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Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Vitamin K deficiency is common among kidney transplant recipients (KTRs) and likely contributes to progressive vascular calcification and stiffness. In this single-center, randomized, double-blind, placebo-controlled trial, we aimed to investigate the effects of vitamin K supplementation on the primary end point, serum calcification propensity (calciprotein particle maturation time, T50), and secondary end points arterial stiffness (pulse wave velocity [PWV]) and vitamin K status in 40 vitamin K-deficient KTRs (plasma dephosphorylated uncarboxylated matrix Gla protein [dp-ucMGP] ≥500 pmol/L). Participants (35% female; age, 57 ± 13 years) were randomized 1:1 to vitamin K2 (menaquinone-7, 360 μg/day) or placebo for 12 weeks. Vitamin K supplementation had no effect on calcification propensity (change in T50 vs baseline +2.3 ± 27.4 minutes) compared with placebo (+0.8 ± 34.4 minutes; Pbetween group = .88) but prevented progression of PWV (change vs baseline -0.06 ± 0.26 m/s) compared with placebo (+0.27 ± 0.43 m/s; Pbetween group = .010). Vitamin K supplementation strongly improved vitamin K status (change in dp-ucMGP vs baseline -385 [-631 to -269] pmol/L) compared with placebo (+39 [-188 to +183] pmol/L; Pbetween group < .001), although most patients remained vitamin K-deficient. In conclusion, vitamin K supplementation did not alter serum calcification propensity but prevented progression of arterial stiffness, suggesting that vitamin K has vascular effects independent of calciprotein particles. These results set the stage for longer-term intervention studies with vitamin K supplementation in KTRs.TRIAL REGISTRY: EU Clinical Trials Register (EudraCT Number: 2019-004906-88) and the Dutch Trial Register (NTR number: NL7687).

Background: Observational studies suggest that adequate dietary potassium intake (90-120 mmol/day) may be renoprotective, but the effects of increasing dietary potassium and the risk of hyperkalemia are unknown. Methods: This is a pre-specified analysis of the run-in phase of a clinical trial in which 191 patients (age 68 +/- 11 years, 74% males, 86% European ancestry, eGFR 31 +/- 9 mL/min/1.73 m(2), 83% renin-angiotensin system inhibitors, 38% diabetes) were treated with 40 mmol KCl/day for two weeks. Results: KCl supplementation significantly increased urinary potassium excretion (72 +/- 24 to 107 +/- 29 mmol/day), plasma potassium (4.3 +/- 0.5 to 4.7 +/- 0.6 mmol/L), and plasma aldosterone (281 [198-431] to 351 [241-494] ng/L), but had no significant effect on urinary sodium excretion, plasma renin, blood pressure, eGFR, or albuminuria. Furthermore, KCl supplementation increased plasma chloride (104 +/- 3 to 105 +/- 4 mmol/L), reduced plasma bicarbonate (24.5 +/- 3.4 to 23.7 +/- 3.5 mmol/L) and urine pH (all P < 0.001), but did not change urinary ammonium excretion. Twenty-one participants (11%) developed hyperkalemia (plasma potassium 5.9 +/- 0.4 mmol/L). They were older and had higher baseline plasma potassium. Conclusions: In patients with CKD stage G3b-4, increasing dietary potassium intake to recommended levels with potassium chloride supplementation raises plasma potassium by 0.4 mmol/L. This may result in hyperkalemia in older patients or those with higher baseline plasma potassium. Longer-term studies should address whether cardiorenal protection outweighs the risk of hyperkalemia.

Funder: Dutch Kidney Foundation, AIMS: A potassium replete diet is associated with lower blood pressure (BP) and lower risk of cardiovascular disease (CVD). Whether these associations differ between men and women and whether they depend on daily sodium intake is unknown. METHODS AND RESULTS: An analysis was performed in 11 267 men and 13 696 women from the EPIC-Norfolk cohort. Twenty-four hour excretion of sodium and potassium, reflecting intake, was estimated from sodium and potassium concentration in spot urine samples using the Kawasaki formula. Linear and Cox regression were used to explore the association between potassium intake, systolic BP (SBP), and CVD events (defined as hospitalization or death due to CVD). After adjustment for confounders, interaction by sex was found for the association between potassium intake and SBP (P < 0.001). In women, but not in men, the inverse slope between potassium intake and SBP was steeper in those within the highest tertile of sodium intake compared with those within the lowest tertile of sodium intake (P < 0.001 for interaction by sodium intake). Both in men and women, higher potassium intake was associated with a lower risk of CVD events, but the hazard ratio (HR) associated with higher potassium intake was lower in women than in men [highest vs. lowest potassium intake tertile: men: HR 0.93, 95% confidence interval (CI) 0.87-1.00; women: HR 0.89, 95% CI 0.83-0.95, P = 0.033 for interaction by sex]. CONCLUSION: The association between potassium intake, SBP, and CVD events is sex specific. The data suggest that women with a high sodium intake in particular benefit most from a higher potassium intake with regard to SBP.

