public health authorities to develop tailored guidelines targeting specific CVD subtypes, genders, and age groups to prevent the further escalation of the KD-induced CVD burden.
... with various clinical issues, including renal bone disease, increased calcium burden, higher risk of ectopic calcification, abnormalities in lipid and glucose metabolism, uncontrolled bone pain, and anemia [2]. These complications may complicate the clinical management of patients and negatively affect their quality of life [3][4][5]. ...
Purpose
This study compares the efficacy of two different ranges of parathyroid transplantation weights with the aim of determining a preferable range for transplantation weight.
Methods
From May 2018 to June 2023, 79 patients underwent total parathyroidectomy with autotransplantation. Demographic data, symptoms, and pre- or postoperative biochemical indicators were compared between two different ranges of parathyroid transplantation weights.
Results
All 79 surgeries were successful, with a total of 316 parathyroid glands reported among the patients. The patients were diagnosed with parathyroid hyperplasia. Postoperatively, itching, bone pain, and muscle weakness disappeared, while serum parathyroid hormone and phosphate levels significantly decreased. With an average follow-up of 12 months, no transplant-dependent recurrence was observed.
Conclusion
Parathyroid transplantation with a weight of 30–50 mg is a feasible, safe, and effective surgical approach.
... Kidney is the critical site for mineral reabsorption/ urinary excretion controlled by endocrine factors fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D (1,25D) [7][8][9]. Thus, disruptions in kidney function can feed back onto the bone leading to increased fragility [10] and the progressive derangement in mineral homeostasis leads to incidence of vascular calcifications [11][12][13]. Therapies for improving bone during CKD remain suboptimal especially for subjects with late-stage CKD [14]. When evaluating bone samples from patients with CKD increases in mineralization lag time [15]. ...
Purpose of Review
Bone homeostasis is balanced between formation and resorption activities and remain in relative equilibrium. Under disease states this process is disrupted, favoring more resorption over formation, leading to significant bone loss and fracture incidence. This aspect is a hallmark for patients with chronic kidney disease mineral and bone disorder (CKD-MBD) affecting a significant portion of the population, both in the United States and worldwide. Further study into the underlying effects of the uremic microenvironment within bone during CKD-MBD are critical as fracture incidence in this patient population not only leads to increased morbidity, but also increased mortality. Lack of bone homeostasis also leads to mineral imbalance contributing to cardiovascular calcifications. One area understudied is the possible involvement of bone marrow adipose tissue (BMAT) during the progression of CKD-MBD.
Recent Findings
BMAT accumulation is found during aging and in several disease states, some of which overlap as CKD etiologies. Importantly, research has found presence of BMAT inversely correlates with bone density and volume.
Summary
Understanding the underlying molecular mechanisms for BMAT formation and accumulation during CKD-MBD may offer a potential therapeutic avenue to improve bone homeostasis and ultimately mineral metabolism.
... Mitral VC stiffens mitral leaflets and distends the left atrium, causing arrhythmia, pulmonary congestion, and heart failure. The sequelae of VC tend to be more severe among patients with ESKD, as this population suffers from a disproportionately high number cardiovascular events due to the presence of atypical cardiovascular risk factors [11]. Among patients under chronic peritoneal dialysis, VC was shown to increase the risk of cardiovascular events and morality by 2-to 3-fold, especially among those with more severe inflammation [12]. ...
Background
Valvular calcification (VC) refers to the calcified valvular remodeling associated with kidney dysfunction, especially end-stage kidney disease (ESKD). ESKD patients with VC had significantly higher cardiovascular risk than those without. Factors interacted with VC regarding prognostic prediction in this population were seldom investigated. We aimed to examine the potential synergetic effects of VC and alkaline phosphatase (Alk-P) on ESKD patients’ cardiovascular risk and mortality.
Methods
ESKD patients undergoing hemodialysis were prospectively enrolled from a medical center in 2018. We identified patients with echocardiography and available serum Alk-P levels. Cox proportional hazard regression was performed to analyze the risk of major adverse cardiovascular events (MACEs), cardiovascular and overall mortality among 4 participant groups (with or without VC versus low or high Alk-P levels). The models were further adjusted for age, sex, and clinical variables.
Results
Of the 309 ESKD patients, 38, 46, 112, and 113 had no VC with low Alk-P, no VC with high Alk-P, VC with low Alk-P, and VC with high Alk-P, respectively. After adjusting for age and sex, patients with VC and high Alk-P had a higher risk of developing MACE, cardiovascular and overall mortality (HR, 3.07, 3.67, 3.65; 95% CI 1.38–6.84, 1.1–12.24, 1.29–10.36, respectively). Patients with VC and high Alk-P remained at higher risk of MACE (HR, 2.76; 95% CI 1.17–6.48) than did those without VC and with low Alk-P.
Conclusion
Serum Alk-P could be used to identify a subgroup of ESKD patients with elevated cardiovascular risk among those with VC.
... Vascular calcification, closely associated with decreased bone mass, is a common complication and a leading cause of mortality among the elderly, particularly in patients with chronic kidney disease (CKD) [21,22]. The RANK/RANKL/OPG system, along with the recently identified member LGR4, plays a crucial role in both bone and vascular mineralization. ...
Vascular calcification has a global health impact that is closely linked to bone loss. The Receptor Activator of Nuclear Factor Kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, fundamental for bone metabolism, also plays an important role in vascular calcification. The Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), a novel receptor for RANKL, regulates bone remodeling, and it appears to be involved in vascular calcification. Besides RANKL, LGR4 interacts with R-spondins (RSPOs), which are known for their roles in bone but are less understood in vascular calcification. Studies were conducted in rats with chronic renal failure fed normal or high phosphorus diets for 18 weeks, with and without control of circulating parathormone (PTH) levels, resulting in different degrees of aortic calcification. Additionally, vascular smooth muscle cells (VSMCs) were cultured under non-calcifying (1 mM phosphate) and calcifying (3 mM phosphate) media with different concentrations of PTH. To explore the role of RANKL in VSMC calcification, increasing concentrations of soluble RANKL were added to non-calcifying and calcifying media. The effects mediated by RANKL binding to its receptor LGR4 were investigated by silencing the LGR4 receptor in VSMCs. Furthermore, the gene expression of the RANK/RANKL/OPG system and the ligands of LGR4 was assessed in human epigastric arteries obtained from kidney transplant recipients with calcification scores (Kauppila Index). Increased aortic calcium in rats coincided with elevated systolic blood pressure, upregulated Lgr4 and Rankl gene expression, downregulated Opg gene expression, and higher serum RANKL/OPG ratio without changes in Rspos gene expression. Elevated phosphate in vitro increased calcium content and expression of Rankl and Lgr4 while reducing Opg. Elevated PTH in the presence of high phosphate exacerbated the increase in calcium content. No changes in Rspos were observed under the conditions employed. The addition of soluble RANKL to VSMCs induced genotypic differentiation and calcification, partly prevented by LGR4 silencing. In the epigastric arteries of individuals presenting vascular calcification, the gene expression of RANKL was higher. While RSPOs show minimal impact on VSMC calcification, RANKL, interacting with LGR4, drives osteogenic differentiation in VSMCs, unveiling a novel mechanism beyond RANKL-RANK binding.
... These prognostic influences become more prominent in specific at-risk populations, including those with chronic kidney disease (CKD) and end-stage kidney disease (ESKD), and another meta-analysis revealed that greater coronary calcification was associated with a 2-to 3-fold higher risk of cardiovascular events and mortality among those with CKD [10]. VC has been touted as the vascular manifestation of CKD-mineral bone disorder (CKD-MBD), which encompasses divalent ion imbalances, osteodystrophy and ectopic calcification [11,12]. Besides its prognostic influences, VC contributes to increased vascular stiffness, soaring pulse wave velocity, precipitating myocardial remodeling, and diastolic dysfunction [13]. ...
Vascular calcification (VC) is the ectopic deposition of calcium-containing apatite within vascular walls, exhibiting a high prevalence in older adults, and those with diabetes or chronic kidney disease. VC is a subclinical cardiovascular risk trait that increases mortality and functional deterioration. However, effective treatments for VC remain largely unavailable despite multiple attempts. Part of this therapeutic nihilism results from the failure to appreciate the diversity of VC as a pathological complex, with unforeseeable variations in morphology, risk associates, and anatomical and molecular pathogenesis, affecting clinical management strategies. VC should not be considered a homogeneous pathology because accumulating evidence refutes its conceptual and content uniformity. Here, we summarize the pathophysiological sources of VC heterogeneity from the intersecting pathways and networks of cellular, subcellular, and molecular crosstalk. Part of these pathological connections are synergistic or mutually antagonistic. We then introduce clinical implications related to the VC heterogeneity concept. Even within the same individual, a specific artery may exhibit the strongest tendency for calcification compared with other arteries. The prognostic value of VC may only be detectable with a detailed characterization of calcification morphology and features. VC heterogeneity is also evident, as VC risk factors vary between different arterial segments and layers. Therefore, diagnostic and screening strategies for VC may be improved based on VC heterogeneity, including the use of radiomics. Finally, pursuing a homogeneous treatment strategy is discouraged and we suggest a more rational approach by diversifying the treatment spectrum. This may greatly benefit subsequent efforts to identify effective VC therapeutics.
... For instance, Figure 8. Processes of the major mechanism of adenine-induced renal fibroblast/myofibroblast activation. vascular calcification and bone pathology are frequent complications in cKD progression, scenarios often observed in clinical cKD patients [238][239][240][241]. Most of the cKD animal models do not report cardiovascular-related complications. ...
Chronic kidney disease (CKD) with high morbidity and mortality all over the world is characterized by decreased kidney function, a condition which can result from numerous risk factors, including diabetes, hypertension and obesity. Despite significant advances in our understanding of the pathogenesis of CKD, there are still no treatments that can effectively combat CKD, which underscores the urgent need for further study into the pathological mechanisms underlying this condition. In this regard, animal models of CKD are indispensable. This article reviews a widely used animal model of CKD, which is induced by adenine. While a physiologic dose of adenine is beneficial in terms of biological activity, a high dose of adenine is known to induce renal disease in the organism. Following a brief description of the procedure for disease induction by adenine, major mechanisms of adenine-induced CKD are then reviewed, including inflammation, oxidative stress, programmed cell death, metabolic disorders, and fibrillation. Finally, the application and future perspective of this adenine-induced CKD model as a platform for testing the efficacy of a variety of therapeutic approaches is also discussed. Given the simplicity and reproducibility of this animal model, it remains a valuable tool for studying the pathological mechanisms of CKD and identifying therapeutic targets to fight CKD.
... Although CKD MBD is characteristic of this condition, is not solely responsible for vascular calcification. CKD acts as an accelerator of ongoing calcification processes associated with aging [112]. VC is an intricate, active process, not a mere deposition of calcium and phosphate. ...
Chronic kidney disease (CKD) is a global health issue with a rising prevalence, affecting 697.5 million people worldwide. It imposes a substantial burden, contributing to 35.8 million disability-adjusted life years (DALYs) and 1.2 million deaths in 2017. The mortality rate for CKD has increased by 41.5% between 1990 and 2017, positioning it as a significant cause of global mortality. CKD is associated with diverse health complications, impacting cardiovascular, neurological, nutritional, and endocrine aspects. One prominent complication is CKD–mineral and bone disorder (MBD), a complex condition involving dysregulation of bone turnover, mineralization, and strength, accompanied by soft tissue and vascular calcification. Alterations in mineral metabolism, including calcium, phosphate, parathyroid hormone (PTH), vitamin D, fibroblast growth factor-23 (FGF-23), and Klotho, play pivotal roles in CKD-MBD. These disturbances, observed early in CKD, contribute to the progression of bone disorders and renal osteodystrophy (ROD). Vascular calcification (VC) is a key component of CKD-MBD, accelerated by CKD. The pathophysiology involves complex processes in vascular smooth muscle cells and the formation of calciprotein particles (CPP). VC is closely linked to cardiovascular events and mortality, emphasizing its prognostic significance. Various serum markers and imaging techniques, including lateral plain X-ray, Kauppila Score, Adragao Score, and pulse wave velocity, aid in VC detection. Additionally, pQCT provides valuable information on arterial calcifications, offering an advantage over traditional scoring systems. CKD poses a substantial global health burden, and its complications, including CKD-MBD and VC, significantly contribute to morbidity and mortality. Understanding the intricate relationships between mineral metabolism, bone disorders, and vascular calcification is crucial for effective diagnosis and therapeutic interventions.
... As the disease progresses, patients experience a gradual loss of residual kidney function, ultimately leading to end-stage renal disease (Lv and Zhang 2019). The mortality rate among patients with CRF accounts for 1.5% of global mortality and has become a significant global public health issue (Covic et al. 2018). Therefore, research on the prevention and treatment of CRF holds great scientific significance and practical value. ...
The pursuit of clinical effectiveness in real-world settings is at the core of clinical practice progression. In this study, we address a long-term clinical efficacy evaluation decision-making problem with temporal correlation hybrid attribute characteristics. To address this problem, we propose a novel approach that combines a temporal correlation feature rough set model with machine learning techniques and nonadditive measures. Our proposed approach involves several steps. First, over the framework of granular computing, we construct a temporal correlation hybrid information system, the gradient method is employed to characterize the temporal attributes and the similarity between objects is measured using cosine similarity. Second, based on the similarity of gradient and cosine, we construct a composite binary relation of temporal correlation hybrid information, enabling effective classification of this information. Third, we develop a rough set decision model based on the Choquet integral, which describes temporal correlation decision process. We provide the ranking results of decision schemes with temporal correlation features. To demonstrate the practical applications of our approach, we conduct empirical research using an unlabeled dataset consisting of 3094 patients with chronic renal failure (CRF) and 80,139 EHRs from various clinical encounters. These findings offer valuable support for clinical decision-making. Two main innovations are obtained from this study. First, it establishes general theoretical principles and decision-making methods for temporal correlation and hybrid rough sets. Second, it integrates data-driven clinical decision paradigms with traditional medical research paradigms, laying the groundwork for exploring the feasibility of data-driven clinical decision-making in the field.
... In essence, vascular calcification is the trans-differentiation of blood vessels into an osteoblastic phenotype and a transformation of vascular tissues into bone-like tissues. This phenomenon typically occurs in ageing people, in diabetics and in renal failure patients [14]. The current knowledge of the pathogenesis of vascular calcification is still incomplete, but highlights the role of deranged calcium and phosphorus metabolism and of the balance between calcification inhibiting and promoting factors. ...
Introduction: The process of vascular calcification has severe clinical consequences in a number of diseases, including diabetes, atherosclerosis, and end-stage renal disease. In the present study, we investigated the effect of Policosanol, Genistein and Vitamin D separately and in association to evaluate the possible synergistic action on inorganic phosphate (Pi)-induced calcification of Vascular Smooth Muscle Cells (VSMCs) Methods: Primary Human VSMCs were cultured with either Growth Medium or Growth medium Supplemented with Calcium and Phosphorus (Calcification Medium) in combination with Policosanol, Genistein and Vitamin D. Alizarin red staining, Mineralization and the protein expression of RUNX2 and Superoxide Dismutase-2 (SOD-2) were investigated. Results: All three substances tested were effective at reducing osteogenic differentiation of VSMCs in a dose-dependent manner. Poli+Gen, Poli+VitD, Gen+VitD treatment induced a greater inhibition of calcification and RUNX2 expression compared to single compounds treatments. Moreover the association of Poli+Gen+VitD (Reduplaxin®) was more effective at inhibiting VSMCs mineralization and preventing the increase in RUNX-2 expression induced by Calcification Medium but not modified SOD-2 expression. Conclusions: The association of Pol, Gen and Vit D (Reduplaxin®) has an additive inhibitory effect on the calcification process of VSMCs induced in vitro by a pro-calcifying medium.
... One study revealed that CKD-MBD may account for an important share of the residual cardiovascular risk in patients with and even without CKD. 8 Vascular calcification is a manifestation of ectopic calcification caused by CKD-MBD and is an integral part of the bone-vascular axis of derangement that occurs with uremia. A meta-analysis reports that the prevalence of vascular calcification is as high as 60% among CKD patients. ...
Background
The factors affecting cardiovascular risk associated with vascular calcification in patients with chronic kidney disease are less well addressed. Distinct risk factors may contribute synergistically to this elevated cardiovascular risk in this population.
Objectives
We aimed to determine whether echocardiographic left ventricular hypertrophy (LVH) affects the risk of major adverse cardiac events (MACE) associated with vascular calcification in end-stage kidney disease (ESKD) patients.
