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Vitamin D deficiency is common in patients with chronic kidney disease (CKD) and associates with poor outcomes. Current clinical practice guidelines recommend supplementation with nutritional vitamin D as for the general population. However, recent large-scale, clinical trials in the general population failed to demonstrate a benefit of vitamin D supplementation on skeletal or non-skeletal outcomes, fueling a debate on the rationale for screening for and correcting vitamin D deficiency, both in non-CKD and CKD populations. In a collaboration between the European Renal Osteodystrophy initiative of the European Renal Association (ERA) and the European Society for Paediatric Nephrology (ESPN), an expert panel performed an extensive literature review and formulated clinical practice points on vitamin D supplementation in children and adults with CKD and after kidney transplantation. These were reviewed by a Delphi panel of members from relevant working groups of the ERA and ESPN. Key clinical practice points include recommendations to monitor for, and correct, vitamin D deficiency in children and adults with CKD and after kidney transplantation, targeting 25-hydroxyvitamin D levels >75 nmol/L (>30 ng/mL). While vitamin D supplementation appears well-tolerated and safe, it is recommended to avoid mega-doses (≥100 000 IU) and very high levels of 25 hydroxyvitamin D (>150-200 nmol/L, or 60-80 ng/mL) to reduce the risk of toxicity. Future clinical trials should investigate the benefit of vitamin D supplementation on patient-relevant outcomes in the setting of vitamin D deficiency across different stages of CKD., (© The Author(s) 2025. Published by Oxford University Press on behalf of the ERA.)

Aim: Malnutrition has been linked to cardiovascular diseases. Both selenium and iron deficiency have been associated with worse prognosis in patients with heart failure (HF). Yet, little is known about the role of micronutrients in the development of atrial fibrillation (AFib). In this study, we aimed to elucidate the association of micronutrient deficiencies with new-onset AFib., Methods: Selenium, magnesium, and iron parameters were measured in a well-characterized prospective cohort study (N = 5452). Selenium deficiency was defined as serum selenium < 70 μg/L, iron deficiency as serum ferritin < 30 μg/L, and magnesium deficiency as plasma magnesium < 0.85 mmol/L. New-onset AFib was the primary outcome. Additionally, we tested for previously reported effect-modifiers where applicable., Results: Selenium, iron, and magnesium deficiency was observed in 1155 (21.2%), 797 (14.6%), and 3600 (66.0%) participants, respectively. During a mean follow-up of 6.2 years, 136 (2.5%) participants developed new-onset AFib. Smoking status significantly interacted with selenium deficiency on outcome (p = 0.079). After multivariable adjustment for components of the CHARGE-AF model, selenium deficiency was associated with new-onset AFib in non-smokers (HR 1.69, 95% CI 1.09-2.64, p = 0.020), but not in smokers (HR 0.78, 95% CI 0.29-2.08, p = 0.619). Magnesium deficiency (HR 1.40, 95% CI 0.93-2.10, p = 0.110) and iron deficiency (HR 0.62, 95% CI 0.25-1.54, p = 0.307) were not significantly associated with new-onset AFib., Conclusion: Selenium deficiency was associated with new-onset AFib in non-smoking participants. Interventional studies that investigate the effects of optimizing micronutrients status in a population at risk are needed to assess causality, especially in those with selenium deficiency., Competing Interests: Declarations. Conflict of interest: The UMCG, which employs several of the authors has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc., Novo Nordisk, Vifor, and Roche. M.R. received consultancy fees from Medtronic, Arca Biopharma Inc, and Roche to the institution. The remaining authors have nothing to disclose., (© 2023. The Author(s).)

The susceptibility of patients with chronic kidney disease to develop postprandial hyperkalemia suggests alterations in normal kidney sodium (Na + ) and potassium (K + ) handling, but the exact nature of these changes is largely unknown. To address this, we analyzed the natriuretic and kaliuretic responses to diuretics and acute K + loading in rats who underwent 5/6 nephrectomy (5/6Nx) and compared this with the response in sham-operated rats. The natriuretic and kaliuretic responses to furosemide, hydrochlorothiazide, and amiloride were largely similar between 5/6Nx and sham rats except for a significantly reduced kaliuretic response to hydrochlorothiazide in 5/6Nx rats. Acute dietary K + loading with either 2.5% potassium chloride or 2.5% potassium citrate caused lower natriuretic and kaliuretic responses in 5/6Nx rats compared with sham rats. This resulted in significantly higher plasma K + concentrations in 5/6Nx rats, which were accompanied by corresponding increases in plasma aldosterone. Acute K + loading caused dephosphorylation of Ste20-related proline/alanine-rich kinase and the sodium-chloride cotransporter both in sham and 5/6Nx rats. In contrast, the acute K + load decreased the Na + /hydrogen exchanger 3 and increased serum- and glucocorticoid-regulated kinase 1 and the α-subunit of the epithelial sodium channel (ENaC) only in sham rats. Together, our data show that 5/6Nx impairs the natriuretic and kaliuretic response to an acute dietary K + load, which is further characterized by a loss of ENaC adaptation and the development of postprandial hyperkalemia. NEW & NOTEWORTHY Rats who underwent 5/6 nephrectomy demonstrate a reduced ability to excrete an acute K + load with the development of postprandial hyperkalemia. 5/6 Nephrectomy attenuates K + -induced natriuresis and impairs ENaC regulation despite intact NCC dephosphorylation and increased plasma aldosterone. This offers a potential explanation for why patients with chronic kidney disease are predisposed to postprandial hyperkalemia.

