Urinary Copper Excretion Is Associated with Long-Term Graft Failure in Kidney Transplant Recipients.

INTRODUCTION: In chronic kidney disease, proteinuria increases urinary copper excretion, inducing oxidative tubular damage and worsening kidney function. We investigated whether this phenomenon occurred in kidney transplant recipients (KTRs). In addition, we studied the associations of urinary copper excretion with the biomarker of oxidative tubular damage urinary liver-type fatty-acid binding protein (u-LFABP) and death-censored graft failure. METHODS: This prospective cohort study was performed in the Netherlands between 2008 and 2017, including outpatient KTR with a functioning graft for longer than 1 year, who were extensively phenotyped at baseline. Twenty-four-hour urinary copper excretion was measured by inductively coupled plasma mass spectrometry. Multivariable linear and Cox regression analyses were performed. RESULTS: In 693 KTR (57% men, 53 ± 13 years, estimated glomerular filtration rate [eGFR] 52 ± 20 mL/min/1.73 m2), baseline median urinary copper excretion was 23.6 (interquartile range 11.3-15.9) µg/24 h. Urinary protein excretion was positively associated with urinary copper excretion (standardized ß = 0.39, p < 0.001), and urinary copper excretion was positively associated with u-LFABP (standardized ß = 0.29, p < 0.001). During a median follow-up of 8 years, 109 (16%) KTR developed graft failure. KTR with relatively high copper excretion were at higher risk of long-term graft failure (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.32-1.86 per log2, p < 0.001), independent of multiple potential confounders like eGFR, urinary protein excretion, and time after transplantation. A dose-response relationship was observed over increasing tertiles of copper excretion (HR: 5.03, 95% CI: 2.75-9.19, tertile 3 vs. 1, p < 0.001). u-LFABP was a significant mediator of this association (74% of indirect effect, p < 0.001). CONCLUSION: In KTR, urinary protein excretion is positively correlated with urinary copper excretion. In turn, higher urinary copper excretion is associated with an independent increased risk of kidney graft failure, with a substantial mediating effect through oxidative tubular damage. Further studies are warranted to investigate whether copper excretion-targeted interventions could improve kidney graft survival.

Low selenium intake is associated with risk of all-cause mortality in kidney transplant recipients.

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

Plasma Copper Concentration Is Associated with Cardiovascular Mortality in Male Kidney Transplant Recipients.

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.

Clinical and hemodynamic outcomes and mortality risk factors in patients undergoing pulmonary thromboendarterectomy / Resultados clínicos y hemodinámicos y factores de riesgo de mortalidad en pacientes sometidos a tromboendarterectomía pulmonar

Abstract Background: Pulmonary thromboendarterectomy is the current treatment of choice in patients with chronic thromboembolic pulmonary hypertension. The objective of the present study was to analyze the clinical and hemodynamic outcomes and the risk factors for mortality in a cardiovascular center in Colombia. Methods: Cohort study, conducted between 2001 and 2019. All operated patients were included in the study. Risk factors associated with mortality were established by means of a multivariate regression using the COX method and survival was established using the Kaplan-Meier method. p < 0.05 was considered statistically significant. Results: Seventy-three patients were operated. Median age was 51 years, 55% of females, 79% had functional Class III and IV. The mean pulmonary arterial pressure was 50 mmHg and 640 dyn.s.cm−5 for pulmonary vascular resistance (PVR). After the intervention, there was a decrease in mean pulmonary artery pressure (p ≤ 0.001) and in PVR (p = 0.357); 21% had evidence of residual pulmonary hypertension. Only 8% and 6% continued with functional Class III and IV at 6 and 12 months, respectively. There were 15 deaths (19.1%; 12% at 30 days). The factors associated with mortality were the diastolic diameter of the right ventricle measured postoperatively (hazard ratio [HR] 10.88 95% confidence interval [CI] 1.97-62, p = 0.007), time of invasive mechanical ventilation (HR 1.06 95% CI 1.02-1.09 p = 0.004), and the presence of complications during the surgical procedure (HR 5.62 95% CI 1.94-16.22 p = 0.001). Conclusions: Pulmonary thromboendarterectomy is associated with excellent clinical and hemodynamic outcomes. The mortality risk factors found are not those usually described in the literature.