Methods
In this retrospective cohort study, ESKD patients underwent chest radiography and echocardiography to assess aortic arch calcification (AoAC) and LVH, respectively, and were classified into three groups accordingly: non-to-mild AoAC without LVH, non-to-mild AoAC with LVH, and moderate-to-severe AoAC. The risks of MACE, cardiovascular mortality, and overall mortality were assessed using Cox proportional hazard analysis.
Results
Of the 283 enrolled ESKD patients, 44 (15.5%) had non-to-mild AoAC without LVH, 117 (41.3%) had non-to-mild AoAC with LVH, and 122 (43.1%) had moderate-to-severe AoAC. After 34.1 months, 107 (37.8%) participants developed MACE, including 6 (13.6%), 40 (34.2%), and 61 (50%) from each respective group. Those with moderate-to-severe AoAC (Hazard ratio, 3.72; 95% confidence interval, 1.58–8.73) had a significantly higher risk of MACE than did those with non-to-mild AoAC without LVH or with non-to-mild AoAC and LVH (Hazard ratio, 2.73; 95% confidence interval, 1.16–6.46). A similar trend was observed for cardiovascular and overall mortality.
Conclusion
Echocardiographic LVH could modify the risk of adverse cardiovascular events associated with vascular calcification in ESKD patients. Interventions aiming to ameliorate both morbidities might be translated into a lower MACE risk in this population.
... Individuals with kidney disease face an increased risk of cardiovascular issues like heart disease and stroke. Incorporating mono-and poly-unsaturated fats, such as those found in nuts, seeds, avocados, and olive oil, can assist in reducing inflammation, enhancing blood lipid profiles, and providing protection against cardiovascular complications [59][60][61]. ...
About 40% of people with diabetes experience diabetic nephropathy (DN), which is the main cause of renal problems. The aberrant urine albumin excretion rate, diabetic glomerular lesions, and a reduction in glomerular filtration rate are its defining characteristics. Numerous studies have found a strong link between eating animal protein and conditions like glucagon activation, insulin resistance, proteinuria, microalbuminuria, and the worsening of kidney problems in diabetic individuals. A vegan diet, which forgoes all animal products including leather and other non-edibles like fish, shellfish, and insects as well as dairy, eggs, and honey, has demonstrated significant benefits. It has been connected to enhanced insulin sensitivity, less glucagon activation, a decreased risk of developing chronic kidney disease (CKD), and a slowed rate of DN progression. According to several studies, avoiding animal products and switching to plant-based protein sources can be a better nutritional plan than simply limiting dietary protein. This change may prove very helpful in reducing the risk of kidney and cardiovascular illnesses, especially for those who have diabetes and severe insulin resistance in addition to CKD. A vegan diet contains considerable benefits for those with diabetes and CKD, acting as a brake on the advancement of DN and renal failure, according to the literature evaluation done for this study. Nevertheless, more interventional studies involving humans are needed to elucidate the processes underlying the increased insulin sensitivity brought on by vegan diets. It is also advised to conduct more research to fully explore the effectiveness and security of vegan diets in people with diabetes and DN.
... However, excess phosphate retention with/without excess calcium excretion, can increase FGF23 expression and consequently lower 1-α-hydroxylation of the endogenously circulated cholecalciferol or 25-OH-cholecalciferol. Both hypertension and chronic kidney diseases are known independent risk factors for osteoporosis complications [4][5][6][7][8]. ...
Background: Osteoporosis and hypertension (HTN) are frequent and often coexisting diseases among the elderly. Recent studies suggested that both diseases may share the same etiopathology. Moreover, the treatment of hypertension can either positively or negatively affect the bone mineral density (BMD) and consequently, either improving or worsening the patients’ osteoporosis statuses, respectively. Aim: The primary aim of this study is to determine the odd ratios, pearson and spearman correlations, and the distribution rates of the HTN statuses and their corresponding anti-HTN medications, in addition to other investigated comparative variables, across two categorized cohorts; the lower risk of femoral hip osteoporotic fracture (fHOPF) cohort [Cohort I] versus the higher fHOPF cohort [Cohort II], in Jordanian cohort. Methods: The investigated studied participants were either allocated to non-HTN versus HTN cohorts (Cohort I vs Cohort II, respectively). Also, the anti-HTN medications were categorized into 6 major medication’s group; Group I-VI. Both aforementioned categorized 2 patients’ cohorts and 6 medications’ groups were analyzed via chi square test to express the comparison results as distribution rates strength of associations (odd ratios), Pearson chi-square statistic (χ 2), Goodness of Fit (G-Test of independence), and Pearson (r) and Spearman (ρ) correlations. Patients who were on thiazide or thiazide like diuretics with ACEIs or ARBs had the lowest incidence rate of higher risk of fHOPF (50%), followed by patients who were on BBs with thiazide or thiazide like diuretics (66.7%), CCBs with thiazide or thiazide like diuretics (85%), CCBs with ACEIs or ARBs (85.7%), and lastly for patients who took CCBs with or without BBS (100%) [R & ρ [-0.390±0.081 &-0.362±0.068], χ 2 & G-Test [18.685 & 18.805], p-Value [0.002 &0.002]]. Results: Overall, 206 participants who were clinically diagnosed for osteoporotic fracture risk at our rehabilitation and rheumatology clinic between Sep 2021 and Nov 2021, were studied to investigate the differences of the various investigated independent variables across the 2 dichotomized HTN related cohorts; Cohort I-II. In this study, 49.03% (101 of the eligible patients) were allocated to the non-HTN affected cohort (Cohort I) and 50.97% (101 of the overall participants) were comparatively allocated to the HTN affected cohort (Cohort II). Conclusion: The thiazide or thiazide like diuretics and ACEIs or ARBs, alone or in combination, may positively improve the femoral hip bone mineral densities and consequently mitigate the risk of osteoporotic fractures.
... Additionally, VDR polymorphisms could lead to an increase in the renal expression of inflammatory cytokines, which are associated with CKD progression 14,15 . Furthermore, VDR polymorphisms may also lead to increased levels of fibroblast growth factor 23, a hormone that plays a role in CKD 16 . Previously, in a meta-analysis 17 , VDR FokI gene polymorphism was not found to be associated with CKD susceptibility for overall populations, however, the FokI f allele, ff genotype and FF genotype were seen to be associated with CKD in Asians. ...
Most of the chronic kidney disease (CKD) stage IV-V patients have deficiency of vitamin D. Active vitamin D binds to vitamin D receptor (VDR) to regulate target gene transcription and mediates diverse biological functions. Various genetic variations such as FokI polymorphism, may affect the VDR gene expression and may play an important role in pathogenesis of CKD. In this context, here, we looked into the association of FokI polymorphism of VDR gene with serum vitamin D and PTH levels in stage IV-V CKD patients. A total of 150 patients of CKD stage IV-V, aged 25-60 years, and 150 healthy controls (HC), age and sex matched, were enrolled for the study. FokI polymorphism was analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in the study subjects. The prevalence of different genotypes and allelic frequency distributions were compared in study subjects. Serum PTH and vitamin D were estimated by eCLIA method. No significant differences in genotype and in allelic frequencies between CKD patients and HC were observed. No significant differences in biochemical parameters based on genotypic variations were observed. The results suggest no association of VDR FokI polymorphism with CKD. No significant association was noticed between FokI variants and PTH or VitD.
... According to the data from the Global Burden of Disease Study 2019 (GBD 2019), while some environmental and behavioral risk factors showed a decline, metabolic risk factors increased significantly from 2010 to 2019 (10), and the influence of metabolic factors (including hypertension, diabetes, obesity, dyslipidemia, and kidney dysfunction) on the occurrence, development, and prognosis of cardiovascular disease is becoming increasingly important (11)(12)(13)(14). It is estimated that in 2019, 42% of female deaths and 51% of male deaths were related to metabolic risk factors (10). ...
Background
Metabolic disorders are the most important risk factors for cardiovascular diseases (CVDs). The purpose of this study was to systematically analyze and summarize the most recent data by age, sex, region, and time, and to forecast the future burden of diseases.
Methods
Data on the burden of CVDs associated with metabolic risk factors were obtained from the Global Burden of Disease (GBD) Study 2019; and then the burden of disease was assessed using the numbers and age-standardized rates (ASR) of deaths, years of life lost (YLLs), years of life lived with disability (YLDs), and disability-adjusted life-years (DALYs) and analyzed for temporal changes, differences in age, region, sex, and socioeconomic aspects; finally, the burden of disease was predicted using an autoregressive integrated moving average (ARIMA) model.
Results
From 1990 to 2019, the numbers of deaths, DALYs, YLDs, and YLLs attributed to metabolic risk factors increased by 59.3%, 51.0%, 104.6%, and 47.8%, respectively. The ASR decreased significantly. The burden of metabolic risk factor-associated CVDs was closely related to socioeconomic position and there were major geographical variations; additionally, men had a significantly greater disease burden than women, and the peak shifted later based on the age group. We predicted that the numbers of deaths and DALYs would reach 16.5 million and 324.8 million, respectively, by 2029.
Conclusions
The global burden of CVDs associated with metabolic risk factors is considerable and still rising, and more effort is needed to intervene in metabolic disorders.
... Aside from its effect on calcium absorption, vitamin D is associated with myoblast differentiation and damage to type II myofibres [38]. As CKD progresses, several biochemical changes occur, including hyperphosphatemia, hypocalcemia, increased fibroblast growth factor 23 (FGF-23) and PTH levels, as well as vitamin D concentrations [39]. CKD has been associated with increased susceptibility to vitamin D insufficiency and deficiency states. ...
Background
Hemodialysis (HD) patients are at risk for sarcopenia (SP) and bone loss, which may impact falls and bone fragility and lead to poor prognosis. Patients with HD and those with osteoporosis (OP) are still underdiagnosed and untreated. The aims of the present study were to evaluate the factors that affect bone mineral density (BMD) loss in HD patients, and explore traditional and novel approaches to manage chronic kidney disease–mineral-bone disorder (CKD-MBD).
Methods
Patients who underwent regular HD at the First Affiliated Hospital of Soochow University were retrospectively evaluated. According to the WHO osteoporosis criteria, patients were categorized into three groups: normal BMD, osteopenia, and osteoporosis. Demographic and clinical data, skeletal muscle mass, and bone turnover markers(BTM) were compared between the three groups. The correlation between bone density and muscle mass was calculated, and related risk factors were analyzed.
Results
This study enrolled 130 HD patients, 36 patients were diagnosed with sarcopenia (27.7%), 44 patients were diagnosed with osteopenia (33.8%), 19 patients were diagnosed with osteoporosis (14.6%), and 23 patients were diagnosed with osteosarcopenia (17.7%). The SMI was positively correlated with the BMD of the lumbar spine (r = 0.23, p < 0.01) and femoral neck (r = 0.22, p < 0.05). In ordinal logistic regression analysis, the odds ratio (OR) for low BMD was high for patients with sarcopenia (OR = 5.894, 95% CI 1.592–21.830, p < 0.01), older age (OR = 1.095, 95% CI 1.041–1.153, p < 0.001), higher TRACP-5b levels (OR = 1.597, 95% CI 1.230–2.072, p < 0.01), and lower 25-OH vitamin D levels (OR = 0.631, 95% CI 0.544–0.733, p < 0.001).
Conclusion
The preservation of skeletal muscle mass could be important to prevent a BMD decrease in HD patients. Adequate intake of vitamin D and control of TRACP-5b levels will help reduce the occurrence and progression of osteopenia/sarcopenia in HD patients.
... Active vitamin D is important for the absorption of calcium from the intestine into the blood. A decrease in vitamin D in CKD and thereby reduced calcium intestinal uptake, together with a reduction of phosphate urine excretion, triggers a compensatory increase in PTH and FGF23, which can lead to secondary hyperparathyroidism [100,101]. Furthermore, vitamin D deficiency is associated with cardiovascular outcomes, sudden cardiac death and inflammation in CKD/dialysis [102][103][104]. ...
The cardiorenal syndrome (CRS) is described as a multi-organ disease encompassing bidirectionally heart and kidney. In CRS type 4, chronic kidney disease (CKD) leads to cardiac injury. Different pathological mechanisms have been identified to contribute to the establishment of CKD-induced cardiomyopathy, including a neurohormonal dysregulation, disturbances in the mineral metabolism and an accumulation of uremic toxins, playing an important role in the development of inflammation and oxidative stress. Combined, this leads to cardiac dysfunction and cardiac pathophysiological and morphological changes, like left ventricular hypertrophy, myocardial fibrosis and cardiac electrical changes. Given that around 80% of dialysis patients suffer from uremic cardiomyopathy, the study of cardiac outcomes in CKD is clinically highly relevant. The present review summarizes clinical features and biomarkers of CKD-induced cardiomyopathy and discusses underlying pathophysiological mechanisms recently uncovered in the literature. It discloses how animal models have contributed to the understanding of pathological kidney-heart crosstalk, but also provides insights into the variability in observed effects of CKD on the heart in different CKD mouse models, covering both ‘single hit’ as well as ‘multifactorial hit’ models. Overall, this review aims to support research progress in the field of CKD-induced cardiomyopathy.
... It is possible that the approaches that we took to correct VD deficiency are at least partially wrong and that current interventions with native and/or active VD were not properly targeted at more effective goals. This new era of nephrology, in which it is proposed that we return to basics and to a holistic view focusing in particular on the early stages of CKD, is the ideal scenario for the procurement of more evidence in an area of vital importance for cardiovascular health, including the kidney-heart-bone interaction [118,119]. In any case, we cannot sit back, and it is to be emphasized that large RCTs are still needed to confirm that VD and precise control of these and other CKD-MBD biomarkers are directly and unequivocally related to improved hard outcomes in CKD patients. ...
Chronic kidney disease (CKD) is a highly prevalent condition worldwide in which the kidneys lose many abilities, such as the regulation of vitamin D (VD) metabolism. Moreover, people with CKD are at a higher risk of multifactorial VD deficiency, which has been extensively associated with poor outcomes, including bone disease, cardiovascular disease, and higher mortality. Evidence is abundant in terms of the association of negative outcomes with low levels of VD, but recent studies have lowered previous high expectations regarding the beneficial effects of VD supplementation in the general population. Although controversies still exist, the diagnosis and treatment of VD have not been excluded from nephrology guidelines, and much data still supports VD supplementation in CKD patients. In this narrative review, we briefly summarize evolving controversies and useful clinical approaches, underscoring that the adverse effects of VD derivatives must be balanced against the need for effective prevention of progressive and severe secondary hyperparathyroidism. Guidelines vary, but there seems to be general agreement that VD deficiency should be avoided in CKD patients, and it is likely that one should not wait until severe SHPT is present before cautiously starting VD derivatives. Furthermore, it is emphasized that the goal should not be the complete normalization of parathyroid hormone (PTH) levels. New developments may help us to better define optimal VD and PTH at different CKD stages, but large trials are still needed to confirm that VD and precise control of these and other CKD-MBD biomarkers are unequivocally related to improved hard outcomes in this population.
... Magnesium homeostasis and excretion in CKD patients has received little attention. Despite the gap, in cases where GFR falls below 20-30 mL/min, there are increase in serum magnesium levels; however, variations in serum magnesium levels in patients with CKD stages 1-3, GFR > 30 mL/min is yet to be determined [19]. ...
