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Item does not contain fulltext Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m(2) This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR

Objectives: To describe the step-by-step person-centered, theory-based development of the KELA.AE app for Arabic speaking hemodialysis patients. Methods: A step-by-step person-driven theory-based approach was conducted to develop a self-monitoring and educational dietary app for hemodialysis patients. The development follows the Integration, Design, Assessment, and Sharing (IDEAS) framework Qualitative, semi-structured interviews with 6 hemodialysis patients and 6 healthcare practitioners (dietitians and nephrologists) were performed to assess the need for an app, the willingness to use an app, and features desired in an app. Results: The KEI,A.AE app, which includes a self-monitoring feature, CKD-friendly recipes, and a theory-based, evidence-based educational feature was developed. Qualitative analysis of interviews revealed two predominant themes from patient interviews 'Experience with the diet', 'App evaluation, and one theme from interviews with healthcare practitioners 'App evaluation. Patients expressed frustration with current accessibility of dietary information along with the need for educational materials in the app. The review of the KELA.AE prototype was positive overall, and patients reported a willingness to use the app. Healthcare practitioners considered the app accurate, simple, and culturally sensitive but expressed concerns about app misuse and the replacement of healthcare practitioners. Conclusions: The KELA.AE app was found to be satisfactory and supportive of the participants' needs. Changes were made to the app as suggested during the interviews.

Rationale & Objective: Pneumococcal vaccine is recommended for adults 65 years and older and those younger than 65 years with clinical indications (eg, diabetes, lung/heart disease, kidney failure, and nephrotic syndrome). Its cost-effectiveness in less severe chronic kidney disease (CKD) is uncharacterized.Study Design: Cost-effectiveness analysis.Setting & Population: US adults aged 50 to 64 and 65 to 79 years stratified by CKD risk status: no CKD (estimated glomerular filtration rate >= 60 mL/min/1.73 m(2) and urinary albumincreatinine ratio = 2,000 mg/g). Data sources were the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004, Centers for Disease Control and Prevention, and the Atherosclerosis Risk in Communities (ARIC) Study.Intervention(s): Vaccination compared to no vaccination.Outcomes: Incremental cost-effectiveness ratios based on US dollars per quality-adjusted life-year (QALY).Model, Perspective, & Timeframe: Markov model, US health sector perspective, and lifetime horizon.Results: The prevalence of pneumococcal vaccination in NHANES 1999 to 2004 was 56.6% (aged 65-79 years), 28.5% (aged 50-64 years with an indication), and 9.7% (aged 5064 years without an indication), with similar prevalences across CKD risk status. Pneumococcal vaccination was overall cost-effective (Limitations: Some model parameters were based on data from the general population. Analysis did not consider costs associated with kidney disease progression.Conclusions: Uptake of pneumococcal vaccination should be improved in general. Our results also suggest the cost-effectiveness of expanding its indication to younger adults with CKD less severe than kidney failure or nephrotic syndrome.

BackgroundAnemia at hemodialysis (HD) initiation is common. Correcting low hemoglobin (Hgb) before HD initiation may improve survival by avoiding potential harms of chronic anemia, high doses of erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron in the early HD period, and/or rapid Hgb rise.MethodsWe included 4604 incident HD patients from 21 countries in the Dialysis Outcomes and Practice Patterns Study Phases 4–5 (2009–15). Because low Hgb at HD start may reflect comorbidity or ESA hyporesponse, we restricted our analysis to the 80% of patients who achieved Hgb ≥10 g/dL 91–120 days after HD start (Month 4).ResultsAbout 53% of these patients had Hgb ConclusionsEven among patients with Hgb ≥10 g/dL 3 months later, anemia at HD initiation was common and associated with elevated mortality. A more proactive approach to anemia management in advanced chronic kidney disease (CKD) may thus improve survival on HD, though long-term prospective studies of non-dialysis CKD patients are needed.

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan.

Objective: Hypertension continues to be the leading risk factor for cardiovascular disease (CVD) and mortality worldwide. The purpose of the present study was to analyze the long-term trends of hypertension mortality in Turkey between 2000 and 2014 (for males and females). Methods: Analyses were based on hypertension mortality data obtained from the Turkish Statistical Institute death database. Age-standardized mortality rates were calculated using direct standardization for each calendar year. We estimated the age-adjusted linear trend for annual percent change and average annual percent change (AAPC) with the corresponding 95% confidence interval (CI) using the joinpoint regression analysis. Furthermore, we conducted an age-period-cohort analysis to quantify recent time trends and to evaluate the significance of cohort and period effects. Results: During the study period, a significant upward trend in the mortality of hypertension in Turkey is observed (AAPC=2.7%, 95% CI 1.9%-3.4%). The trend of hypertension mortality has increased in both males (AAPC=7.4%, 95% CI 3.0%-11.9%) and females (AAPC=8.7%, 95% CI 4.1%-13.5%). We found that the net drift rateswere 2.1% (95% CI 0.6%-3.6%) per year for males and 2.0% (95% CI 0.4%-3.7%) per year for females. According to longitudinal age curves, the mortality of hypertension increased with age in both males and females. The period and cohort effects are highly significant in both males and females. Conclusion: Hypertension is one of the leading causes of mortality causing CVD. Knowing the risk factors and preventive methods could help to reduce hypertension-related mortalities.

Asymmetric dimethylarginine (ADMA) is a methylated form of arginine and an endogenous nitric oxide synthase inhibitor. Renal function decline is associated with increase of plasma ADMA in chronic kidney disease populations. It is yet unknown how isolated renal function impairment affects ADMA homeostasis in healthy humans. Here, we measured plasma concentrations and urinary excretion of ADMA using GC-MS/MS in 130 living kidney donors before and at 1.6 (1.6-1.9) months after donation. We additionally analyzed 201 stable renal transplant recipients (RTR) that were included > 1 year after transplantation, as a model for kidney disease in the context of single kidney state. We measured true glomerular filtration rate (mGFR) using 125I-iothalamate. To study enzymatic metabolism of ADMA, we also measured L-citrulline as primary metabolite. Mean age was 52 ± 10 years in donors and 54 ± 12 years in RTR. Renal function was significantly reduced from pre- to post-donation (mGFR: 104 ± 17 vs. 66 ± 10 ml/min per 1.73 m2 BSA, - 36 ± 7%, P

Calcium supplements are broadly prescribed to treat osteoporosis either asmonotherapy or together with vitamin D to enhance calcium absorption. It is still unclear whether calcium supplementation significantly contributes to the reduction of bone fragility and fracture risk. Data suggest that supplementing post-menopausal women with high doses of calcium has a detrimental impact on cardiovascular morbidity and mortality. Chronic kidney disease (CKD) patients are prone to vascular calcification in part due to impaired phosphate excretion. Calcium-based phosphate binders further increase risk of vascular calcification progression. In both bone and vascular tissue, vitamin K-dependent processes play an important role in calcium homeostasis and it is tempting to speculate that vitamin K supplementation might protect from the potentially untoward effects of calcium supplementation. This review provides an update on current literature on calcium supplementation among post-menopausal women and CKD patients and discusses underlying molecular mechanisms of vascular calcification. We propose therapeutic strategies with vitamin K2 treatment to prevent or hold progression of vascular calcification as a consequence of excessive calcium intake.