Resumen Antecedentes: La tromboendarterectomía pulmonar es el tratamiento de elección actual en pacientes con hipertensión pulmonar tromboembólica crónica. El objetivo del presente estudio fue analizar los resultados clínicos y hemodinámicos y los factores de riesgo de mortalidad en un centro cardiovascular de Colombia. Métodos: Estudio de cohorte entre 2001 y 2019. Se incluyeron todos los pacientes operados. Los factores de riesgo asociados a la mortalidad se establecieron mediante una regresión multivariante mediante el método COX y la supervivencia se estableció mediante el método de Kaplan-Meier. Los valores de p < 0.05 se consideraron estadísticamente significativos. Resultados: se operaron 73 pacientes. La mediana de edad fue de 51 años, 55% mujeres, 79% tenían clase funcional III y IV. La presión arterial pulmonar media fue de 50 mmHg y 640 dyn.s.cm−5 para la resistencia vascular pulmonar. Después de la intervención, hubo una disminución en la presión arterial pulmonar media (p ≤ 0.001) y en la resistencia vascular pulmonar (p = 0.357). El 21% tenía evidencia de hipertensión pulmonar residual. Solo el 8% y el 6% continuaron con clase funcional III y IV a los 6 y 12 meses respectivamente. Hubo 15 muertes (19.1%; 12% a los 30 días). Los factores asociados con la mortalidad fueron el diámetro diastólico del ventrículo derecho medido en el postoperatorio (HR 10.88 IC 95% 1.97-62, p = 0.007), el tiempo de ventilación mecánica invasiva (HR 1.06 IC 95% 1.02-1.09 p = 0.004) y el presencia de complicaciones durante el procedimiento quirúrgico (HR 5.62 IC 95% 1.94-16.22 p = 0.001). Conclusiones: La tromboendartectomía pulmonar se asocia con excelentes resultados clínicos y hemodinámicos. Los factores de riesgo de mortalidad encontrados no son los habitualmente descritos en la literatura.

Clinical and hemodynamic outcomes and mortality risk factors in patients undergoing pulmonary thromboendarterectomy.

BACKGROUND: Pulmonary thromboendarterectomy is the current treatment of choice in patients with chronic thromboembolic pulmonary hypertension. The objective of the present study was to analyze the clinical and hemodynamic outcomes and the risk factors for mortality in a cardiovascular center in Colombia. METHODS: Cohort study, conducted between 2001 and 2019. All operated patients were included in the study. Risk factors associated with mortality were established by means of a multivariate regression using the COX method and survival was established using the Kaplan-Meier method. p < 0.05 was considered statistically significant. RESULTS: Seventy-three patients were operated. Median age was 51 years, 55% of females, 79% had functional Class III and IV. The mean pulmonary arterial pressure was 50 mmHg and 640 dyn.s.cm-5 for pulmonary vascular resistance (PVR). After the intervention, there was a decrease in mean pulmonary artery pressure (p ≤ 0.001) and in PVR (p = 0.357); 21% had evidence of residual pulmonary hypertension. Only 8% and 6% continued with functional Class III and IV at 6 and 12 months, respectively. There were 15 deaths (19.1%; 12% at 30 days). The factors associated with mortality were the diastolic diameter of the right ventricle measured postoperatively (hazard ratio [HR] 10.88 95% confidence interval [CI] 1.97-62, p = 0.007), time of invasive mechanical ventilation (HR 1.06 95% CI 1.02-1.09 p = 0.004), and the presence of complications during the surgical procedure (HR 5.62 95% CI 1.94-16.22 p = 0.001). CONCLUSIONS: Pulmonary thromboendarterectomy is associated with excellent clinical and hemodynamic outcomes. The mortality risk factors found are not those usually described in the literature.

