The Effect of Magnesium Supplementation on Vascular Calcification in CKD: A Randomized Clinical Trial (MAGiCAL-CKD).

SIGNIFICANCE STATEMENT: Magnesium prevents vascular calcification in animals with CKD. In addition, lower serum magnesium is associated with higher risk of cardiovascular events in CKD. In a randomized, double-blinded, placebo-controlled trial, the authors investigated the effects of magnesium supplementation versus placebo on vascular calcification in patients with predialysis CKD. Despite significant increases in plasma magnesium among study participants who received magnesium compared with those who received placebo, magnesium supplementation did not slow the progression of vascular calcification in study participants. In addition, the findings showed a higher incidence of serious adverse events in the group treated with magnesium. Magnesium supplementation alone was not sufficient to delay progression of vascular calcification, and other therapeutic strategies might be necessary to reduce the risk of cardiovascular disease in CKD. BACKGROUND: Elevated levels of serum magnesium are associated with lower risk of cardiovascular events in patients with CKD. Magnesium also prevents vascular calcification in animal models of CKD. METHODS: To investigate whether oral magnesium supplementation would slow the progression of vascular calcification in CKD, we conducted a randomized, double-blinded, placebo-controlled, parallel-group, clinical trial. We enrolled 148 subjects with an eGFR between 15 and 45 ml/min and randomly assigned them to receive oral magnesium hydroxide 15 mmol twice daily or matching placebo for 12 months. The primary end point was the between-groups difference in coronary artery calcification (CAC) score after 12 months adjusted for baseline CAC score, age, and diabetes mellitus. RESULTS: A total of 75 subjects received magnesium and 73 received placebo. Median eGFR was 25 ml/min at baseline, and median baseline CAC scores were 413 and 274 in the magnesium and placebo groups, respectively. Despite plasma magnesium increasing significantly during the trial in the magnesium group, the baseline-adjusted CAC scores did not differ significantly between the two groups after 12 months. Prespecified subgroup analyses according to CAC>0 at baseline, diabetes mellitus, or tertiles of serum calcification propensity did not significantly alter the main results. Among subjects who experienced gastrointestinal adverse effects, 35 were in the group receiving magnesium treatment versus nine in the placebo group. Five deaths and six cardiovascular events occurred in the magnesium group compared with two deaths and no cardiovascular events in the placebo group. CONCLUSIONS: Magnesium supplementation for 12 months did not slow the progression of vascular calcification in CKD, despite a significant increase in plasma magnesium. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov ( NCT02542319 ).

Cardiovascular Risk Following Conversion to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: A Randomized Clinical Trial.

Rationale & Objective: In kidney transplant recipients (KTRs), a belatacept-based immunosuppressive regimen is associated with beneficial effects on cardiovascular (CV) risk factors compared with calcineurin inhibitor (CNI)-based regimens. Our objective was to compare the calculated CV risk between belatacept and CNI (predominantly tacrolimus) treatments using a validated model developed for KTRs. Study Design: Prospective, randomized, open-label, parallel-group, investigator-initiated, international multicenter trial. Setting & Participants: KTRs aged 18-80 years with a stable graft function (estimated glomerular filtration rate > 20 mL/min/1.73 m2), 3-60 months after transplantation, treated with tacrolimus or cyclosporine A, were eligible for inclusion. Intervention: Continuation with a CNI-based regimen or switch to belatacept for 12 months. Outcomes: Comparison of the change in the estimated 7-year risk of major adverse CV events and all-cause mortality, changes in traditional markers of CV health, as well as measures of arterial stiffness. Results: Among the 105 KTRs randomized, we found no differences between the treatment groups in the predicted risk for major adverse CV events or mortality. Diastolic blood pressure, measured both centrally by using a SphygmoCor device and peripherally, was lower after the belatacept treatment than after the CNI treatment. The mean changes in traditional cardiovascular (CV) risk factors, including kidney transplant function, were otherwise similar in both the treatment groups. The belatacept group had 4 acute rejection episodes; 2 were severe rejections, of which 1 led to graft loss. Limitations: The heterogeneous baseline estimated glomerular filtration rate and time from transplantation to trial enrollment in the participants. A limited study duration of 1 year. Conclusions: We found no effects on the calculated CV risk by switching to the belatacept treatment. Participants in the belatacept group had not only lower central and peripheral diastolic blood pressure but also a higher rejection rate. Funding: The trial has received a financial grant from Bristol-Myers Squibb. Trial Registration: EudraCT no. 2013-001178-20.