Background One of the challenges in living kidney donor screening is to estimate remaining kidney function after donation. Here we developed a new model to predict post-donation measured glomerular filtration rate (mGFR) from pre-donation serum creatinine, age and sex. Methods In the prospective development cohort (TransplantLines, n = 511), several prediction models were constructed and tested for accuracy, precision and predictive capacity for short- and long-term post-donation 125I-iothalamate mGFR. The model with optimal performance was further tested in specific high-risk subgroups (pre-donation eGFR 65 years) and validated in internal (n = 509) and external (Mayo Clinic, n = 1087) cohorts. Results In the development cohort, pre-donation estimated GFR (eGFR) was 86 ± 14 mL/min/1.73 m2 and post-donation mGFR was 64 ± 11 mL/min/1.73 m2. Donors with a pre-donation eGFR ≥90 mL/min/1.73 m2 (present in 43%) had a mean post-donation mGFR of 69 ± 10 mL/min/1.73 m2 and 5% of these donors reached an mGFR 65 years of age [bias 0.003 mL/min/1.73 m2 (IQR 9)]. Conclusions We developed a novel post-donation mGFR prediction model based on pre-donation serum creatinine, age and sex.

BACKGROUND: Post-transplant anaemia and reduced muscle mass and strength are highly prevalent in kidney transplant recipients (KTRs). Decreased haemoglobin levels, a marker of anaemia, could adversely affect muscle mass and strength through multiple mechanisms, among others, through diminished tissue oxygenation. We aimed to investigate the association between haemoglobin levels with muscle mass and strength in KTRs.METHODS: We included stable KTRs from the TransplantLines Biobank and Cohort study with a functional graft ≥1 year post-transplantation. Muscle mass was assessed using 24 h urinary creatinine excretion rate (CER) and bioelectrical impedance analysis (BIA). Muscle strength was assessed with a handgrip strength test using a dynamometer and, in a subgroup (n = 290), with the five-times sit-to-stand (FTSTS) test. We used multivariable linear and logistic regression analyses to investigate the associations of haemoglobin levels with muscle mass and strength.RESULTS: In 871 included KTRs [median age 58 (interquartile range (IQR), 48-66)] years; 60% men; eGFR 51 ± 18 mL/min/1.73 m2 ) who were 3.5 (1.0-10.2) years post-transplantation, the mean serum haemoglobin level was 13.9 ± 1.8 g/dL in men and 12.8 ± 1.5 g/dL in women. Lower haemoglobin levels were independently associated with a lower CER (std. β = 0.07, P = 0.01), BIA-derived skeletal muscle mass (std. β = 0.22, P < 0.001), handgrip strength (std. β = 0.15, P < 0.001), and worse FTSTS test scores (std. β = -0.17, P = 0.02). KTRs in the lowest age-specific and sex-specific quartile of haemoglobin levels had an increased risk of being in the worst age-specific and sex-specific quartile of CER (fully adjusted OR, 2.09; 95% CI 1.15-3.77; P = 0.02), handgrip strength (fully adjusted OR, 3.30; 95% CI 1.95-5.59; P < 0.001), and FTSTS test score (fully adjusted OR, 7.21; 95% CI 2.59-20.05; P < 0.001).CONCLUSIONS: Low haemoglobin levels are strongly associated with decreased muscle mass and strength in KTRs. Future investigation will need to investigate whether maintaining higher haemoglobin levels may improve muscle mass and strength in KTRs.

Background. The effect of pregnancy on the course of estimated glomerular filtration rate (eGFR) is unknown in kidney transplant recipients (KTRs). Methods. We conducted a nationwide multicenter cohort study in KTRs with pregnancy (>20 wk) after kidney transplantation (KT). Annual eGFRs after KT until death or graft loss and additional eGFRs before each pregnancy were collected according to protocol. Changes in eGFR slope before and after each pregnancy were analyzed by generalized estimating equations multilevel analysis adjusted for transplant vintage. Results. We included 3194 eGFR measurements before and after pregnancy in 109 (55%) KTRs with 1, 78 (40%) with 2, and 10 (5%) with 3 pregnancies after KT. Median follow-up after first delivery post-KT was 14 y (interquartile range, 18 y). Adjusted mean eGFR prepregnancy was 59 mL/min/1.73 m2(SEM [standard error of the mean] 1.72; 95% confidence interval [CI], 56-63), after the first pregnancy 56 mL/min/1.73 m2(SEM 1.70; 95% CI, 53-60), after the second pregnancy 56 mL/min/1.73 m2(SEM 2.19; 95% CI, 51-60), and after the third pregnancy 55 mL/min/1.73 m2(SEM 8.63; 95% CI, 38-72). Overall eGFR slope after the first, second, and third pregnancies was not significantly worse than prepregnancy (P = 0.28). However, adjusted mean eGFR after the first pregnancy was 2.8 mL/min/1.73 m2(P = 0.08) lower than prepregnancy. Conclusions. The first pregnancy has a small, but insignificant, effect on eGFR slope in KTRs. Midterm hyperfiltration, a marker for renal reserve capacity, was associated with better eGFR and death-censored graft survival. In this KTR cohort with long-term follow-up, no significant effect of pregnancy on kidney function was detected.

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.