Efficacy of high-intensity interval- or continuous aerobic-training on insulin resistance and muscle function in adults with metabolic syndrome: a clinical trial.

PURPOSE: We carried out a randomized, clinical trial in adults of both sexes with metabolic syndrome (MS) to assess the efficacy of high-intensity, low-volume interval training (HIIT) compared to moderate-intensity continuous training (MICT) on insulin resistance (IR), muscle mass, muscle activation, and serum musclin. METHODS: Fasting glycemia, insulinemia, and glycated haemoglobin were determined by conventional methods, IR by Homeostatic model assessment (HOMA), lean mass by Dual-Energy X-ray Absorptiometry, muscle activation through carnosine by Proton Magnetic Resonance Spectroscopy, and musclin by Enzyme-Linked ImmunoSorbent Assay before and after a supervised, three-times/week, 12-week treadmill programme. HIIT (n = 29) consisted of six intervals with one-minute, high-intensity phases at 90% of peak oxygen consumption (VO2peak). MICT (n = 31) trained at 60% of VO2peak for 30 min. RESULTS: Patients had a mean age of 50.8 ± 6.0 years, body mass index of 30.6 ± 4.0 kg/m2, and VO2peak of 29.0 ± 6.3 mL.kg-1.min-1. Compared to MICT, HIIT was not superior at reducing Ln HOMA-IR (adjusted mean difference: 0.083 [95%CI - 0.092 to 0.257]), carnosine or musclin or at increasing thigh lean mass. HIIT increased carnosine by 0.66 mmol/kg.ww (95% CI 0.08-1.24) after intervention. Both interventions reduced IR, body fat percentage and increased total lean mass/height2 and VO2peak. Musclin showed a non-significant reduction with a small effect size after both interventions. CONCLUSION: Compared to MICT, HIIT is not superior at reducing IR, carnosine or musclin or at increasing skeletal muscle mass in adults with MS. Both training types improved IR, muscle mass and body composition. NCT03087721, March 22nd, 2017. TRIAL REGISTRATION NUMBER: NCT03087721. Registered March 22nd, 2017.

Effects of Low-Volume, High-Intensity Interval Training Compared with Continuous Training on Regional and Global Body Composition in Adults with Metabolic Syndrome: A post hoc Analysis of a Randomized Clinical Trial.

OBJECTIVE: The aim of this study was to compare the effects of low-volume, high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT) on body composition in adults with metabolic syndrome (MS). METHODS: This is a post hoc analysis of the randomized clinical trial Intraining-MET. Sixty adults (40-60 years old) were randomized to an MICT (n = 31) or HIIT (n = 29) supervised programme 3 days/week for 12 weeks. MICT sessions were conducted for 36 min at 60% of peak oxygen consumption (VO2peak). HIIT sessions included 6 intervals at 90% VO2peak for 1 min, followed by 2 min at 50% VO2peak. Body composition was assessed with dual energy X-ray absorptiometry. RESULTS: Body weight did not change from pre- to post-training in either MICT (78.9 ± 15.6 kg; 77.7 ± 16.5 kg, p = 0.280) or HIIT groups (76.3 ± 13.4 kg; 76.3 ± 13.7 kg, p = 0.964). Body fat percentage and fat mass (FM) decreased post-training in the MICT (-0.9%; 95% confidence interval [CI]: -0.27 to -1.47 and -0.7 kg; 95% CI: -0.12 to -1.30) and HIIT groups (-1.0%; 95% CI: -0.32 to -1.68 and -0.8 kg; 95% CI: -0.17 to -1.47). Compared to the HIIT programme, MICT significantly reduced android FM (-0.14 kg; 95% CI: -0.02 to -0.26). Lean mass (LM) increased post-training in MICT (+0.7 kg; 95% CI: 0.01-1.41) and HIIT groups (+0.9 kg; 95% CI: 0.12-1.64), but only HIIT increased the trunk LM (+0.6 kg; 95% CI: 0.06-1.20). CONCLUSIONS: Both MICT and HIIT reduced FM without changing body weight in adults with MS. MICT had additional benefits by reducing the android FM, whereas HIIT seemed to increase LM. Given the characteristics of the post hoc analysis, further research is required to confirm these results.