Novel Biomarkers Detected by Proteomics Predict Death and Cardiovascular Events in Hemodialysis Patients.

End-stage kidney disease increases mortality and the risk of cardiovascular (CV) disease. It is crucial to explore novel biomarkers to predict CV disease in the complex setting of patients receiving hemodialysis (HD). This study investigated the association between 92 targeted proteins with all-cause death, CV death, and composite vascular events (CVEs) in HD patients. From December 2010 to March 2011, 331 HD patients were included and followed prospectively for 5 years. Serum was analyzed for 92 CV-related proteins using Proseek Multiplex Cardiovascular I panel, a high-sensitivity assay based on proximity extension assay (PEA) technology. The association between biomarkers and all-cause death, CV death, and CVEs was evaluated using Cox-regression analyses. Of the PEA-based proteins, we identified 20 proteins associated with risk of all-cause death, 7 proteins associated with risk of CV death, and 17 proteins associated with risk of CVEs, independent of established risk factors. Interleukin-8 (IL-8), T-cell immunoglobulin and mucin domain 1 (TIM-1), and C-C motif chemokine 20 (CCL20) were associated with increased risk of all-cause death, CV death, and CVE in multivariable-adjusted models. Stem cell factor (SCF) and Galanin peptides (GAL) were associated with both decreased risk of all-cause death and CV death. In conclusion, IL-8, TIM-1, and CCL20 predicted death and CV outcomes in HD patients. Novel findings were that SCF and GAL were associated with a lower risk of all-cause death and CV death. The SCF warrants further study with regard to its possible biological effect in HD patients.

Prognostic value of computed tomography derived fractional flow reserve for predicting cardiac events and mortality in kidney transplant candidates.

BACKGROUND: Cardiac screening using coronary computed tomography angiography (CCTA) in kidney transplant candidates before transplantation yields both diagnostic and prognostic information. Whether CT-derived fractional flow reserve (FFRCT) analysis provides prognostic information is unknown. This study aimed to assess the prognostic value of FFRCT for predicting major adverse cardiac events (MACE) and all-cause mortality in kidney transplant candidates. METHODS: Among 553 consecutive kidney transplant candidates, 340 CCTA scans (61%) were evaluated with FFRCT analysis. Patients were categorized into groups based on lowest distal FFRCT; normal >0.80, intermediate 0.80-0.76, and low ≤0.75. In patients with ≥50% stenosis, a lesion-specific FFRCT was defined as; normal >0.80 and abnormal ≤0.80. The primary endpoint was MACE (cardiac death, resuscitated cardiac arrest, myocardial infarction or revascularization). The secondary endpoint was all-cause mortality. RESULTS: Median follow-up was 3.3 years [2.0-5.1]. MACE occurred in 28 patients (8.2%), 29 patients (8.5%) died. When adjusting for risk factors and transplantation during follow-up, MACE occurred more frequently in patients with distal FFRCT ≤0.75 compared to patients with distal FFRCT >0.80: Hazard Ratio (HR): 3.8 (95%CI: 1.5-9.7), p â€‹< â€‹0.01. In the lesion-specific analysis with <50% stenosis as reference, patients with lesion-specific FFRCT >0.80 had a HR for MACE of 1.5 (95%CI: 0.4-4.8), p â€‹= â€‹0.55 while patients with lesion-specific FFRCT ≤0.80 had a HR of 6.0 (95%CI: 2.5-14.4), p â€‹< â€‹0.01. Abnormal FFRCT values were not associated with increased mortality. CONCLUSION: In kidney transplant candidates, abnormal FFRCT values were associated with increased MACE but not mortality. Use of FFRCT may improve cardiac evaluation prior to transplantation.

Associations of Serum Uromodulin and Urinary Epidermal Growth Factor with Measured Glomerular Filtration Rate and Interstitial Fibrosis in Kidney Transplantation.