BACKGROUND AND OBJECTIVES: The estimated glomerular filtration rate (eGFR) is a crucial parameter in heart failure. Much less is known about the importance of tubular function. We addressed the effect of tubular maximum phosphate reabsorption capacity (TmP/GFR), a parameter of proximal tubular function, in patients with heart failure.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We established TmP/GFR (Bijvoet formula) in 2085 patients with heart failure and studied its association with deterioration of kidney function (>25% eGFR decrease from baseline) and plasma neutrophil gelatinase-associated lipocalin (NGAL) doubling (baseline to 9 months) using logistic regression analysis and clinical outcomes using Cox proportional hazards regression. Additionally, we evaluated the effect of sodium-glucose transport protein 2 (SGLT2) inhibition by empagliflozin on tubular maximum phosphate reabsorption capacity in 78 patients with acute heart failure using analysis of covariance.RESULTS: Low TmP/GFR (CONCLUSIONS: TmP/GFR, a measure of proximal tubular function, is frequently reduced in heart failure, especially in patients with more advanced heart failure. Lower TmP/GFR is furthermore associated with future risk of plasma NGAL doubling and worse clinical outcomes, independent of glomerular function.

Objectives Most data on glomerular filtration rate (GFR) originate from subjects Methods mGFR percentiles were calculated from a development cohort of French/Belgian living kidney donors Results Individuals in the development cohort had a higher mGFR (99.9 ± 16.4 vs. 86.4 ± 14 and 82.7 ± 15.5 mL/min/1.73 m2) compared to the individuals in the validation cohorts. In the internal validation cohort, none (0%) had mGFR below the extrapolated P5, 12 (8.2%) above P95 and 135 (91.8%) between P5–P95. In the external validation cohort, five subjects had mGFR below the extrapolated P5 (1.5%), 25 above P95 (7.6%) and 299 (90.9%) between P5–P95. Conclusions We demonstrate that extrapolation of mGFR from younger donors is possible and might aid with decision-making in elderly donors.

IntroductionIron deficiency (ID) is common and has been associated with an excess mortality risk in kidney transplant recipients (KTRs). In patients with chronic heart failure and ID, intravenous iron improves exercise capacity and quality of life. Whether these beneficial effects also occur in KTRs is unknown. The main objective of this trial is to address whether intravenous iron improves exercise tolerance in iron-deficient KTRs.Methods and analysisThe Effect of Ferric Carboxymaltose on Exercise Capacity after Kidney Transplantation study is a multicentre, double-blind, randomised, placebo-controlled clinical trial that will include 158 iron-deficient KTRs. ID is defined as plasma ferritin 3+/mL, intravenously) or placebo (0.9% sodium chloride solution) every 6 weeks, four dosages in total. The primary endpoint is change in exercise capacity, as quantified by the 6 min walk test, between the first study visit and the end of follow-up, 24 weeks later. Secondary endpoints include changes in haemoglobin levels and iron status, quality of life, systolic and diastolic heart function, skeletal muscle strength, bone and mineral parameters, neurocognitive function and safety endpoints. Tertiary (explorative) outcomes are changes in gut microbiota and lymphocyte proliferation and function.Ethics and disseminationThe protocol of this study has been approved by the medical ethical committee of the University Medical Centre Groningen (METc 2018/482;) and is being conducted in accordance with the principles of the Declaration of Helsinki, the Standard Protocol Items: Recommendations for Interventional Trials checklist and the Good Clinical Practice guidelines provided by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Study results will be disseminated through publications in peer-reviewed journals and conference presentations.Trial registration numberNCT03769441.

Kidney transplant recipients (KTR) are at increased risk of cardiovascular mortality. We investigated whether, in KTR, post-transplantation copper status is associated with the risk of cardiovascular mortality and potential effect modification by sex. In this cohort study, plasma copper was measured using mass spectrometry in extensively-phenotyped KTR with a functioning allograft >1-year. Cox regression analyses with the inclusion of multiplicative interaction terms were performed. In 660 KTR (53 ± 13 years old, 56% male), the median baseline plasma copper was 15.42 (IQR 13.53–17.63) µmol/L. During a median follow-up of 5 years, 141 KTR died, 53 (38%) due to cardiovascular causes. Higher plasma copper was associated with an increased risk of cardiovascular mortality in the overall KTR population (HR 1.37; 95% CI, 1.07–1.77 per 1-SD, p = 0.01). Sex was a significant effect modifier of this association (Pinteraction = 0.01). Among male KTR, higher plasma copper concentration was independently associated with a two-fold higher risk of cardiovascular mortality (HR 2.09; 95% CI, 1.42–3.07 per 1-SD, p < 0.001). Among female KTR, this association was absent. This evidence offers a rationale for considering a sex-specific assessment of copper’s role in cardiovascular risk evaluation. Further studies are warranted to elucidate whether copper-targeted interventions may decrease cardiovascular mortality in male KTR.

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 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.