Background and Aim: Chronic kidney disease (CKD) patients who have hypomagnesemia are at greater risk of mortality and progression. A limited amount of data is available on the prevalence of hypomagnesemia in kidney-related risk factors and chronic kidney disease patients. The present study aimed to assess the Proteinuria-associated hypomagnesemia in chronic renal disease patients: prevalence, risk factors, and effect. Patients and Method: This cross-sectional study was carried out on 128 chronic kidney disease patients in the Medicine Department of Shifa International Hospital, Rawalpindi from January 2022 to August 2022. Patients were categorized into two groups based on estimated glomerular filtration rate (eGFR) are as follows: group-I composed of Proteinuric and group-II non-proteinuric. Prior to study conduction, the ethical committee approved the protocol. Patients with prior history of ileostomy, malignancy, chronic diarrhea, colostomy, and using magnesium based medications were excluded. Detailed history, physical examination, and investigations such as serum total magnesium level (mg/dl), serum sodium level (mg/dl), serum creatinine (mg/dl), and total cholesterol and triglycerides (mg/dl) were recorded. Hypomagnesemia was defined as a serum magnesium level < 1.8 mg/dL. Results: Of the total 128 CKD patients, there were 66 (51.6%) male and 62 (48.4%) females. Group I and II had 64 patients each. The overall mean age of group-I and group-II was 48.82±12.52 and 48.21±10.64 years respectively. The prevalence of hypomagnesemia (<1.8 mg/dL) in the proteinuric group was 20 (31.3%). Diabetic patients are more susceptible to hypomagnesemia. The incidence of diabetic, hypertensive, and both diabetic and hypertensive was 12 (60%), 3 (15%), and 5 (25%) respectively among 20 hypomagnesemia. Hypomagnesemia patients had higher CRP (46 mg/L), UACR (2064 mg/g), lower serum potassium (56.4%), lower mean hemoglobin levels (10.2 g/dL), and lower serum sodium (34.9%) as compared to normomagnesemic patients 12 mg/L, 810 mg/g, 24.8%, 11.25 g/dL, and 8.6% respectively. Conclusion: The present study found that there is an independent association between hypomagnesemia and proteinuria in non-dialysis CKD patients. Anemia and hyperparathyroidism are risk factors for inflammation and anemia in CKD patients pre-dialysis. Dietary magnesium supplementation and hypomagnesemia correction may retard proteinuria and CKD progression in CKD patients. Keywords: Chronic kidney disease, Proteinuria-associated hypomagnesemia, Risk factors
... Animal studies suggest direct (i.e. Klotho-independent effect) cardiotoxicity 10 , leading to hypotheses that FGF23 should be considered not just as a marker for cardiovascular disease, but also as a causal contributory factor 11 . Meta-analysis of conventional epidemiological studies has found independent associations between higher circulating FGF-23 concentration with higher risk of atherosclerotic cardiovascular diseases (i.e. ...
Background: Fibroblast growth factor 23 (FGF-23) is associated with a range of cardiovascular and non-cardiovascular diseases in conventional epidemiological studies, but substantial residual confounding may exist. Mendelian randomization approaches can help control for such confounding.
Methods: SCALLOP consortium data on 19,195 participants were used to generate an FGF23 genetic score. Data from 337,448 UK Biobank participants were used to estimate associations between higher genetically-predicted FGF-23 concentration and the odds of any atherosclerotic cardiovascular disease (n=26,266 events), of any non-atherosclerotic cardiovascular disease (n=12,652), and of non-cardiovascular diseases previously linked to FGF-23. Measurements of carotid intima-media thickness and left ventricular mass were available in a subset. Associations with cardiovascular outcomes were also tested in three large case-control consortia: CARDIOGRAMplusC4D (coronary artery disease, n=181,249 cases), MEGASTROKE (stroke, n=34,217), and HERMES (heart failure, n=47,309).
Results: We identified 34 independent variants for circulating FGF-23 which formed a validated genetic score. There were no associations between genetically-predicted FGF-23 and any of the cardiovascular or non-cardiovascular outcomes. In UK Biobank, the odds ratio for any atherosclerotic cardiovascular disease per 1-SD higher genetically-predicted logFGF23 was 1.03 (95% confidence interval [CI] 0.98-1.08), and for any non-atherosclerotic cardiovascular disease was 1.01 (0.94-1.09). The odds ratios in the case-control consortia were 1.00 (0.97-1.03) for coronary artery disease, 1.01 (0.95-1.07) for stroke, and 1.00 (0.95-1.05) for heart failure. In those with imaging, logFGF-23 was not associated with carotid or cardiac abnormalties.
Conclusions: Genetically predicted FGF-23 levels are not associated atherosclerotic and non-atherosclerotic cardiovascular diseases, suggesting no important causal link.
... Even though other sources of inflammation beyond CKD/uremic toxins (more than 25% of which are dietary o gut-derived) [24][25][26], such as infections or thrombotic events related to vascular access in HD patients, peritonitis in patients undergoing peritoneal dialysis, infections and immunosuppression in transplant patients, the intrinsic mechanisms associated with the development of a proinflammatory milieu is comparable in all CKD patients [2]. Further inflammatory factors are summarized in Figure 1. ...
While patient care, kidney replacement therapy, and transplantation techniques for chronic kidney disease (CKD) have continued to progress, the incidence of malnutrition disorders in CKD appears to have remained unchanged over time. However, there is now a better understanding of the underlying pathophysiology according to the disease background, disease stage, and the treatment received. In CKD patients, the increased production of proinflammatory cytokines and oxidative stress lead to a proinflammatory milieu that is at least partially responsible for the increased morbidity and mortality in this patient population. New insights into the pathogenic role of innate immunity and the proinflammatory cytokine profile, characterized, for instance, by higher levels of IL-6 and TNF-α, explain some of the clinical and laboratory abnormalities observed in these patients. In this article, we will explore currently available nutritional–inflammatory biomarkers in distinct CKD populations (hemodialysis, peritoneal dialysis, transplantation) with a view to evaluating their efficacy as predictors of malnutrition and their involvement in the common proinflammatory process. Although there is a direct relationship between inflammatory-nutritional status, signs and symptoms [e.g., protein-energy wasting (PEW), anorexia], and comorbidities (e.g., atheromatosis, atherosclerosis), we are in need of clearly standardized markers for nutritional-inflammatory assessment to improve their performance and design appropriate bidirectional interventions.
... Elderly patients are more likely to represent an extreme model for arteriosclerosis, vascular calcification, and bone disorders with the progression of ESRD. Additionally, these pathological features are also relevant in other common chronic health abnormalities, such as diabetes mellitus and chronic inflammatory and electrolyte disturbances [26]. Thus, patients with higher age, comorbidity of diabetes mellitus, and high preoperative phosphorus concentrations may be vulnerable to SHPT recurrence. ...
Background:
Recurrence of secondary hyperparathyroidism (SHPT) remains a big challenge in uremic patients who underwent total parathyroidectomy with auto-transplantation (tPTX-AT). However, the relationship between perioperative intervention and recurrence of SHPT remains unclear. Dexmedetomidine has been used safely and effectively in uremic patients' anesthesia. The aim of the study was to explore the effect of dexmedetomidine on the recurrence of SHPT and identify the possible mechanism of action.
Methods:
Records of patients who underwent tPTX-AT between 2017 and 2018 were retrospectively analyzed. The study consisted of patients who received dexmedetomidine intra-operatively and the control patients who did not receive dexmedetomidine. The primary endpoint was the difference in the recurrence of SHPT one year after the surgery between the two groups. The secondary endpoint was health-related quality of life scores. Analysis included propensity score matching and multivariable logistic regression.
Results:
Of 354 patients, 133 patients received dexmedetomidine intra-operatively, and the total recurrence rate of SHPT was 10.2%. After propensity score matching, we found that patients' age, dexmedetomidine infusion, comorbidity of diabetes, and preoperative serum phosphorus were independent factors for SHPT recurrence, and that patients who received dexmedetomidine had an estimated 3.80-fold decrease in the risk of SHPT recurrence (odds ratio, 0.263; 95% confidence interval, 0.081 to 0.854; P=0.026). Patients receiving intraoperative dexmedetomidine infusion exhibited a better quality of life in terms of physical functioning and general health, and less emotional role limitations compared with those in the control group.
Conclusion:
In uremic patients who received tPTX-AT, there was an association between dexmedetomidine use and decreased risk of SHPT recurrence one year after the surgery. Further studies are needed to accurately assess the effects and mechanism of action of dexmedetomidine on the prognosis of this population.
... The definition of LVH in XLH remains controversial because of abnormalities in body surface area and height and it is difficult to differentiate primary defects in XLH from complications of treatment 91,92 . Also, some clinical studies conclude there is no relationship between circulating FGF23 and cardiovascular outcomes for CKD-MBD and XLH 93,94 . Moreover, XLH-mice with excessively high levels of FGF23, increased serum ASARM peptides and hypophosphatemia, do not develop LVH and cardiovascular hypertrophy 95,96 . ...
Background
Abnormalities in calcium, phosphorus, PTH, vitamin D metabolism, bone, and vascular calcification occur in chronic kidney disease mineral bone disorder (CKD-MBD). Calciphylaxis, involving painful, ulcerative skin lesions, is also a major problem associated with CKD-MBD. There are no quality medical interventions to address these clinical issues. Bone ASARM peptides are strong inhibitors of mineralization and induce hypophosphatemia by inhibiting phosphate uptake from the gut. We hypothesize treatment of CKD-MBD rats with ASARM peptides will reverse hyperphosphatemia, reduce soft-tissue calcification, and prevent calciphylaxis.
Methods
To test our hypothesis, we assessed the effects of synthetic ASARM peptide in rats that had undergone a subtotal 5/6th nephrectomy (56NEPHREX), a rodent model of CKD-MBD. All rats were fed a high phosphate diet (2% Pi) to worsen mineral metabolism defects. Changes in serum potassium, phosphate, BUN, creatinine, PTH, FGF23, and calcium were assessed in response to 28 days of ASARM peptide infusion. Also, changes in bone quality, soft-tissue calcification, and expression of gut Npt2b (Slc34a2) were studied following ASARM peptide treatment.
Results
Rats that had undergone 56NEPHREX treated with ASARM peptide showed major improvements in hyperphosphatemia, blood urea nitrogen (BUN), and bone quality compared with vehicle controls. Also, ASARM-infused 56NEPHREX rats displayed improved renal, brain, and cardiovascular calcification. Notably, ASARM peptide infusion prevented the genesis of subdermal medial blood vessel calcification and calciphylaxis-like lesions in 56NEPHREX rats compared with vehicle controls.
Conclusions
ASARM peptide infusion corrects hyperphosphatemia and improves vascular calcification, renal calcification, brain calcification, bone quality, renal function, and skin mineralization abnormalities in 56NEPHREX rats. These findings confirm our hypothesis and support the utility of ASARM peptide treatment in patients with CKD-MBD.
... Both phosphate and fibroblast growth factor 23 are causes of cardiovascular mortality in CKD [63]. Thus, nephrologists used to say that K + kills rapidly, whereas phosphate kills slowly [64,65]. ...
Hyperkalemia (HK) is one of the most common electrolyte disorders and a frequent reason for nephrological consultations. High serum potassium (K+) levels are associated with elevated morbidity and mortality, mainly due to life-threatening arrhythmias. In the majority of cases, HK is associated with chronic kidney disease (CKD), or with the use of renin–angiotensin–aldosterone system inhibitors (RAASis) and/or mineral corticoid antagonists (MRAs). These drugs represent the mainstays of treatment in CKD, HF, diabetes, hypertension, and even glomerular diseases, in consideration of their beneficial effect on hard outcomes related to cardiovascular events and CKD progression. However, experiences in relation to the Randomised Aldactone Evaluation Study (RALES) cast a long shadow that extends to the present day, since the increased risk for HK remains a major concern. In this article, we summarise the physiology of K+ homeostasis, and we review the effects of dietary K+ on blood pressure and cardiovascular risk in the general population and in patients with early CKD, who are often not aware of this disease. We conclude with a note of caution regarding the recent publication of the SSaSS trial and the use of salt substitutes, particularly in patients with a limited capacity to increase K+ secretion in response to an exogenous load, particularly in the context of “occult” CKD, HF, and in patients taking RAASis and/or MRAs.
Uremic secondary hyperparathyroidism (SHP) refers to the biochemical abnormalities that characterize CKD-MBD. However, historically parathyroid hormone (PTH) is identified as the key culprit hormone and the essential biomarker of secondary hyperparathyroidism. SHP represents the adaptive response to several mineral abnormalities that initiate and maintain increased PTH secretion through classical mineral derangements and more recently elucidated hormonal dysregulations. Among classic factors involved in the pathogenesis of SHP, phosphate, calcium, and calcitriol have a prominent role. The discovery of new pathogenetic factors involved in the development of SHP (and the eventual CKD-MBD) including fibroblast growth factor-23 (FGF23) and klotho provides new hypothesis and perspectives to our understanding of this complex metabolic disturbance. Recently more than serum phosphate a critical role in regulating FGF23 synthesis and the progression of CKD is ascribed to phosphate pool, reflected by production of glycerol-3-phosphate and the formation of excessive CPP-2. Finally, also skeletal resistance to PTH action, due to dysregulation of the Wnt–β-catenin system and intestinal dysbiosis, affecting the PTH actions on bone are causal factor of SHP. Identifying all the actors at play is mandatory to allow the most precise therapeutic prescription in the individual patient. This paper aims to review, in particular, the pathophysiology of SHP, which is essential to envisage the eventual therapeutic options for the associated MBD.
Myxomatous mitral valve degeneration (MMVD) is one of the most important age-dependent degenerative heart valve disorders in both humans and dogs. It is characterized by the aberrant remodeling of extracellular matrix (ECM), regulated by senescent myofibroblasts (aVICs) transitioning from quiescent valve interstitial cells (qVICs), primarily under TGFB1/TGF-β1 control. In the present study, we found senescent aVICs exhibited impaired macroautophagy/autophagy as evidenced by compromised autophagy flux and immature autophagosomes. MTOR-dependent autophagy induced by rapamycin and torin-1 attenuated cell senescence and decreased the expression of cyclin-dependent kinase inhibitors (CDKIs) CDKN2A/p16INK4A and CDKN1A/p21CIP1. Furthermore, induction of autophagy in aVICs by ATG (autophagy related) gene overexpression restored autophagy flux, with a concomitant reduction in CDKN1A and CDKN2A expression and senescence-associated secretory phenotype (SASP). Conversely, autophagy deficiency induced CDKN1A and CDKN2A accumulation and SASP, whereas ATG re-expression alleviated senescent phenotypic transformation. Notably, CDKN1A and CDKN2A localized to autophagosomes and lysosomes following MTOR antagonism or MG132 treatment. SQSTM1/p62 was identified as the autophagy receptor to selectively sequester CDKN1A and CDKN2A cargoes for autophagic degradation. Our findings are the first demonstration that CDKN1A and CDKN2A are degraded through SQSTM1-mediated selective autophagy, independent of the ubiquitin-proteasome pathway. These data will inform development of therapeutic strategies for the treatment of canine and human MMVD, and for the treatment of Alzheimer disease, Parkinson disease and other age-related degenerative disorders.Abbreviations: ACTA2/α-SMA: actin alpha 2, smooth muscle; AKT: AKT serine/threonine kinase; aVICs: activated valve interstitial cells; ATG: autophagy related; baf-A1: bafilomycin A1; BrdU, bromodeoxyuridine; BSA: bovine serum albumin; CDKIs, cyclin-dependent kinase inhibitors; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; co-IP: co-immunoprecipitation; DMSO: dimethylsulfoxide; ECM, extracellular matrix; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; eGFP: green fluorescent protein; ELISA: enzyme-linked immunosorbent assay; HEK-293T, human embryonic kidney 293T; HRP: horseradish peroxidase; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LIR: MAP1LC3/LC3-interacting region; MFS: Marfan syndrome; MKI67/Ki-67: marker of proliferation Ki-67; MMVD: myxomatous mitral valve degeneration; MTOR: mechanistic target of rapamycin kinase; MTORC: MTOR complex; OE: overexpression; PBST, phosphate-buffered saline with 0.1% Tween-20; PCNA: proliferating cell nuclear antigen; PIK3CA/PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PLA: proximity ligation assays; PSMA1: proteasome 20S subunit alpha 1; PSMB5: proteasome 20S subunit beta 5; qVICs: quiescent valve interstitial cells; qRT-PCR: quantitative real-time PCR; SA-GLB1/β-gal: SA-senescence-associated GLB1/β-galactosidase; ROS: reactive oxygen species; SASP: senescence-associated secretory phenotype; RPS6KB1/p70 S6K: ribosomal protein S6 kinase B1; SMAD: SMAD family member; SQSTM1/p62: sequestosome 1; STEM: scanning transmission electron microscopy; TGFB: transforming growth factor beta; TGFBR: transforming growth factor beta receptor; TP53/p53: tumor protein p53; UPS: ubiquitin-proteasome system; WT, wild-type.
Diabetes is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide. While both haemodialysis (HD) and peritoneal dialysis (PD) are commonly used treatment options for ESKD, the choice of dialysis modality in diabetic ESKD patients remains a critical decision influenced by various patient-related, healthcare system, and socioeconomic factors. This article examines the factors influencing the selection of dialysis modalities for diabetic patients, with a focus on the challenges and opportunities in low-resource settings. Key considerations include the impact of comorbidities such as peripheral arterial disease and CKD-related mineral bone disorder (MBD), as well as patient preferences, caregiver burden, and the availability of healthcare infrastructure. The article highlights the need for personalized approaches to dialysis selection, considering both clinical outcomes and quality of life. It also emphasizes the potential benefits of home dialysis, including home HD and PD, in improving patient autonomy and long-term survival. The article advocates for better government policies, increased awareness, and improved support systems to enhance the accessibility and efficacy of dialysis treatments, particularly in underserved populations. Further research comparing the outcomes of different dialysis modalities across diverse settings is essential to guide global treatment strategies for diabetic ESKD patients.
