New insights into acute-on-chronic kidney disease in nephrology patients: the CKD-REIN study.

BACKGROUND: Acute-on-chronic kidney disease (ACKD) is poorly understood and often overlooked. We studied its incidence, circumstances, determinants and outcomes in patients with CKD. METHODS: We used the Kidney Disease: Improving Global Outcomes criteria to identify all-stage acute kidney injury (AKI) events in 3033 nephrology outpatients with CKD Stages 3-5 participating in the CKD-Renal Epidemiology and Information Network cohort study (2013-20), and cause-specific Cox models to estimate hazard ratios [HRs; 95% confidence intervals (CIs)] of AKI-associated risk factors. RESULTS: At baseline, 22% of the patients [mean age 67 years, 65% men, mean estimated glomerular filtration rate (eGFR) 32 mL/min/1.73 m2] had a history of AKI. Over a 3-year follow-up, 443 had at least one AKI event: 27% were Stage 2 or 3 and 11% required dialysis; 74% involved hospitalization including 47% acquired as hospital inpatients; and a third were not reported in hospital discharge reports. Incidence rates were 10.1 and 4.8/100 person-years in patients with and without an AKI history, respectively. In 2375 patients without this history, male sex, diabetes, cardiovascular disease, cirrhosis, several drugs, low eGFR and serum albumin levels were significantly associated with a higher risk of AKI, as were low birth weight (<2500 g) (adjusted HR 1.98; 95% CI 1.35-2.91) and haemoglobin level (HR 1.21; 1.12-1.32 per 1 g/dL decrease). Within 1 year, only 63% of the patients had recovered their previous kidney function, 13.7% had started kidney replacement therapy and 12.7% had died. CONCLUSIONS: The study highlights the high rate of hospital-acquired AKI events in patients with CKD, and their underreporting at hospital discharge. It also reveals low birth weight and anaemia as possible new risk factors in CKD patients.

Urgent-start dialysis in patients referred early to a nephrologist-the CKD-REIN prospective cohort study.

BACKGROUND: The lack of a well-designed prospective study of the determinants of urgent dialysis start led us to investigate its individual- and provider-related factors in patients seeing nephrologists. METHODS: The Chronic Kidney Disease Renal Epidemiology and Information Network (CKD-REIN) is a prospective cohort study that included 3033 patients with CKD [mean age 67 years, 65% men, mean estimated glomerular filtration rate (eGFR) 32 mL/min/1.73 m2] from 40 nationally representative nephrology clinics from 2013 to 2016 who were followed annually through 2020. Urgent-start dialysis was defined as that 'initiated imminently or <48 hours after presentation to correct life-threatening manifestations' according to the Kidney Disease: Improving Global Outcomes 2018 definition. RESULTS: Over a 4-year (interquartile range 3.0-4.8) median follow-up, 541 patients initiated dialysis with a known start status and 86 (16%) were identified with urgent starts. The 5-year risks for the competing events of urgent and non-urgent dialysis start, pre-emptive transplantation and death were 4, 17, 3 and 15%, respectively. Fluid overload, electrolytic disorders, acute kidney injury and post-surgery kidney function worsening were the reasons most frequently reported for urgent-start dialysis. Adjusted odds ratios for urgent start were significantly higher in patients living alone {2.14 [95% confidence interval (CI) 1.08-4.25] or with low health literacy [2.22 (95% CI 1.28-3.84)], heart failure [2.60 (95% CI 1.47-4.57)] or hyperpolypharmacy [taking >10 drugs; 2.14 (95% CI 1.17-3.90)], but not with age or lower eGFR at initiation. They were lower in patients with planned dialysis modality [0.46 (95% CI 0.19-1.10)] and more nephrologist visits in the 12 months before dialysis [0.81 (95% CI 0.70-0.94)] for each visit. CONCLUSIONS: This study highlights several patient- and provider-level factors that are important to address to reduce the burden of urgent-start dialysis.

Risk profile, quality of life and care of patients with moderate and advanced CKD: The French CKD-REIN Cohort Study.

Background: The French Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort study was designed to investigate the determinants of prognosis and care of patients referred to nephrologists with moderate and advanced chronic kidney disease (CKD). We examined their baseline risk profile and experience. Methods: We collected bioclinical and patient-reported information from 3033 outpatients with CKD and estimated glomerular filtration rates (eGFRs) of 15-60 mL/min/1.73 m2 treated at 40 nationally representative public and private facilities. Results: The patients' median age was 69 (60-76) years, 65% were men, their mean eGFR was 33 mL/min/1.73 m2, 43% had diabetes, 24% had a history of acute kidney injury (AKI) and 57% had uncontrolled blood pressure (BP; >140/90 mmHg). Men had worse risk profiles than women and were more likely to be past or current smokers (73% versus 34%) and have cardiovascular disease (59% versus 42%), albuminuria >30 mg/mmol (or proteinuria > 50) (40% versus 30%) (all P < 0.001) and a higher median risk of end-stage renal disease within 5 years, predicted by the kidney failure risk equation {12% [interquartile range (IQR) 3-37%] versus 9% [3-31%], P = 0.008}. During the previous year, 60% of patients reported one-to-two nephrologist visits and four or more general practitioner visits; only 25% saw a dietician and 75% were prescribed five or more medications daily. Physical and mental quality of life (QoL) were poor, with scores <50/100. Conclusions: The CKD-REIN study highlights high-risk profiles of cohort members and identifies several priorities, including improving BP control and dietary counselling and increasing doctors' awareness of AKI, polypharmacy and QoL. Trial registration: ClinicalTrials.gov identifier: NCT03381950.