Background and Hypothesis: Chronic kidney disease (CKD) remains unexplained in at least 20% of patients. Massively parallel sequencing (MPS) can be a valuable diagnostic tool in patients with unexplained CKD, but prospective data from routine clinical practice are limited. We aimed to determine the diagnostic yield and relevance of MPS-based gene panel testing in patients with unexplained CKD in a real-world context. We additionally examined barriers to implementation of genetic testing., Methods: In this prospective cohort study, we recruited patients with unexplained CKD (eGFR <60mL/min/1.73 m2 without underlying clinical diagnosis) with onset <50 years who underwent MPS-based multi-gene panel testing from 11 academic and non-academic hospitals across the Netherlands. In patients with a (likely) pathogenic variant, we verified that the variant likely explained the clinical phenotype. A nationwide online survey was sent out to all Dutch nephrologists and residents to investigate potential barriers for gene panel testing., Results: A diagnostic variant was identified in 59/340 participants (17%). Most common diagnostic variants were in NPHP1 (13 patients), COL4A3 (12 patients), COL4A4 (5 patients), COL4A5 (6 patients), and PAX2 (5 patients). A genetic diagnosis led to at least one clinical consequence in 73% of patients. Main barriers reported by Dutch nephrologists (N=71) included genetic illiteracy (53%), difficulties with test selection (51%), and lack of time (43%)., Conclusion: MPS-based multi-gene panel testing yielded a genetic diagnosis in 17% of patients with unexplained CKD. Our findings support the relevance of MPS in the diagnostic workup of adults with unexplained CKD with onset <50 years. Additionally, our results underline the need to improve genetic education among nephrologists to better the implementation of MPS-based diagnostic testing in clinical practice., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Accurate estimation of glomerular filtration rate (GFR) is crucial in living kidney donation. While most estimated GFR (eGFR) equations are based on plasma creatinine, its levels are strongly influenced by muscle mass. Application of cystatin C (cysC)-based estimates before donation may improve both estimation of current GFR and prediction of post-donation GFR., Methods: We assessed the performance of Chronic Kidney Disease Epidemiology Collaboration equations based on creatinine (eGFRcreat-2009, eGFRcreat-2021), cysC (eGFRCysC-2012) or both (eGFRcombined-2012, eGFRcombined-2021) for estimating pre- and post-donation (mGFR) GFR in 486 living kidney donors. We subsequently focused on a subgroup of individuals with high/low muscle mass (25% highest/lowest 24-hour urinary creatinine excretion, sex stratified and height indexed)., Results: Pre-donation eGFRcombined-2012 and eGFRcombined-2021 showed the strongest associations with pre- and post-donation mGFR. Pre-donation eGFRcombined-2021 was most accurate for estimating both pre-donation (bias 0.01 ± 11.9 ml/min/1.73 m2) and post-donation mGFR (bias 1.3 ± 8.5 ml/min/1.73 m2). In donors with high/low muscle mass, cysC-based equations (with or without creatinine) performed better compared with equations based on only creatinine., Conclusions: Combined eGFR equations yielded a better estimate of pre- and post-donation mGFR compared with estimates based on creatinine or cysC only. The added value of cysC seems particularly pronounced in donors with high or low muscle mass., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Post-COVID-19 syndrome (PCS) remains a major health issue worldwide, while its pathophysiology is still poorly understood. Systemic oxidative stress (OS) may be involved in PCS, which is reflected by lower circulating free thiols (R-SH, sulfhydryl groups), as they are receptive to rapid oxidation by reactive species. This study aimed to investigate the longitudinal dynamics of serum R-SH after SARS-CoV-2 infection and its association with the development of PCS in individuals with mild COVID-19., Methods: Baseline serum R-SH concentrations were measured and compared between 135 non-hospitalized COVID-19 subjects and 82 healthy controls (HC). In COVID-19 subjects, serum R-SH concentrations were longitudinally measured during the acute disease phase (up to 3 weeks) and at 3, 6, and 12 months of follow-up, and their associations with relevant clinical parameters were investigated, including the development of PCS., Results: Baseline albumin-adjusted serum R-SH were significantly reduced in non-hospitalized COVID-19 subjects as compared to HC (p = 0.041), reflecting systemic OS. In mild COVID-19 subjects, trajectories of albumin-adjusted serum R-SH levels over a course of 12 months were longitudinally associated with the future presence of PCS 18 months after initial infection (b = -9.48, p = 0.023)., Conclusion: Non-hospitalized individuals with COVID-19 show evidence of systemic oxidative stress, which is longitudinally associated with the development of PCS. Our results provide a rationale for future studies to further investigate the value of R-SH as a monitoring biomarker and a potential therapeutic target in the development of PCS., Competing Interests: Declaration of competing interest A.R.B. has received a research grant from Janssen Pharmaceuticals and received speaker's fees from AbbVie, outside the submitted work. All other authors have no conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Transplant vasculopathy resembles atherosclerotic plaque formation and is a major contributor to late graft failure in kidney transplant recipients (KTR). Remnant lipoproteins and associated triglycerides are causal risk factors for atherosclerotic plaques and have been implicated in late kidney graft failure. However, whether remnants derived from liver (containing apolipoprotein [apo] B100) or intestine (containing apoB48) are clinically more important is unclear. The current study investigated the association between baseline fasting apoB48 levels and late kidney graft failure., Methods: 481 KTR with a functioning graft for at least 1 year were included in this retrospective, observational longitudinal single center cohort study. The primary endpoint was death-censored late graft failure, defined as need for initiation of dialysis or re-transplantation. ApoB48 was measured by enzyme-linked immunosorbent assay., Results: During a median follow-up of 9.5 years, 61 KTR developed graft failure (12.7%). At baseline, KTR with higher apoB48 levels had lower eGFR ( P  < .001), lower high-density lipoprotein (HDL) cholesterol ( P  < .001), increased triglycerides ( P  < .001) and used cyclosporine more frequently ( P  = .003). Cox regression showed that higher baseline apoB48 was associated with higher risk of late graft failure [hazard ratio (95% confidence interval), 1.59 (1.22, 2.07), P  < .001], independent of stepwise adjustment for potential confounders, including age and sex, immunosuppression type and proteinuria, triglycerides, and waist circumference (fully adjusted HR, 1.78 (1.29, 2.47), P  < .001]., Conclusion: ApoB48 is strongly associated with late graft failure, independent of potential confounders. Since apoB48-containing lipoproteins originate from the intestine, this study provides a rationale for considering pharmacological interventions targeting lipid absorption to improve graft outcome., Competing Interests: The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Purpose: Vitamin C deficiency is associated with excess mortality in kidney transplant recipients (KTR). We aim to evaluate plasma vitamin C status at different post-transplantation moments and assess the main characteristics associated with vitamin C deficiency in KTR., Methods: Plasma vitamin C was assessed in 598 KTR at 3-, 6-, 12-, 24-, and 60-months post-transplantation, 374 late KTR with a functioning graft ≥ 1 year, and 395 potential donors. Vitamin C deficiency was defined as plasma vitamin C ≤ 28 µmol/L. Diet was assessed by a 177-item food frequency questionnaire. Data on vitamin C-containing supplements use were extracted from patient records and verified with the patients., Results: Vitamin C deficiency ranged from 46% (6-months post-transplantation) to 30% (≥ 1 year post-transplantation). At all time points, KTR had lower plasma vitamin C than potential donors (30-41 µmol/L vs 58 µmol/L). In cross-sectional analyses of the 953 KTR at their first visit ≥ 12 months after transplantation (55 ± 14 years, 62% male, eGFR 55 ± 19 mL/min/1.73 m 2 ), the characteristics with the strongest association with vitamin C deficiency were diabetes and smoking (OR 2.67 [95% CI 1.84-3.87] and OR 1.84 [95% CI 1.16-2.91], respectively). Dietary vitamin C intake and vitamin C supplementation were associated with lower odds (OR per 100 mg/day 0.38, 95% CI 0.24-0.61 and OR 0.21, 95% CI 0.09-0.44, respectively)., Conclusion: Vitamin C deficiency is frequent among KTR regardless of the time after transplantation, especially among those with diabetes and active smokers. The prevalence of vitamin C deficiency was lower among KTR with higher vitamin C intake, both dietary and supplemented. Further research is warranted to assess whether correcting this modifiable risk factor could improve survival in KTR., (© 2024. The Author(s).)

