Jean Michel Halimi

Renal impairment and ischemic stroke risk assessment in patients with atrial fibrillation: the Loire Valley Atrial Fibrillation Project.

OBJECTIVESnThis study sought to determine the risk of ischemic stroke (IS)/thromboembolism (TE) associated with renal impairment and its incremental predictive value over established risk stratification scores (congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke [CHADS2] and congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke, vascular disease, age 65 to 74 years, sex category (female) [CHA₂DS₂-VASc]) in patients with atrial fibrillation (AF).nnnBACKGROUNDnRisk stratification schemes for prediction of IS/TE in patients with AF are validated but do not include renal impairment.nnnMETHODSnPatients diagnosed with nonvalvular AF and available estimated glomerular filtration rate (eGFR) data in a 4-hospital institution between 2000 and 2010 were identified. The study population was stratified by renal impairment defined by serum creatinine level and by eGFR measured at time of diagnosis of AF. Independent risk factors of IS/TE (including renal impairment) were investigated in Cox regression models. The incremental predictive value of renal impairment over CHADS₂ and CHA₂DS₂-VASc were assessed with the c-statistic, net reclassification improvement, and integrated discrimination improvement. We focused on the 1-year outcomes in our analyses.nnnRESULTSnOf 8,962 eligible individuals, 5,912 (66%) had nonvalvular AF and available eGFR data. Renal impairment by both creatinine and eGFR definitions was associated with higher rates of IS/TE at 1 year, compared with normal renal function. After adjustment for CHADS₂ risk factors, renal impairment did not significantly increase the risk of IS/TE at 1 year (hazard ratio: 1.06; 95% confidence interval [CI]: 0.75 to 1.49 for renal impairment; and hazard ratio: 1.09; 95% CI: 0.84 to 1.41 for eGFR). When renal impairment was added to existing risk scoring systems for stroke/TE (CHADS₂ and CHA₂DS₂-VASc), it did not independently add to the predictive value of the scores, whether defined by serum creatinine level or eGFR. This was evident even when the analysis was confined to only those patients with at least 1 year of follow-up.nnnCONCLUSIONSnRenal impairment was not an independent predictor of IS/TE in patients with AF and did not significantly improve the predictive ability of the CHADS₂ or CHA₂DS₂-VASc scores.

A Prospective Study of Estimated Glomerular Filtration Rate and Outcomes in Patients With Atrial Fibrillation: The Loire Valley Atrial Fibrillation Project

BACKGROUNDnAtrial fibrillation (AF) is more likely to develop in patients with chronic kidney disease (CKD) than in individuals with normal renal function, and patients with CKD are more likely to suffer ischemic stroke (IS)/thromboembolism (TE). To our knowledge, no prior study has considered the impact of estimated glomerular filtration rate (eGFR) on bleeding. We investigated the relationship of eGFR to IS/TE, mortality, and bleeding in an AF population unrestricted by age or comorbidity.nnnMETHODSnPatients with nonvalvular AF (NVAF) were stratified into five categories according to eGFR (≥ 90, 60-89, 30-59, 15-29, and < 15 mL/min/1.73 m2), analyzing risk factors, all-cause mortality, bleeding, and IS/TE. Of 8,962 eligible individuals, 5,912 had NVAF and available serum creatinine data, with 14,499 patient-years of follow-up.nnnRESULTSnThe incidence rates of IS/TE were 7.4 and 7.2 per 1,000 person-years in individuals not receiving and receiving anticoagulation therapy, respectively. Rates of all-cause mortality were 13.4 and 9.4 per 1,000 person-years, respectively, and of major bleeding, 6.2 and 9.0 per 1,000 person-years, respectively. Rates increased with decreasing eGFR, with IS/TE rates being lower in individuals receiving oral anticoagulation (OAC) therapy. eGFR was not an independent predictor of IS/TE on multivariate analyses. When the benefit of IS reduction is balanced against the increased risk of hemorrhagic stroke, the net clinical benefit (NCB) was clearly positive in favor of OAC use.nnnCONCLUSIONSnIncidence rates of IS/TE, mortality, and bleeding increased with reducing eGFR across the whole range of renal function. OAC use was associated with a lower incidence of IS/TE and mortality at 1 year compared with individuals not receiving anticoagulants in all categories of renal function as measured by eGFR. The NCB balancing IS against serious bleeding was positive in favor of OAC use among patients with renal impairment.