Renal hyperfiltration, defined as an increased glomerular filtration rate above normal values, is associated with early phases of kidney disease in the setting of various conditions such as obesity and diabetes. Although it is recognized that glomerular hyperfiltration, that is, increased filtration per nephron unit (usually studied at low glomerular filtration levels and often referred to as single nephron hyperfiltration), is a risk factor for the progression of chronic kidney disease, the implications of having renal hyperfiltration for cardiovascular disease and mortality risk are incompletely understood. Recent evidence from diverse populations, including healthy individuals and patients with diabetes or established cardiovascular disease, suggests that renal hyperfiltration is associated with a higher risk of cardiovascular disease and all-cause mortality. In this review, we critically summarize the existing studies, discuss possible mechanisms, and describe the remaining gaps in our knowledge regarding the association of renal hyperfiltration with cardiovascular disease and mortality risk.

Patients with end-stage renal disease (ESRD) experience unique patterns in their lifetime, such as the start of dialysis and renal transplantation. In addition, there is also an intricate link between ESRD and biological time patterns. In terms of cyclic patterns, the circadian blood pressure (BP) rhythm can be flattened, contributing to allostatic load, whereas the circadian temperature rhythm is related to the decline in BP during hemodialysis (HD). Seasonal variations in BP and interdialytic-weight gain have been observed in ESRD patients in addition to a profound relative increase in mortality during the winter period. Moreover, nonphysiological treatment patters are imposed in HD patients, leading to an excess mortality at the end of the long interdialytic interval. Recently, new evidence has emerged on the prognostic impact of trajectories of common clinical and laboratory parameters such as BP, body temperature, and serum albumin, in addition to single point in time measurements. Backward analysis of changes in cardiovascular, nutritional, and inflammatory parameters before the occurrence as hospitalization or death has shown that changes may already occur within months to even 1-2 years before the event, possibly providing a window of opportunity for earlier interventions. Disturbances in physiological variability, such as in heart rate, characterized by a loss of fractal patterns, are associated with increased mortality. In addition, an increase in random variability in different parameters such as BP and sodium is also associated with adverse outcomes. Novel techniques, based on time-dependent analysis of variability and trends and interactions of multiple physiological and laboratory parameters, for which machine-learning -approaches may be necessary, are likely of help to the clinician in the future. However, upcoming research should also evaluate whether dynamic patterns observed in large epidemiological studies have relevance for the individual risk profile of the patient. (c) 2018 S. Karger AG, Basel

Patients with end-stage renal disease (ESRD) experience unique patterns in their lifetime, such as the start of dialysis and renal transplantation. In addition, there is also an intricate link between ESRD and biological time patterns. In terms of cyclic patterns, the circadian blood pressure (BP) rhythm can be flattened, contributing to allostatic load, whereas the circadian temperature rhythm is related to the decline in BP during hemodialysis (HD). Seasonal variations in BP and interdialytic-weight gain have been observed in ESRD patients in addition to a profound relative increase in mortality during the winter period. Moreover, nonphysiological treatment patters are imposed in HD patients, leading to an excess mortality at the end of the long interdialytic interval. Recently, new evidence has emerged on the prognostic impact of trajectories of common clinical and laboratory parameters such as BP, body temperature, and serum albumin, in addition to single point in time measurements. Backward analysis of changes in cardiovascular, nutritional, and inflammatory parameters before the occurrence as hospitalization or death has shown that changes may already occur within months to even 1-2 years before the event, possibly providing a window of opportunity for earlier interventions. Disturbances in physiological variability, such as in heart rate, characterized by a loss of fractal patterns, are associated with increased mortality. In addition, an increase in random variability in different parameters such as BP and sodium is also associated with adverse outcomes. Novel techniques, based on time-dependent analysis of variability and trends and interactions of multiple physiological and laboratory parameters, for which machine-learning -approaches may be necessary, are likely of help to the clinician in the future. However, upcoming research should also evaluate whether dynamic patterns observed in large epidemiological studies have relevance for the individual risk profile of the patient. (c) 2018 S. Karger AG, Basel

Hepatic uptake of triglyceride-rich remnant lipoproteins is mediated by the low-density lipoprotein receptor, a low-density lipoprotein receptor related protein and the heparan sulfate proteoglycan, syndecan-1. Heparan sulfate proteoglycan also mediates low-density lipoprotein receptor degradation by a regulator of cholesterol homeostasis, proprotein convertase subtilisin kexin type 9 (PCSK9), thereby hampering triglyceride-rich remnant lipoproteins uptake. In this study, we investigated the effects of proteinuria on PCSK9, hepatic heparan sulfate proteoglycan and plasma triglyceride-rich remnant lipoproteins. Adriamycin-injected rats developed proteinuria, elevated triglycerides and total cholesterol (all significantly increased). Proteinuria associated with triglycerides and total cholesterol and serum PCSK9 (all significant associations) without loss of the low-density lipoprotein receptor as evidenced by immunofluorescence staining and western blotting. In proteinuric rats, PCSK9 accumulated in sinusoids, whereas in control rats PCSK9 was localized in the cytoplasm of hepatocytes. Molecular profiling revealed that the heparan sulfate side chains of heparan sulfate proteoglycan to be hypersulfated in proteinuric rats. Competition assays revealed sulfation to be a major determinant for PCSK9 binding. PCSK9 partly colocalized with hypersulfated heparan sulfate in proteinuric rats, but not in control rats. Hence, proteinuria induces hypersulfated hepatic heparan sulfate proteoglycans, increasing their affinity to PCSK9. This might impair hepatic triglyceride-rich remnant lipoproteins uptake, causing proteinuria-associated dyslipidemia. Thus, our study reveals PCSK9/heparan sulfate may be a novel target to control dyslipidemia.

Dyskalemias are often seen in children with chronic kidney disease (CKD). While hyperkalemia is common, with an increasing prevalence as glomerular filtration rate declines, hypokalemia may also occur, particularly in children with renal tubular disorders and those on intensive dialysis regimens. Dietary assessment and adjustment of potassium intake is critically important in children with CKD as hyperkalemia can be life-threatening. Manipulation of dietary potassium can be challenging as it may affect the intake of other nutrients and reduce palatability. The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric renal dietitians and pediatric nephrologists, has developed clinical practice recommendations (CPRs) for the dietary management of potassium in children with CKD stages 2–5 and on dialysis (CKD2–5D). We describe the assessment of dietary potassium intake, requirements for potassium in healthy children, and the dietary management of hypo- and hyperkalemia in children with CKD2–5D. Common potassium containing foods are described and approaches to adjusting potassium intake that can be incorporated into everyday practice discussed. Given the poor quality of evidence available, a Delphi survey was conducted to seek consensus from international experts. Statements with a low grade or those that are opinion-based must be carefully considered and adapted to individual patient needs, based on the clinical judgment of the treating physician and dietitian. These CPRs will be regularly audited and updated by the PRNT. Supplementary Information The online version contains supplementary material available at 10.1007/s00467-021-04923-1.