Objective:
To explore the association between oxidative balance score (OBS) and osteoporosis risk, as well as to identify the specific population group.
Methods:
In this cross-sectional study, we included the data of 5,413 participants using the National Health and Nutrition Examination Survey of 2013-2014 and 2017-2018. Restricted cubic spline (RCS) curves, logistic regression models, trend tests, and stratification analyses were used to evaluate the association between the OBS and osteoporosis risk. Generalized linear models (GLM) were used to identify independent factors related to OBS. Finally, whether OBS played a mediating role in osteoporosis was evaluated using a mediation analysis.
Results:
Patients with osteoporosis had a lower OBS, and a high OBS score was associated with a decreased risk of osteoporosis (p < 0.05). Further stratification analysis revealed that the relationship between OBS and osteoporosis was robust in the three models in female patients aged < 70 years, which was validated using a trend test (p < 0.05). Age and sex were independent predictors of osteoporosis and the OBS. The OBS was a mediator in the association between sex, but not age, and disease.
Conclusion:
Our findings indicate a negative relationship between OBS and osteoporosis risk, which was pronounced in younger women and individuals aged < 70 years. Moreover, sex may be related to osteoporosis through the regulation of OBS.
During the progression of chronic kidney disease (CKD), the retention of uremic toxins plays a key role in the development of uremic syndrome. Knowledge about the nature and biological impact of uremic toxins has grown exponentially over the past decades. However, the science on reducing the concentration and effects of uremic toxins has not advanced in parallel. Additionally, the focus has remained for too long on dialysis strategies, which only benefit the small fraction of people with CKD who suffer from advanced kidney disease, whereas uremic toxicity effects are only partially prevented. This article reviews recent research on alternative methods to counteract uremic toxicity, emphasizing options that are also beneficial in the earlier stages of CKD, with a focus on both established methods and approaches which are still under investigation or at the experimental stage. We will consequently discuss the preservation of kidney function, the prevention of cardiovascular damage, gastro-intestinal interventions, including diet and biotics, and pharmacologic interventions. In the final part, we also review alternative options for extracorporeal uremic toxin removal. The future will reveal which of these options are valid for further development and evidence-based assessment, hopefully leading to a more sustainable treatment model for CKD than the current one.
Purpose
This study compares the efficacy of two different ranges of parathyroid transplantation weights with the aim of determining a preferable range for transplantation weight.
Methods
From May 2018 to June 2023, 79 patients underwent total parathyroidectomy with autotransplantation. Demographic data, symptoms, and pre- or postoperative biochemical indicators were compared between two different ranges of parathyroid transplantation weights.
Results
All 79 surgeries were successful, with a total of 316 parathyroid glands reported among the patients. The patients were diagnosed with parathyroid hyperplasia. Postoperatively, itching, bone pain, and muscle weakness disappeared, while serum parathyroid hormone and phosphate levels significantly decreased. With an average follow-up of 12 months, no transplant-dependent recurrence was observed.
Conclusion
Parathyroid transplantation with a weight of 30–50 mg is a feasible, safe, and effective surgical approach.
Background
Fibroblast growth factor 23 (FGF-23) and other markers of chronic kidney disease–mineral and bone disorder (CKD-MBD) provide valuable insights into disease processes, treatment options and patient prognosis. However, limited research has explored potential associations with ethnicity or season, particularly in multi-ethnic populations residing in high-latitude regions.
Methods
We evaluated CKD-BMD markers in a diverse cohort of CKD patients, who were participants of The CANADIAN AIM to PREVENT (the CAN AIM to PREVENT) study. FGF-23, calcium, phosphate, 25-hydroxyvitamin D (25-OHD) and intact parathyroid hormone (iPTH) in 1234 participants with pre-dialysis CKD (mean estimated glomerular filtration rate: 41.8 ± 14.3 mL/min) were analyzed. Mixed-effects general linear regression models adjusted for demographic and biological factors were used to compare repeated measurements across patient groups categorized by ethnicity (East Asian, White, South Asian, Black, Southeast Asian) and seasons.
Results
Compared with other groups, White participants exhibited 8.0%–18.5% higher FGF-23 levels, Black participants had 0.17–0.32 mg/dL higher calcium levels, White participants had 10.0%–20.1% higher 25-OHD levels, South Asian participants had 7.3%–20.1% lower 25-OHD levels and Black participants had 22.1–73.8% higher iPTH levels, while East Asian participants had 10.7%–73.8% lower iPTH levels. Seasonal variations were also observed. FGF-23 levels were 11.9%–15.5% higher in summer compared with other seasons, while calcium levels were 0.03–0.06 mg/dL lower in summer. 25-OHD levels were 5.6%–10.6% higher in summer and autumn compared with other seasons.
Conclusions
This study shows that FGF-23 and CKD-MBD markers in a Canadian pre-dialysis CKD cohort vary independently by ethnicity and season. Further research is needed to understand the reasons and clinical significance of these findings.
Bone represents a metabolically active tissue subject to continuous remodeling orchestrated by the dynamic interplay between osteoblasts and osteoclasts. These cellular processes are modulated by a complex interplay of biochemical and mechanical factors, which are instrumental in assessing bone remodeling. This comprehensive evaluation aids in detecting disorders arising from imbalances between bone formation and reabsorption. Osteoporosis, characterized by a reduction in bone mass and strength leading to heightened bone fragility and susceptibility to fractures, is one of the more prevalent chronic diseases. Some epidemiological studies, especially in patients with chronic kidney disease (CKD), have identified an association between osteoporosis and vascular calcification. Notably, low bone mineral density has been linked to an increased incidence of aortic calcification, with shared molecules, mechanisms, and pathways between the two processes. Certain molecules emerging from these shared pathways can serve as biomarkers for bone and mineral metabolism. Detecting and evaluating these alterations early is crucial, requiring the identification of biomarkers that are reliable for early intervention. While traditional biomarkers for bone remodeling and vascular calcification exist, they suffer from limitations such as low specificity, low sensitivity, and conflicting results across studies. In response, efforts are underway to explore new, more specific biomarkers that can detect alterations at earlier stages. The aim of this review is to comprehensively examine some of the emerging biomarkers in mineral metabolism and their correlation with bone mineral density, fracture risk, and vascular calcification as well as their potential use in clinical practice.
A growing appreciation of the pathophysiological interrelatedness of metabolic risk factors such as obesity and diabetes, chronic kidney disease, and cardiovascular disease has led to the conceptualization of cardiovascular-kidney-metabolic syndrome. The confluence of metabolic risk factors and chronic kidney disease within cardiovascular-kidney-metabolic syndrome is strongly linked to risk for adverse cardiovascular and kidney outcomes. In addition, there are unique management considerations for individuals with established cardiovascular disease and coexisting metabolic risk factors, chronic kidney disease, or both. An extensive body of literature supports our scientific understanding of, and approach to, prevention and management for individuals with cardiovascular-kidney-metabolic syndrome. However, there are critical gaps in knowledge related to cardiovascular-kidney-metabolic syndrome in terms of mechanisms of disease development, heterogeneity within clinical phenotypes, interplay between social determinants of health and biological risk factors, and accurate assessments of disease incidence in the context of competing risks. There are also key limitations in the data supporting the clinical care for cardiovascular-kidney-metabolic syndrome, particularly in terms of early-life prevention, screening for risk factors, interdisciplinary care models, optimal strategies for supporting lifestyle modification and weight loss, targeting of emerging cardioprotective and kidney-protective therapies, management of patients with both cardiovascular disease and chronic kidney disease, and the impact of systematically assessing and addressing social determinants of health. This scientific statement uses a crosswalk of major guidelines, in addition to a review of the scientific literature, to summarize the evidence and fundamental gaps related to the science, screening, prevention, and management of cardiovascular-kidney-metabolic syndrome.
Chronic kidney disease (CKD) is a significant public health concern associated with significant morbidity and has become one of the foremost global causes of death in recent years. A frequent comorbidity of CKD is secondary hyperparathyroidism (SHPT), exemplified by high serum parathyroid hormone (PTH) levels. The mineral metabolism disturbances resulting from CKD and progression to SHPT are currently considered part of the definition of chronic kidney disease–mineral and bone disorder (CKD-MBD). However, CKD-MBD does not only include abnormalities in laboratory-measured parameters; it is a complex condition characterized by dysregulation of bone turnover, mineralization, growth and strength, accompanied by vascular or another soft-tissue calcification. Together, this increases the risk of bone fractures, cardiovascular disease, and overall mortality in CKD-MBD patients. Monitoring serum markers is essential in diagnosing SHPT and CKD-MBD, and there are several recognized indicators for prognosis, optimal clinical management and treatment response in late-stage kidney disease patients receiving dialysis. However, far fewer markers have been established for patients with non-dialysis CKD. This review provides an overview of current and emerging markers and tools used in the diagnosis and management of CKD-MBD in non-dialysis adult patients.
Phosphorus is an essential mineral that is under the form or inorganic phosphate (Pi) required for building cell membranes, DNA and RNA molecules, for energy metabolism, signal transduction or pH buffering. In bone, Pi is essential for bone stability under the form of apatite. Intestinal absorption of dietary Pi depends on its bioavailability and has two distinct modes of active transcellular and passive paracellular absorption. Active transport is transporter mediated and partly regulated, passive absorption depends mostly on bioavailability. Renal excretion is controlling systemic Pi levels, depends on transporters in the proximal tubule and is highly regulated. Deposition and release of Pi into and from soft tissues and bone has to be also tightly controlled. The endocrine network coordinating intestinal absorption, renal excretion and bone turnover integrates dietary intake, metabolic requirements with renal excretion and is critical for bone stability and cardiovascular health during states of hypophosphatemia or hyperphosphatemia as evident from inborn or acquired diseases. This review provides an integrated overview over the biology of phosphate and Pi in the mammalian organism.
As in 2011, when the Spanish Society of Nephrology (SEN) published the Spanish adaptation to the Kidney Disease: Improving Global Outcomes (KDIGO) universal Guideline on Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), this document contains an update and an adaptation of the 2017 KDIGO guidelines to our setting. In this field, as in many other areas of nephrology, it has been impossible to irrefutably answer many questions, which remain pending. However, there is no doubt that the close relationship between the CKD-MBD/cardiovascular disease/morbidity and mortality complex and new randomised clinical trials in some areas and the development of new drugs have yielded significant advances in this field and created the need for this update. We would therefore highlight the slight divergences that we propose in the ideal objectives for biochemical abnormalities in the CKD-MBD complex compared to the KDIGO suggestions (for example, in relation to parathyroid hormone or phosphate), the role of native vitamin D and analogues in the control of secondary hyperparathyroidism and the contribution of new phosphate binders and calcimimetics. Attention should also be drawn to the adoption of important new developments in the diagnosis of bone abnormalities in patients with kidney disease and to the need to be more proactive in treating them. In any event, the current speed at which innovations are taking place, while perhaps slower than we might like, globally drives the need for more frequent updates (for example, through Nefrología al día).
Purpose of review:
Observational data provide compelling evidence for elevated fibroblast growth factor-23 (FGF23) as a risk factor for heart failure (HF), particularly heart failure with preserved ejection fraction (HFpEF). Given the limitations of observational studies, uncertainties persist regarding the causal role of FGF23 in the pathogenesis of HF and HFpEF. Recently, Mendelian randomization (MR) studies have been performed to examine causal associations between FGF23 and HF phenotypes.
Recent findings:
The current review describes the methodological basis of the MR techniques used to examine the causal role of FGF23 on HF phenotypes, highlighting the importance of large-scale multiomics data. The findings from most of the MR studies indicate an absence of evidence of a causal effect of FGF23 on the risk of HF in general population settings. However, analysis using individual-level data showed a strong association between genetically-predicted FGF23 and HFpEF in individuals with a genetic predisposition to low estimated glomerular filtration (eGFR).
Summary:
Evidence from MR analysis suggests a causal role of FGF23 in the pathogenesis of HFpEF in low eGFR settings - a finding supported by experimental, clinical, and epidemiological data. While future MR studies of FGF23 and HFpEF could provide further evidence, randomized trials of FGF23-lowering agents could provide the most definitive answers on the association in chronic kidney disease populations.
Although phosphorus is an essential element for life, it is not found in nature in its native state but rather combined in the form of inorganic phosphates (PO43-), with tightly regulated plasma levels that are associated with deleterious effects and mortality when these are out of bounds. The growing interest in the accumulation of PO43- in human pathophysiology originated in its attributed role in the pathogenesis of secondary hyperparathyroidism (SHPT) in chronic kidney disease. In this article, we review the mechanisms by which this effect was justified and we commemorate the important contribution of a Spanish group led by Dr. M. Rodríguez, just 25 years ago, when they first demonstrated the direct effect of PO43- on the regulation of the synthesis and secretion of parathyroid hormone by maintaining the structural integrity of the parathyroid glands in their original experimental model. In addition to demonstrating the importance of arachidonic acid (AA) and the phospholipase A2-AA pathway as a mediator of parathyroid gland response, these findings were predecessors of the recent description of the important role of PO43- on the activity of the calcium sensor-receptor, and also fueled various lines of research on the importance of PO43- overload not only for the pathophysiology of SHPT but also in its systemic pathogenic role.
Chronic kidney disease (CKD) is an important risk factor for cardiovascular morbidity and mortality. Cardiovascular disease (CVD) is the name for a group of disorders of the heart and blood vessels, including hypertension, coronary heart disease, cerebrovascular disease, peripheral vascular disease, and heart failure. This chapter examines the evidence for the epidemiology, pathophysiology, diagnosis, prognosis, and management of CVD in people with CKD. Systemic vascular remodeling may cause CVD. Low‐grade inflammation is recognized as a common pathway of CKD and CVD. Cardiac and kidney diseases interact in both acute and chronic settings. Echocardiography is useful for the diagnosis of clinical and subclinical cardiac dysfunction, for the prediction of cardiovascular risk, and in the orientation and follow‐up of treatment strategies in CKD patients. Blood pressure lowering may be an important strategy to prevent CVD in CKD patients. Coronary artery bypass grafting is another strategy for coronary revascularization.
Background
Magnesium deficiency is common in patients with chronic kidney diseases (CKD) due to restricted magnesium intake and impaired magnesium reabsorption. Based on pathophysiological risk factors influencing kidney magnesium reabsorption, a magnesium depletion score (MDS) was developed. Using MDS as a novel indicator for assessing body magnesium status, we hypothesized that it was associated with clinical prognosis.Methods
We conducted a prospective population-based cohort study using data from the National Health and Nutrition Examination Survey 1999–2014 to explore the impact of MDS on the clinical outcomes of CKD patients. Propensity score-matched analyses were conducted to increase comparability. The primary outcome was all-cause mortality, and the secondary outcomes were cardiovascular-cause and cancer-cause mortality.ResultsAfter propensity score matching, 3294 CKD patients were divided into 2 groups: MDS ≤ 2 (N = 1647), and MDS > 2 (N = 1647). During a median follow-up of 75 months, Kaplan–Meier analyses showed that MDS > 2 was associated with worse 5- and 10-year overall survival (78.5% vs 73.4%; 53.1% vs 43.1%, P < 0.001). After adjusting for confounding variables, MDS was found to be an independent risk factor for all-cause mortality (HR:1.34, 95% CI 1.20–1.50, P < 0.001). MDS > 2 was also associated with higher cardiovascular-cause mortality (16.2% VS 11.6%, P = 0.005). Multivariate competing risk analysis revealed that MDS > 2 was an independent risk factor (HR: 1.33, 95% CI 1.06–1.66, P = 0.012). Subgroup analyses reported that MDS > 2 increased all-cause mortality and cardiovascular-cause mortality only in patients with inadequate magnesium intake (P < 0.001, P < 0.001) but not in those with adequate intake (P = 0.068, P = 0.920).ConclusionsA magnesium depletion score > 2 was independently associated with higher long-term cardiovascular-cause and all-cause mortality in CKD patients.Graphical Abstract
Electrolyte abnormalities are extremely common both in the hospital and in the community and carry considerable morbidity and mortality. Their impact is predicted to increase due to ageing, comorbidities and multi-drug therapies. Acute electrolyte imbalances may represent medical emergencies, and their treatment itself can have life-threatening consequences. In non-emergency settings, the correct interpretation of electrolyte abnormalities is necessary to prevent long-term sequelae and often provides invaluable hints for the diagnosis of systemic conditions. While some aspects of physiology and therapy remain controversial and complex, basic knowledge on the management of main electrolytes disturbances and the awareness on the role of drugs on electrolyte homeostasis should be in the skillset of every physician. In most cases, application of basic physiology principles, careful planning of action and accurate monitoring of trends rather than isolated measurements allow for a safe and effective management of electrolytes abnormalities. In this chapter, we cover the diagnostic approach and treatment of electrolytes disorders, with useful links to daily clinical practice and tips on how to avoid pitfalls.