HbA1c, fasting and 2 h plasma glucose in current, ex- and never-smokers: a meta-analysis.

AIMS/HYPOTHESIS: The relationships between smoking and glycaemic variables have not been well explored. We compared HbA1c, fasting plasma glucose (FPG) and 2 h plasma glucose (2H-PG) in current, ex- and never-smokers. METHODS: This meta-analysis used individual data from 16,886 men and 18,539 women without known diabetes in 12 DETECT-2 consortium studies and in the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) and Telecom studies. Means of three glycaemic variables in current, ex- and never-smokers were modelled by linear regression, with study as a random factor. The I (2) statistic was used to evaluate heterogeneity among studies. RESULTS: HbA1c was 0.10% (95% CI 0.08, 0.12) (1.1 mmol/mol [0.9, 1.3]) higher in current smokers and 0.03% (0.01, 0.05) (0.3 mmol/mol [0.1, 0.5]) higher in ex-smokers, compared with never-smokers. For FPG, there was no significant difference between current and never-smokers (-0.004 mmol/l [-0.03, 0.02]) but FPG was higher in ex-smokers (0.12 mmol/l [0.09, 0.14]). In comparison with never-smokers, 2H-PG was lower (-0.44 mmol/l [-0.52, -0.37]) in current smokers, with no difference for ex-smokers (0.02 mmol/l [-0.06, 0.09]). There was a large and unexplained heterogeneity among studies, with I (2) always above 50%; I (2) was little changed after stratification by sex and adjustment for age and BMI. In this study population, current smokers had a prevalence of diabetes that was 1.30% higher as screened by HbA1c and 0.52% lower as screened by 2H-PG, in comparison with never-smokers. CONCLUSION/INTERPRETATION: Across this heterogeneous group of studies, current smokers had a higher HbA1c and lower 2H-PG than never-smokers. This will affect the chances of smokers being diagnosed with diabetes.

Study of the association between serum levels of kynurenine and cardiovascular outcomes and overall mortality in chronic kidney disease.

Background: Kynurenine is a protein-bound uremic toxin. Its circulating levels are increased in chronic kidney disease (CKD). Experimental studies showed that it exerted deleterious cardiovascular effects. We sought to evaluate an association between serum kynurenine levels and adverse fatal or nonfatal cardiovascular events and all-cause mortality in CKD patients. Methods: The CKD-REIN study is a prospective cohort of people with CKD having an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m². Baseline frozen samples of total and free fractions of kynurenine and tryptophan were measured using a validated liquid chromatography tandem mass spectrometry technique. Cause-specific Cox models were used to estimate hazard ratios (HRs) for each outcome. Results: Of the 2406 included patients (median age: 68 years; median eGFR: 25 ml/min/1.73 m2), 52% had a history of cardiovascular disease. A doubling of serum-free kynurenine levels was associated with an 18% increased hazard of cardiovascular events [466 events, HR (95%CI):1.18(1.02,1.33)], independently of eGFR, serum-free tryptophan level or other uremic toxins, cardioprotective drugs, and traditional cardiovascular risk factors. Serum-free kynurenine was significantly associated with non-atheromatous cardiovascular events [HR(95%CI):1.26(1.03,1.50)], but not with atheromatous cardiovascular events [HR(95%CI):1.15(0.89,1.50)]. The association of serum-free kynurenine with cardiovascular mortality was also independently significant [87 events; adjusted HR(95%CI):1.64(1.10,2.40)]. However, the association of serum-free kynurenine with all-cause mortality was no more significant after adjustment on serum-free tryptophan [311 events, HR(95%CI):1.12(0.90, 1.40)]. Conclusions: Our findings imply that serum-free kynurenine, independently of other cardiovascular risk factors (including eGFR), is associated with fatal or nonfatal cardiovascular outcomes, particularly non-atheromatous cardiovascular events; in patients with CKD. Strategies to reduce serum kynurenine levels should be evaluated in further studies.

Parental history of type 2 diabetes, TCF7L2 variant and lower insulin secretion are associated with incident hypertension. Data from the DESIR and RISC cohorts.