Objectives: Phosphorus (P)-containing food additives pose a risk for chronic kidney disease (CKD) patients. We aimed to investigate the prevalence of P-containing additives in the Finnish food supply across different food categories to evaluate their burden in CKD, reflecting the situation in Europe. Methods: The dataset of 6,176 products was obtained in June-August 2019 from the foodie.fi website, which contains all foodstuffs sold in the grocery stores of the S Group (46% of the Finnish market share in 2019). The food category, full product name, type of P additive (inorganic, organic, and natural P-containing), and reporting methods (name or E number) of P additives were recorded. Duplicates and products lacking ingredient information were excluded. Results: The prevalence of P additives was 36% in the final sample (n 5 5,149). Among food categories, the prevalence varied from 4% in dairy-based snacks to 67% in meat products. Altogether 17 different P additives were observed. Inorganic P additives were the most common P additive type, present in 20% of foodstuffs. Natural P-containing additives were observed in 19% and organic P additives in 2% of foodstuffs. The most commonly used P additives were lecithin (E 322), pyrophosphate (E 450), and triphosphate (E 451). E number was used as a reporting method in 49% of foodstuffs, and full name in 44% of foodstuffs. Reporting by E number was particularly common in the products containing inorganic P. Conclusions: The use of P additives is common in the Finnish food supply, indicating the situation in Europe. The high prevalence of inorganic, that is, the most absorbable and potentially most harmful P additives in particular food groups, and their usual reporting only by E numbers can create challenges in CKD dietary counseling. (c) 2021 The Authors. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background: Patients on dialysis have a high burden of bone-related comorbidities, including fractures. We report a post hoc analysis of the prospective cohort study HDF, Hearts and Heights (3H) to determine the prevalence and risk factors for chronic kidney disease-related bone disease in children on hemodiafiltration (HDF) and conventional hemodialysis (HD). Methods: The baseline cross-sectional analysis included 144 children, of which 103 (61 HD, 42 HDF) completed 12-month follow-up. Circulating biomarkers of bone formation and resorption, inflammatory markers, fibroblast growth factor-23, and klotho were measured. Results: Inflammatory markers interleukin-6, tumor necrosis factor-alpha, and high-sensitivity C-reactive protein were lower in HDF than in HD cohorts at baseline and at 12 months (P < .001). Concentrations of bone formation (bone-specific alkaline phosphatase) and resorption (tartrate-resistant acid phosphatase 5b) markers were comparable between cohorts at baseline, but after 12-months the bone-specific alkaline phosphatase/tartrate-resistant acid phosphatase 5b ratio increased in HDF (P = .004) and was unchanged in HD (P = .44). On adjusted analysis, the bone-specific alkaline phosphatase/tartrate-resistant acid phosphatase 5b ratio was 2.66-fold lower (95% confidence interval, -3.91 to -1.41; P < .0001) in HD compared with HDF. Fibroblast growth factor-23 was comparable between groups at baseline (P = .52) but increased in HD (P < .0001) and remained unchanged in HDF (P = .34) at 12 months. Klotho levels were similar between groups and unchanged during follow-up. The fibroblast growth factor-23/klotho ratio was 3.86-fold higher (95% confidence interval, 2.15-6.93; P < .0001) after 12 months of HD compared with HDF. Conclusion: Children on HDF have an attenuated inflammatory profile, increased bone formation, and lower fibroblast growth factor-23/klotho ratios compared with those on HD. Long-term studies are required to determine the effects of an improved bone biomarker profile on fracture risk and cardiovascular health., Kidney Research UK; National Institute for Health Research, Career Development Fellowship; National Institute for Health Research; Fresenius Medical Care, The 3H study was sponsored by Kidney Research UK. Part sponsorship was obtained from Fresenius Medical Care, who approved the study protocol, but had no role in data collection, data analysis, or drafting the manuscript. RS is funded by a National Institute for Health Research, Career Development Fellowship for this research project. This publication presents independent research funded by the National Institute for Health Research. The views expressed are those of the author (s) and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health and So-cial Care. A part of the work took place in the Biomedical Research Centre at Great Ormond Street Hospital for Children National Health Service Foundation Trust and University College London.

Background The electronic health record (EHR) of the general physician (GP) is an important tool that can be used to assess and improve the quality of healthcare. However, there are some problems when (re) using the data gathered in the EHR for quality assessments. One problem is the lack of data completeness in the EHR. Audit and feedback (A&F) is a well-known quality intervention that can improve the quality of healthcare. We hypothesize that an automated A&F intervention can be adapted to improve the data completeness of the EHR of the GP, more specifically, the number of correctly registered diagnoses of type 2 diabetes and chronic kidney disease. Methods This study is a pragmatic cluster randomized controlled trial with an intervention at the level of GP practice. The intervention consists of an audit and extended electronically delivered feedback with multiple components that will be delivered 4 times electronically to general practices over 12 months. The data will be analyzed on an aggregated level (per GP practice). The primary outcome is the percentage of correctly registered diagnoses of type 2 diabetes. The key secondary outcome is the registration of chronic kidney disease. Exploratory secondary outcomes are the registration of heart failure, biometric data and lifestyle habits, and the evolution of 4 different EHR-extractable quality indicators. Discussion This cluster randomized controlled trial intends to primarily improve the registration of type 2 diabetes in the EHR of the GP and to secondarily improve the registration of chronic kidney disease. In addition, the registration of heart failure, lifestyle parameters, and biometric data in the EHR of the GP are explored together with 4 EHR-extractable quality indicators. By doing so, this study aims to improve the data completeness of the EHR, paving the way for future quality assessments. Trial registration ClinicalTrials.gov NCT04388228. Registered on May 14, 2020.

Patient‐reported outcome measures (PROMs) are increasingly being used in nephrology care. However, in contrast to well‐known clinical measures such as blood pressure, health‐care professionals are less familiar with PROMs and the interpretation of PROM scores is therefore perceived as challenging. In this paper, we provide insight into the interpretation of PROM scores by introducing the different types and characteristics of PROMs, and the most relevant concepts for the interpretation of PROM scores. Concepts such as minimal detectable change, minimal important change and response shift are explained and illustrated with examples from nephrology care., SUMMARY AT A GLANCE The review provides insight into the interpretation of PROM scores by introducing the different types and characteristics of PROMs, and the most relevant concepts for the interpretation of PROM scores, ie minimal detectable change, minimal important change and response shift.

Background: The Dietary Approach to Stop Hypertension (DASH) and potassium supplementation have been shown to reduce the risk of death with a functioning graft (DWFG) and renal graft failure in renal transplant recipients (RTR). Unfortunately, a key problem for patients is the adherence to these diets. The aim of this study is to evaluate the cost-effectiveness and budget impact of higher adherence to either the DASH or potassium supplementation. Methods: A Markov model was used to simulate the life course of 1000 RTR in the Netherlands. A societal perspective with a lifetime time horizon was used. The potential effect of improvement of dietary adherence was modelled in different scenarios. The primary outcomes are the incremental cost-effectiveness ratio (ICER) and the budget impact. Results: In the base case, improved adherence to the DASH diet saved 27,934,786 and gained 1880 quality-adjusted life years (QALYs). Improved adherence to potassium supplementation saved €1,217,803 and gained 2901 QALYs. Both resulted in dominant ICERs. The budget impact over a five-year period for the entire Dutch RTR population was €8,144,693. Conclusion: Improving dietary adherence in RTR is likely to be cost-saving and highly likely to be cost-effective compared to the current standard of care in the Netherlands.