INTRODUCTION: Noninvasive biomarkers that reflect tubular health and allow early recognition of accelerated graft fibrosis development are warranted. Serum uromodulin (sUmod) and urinary epidermal growth factor (uEGF) originate from kidney tubules and may reflect functional nephron mass. The aim of this study was to investigate the associations between sUmod and uEGF with measured glomerular filtration rate (mGFR) and kidney allograft interstitial fibrosis percentage (IF%) score. METHODS: sUmod and uEGF measurements, mGFR by iohexol-clearance and kidney allograft biopsies were obtained from kidney transplant recipients (KTRs) included in the Omega-3 fatty acids in Renal Transplantation (ORENTRA) trial at 8 weeks (baseline) and at 1 year after transplantation (end of study). Associations were analyzed with univariable and multivariable linear regression. RESULTS: Ninety patients at baseline and 48 patients at end of study had complete study variable assessments. uEGF normalized to urinary creatinine (uEGF/Cr) was associated with mGFR both at baseline (standardized ß-coefficient [Std. ß-coeff] = 0.457 [p = <0.001]) and at end of study (Std. ß-coeff = 0.637 [p = <0.001]). sUmod was only associated with mGFR at end of study (Std. ß-coeff = 0.443 [p = 0.002]). uEGF/Cr, sUmod, and mGFR were associated with graft IF% score both at baseline (Std. ß-coeff = -0.349 [p = 0.001], -0.274 [p = 0.009] and -0.289 [p = 0.006], respectively) and at end of study (Std. ß-coeff = -0.365 [p = 0.011], -0.347 [p = 0.016] and -0.405 [p = 0.004], respectively). The results remained largely unchanged in multivariable analysis. CONCLUSION: uEGF/Cr and sUmod were associated with mGFR and graft IF% score. Our results indicate a possible role of uEGF/Cr and sUmod in the follow-up of KTRs.

Multiplex proteomics as risk predictor of infection in patients treated with hemodialysis-A prospective multicenter study.

INTRODUCTION: Severe infection is a major problem in hemodialysis patients. Multiplex proteomics might reveal novel insights into disease mechanisms increasing the risk of infection and might also be used as a risk prediction tool. The aims of this study were (1) to evaluate associations between 92 proteins assessed by a proximity extension assay and the development of severe infection in patients on hemodialysis and (2) to develop a risk prediction model for severe infection using prespecified clinical variables and proteomics. METHODS: Prospective, observational multicenter cohort study with 5-year follow-up. Patients receiving in-center hemodialysis in five facilities in Denmark were included. The primary composite endpoint was death caused by infection, bacteremia, and infections requiring hospitalization of at least 2 days or prolonging a hospital stay. FINDINGS: Of 331 patients included 210 patients reached the primary endpoint during follow-up. In adjusted Cox regression analyses, 14 plasma proteins were associated with severe infection. Correcting for multiple testing revealed only cathepsin-L1 and interleukin-6 significantly associated with the primary outcome. Cathepsin-L1-hazard ratio: 1.64 (95% confidence interval [CI] 1.24-2.17) and interleukin-6-hazard ratio: 1.16 (95% CI 1.05-1.29). Apparent C-statistics of the risk prediction model using clinical variables was 0.605, addition of cathepsin-L1 and interleukin-6 to the model improved discrimination slightly: C = 0.625. DISCUSSION: Proteomic profiling identified cathepsin-L1 and interleukin-6 as markers for infectious risk in hemodialysis patients. Further studies are needed to replicate the results and to examine possible causality. The developed risk prediction models need considerable improvement before implementation in clinical practice is meaningful.

Osteoprotegerin predicts cardiovascular events in patients treated with haemodialysis.