Resumen
Al igual a como ocurrió en el año 2011, cuando la Sociedad Española de Nefrología (SEN) publicó la adaptación española a las guías universales Kidney Disease Initiative Global Outcomes (KDIGO) sobre alteraciones del metabolismo óseo-mineral en la enfermedad renal crónica (CKD-MBD), este documento contiene una actualización y adaptación a nuestro medio de las guías KDIGO del 2017. En este campo, al igual que en muchos otros nefrológicos, no se ha podido contestar irrefutablemente muchas cuestiones pendientes aún. Sin embargo, no hay duda acerca de la estrecha relación entre el complejo CKD-MBD/patología cardiovascular/morbimortalidad, nuevos ensayos clínicos aleatorizados en algunas áreas o la aparición de nuevos fármacos han proporcionado notables avances en este campo y crearon la necesidad de dicha actualización. Así, destacamos las discretas divergencias que ofrecemos en los objetivos ideales de las alteraciones bioquímicas del complejo CKD-MBD respecto a las sugerencias de las KDIGO (en relación, por ejemplo, con la hormona paratiroidea o fosfato), el papel de la vitamina D nativa y análogos en el control del hiperparatiroidismo secundario, así como la contribución de nuevos captores de fosfato y calcimiméticos. Asimismo, es de destacar la adopción de importantes novedades en el diagnóstico de las alteraciones óseas del paciente renal y la necesidad de tomar actitudes más proactivas en su tratamiento. En cualquier caso, la velocidad a la que acaecen novedades actualmente, aunque menor de la que sería deseable, sí impulsan globalmente la necesidad de actualizaciones con menor demora (por ejemplo, a través de Nefrología al día).
M ineral metabolism is altered early in the course of chronic kidney disease (CKD) 1 as documented by elevations in the serum concentrations of fibroblast growth factor -23 (FGF23) and parathyroid hormone (PTH) in 70% and 30%, respectively, of patients with estimated glomerular filtration rate of 50 mL·min −1 ·1.73 m −2. The levels of both hormones continue to rise over time as CKD progresses, presumably to maintain normal concentrations of phosphate and calcium Background-Patients with kidney disease have disordered bone and mineral metabolism, including elevated serum concentrations of fibroblast growth factor-23 (FGF23). These elevated concentrations are associated with cardiovascular and all-cause mortality. The objective was to determine the effects of the calcimimetic cinacalcet (versus placebo) on reducing serum FGF23 and whether changes in FGF23 are associated with death and cardiovascular events. Methods and Results-This was a secondary analysis of a randomized clinical trial comparing cinacalcet to placebo in addition to conventional therapy (phosphate binders/vitamin D) in patients receiving hemodialysis with secondary hyperparathyroidism (intact parathyroid hormone ≥300 pg/mL). The primary study end point was time to death or a first nonfatal cardiovascular event (myocardial infarction, hospitalization for angina, heart failure, or a peripheral vascular event). This analysis included 2985 patients (77% of randomized) with serum samples at baseline and 2602 patients (67%) with samples at both baseline and week 20. The results demonstrated that a significantly larger proportion of patients randomized to cinacalcet had ≥30% (68% versus 28%) reductions in FGF23. Among patients randomized to cinacalcet, a ≥30% reduction in FGF23 between baseline and week 20 was associated with a nominally significant reduction in the primary composite end point (relative hazard, 0.82; 95% confidence interval, 0.69-0.98), cardiovascular mortality (relative hazard, 0.66; 95% confidence interval, 0.50-0.87), sudden cardiac death (relative hazard, 0.57; 95% confidence interval, 0.37-0.86), and heart failure (relative hazard, 0.69; 95% confidence interval, 0.48-0.99). Conclusions-Treatment with cinacalcet significantly lowers serum FGF23. Treatment-induced reductions in serum FGF23 are associated with lower rates of cardiovascular death and major cardiovascular events. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00345839.
The KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD represents a selective update of the prior CKD-MBD Guideline published in 2009. This update, along with the 2009 publication, is intended to assist the practitioner caring for adults and children with chronic kidney disease (CKD), those on chronic dialysis therapy, or individuals with a kidney transplant. This review highlights key aspects of the 2017 CKD-MBD Guideline Update, with an emphasis on the rationale for the changes made to the original guideline document. Topic areas encompassing updated recommendations include diagnosis of bone abnormalities in CKD–mineral and bone disorder (MBD), treatment of CKD-MBD by targeting phosphate lowering and calcium maintenance, treatment of abnormalities in parathyroid hormone in CKD-MBD, treatment of bone abnormalities by antiresorptives and other osteoporosis therapies, and evaluation and treatment of kidney transplant bone disease.
Background: High serum phosphorus concentrations are associated with an increased risk of cardiovascular disease and progression of chronic kidney disease (CKD). However, the relation between dietary phosphorus intake and CKD development has not been well evaluated.
Objective: In this study, we investigated the impact of dietary phosphorus density on the development of incident CKD in a cohort of subjects with normal renal function.
Design: Data were retrieved from the Korean Genome and Epidemiology Study, a prospective community-based cohort study. The study cohort consisted of subjects aged 40–69 y, who were followed up biennially from 2001 to 2014. A total of 873 subjects with diabetes mellitus (DM) and 5846 subjects without DM (non-DM) were included in the final analysis. The primary endpoint was incident CKD, defined as a composite of estimated glomerular filtration rate <60 mL · min⁻¹ · 1.73 m⁻² and/or the development of proteinuria.
Results: In the DM and non-DM groups, the mean ages of the participants were 55.6 ± 8.7 and 51.4 ± 8.6 y, the numbers of male subjects were 454 (52.0%) and 2784 (47.6%), and the mean estimated glomerular filtration rates were 91.6 ± 14.0 and 94.5 ± 14.0 mL · min⁻¹ · 1.73 m⁻², respectively. The mean values of dietary phosphorus density, defined as the ratio of a single-day dietary phosphorus amount to the total daily calorie intake, were 0.51 ± 0.08 mg/kcal in the DM group and 0.51 ± 0.07 mg/kcal in the non-DM group. During the follow-up, CKD newly developed in 283 (32.4%) and 792 subjects (13.5%) in the DM and non-DM groups, respectively. When the subjects were divided into quartiles according to the dietary phosphorus density in each group, the highest quartile was significantly associated with the development of incident CKD by multiple Cox proportional hazard analysis in the DM group (P = 0.02) but not in the non-DM group (P = 0.72).
Conclusions: High dietary phosphorus density is associated with an increased risk of CKD development in DM patients with normal renal function. The causality in this association needs to be tested in a randomized controlled trial.
Osteoporosis is characterised by trabecular bone loss resulting from increased osteoclast activation and unbalanced coupling between resorption and formation, which induces a thinning of trabeculae and trabecular perforations. Bisphosphonates are the frontline therapy for osteoporosis, which act by reducing bone remodelling, and are thought to prevent perforations and maintain microstructure. However, bisphosphonates may oversuppress remodelling resulting in accumulation of microcracks. This paper aims to investigate the effect of bisphosphonate treatment on microstructure and mechanical strength. Assessment of microdamage within the trabecular bone core was performed using synchrotron X-ray micro-CT linked to image analysis software. Bone from bisphosphonate-treated fracture patients exhibited fewer perforations but more numerous and larger microcracks than both fracture and non-fracture controls. Furthermore, bisphosphonate-treated bone demonstrated reduced tensile strength and Young’s Modulus. These findings suggest that bisphosphonate therapy is effective at reducing perforations but may also cause microcrack accumulation, leading to a loss of microstructural integrity and consequently, reduced mechanical strength.
Background:
Fibroblast growth factor 23 (FGF23) is emerging as a novel biomarker of bone metabolism, chronic kidney disease, and cardiovascular disease (CVD). However, its clinical correlates and potential predictive role in a community-based setting are incompletely understood.
Methods and results:
We evaluated participants of the Framingham Heart Study (seventh examination cycle of the Offspring cohort plus second examination cycle of the multiethnic Omni cohort) to identify clinical correlates of plasma FGF23 (N=3236) and examine its cross-sectional association with vascular function (N=2209), and longitudinal association with 10-year incidence of CVD (N=2823), and all-cause mortality (N=3223).Circulating FGF23 concentrations were positively related to African-American and Asian ethnicity, waist circumference, current smoking, serum glucose, history of CVD, and antihypertensive medication use; and negatively related to male sex, hormone replacement therapy, and estimated glomerular filtration rate. Multivariable-adjusted cross-sectional analyses showed no consistent association of FGF23 with vascular function measures. During a median follow-up time of 10.8 years, 347 incident CVD events and 412 deaths occurred. Multivariable-adjusted Cox regression models revealed a positive association of FGF23 with all-cause mortality (hazard ratio [HR] per SD increase, 1.31; 95% CI, 1.20-1.42), but not with incident CVD (HR per SD increase, 1.05; 95% CI, 0.94-1.17).
Conclusions:
In our large, community-based sample, FGF23 was associated with mortality risk, but not with vascular function or incident CVD.
Background:
There is conflicting evidence regarding the association between decreased bone mineral density (BMD) and atherosclerosis. To this end, we performed a systematic review and meta-analysis to clarify the association.
Methods:
To identify relevant studies, PubMed, Embase, and the Cochrane Library were systematically searched up to November 2015. All observational and comparative studies directly investigating the relationship between decreased BMD and clinical consequences of atherosclerotic vascular abnormalities, including carotid artery calcification (CAC), cardiovascular disease (CAD), and coronary artery disease (CAD) were obtained, without limitation of language or publication year.
Results:
A total of 25 studies involving 10,299 patients were included. The incidence of atherosclerotic vascular abnormalities was significantly increased in low BMD patients, compared to patients with normal BMD (OR, 1.81, 95% CI [1.01, 2.19], p<0.00001)). Similar results were also observed for postmenopausal women (OR, 2.23, 95% CI [1.72, 2.89], p<0.00001). Subgroup analyses of osteopenia, osteoporosis, and normal BMD also revealed that the combined ORs for the incidence of atherosclerotic vascular abnormalities increased as BMD decreased. Of note, after adjusting for age, sex, body mass index (BMI) and other vascular risk factors, decreased BMD remained significantly associated with the incidence of atherosclerotic vascular abnormalities (OR, 2.96, 95% CI [2.25, 3.88], p < 0.00001).
Conclusions:
Based on the results of this study, decreased BMD is an independent predictor for the development of atherosclerosis in elderly individuals. Moreover, the risk of atherosclerotic vascular abnormalities increased as BMD decreased. Future studies focusing on individuals with different severities of atherosclerosis and comorbidities are of interest.
Objective:
To examine the evidence underpinning recommendations to increase calcium intake through dietary sources or calcium supplements to prevent fractures.
Design:
Systematic review of randomised controlled trials and observational studies of calcium intake with fracture as an endpoint. Results from trials were pooled with random effects meta-analyses.
Data sources:
Ovid Medline, Embase, PubMed, and references from relevant systematic reviews. Initial searches undertaken in July 2013 and updated in September 2014.
Eligibility criteria for selecting studies:
Randomised controlled trials or cohort studies of dietary calcium, milk or dairy intake, or calcium supplements (with or without vitamin D) with fracture as an outcome and participants aged >50.
Results:
There were only two eligible randomised controlled trials of dietary sources of calcium (n=262), but 50 reports from 44 cohort studies of relations between dietary calcium (n=37), milk (n=14), or dairy intake (n=8) and fracture outcomes. For dietary calcium, most studies reported no association between calcium intake and fracture (14/22 for total, 17/21 for hip, 7/8 for vertebral, and 5/7 for forearm fracture). For milk (25/28) and dairy intake (11/13), most studies also reported no associations. In 26 randomised controlled trials, calcium supplements reduced the risk of total fracture (20 studies, n=58,573; relative risk 0.89, 95% confidence interval 0.81 to 0.96) and vertebral fracture (12 studies, n=48,967. 0.86, 0.74 to 1.00) but not hip (13 studies, n=56,648; 0.95, 0.76 to 1.18) or forearm fracture (eight studies, n=51,775; 0.96, 0.85 to 1.09). Funnel plot inspection and Egger's regression suggested bias toward calcium supplements in the published data. In randomised controlled trials at lowest risk of bias (four studies, n=44,505), there was no effect on risk of fracture at any site. Results were similar for trials of calcium monotherapy and co-administered calcium and vitamin D. Only one trial in frail elderly women in residential care with low dietary calcium intake and vitamin D concentrations showed significant reductions in risk of fracture.
Conclusions:
Dietary calcium intake is not associated with risk of fracture, and there is no clinical trial evidence that increasing calcium intake from dietary sources prevents fractures. Evidence that calcium supplements prevent fractures is weak and inconsistent.
A new definition and classification of chronic kidney disease-mineral and bone disorder (CKD-MBD) was proposed in 2005 and it was later followed by a guideline publication on this topic from Kidney Disease: Improving Global Outcomes (KDIGO) in 2009. This work recognized that CKD-MBD is a syndrome of bone abnormalities, laboratory abnormalities, and vascular calcification linked to fractures, cardiovascular disease, and mortality. Because of limited data at the time of the original guideline systematic review, many of the recommendations were cautiously vague. KDIGO convened a Controversies Conference in October 2013 to review the CKD-MBD literature published since the 2009 guideline. Specifically, the objective of this conference was to determine whether sufficient new data had emerged to support a reassessment of the CKD-MBD guideline and if so to determine the scope of these potential revisions. This report summarizes the results of these proceedings, highlighting important new studies conducted in the interval since the original KDIGO CKD-MBD guideline.Kidney International advance online publication, 4 February 2015; doi:10.1038/ki.2014.425.
Fractures are common in chronic kidney disease (CKD). The optimal methods by which to assess fracture risk are unknown, in part, due to a lack of prospective studies. We determined if bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA), and/or high resolution peripheral quantitative computed tomography (HRpQCT) could predict fractures in men and women ≥ 18 years old with stages 3 to 5 CKD. BMD was measured by DXA (at the total hip, lumbar spine, ultradistal, and 1/3 radius) and by HRpQCT (at the radius), and subjects were followed for 2 years for incident morphometric spine fractures and low-trauma clinical fractures. The mean age of the subjects was 62 years with equal numbers having stages 3, 4 and 5 CKD. Over 2 years there were 51 fractures in 35 subjects. BMD by DXA at baseline was significantly lower at all sites among those with incident fractures vs. those without. For example, the mean BMD at the total hip in those with incident fractures was 0.77 g/cm2 (95% Confidence Interval (CI): 0.73-0.80) and in those without fracture was 0.95 g/cm2 (95% CI: 0.92-0.98). Almost all baseline HRpQCT measures were lower in those with incident fracture vs. those without. For example, volumetric BMD in those with incident fractures was 232 mgHA/cm3 (95% CI: 213-251) and in those without fracture was 317.6 mgHA/cm3 (95% CI: 306-329.1). Bone loss occurred in all subjects, but was significantly greater among those with incident fractures. Our data demonstrate that low BMD (by DXA and HRpQCT) and a greater annualized percent decrease in BMD are risk factors for subsequent fracture in men and women with predialysis CKD. This article is protected by copyright. All rights reserved
Calcium supplements may induce hypercalcaemia in patients with chronic kidney disease (CKD) or patients on hemodialysis. Even in the absence of overt hypercalcaemia, calcium supplementation may be associated with a positive calcium balance and intracellular calcium overload. There is an increased risk of complex supraventricular, ventricular arrhythmias or the risk of suffering a cardiac arrest in the presence of hypercalcaemia and calcium overload in subjects with impaired or absent renal function. A maximum intake of 1000 mg elemental calcium, combining supplements and dietary calcium, together with a 1.5 mmol/l level in the dialysate, may be a safer (opinion based) recommendation in CKD patients. This is especially the case if the patient already shows signs of extra-skeletal calcification or if they present cardiac comorbidities. Lower calcium levels in the dialysis fluid might reduce the positive calcium balance but can increase intradialytic plasma calcium changes and therefore increase the risk of arrhythmias.