Background The number of elderly patients on renal replacement therapy (RRT) is increasing. The survival and quality of life of these patients may be lower if they have multiple comorbidities at the onset of RRT. The aim of this study was to explore whether the effect of comorbidities on survival is similar in elderly RRT patients compared with younger ones. Methods Included were 9333 patients ≥80 years of age and 48 352 patients 20–79 years of age starting RRT between 2010 and 2015 from 15 national or regional registries submitting data to the European Renal Association–European Dialysis and Transplantation Association Registry. Patients were followed until death or the end of 2016. Survival was assessed by Kaplan–Meier curves and the relative risk of death associated with comorbidities was assessed by Cox regression analysis. Results Patients ≥80 years of age had a greater comorbidity burden than younger patients. However, relative risks of death associated with all studied comorbidities (diabetes, ischaemic heart disease, chronic heart failure, cerebrovascular disease, peripheral vascular disease and malignancy) were significantly lower in elderly patients compared with younger patients. Also, the increase in absolute mortality rates associated with an increasing number of comorbidities was smaller in elderly patients. Conclusions Comorbidities are common in elderly patients who enter RRT, but the risk of death associated with comorbidities is less than in younger patients. This should be taken into account when assessing the prognosis of elderly RRT patients.

Background. Uraemic cardiac remodelling is associated with vitamin D and Klotho deficiency, elevated fibroblast growth factor 23 (FGF23) and activation of the renin-angiotensin system (RAS). The cardioprotective properties of active vitamin D analogues in this setting are unclear. Methods. In rats with 5/6 nephrectomy (5/6Nx) treated with calcitriol, the cardiac phenotype and local RAS activation were investigated compared with controls. A nested case-control study was performed within the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study, including children with chronic kidney disease (CKD) Stages 3-5 [estimated glomerular filtration rate (eGFR) 25 mL/min/1.73 m(2)] treated with and without active vitamin D. Echocardiograms, plasma FGF23 and soluble Klotho (sKlotho) were assessed at baseline and after 9 months. Results. In rats with 5/6Nx, left ventricular (LV) hypertrophy, LV fibrosis and upregulated cardiac RAS were dose-dependently attenuated by calcitriol. Calcitriol further stimulated FGF23 synthesis in bone but not in the heart, and normalized suppressed renal Klotho expression. In the 4C study cohort, treatment over a mean period of 9 months with active vitamin D was associated with increased FGF23 and phosphate and decreased sKlotho and eGFR compared with vitamin D naive controls, whereas LV mass index did not differ between groups. Conclusions. Active vitamin D ameliorates cardiac remodelling and normalizes renal Klotho expression in 5/6Nx rats but does not improve the cardiac phenotype in children with CKD Stages 3-5. This discrepancy may be due to further enhancement of circulating FGF23 and faster progression of CKD associated with reduced sKlotho and higher serum phosphate in vitamin D-treated patients., European Society for Paediatric Nephrology [ESPN2.2018]; University Internal Research Funding Hochschulinterne Leistungsforderung from the Hannover Medical School [79373041]; European Renal Association -European Dialysis and Transplant Association (ERA-EDTA) Research Programme; KfH Foundation for Preventive Medicine; German Federal Ministry of Education and Research [01EOO802], This work was supported by the European Society for Paediatric Nephrology to M.L.-N. (reference number ESPN2.2018), University Internal Research Funding Hochschulinterne Leistungsforderung from the Hannover Medical School to A.S. (reference number 79373041), the European Renal Association -European Dialysis and Transplant Association (ERA-EDTA) Research Programme to F.S., the KfH Foundation for Preventive Medicine to F.S. and the German Federal Ministry of Education and Research to A.M. (reference number 01EOO802).

BACKGROUND: Transplant vasculopathy (TV) is a major contributing factor to chronic graft failure in renal transplant recipients (RTR). TV lesions resemble atherosclerosis in several ways, and it is plausible to believe that some risk factors influence both atherosclerotic plaque formation and formation of TV. OBJECTIVE: The objective of this prospective longitudinal study was to determine if dyslipidemia reflected by the triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio is prospectively associated with death censored chronic graft failure in RTR.METHOD: 454 prospectively included RTR with a functioning graft for at least one year, were followed for a median of 7 years. RTR were matched based on propensity scores to avoid potential confounding and subsequently the association of the TG/HDL-C ratio with the endpoint chronic graft failure, defined as return to dialysis or re-transplantation, was investigated.RESULTS: Linear regression analysis showed that concentration of insulin, male gender, BMI and number of antihypertensives predict the TG/HDL-C ratio. Cox regression showed that the TG/HDL-C ratio is associated with chronic graft failure (HR = 1.43, 95%CI = 1.12-1.84, p = 0.005) in competing risk analysis for mortality. Interaction testing indicated that the relationship of the TG/HDL-C ratio with graft failure is stronger in subjects with a higher insulin concentration.CONCLUSION: Our results demonstrate that the TG/HDL-C ratio has the potential to act as a predictive clinical biomarker. Furthermore, there is a need for closer attention to lipid management in RTR in clinical practice with a focus on triglyceride metabolism. (c) 2021 National Lipid Association. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Summary Epigenetic modifications (e.g. DNA methylation) in NAFLD and their contribution to disease progression and extrahepatic complications are poorly explored. Here, we use an integrated epigenome and transcriptome analysis of mouse NAFLD hepatocytes and identify alterations in glyoxylate metabolism, a pathway relevant in kidney damage via oxalate release—a harmful waste product and kidney stone-promoting factor. Downregulation and hypermethylation of alanine-glyoxylate aminotransferase (Agxt), which detoxifies glyoxylate, preventing excessive oxalate accumulation, is accompanied by increased oxalate formation after metabolism of the precursor hydroxyproline. Viral-mediated Agxt transfer or inhibiting hydroxyproline catabolism rescues excessive oxalate release. In human steatotic hepatocytes, AGXT is also downregulated and hypermethylated, and in NAFLD adolescents, steatosis severity correlates with urinary oxalate excretion. Thus, this work identifies a reduced capacity of the steatotic liver to detoxify glyoxylate, triggering elevated oxalate, and provides a mechanistic explanation for the increased risk of kidney stones and chronic kidney disease in NAFLD patients.