BACKGROUND: Disturbances in bone mineral metabolism are associated with increased mortality and cardiovascular events (CVEs). However, the association between bone-associated protein biomarkers, mortality and CVEs independent of cytokine activation remains unknown. This study aimed to investigate bone-associated protein biomarkers and the association with inflammatory cytokines and cardiovascular (CV) outcomes. METHODS: This prospective study enrolled haemodialysis patients in Denmark between December 2010 and March 2011. Using a proximity extension proteomics assay, nine bone-associated proteins were examined: cathepsin D (CTSD), cathepsin L1 (CTSL1), dickkopf-related protein 1, fibroblast growth factor 23, leptin, osteoprotegerin (OPG), receptor activator of nuclear factor kappa-Β ligand, TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptor 2 (TRAIL-R2). The importance of the bone-associated protein markers was evaluated by a random forest (RF) algorithm. The association between bone-associated proteins with all-cause death, CV death and CVEs was analysed in multivariable Cox models adjusted for age, gender, comorbidities, laboratory data and dialysis duration. RESULTS: We enrolled 331 patients [63.7% men; mean age, 65 years (standard deviation 14.6)] in a prospective cohort study with 5 years of follow-up. When adjusting for confounders, CTSL1 remained associated with all-cause death and four biomarkers were associated with CVEs. However, the association between bone markers and the outcomes was attenuated after adjusting for inflammatory proteins and only OPG remained associated with CVEs in the adjusted model. Evaluating the importance of bone markers by RF, OPG was the most important marker related to CVEs. OPG also improved the prediction of CVEs in integrated discrimination improvement and net reclassification improvement analyses. CONCLUSIONS: OPG, a well-known bone biomarker, was associated with CVEs independent of cytokine activity. In contrast, the association between CVEs and the remaining three bone-associated proteins (TRAIL-R2, CTSD and CTSL1) was affected by cytokine inflammation activity.

Marine n-3 Polyunsaturated Fatty Acids and Cellular Senescence Markers in Incident Kidney Transplant Recipients: The Omega-3 Fatty Acids in Renal Transplantation (ORENTRA) Randomized Clinical Trial.

RATIONALE & OBJECTIVE: Deterioration of kidney graft function is associated with accelerated cellular senescence. Marine n-3 polyunsaturated fatty acids (PUFAs) have favorable properties that may counteract cellular senescence development and damage caused by the senescence-associated secretory phenotype (SASP) secretome. Our objective was to investigate the potential effects of marine n-3 PUFA supplementation on the SASP secretome in kidney transplant recipients. STUDY DESIGN: Exploratory substudy of the Omega-3 Fatty Acids in Renal Transplantation trial. SETTING & PARTICIPANTS: Adult kidney transplant recipients with a functional kidney graft (defined as having an estimated glomerular filtration rate of >30 mL/min/1.73 m2) 8 weeks after engraftment were included in this study conducted in Norway. ANALYTICAL APPROACH: The intervention consisted of 2.6 g of a marine n-3 PUFA or olive oil (placebo) daily for 44 weeks. The outcome was a predefined panel of SASP components in the plasma and urine. RESULTS: A total of 132 patients were enrolled in the Omega-3 Fatty Acids in Renal Transplantation trial, and 66 patients were allocated to receive either the study drug or placebo. The intervention with the marine n-3 PUFA was associated with reduced plasma levels of granulocyte colony-stimulating factor, interleukin 1α, macrophage inflammatory protein 1α, matrix metalloproteinase (MMP)-1, and MMP-13 compared with the intervention in the control group. LIMITATIONS: Post hoc analysis. CONCLUSIONS: The results suggest that marine n-3 PUFA supplementation has mitigating effects on the plasma SASP components granulocyte colony-stimulating factor, interleukin 1α, macrophage inflammatory protein 1α, MMP-1, and MMP-13 in kidney transplant recipients. Future studies with kidney transplant recipients in maintenance phase, combined with an evaluation of cellular senescence markers in kidney transplant biopsies, are needed to further elucidate the potential antisenescent effect of marine n-3 PUFAs. This trial is registered as NCT01744067.

Soluble ST2 concentrations associate with in-hospital mortality and need for mechanical ventilation in unselected patients with COVID-19.