Aims: We aimed to determine the association between serum interleukin-6 (IL-6) concentrations and new-onset heart failure (HF) in persons with type 2 diabetes (T2D)., Methods and Results: We performed a case-control study nested in the Diabetes Care System Cohort, a prospective cohort of persons with T2D in primary care. We included 724 participants, of whom 141 developed HF during 5 years of follow-up and 583 were age- and sex-matched controls. IL-6 was measured at baseline and categorized into four groups: Group 1 was composed of participants with IL-6 below the detection limit of 1.5 pg/mL, and the remainder were divided into tertiles. We performed logistic regression analyses with categorized IL-6 or continuous IL-6 as the determinant and new-onset HF as the outcome adjusted for follow-up time, age, sex, glycated haemoglobin, estimated glomerular filtration rate, albumin/creatinine ratio, and cardiovascular disease at baseline. Effect modification by sex was tested. Participants were 70.7 ± 9.0 years, and 38% were women. In comparison with Group 1, all tertiles were associated with an increased risk of HF with odds ratios of 2.1 [95% confidence interval (CI): 1.2-2.9], 2.8 (95% CI: 2.0-3.7), and 2.1 (95% CI: 1.3-3.0), respectively, for Tertiles 1-3. Continuous IL-6 was associated with the development of HF with an odds ratio of 1.2 (95% CI: 1.0-1.5). No effect modification by sex was observed., Conclusions: Higher IL-6 levels are associated with the development of HF in persons with T2D. Further research should determine whether IL-6-lowering interventions could prevent the development of HF., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Kidney transplant recipients (KTRs) experience more fatigue, anxiety, and depressive symptoms and lower concentration and health-related quality of life (HRQoL) compared with the general population. Anemia is a potential cause that is well-recognized and treated. Iron deficiency, however, is often unrecognized, despite its potential detrimental effects related to and unrelated to anemia. We investigated the interplay of anemia, iron deficiency, and patient-reported outcomes in 814 outpatient KTRs (62% male, age 56 ± 13 years) enrolled in the TransplantLines Biobank and Cohort Study (Groningen, The Netherlands). In total, 28% had iron deficiency (ie, transferrin saturation < 20% and ferritin < 100 μg/L), and 29% had anemia (World Health Organization criteria). In linear regression analyses, iron deficiency, but not anemia, was associated with more fatigue, worse concentration, lower wellbeing, more anxiety, more depressive symptoms, and lower HRQoL, independent of age, sex, estimated glomerular filtration rate, anemia, and other potential confounders. In the fully adjusted logistic regression models, iron deficiency was associated with an estimated 53% higher risk of severe fatigue, a 100% higher risk of major depressive symptoms, and a 51% higher chance of being at risk for sick leave/work disability. Clinical trials are needed to investigate the effect of iron deficiency correction on patient-reported outcomes and HRQoL in KTRs., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. M.F. Eisenga has declared receiving consultant fees from Vifor Pharma and Cablon Medical; serving on the Advisory Board for Cablon Medical and GlaxoSmithKline; and receiving speaker fees from Vifor Pharma, Pharmacosmos, and Astellas. All other authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Aim: Coronary artery calcification (CAC) partially explains the excess cardiovascular morbidity and mortality after kidney transplantation. This study aimed to investigate determinants of CAC in stable kidney transplant recipients at 12 months post-transplantation., Methods and Results: CAC-score was quantified by the Agatston method using non-contrast enhanced computed tomography, and age- and sex-standardized CAC-percentiles were calculated. Univariable and multivariable multinomial logistic regression was performed to study potential determinants of CAC. The independent determinants were included in multivariable multinomial logistic regression adjusting for potential confounders. 203 KTRs (age 54.0 ± 14.7 years, 61.1% male) were included. Participants were categorized into four groups according to CAC percentiles (p = 0 [CAC-score = 0], n = 68; p ≥ 1%-p ≤ 50% [CAC score = 29.0 (4.0-166.0)], n = 31; p > 50 ≤ 75% [CAC score = 101.0 (23.8-348.3)], n = 26; and p>75% [CAC score = 581.0 (148.0-1652)], n = 83). Upon multivariable multinomial logistic regression, patients with a narrower phase angle and patients who had received a graft from a deceased donor had a higher risk of being in the >75th CAC-percentile., Conclusions: This study identifies not only metabolic and transplant-related factors, but also phase angle, a composite marker of cell integrity, as an independent determinant of CAC at 12 months after kidney transplantation. This study offers new perspectives for future research into the value of bioelectrical impedance analysis in relation to vascular calcification in kidney transplant recipients., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Vascular calcification is associated with increased mortality in patients with cardiovascular disease. Secondary calciprotein particles are believed to play a causal role in the pathophysiology of vascular calcification. The maturation time (T 50 ) of calciprotein particles provides a measure of serum calcification propensity. We compared T 50 between patients with ST-segment-elevated myocardial infarction and control subjects and studied the association of T 50 with cardiovascular risk factors and outcome., Methods: T 50 was measured by nephelometry in 347 patients from the GIPS-III trial (Metabolic Modulation With Metformin to Reduce Heart Failure After Acute Myocardial Infarction: Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction: a Randomized Controlled Trial) and in 254 matched general population controls from PREVEND (Prevention of Renal and Vascular End-Stage Disease). We also assessed the association between T 50 and left ventricular ejection fraction, as well as infarct size, the incidence of ischemia-driven reintervention during 5 years of follow-up, and serum nitrite as a marker of endothelial dysfunction., Results: Patients with ST-segment-elevated myocardial infarction had a significantly lower T 50 (ie, higher serum calcification propensity) compared with controls (T 50 : 289±63 versus 338±56 minutes; P <0.001). In patients with ST-segment-elevated myocardial infarction, lower T 50 was associated with female sex, lower systolic blood pressure, lower total cholesterol, lower LDL (low-density lipoprotein) cholesterol, lower triglycerides, and higher HDL (high-density lipoprotein) cholesterol but not with circulating nitrite or nitrate. Ischemia-driven reintervention was associated with higher LDL ( P =0.03) and had a significant interaction term for T 50 and sex ( P =0.005), indicating a correlation between ischemia-driven reintervention and T 50 above the median in men and below the median in women, between 150 days and 5 years of follow-up., Conclusions: Serum calcification propensity is increased in patients with ST-segment-elevated myocardial infarction compared with the general population, and its contribution is more pronounced in women than in men. Its lack of/inverse association with nitrite and blood pressure confirms T 50 to be orthogonal to traditional cardiovascular disease risk factors. Lower T 50 was associated with a more favorable serum lipid profile, suggesting the involvement of divergent pathways of calcification stress and lipid stress in the pathophysiology of myocardial infarction., Competing Interests: A. Pasch is a founder and employee of Calciscon AG, Switzerland, which commercializes the T50 test. The other authors report no conflicts.

Background and Aims: Sodium [ 18 F]fluoride (Na [ 18 F]F) positron emission tomography imaging allows detailed visualization of early arterial micro-calcifications. This study aims to investigate atherosclerosis manifested by micro-calcification, macro-calcification, and aortic stiffness in patients with type 2 diabetes mellitus (T2DM) with and without albuminuria and severely decreased kidney function., Methods: A cohort was stratified in four groups (N = 10 per group), based on KDIGO categories (G1-5 A1-3). G1-2A1 non-diabetic controls (median [IQR] estimated glomerular filtration rate (eGFR) in mL/min/1.73 m 2 91 [81-104]), G1-2A1 with T2DM (eGFR 87 [84-93], and albumin-creatinin-ratio (ACR) in mg/mmol 0.35 [0.25-0.75]), G1-2A3 with T2DM (eGFR 85 [60-103], and ACR 74 [62-122], and G4A3 with T2DM (eGFR 19 [13-27] and ACR 131 [59-304])., Results: Na [ 18 F]F femoral artery grading score differed significantly in the groups with the highest Na [ 18 F]F activity in A3 groups with T2DM (G1-2A3 with T2DM 228 [100-446] and G4A3 with T2DM 198 [113-578]) from the lowest groups of the G1-2A1 with T2DM (33 [0-93]) and in G1-2A1 non-diabetic controls (75 [0-200], p = 0.001). Aortic Na [ 18 F]F activity and femoral artery computed tomography (CT)-assessed macro-calcification was increased in G4A3 with T2DM compared with G1-2A1 with T2DM (47.5 [33.8-73.8] vs. 17.5 [8.8-27.5] (p = 0.006) and 291 [170-511] vs. 12.2 [1.41-44.3] mg (p = 0.032), respectively). Carotid-femoral pulse wave velocity (PWV)-assessed aortic stiffness was significantly higher in both A3 groups with T2DM compared with G1-2A1 with T2DM (11.15 and 12.35 vs. 8.86 m/s, respectively (p = 0.009))., Conclusions: This study indicates that the presence of severely increased albuminuria in patients with T2DM is cross-sectionally associated with subclinical arterial disease in terms of micro-calcification and aortic stiffness. Additional decrease in kidney function was associated with advanced macro-calcifications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Hypothesis: Kidney grafts from donors who died of stroke and related traits have worse outcomes relative to grafts from both living donors and those who died of other causes. We hypothesise that deceased donors, particularly those who died of stroke, have elevated polygenic burden for cerebrovascular traits. We further hypothesise that this donor polygenic burden is associated with inferior graft outcomes in the recipient., Methods: Using a dataset of 6666 deceased and living kidney donors from seven different European ancestry transplant cohorts, we investigated the role of polygenic burden for cerebrovascular traits (hypertension, stroke, and intracranial aneurysm (IA)) on donor age of death and recipient graft outcomes., Results: We found that kidney donors who died of stroke had elevated intracranial aneurysm and hypertension polygenic risk scores, compared to healthy controls and living donors. This burden was associated with age of death among donors who died of stroke. Increased donor polygenic risk for hypertension was associated with reduced long term graft survival (HR: 1.44, 95% CI [1.07, 1.93]) and increased burden for hypertension, and intracranial aneurysm was associated with reduced recipient estimated glomerular filtration rate (eGFR) at 1 year., Conclusions: Collectively, the results presented here demonstrate the impact of inherited factors associated with donors' death on long-term graft function., (© 2024. The Author(s).)