Background and objectives:
Use of bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) is controversial for diagnosing bone loss in CKD patients on dialysis. The alternative quantitative computed tomography (QCT) is expensive and requires high radiation exposure. This study compared the two techniques and evaluated serum biochemical parameters for prediction of bone loss.
Design, setting, participants, & measurements:
This prospective study enrolled patients from dialysis centers throughout Kentucky. BMD of the spine and hip was measured at baseline and after 1 year by DXA and QCT. Customary and novel serum biochemical parameters were obtained at the same times, including calcium, phosphorus, whole and intact parathyroid hormone, bone-specific alkaline phosphatase, procollagen type 1 N-terminal propeptide, tartrate-resistant acid phosphatase-5b, Dickkopf-1, fibroblast growth factor, and sclerostin. Rates of detection of osteoporosis by DXA and QCT were compared. Correlations were calculated between baseline biochemical parameters and BMD at baseline and changes over 1 year. Multivariable regression was performed to adjust for age, sex, body mass index, and race.
Results:
Eighty-one patients completed the study (mean age=52.6 ± 12.3 years, 56% men, 53% African American, and median dialysis vintage=41 months). At baseline, QCT and DXA of the spine identified similar rates of osteoporosis (13.6% and 13.6%), but at the hip, DXA identified more osteoporosis (22.2% versus 13.6%). At any site and by either method, 33.3% of the patients were osteoporotic. Baseline BMD correlated with sclerostin, intact parathyroid hormone, bone-specific alkaline phosphatase, tartrate-resistant acid phosphatase-5b, and fibroblast growth factor. At 1 year, hip QCT identified a higher number of patients experiencing bone loss (51.3%) than DXA (38.5%). After multivariable adjustment, baseline sclerostin and tartrate-resistant acid phosphatase-5b predicted bone loss measured by QCT of the hip; procollagen type 1 N-terminal propeptide predicted cortical spine bone gain by QCT.
Conclusions:
QCT identified prospectively more bone loss at the hip than DXA. The baseline serum biochemical parameters sclerostin and tartrate-resistant acid phosphatase-5b were noninvasive independent predictors of bone loss in CKD patients on dialysis.
Background
Fibroblast growth factor‐23 (FGF‐23) is a hormone involved in phosphorous regulation and vitamin D metabolism that may be associated with cardiovascular risk, and it is a potential target for intervention. We tested whether elevated FGF‐23 is associated with incident coronary heart disease, heart failure, and cardiovascular mortality, even at normal kidney function.
Methods and Results
A total of 11 638 Atherosclerosis Risk In Communities study participants, median age 57 at baseline (1990–1992), were followed through 2010. Cox regression was used to evaluate the independent association of baseline serum active FGF‐23 with incident outcomes. Models were adjusted for traditional cardiovascular risk factors and estimated glomerular filtration rate. During a median follow‐up of 18.6 years, 1125 participants developed coronary heart disease, 1515 developed heart failure, and 802 died of cardiovascular causes. For all 3 outcomes, there was a threshold, whereby FGF‐23 was not associated with risk at <40 pg/mL but was positively associated with risk at >40 pg/mL. Compared with those with FGF‐23 <40 pg/mL, those in the highest FGF‐23 category (≥58.8 pg/mL) had a higher risk of incident coronary heart disease (adjusted hazard ratio, 95% CIs: 1.65, 1.40 to 1.94), heart failure (1.75, 1.52 to 2.01), and cardiovascular mortality (1.65, 1.36 to 2.01). Associations were modestly attenuated but remained statistically significant after further adjustment for estimated glomerular filtration rate. In stratified analyses, similar results were observed in African Americans and among persons with normal kidney function.
Conclusions
High levels of serum FGF‐23 were associated with increased risk of coronary heart disease, heart failure, and cardiovascular mortality in this large, biracial, population‐based cohort. This association was independent of traditional cardiovascular risk factors and kidney function.
Abnormalities in bone turnover, mineralization, and volume represent one of the three components of chronic kidney disease–related mineral and bone disorder (CKD-MBD). The risk of hip fracture is considerably high, while the risk of spinal compression fracture may not be more elevated among CKD patients than in general population. The relationship between bone fracture and bone mineral density in CKD patients is more complex than in those without kidney disease. An increase in the rate of falls has been reported to be a major cause of high hip fracture risk among CKD patients; however, it certainly is not the only underlying mechanism. Abnormal parathyroid function is not likely to be a major cause of hip fracture among CKD patients. In experimental CKD animals, mechanical elasticity properties of long bones showed an inverse correlation with kidney function. The deterioration of bone elasticity showed a significant correlation with bone biochemical changes. Of note, administration of the oral absorbent AST-120 was capable of preventing both changes. These findings suggest that uremic toxins cause a deterioration of bone material properties, and changes in material properties disturb bone elasticity. This disease concept cannot be considered to be a direct consequence of CKD-MBD. We therefore would like to call it ‘uremic osteoporosis’. This entity may be a major cause of increased hip fracture risk among CKD patients.
Klotho acts as a co-receptor for and dictates tissue specificity of circulating FGF23. FGF23 inhibits PTH secretion, and reduced Klotho abundance is considered a pathogenic factor in renal secondary hyperparathyroidism. To dissect the role of parathyroid gland resident Klotho in health and disease, we generated mice with a parathyroid-specific Klotho deletion (PTH-KL(-/-) ). PTH-KL(-/-) mice had a normal gross phenotype and survival; normal serum PTH and calcium; unaltered expression of the PTH gene in parathyroid tissue; and preserved PTH response and sensitivity to acute changes in serum calcium. Their PTH response to intravenous FGF23 delivery or renal failure did not differ compared to their wild-type littermates despite disrupted FGF23-induced activation of the MAPK/ERK pathway. Importantly, calcineurin-NFAT signaling, defined by increased MCIP1 level and nuclear localization of NFATC2, was constitutively activated in PTH-KL(-/-) mice. Treatment with the calcineurin-inhibitor cyclosporine A abolished FGF23-mediated PTH suppression in PTH-KL(-/-) mice whereas wild-type mice remained responsive. Similar results were observed in thyro-parathyroid explants ex vivo. Collectively, we present genetic and functional evidence for a novel, Klotho-independent, calcineurin-mediated FGF23 signaling pathway in parathyroid glands that mediates suppression of PTH. The presence of Klotho-independent FGF23 effects in a Klotho-expressing target organ represents a paradigm shift in the conceptualization of FGF23 endocrine action.
Elevated serum phosphorus is associated with all-cause mortality, but little is known about risk associated with dietary phosphorus intake.
We investigated the association between phosphorus intake and mortality in a prospective cohort of healthy US adults (NHANES III; 1998-1994).
Study participants were 9686 nonpregnant adults aged 20-80 y without diabetes, cancer, or kidney or cardiovascular disease. Exposure to dietary phosphorus, which was assessed by using a 24-h dietary recall, was expressed as the absolute intake and phosphorus density (phosphorus intake divided by energy intake). All-cause and cardiovascular mortality was assessed through 31 December 2006.
Median phosphorus intake was 1166 mg/d (IQR: 823-1610 mg/d); median phosphorus density was 0.58 mg/kcal (0.48-0.70 mg/kcal). Individuals who consumed more phosphorus-dense diets were older, were less often African American, and led healthier lifestyles (smoking, physical activity, and Healthy Eating Index). In analyses adjusted for demographics, cardiovascular risk factors, kidney function, and energy intake, higher phosphorus intake was associated with higher all-cause mortality in individuals who consumed >1400 mg/d [adjusted HR (95% CI): 2.23 (1.09, 4.5) per 1-unit increase in ln(phosphorus intake); P = 0.03]. At <1400 mg/d, there was no association. A similar association was seen between higher phosphorus density and all-cause mortality at a phosphorus density amount >0.35 mg/kcal [adjusted HR (95% CI): 2.27 (1.19, 4.33) per 0.1-mg/kcal increase in phosphorus density; P = 0.01]. At <0.35 mg/kcal (approximately the fifth percentile), lower phosphorus density was associated with increased mortality risk. Phosphorus density was associated with cardiovascular mortality [adjusted HR (95% CI): 3.39 (1.43, 8.02) per 0.1 mg/kcal at >0.35 mg/kcal; P = 0.01], whereas no association was shown in analyses with phosphorus intake. Results were similar by subgroups of diet quality and in analyses adjusted for sodium and saturated fat intakes.
High phosphorus intake is associated with increased mortality in a healthy US population. Because of current patterns in phosphorus consumption in US adults, these findings may have important public health implications.
Serum phosphate is a known risk factor for cardiovascular events and mortality in people with chronic kidney disease (CKD), however data on the association of these outcomes with serum phosphate in the general population are scarce. We investigate this relationship in people with and without CKD in a large community-based population.
Three groups from an adult cohort of the Quality Improvement in Chronic Kidney Disease (QICKD) cluster randomised trial (ISRCTN56023731) were followed over a period of 2.5 years: people with normal renal function (N = 24,184), people with CKD stages 1-2 (N = 20,356), and people with CKD stages 3-5 (N = 13,292). We used a multilevel logistic regression model to determine the association between serum phosphate, in these groups, and a composite outcome of all-cause mortality, cardiovascular events, and advanced coronary artery disease. We adjusted for known cardiovascular risk factors.
Higher phosphate levels were found to correlate with increased cardiovascular risk. In people with normal renal function and CKD stages 1-2, Phosphate levels between 1.25 and 1.50 mmol/l were associated with increased cardiovascular events; odds ratio (OR) 1.36 (95% CI 1.06-1.74; p = 0.016) in people with normal renal function and OR 1.40 (95% CI 1.09-1.81; p = 0.010) in people with CKD stages 1-2. Hypophosphatemia (<0.75 mmol/l) was associated with fewer cardiovascular events in people with normal renal function; OR 0.59 (95% CI 0.36-0.97; p = 0.049). In people with CKD stages 3-5, hyperphosphatemia (>1.50 mmol/l) was associated with increased cardiovascular risk; OR 2.34 (95% CI 1.64-3.32; p<0.001). Other phosphate ranges were not found to have a significant impact on cardiovascular events in people with CKD stages 3-5.
Serum phosphate is associated with cardiovascular events in people with and without CKD. Further research is required to determine the mechanisms underlying these associations.
Background: The role of total calcium intake in the prevention of hip fracture risk has not been well established.
Objective: The objective of the study was to assess the relation of calcium intake to the risk of hip fracture on the basis of meta-analyses of cohort studies and clinical trials.
Results: In women (7 prospective cohort studies, 170 991 women, 2954 hip fractures), there was no association between total calcium intake and hip fracture risk [pooled risk ratio (RR) per 300 mg total Ca/d = 1.01; 95% CI: 0.97, 1.05]. In men (5 prospective cohort studies, 68 606 men, 214 hip fractures), the pooled RR per 300 mg total Ca/d was 0.92 (95% CI: 0.82, 1.03). On the basis of 5 clinical trials (n = 5666 women, primarily postmenopausal, plus 1074 men) with 814 nonvertebral fractures, the pooled RR for nonvertebral fractures between calcium supplementation (800–1600 mg/d) and placebo was 0.92 (95% CI: 0.81, 1.05). On the basis of 4 clinical trials with separate results for hip fracture (6504 subjects with 139 hip fractures), the pooled RR between calcium and placebo was 1.64 (95% CI:1.02, 2.64). Sensitivity analyses including 2 additional small trials with <100 participants or per-protocol results did not substantially alter results.
Conclusions: Pooled results from prospective cohort studies suggest that calcium intake is not significantly associated with hip fracture risk in women or men. Pooled results from randomized controlled trials show no reduction in hip fracture risk with calcium supplementation, and an increased risk is possible. For any nonvertebral fractures, there was a neutral effect in the randomized trials.
Background:
Complications of chronic kidney disease (CKD) include weak bones and increased fracture risk.
Purpose:
To review the benefits and harms of osteoporosis medications (bisphosphonates, teriparatide, raloxifene, and denosumab) compared with placebo, usual care, or active control in terms of bone mineral density (BMD), fractures, and safety in patients with CKD.
Data sources:
PubMed and the Cochrane Central Register of Controlled Trials from December 2006 through December 2016.
Study selection:
Paired reviewers independently screened abstracts and full-text articles for English-language, randomized, controlled trials that had at least 6 months of follow-up; evaluated osteoporosis medications among patients with CKD; and reported on BMD, fractures, or safety (mortality and adverse events).
Data extraction:
Two reviewers serially abstracted data and independently assessed risk of bias and graded the strength of evidence (SOE).
Data synthesis:
There were 13 trials (n = 9850) that included kidney transplant recipients (6 trials), patients who had stage 3 to 5 CKD or were receiving dialysis (3 trials), or postmenopausal women with CKD (4 trials). Evidence showed that bisphosphonates may slow loss of BMD among transplant recipients (moderate SOE), but their effects on fractures and safety in transplant recipients and others with CKD are unclear. Raloxifene may prevent vertebral fractures but may not improve BMD (low SOE). Effects of teriparatide and denosumab on BMD and fractures are unclear (very low SOE), and these medications may increase risk for some safety outcomes.
Limitation:
Unclear rigor of evidence, possible reporting biases, and scant evidence among patients with stage 3 to 5 CKD.
Conclusion:
Effects of osteoporosis medications on BMD, fracture risk, and safety among patients with CKD are not clearly established.
Primary funding source:
Kidney Disease: Improving Global Outcomes.
Importance:
Coronary artery calcification (CAC) is highly prevalent in dialysis-naive patients with chronic kidney disease (CKD). However, there are sparse data on the association of CAC with subsequent risk of cardiovascular disease and all-cause mortality in this population.
Objective:
To study the prospective association of CAC with risk of cardiovascular disease and all-cause mortality among dialysis-naive patients with CKD.
Design, setting, and participants:
The prospective Chronic Renal Insufficiency Cohort study recruited adults with an estimated glomerular filtration rate of 20 to 70 mL/min/1.73 m2 from 7 clinical centers in the United States. There were 1541 participants without cardiovascular disease at baseline who had CAC scores.
Exposures:
Coronary artery calcification was assessed using electron-beam or multidetector computed tomography.
Main outcomes and measures:
Incidence of cardiovascular disease (including myocardial infarction, heart failure, and stroke) and all-cause mortality were reported every 6 months and confirmed by medical record adjudication.
Results:
During an average follow-up of 5.9 years in 1541 participants aged 21 to 74 years, there were 188 cardiovascular disease events (60 cases of myocardial infarction, 120 heart failures, and 27 strokes; patients may have had >1 event) and 137 all-cause deaths. In Cox proportional hazards models adjusted for age, sex, race, clinical site, education level, physical activity, total cholesterol level, high-density lipoprotein cholesterol level, systolic blood pressure, use of antihypertensive treatment, current cigarette smoking, diabetes status, body mass index, C-reactive protein level, hemoglobin A1c level, phosphorus level, troponin T level, log N-terminal pro-B-type natriuretic peptide level, fibroblast growth factor 23 level, estimated glomerular filtration rate, and proteinuria, the hazard ratios associated with per 1 SD log of CAC were 1.40 (95% CI, 1.16-1.69; P < .001) for cardiovascular disease, 1.44 (95% CI, 1.02-2.02; P = .04) for myocardial infarction, 1.39 (95% CI, 1.10-1.76; P = .006) for heart failure, and 1.19 (95% CI, 0.94-1.51; P = .15) for all-cause mortality. In addition, inclusion of CAC score led to an increase in the C statistic of 0.02 (95% CI, 0-0.09; P < .001) for predicting cardiovascular disease over use of all the above-mentioned established and novel cardiovascular disease risk factors.
Conclusions and relevance:
Coronary artery calcification is independently and significantly related to the risks of cardiovascular disease, myocardial infarction, and heart failure in patients with CKD. In addition, CAC improves risk prediction for cardiovascular disease, myocardial infarction, and heart failure over use of established and novel cardiovascular disease risk factors among patients with CKD; however, the changes in the C statistic are small.