Musclin Is Related to Insulin Resistance and Body Composition, but Not to Body Mass Index or Cardiorespiratory Capacity in Adults.

BACKGROUND: We studied whether musclin function in humans is related to glycemic control, body composition, and cardiorespiratory capacity. METHODS: A cross-sectional study was performed in sedentary adults with or without metabolic syndrome (MS). Serum musclin was measured by enzyme-linked immunosorbent assay. Insulin resistance (IR) was evaluated by the homeostatic model assessment (HOMA-IR). Body composition was determined by dual-energy X-ray absorptiometry and muscle composition by measuring carnosine in the thigh, a surrogate of fiber types, through proton magnetic resonance spectroscopy. Cardiorespiratory capacity was assessed through direct ergospirometry. RESULTS: The control (n=29) and MS (n=61) groups were comparable in age (51.5±6.5 years old vs. 50.7±6.1 years old), sex (72.4% vs. 70.5% women), total lean mass (58.5%±7.4% vs. 57.3%±6.8%), and peak oxygen consumption (VO2peak) (31.0±5.8 mL O2./kg.min vs. 29.2±6.3 mL O2/kg.min). Individuals with MS had higher body mass index (BMI) (30.6±4.0 kg/m2 vs. 27.4± 3.6 kg/m2), HOMA-IR (3.5 [95% confidence interval, CI, 2.9 to 4.6] vs. 1.7 [95% CI, 1.1 to 2.0]), and musclin (206.7 pg/mL [95% CI, 122.7 to 387.8] vs. 111.1 pg/mL [95% CI, 63.2 to 218.5]) values than controls (P˂0.05). Musclin showed a significant relationship with HOMA-IR (ß=0.23; 95% CI, 0.12 to 0.33; P˂0.01), but not with VO2peak, in multiple linear regression models adjusted for age, sex, fat mass, lean mass, and physical activity. Musclin was significantly associated with insulin, glycemia, visceral fat, and regional muscle mass, but not with BMI, VCO2peak, maximum heart rate, maximum time of work, or carnosine. CONCLUSION: In humans, musclin positively correlates with insulinemia, IR, and a body composition profile with high visceral adiposity and lean mass, but low body fat percentage. Musclin is not related to BMI or cardiorespiratory capacity.

Plasma Vitamin C and Risk of Late Graft Failure in Kidney Transplant Recipients: Results of the TransplantLines Biobank and Cohort Study.

Recent studies have shown that depletion of vitamin C is frequent in outpatient kidney transplant recipients (KTR) and that vitamin C is inversely associated with risk of death. Whether plasma vitamin C is associated with death-censored kidney graft failure remains unknown. We investigated KTR who participated in the TransplantLines Insulin Resistance and Inflammation Biobank and Cohort Study. The primary outcome was graft failure (restart of dialysis or re-transplantation). Overall and stratified (pinteraction < 0.1) multivariable-adjusted Cox regression analyses are presented here. Among 598 KTR (age 51 ± 12 years-old; 55% males), baseline median (IQR) plasma vitamin C was 44.0 (31.0-55.3) µmol/L. Through a median follow-up of 9.5 (IQR, 6.3‒10.2) years, 75 KTR developed graft failure (34, 26, and 15 events over increasing tertiles of vitamin C, log-rank p < 0.001). Plasma vitamin C was inversely associated with risk of graft failure (HR per 1-SD increment, 0.69; 95% CI 0.54-0.89; p = 0.004), particularly among KTR with triglycerides ≥1.9 mmol/L (HR 0.46; 95% CI 0.30-0.70; p < 0.001; pinteraction = 0.01) and among KTR with HDL cholesterol ≥0.91 mmol/L (HR 0.56; 95% CI 0.38-0.84; p = 0.01; pinteraction = 0.04). These findings remained materially unchanged in multivariable-adjusted analyses (donor, recipient, and transplant characteristics, including estimated glomerular filtration rate and proteinuria), were consistent in categorical analyses according to tertiles of plasma vitamin C, and robust after exclusion of outliers. Plasma vitamin C in outpatient KTR is inversely associated with risk of late graft failure. Whether plasma vitamin C‒targeted therapeutic strategies represent novel opportunities to ease important burden of graft failure necessitates further studies.