Therapeutic drug monitoring of eculizumab: Rationale for an individualized dosing schedule.

The annual cost of eculizumab maintenance therapy in paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic–uremic syndrome (aHUS) exceeds

Impact of Natriuretic Peptide Clearance Receptor (NPR3) Gene Variants on Blood Pressure in Type 2 Diabetes

300,000 per patient. A better understanding of eculizumab pharmacokinetics and subsequent individual dose adjustment could reduce this cost. We measured the trough eculizumab concentration in 9 patients with maintenance therapy (aHUS, n = 7; PNH, n = 2) and determined: 1) the intra- and inter-individual variability; 2) the influence of weight on eculizumab pharmacokinetics; and 3) the rate of elimination of eculizumab following discontinuation. A one-compartment model was developed to describe the pharmacokinetics of eculizumab and predicted complement activity by body weight. Trough eculizumab concentrations were >50 µg/mL in 9/9, >100 µg/mL in 8/9, and >300 µg/mL in 5/9 of patients. Intra-individual variability was low but eculizumab concentrations, closely correlated with patient weight (R2 = 0.66, p = 0.034), varied broadly (55 ± 12 to 733 ± 164 µg/mL). Pharmacokinetic modeling showed that the elimination half-life varied greatly, with an increase from 7.8 d in a patient weighing 100 kg to 19.5 d in a 40 kg patient. We predicted that infusions of 1200 mg could be spaced every 4 or 6 weeks in patients weighing <90 and <70 kg, respectively. In this pilot study, the current recommended use of a fixed eculizumab dose for maintenance therapy is associated with excessively high trough concentrations in many patients. Further prospective larger studies are now required to support an individualized schedule adjusted for patient weight and based on the observed trough serum eculizumab concentration.

Autosomal dominant polycystic kidney disease: risk factor for nonmelanoma skin cancer following kidney transplantation

OBJECTIVE Hypertension in diabetes is characterized by abnormal sodium homeostasis, suggesting a particular role of natriuretic peptide pathway. Natriuretic peptides can affect blood pressure (BP) through their plasma concentrations, which are dependent on their receptor activities. We thus assessed the association between nine NPR3 gene polymorphisms and BP levels in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Nine single nucleotide polymorphisms (SNPs) tagging the haplotype structure of the NPR3 gene were genotyped in the 3,126 French Non-insulin-dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) trial participants. We then used a second population (Diabete de type 2, Nephropathie et Genetique [DIAB2NEPHROGENE]/Survie, Diabete de type 2 et Genetique [SURDIAGENE] study) of 2,452 patients for the purpose of replication. Finally, we separately investigated subjects selected according to their rs 2270915SNP genotypes for their BP response to salt restriction. RESULTS In DIABHYCAR patients, three SNPs (rs6889608, rs1173773, and rs2270915) were significantly associated with systolic BP (SBP). The effect of the rs2270915 was replicated in the second step population: AA homozygotes had a lower SBP than G carriers (137.4 ± 19.1 vs. 140.0 ± 20.2 mmHg, P = 0.004). The rs2270915 influenced the response of SBP to salt reduction, with AA homozygous patients showing greater reductions after restriction of salt intake compared with G carriers: −20 mmHg (−43 to −8) vs. −3 (−20 to +7); P = 0.006. CONCLUSIONS We found a consistent and significant association between the rs2270915 polymorphism of the NPR3 gene and SBP in diabetic patients. This genetic variation may affect pressure response to changes in dietary sodium.