Trabecular bone score (TBS) is a texture index derived from standard lumbar spine dual energy X-ray absorptiometry (DXA) images and provides information about the underlying bone independent of the bone mineral density (BMD). Several salient observations have emerged. Numerous studies have examined the relationship between TBS and fracture risk and have shown that lower TBS values are associated with increased risk for major osteoporotic fracture in postmenopausal women and older men, with this result being independent of BMD values and other clinical risk factors. Therefore, despite being derived from standard DXA images, the information contained in TBS is independent and complementary to the information provided by BMD and the FRAX® tool. A procedure to generate TBS-adjusted FRAX probabilities has become available with the resultant predicted fracture risks shown to be more accurate than the standard FRAX tool. With these developments, TBS has emerged as a clinical tool for improved fracture risk prediction and guiding decisions regarding treatment initiation, particularly for patients with FRAX probabilities around an intervention threshold. In this article, we review the development, validation, clinical application, and limitations of TBS.
Importance:
The role of coronary artery calcium (CAC) testing for guiding preventive strategies among women at low cardiovascular disease (CVD) risk based on the American College of Cardiology and American Heart Association CVD prevention guidelines is unclear.
Objective:
To assess the potential utility of CAC testing for CVD risk estimation and stratification among low-risk women.
Design, setting, and participants:
Women with 10-year atherosclerotic CVD (ASCVD) risk lower than 7.5% from 5 large population-based cohorts: the Dallas Heart Study (United States), the Framingham Heart Study (United States), the Heinz Nixdorf Recall study (Germany), the Multi-Ethnic Study of Atherosclerosis (United States), and the Rotterdam Study (the Netherlands). The 5 cohorts were selected based on the availability of CAC data in a sizable group of low-risk women from the general population together with the long detailed follow-up data. Across the cohorts, events were assessed from the date of CAC scan (performed from 1998 through 2006) until January 1, 2012; January 1, 2014; or March 6, 2015. Fixed-effects meta-analysis was conducted to combine the results of the 5 studies.
Exposures:
CAC score by computed tomography.
Main outcomes and measures:
Main outcome was incident ASCVD, including nonfatal myocardial infarction, coronary heart disease (CHD) death, and stroke. Association of CAC with ASCVD was examined using Cox proportional hazards models. To assess whether CAC was associated with improved ASCVD risk predictions beyond the traditional risk factors, the C statistic and the continuous net reclassification improvement (cNRI) index were calculated.
Results:
Among 6739 women with low ASCVD risk from the 5 studies, mean age ranged from 44 to 63 years and CAC was present in 36.1%. Across the cohorts, median follow-up ranged from 7.0 to 11.6 years. A total of 165 ASCVD events occurred (64 nonfatal myocardial infarctions, 29 CHD deaths, and 72 strokes), with the ASCVD incidence rates ranging from 1.5 to 6.0 per 1000 person-years. Compared with the absence of CAC (CAC = 0), presence of CAC (CAC >0) was associated with an increased risk of ASCVD (incidence rates per 1000 person-years, 1.41 for CAC absence vs 4.33 for CAC presence; difference, 2.92 [95% CI, 2.02-3.83]; multivariable-adjusted hazard ratio, 2.04 [95% CI, 1.44-2.90]). The addition of CAC to traditional risk factors improved the C statistic from 0.73 (95% CI, 0.69-0.77) to 0.77 (95% CI, 0.74-0.81) and provided a cNRI of 0.20 (95% CI, 0.09-0.31) for ASCVD prediction.
Conclusions and relevance:
Among women at low ASCVD risk, CAC was present in approximately one-third and was associated with an increased risk of ASCVD and modest improvement in prognostic accuracy compared with traditional risk factors. Further research is needed to assess the clinical utility and cost-effectiveness of this additional accuracy.
Arterial calcification is commonly seen in atherosclerosis, chronic kidney disease (CKD) and diabetes and has long been considered a natural progression of atherosclerosis. Yet it is a systemic condition, occurring in a wide and diverse range of disease states and no medical treatment for cardiovascular disease has yet found a way to regress it; on the contrary, lipid-lowering therapy may worsen its progression. Although numerous studies have found associations between calcification and biomarkers, none has yet found a unifying mechanism that explains the calcification found in atherosclerosis, CKD or diabetes and many of the biomarkers are equally associated with atheroma development and cardiovascular events. Furthermore, both presence and absence of coronary artery calcification appear predictive of plaque rupture and cardiovascular events, indicating that the association is not causal. This suggests that we are no further forward in understanding the true nature of arterial calcification or its pathogenesis, other than noting that it is ‘multifactorial’. This is because most researchers view arterial calcification as a progressive pathological condition which must be treated. Instead, we hypothesise that calcification develops as an immune response to endothelial injury, such as shear stress or oxidative stress in diabetics, and is consequently part of the body's natural defences. This would explain why it has been found to be protective of plaque rupture and why it is unresponsive to lipid-lowering agents. We propose that instead of attempting to treat arterial calcification, we should instead be attempting to prevent or treat all causes of endothelial injury.
Circulating parathyroid hormone (PTH) shows a complex relationship with hard outcomes in subjects with chronic kidney disease (CKD). Moreover, intervention studies directly targeting PTH failed to yield unequivocal results. Disturbed PTH metabolism, posttranslational modifications of PTH, and end-organ hyporesponsiveness to PTH may explain the poor performance of PTH as an outcome biomarker and precise target of therapy in the setting of CKD, at least in the gray middle target zone. PTH fragments accumulate in CKD patients and may exert effects that are distinct from, if not opposite to biointact (1-84)PTH. Posttranslational modification of PTH and especially oxidation may alter the interaction of PTH with its receptor. Its clinical relevance, however, remains a matter of ongoing debate. Less controversial is the issue of end-organ hyporesponsiveness to PTH. This phenomenon, formally referred to as PTH resistance, has long been recognized in CKD, but factors and mechanisms contributing to it remain poorly defined. Subsequent evidence identified downregulation of the PTH receptor and competing downstream signals as underlying pathophysiologic mechanisms. End-organ hyporesponsiveness to PTH in CKD, along with important analytical and biological variability, renders defining the PTH target range in CKD challenging. Although this may still be accomplished at the population level, it may prove to be very difficult at the individual level. This is a disillusioning thought in an era of personalized medicine. Parallel to the search of a functional and readily available assay quantifying PTH signaling tone or sensitivity, additional biomarkers (or a panel of biomarkers) should be formally evaluated.
Context:
An elevated fibroblast growth factor (FGF) 23 is an independent risk factor for cardiovascular disease and mortality in patients with kidney disease. The relationship between FGF23 and cause-specific mortality in the general population is unknown.
Objective:
To investigate the association of elevated FGF23 with risk of cause-specific mortality in a racially and ethnically diverse urban general population.
Design, setting, participants:
The Northern Manhattan Study is a population-based prospective cohort study. Residents who were >39 years old, with no history of stroke were enrolled between 1993 and 2001. Participants with available blood samples for baseline FGF23 testing were included in the current study (n=2525).
Main outcome measures:
Cause-specific death events.
Results:
A total of 1198 deaths (474 vascular, 612 non-vascular, 112 unknown cause) occurred during a median follow-up of 14 years. Compared to participants in the lowest FGF23 quintile, those in the highest quintile had a 2.07-fold higher risk (95% confidence interval [CI] 1.45, 2.94) of vascular death and a 1.64-fold higher risk (95% CI 1.22, 2.20) of non-vascular death in fully adjusted models. Higher FGF23 was independently associated with increased risk of mortality due to cancer, but only in Hispanic participants (hazard ratio per 1 unit increase in ln FGF23 of 1.87; 95% CI 1.40, 2.50; P for interaction = 0.01).
Conclusions:
Elevated FGF23 was independently associated with increased risk of vascular and non-vascular mortality in a diverse general population, and with increased risk of cancer death specifically in Hispanic individuals.
It is commonly held that osteitis fibrosa and mixed uremic osteodystrophy are the predominant forms of renal osteodystrophy in patients with chronic kidney disease. Osteitis fibrosa is a high-turnover bone disease resulting mainly from secondary hyperparathyroidism, and mixed uremic osteodystrophy is in addition characterized by a mineralization defect most often attributed to vitamin D deficiency. However, there is ancient and more recent evidence that in early chronic kidney disease stages adynamic bone disease characterized by low bone turnover occurs first, at least in a significant proportion of patients. This could be due to the initial predominance of bone turnover-inhibitory conditions such as resistance to the action of parathyroid hormone (PTH), reduced calcitriol levels, sex hormone deficiency, diabetes, and, last but not least, uremic toxins leading to repression of osteocyte Wnt/β-catenin signaling and increased expression of Wnt antagonists such as sclerostin, Dickkopf-1, and sFRP4. The development of high-turnover bone disease would occur only later on, when serum PTH levels are able to overcome peripheral PTH resistance and the other inhibitory factors of bone formation. Whether FGF23 and Klotho play a direct role in the transition from low- to high-turnover bone disease or participate only indirectly via regulating PTH secretion remains to be seen.
Once-weekly 56.5-μg teriparatide treatment was significantly associated with the increase in lumbar spine bone mineral density at 48 weeks among hemodialysis patients with hypoparathyroidism and low bone mass; however, discontinuation of treatment because of adverse events was frequently observed. Careful monitoring for adverse events should be required.
Introduction
Once-weekly 56.5-μg teriparatide is reportedly effective for treating osteoporotic patients without renal insufficiency. However, little is known about the efficacy and safety of once-weekly teriparatide in hemodialysis patients.
Methods
We conducted a 48-week prospective, observational cohort study including 22 hemodialysis patients aged 20 years or older with hypoparathyroidism and low bone mass who received once-weekly teriparatide at 56.5 μg at a tertiary care hospital between January 2013 and January 2015. Primary outcomes were within-subject percent changes of bone mineral density (BMD) at the lumbar spine, femoral neck, and distal one-third radius at 24 and 48 weeks. Secondary outcomes included percent changes of serum bone turnover markers (osteocalcin, bone-specific alkaline phosphatase (BAP), N-terminal propeptide of procollagen type 1 (P1NP), and tartrate-resistant acid phosphatase 5b (TRAP-5b)). Adverse events were evaluated.
Results
The BMD increased at the lumbar spine by 3.3 ± 1.9 % (mean ± SEM) and 3.0 ± 1.8 % at 24 and 48 weeks but not in the femoral neck and distal one-third radius. Serum osteocalcin, BAP, and P1NP increased significantly at 4 weeks, maintaining higher concentrations up to 48 weeks, although TRAP-5b decreased gradually during treatment. The baseline BAP was significantly associated with the 48-week percent change in lumbar spine BMD. Transient hypotension was the most common adverse event. Ten patients discontinued treatment because of adverse events.
Conclusions
Once-weekly teriparatide was associated with increased lumbar spine BMD in hemodialysis patients with hypoparathyroidism and low bone mass. Careful monitoring should be required for treatment of such patients.
This study estimated the fracture-related mortality and direct medical costs among postmenopausal women in Taiwan by fracture types and age groups by utilizing a nationwide population-based database. Results demonstrated that hip fractures constituted the most severe and expensive complication of osteoporosis across fracture sites.
Introduction
The aims of the study were to evaluate the risk of death and direct medical costs associated with osteoporotic fractures by fracture types and age groups among postmenopausal women in Taiwan.
Methods
This nationwide, population-based study was based on data from the National Health Insurance Research Database in Taiwan. Female patients aged 50 years and older in the fracture case cohort were matched in 1:1 ratio with randomly selected subjects in the reference control cohort by age, income-related insurance amount, urbanization level, and the Charlson comorbidity index. There were two main outcome measures of the study: age-differentiated mortality and direct medical costs in the first and subsequent years after osteoporotic fracture events among postmenopausal women. The bootstrap method by resampling with replacement was conducted to generate descriptive statistics of mortality and direct medical costs of the case and control cohorts. Student’s t tests were then performed to compare mortality and costs between the two cohorts.
Results
A total of 155,466 postmenopausal women in the database met the inclusion criteria for the fracture case cohort, including 22,791 hip fractures, 72,292 vertebral fractures, 15,621 upper end humerus (closed) fractures, 36,774 wrist fractures, and 7,988 multiple fractures. Analytical results demonstrated that patients experiencing osteoporotic fractures were at considerable excess risk of death and incurred substantially higher treatment costs, notably for hip fractures. Furthermore, results also revealed that the risk of mortality increased with advancing age across the spectrum of fracture sites.
Conclusions
The present study confirmed an excess mortality and higher direct medical costs associated with osteoporotic fractures. Moreover, hip fractures constituted the most severe and expensive complication of osteoporosis among fracture types.
Adynamic bone is the most frequent type of bone lesion in patients with chronic kidney disease; long-term use of antiresorptive therapy may also lead to the adynamic bone condition. The hallmark of adynamic bone is a loss of bone turnover, and a major clinical concern of adynamic bone is diminished bone quality and an increase in fracture risk. Our current study aims to investigate how bone quality changes with age in our previously established mouse model of adynamic bone. Young and old mice (4 months old and 16 months old, respectively) were used in this study. Col2.3Δtk (DTK) mice were treated with ganciclovir and pamidronate to create the adynamic bone condition. Bone quality was evaluated using established techniques including bone histomorphometry, microcomputed tomography, quantitative backscattered electron imaging, and biomechanical testing. Changes in mineral and matrix properties were examined by powder X-ray diffraction and Raman spectroscopy. Aging controls had a natural decline in bone formation and resorption with a corresponding deterioration in trabecular bone structure. Bone turnover was severely blunted at all ages in adynamic animals, which preserved trabecular bone loss normally associated with aging. However, the preservation of trabecular bone mass and structure in old adynamic mice did not rescue deterioration of bone mechanical properties. There was also a decrease in cortical bone toughness in old adynamic mice that was accompanied by a more mature collagen matrix and longer bone crystals. Little is known about the effects of metabolic bone disease on bone fracture resistance. We observed an age-related decrease in bone toughness that was worsened by the adynamic condition, and this decrease may be due to material level changes at the tissue level. Our mouse model may be useful in the investigation of the mechanisms involved in fractures occurring in elderly patients on antiresorptive therapy who have very low bone turnover.
Assess the effect of intensive nutrition education by trained dedicated dietitians on osteodystrophy management among hemodialysis patients.
Randomized controlled trial in 12 hospital-based hemodialysis units equally distributed over clusters 1 and 2. Cluster 1 patients were either assigned to usual care (n=96) or to individualized intensive staged-based nutrition education by a dedicated renal dietitian (n=88). Cluster 2 patients (n=210) received nutrition education from general hospital dietitians, educating their patients at their spare time from hospital duties. Main outcomes were: (1) dietary knowledge(%), (2) behavioral change, (3) serum phosphorus (mmol/L), each measured at T0 (baseline), T1 (post 6 month intervention) and T2 (post 6 month follow up).
Significant improvement was found only among patients receiving intensive education from a dedicated dietitian at T1; the change regressed at T2 without statistical significance: knowledge (T0: 40.3; T1: 64; T2: 63) and serum phosphorus (T0: 1.79; T1: 1.65; T2: 1.70); behavioral stages changed significantly throughout the study (T0: Preparation, T1: Action, T2: Preparation).
The intensive protocol showed to be the most effective.
Integrating dedicated dietitians and stage-based education in hemodialysis units may improve the nutritional management of patients in Lebanon and countries with similar health care systems.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Men and women with chronic kidney disease (CKD) are at an increased risk of fracture, and this risk increases as kidney function deteriorates. Fractures are associated with morbidity, mortality, and economic costs. Despite this there is a paucity of data regarding how to evaluate risk for fractures in CKD and how to treat high-risk patients. Evidence suggests that bone mineral density (BMD) as assessed by dual energy x-ray absorptiometry (DXA) is associated with fractures and can also predict future fractures in predialysis (stages 1-3) CKD patients. In the absence of considerable abnormalities in markers of mineral metabolism, treatment with antiresorptive agents in men and women with early CKD at high fracture risk may be appropriate. Of note, recent data suggest that low BMD as measured by DXA can also predict fractures in patients with more advanced CKD (stages 4, 5, and 5D). However, treatment in patients with advanced CKD requires bone biopsy, the gold standard to assess bone turnover, prior to treatment. Further research, focusing on non-invasive methods to assess fracture risk and bone turnover, together with randomized controlled trials of treatments to reduce fractures in patients at all stages of CKD, are required. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
A number of cancer therapy agents are cleared by the kidney and may affect renal function, including cytotoxic chemotherapy agents, molecular targeted therapies, analgesics, antibiotics, radiopharmaceuticals and radiation therapy, and bone-targeted therapies. Many of these agents can be nephrotoxic including, targeted cancer therapies. The incidence, severity, and pattern of renal toxicities may vary according to the respective target of the drug. Here we review the renal effects associated with a selection of currenty approved targeted cancer therapies, directed to VEGF/VEGFR, EGFR, HER2, BRAF, ALK, PD1/PDL1, RANKL, mTOR. The early diagnosis and prompt treatment of these renal alterations are essential in the daily practice where molecular targeted therapies have a definitive role in the armamentarium used in many cancers.