Urinary liver-type fatty acid-binding protein is independently associated with graft failure in outpatient kidney transplant recipients.

Urinary liver-type fatty acid-binding protein (uL-FABP) is a biomarker of kidney hypoxia and ischemia, and thus offers a novel approach to identify early kidney insults associated with increased risk of graft failure in outpatient kidney transplant recipients (KTR). We investigated whether uL-FABP is associated with graft failure and whether it improves risk prediction. We studied a cohort of 638 outpatient KTR with a functional graft ≥1-year. During a median follow-up of 5.3 years, 80 KTR developed graft failure. uL-FABP (median 2.11, interquartile range 0.93-7.37 µg/24"/>h) was prospectively associated with the risk of graft failure (hazard ratio 1.75; 95% confidence interval 1.27-2.41 per 1-SD increment; P = .001), independent of potential confounders including estimated glomerular filtration rate and proteinuria. uL-FABP showed excellent discrimination ability for graft failure (c-statistic of 0.83) and its addition to a prediction model composed by established clinical predictors of graft failure significantly improved the c-statistic to 0.89 (P for F-test <.001). These results were robust to several sensitivity analyses. Further validation studies are warranted to evaluate the potential use of a risk-prediction model including uL-FABP to improve identification of outpatient KTR at high risk of graft failure in clinical care.

Arterial lactate levels and their prognostic value in patients undergoing pulmonary thromboendarterectomy.

Objective: Evaluate the change of lactate levels and its prognostic role in the postoperative period of patients undergoing pulmonary thromboendarterectomy. Methods: Retrospective study between 2001 and 2019. Patients older than 18 years and who underwent pulmonary thromboendarterectomy were included. The U Mann Whitney test was performed to evaluate the change between lactate levels, and Cox regression analysis to evaluate the relationship with mortality. Areas under the curve were constructed for lactate levels. Results: Seventy-three patients were operated on during the study period. Median age was 51 years, 55% female. The median lactate on days 1 was 4.65 mml/L and on day 2 it was 1.62 mml/L with a change of 2.87 mml/L. No differences were found between the levels measured on day 1 and 2 between the people who died and those who did not on day 30. In the multivariate regression of COX, no relationship with mortality was found. The area under the curve shows regular performance on both day 1 and day 2 in predicting mortality outcomes. Conclusions: The behavior of the lactate in patients undergoing pulmonary thromboendarterectomy shows a rapid change during the first hours after the procedure. No role was found as a predictor of mortality neither in-hospital nor in follow-up.