OBJECTIVE: Soluble ST2 (sST2) reflects inflammation, endothelial dysfunction and myocardial fibrosis, is produced in the lungs and is an established biomarker in heart failure. We sought to determine the role of sST2 in COVID-19 by assessing pathophysiological correlates and its association to in-hospital outcomes. METHODS: We enrolled 123 consecutive, hospitalised patients with COVID-19 in the prospective, observational COVID-19 MECH study. Biobank samples were collected at baseline, day 3 and day 9. The key exposure variable was sST2, and the outcome was ICU treatment with mechanical ventilation or in-hospital death. RESULTS: Concentrations of sST2 at baseline was median 48 (IQR 37-67) ng/mL, and 74% had elevated concentrations (>37.9 ng/mL). Higher baseline sST2 concentrations were associated with older age, male sex, white race, smoking, diabetes, hypertension and chronic kidney disease. Baseline sST2 also associated with the presence of SARS-CoV-2 viraemia, lower oxygen saturation, higher respiratory rate and increasing concentrations of biomarkers reflecting inflammation, thrombosis and cardiovascular disease. During the hospitalisation, 8 (7%) patients died and 27 (22%) survivors received intensive care unit (ICU) treatment. Baseline sST2 concentrations demonstrated a graded association with disease severity (median, IQR): medical ward 43 (36-59) ng/mL; ICU 67 (39-104) ng/mL and non-survivors 107 (72-116) ng/mL (p<0.001 for all comparisons). These associations persisted at day 3 and day 9 . CONCLUSIONS: sST2 concentrations associate with SARS-CoV-2 viraemia, hypoxaemia and concentrations of inflammatory and cardiovascular biomarkers. There was a robust association between baseline sST2 and disease severity that was independent of, and superior to, established risk factors. sST2 reflects key pathophysiology and may be a promising biomarker in COVID-19. TRIAL REGISTRATION NUMBER: NCT04314232.

Marine n-3 Polyunsaturated Fatty Acids and Bone Mineral Density in Kidney Transplant Recipients: A Randomized, Placebo-Controlled Trial.

Kidney transplant recipients are at high risk of progressive bone loss and low-energy fractures in the years following transplantation. Marine n-3 polyunsaturated fatty acids (n-3 PUFA) supplementation may have beneficial effects on bone strength. The Omega-3 fatty acids in Renal Transplantation (ORENTRA) trial was an investigator initiated, randomized, placebo-controlled trial investigating the effects of marine n-3 PUFA supplementation after kidney transplantation. Effects of supplementation on bone mineral density (BMD) and calcium metabolism were pre-defined secondary endpoints. Adult kidney transplant recipients (n = 132) were randomized to 2.6 g marine n-3 PUFA supplement or olive oil (control) from 8 to 52 weeks post-transplant. Dual energy X-ray absorptiometry was performed to assess changes in bone mineral density of hip, spine, and forearm, as well as trabecular bone score (TBS) of the lumbar spine. Student's t test was used to assess between-group differences. There were no differences in ΔBMD between the two groups (intervention vs. control) at lumbar spine (-0.020 ± 0.08 vs. -0.007 ± 0.07 g/cm², p = 0.34), total hip (0.001 ± 0.03 vs. -0.005 ± 0.04, p = 0.38), or other skeletal sites in the intention-to-treat analyses. There was no difference in the change in TBS score (0.001 ± 0.096 vs. 0.009 ± 0.102, p = 0.62). Finally, no effect on biochemical parameters of mineral metabolism was seen. Results were similar when analyzed per protocol. In conclusion, we found no significant effect of 44 weeks of supplementation with 2.6 g of marine n-3 PUFA on BMD in kidney transplant recipients.

Severe Acute Respiratory Syndrome Coronavirus 2 RNA in Plasma Is Associated With Intensive Care Unit Admission and Mortality in Patients Hospitalized With Coronavirus Disease 2019.

The clinical significance of severe acute respiratory syndrome coronavirus 2 RNA in the circulation is unknown. In this prospective cohort study, we detected viral RNA in the plasma of 58 of 123 (47%) patients hospitalized with coronavirus disease 2019. RNA was detected more frequently, and levels were higher, in patients who were admitted to the intensive care unit and/or died.

Marine n-3 fatty acid consumption in a Norwegian renal transplant cohort: Comparison of a food frequency questionnaire with plasma phospholipid marine n-3 levels.

