Potential Mediating Role of Iron Biomarkers in the Association of Sex With Glucose, Insulin, and Type 2 Diabetes.

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 (ß = -.01; 95% CI -0.02, -0.01) and FPI (ß = -.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.

Vitamin C deficiency after kidney transplantation: a cohort and cross-sectional study of the TransplantLines biobank.

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 m2), 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.

Pre-donation Assessment of Cystatin C to Improve Prediction of Pre- and Post-Donation GFR in Potential Living Kidney Donors.

BACKGROUND AND HYPOTHESIS: Accurate estimation of glomerular filtration rate (GFR) is crucial in living kidney donation. While most 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 CKD-EPI equations based on creatinine (eGFRcreat-2009, eGFRcreat-2021), cystatin C (eGFRCysC-2012), or both (eGFRcombined-2012, eGFRcombined-2021) for estimating pre- and post-donation measured 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/1.73m2) 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 to equations based on only creatinine. CONCLUSIONS: In conclusion, combined eGFR equations yielded a better estimate of pre- and post-donation mGFR, compared to estimates based on creatinine or CysC only. The added value of CysC seems particularly pronounced in donors with high or low muscle mass.

Iron deficiency, anemia, and patient-reported outcomes in kidney transplant recipients.

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.

Serum T50 predicts cardiovascular mortality in individuals with type 2 diabetes: A prospective cohort study.

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 T50. 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 T50 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 m2 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.

Urinary vanin-1, tubular injury, and graft failure in kidney transplant recipients.

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 m2) 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.

Coffee consumption and risk of kidney function decline in a Dutch population-based cohort.

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 m2 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 m2. 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 (ß [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.

Utility of iron biomarkers in differentiating menopausal status: Findings from CoLaus and PREVEND.

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.

Fibroblast growth factor 23 and calcium-phosphate metabolism in relation to cardiovascular risk factors in patients with type 1 diabetes.

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.

Micronutrient deficiencies and new-onset atrial fibrillation in a community-based cohort: data from PREVEND.

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. Micronutrients deficiencies (selenium, iron, and magnesium) have been associated with cardiovascular diseases and mitochondrial dysfunction in human cardiomyocytes. However, it is not known whether these deficiencies are associated with atrial fibrillation. To investigate this question, we measured all three micronutrients in 5452 apparently healthy individuals. After a mean follow-up of 6.2 years, there were 136 participants who developed atrial fibrillation. Participants with selenium deficiency had a significant increased risk to develop atrial fibrillation, as did the participants with two or more deficiencies.

Iron deficiency is related to lower muscle mass in community-dwelling individuals and impairs myoblast proliferation.

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.

Fabry disease with atypical phenotype identified by massively parallel sequencing in early-onset kidney failure.

Background: The cause of chronic kidney disease (CKD) remains unknown in ∼20% of patients with kidney failure. Massively parallel sequencing (MPS) can be a valuable diagnostic tool in patients with unexplained CKD, with a diagnostic yield of 12%-56%. Here, we report the use of MPS to establish a genetic diagnosis in a 24-year-old index patient who presented with hypertension, nephrotic-range proteinuria and kidney failure of unknown origin. Additionally, we describe a second family with the same mutation presenting with early-onset CKD. Results: In Family 1, MPS identified a known pathogenic variant in GLA (p.Ile319Thr), and plasma globotriaosylsphingosine and α-galactosidase A activity were compatible with the diagnosis of Fabry disease (FD). Segregation analysis identified three other family members carrying the same pathogenic variant who had mild or absent kidney phenotypes. One family member was offered enzyme therapy. While FD could not be established with certainty as the cause of kidney failure in the index patient, no alternative explanation was found. In Family 2, the index patient had severe glomerulosclerosis and a kidney biopsy compatible with FD at the age of 30 years, along with cardiac involvement and a history of acroparesthesia since childhood, in keeping with a more classical Fabry phenotype. Conclusion: These findings highlight the large phenotypic heterogeneity associated with GLA mutations in FD and underline several important implications of MPS in the work-up of patients with unexplained kidney failure.

Iron Deficiency and Nephrotoxic Heavy Metals: A Dangerous Interplay?