Objetivo: Evaluar el cambio de los niveles de lactato y su rol pronóstico en el posoperatorio de pacientes sometidos a tromboendarterectomía pulmonar. Métodos: Estudio retrospectivo entre 2001 y 2019. Se incluyeron pacientes mayores de 18 años que fueron sometidos a tromboendarterectomía pulmonar. Para evaluar el cambio entre los niveles de lactato se realizó la prueba de U Mann Whitney. Para evaluar la relación con la mortalidad se realizó un análisis multivariado de Cox. Se construyeron áreas bajo la curva para los niveles de lactato. Resultados: . Setenta y tres pacientes fueron operados durante el período de estudio. La mediana de edad fue de 51 años, 55% mujeres. La mediana de lactato en el día 1 fue de 4,65 mmL/L y en el día 2 fue de 1,62 mmL/L con un cambio de 2,87 mmL/L. No se encontraron diferencias entre los niveles medidos el día 1 y 2 entre las personas que murieron y las que no al día 30 hospitalario. En la regresión multivariada de COX no se encontró relación con la mortalidad. El área bajo la curva muestra un desempeño regular tanto en el día 1 como en el día 2 para predecir el resultado de la mortalidad en especial intrahospitalaria. Conclusiones: El comportamiento del lactato en pacientes sometidos a tromboendarterectomía pulmonar muestra un cambio rápido durante las primeras horas posteriores al procedimiento. No se encontró que sea un predictor de mortalidad ni hospitalaria ni durante el seguimiento.

Biopsy-Controlled Non-Invasive Quantification of Collagen Type VI in Kidney Transplant Recipients: A Post-Hoc Analysis of the MECANO Trial.

The PRO-C6 assay, a reflection of collagen type VI synthesis, has been proposed as a non-invasive early biomarker of kidney fibrosis. We aimed to investigate cross-sectional and longitudinal associations between plasma and urine PRO-C6 and proven histological changes after kidney transplantation. The current study is a post-hoc analysis of 94 participants of the MECANO trial, a 24-month prospective, multicenter, open-label, randomized, controlled trial aimed at comparing everolimus-based vs. cyclosporine-based immunosuppression. PRO-C6 was measured in plasma and urine samples collected 6 and 24 months post-transplantation. Fibrosis was evaluated in biopsies collected at the same time points by Banff interstitial fibrosis/tubular atrophy (IF/TA) scoring and collagen staining (Picro Sirius Red; PSR); inflammation was evaluated by the tubulo-interstitial inflammation score (ti-score). Linear regression analyses were performed. Six-month plasma PRO-C6 was cross-sectionally associated with IF/TA score (Std. ß = 0.34), and prospectively with 24-month IF/TA score and ti-score (Std. ß = 0.24 and 0.23, respectively) (p < 0.05 for all). No significant associations were found between urine PRO-C6 and any of the biopsy findings. Fibrotic changes and urine PRO-C6 behaved differentially over time according to immunosuppressive therapy. These results are a first step towards non-invasive fibrosis detection after kidney transplantation by means of collagen VI synthesis measurement, and further research is required.

Post-transplantation plasma malondialdehyde is associated with cardiovascular mortality in renal transplant recipients: a prospective cohort study.

BACKGROUND: In renal transplant recipients (RTRs), cardiovascular mortality is the most common cause of long-term renal graft loss. Oxidative stress (OS) has been associated with cardiovascular disease and is known to be enhanced in RTRs. We aimed to prospectively investigate whether the concentration of the OS biomarker malondialdehyde (MDA) is associated with long-term risk of cardiovascular mortality in a large cohort of RTRs. METHODS: The plasma MDA concentration was measured using the thiobarbituric acid reaction assay in 604 extensively phenotyped RTRs with a functioning allograft for ≥1 year. The association between MDA and cardiovascular mortality was assessed using Cox proportional hazard regression analyses in the overall cohort and within subgroups according to significant effect modifiers. RESULTS: Median circulating MDA concentration at baseline was 5.38 [interquartile range (IQR) 4.31-6.45] µmol/L. During a follow-up period of 6.4 (IQR 5.6-6.8) years, 110 (18%) RTRs died, with 40% of deaths due to cardiovascular causes. MDA concentration was significantly associated with the risk for cardiovascular mortality {hazard ratio [HR] 1.31 [95% confidence interval (CI) 1.03-1.67] per 1-SD increment}, independent of adjustment for potential confounders, including renal function, immunosuppressive therapy, smoking status and blood pressure. The association between MDA concentration and the risk for cardiovascular mortality was stronger in RTRs with relatively lower plasma ascorbic acid concentrations [≤42.5 µmol/L; HR 1.79 (95% CI 1.30-2.48) per 1-SD increment] or relatively lower estimated glomerular filtration rates [≤45 mL/min/1.73 m2; HR 2.09 (95% CI 1.45-3.00) per 1-SD increment]. CONCLUSIONS: Circulating MDA concentration is independently associated with long-term risk for cardiovascular mortality, particularly in RTRs with relatively lower ascorbic acid concentrations or renal function. Further studies are warranted to elucidate whether OS-targeted interventions could decrease cardiovascular mortality in RTRs.