BACKGROUND: High levels of plasma marine n-3 fatty acids (n-3FAs) are associated with improved patient and graft survival in renal transplant recipients (RTRs). The aim of this study was to evaluate the utility of a new food frequency questionnaire (FFQ) to estimate marine n-3FA consumption in future epidemiological research. METHODS: We developed an FFQ with a simple design of 10 questions to assess intake of marine sources of n-3FAs. RTRs included in the recent ORENTRA trial (n = 132) completed the study FFQ at the baseline visit eight weeks after engraftment and at the end of study visit one year post-transplant. We measured the reference biomarker plasma phospholipid (PL) marine n-3FA levels by gas chromatography at the same time points to evaluate association and degree of agreement between FFQ based marine n-3FA consumption estimates and the biomarker. RESULTS: The median plasma PL marine n-3FA level was 6.0 weight percentage (wt)% (interquartile range [IQR] 4.7 to 7.3) at baseline and 6.3 wt% (IQR 4.8 to 7.4) at end of study. Median FFQ based marine n-3FA consumption estimates were 22.8 g/month (IQR 13.0 to 34.0) at baseline and 20.3 g/month (IQR 14.5 to 32.3) at end of study. FFQ based marine n-3FA consumption estimates showed a moderate correlation with plasma PL marine n-3FA levels at baseline (Spearman's correlation coefficient rs = 0.43, p<0.001) and a stronger correlation at end of study (rs = 0.62, p<0.001). Bland Altman plots showed a reasonable degree of agreement between the two methods at both time points. CONCLUSIONS: Marine n-3FA consumption estimates based on the FFQ showed a moderate correlation with the reference biomarker plasma PL marine n-3FA levels. The FFQ might be useful in epidemiological studies where resources are limited.

Growth Differentiation Factor 15 Provides Prognostic Information Superior to Established Cardiovascular and Inflammatory Biomarkers in Unselected Patients Hospitalized With COVID-19.

BACKGROUND: Growth differentiation factor 15 (GDF-15) is a strong prognostic marker in sepsis and cardiovascular disease (CVD). The prognostic value of GDF-15 in coronavirus disease 2019 (COVID-19) is unknown. METHODS: Consecutive, hospitalized patients with laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and symptoms of COVID-19 were enrolled in the prospective, observational COVID Mechanisms Study. Biobank samples were collected at baseline, day 3 and day 9. The primary end point was admission to the intensive care unit or death during hospitalization, and the prognostic performance of baseline and serial GDF-15 concentrations were compared with that of established infectious disease and cardiovascular biomarkers. RESULTS: Of the 123 patients enrolled, 35 (28%) reached the primary end point; these patients were older, more often had diabetes, and had lower oxygen saturations and higher National Early Warning Scores on baseline. Baseline GDF-15 concentrations were elevated (>95th percentile in age-stratified healthy individuals) in 97 (79%), and higher concentrations were associated with detectable SARS-CoV-2 viremia and hypoxemia (both P<0.001). Patients reaching the primary end point had higher concentrations of GDF-15 (median, 4225 [IQR, 3197-5972] pg/mL versus median, 2187 [IQR, 1344-3620] pg/mL, P<0.001). The area under the receiver operating curve was 0.78 (95% CI, 0.70-0.86). The association between GDF-15 and the primary end point persisted after adjusting for age, sex, race, body mass index, estimated glomerular filtration rate, previous myocardial infarction, heart failure, and atrial fibrillation (P<0.001) and was superior and incremental to interleukin-6, C-reactive protein, procalcitonin, ferritin, D-dimer, cardiac troponin T, and N-terminal pro-B-type natriuretic peptide. Increase in GDF-15 from baseline to day 3 was also greater in patients reaching the primary end point (median, 1208 [IQR, 0-4305] pg/mL versus median, -86 [IQR, -322 to 491] pg/mL, P<0.001). CONCLUSIONS: GDF-15 is elevated in the majority of patients hospitalized with COVID-19, and higher concentrations are associated with SARS-CoV-2 viremia, hypoxemia, and worse outcome. The prognostic value of GDF-15 was additional and superior to established cardiovascular and inflammatory biomarkers. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04314232.

Relative and absolute cancer risks among Nordic kidney transplant recipients-a population-based study.