Background The kidneys have many essential metabolic functions, and metabolic disturbances during decreased renal function have not been studied extensively. Objectives To identify metabolic changes in blood samples with increased serum creatinine concentration, indicating decreased glomerular filtration. Animals Clinical samples analyzed using a nuclear magnetic resonance (NMR) based metabolomics platform. The case group consisted of 23 samples with serum creatinine concentration >125 mu mol/L, and the control group of 873 samples with serum creatinine concentration within the reference interval. Methods Biomarker association with increased serum creatinine concentration was evaluated utilizing 3 statistical approaches: Wilcoxon rank-sum test, logistic regression analysis (false discovery rate (FDR)-corrected P-values), and random forest classification. Medians of the biomarkers were compared to reference intervals. A heatmap and box plots were used to represent the differences. Results All 3 statistical approaches identified similar analytes associated with increased serum creatinine concentrations. The percentages of citrate, tyrosine, branched-chain amino acids, valine, leucine, albumin, linoleic acid and the ratio of phenylalanine to tyrosine differed significantly using all statistical approaches, acetate differed using the Wilcoxon test and random forest, docosapentaenoic acid percentage only using logistic regression (P

Purpose: During the past 20 years, a plethora of research reports has been published showing a statistical association between poor oral health and cardiovascular diseases. The aim of this narrative review was to focus on associations between oral infections and non-atherosclerosis-related systemic diseases. Materials and Methods: An open literature search and evaluation of articles were conducted on Medline and Cochrane databases with the key words 'oral infection', 'periodontitis', 'pneumonia', 'osteoarthritis', 'rheumatic diseases', 'inflammatory bowel disease', 'kidney disease', 'liver diseases', 'metabolic syndrome', 'diabetes', 'cancer', 'Alzheimer's disease'. Cardiovascular diseases were excluded from the analysis. Results: The scarcity of controlled studies did not allow conducting a systematic review with meta-analysis on the topics, but dental infections have been shown be associated with several general diseases also beyond the atherosclerosis paradigm. However, there is no causal evidence of the role of dental infections in this regard. Poor oral health has nevertheless often been observed to be associated with worsening of the diseases and may also affect treatments Conclusions: Maintaining good oral health is imperative regarding many diseases, and its importance in the daily life of any patient group cannot be over emphasised.

Hyperkalemia is a common electrolyte abnormality in heart failure (HF) that can cause potentially life-threatening cardiac arrhythmias and sudden cardiac death. HF patients with diabetes, chronic kidney disease and older age are at higher risk of hyperkalemia. Moreover, hyperkalemia is also often associated with the use of renin-angiotensin-aldosterone system inhibitors (RAASi) including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists and sacubitril-valsartan. In clinical practice, the occurrence of hyperkalemia is a major concern among the clinicians and often limits RAASi use and/ or lead to dose reduction or discontinuation, thereby reducing their potential benefits for HF. Furthermore, recurrent hyperkalemia is frequent in the long-term and is associated with an increase in hyperkalemia-related hospitalizations. Therefore, management of hyperkalemia has a special importance in HF patients. However, treatment options in chronic management are currently limited. Dietary restriction of potassium is usually ineffective with variable adherence. Sodium polystyrene sulfonate is commonly used, but its effectiveness is uncertain and reported to be associated with intestinal toxicity. New therapeutic options such as potassium binders have been suggested as potentially beneficial agents in the management of hyperkalemia. This document discusses prevalence, predictors and management of hyperkalemia in HF, emphasizing the importance of careful patient selection for medical treatment, uptitration of the doses of RAASi, regular surveillance of potassium and treatment options of hyperkalemia.

Background Chronic kidney disease (CKD) shows different clinical features in Types1 (T1D) and 2 diabetes (T2D). Metabolomics have recently provided useful contribution to the identification of biomarkers of CKD progression in either form of the disease. However, no studies have so far compared plasma metabolomics between T1D and T2D in order to identify differential signatures of progression of estimated glomerular filtration rate (eGFR) decline. Methods We used two large cohorts of T1D (from Finland) and T2D (from Italy) patients followed up to 7 and 3 years, respectively. In both groups, progression was defined as the top quartile of yearly decline in eGFR. Pooled data from the two groups were analysed by univariate and bivariate random forest (RF), and confirmed by bivariate partial least squares (PLS) analysis, the response variables being type of diabetes and eGFR progression. Results In progressors, yearly eGFR loss was significantly larger in T2D [−5.3 (3.0), median (interquartile range)mL/min/1.73 m2/year] than T1D [−3.7 (3.1) mL/min/1.73 m2/year ; P = 0.018]. Out of several hundreds, bivariate RF extracted 22 metabolites associated with diabetes type (all higher in T1D than T2D except for 5-methylthioadenosine, pyruvate and β-hydroxypyruvate) and 13 molecules associated with eGFR progression (all higher in progressors than non-progressors except for sphyngomyelin). Three of the selected metabolites (histidylphenylalanine, leucylphenylalanine, tryptophylasparagine) showed a significant interaction between disease type and progression. Only eight metabolites were common to both bivariate RF and PLS. Conclusions Identification of metabolomic signatures of CKD progression is partially dependent on the statistical model. Dual analysis identified molecules specifically associated with progressive renal impairment in both T1D and T2D.

Advanced age, diabetes, and chronic kidney disease not only increase the risk for ischaemic events in chronic coronary syndromes (CCS) but also confer a high bleeding risk during antiplatelet therapy. These special populations may warrant modification of therapy, especially among Asians, who have displayed characteristics that are clinically distinct from Western patients. Previous guidance has been provided regarding the classification of high-risk CCS and the use of newer-generation P2Y(12) inhibitors (i.e. ticagrelor and prasugrel) after acute coronary syndromes (ACS) in Asia. The authors summarise evidence on the use of these P2Y(12) inhibitors during the transition from ACS to CCS and among special populations. Specifically, they present recommendations on the roles of standard dual antiplatelet therapy, shortened dual antiplatelet therapy and single antiplatelet therapy among patients with coronary artery disease, who are either transitioning from ACS to CCS; elderly; or with chronic kidney disease, diabetes, multivessel coronary artery disease and bleeding events during therapy. Asian Pacific Society of Cardiology (APSC); Abbott VascularAbbott Laboratories; AmgenAmgen; AstraZenecaAstraZeneca; BayerBayer AG; Roche Diagnostics; Daiichi SankyoDaiichi Sankyo Company Limited This work was funded through the Asian Pacific Society of Cardiology (APSC) with unrestricted educational grants from Abbott Vascular, Amgen, AstraZeneca, Bayer and Roche Diagnostics. JWCT reports honoraria from AstraZeneca, Bayer, Amgen, Medtronic, Abbott Vascular, Biosensors, Alvimedica, Boehringer Ingelheim and Pfizer; research and educational grants from Medtronic, Biosensors, Biotronik, Philips, Amgen, AstraZeneca, Roche, Otsuka, Terumo and Abbott Vascular; and consulting fees from Elixir and CSL Behring; and is on the European Cardiology Review editorial board; this did not influence peer review. JA reports honoraria from AstraZeneca, Daiichi Sankyo, Bayer and Sanofi; and grants/grants pending from Daiichi Sankyo. DPC reports consulting fees from APSC; support for travel to meetings for the study or otherwise from APSC; grants/grants pending from Roche Diagnostics; payment for development of educational presentations including service on speakers' bureaus from AstraZeneca. JD reports honoraria from Bayer and Pfizer. CTC reports honoraria from Abbott Vascular, AstraZeneca, Boston Scientific, Biotronik, Biosensors, Medtronic; consulting and ad boards from AstraZeneca, Boston Scientific; and research and educational support from AstraZeneca, Eli Lilly. AH reports consulting fee or honorarium from AstraZeneca. MC reports consulting fee or honorarium from AstraZeneca. AYYF reports honoraria and educational support from AstraZeneca. BK reports consulting fee or honorarium from AstraZeneca, Abbott, IE Menarini, Daiichi Sankyo, Sanovel and ARIS. UB reports honoraria from Amgen and AstraZeneca. All other authors have no conflicts of interest to declare.