Developing Consensus-Based Priority Outcome Domains for Trials in Kidney Transplantation: A Multinational Delphi Survey with Patients, Caregivers, and Health Professionals

Nonmelanoma skin cancers (NMSC) are the most common malignant tumors following solid organ transplantation. Risk factors for NMSC mainly include immunosuppression, age, sun exposure and patient phototype. Recent findings have suggested that autosomal dominant polycystic kidney disease (ADPKD) may increase the risk of developing NMSC. We performed a monocenter retrospective study including all kidney recipients between 1985 and 2006 (nu2003=u20031019). We studied the incidence of NMSC, solid cancers and post‐transplantation lymphoproliferative disease (PTLD), and analyzed the following parameters: age, gender, phototype, time on dialysis, graft rank, immunosuppressive regimen, history of cancer and kidney disease (ADPKD versus others). Median follow‐up was 5.5u2003years (range: 0.02–20.6; 79u2003838 patient‐years). The cumulated incidence of NMSC 10u2003years after transplantation was 12.7% (9.3% for solid cancers and 3.5% for PTLD). Autosomal dominant polycystic kidney disease and age were risk factors for NMSC (HR 2.63; Pu2003<u20030.0001 and HR 2.21; Pu2003<u20030.001, respectively) using univariate analysis. The association between ADPKD and NMSC remained significant after adjustments for age, gender and phototype using multivariate analysis (HR 1.71; Pu2003=u20030.0145) and for immunosuppressive regimens (Pu2003<u20030.0001). Autosomal dominant polycystic kidney disease was not a risk factor for the occurrence of solid cancers after transplantation (HR 0.96; Pu2003=u20030.89). Our findings suggest that ADPKD is an independent risk factor for developing NMSC after kidney transplantation.

Association of Circulating Biomarkers (Adrenomedullin, TNFR1, and NT-proBNP) With Renal Function Decline in Patients With Type 2 Diabetes: A French Prospective Cohort.

Background Inconsistencies in outcome reporting and frequent omission of patient-centered outcomes can diminish the value of trials in treatment decision making. We identified critically important outcome domains in kidney transplantation based on the shared priorities of patients/caregivers and health professionals. Methods In a 3-round Delphi survey, patients/caregivers and health professionals rated the importance of outcome domains for trials in kidney transplantation on a 9-point Likert scale and provided comments. During rounds 2 and 3, participants rerated the outcomes after reviewing their own score, the distribution of the respondents scores, and comments. We calculated the median, mean, and proportion rating 7 to 9 (critically important), and analyzed comments thematically. Results One thousand eighteen participants (461 [45%] patients/caregivers and 557 [55%] health professionals) from 79 countries completed round 1, and 779 (77%) completed round 3. The top 8 outcomes that met the consensus criteria in round 3 (mean, ≥7.5; median, ≥8; proportion, >85%) in both groups were graft loss, graft function, chronic rejection, acute rejection, mortality, infection, cancer (excluding skin), and cardiovascular disease. Compared with health professionals, patients/caregivers gave higher priority to 6 outcomes (mean difference of 0.5 or more): skin cancer, surgical complications, cognition, blood pressure, depression, and ability to work. We identified 5 themes: capacity to control and inevitability, personal relevance, debilitating repercussions, gaining awareness of risks, and addressing knowledge gaps. Conclusions Graft complications and severe comorbidities were critically important for both stakeholder groups. These stakeholder-prioritized outcomes will inform the core outcome set to improve the consistency and relevance of trials in kidney transplantation.

Twenty-Four-Hour Blood Pressure Monitoring to Predict and Assess Impact of Renal Denervation: The DENERHTN Study (Renal Denervation for Hypertension).

OBJECTIVE We explored the prognostic value of three circulating candidate biomarkers—midregional-proadrenomedullin (MR-proADM), soluble tumor necrosis factor receptor 1 (sTNFR1), and N-terminal prohormone brain natriuretic peptide (NT-proBNP)—for change in renal function in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Outcomes were defined as renal function loss (RFL), ≥40% decline of estimated glomerular filtration rate (eGFR) from baseline, and rapid renal function decline (RRFD), absolute annual eGFR slope <–5 mL/min/year. We used a proportional hazard model for RFL and a logistic model for RRFD. Adjustments were performed for established risk factors (age, sex, diabetes duration, HbA1c, blood pressure, baseline eGFR, and urinary albumin-to-creatinine ratio [uACR]). C-statistics were used to assess the incremental predictive value of the biomarkers to these risk factors. RESULTS Among 1,135 participants (mean eGFR 76 mL/min, median uACR 2.6 mg/mmol, and median GFR slope −1.6 mL/min/year), RFL occurred in 397, RRFD developed in 233, and 292 died during follow-up. Each biomarker predicted RFL and RRFD. When combined, MR-proADM, sTNFR1, and NT-proBNP predicted RFL independently from the established risk factors (adjusted hazard ratio 1.59 [95% CI 1.34–1.89], P < 0.0001; 1.33 [1.14–1.55], P = 0.0003; and 1.22 [1.07–1.40], P = 0.004, respectively) and RRFD (adjusted odds ratio 1.56 [95% CI 1.7–2.09], P = 0.003; 1.72 [1.33–2.22], P < 0.0001; and 1.28 [1.03–1.59], P = 0.02, respectively). The combination of the three biomarkers yielded the highest discrimination (difference in C-statistic = 0.054, P < 0.0001; 0.067, P < 0.0001 for RFL; and 0.027, P < 0.0001 for RRFD). CONCLUSIONS In addition to established risk factors, MR-proADM, sTNFR1, and NT-proBNP improve risk prediction of loss of renal function in patients with type 2 diabetes.