Normothermic machine perfusion (NMP) has emerged as a promising tool for the preservation, viability assessment, and repair of deceased-donor kidneys prior to transplantation. These kidneys inevitably experience a period of ischemia during donation, which leads to ischemia-reperfusion injury when NMP is subsequently commenced. Ischemia-reperfusion injury has a major impact on the renal vasculature, metabolism, oxygenation, electrolyte balance, and acid-base homeostasis. With an increased understanding of the underlying pathophysiological mechanisms, renoprotective strategies and therapeutic interventions can be devised to minimize additional injury during normothermic reperfusion, ensure the safe implementation of NMP, and improve kidney quality. This review discusses the pathophysiological alterations in the vasculature, metabolism, oxygenation, electrolyte balance, and acid-base homeostasis of deceased-donor kidneys and delineates renoprotective strategies and therapeutic interventions to mitigate renal injury and improve kidney quality during NMP., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Patients with autosomal dominant polycystic kidney disease (ADPKD) have disproportionately high levels of fibroblast growth factor 23 (FGF-23) for their chronic kidney disease stage, however only a subgroup develops kidney phosphate wasting. We assessed factors associated with phosphate wasting and hypothesize that it identifies patients with more severe disease and predicts disease progression., Methods: We included 604 patients with ADPKD from a multicenter prospective observational cohort (DIPAK; Developing Intervention Strategies to Halt Progression of Autosomal Dominant Polycystic Kidney Disease) in four university medical centers in the Netherlands. We measured parathyroid hormone (PTH) and total plasma FGF-23 levels, and calculated the ratio of tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) with <0.8 mmol/L defined as kidney phosphate wasting. We analysed the association of TmP/GFR with estimated GFR (eGFR) decline over time and the risk for a composite kidney outcome (≥30% eGFR decline, kidney failure or kidney replacement therapy)., Results: In our cohort (age 48 ± 12 years, 39% male, eGFR 63 ± 28 mL/min/1.73 m2), 59% of patients had phosphate wasting. Male sex [coefficient -0.2, 95% confidence interval (CI) -0.2; -0.1], eGFR (0.002, 95% CI 0.001; 0.004), FGF-23 (0.1, 95% CI 0.03; 0.2), PTH (-0.2, 95% CI -0.3; -0.06) and copeptin (-0.08, 95% CI -0.1; -0.08) were associated with TmP/GFR. Corrected for PTH, FGF-23 and eGFR, every 0.1 mmol/L decrease in TmP/GFR was associated with a greater eGFR decline of 0.2 mL/min/1.73 m2/year (95% CI 0.01; 0.3) and an increased hazard ratio of 1.09 (95% CI 1.01; 1.18) of the composite kidney outcome., Conclusion: Our study shows that in patients with ADPKD, phosphate wasting is prevalent and associated with more rapid disease progression. Phosphate wasting may be a consequence of early proximal tubular dysfunction and insufficient suppression of PTH., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Gut dysbiosis has been associated with impaired outcomes in liver and kidney transplant recipients, but the gut microbiome of lung transplant recipients has not been extensively explored. We assessed the gut microbiome in 64 fecal samples from end-stage lung disease patients before transplantation and 219 samples from lung transplant recipients after transplantation using metagenomic sequencing. To identify dysbiotic microbial signatures, we analyzed 243 fecal samples from age-, sex-, and BMI-matched healthy controls. By unsupervised clustering, we identified five groups of lung transplant recipients using different combinations of immunosuppressants and antibiotics and analyzed them in relation to the gut microbiome. Finally, we investigated the gut microbiome of lung transplant recipients in different chronic lung allograft dysfunction (CLAD) stages and longitudinal gut microbiome changes after transplantation. We found 108 species (58.1%) in end-stage lung disease patients and 139 species (74.7%) in lung transplant recipients that were differentially abundant compared with healthy controls, with several species exhibiting sharp longitudinal increases from before to after transplantation. Different combinations of immunosuppressants and antibiotics were associated with specific gut microbial signatures. We found that the gut microbiome of lung transplant recipients in CLAD stage 0 was more similar to healthy controls compared to those in CLAD stage 1. Finally, the gut microbial diversity of lung transplant recipients remained lower than the average gut microbial diversity of healthy controls up to more than 20 years post-transplantation. Gut dysbiosis, already present before lung transplantation was exacerbated following lung transplantation.IMPORTANCEThis study provides extensive insights into the gut microbiome of end-stage lung disease patients and lung transplant recipients, which warrants further investigation before the gut microbiome can be used for microbiome-targeted interventions that could improve the outcome of lung transplantation., Competing Interests: The authors declare no conflict of interest.

Background and Aims: Individuals with type 2 diabetes (T2D) have a higher risk of cardiovascular disease, compared with those without T2D. The serum T50 test captures the transformation time of calciprotein particles in serum. We aimed to assess whether serum T50 predicts cardiovascular mortality in T2D patients, independent of traditional risk factors., Methods: We analyzed 621 individuals with T2D in this prospective cohort study. Cox regression models were performed to test the association between serum T50 and cardiovascular and all-cause mortality. Causes of death were categorized according to ICD-10 codes. Risk prediction improvement was assessed by comparing Harrell's C for models without and with T 50. RESULTS: The mean age was 64.2 ± 9.8 years, and 61% were male. The average serum T50 time was 323 ± 63 min. Higher age, alcohol use, high-sensitive C-reactive protein, and plasma phosphate were associated with lower serum T 50 levels. Higher plasma triglycerides, venous bicarbonate, sodium, magnesium, and alanine aminotransferase were associated with higher serum T50 levels. After a follow-up of 7.5[5.4-10.7] years, each 60 min decrease in serum T50 was associated with an increased risk of cardiovascular (fully adjusted HR 1.32, 95% CI 1.08-1.50, and p = 0.01) and all-cause mortality (HR 1.15, 95%CI 1.00-1.38, and p = 0.04). Results were consistent in sensitivity analyses after exclusion of individuals with estimated glomerular filtration rate <45 or <60 mL/min/1.73 m 2 and higher plasma phosphate levels., Conclusions: Serum T50 improves prediction of cardiovascular and all-cause mortality risk in individuals with T2D. Serum T50 may be useful for risk stratification and to guide therapeutic strategies aiming to reduce cardiovascular mortality in T2D., (© 2024 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background: Cardiovascular disease (CVD) is the major cause of mortality in type 1 diabetes (T1D). The objective of this study is to evaluate fibroblast growth factor 23 (FGF23) and calcium-phosphate metabolism in relation to cardiovascular risk factors in adults with and without T1D., Methods: A case-control study was conducted using data from patients with T1D and age- and sex matched controls without T1D from the Lifelines Cohort Study., Results: We included 302 adults in the T1D group and 302 adults in the control group. Median age was 42 years. Median glycosylated hemoglobin (HbA1c) in the T1D group was 7.8%. FGF23 of all patients with T1D was not significantly different from controls. Females with T1D had significantly higher FGF23 than males with T1D (83.3 vs 69.3 U/mL, p = 0.002), this was not observed in controls. Serum phosphate, calcium, and alkaline phosphatase were higher and parathyroid hormone was lower in patients with T1D, compared to controls (all p < .001), all within normal range. In the T1D group, FGF23 was positively correlated with serum phosphate (p < .001), alkaline phosphatase (p = .01), and calcium (p = .030), these correlations were not observed in controls. Median FGF23 was significantly higher in current smokers than in nonsmokers with T1D (84.9 vs 73.5 U/mL, p < .05)., Conclusions: Serum calcium, phosphate, and alkaline phosphatase were higher in patients with T1D than in controls and were positively correlated to FGF23 in patients with T1D. Current smokers with T1D had higher FGF23 than nonsmokers with T1D. These findings may contribute to the increased risk of CVD in patients with T1D., (© 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Context: Sex-specific prevalence and incidence of type 2 diabetes (T2D) have been reported, but the underlying mechanisms are uncertain., Objective: In this study, we aimed to investigate whether iron biomarkers mediate the association between biological sex and glucose metabolism and the incidence of T2D., Methods: We used data from the general population enrolled in the prospective Prevention of REnal and Vascular ENd-stage Disease study in Groningen, The Netherlands. We measured ferritin, transferrin saturation (TSAT), hepcidin, soluble transferrin receptor (sTfR), fasting plasma glucose (FPG), fasting plasma insulin (FPI) levels, and incidence of T2D. We used multivariable regression and mediation analyses to investigate our hypothesis. All iron biomarkers, FPG, and FPI were log-transformed., Results: The mean (SD) age of the 5312 (51.3% female) individuals was 52.2 (11.6) years. Compared with males, females had lower FPG (β = -.01; 95% CI -0.02, -0.01) and FPI (β = -.03; 95% CI -0.05, -0.02) levels. Ferritin, hepcidin, and sTfR showed potential mediating effects on the association between sex and FPG, 21%, 5%, and 7.1%, respectively. Furthermore, these variables mediated 48.6%, 5.7%, and 3.1% of the association between sex and FPI, respectively. Alternatively, TSAT had a suppressive mediating role in the association of sex with FPG and FPI. The incidence of T2D was lower in females than in males (hazard ratio 0.58; 95% CI 0.44, 0.77), with 19.2% of this difference being mediated by ferritin., Conclusion: Iron biomarkers may partially mediate the association between sex and glucose homeostasis. Future studies addressing the causality of our findings are needed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10 -8 ) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10 -126 ) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10 -44 ) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10 -34 ). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research., (© 2024. The Author(s).)