Heavy metals are common in our environment, and all individuals are exposed to them to some extent. These toxic metals have several harmful effects on the body, including the kidney, which is a very sensitive organ. Indeed, heavy metal exposure has been linked to an increased risk of chronic kidney disease (CKD) and its progression, which may be explained by the well-established nephrotoxic effects of these metals. In this hypothesis and narrative literature review, we will shed light on the potential role that another highly common problem in patients with CKD, iron deficiency, may play in the damaging effects of heavy metal exposure in this patient group. Iron deficiency has previously been linked with an increased uptake of heavy metals in the intestine due to the upregulation of iron receptors that also take up other metals. Furthermore, recent research suggests a role of iron deficiency in the retention of heavy metals in the kidney. Therefore, we hypothesize that iron deficiency plays a crucial role in the damaging effects of heavy metal exposure in patients with CKD and that iron supplementation might be a strategy to combat these detrimental processes.

Plasma Neutrophil Gelatinase-Associated Lipocalin Associates with New-Onset Chronic Kidney Disease in the General Population.

Circulating levels of neutrophil gelatinase-associated lipocalin (NGAL) have been associated with acute kidney injury and the severity and progression of chronic kidney disease (CKD). This study investigated its potential utility as a biomarker for the risk of new-onset CKD in a population-based cohort study. Individuals without CKD at baseline (n = 4660) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) prospective population-based cohort study in the Netherlands were included. Baseline plasma NGAL concentrations were investigated for their associations with new-onset CKD, defined as a composite outcome of an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, urinary albumin excretion (UAE) > 30 mg/24-h, or both. Mean (±SD) plasma NGAL concentrations were 104.0 (±34.7) µg/L and median eGFR was 96 [IQR: 85.3-105.8] mL/min/1.73 m2. After median follow-up of 8.3 [IQR: 7.8-8.9] years, 467 participants developed new-onset CKD. Plasma NGAL concentrations were significantly associated with an increased risk of new-onset CKD (hazard ratio [HR] per doubling 1.35 [95% CI: 1.11-1.63], p = 0.002), even after adjustment for potentially confounding factors (1.37 [1.09-1.73], p = 0.007) except baseline eGFR (1.09 [0.86-1.37], p = 0.490). In secondary analyses, plasma NGAL concentrations were significantly associated with new-onset CKD as defined by eGFR < 60 mL/min/1.73 m2 alone (adjusted HR per doubling 2.54 [1.69-3.80], p < 0.001), which was abrogated after adjustment for eGFR (1.05 [0.69-1.59], p = 0.828), also when UAE > 30 mg/24-h was set as individual outcome (1.05 [0.82-1.35], p = 0.705). Higher plasma NGAL concentrations are associated with an increased risk of developing CKD in the general population. This association is dependent on renal function, and mainly driven by new-onset CKD as defined by renal function decline.

Iron deficiency and cognitive functioning in kidney transplant recipients: findings of the TransplantLines biobank and cohort study.

BACKGROUND: Neurocognitive impairment is common in kidney transplant recipients (KTRs). Adequate brain functioning requires energy and neurotransmitter activity, for which iron is essential. We aimed to investigate iron deficiency (ID) as a potentially modifiable risk factor for cognitive impairment in KTRs. METHODS: We analyzed stable KTRs participating in the TransplantLines Biobank and Cohort study. Participants underwent neuropsychological tests for memory, mental speed, and attention and executive functioning. ID was defined as ferritin <100 µg/mL or 100-299 µg/mL with transferrin saturation (TSAT) ≤20%. Associations between iron status and norm scores of neurocognitive outcomes, corrected for age, sex and education, were assessed using multivariable linear regression analyses adjusted for potential confounders including hemoglobin. RESULTS: We included 166 KTRs [median (IQR) age 57 (45-65) years, 59% male, estimated glomerular filtration rate 51±18 mL/min/1.73 m2]. Time since transplantation was 5.8 (1.0-12.0) years. Prevalence of ID was 65%. ID was independently associated with lower scores for mental speed (std.ß = -0.19, P = .02) and attention and executive functioning (std.ß = -0.19, P = .02), and tended to be associated with worse memory (std.ß = -0.16, P = .07). Lower plasma ferritin levels were associated with worse memory (std.ß = 0.23, P = .007), mental speed (std.ß = 0.34, P < .001), and attention and executive functioning (std.ß = 0.30, P = .001). Lower TSAT was associated with worse memory (std.ß = 0.19, P = .04) and mental speed (std.ß = 0.27, P = .003), and tended to be associated with worse attention and executive functioning (std.ß = 0.16, P = .08). CONCLUSIONS: Iron-deficient KTRs performed worse on neurocognitive tasks measuring memory, mental speed, and attention and executive functioning. These findings set the stage for prospective studies addressing whether ID correction restores cognitive function after kidney transplantation.