Background: Several studies have found a U-shaped association between sodium intake and mortality. The increased mortality risk of low sodium intake has raised debates and hampers widespread acceptance of public health campaigns and dietary guidelines on reducing sodium intake. Whether the excess risk can be attributed to low sodium intake alone or concomitant inadequate intake of other relevant nutrients is unknown. Objective: We investigated whether concomitant low protein intake could explain the lower part of the U-shaped association of sodium intake with all-cause mortality. Methods: We included 1603 individuals aged between 60 and 75 years old from the gender- and socioeconomic status-balanced prospective Lifelines-MINUTHE cohort study. Using multivariable Cox regression analyses, we investigated the association of sodium intake (24 h urinary sodium excretion) with all-cause mortality, including the interaction with protein intake calculated from the Maroni formula. Results: Mean intakes of sodium and protein were 3.9 ± 1.6 g/day and 1.1 ± 0.3 g/kg/day, respectively. After a median follow-up of 8.9 years, 125 individuals (7.8%) had died. The proportion of participants with insufficient protein intake (4.7 g/day; hazard ratio (HR) 1.74 (95% confidence interval (CI) 1.03–2.95)) and the lowest two quartiles of sodium intake (Q1, 0.7–2.8 g/day; 2.05 (1.16–3.62); p = 0.01 and Q2, 2.8–3.6 g/day; 1.85 (1.08–3.20); p = 0.03), compared with the third quartile of sodium intake (Q3, 3.6–4.7 g/day). This U-shaped association was significantly modified by protein intake (Pinteraction = 0.006), with the increased mortality risk of low sodium intake being reversed to the lowest mortality risk with concomitant high protein intake. In contrast, the increased mortality risk of low sodium intake was magnified by concomitant low protein intake. Conclusions: We found that a higher protein intake counteracts the increased mortality risk observed in subjects with a low sodium intake. In contrast, a joint low intake of sodium and protein is associated with an increased mortality risk, allegedly due to poor nutritional status. These findings support the guidelines that advocate a lower sodium intake, while highlighting the importance of recognizing overall nutritional status among older adults.

BackgroundKidney transplant recipients (KTRs) have an impaired immune response after vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Iron deficiency (ID) may adversely affect immunity and vaccine efficacy. We aimed to investigate whether ferric carboxymaltose (FCM) treatment improves humoral and cellular responses after SARS-CoV-2 vaccination in iron-deficient KTRs.MethodsWe randomly assigned 48 iron-deficient KTRs to intravenous FCM (1-4 doses of 500mg with six-week intervals) or placebo. Co-primary endpoints were SARS-CoV-2-specific anti-Receptor Binding Domain (RBD) Immunoglobulin G (IgG) titers and T-lymphocyte reactivity against SARS-CoV-2 at four weeks after the second vaccination with mRNA-1273 or mRNA-BNT162b2.ResultsAt four weeks after the second vaccination, patients receiving FCM had higher plasma ferritin and transferrin saturation (PP=0.07) and SARS-CoV-2-specific T-lymphocyte activation (FCM: 93.3 [0.85-342.5] IFN-ɣ spots per 106 peripheral blood mononuclear cells (PBMCs), placebo: 138.3 [0.0-391.7] IFN-ɣ spots per 106 PBMCs, P=0.83) were not significantly different among both arms. After the third vaccination, SARS-CoV-2-specific anti-RBD IgG titers remained similar between treatment groups (P=0.99).ConclusionsIntravenous iron supplementation efficiently restored iron status but did not improve the humoral or cellular immune response against SARS-CoV-2 after three vaccinations.

Rationale & Objective: Prior studies report that the use of proton pump inhibitors (PPIs) can adversely affect gut microbiota and gastrointestinal uptake of micronutrients, in particular iron and magnesium, and are used frequently by kidney transplant recipients. Altered gut microbiota, iron deficiency, and magnesium deficiency have been implicated in the pathogenesis of chronic fatigue. Therefore, we hypothesized that PPI use may be an important and underappreciated cause of fatigue and reduced health-related quality of life (HRQoL) in this population. Study Design: Cross-sectional study. Setting & Participants: Kidney transplant recipients (≥1 year after transplantation) enrolled in the TransplantLines Biobank and Cohort Study. Exposure: PPI use, PPI type, PPI dosage, and duration of PPI use. Outcome: Fatigue and HRQoL, assessed using the validated Checklist Individual Strength 20 Revised questionnaire and Short Form-36 questionnaire. Analytical Approach: Logistic and linear regression. Results: We included 937 kidney transplant recipients (mean age 56 ± 13 years, 39% female) at a median of 3 (1-10) years after transplantation. PPI use was associated with fatigue severity (regression coefficient 4.02, 95% CI, 2.18 to 5.85, P < 0.001), a higher risk of severe fatigue (OR 2.05, 95% CI, 1.48 to 2.84, P < 0.001), lower physical HRQoL (regression coefficient −8.54, 95% CI, −11.54 to −5.54, P < 0.001), and lower mental HRQoL (regression coefficient −4.66, 95% CI, −7.15 to −2.17, P < 0.001). These associations were independent of potential confounders including age, time since transplantation, history of upper gastrointestinal disease, antiplatelet therapy, and the total number of medications. They were present among all individually assessed PPI types and were dose dependent. Duration of PPI exposure was only associated with fatigue severity. Limitations: Residual confounding and inability to assess causal relationships. Conclusions: PPI use is independently associated with fatigue and lower HRQoL among kidney transplant recipients. PPI use might be an easily accessible target for alleviating fatigue and improving HRQoL among kidney transplant recipients. Further studies examining the effect of PPI exposure in this population are warranted.