Background: Dietary potassium (K+) has emerged as a modifiable factor for cardiovascular and kidney health in the general population, but its role in people with chronic kidney disease (CKD) is unclear. Here, we hypothesize that CKD increases the susceptibility to the negative effects of low and high K+ diets., Methods: We compared the effects of low, normal and high KChloride (KCl) diets and a high KCitrate diet for 4 weeks in male rats with normal kidney function and in male rats with CKD using the 5/6th nephrectomy model (5/6Nx)., Results: Compared with rats with normal kidney function, 5/6Nx rats on the low KCl diet developed more severe extracellular and intracellular K+ depletion and more severe kidney injury, characterized by nephromegaly, infiltration of T cells and macrophages, decreased estimated glomerular filtration rate and increased albuminuria. The high KCl diet caused hyperkalemia, hyperaldosteronism, hyperchloremic metabolic acidosis and severe hypertension in 5/6Nx but not in sham rats. The high KCitrate diet caused hypochloremic metabolic alkalosis but attenuated hypertension despite higher abundance of the phosphorylated sodium chloride cotransporter (pNCC) and similar levels of plasma aldosterone and epithelial sodium channel abundance. All 5/6Nx groups had more collagen deposition than the sham groups and this effect was most pronounced in the high KCitrate group. Plasma aldosterone correlated strongly with kidney collagen deposition., Conclusions: CKD increases the susceptibility to negative effects of low and high K+ diets in male rats, although the injury patterns are different. The low K+ diet caused inflammation, nephromegaly and kidney function decline, whereas the high K+ diet caused hypertension, hyperaldosteronism and kidney fibrosis. High KCitrate attenuated the hypertensive but not the pro-fibrotic effect of high KCl, which may be attributable to K+-induced aldosterone secretion. Our data suggest that especially in people with CKD it is important to identify the optimal threshold of dietary K+ intake., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Objective: This work aimed to study whether fibroblast growth factor 23 (FGF23) is predictive for incident posttransplant diabetes mellitus (PTDM) in kidney transplant recipients (KTRs)., Methods: We repeatedly analyzed plasma C-terminal FGF23 concentrations in 170 KTRs enrolled in the TransplantLines Biobank and Cohort Study. Associations of time-updated plasma FGF23 with incident PTDM were studied by Cox regression., Results: A total of 170 KTRs (46% female, aged 54.4 ± 12.4 years) with 540 FGF23 measurements were included. Plasma FGF23 concentrations at transplantation were 31.1 (0.76-2576) pmol/L. During a follow-up of 24 (12-24) months, 38 patients developed PTDM. The highest FGF23 tertile (compared to the lowest) was associated with an increased risk for PTDM (fully adjusted hazard ratio 20.9; 95% CI, 3.4-130.0; P < .001)., Conclusion: In KTRs without diabetes at baseline, the highest tertile of FGF23, compared to the lowest, is predictive for development of PTDM., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: In most screening guidelines, high body mass index (BMI) is considered a contraindication for kidney donation. New insights suggest that central body fat distribution might provide greater power in assessing kidney risk. This study aimed to determine whether BMI and central body fat distribution measures are associated with long-term kidney function after donor nephrectomy. We hypothesized that higher BMI, waist circumference (WC), and waist-to-height ratio (WHtR) were associated with lower kidney function long term after donation., Methods: The study population consisted of living kidney donors. BMI, WC, and WHtR were measured during donor screening. The outcome postdonation kidney function was assessed using measured GFR (mGFR) (mGFR, 125 I-iothalamate infusion) at 3 months ( n =1042), 5 years ( n =556), and 10 years ( n =210) of follow-up. Primary multivariable linear regression analyses were performed with BMI and WC and secondary analyses with WHtR. Linear mixed models were performed to investigate change in postdonation eGFR., Results: The donor age was 52±11 years, and 48% were male. The mean BMI was 26.1±3.6 kg/m 2 , and WC was 91±11 cm. Higher predonation BMI was associated with lower mGFR throughout follow-up: -1.35 (95% confidence interval [CI], -1.95 to -0.80), -1.55 (95% CI, -2.50 to -0.65), and -2.35 (95% CI, -4.10 to -0.60) ml/min per m 2 per 5 kg/m 2 higher BMI at 3 months, 5, and 10 years after donation, respectively, adjusted for sex, age, and predonation GFR. For WC, differences in mGFR were -1.30 (95% CI, -1.70 to -0.90), -1.50 (95% CI, -2.20 to -0.80), and -1.70 (95% CI, -3.00 to -0.50) ml/min per m 2 per 10 cm higher WC at 3 months, 5, and 10 years after donation, respectively. In male donors, BMI and WC were significantly associated with a negative postdonation change in eGFR., Conclusions: Higher BMI and WC were independently associated with lower GFR (long term) after living kidney donation., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Background: In the ageing population, issues with bone and joint health are highly prevalent. Both beneficial and potential risks of dairy products on bone and joint health are reported in epidemiological studies. Furthermore, the phosphorus (P) load from dairy could potentially lead to unfavorable changes in P metabolism., Objective: To investigate the effect of dairy intake on markers of bone and joint metabolism and P metabolism in an intervention study with high and low dairy intake., Methods: In a post hoc analysis of a randomized cross-over trial with overweight adults, the effect of a standardized high dairy intake [HDI (5-6 dairy portions per day) versus low dairy intake (LDI, ≤ 1 dairy portion/day)] for 6 weeks on markers of bone and joint health was assessed using enzyme-linked immunosorbent assays and electrochemiluminescence immunoassays. Markers indicative for cartilage breakdown, including urinary CTX-II, serum COMP and 4-hydroxyproline, and markers indicative for bone remodeling, such as serum CTX-I, PTH, 25(OH)D, osteocalcin, P1NP and FGF23, were investigated using linear mixed models. Furthermore, changes in P metabolism, including the main phosphate-regulating hormone FGF23 were explored., Results: This study was completed by 46 adults (57% female, age 59 ± 4 years, BMI 28 ± 2 kg/m 2 ). Following HDI, markers such as urinary CTX-II excretion, COMP, 25(OH)D, PTH and CTX-I were significantly lower after HDI, as compared to LDI. For example, CTX-II excretion was 1688 ng/24 h at HDI, while it was 2050 ng/24 h at LDI (p < 0.001). Concurrently, P intake was higher at HDI than at LDI (2090 vs 1313 mg/day, p < 0.001). While plasma P levels did not differ (1.03 vs 1.04 mmol/L in LDI, p = 0.36), urinary P excretion was higher at HDI than at LDI (31 vs 28 mmol/L, p = 0.04). FGF23 levels tended to be higher at HDI than at LDI (76.3 vs. 72.9 RU/mL, p = 0.07)., Conclusions: HDI, as compared to LDI, reduced markers that are indicative for joint and bone resorption and bone turnover. No changes in P metabolism were observed., Clinical Trial Registry: This trial was registered at https://trialsearch.who.int/Trial2.aspx?TrialID=NTR4899 as NTR4899., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

X-linked hypophosphatemia (XLH) is the most common monogenetic cause of chronic hypophosphatemia, characterized by rickets and osteomalacia. Disease manifestations and treatment of XLH patients in the Netherlands are currently unknown. Characteristics of XLH patients participating in the Dutch observational registry for genetic hypophosphatemia and acquired renal phosphate wasting were analyzed. Eighty XLH patients, including 29 children, were included. Genetic testing, performed in 78.8% of patients, showed a PHEX mutation in 96.8%. Median (range) Z-score for height was - 2.5 (- 5.5; 1.0) in adults and - 1.4 (- 3.7; 1.0) in children. Many patients were overweight or obese: 64.3% of adults and 37.0% of children. All children received XLH-related medication e.g., active vitamin D, phosphate supplementation or burosumab, while 8 adults used no medication. Lower age at start of XLH-related treatment was associated with higher height at inclusion. Hearing loss was reported in 6.9% of children and 31.4% of adults. Knee deformities were observed in 75.0% of all patients and osteoarthritis in 51.0% of adult patients. Nephrocalcinosis was observed in 62.1% of children and 33.3% of adults. Earlier start of XLH-related treatment was associated with higher risk of nephrocalcinosis and detection at younger age. Hyperparathyroidism longer than six months was reported in 37.9% of children and 35.3% of adults. This nationwide study confirms the high prevalence of adiposity, hearing loss, bone deformities, osteoarthritis, nephrocalcinosis and hyperparathyroidism in Dutch XLH patients. Early start of XLH-related treatment appears to be beneficial for longitudinal growth but may increase development of nephrocalcinosis., (© 2024. The Author(s).)