Prediction of measured GFR after living kidney donation from pre-donation parameters.

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 <90 mL/min/1.73 m2, a declining 5-year post-donation mGFR slope or age >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 <55 mL/min/1.73 m2. A model using pre-donation serum creatinine, age and sex performed optimally, predicting mGFR with good accuracy (mean bias 2.56 mL/min/1.73 m2, R2 = 0.29, root mean square error = 11.61) and precision [bias interquartile range (IQR) 14 mL/min/1.73 m2] in the external validation cohort. This model also performed well in donors with pre-donation eGFR <90 mL/min/1.73 m2 [bias 0.35 mL/min/1.73 m2 (IQR 10)], in donors with a negative post-donation mGFR slope [bias 4.75 mL/min/1.73 m2 (IQR 13)] and in donors >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.

Sex and N-terminal pro B-type natriuretic peptide: The potential mediating role of iron biomarkers.

Background: Levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), a marker of heart failure and cardiovascular risk, are generally higher in women than men. We explored whether iron biomarkers mediate sex differences in NT-proBNP levels. Methods: We included 5,343 community-dwelling individuals from the Prevention of Renal and Vascular Endstage Disease study. With linear regression analyses, we investigated the association of sex and iron biomarkers with NT-proBNP levels, independent of adjustment for potential confounders. The assessed iron biomarkers included ferritin, transferrin saturation (TSAT), hepcidin, and soluble transferrin receptor (sTfR). Next, we performed mediation analyses to investigate to which extent iron biomarkers influence the association between sex and NT-proBNP. Results: Of the included 5,343 participants, the mean standard deviation age was 52.2 ± 11.6 years and 52% were females. After adjustment for potential confounders, women compared to men, had higher NT-proBNP (ß = 0.31; 95%CI = 0.29, 0.34), but lower ferritin (ß = -0.37; 95%CI = -0.39, -0.35), hepcidin (ß = -0.22, 95%CI = -0.24, -0.20), and TSAT (ß = -0.07, 95% CI = -0.08, -0.06). Lower ferritin (ß = -0.05, 95%CI = -0.08, -0.02), lower hepcidin (ß = -0.04, 95%CI = -0.07, -0.006), and higher TSAT (ß = 0.07; 95%CI = 0.01, 0.13) were associated with higher NT-proBNP. In mediation analyses, ferritin and hepcidin explained 6.5 and 3.1% of the association between sex and NT-proBNP, respectively, while TSAT minimally suppressed (1.9%) this association. Conclusion: Our findings suggest that iron biomarkers marginally explain sex differences in levels of NT-proBNP. Future studies are needed to explore causality and potential mechanisms underlying these pathways.

Microscopic Hematuria at Kidney Donor Screening and Post-Donation Kidney Outcomes.

Although guidelines recommend a kidney biopsy in prospective living kidney donors with unexplained microscopic hematuria, individuals with mild hematuria are commonly allowed to donate without a biopsy. However, the prognostic implications of pre-donation hematuria are unclear. We investigated whether pre-donation microscopic hematuria is associated with changes in post-donation eGFR, proteinuria, or blood pressure. We included 701 living kidney donors with two pre-donation urinalyses and post-donation annual evaluations of the estimated glomerular filtration rate (eGFR), protein/creatinine ratio (PCR), and systolic blood pressure (SBP). The association between pre-donation microscopic hematuria and outcomes was assessed using generalized linear mixed models. The median [interquartile range] follow-up was 5 (2-8) years. Eighty-eight donors had pre-donation microscopic hematuria. There were no significant associations between microscopic hematuria at screening and the course of eGFR (0.44 mL/min/1.73 m2 increase/year for hematuria donors vs. 0.34 mL/min/1.73 m2 increase/year for non-hematuria donors (p = 0.65)), PCR (0.02 vs. 0.04 mg/mmol increase/year, p = 0.38), or SBP (1.42 vs. 0.92 mmHg increase/year, p = 0.17) post-donation, even after adjusting for potential confounders. Additional analyses in high-risk subgroups yielded similar results. In this study, pre-donation microscopic hematuria was not associated with post-donation eGFR decline, proteinuria, or hypertension. Microscopic hematuria may reflect primary kidney disease in only a limited subset of donors. Future studies should identify high-risk donor profiles that require further investigation.