Background Acidosis-induced kidney injury is mediated by the intrarenal renin-angiotensin system, for which urinary renin is a potential marker. Therefore, we hypothesized that sodium bicarbonate supplementation reduces urinary renin excretion in patients with chronic kidney disease (CKD) and metabolic acidosis. Methods Patients with CKD stage G4 and plasma bicarbonate 15–24 mmol/l were randomized to receive sodium bicarbonate (3 × 1000 mg/day, ~ 0.5 mEq/kg), sodium chloride (2 × 1,00 mg/day), or no treatment for 4 weeks (n = 15/arm). The effects on urinary renin excretion (primary outcome), other plasma and urine parameters of the renin-angiotensin system, endothelin-1, and proteinuria were analyzed. Results Forty-five patients were included (62 ± 15 years, eGFR 21 ± 5 ml/min/1.73m2, plasma bicarbonate 21.7 ± 3.3 mmol/l). Sodium bicarbonate supplementation increased plasma bicarbonate (20.8 to 23.8 mmol/l) and reduced urinary ammonium excretion (15 to 8 mmol/day, both P P = 0.07) and potassium (5.1 to 4.8 mmol/l, P = 0.06) was observed in patients receiving sodium bicarbonate. Sodium bicarbonate did not significantly change the urinary excretion of renin, angiotensinogen, aldosterone, endothelin-1, albumin, or α1-microglobulin. Sodium chloride supplementation reduced plasma renin (166 to 122 ng/L), and increased the urinary excretions of angiotensinogen, albumin, and α1-microglobulin (all P Conclusions Despite correction of acidosis and reduction in urinary ammonium excretion, sodium bicarbonate supplementation did not improve urinary markers of the renin-angiotensin system, endothelin-1, or proteinuria. Possible explanations include bicarbonate dose, short treatment time, or the inability of urinary renin to reflect intrarenal renin-angiotensin system activity. Graphic abstract

Background: Low 24-h urinary potassium excretion, reflecting low potassium intake, is associated with premature mortality in the general population.Objectives: To determine whether urinary potassium excretion is associated with all-cause mortality in patients with type 2 diabetes.Methods: We performed a prospective cohort study in 654 patients with type 2 diabetes in the Diabetes and Lifestyle Cohort Twente (DIALECT). Sex-specific tertiles of 24-h urinary potassium excretion were analyzed in a multivariable Cox regression model with all-cause mortality. The outpatient program of the hospital uses a continuous surveillance system by the municipal registry of death to ensure up-to-date information on the patient's status (alive or deceased). FFQs were used to study associations between urinary potassium excretion and food products.Results: Urinary potassium excretion at baseline was 84 ± 25 mmol/d in males and 65 ± 22 mmol/d in females, corresponding to estimated potassium intakes of 4250 ± 1270 mg/d and 3300 ± 875 mg/d. During a median follow-up of 5.2 (IQR: 2.7−7.9] y, 96 participants died. In a fully adjusted model, patients in the lowest sex-specific tertile had a higher risk of all-cause mortality, compared with patients in the highest sex-specific tertile (HR: 2.09; 95% CI: 1.06, 4.10; P = 0.03). Patients in the lowest sex-specific tertile consumed fewer fruits and vegetables, dairy, coffee, and potato products compared with patients in the highest sex-specific tertile (all P < 0.05).Conclusions: Low potassium intake is associated with a higher risk of all-cause mortality in Dutch patients with type 2 diabetes. Intervention studies are needed to determine whether potassium supplementation improves longevity in patients with type 2 diabetes. This trial was registered in the Dutch Trial Register as NTR trial code 5855.

BACKGROUND AND OBJECTIVES: High dietary acid load may accelerate a decline in kidney function. We prospectively investigated whether dietary acid load is associated with graft outcomes in kidney transplant recipients, and whether venous bicarbonate mediates this association.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used data from 642 kidney transplant recipients with a functioning graft ≥1 year after transplantation. Net endogenous acid production was estimated using food frequency questionnaires and, alternatively, 24-hour urinary urea and potassium excretion to estimate net endogenous acid production. We defined the composite kidney end point as a doubling of plasma creatinine or graft failure. Multivariable Cox regression analyses, adjusted for potential confounders, were used to study the associations of dietary acid load with the kidney end point. We evaluated potential mediation effects of venous bicarbonate, urinary bicarbonate excretion, urinary ammonium excretion, titratable acid excretion, and net acid excretion on the association between net endogenous acid production and the kidney end point.RESULTS: The median net endogenous acid production using food frequency questionnaires and net endogenous acid production using urinary excretion were 40 (interquartile range, 35-45) and 54 (interquartile range, 44-66) mEq/day, respectively. During a median follow-up of 5.3 years (interquartile range, 4.1-6.0), 121 (19%) participants reached the kidney end point. After multivariable adjustment, net endogenous acid production using food frequency questionnaires and net endogenous acid production using urinary excretion (per SD higher) were independently associated with higher risk for kidney end point (hazard ratio, 1.33; 95% confidence interval, 1.12 to 1.57, P=0.001 and hazard ratio, 1.44; 95% confidence interval, 1.24 to 1.69, PCONCLUSIONS: Higher dietary acid load was associated with a higher risk of doubling of plasma creatinine or graft failure, and this association was partly mediated by venous bicarbonate, urinary ammonium, and net acid excretion.