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
In chronic kidney disease the excessive production of parathyroid hormone increases the bone resorption rate and leads to histologic bone signs of secondary hyperparathyroidism. However, in other situations, the initial increase in parathyroid hormone and bone remodeling may be slowed down excessively by a multitude of factors including age, ethnic origin, sex, and treatments such as vitamin D, calcium salts, calcimimetics, steroids, and so forth, leading to low bone turnover or adynamic bone disease. Both high and low bone turnover diseases actually are observed equally in chronic kidney disease patients treated by dialysis, and all types of renal osteodystrophy are associated with an increased risk of skeletal fractures, reduced quality of life, and poor clinical outcomes. Unfortunately, the diagnosis of these bone abnormalities cannot be obtained correctly by current clinical, biochemical, and imaging methods. Therefore, bone biopsy has been, and still remains, the gold standard analysis for assessing the exact type of renal osteodystrophy. It is also the unique way to assess the mechanisms of action, safety, and efficacy of new bone-targeting therapies.
Copyright © 2014 Elsevier Inc. All rights reserved.
Adynamic bone disease (ABD) is a well-recognized clinical entity in the complex chronic kidney disease (CKD)-mineral and bone disorder. Although the combination of low intact parathyroid hormone (PTH) and low bone alkaline phosphatase levels may be suggestive of ABD, the gold standard for precise diagnosis is histomorphometric analysis of tetracycline double-labeled bone biopsies. ABD essentially is characterized by low bone turnover, low bone volume, normal mineralization, and markedly decreased cellularity with minimal or no fibrosis. ABD is increasing in prevalence relative to other forms of renal osteodystrophy, and is becoming the most frequent type of bone lesion in some series. ABD develops in situations with reduced osteoanabolic stimulation caused by oversuppression of PTH, multifactorial skeletal resistance to PTH actions in uremia, and/or dysregulation of Wnt signaling. All may contribute not only to bone disease but also to the early vascular calcification processes observed in CKD. Various risk factors have been linked to ABD, including calcium loading, ageing, diabetes, hypogonadism, parathyroidectomy, peritoneal dialysis, and antiresorptive therapies, among others. The relationship between low PTH level, ABD, increased risk fracture, and vascular calcifications may at least partially explain the association of ABD with increased mortality rates. To achieve optimal bone and cardiovascular health, attention should be focused not only on classic control of secondary hyperparathyroidism but also on prevention of ABD, especially in the steadily growing proportions of diabetic, white, and elderly patients. Overcoming the insufficient osteoanabolic stimulation in ABD is the ultimate treatment goal.
Copyright © 2014 Elsevier Inc. All rights reserved.
Awareness of chronic kidney disease (CKD), defined by kidney damage or reduced glomerular filtration rate, remains low in the United States, and few estimates of its future burden exist.
We used the CKD Health Policy Model to simulate the residual lifetime incidence of CKD and project the prevalence of CKD in 2020 and 2030. The simulation sample was based on nationally representative data from the 1999 to 2010 National Health and Nutrition Examination Surveys.
Current US population.
Simulation model following up individuals from current age through death or age 90 years.
Residual lifetime incidence represents the projected percentage of persons who will develop new CKD during their lifetimes. Future prevalence is projected for 2020 and 2030.
Development and progression of CKD are based on annual decrements in estimated glomerular filtration rates that depend on age and risk factors.
For US adults aged 30 to 49, 50 to 64, and 65 years or older with no CKD at baseline, the residual lifetime incidences of CKD are 54%, 52%, and 42%, respectively. The prevalence of CKD in adults 30 years or older is projected to increase from 13.2% currently to 14.4% in 2020 and 16.7% in 2030.
Due to limited data, our simulation model estimates are based on assumptions about annual decrements in estimated glomerular filtration rates.
For an individual, lifetime risk of CKD is high, with more than half the US adults aged 30 to 64 years likely to develop CKD. Knowing the lifetime incidence of CKD may raise individuals' awareness and encourage them to take steps to prevent CKD. From a national burden perspective, we estimate that the population prevalence of CKD will increase in coming decades, suggesting that development of interventions to slow CKD onset and progression should be considered.
Copyright © 2014 National Kidney Foundation, Inc. All rights reserved.
Phosphate metabolism is crucial in the pathophysiology of secondary hyperparathyroidism and vascular calcification. High phosphate levels have been consistently associated with unfavorable outcomes in dialysis patients, but several limitations are still hampering a resolutive definition of the optimal targets of phosphate serum levels to be achieved in this cohort. Nonetheless, hyperphosphatemia is a late marker of phosphate overload in humans. Clinical nephrologists routinely counteract the positive phosphate balance in dialysis patients through nutritional counseling, stronger phosphate removal by dialysis and prescription of phosphate binders. However, the superiority against placebo of phosphate control by diet, dialysis or binders in terms of survival has never been tested in dedicated randomized controlled trials. The present review discusses this conundrum with particular emphasis on the rationale supporting the value of a simultaneous intervention against phosphate overload in dialysis patients via the improvement of dietary intakes, dialysis efficiency and an individualized choice of phosphate binders.
Calcium supplementation, particularly with vitamin D has been an approved public health intervention to reduce fracture risk. Enthusiasm for this intervention has been mitigated by meta-analyses suggesting calcium supplementation with or without vitamin D increase myocardial infarction (MI) risk; however concern has been raised over the design of these meta-analyses. We therefore undertook a meta-analysis of randomized controlled trials with placebo or no-treatment control groups to determine if these supplements increase all-cause mortality and coronary heart disease (CHD) risk including: MI, angina pectoris and acute coronary syndrome, and chronic CHD verified by clinical review, hospital record or death certificate in elderly women. The Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE databases were searched from January 1, 1966 to May 24, 2013 for potentially eligible studies, reference lists were checked, and trial investigators contacted where additional unpublished data was required. The search yielded 661 potentially eligible reports of which 18 met the inclusion criteria and contributed information on 63,563 participants with 3,390 CHD events and 4,157 deaths. Two authors extracted the data independently with trial data combined using random-effects meta-analysis to calculate the relative risk (RR). Five trials contributed CHD events with pooled relative RR of 1.02 (95% CI, 0.96-1.09; P = 0.51). Seventeen trials contributed all-cause mortality data with pooled RR of 0.96 (95%CI, 0.91-1.02; P = 0.18). Heterogeneity among the trials was low for both primary outcomes (I2 = 0%). For secondary outcomes the RR for MI was 1.08; 95% CI, 0.92-1.26; P = 0.32, angina pectoris and acute coronary syndrome 1.09; 95% CI, 0.95-1.24; P = 0.22 and chronic CHD 0.92; 95% CI, 0.73-1.15; P = 0.46. In conclusion, current evidence does not support the hypothesis that calcium supplementation with or without vitamin D increase coronary heart disease or all-cause mortality risk in elderly women. © 2014 American Society for Bone and Mineral Research
Klotho was discovered as an antiaging gene, and α-Klotho (Klotho) is expressed in multiple tissues with a broad set of biologic functions. Membrane-bound Klotho binds fibroblast growth factor 23 (FGF23), but a soluble form of Klotho is also produced by alternative splicing or cleavage of the extracellular domain of the membrane-bound protein. The relative organ-specific contributions to the levels and effects of circulating Klotho remain unknown. We explored these issues by generating a novel mouse strain with Klotho deleted throughout the nephron (Six2-KL(-/-)). Klotho shedding from Six2-KL(-/-) kidney explants was undetectable and the serum Klotho level was reduced by approximately 80% in Six2-KL(-/-) mice compared with wild-type littermates. Six2-KL(-/-) mice exhibited severe growth retardation, kyphosis, and premature death, closely resembling the phenotype of systemic Klotho knockout mice. Notable biochemical changes included hyperphosphatemia, hypercalcemia, hyperaldosteronism, and elevated levels of 1,25-dihydroxyvitamin D and Fgf23, consistent with disrupted renal Fgf23 signaling. Kidney histology demonstrated interstitial fibrosis and nephrocalcinosis in addition to absent dimorphic tubules. A direct comparative analysis between Six2-KL(-/-) and systemic Klotho knockout mice supports extensive, yet indistinguishable, extrarenal organ manifestations. Thus, our data reveal the kidney as the principal contributor of circulating Klotho and Klotho-induced antiaging traits.
Chronic kidney disease increases the risk for hip fractures. Hip fractures are associated with increased mortality, decreased quality of life, and higher economic burden. To determine whether dialysis modality is associated with a higher incidence of hip fractures in patients with end-stage renal disease (ESRD), we used the Taiwan National Health Insurance Research Database to examine the records of 51,473 patients who began dialysis between 1999 and 2005. The patients were followed until death, transplantation, dialysis cessation, or 31 December 2008. The follow-up period was (mean±SD) 4.14±2.48years. The cumulative incidence rate of hip fracture was calculated using Kaplan-Meier methods. Predictors of hip fracture determined using Cox models. During the study period, 1903 patients had a hip fracture. The overall incidence rate of hip fracture was 89.21/10,000 patient-years. Patients on hemodialysis (HD) had a 31% higher incidence of hip fracture than those on peritoneal dialysis (PD) (HR 1.31, 95% CI: 1.01-1.70). Patients≥65years old had more than 13 times the risk of a hip fracture than did those 18-44 years old (HR: 13.65; 95% CI: 10.12-18.40). Other factors that increased the risk of a hip fracture were a prior hip fracture (HR: 1.44; 95% CI: 1.15-1.80), osteoporosis (HR: 1.24; 95% CI: 1.07-1.45), DM (HR: 1.66; 95% CI: 1.51-1.83), and liver cirrhosis (HR: 1.37, 95% CI: 1.15-1.64).The overall in-hospital mortality rate was 3.2%. The cumulative survival rates after a hip fracture were 74.6% at one year and only 29.6 % at seven years. Our findings supported the notion that being on HD is a risk for hip fracture. Additionally, old age, female gender, a prior hip fracture, osteoporosis, DM and liver cirrhosis were also risk factors for hip fracture in patients with ESRD and undergoing dialysis.
The goal of our study was to estimate the prevalence of osteoporosis and low bone mass based on bone mineral density (BMD) at the femoral neck and the lumbar spine in adults 50 years and older in the United States (US). We applied prevalence estimates of osteoporosis or low bone mass at the femoral neck or lumbar spine (adjusted by age, sex, and race/ethnicity to the 2010 Census) for the non-institutionalized population age 50 years and older from the National Health and Nutrition Examination Survey 2005–2010 to 2010 US Census population counts to determine the total number of older US residents with osteoporosis and low bone mass. There were over 99 million adults 50 years and older in the US in 2010. Based on an overall 10.3% prevalence of osteoporosis, we estimated that in 2010 10.2 million older adults had osteoporosis. The overall low bone mass prevalence was 43.9%, from which we estimated that 43.4 million older adults had low bone mass. We estimated that 7.7 million non-Hispanic White, 0.5 million non-Hispanic Black, and 0.6 million Mexican American adults had osteoporosis and another 33.8, 2.9, and 2.0 million had low bone mass, respectively. When combined, osteoporosis and low bone mass at the femoral neck or lumbar spine affected an estimated 53.6 million older US adults in 2010. Although most of the individuals with osteoporosis or low bone mass were non-Hispanic White women, a substantial number of men and women from other racial/ethnic groups also had osteoporotic BMD or low bone mass. © 2014 American Society for Bone and Mineral Research
-Fibroblast growth factor-23 (FGF-23) is a phosphate regulatory hormone that directly stimulates left ventricular hypertrophy in experimental models. The role of FGF-23 in cardiovascular disease development in the general population is unclear. We tested associations of FGF-23 with major subclinical and clinical cardiovascular disease outcomes in a large prospective cohort.
-We evaluated 6,547 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who were initially free of cardiovascular disease. We measured serum FGF-23 using the Kainos immunoassay. The MESA measured left ventricular (LV) mass by magnetic resonance imaging, coronary calcium (CAC) by computed tomography, and carotid intima-medial thickness (IMT) by ultrasound. The MESA adjudicated incident heart failure, coronary heart disease, and stoke by medical record review. After adjustment, the highest FGF-23 quartile was associated with an estimated 2.4 gram greater LV mass (95% CI 0.4, 4.5 greater) and a 26% greater odds of higher CAC scores (95% CI 9% to 46% greater) compared to the lowest quartile. Over 7.5 years follow-up, each 20-pg/mL higher FGF-23 concentration was associated with a 19% greater risk of heart failure (95% CI 3% to 37% greater) and a 14% greater risk of coronary heart disease (95% CI 1% to 28% greater). FGF-23 was not associated with carotid IMT or stroke.
-Higher serum FGF-23 concentrations are associated with subclinical cardiac disease and with new heart failure and coronary disease events, but not with carotid IMT or stroke. FGF-23 may be a novel cardiovascular risk factor in the general population.
The World Health Organization Fracture Risk Assessment Tool (FRAX) estimates the 10-year fracture probability. We assessed the prognostic value of FRAX in kidney transplant recipients, as its utility in recipients is unknown.
We considered 458 individuals (mean age 45 years, 64% men) who received a kidney transplant in the province of Manitoba, Canada at the time of their first bone mineral density (BMD) test posttransplant (mean 1.1 years posttransplant; transplant years 1996-2011). FRAX probabilities were calculated from baseline information (age, sex, clinical risk factors, with or without BMD). Recipients were followed a mean of 6.4 years (interquartile range 3.0-10.0 years) after cohort entry for an incident major osteoporotic fracture.
In follow-up, 21 (4.6%) recipients experienced a major osteoporotic fracture. The observed 10-year major osteoporotic fracture risk of 6.3% (95% CI, 3.4-9.2%) was concordant with FRAX predictions (5.0% with BMD, 5.6% without BMD). Major osteoporotic fracture scores showed significant fracture prediction (hazard ratio per standard deviation, FRAX without BMD 1.66, 95% CI, 1.10-2.50; FRAX with BMD 1.64, 95% CI, 1.07-2.51). Area under the curve (AUC) for incident major osteoporotic fracture discrimination (AUC: FRAX with BMD 0.62, 95% CI, 0.50-0.74) was similar to the general population.
FRAX scores categorized most kidney transplant recipients as a low-risk fracture group, and the low observed fracture rates were consistent with the 10-year fracture predictions. FRAX showed modest fracture prediction and discrimination similar to the general population. Independent validation is needed before clinicians can routinely use FRAX in kidney transplant recipients.
We assessed the ability of the World Health Organization's fracture risk assessment tool (FRAX), bone mineral density (BMD), and age to discriminate fracture status in adults with pre-dialysis chronic kidney disease (CKD). In adults with CKD, FRAX was able to discriminate fracture status but performed no better than BMD alone.
Patients with CKD are at increased risk for fracture but the best method to assess fracture risk is not known.
We assessed the ability of the World Health Organization's FRAX, compared with BMD at the femoral neck (FN), and age to discriminate fracture status (prevalent clinical nonspine and/or morphometric vertebral) in men and women, 18 years and older with pre-dialysis CKD. Results are presented as area under receiver operator characteristic curves (AUC) with 95 % confidence intervals (CI).
We enrolled 353 subjects; mean age was 65 ± 14 years; weight was 79 ± 18 kg, and estimated glomerular filtration rate was 28 ml/min/1.73 m(2). About one third of the subjects had a prevalent clinical nonspine and/or morphometric vertebral fracture. FRAX was able to discriminate among those with prevalent clinical nonspine fractures (AUC, 0.72; 95 % CI, 0.65-0.78), morphometric vertebral fractures (AUC, 0.66; 95 % CI, 0.59-0.73), and any fracture (AUC, 0.71; 95 % CI, 0.65-0.77). The discriminative ability of BMD at the FN alone was similar to FRAX for morphometric vertebral and any fractures; FRAX performed better than BMD for prevalent clinical nonspine fractures (AUC for BMD alone, 0.66; 95 % CI, 0.60-0.73). Compared to FRAX, the AUC for age alone was lower for all fracture types.
Among men and women with CKD, FRAX is able to discriminate fracture status but performs no better than BMD alone.