Urinary Epidermal Growth Factor/Creatinine Ratio and Graft Failure in Renal Transplant Recipients: A Prospective Cohort Study.

Graft failure (GF) remains a significant limitation to improve long-term outcomes in renal transplant recipients (RTR). Urinary epidermal growth factor (uEGF) is involved in kidney tissue integrity, with a reduction of its urinary excretion being associated with fibrotic processes and a wide range of renal pathologies. We aimed to investigate whether, in RTR, uEGF is prospectively associated with GF. In this prospective cohort study, RTR with a functioning allograft ≥1-year were recruited and followed-up for three years. uEGF was measured in 24-hours urine samples and normalized by urinary creatinine (Cr). Its association with risk of GF was assessed by Cox-regression analyses and its predictive ability by C-statistic. In 706 patients, uEGF/Cr at enrollment was 6.43 [IQR 4.07-10.77] ng/mg. During follow-up, 41(6%) RTR developed GF. uEGF/Cr was inversely associated with the risk of GF (HR 0.68 [95% CI 0.59-0.78]; P < 0.001), which remained significant after adjustment for immunosuppressive therapy, estimated Glomerular Filtration Rate, and proteinuria. C-statistic of uEGF/Cr for GF was 0.81 (P < 0.001). We concluded that uEGF/Cr is independently and inversely associated with the risk of GF and depicts strong prediction ability for this outcome. Further studies seem warranted to elucidate whether uEGF might be a promising marker for use in clinical practice.

Plasma Malondialdehyde and Risk of New-Onset Diabetes after Transplantation in Renal Transplant Recipients: A Prospective Cohort Study.

New-onset diabetes after transplantation (NODAT) is a frequent complication in renal transplant recipients (RTR). Although oxidative stress has been associated with diabetes mellitus, data regarding NODAT are limited. We aimed to prospectively investigate the long-term association between the oxidative stress biomarker malondialdehyde (measured by high-performance liquid chromatography) and NODAT in an extensively phenotyped cohort of non-diabetic RTR with a functioning graft ≥1 year. We included 516 RTR (51 ± 13 years-old, 57% male). Median plasma malondialdehyde (MDA) was 2.55 (IQR, 1.92-3.66) µmol/L. During a median follow-up of 5.3 (IQR, 4.6-6.0) years, 56 (11%) RTR developed NODAT. In Cox proportional-hazards regression analyses, MDA was inversely associated with NODAT, independent of immunosuppressive therapy, transplant-specific covariates, lifestyle, inflammation, and metabolism parameters (HR, 0.55; 95% CI, 0.36-0.83 per 1-SD increase; p < 0.01). Dietary antioxidants intake (e.g., vitamin E, α-lipoic acid, and linoleic acid) were effect-modifiers of the association between MDA and NODAT, with particularly strong inverse associations within the subgroup of RTR with relatively higher dietary antioxidants intake. In conclusion, plasma MDA concentration is inversely and independently associated with long-term risk of NODAT in RTR. Our findings support a potential underrecognized role of oxidative stress in post-transplantation glucose homeostasis.