Competing Interests: None declared.

The impact of pre-transplant parathyroid hormone (PTH) levels on early or long-term kidney function after kidney transplantation is subject of debate. We assessed whether severe hyperparathyroidism is associated with delayed graft function (DGF), death-censored graft failure (DCGF), or all-cause mortality. In this single-center cohort study, we studied the relationship between PTH and other parameters related to bone and mineral metabolism, including serum alkaline phosphatase (ALP) at time of transplantation with the subsequent risk of DGF, DCGF and all-cause mortality using multivariable logistic and Cox regression analyses. In 1,576 kidney transplant recipients (51.6 ± 14.0 years, 57.3% male), severe hyperparathyroidism characterized by pre-transplant PTH ≥771 pg/mL (>9 times the upper limit) was present in 121 patients. During 5.2 [0.2-30.0] years follow-up, 278 (15.7%) patients developed DGF, 150 (9.9%) DCGF and 432 (28.6%) died. A higher pre-transplant PTH was not associated with DGF (HR 1.06 [0.90-1.25]), DCGF (HR 0.98 [0.87-1.13]), or all-cause mortality (HR 1.02 [0.93-1.11]). Results were consistent in sensitivity analyses. The same applied to other parameters related to bone and mineral metabolism, including ALP. Severe pre-transplant hyperparathyroidism was not associated with an increased risk of DGF, DCGF or all-cause mortality, not supporting the need of correction before kidney transplantation to improve graft or patient survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rodrigues, Van Der Plas, Sotomayor, Van Der Vaart, Kremer, Pol, Kruijff, Heilberg, Bakker, TransplantLines Investigators and De Borst.)

Background and Aims: Whether coffee consumption is associated with changes in estimated glomerular filtration rate (eGFR) is unknown. We investigated the relationship between coffee consumption and annual eGFR change in a large Dutch population-based study., Methods and Results: This study was performed in 78,346 participants without chronic kidney disease (CKD) in the population-based Lifelines Cohort Study. Coffee consumption was assessed at baseline using food frequency questionnaires. Outcomes were annual eGFR change and a composite kidney outcome (defined as eGFR <60 mL/min per 1.73 m 2 or >20 % eGFR decline). Multivariable linear and logistic regression analyses were used to evaluate the associations of coffee consumption (categories and cups/day) with kidney outcomes. Overall, 90 % of the participants drank coffee daily and 36 % drank >2-4 cups/day. Unadjusted mean ± SD annual eGFR change ranged from -2.86 ± 2.96 (for non-coffee drinkers) to -2.35 ± 2.62 (for participants consuming >6 cups/day) mL/min per 1.73 m 2 . During 3.6 ± 0.9 years follow-up, 11.1 % of participants reached the composite kidney outcome. As compared to non-coffee drinkers, higher coffee consumption was associated with less annual eGFR decline in multivariable models (β [95 % CIs] ranged from 0.15 [0.07, 0.22] for >0-2 cups/day to 0.29 [0.20, 0.38] for >6 cups/day, P-trend <0.001). Consumption of one more cup of coffee per day was associated with a 3 % lower risk of the composite kidney outcome (OR [95%CI], 0.97 [0.96, 0.99]). The inverse association was more pronounced in a subgroup of individuals with diabetes., Conclusion: Coffee consumption was inversely associated with annual eGFR change and CKD risk in a large Dutch population-based cohort., Competing Interests: Declaration of competing interest The authors declare no relevant financial interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

We investigated whether urinary vascular non-inflammatory molecule-1 (vanin-1), a promising early-onset tubular injury marker, correlates with other established tubular injury markers and is associated with graft failure in kidney transplant recipients (KTR). We measured 24 h urinary vanin-1 excretion in 656 KTR (age 53 ± 13 years, 43% female, estimated glomerular filtration rate (eGFR) 53 ± 21 mL/min/1.73 m 2 ) who had undergone kidney transplantation ≥ 1 year. The median 24 h urinary vanin-1 excretion was 145 [51-331] pmol/24 h. 24 h urinary vanin-1 excretion correlated weakly but significantly with other tubular injury markers (ρ = 0.14, p < 0.001 with urinary liver-type fatty acid binding protein, ρ = 0.13, p = 0.001 with urinary post-translationally modified fetuin-A protein, and ρ = 0.10, p = 0.011 with plasma neutrophil gelatinase-associated lipocalin) and with eGFR (ρ = - 0.13, p = 0.001). During a median follow-up of 7.4 [4.9-8.0] years, 94 (14%) KTR developed death-censored graft failure. In multivariable Cox regression analyses, 24 h urinary vanin-1 excretion was not associated with an increased risk of death-censored graft failure (adjusted hazard ratio [95% confidence interval] = 0.96 [0.86-1.07], p = 0.5). In conclusion, our findings do not support the role of urinary vanin-1 as a biomarker of graft failure after kidney transplantation., (© 2024. The Author(s).)

Aim: To examine the association of iron biomarkers with menopausal status and assess whether these biomarkers can help differentiate menopausal status beyond age., Methods: In this cross-sectional study we included 1679 women from the CoLaus and 2133 from the PREVEND cohorts, with CoLaus used as primary cohort and PREVEND for replication. Ferritin, transferrin, iron, and transferrin saturation (TSAT) were used to assess iron status. Hepcidin and soluble transferrin receptor were assessed only in PREVEND. Menopausal status was self-reported and defined as menopausal or non-menopausal. Logistic regressions were used to explore the association of these iron biomarkers with menopause status. Sensitivity, specificity, area under the receiver operating characteristic curves (AUC), positive and negative predictive values as well as cut-off points for the iron biomarkers were calculated. The model with the highest AUC was defined as the best., Results: In the CoLaus and PREVEND cohorts, respectively, 513 (30.6 %) and 988 (46.3 %) women were postmenopausal. Ferritin (OR, 2.20; 95 % CI 1.72-2.90), transferrin (OR, 0.03; 95 % CI 0.01-0.10), and TSAT (OR, 1.28; 95 % CI 1.06-1.54) were significantly associated with menopausal status in CoLaus, with the findings replicated in PREVEND. AUC of age alone was 0.971. The best model resulted from combining age, ferritin, and transferrin, with an AUC of 0.976, and sensitivity and specificity of 87.1 % and 96.5 %, respectively. Adding transferrin and ferritin to a model with age improved menopause classification by up to 7.5 %. In PREVEND, a model with age and hepcidin outperformed a model with age, ferritin, and transferrin., Conclusion: Iron biomarkers were consistently associated with menopausal status in both cohorts, and modestly improved a model with age alone for differentiating menopause status. Our findings on hepcidin need replication., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Platelet count has been associated with blood pressure, but whether this association reflects causality remains unclear. To strengthen the evidence, we conducted a traditional observational analysis in the Lifelines Cohort Study ( n = 167,785), and performed bi-directional Mendelian randomization (MR) with summary GWAS data from the UK Biobank ( n = 350,475) and the International Consortium of Blood Pressure (ICBP) ( n = 299,024). Observational analyses showed positive associations between platelet count and blood pressure (OR = 1.12 per SD, 95% CI: 1.10 to 1.14 for hypertension; B = 0.07, 95% CI: 0.07 to 0.08 for SBP; B = 0.07 per SD, 95% CI: 0.06 to 0.07 for DBP). In MR, a genetically predicted higher platelet count was associated with higher SBP (B = 0.02 per SD, 95% CI = 0.00 to 0.04) and DBP (B = 0.03 per SD, 95% CI = 0.01 to 0.05). IVW models and sensitivity analyses of the association between platelet count and DBP were consistent, but not all sensitivity analyses were statistically significant for the platelet count-SBP relation. Our findings indicate that platelet count has modest but significant effects on SBP and DBP, suggesting causality and providing further insight into the pathophysiology of hypertension.