Association Between Diabetic Macular Edema and Cardiovascular Events in Type 2 Diabetes Patients: A Multicenter Observational Study

The DENERHTN trial (Renal Denervation for Hypertension) confirmed the blood pressure (BP) lowering efficacy of renal denervation added to a standardized stepped-care antihypertensive treatment for resistant hypertension at 6 months. We report here the effect of denervation on 24-hour BP and its variability and look for parameters that predicted the BP response. Patients with resistant hypertension were randomly assigned to denervation plus stepped-care treatment or treatment alone (control). Average and standard deviation of 24-hour, daytime, and nighttime BP and the smoothness index were calculated on recordings performed at randomization and 6 months. Responders were defined as a 6-month 24-hour systolic BP reduction ≥20 mmu2009Hg. Analyses were performed on the per-protocol population. The significantly greater BP reduction in the denervation group was associated with a higher smoothness index (P=0.02). Variability of 24-hour, daytime, and nighttime BP did not change significantly from baseline to 6 months in both groups. The number of responders was greater in the denervation (20/44, 44.5%) than in the control group (11/53, 20.8%; P=0.01). In the discriminant analysis, baseline average nighttime systolic BP and standard deviation were significant predictors of the systolic BP response in the denervation group only, allowing adequate responder classification of 70% of the patients. Our results show that denervation lowers ambulatory BP homogeneously over 24 hours in patients with resistant hypertension and suggest that nighttime systolic BP and variability are predictors of the BP response to denervation. Clinical Trial Registration— URL: https://www.clinicaltrials.gov. Unique identifier: NCT01570777.

Abdominal Aortic Calcifications Influences the Systemic and Renal Hemodynamic Response to Renal Denervation in the DENERHTN (Renal Denervation for Hypertension) Trial

AbstractDiabetic macular edema (DME) is the main cause of visual loss associated with diabetes but any association between DME and cardiovascular events is unclear.This study aims to describe the possible association between DME and cardiovascular events in a multicenter cross-sectional study of patients with type 2 diabetes.Two thousand eight hundred seven patients with type 2 diabetes were recruited from diabetes and nephrology clinical institutional centers participating in the DIAB 2 NEPHROGENE study focusing on diabetic complications. DME (presence/absence) and diabetic retinopathy (DR) classification were based on ophthalmological report and/or on 30° color retinal photographs. DR was defined as absent, nonproliferative (background, moderate, or severe) or proliferative. Cardiovascular events were stroke, myocardial infarction, and lower limb amputation.Details regarding associations between DME and cardiovascular events were evaluated.The study included 2807 patients with type 2 diabetes, of whom 355 (12.6%) had DME. DME was significantly and independently associated with patient age, known duration of diabetes, HbA1c, systolic blood pressure, and DR stage. Only the prior history of lower limb amputation was strongly associated with DME in univariate and multivariate analyses, whereas no association was found with regard to myocardial infarction or stroke. Moreover, both major (nu200a=u200a32) and minor lower limb (nu200a=u200a96) amputations were similarly associated with DME, with respective odds ratio of 3.7 (95% confidence interval [CI], 1.77–7.74; Pu200a=u200a0.0012) and of 4.29 (95% CI, 2.79–6.61; Pu200a<u200a0.001).DME is strongly and independently associated with lower limb amputation in type 2 diabetic patients.