Chronic kidney disease (CKD) is a pathology that affects 7 to 10% of the French population and involves heavy treatment in its most advanced stages. The most common treatment available for severe forms of CKD is dialysis. It is now clear that physical activity is essential in these patients in order to improve negative symptoms such as fatigue, sleep disorders or muscle dysfunction. However, symptomatic fatigue and dialysis induce a high rate of inactivity in these patients who are forced to perform dialysis sessions of 3 to 4 hours, at a rate of 3 times per week. As a result, these patients are inactive and deconditioned, leading to a decrease in quality of life and increasing their mortality. The objective of this project is to study another way of practising physical activity that seems relevant to the constraints stated in these patients: intradialytic practice. This involves performing exercises during dialysis connection. This project therefore consists of proposing one session per week of resistance exercise during the dialysis session for one year. The scientific literature was mainly concerned with the effects of intradialytic aerobic exercise, we will focus here on the effects of resistance training on muscle strength. The variables tested will be functional strength, metabolic profile and quality of life. At this stage of the project, the T1 middle project evaluations have not yet taken place. This work is therefore the presentation of the project.; L’insuffisance rénale chronique (IRC) est une pathologie qui touche 7 à 10% de la population française et qui implique un traitement lourd dans ses stades les plus évolués. Parmi les traitements existants pour les formes graves d’IRC, le plus répandu est la dialyse. Il est aujourd’hui évident qu’une prise en charge en activité physique est indispensable chez ces patients afin d’améliorer les symptômes négatifs rencontrés tels que la fatigue, les troubles du sommeil ou encore la dysfonction musculaire. Cependant, la fatigue symptomatique ainsi que la prise en charge en dialyse induisent un fort taux de sédentarité chez ces patients qui sont obligés de réaliser leurs séances de 3 à 4h, et cela à raison de 3 fois par semaine. De ce fait, ces patients sont inactifs et déconditionnés, induisant une baisse de la qualité de vie et augmentant leur mortalité. Ce projet a pour objectif d’étudier une autre manière de pratiquer une activité physique qui semble pertinente face aux contraintes énoncées chez ces patients : la pratique intra-dialytique. Celle-ci consiste à réaliser des exercices lors du branchement en dialyse. Ce projet consiste donc à proposer une séance par semaine d’exercice en résistance pendant la séance de dialyse et cela pendant un an. La littérature scientifique s’étant principalement intéressée aux effets de l’exercice aérobie intra-dialytique, nous nous intéresserons ici aux effets d’un entraînement en résistance sur la force musculaire. Les variables testées seront la force fonctionnelle, le profil métabolique par impédancemétrie ainsi que la qualité de vie. À ce stade du projet, les évaluations intermédiaires T1 n’ont pas encore eu lieu. Ce travail est donc la présentation du projet.

Sudden cardiac death (SCD) represents a major cause of death in end-stage kidney disease (ESKD). The precise estimate of its incidence is difficult to establish because studies on the incidence of SCD in ESKD are often combined with those related to sudden cardiac arrest (SCA) occurring during a haemodialysis (HD) session. The aim of the European Dialysis Working Group of ERA-EDTA was to critically review the current literature examining the causes of extradialysis SCD and intradialysis SCA in ESKD patients and potential management strategies to reduce the incidence of such events. Extradialysis SCD and intradialysis SCA represent different clinical situations and should be kept distinct. Regarding the problem, numerically less relevant, of patients affected by intradialysis SCA, some modifiable risk factors have been identified, such as a low concentration of potassium and calcium in the dialysate, and some advantages linked to the presence of automated external defibrillators in dialysis units have been documented. The problem of extra-dialysis SCD is more complex. A reduced left ventricular ejection fraction associated with SCD is present only in a minority of cases occurring in HD patients. This is the proof that SCD occurring in ESKD has different characteristics compared with SCD occurring in patients with ischaemic heart disease and/or heart failure and not affected by ESKD. Recent evidence suggests that the fatal arrhythmia in this population may be due more frequently to bradyarrhythmias than to tachyarrhythmias. This fact may partly explain why several studies could not demonstrate an advantage of implantable cardioverter defibrillators in preventing SCD in ESKD patients. Electrolyte imbalances, frequently present in HD patients, could explain part of the arrhythmic phenomena, as suggested by the relationship between SCD and timing of the HD session. However, the high incidence of SCD in patients on peritoneal dialysis suggests that other risk factors due to cardiac comorbidities and uraemia per se may contribute to sudden mortality in ESKD patients.

Background Dialysis patients experience a high burden of physical and emotional symptoms directly affecting their sleep and quality of life. In this study, objective and subjective measurements to quantify sleep were performed, compared with those of healthy controls, and associated with burden of comorbidity and uraemic toxicity. Methods A total of 64 dialysis patients were included—10 peritoneal dialysis, 42 in-centre daytime haemodialysis (HD) and 12 in-centre nocturnal HD patients—as well as one-to-one age- and gender-matched healthy controls. Assumed and actual sleep time, sleep efficiency and fragmentation index were measured by actigraphy for at least two consecutive nights. Patients and controls also completed Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI) questionnaires. The patients’ blood was sampled to determine concentrations of a representative series of uraemic toxins and the Davies–Stoke comorbidity index was derived from medical records. Results Apart from the assumed sleep time, all objectively and subjectively measured sleep parameters were worse in the dialysis group compared with the healthy controls. No differences were seen in any of the measured sleep parameters among the different dialysis groups. None of the objectively measured sleep parameters were associated with ISI or PSQI scores in dialysis patients, while sleep times were related to the subjective scores in the healthy cohort. Objectively assessed sleep parameters were associated to neither the uraemic toxicity load nor the Davies–Stoke score. Conclusions Independent of the modality, dialysis patients have sleep quality much worse than age- and gender-matched healthy controls. The objectively measured sleep parameters could not be associated to the subjective score, uraemic toxicity or comorbidity score, highlighting the need for objective measurements of sleep and clinical guidelines to aid patient management.

The number of lung transplantations has been rising constantly. However, use of this therapeutic resource is limited by several issues that are difficult to resolve, such as chronic graft rejection and complications secondary to immunosuppression.