Background: FGF23 (fibroblast growth factor 23) is associated with a higher mortality risk in type 2 diabetes, but the mechanism is unclear. We aimed to study whether NT-proBNP (N-terminal pro-brain natriuretic peptide) mediates the association between FGF23 and mortality., Methods and Results: We analyzed C-terminal FGF23 and NT-proBNP levels in 399 patients with type 2 diabetes. Cox regression analyses were performed, followed by mediation analyses using Structural Equation Modeling. During follow-up of 9.2 [7.6-11.3] years, 117 individuals died. FGF23 was associated with all-cause mortality, independent of potential confounders (fully adjusted hazard ratio [HR], 2.32 [95% CI, 1.21-4.43], P =0.01). The association was lost upon further adjustment for NT-proBNP (HR, 1.84; 95% CI, 0.91-3.73). NT-proBNP accounted for 26% of the mediation effect between FGF23 and all-cause mortality., Conclusions: These findings suggest that a higher FGF23 level is associated with increased mortality in individuals with type 2 diabetes through an effect on volume homeostasis.

Kidney transplant recipients (KTR) have impaired health-related quality of life (HRQoL) and suffer from intestinal dysbiosis. Increasing evidence shows that gut health and HRQoL are tightly related in the general population. Here, we investigate the association between the gut microbiome and HRQoL in KTR, using metagenomic sequencing data from fecal samples collected from 507 KTR. Multiple bacterial species are associated with lower HRQoL, many of which have previously been associated with adverse health conditions. Gut microbiome distance to the general population is highest among KTR with an impaired physical HRQoL (R = -0.20, P = 2.3 × 10 -65 ) and mental HRQoL (R = -0.14, P = 1.3 × 10 -3 ). Physical and mental HRQoL explain a significant part of variance in the gut microbiome (R 2  = 0.58%, FDR = 5.43 × 10 -4 and R 2  = 0.37%, FDR = 1.38 × 10 -3 , respectively). Additionally, multiple metabolic and neuroactive pathways (gut brain modules) are associated with lower HRQoL. While the observational design of our study does not allow us to analyze causality, we provide a comprehensive overview of the associations between the gut microbiome and HRQoL while controlling for confounders., (© 2023. The Author(s).)

Background: A potassium replete diet is associated with lower cardiovascular risk but may increase the risk of hyperkalemia, particularly in people using renin-angiotensin-aldosterone system inhibitors. We investigated whether intracellular uptake and potassium excretion after an acute oral potassium load depend on the accompanying anion and/or aldosterone and whether this results in altered plasma potassium change., Methods: In this placebo-controlled interventional cross-over trial including 18 healthy individuals, we studied the acute effects of one oral load of potassium citrate (40 mmol), potassium chloride (40 mmol), and placebo in random order after overnight fasting. Supplements were administered after a 6-week period with and without lisinopril pretreatment. Linear mixed effect models were used to compare blood and urine values before and after supplementation and between the interventions. Univariable linear regression was used to determine the association between baseline variables and change in blood and urine values after supplementation., Results: During the 4-hour follow-up, the rise in plasma potassium was similar for all interventions. After potassium citrate, both red blood cell potassium-as measure of the intracellular potassium-and transtubular potassium gradient (TTKG)-reflecting potassium secretory capacity-were higher than after potassium chloride or potassium citrate with lisinopril pretreatment. Baseline aldosterone was significantly associated with TTKG after potassium citrate, but not after potassium chloride or potassium citrate with lisinopril pretreatment. The observed TTKG change after potassium citrate was significantly associated with urine pH change during this intervention ( R =0.60, P < 0.001)., Conclusions: With similar plasma potassium increase, red blood cell potassium uptake and kaliuresis were higher after an acute load of potassium citrate as compared with potassium chloride alone or pretreatment with lisinopril., Clinical Trial Registry Name and Registration Number: Potassium supplementation in patients with chronic kidney disease and healthy subjects: effects on potassium and sodium balance, NL7618., (Copyright © 2023 by the American Society of Nephrology.)

Background: Deficiency of the essential trace element selenium is common in kidney transplant recipients (KTR), potentially hampering antioxidant and anti-inflammatory defence. Whether this impacts the long-term outcomes of KTR remains unknown. We investigated the association of urinary selenium excretion, a biomarker of selenium intake, with all-cause mortality; and its dietary determinants., Methods: In this cohort study, outpatient KTR with a functioning graft for longer than 1 year were recruited (2008-11). Baseline 24-h urinary selenium excretion was measured by mass spectrometry. Diet was assessed by a 177-item food frequency questionnaire, and protein intake was calculated by the Maroni equation. Multivariable linear and Cox regression analyses were performed., Results: In 693 KTR (43% men, 52 ± 12 years), baseline urinary selenium excretion was 18.8 (interquartile range 15.1-23.4) μg/24-h. During a median follow-up of 8 years, 229 (33%) KTR died. KTR in the first tertile of urinary selenium excretion, compared with those in the third, had over a 2-fold risk of all-cause mortality [hazard ratio 2.36 (95% confidence interval 1.70-3.28); P < .001], independent of multiple potential confounders including time since transplantation and plasma albumin concentration. The most important dietary determinant of urinary selenium excretion was protein intake (Standardized β 0.49, P < .001)., Conclusions: Relatively low selenium intake is associated with a higher risk of all-cause mortality in KTR. Dietary protein intake is its most important determinant. Further research is required to evaluate the potential benefit of accounting for selenium intake in the care of KTR, particularly among those with low protein intake., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Context: The phosphate-regulating hormone fibroblast growth factor 23 (FGF23) has been linked to deregulations in glucose metabolism, but its role is insufficiently understood., Objective: This study investigates potential crosstalk between FGF23 and glucose homeostasis., Methods: First, we investigated the effect of glucose loading on plasma C-terminal FGF23 levels and its temporal relationship with changes in plasma phosphate in 45 overweight (body mass index [BMI] 25-30) individuals using time-lag analyses. Second, we studied cross-sectional associations of plasma C-terminal FGF23 levels with glucose homeostasis using multivariable linear regression in a population-based cohort. We also investigated associations of FGF23 with incident diabetes and obesity (BMI > 30) in individuals without diabetes or obesity at baseline, respectively, using multivariable Cox regression analyses. Finally, we explored whether the association between FGF23 and diabetes depends on BMI., Results: After glucose loading, changes in FGF23 preceded changes in plasma phosphate (Ptime-lag = .04). In the population-based cohort (N = 5482; mean age 52 years, 52% women, median FGF23 69 RU/mL), FGF23 was associated with plasma glucose (β = .13 [.03-.23]; P = .01), insulin (β = .10 [.03-.17]; P < .001), and proinsulin (β = .06 [0.02-0.10]; P = .01) at baseline. On longitudinal analyses, a higher baseline FGF23 was independently associated with development of diabetes (199 events [4%]; fully adjusted hazard ratio [HR] 1.66 [95% CI, 1.06-2.60]; P = .03) and development of obesity (241 events [6%]; fully adjusted HR 1.84 [95% CI, 1.34-2.50]; P < .001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI., Conclusion: Glucose loading has phosphate-independent effects on FGF23 and, vice versa, FGF23 is associated with glucose, insulin and proinsulin levels, and obesity. These findings suggest crosstalk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Previous studies have found associations of red blood cell (RBC) traits (hemoglobin and RBC count) with blood pressure; whether these associations are causal is unknown., Methods: We performed cross-sectional analyses in the Lifelines Cohort Study (n = 167,785). Additionally, we performed bidirectional 2 sample Mendelian randomization (MR) analyses to explore the causal effect of the 2 traits on systolic (SBP) and diastolic blood pressure (DBP), using genetic instrumental variables regarding hemoglobin and RBC identified in UK Biobank (n = 350,475) and International Consortium of Blood Pressure studies for SBP and DBP (n = 757,601)., Results: In cross-sectional analyses, we observed positive associations with hypertension and blood pressure for both hemoglobin (odds ratio [OR] = 1.18, 95% confidence interval [CI]: 1.16-1.20 for hypertension; B = 0.11, 95% CI: 0.11-0.12 for SBP; B = 0.11, 95% CI: 0.10-0.11 for DBP, all per SD) and RBC (OR = 1.14, 95% CI: 1.12-1.16 for hypertension; B = 0.11, 95% CI: 0.10-0.12 for SBP; B = 0.08, 95% CI: 0.08-0.09 for DBP, all per SD). MR analyses suggested that higher hemoglobin and RBC cause higher DBP (inverse-variance weighted B = 0.11, 95% CI: 0.07-0.16 for hemoglobin; B = 0.07, 95% CI: 0.04-0.10 for RBC, all per SD). Reverse MR analyses (all per SD) suggested causal effects of DBP on both hemoglobin (B = 0.06, 95% CI: 0.03-0.09) and RBC (B = 0.08, 95% CI: 0.04-0.11). No significant effects on SBP were found., Conclusions: Our results suggest bidirectional causal relationships of hemoglobin and RBC with DBP, but not with SBP., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.)