RATIONALE & AIMS: Healthy dietary patterns have been associated with a lower risk of chronic kidney disease (CKD). We aimed to investigate the association of a fully food-based diet quality score assessed by the Lifelines Diet Score (LLDS) with either incident CKD or eGFR decline in the general population.METHODS: For this study, data from a prospective general population-based Lifelines cohort in the Northern Netherlands was used. Diet was assessed with a 110-item food frequency questionnaire at baseline. The LLDS, based on international evidence for diet-disease relations at the food group level, was calculated to assess diet quality. For the analysis, the score was divided into tertiles. Logistic regression was performed to evaluate the association of the LLDS at baseline with either incident CKD (eGFR RESULTS: A total of 78 346 participants free of CKD at baseline were included. During a mean (SD) follow-up of 3.6 ± 0.9 years, 2071 (2.6%) participants developed CKD and 7611 (9.7%) had a ≥20% eGFR decline. Participants in the highest tertile of LLDS had a lower risk of incident CKD (fully adjusted OR 0.83, [95% CI: 0.72-0.96]) and ≥20% eGFR decline (fully adjusted OR 0.80, [95% CI: 0.75-0.86]), compared with those in the lowest tertile. Similar dose-response associations were observed in continuous LLDS.CONCLUSIONS: Higher adherence to a high-quality diet was associated with a lower risk of incident CKD or ≥20% eGFR decline in the general population.

Disturbances in calcium‐phosphate homeostasis are common after kidney transplantation. We aimed to assess the relationship between deregulations in plasma calcium and phosphate over time and mortality and death‐censored graft failure (DCGF). In this prospective cohort study, we included kidney transplant recipients with ≥2 plasma calcium and phosphate measurements. Data were analyzed using time‐updated Cox regression analyses adjusted for potential confounders including time‐updated kidney function. We included 2769 patients (mean age 47 ± 14 years, 42.3% female) with 138 496 plasma calcium and phosphate levels (median [IQR] 43 [31–61] measurements per patient). During follow‐up of 16.3 [8.7–25.2] years, 17.2% developed DCGF and 7.9% died. Posttransplant hypercalcemia was associated with an increased risk of mortality (1.63 [1.31–2.00], p, This prospective cohort study shows that, in patients with preserved kidney function, hypercalcemia is associated with increased mortality risk.

The kidney is one of the most sensitive organs to cadmium-induced toxicity, particularly in conditions of long-term oxidative stress. We hypothesized that, in kidney transplant recipients, nephrotoxic exposure to cadmium represents an overlooked hazard for optimal graft function. To test this, we performed a prospective cohort study and included 672 outpatient kidney transplant recipients with a functioning graft of beyond one year. The median plasma cadmium was 58 ng/L. During a median 4.9 years of follow-up, 78 kidney transplant recipients developed graft failure with a significantly different distribution across tertiles of plasma cadmium (13, 26, and 39 events, respectively). Plasma cadmium was associated with an increased risk of graft failure (hazard ratio 1.96, 95% confidence interval 1.56-2.47 per log(2) ng/L). Similarly, a dose-response relationship was observed over increasing tertiles of plasma cadmium, after adjustments for potential confounders (donor, recipient, transplant and lifestyle characteristics), robust in both competing risk and sensitivity analyses. These findings were also consistent for kidney function decline (graft failure or doubling of serum creatinine). Thus, plasma cadmium is independently associated with an increased risk of long-term kidney graft failure and decline in kidney function. Further studies are needed to investigate whether exposure to cadmium represents an otherwise overlooked modifiable risk factor for adverse long-term graft outcomes in different populations.

Objective To explore the association of both plasma vitamin D and K concentrations with all-cause mortality, cardiovascular mortality, and cardiovascular events in the general population. Methods We studied 4742 participants of the Prevention of REnal and Vascular ENd-Stage Disease (PREVEND) Study. At baseline, vitamin D and K status was determined by measurement of 25-hydroxyvitamin D [25(OH)D] and dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP), respectively. Patients were categorized into: 25(OH)D 75 nmol/L and dp-ucMGP Results Mean age was 52.6 ± 11.9 years and 2513 (53%) were female. During a median of 14.2 year follow-up, 620 participants died of which 142 were due to cardiovascular causes. Combined low vitamin D and K status was present in 970 participants (20%) and was associated with a greater risk of all-cause mortality compared to high vitamin D and high vitamin K status group (n = 1424) after adjusting for potential confounders: hazard ratio 1.46 (95% confidence intervals 1.12–1.90). We observed similar trends, albeit non-significant for cardiovascular mortality, and cardiovascular events: 1.42 (0.79–2.55), 1.28 (0.93–1.77), respectively. Conclusions Combined low vitamin D and K status are associated with increased all-cause mortality risk and possibly with cardiovascular mortality and cardiovascular events compared with adequate vitamin D and K status. Future studies should investigate the effect of combined vitamin D and K supplementation on clinical outcomes.