OBJECTIVE To investigate the relationship between depression and diabetic nephropathy progression in type 1 diabetes. RESEARCH DESIGN AND METHODS Data from 3,730 participants without end-stage renal disease (ESRD) at baseline, participating in the Finnish Diabetic Nephropathy Study, were included. Depression was assessed in three ways. Depression diagnoses were obtained from the Finnish Care Register for Health Care. Antidepressant agent purchase data were obtained from the Drug Prescription Register. Symptoms of depression were assessed using the Beck Depression Inventory (BDI). Based on their urinary albumin excretion rate (AER), participants were classified as those with normal AER, microalbuminuria, and macroalbuminuria. Progression from normal AER to microalbuminuria, macroalbuminuria, or ESRD; from microalbuminuria to macroalbuminuria or ESRD; or from macroalbuminuria to ESRD, during the follow-up period, was investigated. RESULTS Over a mean follow-up period of 9.6 years, renal status deteriorated in 18.4% of the participants. Diagnosed depression and antidepressant purchases before baseline were associated with 53% and 32% increased risk of diabetic nephropathy progression, respectively. Diagnosed depression assessed during follow-up remained associated with increased risk of disease progression (32%). BDI-derived symptoms of depression showed no association with the progression, but the total number of antidepressant purchases modestly reduced the risk (hazard ratio 0.989 [95% CI 0.982–0.997]), P = 0.008). With the sample divided based on median age, the observations followed those seen in the whole group. However, symptoms of depression additionally predicted progression in those age ≤36.5 years. CONCLUSIONS Diagnosed depression and antidepressant purchases are associated with the progression of diabetic nephropathy in type 1 diabetes. Whether successful treatment of depression reduces the risk needs to be determined.

The worldwide landscape of an ageing population and age-related disease brings with it huge socio-economic and public healthcare concerns across nations. Correspondingly, monumental human and financial resources have been invested in biomedical research, with a mission to decode the mechanisms of ageing and how these contribute to age-related disease. Multiple hallmarks of ageing have been identified that are common across taxa, highlighting their fundamental importance. These include dysregulated mitochondrial metabolism and telomeres biology, epigenetic modifications, cell–matrix interactions, proteostasis, dysregulated nutrient sensing, stem cell exhaustion, inflammageing and immuno-senescence. While our understanding of the molecular basis of ageing is improving, it remains a complex and multifactorial process that remains to be fully understood. A key aspect of the shortfall in our understanding of the ageing process lies in translating data from standard animal models to humans. Consequently, we suggest that a ‘biomimetic’ and comparative approach, integrating knowledge from species in the wild, as opposed to inbred genetically homogenous laboratory animals, can provide powerful insights into human ageing processes. Here we discuss some particularities and comparative patterns among several species from the animal kingdom, endowed with longevity or short lifespans and unique metabolic profiles that could be potentially exploited to the understanding of ageing and age-related diseases. Based upon lessons from nature, we also highlight several avenues for renewed focus in the pathophysiology of ageing and age-related disease (i.e. diet-microbiome-health axis, oxidative protein damage, adaptive homoeostasis and planetary health). We propose that a biomimetic alliance with collaborative research from different disciplines can improve our understanding of ageing and age-related diseases with long-term sustainable utility.

Background: Obesity is one of the most popular topic in the field of research. In order to defeat this highly widespread disease, the mechanism of fat accumulation at the molecular level and its elimination are crucial. The use of boron has been showing promising results during the recent years. Methods: In this study, anti-obesity potential of Sodium Pentaborate Pentahydrate (SPP) used as a dietary supplement on BALB/c mice fed with a high-fat diet was evaluated. Mice were divided into four groups with different diets, consisting of a normal diet, a high-fat diet (HFD) (containing 60 % fat), a HFD-supplemented with 0.5 mg/g body weight (BW) of SPP and a HFD-supplemented with 1.5 mg/g body weight (BW) of SPP. The animals were then observed for 10 weeks and physically monitored, and were sacrificed at the end of the experiment for physical and physicochemical evaluation. Results: According to the physical parameters measured -body weight, food and water intake ratios-, the results indicate that SPP decreased weight gain in a dose dependent manner. Measurement of the hormone levels in the blood and fat accumulation in organs of mice also supported the anti-obesity effects of SPP. Expressions of adipogenesis related genes were also negatively regulated by SPP administration in white adipose tissue (WAT) tissue. Conclusion: These findings promise a treatment approach and drug development that can be used against obesity when SPP is used in the right doses. As a future aspect, clinical studies with SPP will reveal the effect of boron derivatives on obesity. Yeditepe UniversityYeditepe University We would like to acknowledge the Yeditepe University for supporting this work. The authors thank all the personnel of the YUDETAM for mouse care.

Patients treated with hemodialysis (HD) repeatedly undergo intradialytic low arterial oxygen saturation and low central venous oxygen saturation, reflecting an imbalance between upper body systemic oxygen supply and demand, which are associated with increased mortality. Abnormalities along the entire oxygen cascade, with impaired diffusive and convective oxygen transport, contribute to the reduced tissue oxygen supply. HD treatment impairs pulmonary gas exchange and reduces ventilatory drive, whereas ultrafiltration can reduce tissue perfusion due to a decline in cardiac output. In addition to these factors, capillary rarefaction and reduced mitochondrial efficacy can further affect the balance between cellular oxygen supply and demand. Whereas it has been convincingly demonstrated that a reduced perfusion of heart and brain during HD contributes to organ damage, the significance of systemic hypoxia remains uncertain, although it may contribute to oxidative stress, systemic inflammation, and accelerated senescence. These abnormalities along the oxygen cascade of patients treated with HD appear to be diametrically opposite to the situation in Tibetan highlanders and Sherpa, whose physiology adapted to the inescapable hypobaric hypoxia of their living environment over many generations. Their adaptation includes pulmonary, vascular, and metabolic alterations with enhanced capillary density, nitric oxide production, and mitochondrial efficacy without oxidative stress. Improving the tissue oxygen supply in patients treated with HD depends primarily on preventing hemodynamic instability by increasing dialysis time/frequency or prescribing cool dialysis. Whether dietary or pharmacological interventions, such as the administration of L-arginine, fermented food, nitrate, nuclear factor erythroid 2-related factor 2 agonists, or prolyl hydroxylase 2 inhibitors, improve clinical outcome in patients treated with HD warrants future research.

Prevalence of type 1 diabetes mellitus (T1DM) is globally continuously increasing. T1DM is accompanied by a high risk of developing cardiovascular and renal comorbidities and is one of the leading causes of end-stage renal disease (ESRD). However, current therapeutic approaches for chronic and/or diabetic kidney disease (CKD/DKD) existed for a long time, and offer room for improvement, particularly in T1DM. In 2019, the European Medicines Agency (EMA) approved a first sodium/glucose co-transporter 2 inhibitor (SGLT-2i) and a first dual SGLT-1/-2i to improve glycaemic control, as an adjunctive treatment to insulin in persons with T1DM and a body mass index >27 kg/m(2). Of note, SGLT-1/2is and SGLT-2is are not approved by the Food and Drug Administration (FDA) as an adjunct treatment in T1DM, nor approved for the treatment of CKD or DKD by EMA and FDA. SGLT is have shown to mediate different renoprotective effects in type 2 diabetes mellitus in corresponding cardiovascular and renal outcome trials. First efficacy trials offer insights into potential positive effects on renal function and kidney disease of SGLTis in T1DM. This review summarizes and discusses latest available data on SGLT inhibition and provides an update on the nephrological perspective on SGLTis, specifically in T1DM. (c) 2020 Published by Elsevier B.V.