Background: Peritubular capillary rarefaction plays an important role in the progression of chronic kidney disease. Little is known about the relation between peritubular capillary density, glomerular volume and filtration rate in the healthy kidney., Methods: In this single-center study, we included 69 living kidney donors who donated between 2005 and 2008 and had representative renal biopsies available. In all donors, glomerular filtration rate was measured using 125 I-Iothalamate before donation and at five years after donation. Before donation, the increase in glomerular filtration rate after dopamine stimulation was measured. Glomerular volume and peritubular capillary density were determined in biopsies taken at the time of transplantation. Pearson's correlation coefficient and linear regression were used to assess relations between parameters., Results: Mean donor age was 52 ± 11 years and mean measured glomerular filtration rate was 119 ± 22 mL/min before donation and 82 ± 15 mL/min at five years after donation. While peritubular capillary density (measured by either number of peritubular capillaries/50,000 μm 2 or number of peritubular capillaries/tubule) was not associated with measured glomerular filtration rate before or after donation, number of peritubular capillaries/tubule was associated with the increase in measured glomerular filtration rate after dopamine stimulation (St.β = 0.33, p = 0.004), and correlated positively with glomerular volume (R = 0.24, p = 0.047). Glomerular volume was associated with unstimulated measured glomerular filtration rate before donation (St.β = 0.31, p = 0.01) and at five years (St.β = 0.30, p = 0.01) after donation, independent of age., Conclusions: In summary, peritubular capillary density was not related to unstimulated kidney function before or after kidney donation, in contrast to glomerular volume. However, number of peritubular capillaries/tubule correlated with the increase in glomerular filtration rate after dopamine stimulation in healthy kidneys, and with glomerular volume. These findings suggest that peritubular capillary density and glomerular volume differentially affect kidney function in healthy living kidney donors., (© 2023. The Author(s).)

With rising incidence and prevalence of type 2 diabetes, prevention including identification of prospective biomarkers becomes increasingly relevant. Although ketone bodies recently received a renewed interest as potential biomarkers, data linking these metabolites to diabetes risk are scarce. Therefore, the present prospective study investigated a potential association between fasting ketone bodies and incident type 2 diabetes in the general population. This study from the PREVEND cohort included 3,307 participants from the general population initially free of diabetes or impaired fasting glucose. Baseline fasting ketone body concentrations were measured by nuclear magnetic resonance spectroscopy. One hundred twenty-six participants (3.8%) developed type 2 diabetes during a median (interquartile range) follow-up of 7.3 (6.3-7.6) years. In Kaplan-Meier analysis, sex-stratified ketone body levels strongly positively associated with incident type 2 diabetes, which was confirmed in Cox regression analyses adjusted for several potential confounders. There was no significant interaction by sex. Both 3-β-hydroxybutyrate and acetoacetate+acetone individually associated with incident type 2 diabetes. In conclusion, fasting plasma ketone body levels are strongly positively associated with incident type 2 diabetes in the general population independent of several other recognized risk factors. These results may have important implications for diabetes prevention including dietary strategies., Article Highlights: The identification of biomarkers that predict type 2 diabetes is increasingly relevant for personalized medicine strategies. Data regarding ketone bodies and incident type 2 diabetes are scarce. This study shows that ketone bodies, either combined or as individual subspecies, are strongly associated with incident type 2 diabetes in the general population, independent of potential confounders. These results may have important implications for diabetes prevention including dietary strategies., (© 2023 by the American Diabetes Association.)

Introduction: Despite recognized geographic and sex-based differences in hemoglobin in the general population, these factors are typically ignored in patients with chronic kidney disease (CKD) in whom a single therapeutic range for hemoglobin is recommended. We sought to compare the distribution of hemoglobin across international nondialysis CKD populations and evaluate predictors of hemoglobin., Methods: In this cross-sectional study, hemoglobin distribution was evaluated in each cohort overall and stratified by sex and estimated glomerular filtration rate (eGFR). Relationships between candidate predictors and hemoglobin were assessed from linear regression models in each cohort. Estimates were subsequently pooled in a random effects model., Results: A total of 58,613 participants from 21 adult cohorts (median eGFR range of 17-49 ml/min) and 3 pediatric cohorts (median eGFR range of 26-45 ml/min) were included with broad geographic representation. Hemoglobin values varied substantially among the cohorts, overall and within eGFR categories, with particularly low mean hemoglobin observed in women from Asian and African cohorts. Across the eGFR range, women had a lower hemoglobin compared to men, even at an eGFR of 15 ml/min (mean difference 5.3 g/l, 95% confidence interval [CI] 3.7-6.9). Lower eGFR, female sex, older age, lower body mass index, and diabetic kidney disease were all independent predictors of a lower hemoglobin value; however, this only explained a minority of variance (R 2 7%-44% across cohorts)., Conclusion: There are substantial regional differences in hemoglobin distribution among individuals with CKD, and the majority of variance is unexplained by demographics, eGFR, or comorbidities. These findings call for a renewed interest in improving our understanding of hemoglobin determinants in specific CKD populations., (© 2023 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.)

Background: Loss of muscle mass is linked with impaired quality of life and an increased risk of morbidity and premature mortality. Iron is essential for cellular processes such as energy metabolism, nucleotide synthesis and numerous enzymatic reactions. As the effects of iron deficiency (ID) on muscle mass and function are largely unknown, we aimed to assess the relation between ID and muscle mass in a large population-based cohort, and subsequently studied effects of ID on cultured skeletal myoblasts and differentiated myocytes., Methods: In a population-based cohort of 8592 adults, iron status was assessed by plasma ferritin and transferrin saturation, and muscle mass was estimated using 24-h urinary creatinine excretion rate (CER). The relationships of ferritin and transferrin saturation with CER were assessed by multivariable logistic regression. Furthermore, mouse C2C12 skeletal myoblasts and differentiated myocytes were subjected to deferoxamine with or without ferric citrate. Myoblast proliferation was measured with a colorimetric 5-bromo-2'-deoxy-uridine ELISA assay. Myocyte differentiation was assessed using Myh7-stainings. Myocyte energy metabolism, oxygen consumption rate and extracellular acidification rate were assessed using Seahorse mitochondrial flux analysis, and apoptosis rate with fluorescence-activated cell sorting. RNA sequencing (RNAseq) was used to identify ID-related gene and pathway enrichment in myoblasts and myocytes., Results: Participants in the lowest age- and sex-specific quintile of plasma ferritin (OR vs middle quintile 1.62, 95% CI 1.25-2.10, P < 0.001) or transferrin saturation (OR 1.34, 95% CI 1.03-1.75, P = 0.03) had a significantly higher risk of being in the lowest age- and sex-specific quintile of CER, independent of body mass index, estimated GFR, haemoglobin, hs-CRP, urinary urea excretion, alcohol consumption and smoking status. In C2C12 myoblasts, deferoxamine-induced ID reduced myoblast proliferation rate (P-trend <0.001) but did not affect differentiation. In myocytes, deferoxamine reduced myoglobin protein expression (-52%, P < 0.001) and tended to reduce mitochondrial oxygen consumption capacity (-28%, P = 0.10). Deferoxamine induced gene expression of cellular atrophy markers Trim63 (+20%, P = 0.002) and Fbxo32 (+27%, P = 0.048), which was reversed by ferric citrate (-31%, P = 0.04 and -26%, P = 0.004, respectively). RNAseq indicated that both in myoblasts and myocytes, ID predominantly affected genes involved in glycolytic energy metabolism, cell cycle regulation and apoptosis; co-treatment with ferric citrate reversed these effects., Conclusions: In population-dwelling individuals, ID is related to lower muscle mass, independent of haemoglobin levels and potential confounders. ID impaired myoblast proliferation and aerobic glycolytic capacity, and induced markers of myocyte atrophy and apoptosis. These findings suggest that ID contributes to loss of muscle mass., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)