Low 24 h urinary potassium excretion, reflecting low potassium intake, is associated with premature mortality in the general population.Whether urinary potassium excretion is associated with all-cause mortality in patients with type 2 diabetes is unknown.We performed a prospective cohort study in 654 patients with type 2 diabetes of the Diabetes and Lifestyle Cohort Twente (DIALECT). Sex-specific tertiles of 24 h urinary potassium excretion were analysed in a multivariable Cox regression model with all-cause mortality. The outpatient program of the hospital uses a continuous surveillance system by the municipal registry of death to ensure up-to-date information on the patient's status (alive or deceased). Food frequency questionnaires were used to study associations between urinary potassium excretion and food products.Urinary potassium excretion at baseline was 84 ± 25 mmol·day-1 in males and 65 ± 22 mmol·day-1 in females, corresponding to estimated potassium intakes of 4250 ± 1270 mg·day-1 and 3300 ± 875 mg·day-1. During median follow-up for 5.2 [interquartile range 2.7 - 7.9] years, 96 participants died. In a fully adjusted model, patients in the lowest sex-specific tertile had a higher risk of all-cause mortality, compared with patients in the highest sex-specific tertile (HR: 2.09; 95% CI: 1.06, 4.10; P = 0.03). Patients in the lowest sex-specific tertile consumed less fruits and vegetables, dairy, coffee, and potato products compared with patients in the highest sex-specific tertile (all P 0.05).Low potassium intake is associated with a higher risk of all-cause mortality in Dutch patients with type 2 diabetes. Intervention studies are needed to determine whether potassium supplementation improves longevity in patients with type 2 diabetes.

Background Arterial stiffness and calcification propensity are associated with high cardiovascular risk and increased mortality in chronic kidney disease (CKD). Both magnesium and phosphate are recognized as modulators of vascular calcification and chronic inflammation, both features of CKD that contribute to arterial stiffness. In this paper, we outline the rationale and design of a randomized controlled trial (RCT) investigating whether 24 weeks of oral magnesium supplementation with or without additional phosphate-binding therapy can improve arterial stiffness and calcification propensity in patients with stage 3–4 CKD. Methods In this multi-center, placebo-controlled RCT, a total of 180 participants with an estimated glomerular filtration rate of 15 to 50 ml/min/1.73 m2 without phosphate binder therapy will be recruited. During the 24 weeks intervention, participants will be randomized to one of four intervention groups to receive either magnesium citrate (350 mg elemental magnesium/day) or placebo, with or without the addition of the phosphate binder sucroferric oxyhydroxide (1000 mg/day). Primary outcome of the study is the change of arterial stiffness measured by the carotid-femoral pulse wave velocity over 24 weeks. Secondary outcomes include markers of calcification and inflammation, among others calcification propensity (T50) and high-sensitivity C-reactive protein. As explorative endpoints, repeated 18F-FDG and 18F-NaF PET-scans will be performed in a subset of participants (n = 40). Measurements of primary and secondary endpoints are performed at baseline, 12 and 24 weeks. Discussion The combined intervention of magnesium citrate supplementation and phosphate-lowering therapy with sucroferric oxyhydroxide, in stage 3–4 CKD patients without overt hyperphosphatemia, aims to modulate the complex and deregulated mineral metabolism leading to vascular calcification and arterial stiffness and to establish to what extent this is mediated by T50 changes. The results of this combined intervention may contribute to future early interventions for CKD patients to reduce the risk of CVD and mortality. Trial registration Netherlands Trial Register, NL8252 (registered December 2019), EU clinical Trial Register 2019-001306-23 (registered November 2019).

Introduction: Fasting plasma ketone bodies (KB) are elevated in individuals with type 2 diabetes (T2D) and could affect glycemic control and disease progression. Prolonged KB exposure may result in adaptive beneficial responses, counteracting glycemic dysregulation. In the current proof-of-concept study in adults with T2D, we hypothesized that fasting plasma KB are cross-sectionally associated with poorer glycemic control but prospectively with better glycemic control. Materials and Methods: Fasting plasma KB were measured via nuclear magnetic resonance spectroscopy in patients with T2D treated in primary care (Zodiac cohort; The Netherlands). We analyzed the associations between KB and HbA1c at baseline using linear regression analyses and HbA1c changes over time using linear mixed models. We adjusted for potential confounders, including risk factors for poor glycemic control. Individuals with T2D participating in the general population-based PREVEND study were used as a replication cohort. Results: We included 271 individuals with T2D with a total of 859 HbA1c measurements during a follow-up period of 3.0 (2.0–3.2) years. At baseline, the total amount of fasting plasma KB was independently and positively associated with HbA1c levels (regression coefficient in the fully adjusted analysis = 0.31; 95% CI 0.06–0.57, per doubling of KB; p = 0.02). In contrast, in the longitudinal analyses, fasting plasma KB were associated with a yearly HbA1c (%) decrease of −0.10 (95% CI −0.19 to −0.00 per doubling baseline KB; p = 0.05). Results were replicated in 387 individuals with T2D from a general population cohort with a total of 1115 glucose measurements during a follow-up period of 7.5 (7.2–8.0) years. A yearly decrease in fasting plasma glucose (mmol/L) of 0.09 was found per doubling of baseline KB. Conclusions: This study is the first to suggest a paradoxical role of circulating KB on glycemic control in T2D: elevated KB are associated with cross-sectionally poorer glycemic control but longitudinally with better long-term glycemic control.