Cardiovascular calcification is highly prevalent and associated with increased morbidity in chronic kidney disease (CKD). This review examines the impact of uremic toxins, which accumulate in CKD due to a failing kidney function, on cardiovascular calcification. A systematic literature search identified 41 uremic toxins that have been studied in relation to cardiovascular calcification. For 29 substances, a potentially causal role in cardiovascular calcification was addressed in in vitro or animal studies. A calcification-inducing effect was revealed for 16 substances, whereas for three uremic toxins, namely the guanidino compounds asymmetric and symmetric dimethylarginine, as well as guanidinosuccinic acid, a calcification inhibitory effect was identified in vitro. At a mechanistic level, effects of uremic toxins on calcification could be linked to the induction of inflammation or oxidative stress, smooth muscle cell osteogenic transdifferentiation and/or apoptosis, or alkaline phosphatase activity. For all middle molecular weight and protein-bound uremic toxins that were found to affect cardiovascular calcification, an increasing effect on calcification was revealed, supporting the need to focus on an increased removal efficiency of these uremic toxin classes in dialysis. In conclusion, of all uremic toxins studied with respect to calcification regulatory effects to date, more uremic toxins promote rather than reduce cardiovascular calcification processes. Additionally, it highlights that only a relatively small part of uremic toxins has been screened for effects on calcification, supporting further investigation of uremic toxins, as well as of associated post-translational modifications, on cardiovascular calcification processes.

International audience; Background: Chronic kidney disease (CKD) is a renal disorder characterized by the accumulation of uremic toxins with limited strategies to reduce their concentrations. A large amount of data supports the pivotal role of intestinal microbiota in CKD complications and as a major source of uremic toxins production. Here, we explored whether fecal microbiota transplantation (FMT) could be attenuated in metabolic complication and uremic toxin accumulation in mice with CKD. Methods: Kidney failure was chemically induced by a diet containing 0.25% (w/w) of adenine for four weeks. Mice were randomized into three groups: control, CKD and CKD + FMT groups. After four weeks, CKD mice underwent fecal microbiota transplantation (FMT) from healthy mice or phosphate buffered saline as control. The gut microbiota structure, uremic toxins plasmatic concentrations, and metabolic profiles were explored three weeks after transplantation. Results: Associated with the increase of alpha diversity, we observed a noticeable improvement of gut microbiota disturbance, after FMT treatment. FMT further decreased p-cresyl sulfate accumulation and improved glucose tolerance. There was no change in kidney function. Conclusions: These data indicate that FMT limited the accumulation of uremic toxins issued from intestinal cresol pathway by a beneficial effect on gut microbiota diversity. Further studies are needed to investigate the FMT efficiency, the timing and feces amount for the transplantation before, to become a therapeutic option in CKD patients.

Visceral fat is associated with cardiovascular and kidney disease. However, the relationship between body composition and anthropometric measures in type 1 diabetes is unknown. Using z-statistics, we ranked the ability of body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), waist-height ratio (WHtR) and a body shape index (ABSI) to capture measures of body composition from 603 Dual-energy-X-Ray-Absorptiometry scans of adults with type 1 diabetes. Albuminuria was defined as urinary albumin excretion rate of at least 30 mg/24 h. Women with albuminuria had higher visceral fat mass % (VFM%) (0.9 vs. 0.5%, p = 0.0017) and lower appendicular lean mass % (AppLM%) (25.4 vs 26.4%, p = 0.03) than those without. Men with albuminuria had higher VFM% (1.5 vs. 1.0%, p = 0.0013) and lower AppLM% (30.0 vs 32.3, p

The cardiorenal syndrome relates to the detrimental interplay between the vascular system and the kidney. The uremic milieu induced by reduced kidney function alters the phenotype of vascular smooth muscle cells (VSMC) and promotes vascular calcification, a condition which is strongly linked to cardiovascular morbidity and mortality. Biological mechanisms involved include generation of reactive oxygen species, inflammation and accelerated senescence. A better understanding of the vasotoxic effects of uremic retention molecules may reveal novel avenues to reduce vascular calcification in CKD. The present review aims to present a state of the art on the role of uremic toxins in pathogenesis of vascular calcification. Evidence, so far, is fragmentary and limited with only a few uremic toxins being investigated, often by a single group of investigators. Experimental heterogeneity furthermore hampers comparison. There is a clear need for a concerted action harmonizing and standardizing experimental protocols and combining efforts of basic and clinical researchers to solve the complex puzzle of uremic vascular calcification. ispartof: TOXINS vol:12 issue:10 ispartof: location:Switzerland status: published

The cardiorenal syndrome relates to the detrimental interplay between the vascular system and the kidney. The uremic milieu induced by reduced kidney function alters the phenotype of vascular smooth muscle cells (VSMC) and promotes vascular calcification, a condition which is strongly linked to cardiovascular morbidity and mortality. Biological mechanisms involved include generation of reactive oxygen species, inflammation and accelerated senescence. A better understanding of the vasotoxic effects of uremic retention molecules may reveal novel avenues to reduce vascular calcification in CKD. The present review aims to present a state of the art on the role of uremic toxins in pathogenesis of vascular calcification. Evidence, so far, is fragmentary and limited with only a few uremic toxins being investigated, often by a single group of investigators. Experimental heterogeneity furthermore hampers comparison. There is a clear need for a concerted action harmonizing and standardizing experimental protocols and combining efforts of basic and clinical researchers to solve the complex puzzle of uremic vascular calcification.

BACKGROUND: Dyslipidemia is an important risk factor in CKD. The liver clears triglyceride-rich lipoproteins (TRL) via LDL receptor (LDLR), LDLR-related protein-1 (LRP-1), and heparan sulfate proteoglycans (HSPGs), mostly syndecan-1. HSPGs also facilitate LDLR degradation by proprotein convertase subtilisin/kexin type 9 (PCSK9). Progressive renal failure affects the structure and activity of hepatic lipoprotein receptors, PCSK9, and plasma cholesterol. METHODS: Uninephrectomy- and aging-induced CKD in normotensive Wistar rats and hypertensive Munich-Wistar-Frömter (MWF) rats. RESULTS: Compared with 22-week-old sex- and strain-matched rats, 48-week-old uninephrectomized Wistar-CKD and MWF-CKD rats showed proteinuria, increased plasma creatinine, and hypercholesterolemia (all P

Purpose of Review Fibroblast growth factor 23 (FGF23) is a key phosphate-regulating hormone that has been associated with adverse outcomes in patients with chronic kidney disease (CKD). Emerging data suggest that FGF23 plays a specific role in type 2 diabetes, partly independent of kidney function. We aimed to summarize current literature on the associations between FGF23 and outcomes in patients with type 2 diabetes with or without CKD. Recent Findings Several cohort studies have shown strong associations between plasma FGF23 and cardiovascular outcomes in diabetic CKD. Moreover, recent data suggest that FGF23 are elevated and may also be a risk factor for cardiovascular disease and mortality in type 2 diabetes patients without CKD, although the magnitude of the association is smaller than in CKD patients. Summary Diabetes-related factors may influence plasma FGF23 levels, and a higher FGF23 levels seem to contribute to a higher cardiovascular and mortality risk in patients with type 2 diabetes. Although this risk may be relevant in diabetic individuals with preserved kidney function, it is strongly accentuated in diabetic nephropathy. Future studies should clarify if FGF23 is merely a disease severity marker or a contributor to adverse outcomes in type 2 diabetes and establish if antidiabetic medication can modify FGF23 levels.