Kidney transplant recipients (KTRs) have an increased cancer risk compared to the general population, but absolute risks that better reflect the clinical impact of cancer are seldom estimated. All KTRs in Sweden, Norway, Denmark, and Finland, with a first transplantation between 1995 and 2011, were identified through national registries. Post-transplantation cancer occurrence was assessed through linkage with cancer registries. We estimated standardized incidence ratios (SIR), absolute excess risks (AER), and cumulative incidence of cancer in the presence of competing risks. Overall, 12 984 KTRs developed 2215 cancers. The incidence rate of cancer overall was threefold increased (SIR 3.3, 95% confidence interval [CI]: 3.2-3.4). The AER of any cancer was 1560 cases (95% CI: 1468-1656) per 100 000 person-years. The highest AERs were observed for nonmelanoma skin cancer (838, 95% CI: 778-901), non-Hodgkin lymphoma (145, 95% CI: 119-174), lung cancer (126, 95% CI: 98.2-149), and kidney cancer (122, 95% CI: 98.0-149). The five- and ten-year cumulative incidence of any cancer was 8.1% (95% CI: 7.6-8.6%) and 16.8% (95% CI: 16.0-17.6%), respectively. Excess cancer risks were observed among Nordic KTRs for a wide range of cancers. Overall, 1 in 6 patients developed cancer within ten years, supporting extensive post-transplantation cancer vigilance.

Plasma Trans Fatty Acid Levels, Cardiovascular Risk Factors and Lifestyle: Results from the Akershus Cardiac Examination 1950 Study.

Intake of industrially produced trans fatty acids (iTFAs) has previously been associated with dyslipidemia, insulin resistance, hypertension and inflammation, as well as increased cardiovascular (CV) morbidity and mortality. iTFA intake declined in Norway after the introduction of legislative bans against iTFA consumption. However, the relationship between the current iTFA intake and CV health is unclear. The aim of the present study was to investigate the association between current iTFA intake, reflected by plasma iTFA levels, and established CV risk factors. We also examined the associations between plasma ruminant TFA levels and CV risk factors. In this cross-sectional study, we included 3706 participants from a Norwegian general population, born in 1950 and residing in Akershus County, Norway. The statistical method was multivariable linear regression. Plasma iTFA levels were inversely associated with serum triglycerides (p < 0.001), fasting plasma glucose (p < 0.001), body mass index (p < 0.001), systolic and diastolic blood pressure (p = 0.001 and p = 0.03) and C-reactive protein (p = 0.001). Furthermore, high plasma iTFA levels were associated with higher education and less smoking and alcohol consumption. We found that plasma ruminant trans fatty acids (rTFA) levels were favorably associated with CV risk factors. Furthermore, plasma iTFA levels were inversely associated with CV risk factors. However, our results might have been driven by lifestyle factors. Overall, our findings suggest that the current low intake of iTFAs in Norway does not constitute a threat to CV health.

Plasma linoleic acid levels and cardiovascular risk factors: results from the Norwegian ACE 1950 Study.

BACKGROUND: A high intake of linoleic acid (LA), the major dietary polyunsaturated fatty acid (PUFA), has previously been associated with reduced cardiovascular (CV) morbidity and mortality in observational studies. However, recent secondary analyses from clinical trials of LA-rich diet suggest harmful effects of LA on CV health. METHODS: A total of 3706 participants, all born in 1950, were included in this cross-sectional study. We investigated associations between plasma phospholipid levels of LA and CV risk factors in a Norwegian general population, characterized by a relative low LA and high marine n-3 PUFA intake. The main statistical approach was multivariable linear regression. RESULTS: Plasma phospholipid LA levels ranged from 11.4 to 32.0 wt%, with a median level of 20.8 wt% (interquartile range 16.8-24.8 wt%). High plasma LA levels were associated with lower serum low-density lipoprotein cholesterol levels (standardized regression coefficient [Std. ß-coeff.] -0.04, p = 0.02), serum triglycerides (Std. ß-coeff. -0.10, p < 0.001), fasting plasma glucose (Std. ß-coeff. -0.10, p < 0.001), body mass index (Std. ß-coeff. -0.13, p < 0.001), systolic and diastolic blood pressure (Std. ß-coeff. -0.04, p = 0.03 and Std. ß-coeff. -0.02, p = 0.02, respectively) and estimated glomerular filtration rate (Std. ß-coeff. -0.09, p < 0.001). We found no association between plasma LA levels and high-density lipoprotein cholesterol levels, glycated hemoglobin, carotid intima-media thickness, or C-reactive protein. CONCLUSION: High plasma LA levels were favorably associated with several CV risk factors in this study of a Norwegian general population.