Background The role of fibroblast growth factor 23 (FGF23) in the development of new‐onset heart failure (HF) with reduced (HFrEF) or preserved ejection fraction (HFpEF) in the general population is unknown. Therefore, we set out to investigate associations of C‐terminal FGF23 with development of new‐onset HF and, more specifically, with HFrEF or HFpEF in a large, prospective, population‐based cohort. Methods and Results We studied 6830 participants (aged 53.8±12.1 years; 49.7% men; estimated glomerular filtration rate, 93.1±15.7 mL/min per 1.73 m 2 ) in the community‐based PREVEND (Prevention of Renal and Vascular End‐Stage Disease) study who were free of HF at baseline. Cross‐sectional multivariable linear regression analysis showed that ferritin (standardized β, −0.24; P P Conclusions Higher FGF23 is independently associated with new‐onset HFrEF in analyses fully adjusted for cardiovascular risk factors and other potential confounders. The association between FGF23 and incident HFpEF lost statistical significance upon multivariable adjustment.

Fasting proinsulin levels may serve as a marker of β-cell dysfunction and predict type 2 diabetes (T2D) development. Kidneys have been found to be a major site for the degradation of proinsulin. We aimed to evaluate the predictive value of proinsulin for the risk of incident T2D added to a base model of clinical predictors and examined potential effect modification by variables related to kidney function. Proinsulin was measured in plasma with U-PLEX platform using ELISA immunoassay. We included 5001 participants without T2D at baseline and during a median follow up of 7.2 years; 271 participants developed T2D. Higher levels of proinsulin were associated with increased risk of T2D independent of glucose, insulin, C-peptide, and other clinical factors (hazard ratio (HR): 1.28; per 1 SD increase 95% confidence interval (CI): 1.08–1.52). Harrell’s C-index for the Framingham offspring risk score was improved with the addition of proinsulin (p = 0.019). Furthermore, we found effect modification by hypertension (p = 0.019), eGFR (p = 0.020) and urinary albumin excretion (p = 0.034), consistent with an association only present in participants with hypertension or kidney dysfunction. Higher fasting proinsulin level is an independent predictor of incident T2D in the general population, particularly in participants with hypertension or kidney dysfunction.

BACKGROUND: Ultra-processing makes food products more convenient, appealing, and profitable. Recent studies show that high ultra-processed food (UPF) intake is associated with the cardio-metabolic disease.OBJECTIVES: The aim of this study is to investigate the association between UPF consumption and risk of kidney function decline in the general population.METHODS: In a prospective general population-based Lifelines cohort from Northern Netherlands, 78 346 participants free of chronic kidney disease (CKD) at baseline responded to a 110-item food frequency questionnaire. We used multivariable regression analysis to study the association of the proportion (in gram/day) of UPF in the total diet with a composite kidney outcome (incident CKD or a ≥ 30% eGFR decline relative to baseline) and annual change in estimated glomerular filtration rate (eGFR).RESULTS: On average, 37.7% of total food intake came from UPF. After 3.6 ± 0.9 years of follow-up, 2 470 participants (3.2%) reached the composite kidney outcome. Participants in the highest quartile of UPF consumption were associated with a higher risk of the composite kidney outcome (OR 1.27, [95% CI: 1.09, 1.47], P = 0.003) compared with those in the lowest quartile, regardless of macro/micronutrient intake or diet quality. Participants in the highest quartile had a more rapid eGFR decline (β -0.17, [95% CI: -0.23, -0.11], P < 0.001) compared with those in the lowest quartile. Associations were generally consistent across different subgroups.CONCLUSIONS: Higher UPF consumption was associated with a higher risk of a composite kidney outcome (incident CKD or ≥ 30% eGFR decline) and a more rapid eGFR decline in the general population, independent of confounders and other dietary indices.

Objective Increasing magnesium intake might reduce the risk of cardiovascular disease (CVD). Whether potential effects on cortisol contribute to these beneficial effects on cardiovascular health remains unclear. We therefore studied effects of long-term oral magnesium supplementation on glucocorticoid metabolism, specifically on the excretion of urinary cortisol, cortisone and their metabolites, as well as on the ratios reflecting enzymatic activity of 11 beta-hydroxysteroid dehydrogenases (11 beta-HSDs) and A-ring reductases.Design A post-hoc analysis of a randomized trial with allocation to a magnesium supplement (350 mg/day) or a placebo for 24-week.Patients Forty-nine overweight men and women, aged between 45 and 70 years.Measurements Cortisol, cortisone and their metabolites (tetrahydrocortisol [THF], allo-tetrahydrocortisol [allo-THF] and tetrahydrocortisone [THE]) were measured in 24-h urine samples. Enzymatic activities of 11 beta-HSD overall and of 11 beta-HSD type 2 were estimated as the urinary (THF + allo-THF [THFs])/THE and cortisol/cortisone ratios, respectively. A-ring reductase activity was assessed by ratios of THF/allo-THF, allo-THF/cortisol, THF/cortisol and THE/cortisone.Results After 24-week, urinary cortisol excretion was decreased in the magnesium group as compared with the placebo group (-32 nmol/24-h, 95% CI: -59; -5 nmol/24-h, p = .021). Ratios of THFs/THE and cortisol/cortisone were decreased following magnesium supplementation by 0.09 (95% CI: 0.02; 0.17, p = .018) and 0.10 (95% CI: 0.03; 0.17, p = .005), respectively. No effects were observed on A-ring reductase activity.Conclusions We observed a beneficial effect of magnesium supplementation towards a lower 24-h urinary cortisol excretion together with an increased activity of 11 beta-HSD type 2. Our findings may provide another potential mechanism by which increased magnesium intake lowers CVD risk (ClinicalTrials.gov identifier: NCT02235805).