Plasma marine n-3 polyunsaturated fatty acids and cardiovascular risk factors: data from the ACE 1950 study.

PURPOSE: A high intake of marine n-3 polyunsaturated fatty acids (PUFAs) might improve cardiovascular (CV) health. We conducted a cross-sectional study to investigate associations between plasma phospholipid levels of marine n-3 PUFAs and CV risk factors, educational level, physical activity and smoking habits. METHODS: A total of 3706 individuals from a general population, all born in 1950 and residing in Akershus County, Norway, were included in this study. The main statistical approach was multivariable adjusted linear regression. RESULTS: Plasma marine n-3 PUFA levels ranged from 2.7 to 20.3 wt%, with a median level of 7.7 wt% (interquartile range 4.3-11.1 wt%). High levels of plasma marine n-3 PUFAs were associated with lower serum triglycerides [Standardized regression coefficient (Std.ß-coeff.) - 0.14, p < 0.001], body mass index (Std. ß-coeff. -0.08, p < 0.001), serum creatinine (Std. ß-coeff. -0.03, p = 0.05), C-reactive protein levels (Std. ß-coeff. - 0.03, p = 0.04), higher levels of serum high-density lipoprotein cholesterol (Std. ß-coeff. 0.08, p < 0.001) and low-density lipoprotein cholesterol (Std. ß-coeff. 0.04, p = 0.003). High levels of plasma marine n-3 PUFAs were also associated with lower glycated hemoglobin (Std. ß-coeff. - 0.04, p = 0.01), however, only in individuals without diabetes. We found no associations between plasma marine n-3 PUFA levels and fasting plasma glucose or carotid intima-media thickness. High levels of plasma marine n-3 PUFAs were associated with higher educational level, more physical activity and lower prevalence of smoking. CONCLUSION: In this cross-sectional study of Norwegian individuals born in 1950, high levels of plasma marine n-3 PUFAs were favourably associated with several CV risk factors, suggesting that fish consumption might improve CV health.

Association between circulating proprotein convertase subtilisin/kexin type 9 levels and prognosis in patients with severe chronic kidney disease.

BACKGROUND: Chronic kidney disease is a risk factor for premature development of coronary atherosclerosis and mortality. A high level of proprotein convertase subtilisin/kexin type 9 (PCSK9) is a recently recognized cardiovascular risk factor and has become the target of effective inhibitory treatment. In 167 kidney transplantation candidates, we aimed to: (i) compare levels of PCSK9 with those of healthy controls, (ii) examine the association between levels of PCSK9 and low-density lipoprotein cholesterol (LDL-c) and the degree of coronary artery disease (CAD) and (iii) evaluate if levels of PCSK9 predict major adverse cardiac events (MACE) and mortality. METHODS: Kidney transplant candidates (n = 167) underwent coronary computed tomography angiography (CCTA) and invasive coronary angiography (ICA) before transplantation. MACE and mortality data were extracted from the Western Denmark Heart Registry, a review of patient records and patient interviews. A group of 79 healthy subjects were used as controls. RESULTS: Mean PCSK9 levels did not differ between healthy controls and kidney transplant candidates. In patients not receiving lipid-lowering therapy, PCSK9 correlated positively with LDL-c (rho = 0.24, P < 0.05). Mean PCSK9 was similar in patients with and without obstructive CAD at both CCTA and ICA. In a multiple regression analysis, PCSK9 was associated with neither LDL-c (ß=-6.45, P = 0.44) nor coronary artery calcium score (ß=2.17, P = 0.84). During a follow-up of 3.7 years, PCSK9 levels were not associated with either MACE or mortality. CONCLUSIONS: The ability of PCSK9 levels to predict cardiovascular disease and prognosis does not seem to apply to a cohort of kidney transplant candidates.