AIMS/HYPOTHESIS: The relationship between insulin secretion and the incidence of hypertension has not been well characterised. We hypothesised that both a parental history of diabetes and TCF7L2 rs7903146 polymorphism, which increases susceptibility to diabetes because of impaired beta cell function, are associated with incident hypertension. In a separate cohort, we assessed whether low insulin secretion is related to incident hypertension. METHODS: Nine year incident hypertension was studied in 2,391 normotensive participants from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort. The relationship between insulin secretion and 3 year incident hypertension was investigated in 1,047 non-diabetic, normotensive individuals from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort. Insulin secretion during OGTT was expressed in relation to the degree of insulin resistance, as assessed by a hyperinsulinaemic-euglycaemic clamp. RESULTS: In the DESIR cohort, a parental history of diabetes and the TCF7L2 at-risk variant were both associated with hypertension incidence at year 9, independently of waist circumference, BP, fasting glucose, insulin levels and HOMA-IR at inclusion (p = 0.02 for parental history, p = 0.006 for TCF7L2). In the RISC cohort, a lower insulin secretion rate during the OGTT at baseline was associated with both higher BP and a greater risk of hypertension at year 3. This inverse correlation between the insulin secretion rate and incident hypertension persisted after controlling for baseline insulin resistance, glycaemia and BP (p = 0.007). CONCLUSIONS/INTERPRETATION: Parental history of diabetes, TCF7L2 rs7903146 polymorphism and a reduced insulin secretion rate were consistently associated with incident hypertension. A low insulin secretion rate might be a new risk factor for incident hypertension, beyond insulin resistance.

Longitudinal uric acid has nonlinear association with kidney failure and mortality in chronic kidney disease.

We investigated the shape of the relationship between longitudinal uric acid (UA) and the hazard of kidney failure and death in chronic kidney disease (CKD) patients, and attempted to identify thresholds associated with increased hazards. We included CKD stage 3-5 patients from the CKD-REIN cohort with one serum UA measurement at cohort entry. We used cause-specific multivariate Cox models including a spline function of current values of UA (cUA), estimated from a separate linear mixed model. We followed 2781 patients (66% men, median age, 69 years) for a median of 3.2 years with a median of five longitudinal UA measures per patient. The hazard of kidney failure increased with increasing cUA, with a plateau between 6 and 10 mg/dl and a sharp increase above 11 mg/dl. The hazard of death had a U-shape relationship with cUA, with a hazard twice higher for 3 or 11 mg/dl, compared to 5 mg/dl. In CKD patients, our results indicate that UA above 10 mg/dl is a strong risk marker for kidney failure and death and that low UA levels below 5 mg/dl are associated with death before kidney failure.

Proton-Pump Inhibitors and Serum Concentrations of Uremic Toxins in Patients with Chronic Kidney Disease.

Use of proton-pump inhibitors (PPIs) is common in patients with chronic kidney disease (CKD). PPIs and many uremic toxins (UTs) are eliminated by the kidney's tubular organic anion transporter system. In a cross-sectional study, we sought to evaluate the association between PPI prescription and serum concentrations of various UTs. We studied a randomly selected sub-group of participants in the CKD-REIN cohort (adult patients with a confirmed diagnosis of CKD and estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2) with available frozen samples collected at baseline. PPI prescription was recorded at baseline. Serum concentrations of 10 UTs were measured using a validated liquid chromatography tandem mass spectrometry technique. Multiple linear regression was performed, with the log UT concentration as the dependent variable. Of the 680 included patients (median age: 68 years; median eGFR: 32 mL/min/1.73 m2), 31% had PPI prescriptions at baseline. Patients using PPIs had higher levels of certain UTs in comparison to other patients, including total and free indoxyl sulfate (IS), total and free p-cresylsulfate, total and free p-cresylglucuronide (PCG), phenylacetylglutamine (PAG), free kynurenine, and free hippuric acid. After adjustment for baseline co-morbidities, number of co-prescribed drugs, and laboratory data, including eGFR, associations between PPI prescription and elevated serum concentrations of free and total IS, free and total PCG, and PAG remained significant. Our results indicate that PPI prescription is independently associated with serum UT retention. These findings are interesting to better understand the factors that may modulate serum UT concentration in CKD patients, however, they will need to be confirmed by longitudinal studies.

[CKD care in French nephrology practices]. / Réalité de la prise en charge de la maladie rénale chronique en néphrologie en France : étude de cohorte CKD-REIN.

BACKGROUND: To be able to assess the impact of the bundled payment system on real-life management of patients with chronic kidney disease, an overview of patient-care management before its implementation is needed. PATIENTS AND METHODS: We describe patterns of nephrology care over 3 years in 2835 patients with moderate to severe chronic kidney disease, who were followed-up from 2013 to 2019 in the CKD-REIN cohort study. Compliance with health authority guidelines during this period is also studied. RESULTS: At baseline, patients' mean age was 67 years, 65% were men, and 43% had chronic kidney disease stage 4 or 5. The mean number of nephrology visits increased from 1.1 to 2.7 per year, from chronic kidney disease stage 3A to stage 5. The minimum number of nephrology visits as recommended by health authorities was achieved in 84%, 63%, and 33% of patients with chronic kidney disease stages 3B, 4, and 5, respectively. In chronic kidney disease stages 4 and 5, only 34% and 40% of patients had seen a dietitian, and 33% and 54% had received information about treatment options, respectively. The average waiting time for a first appointment with a nephrologist was longer, 60 days and its duration shorter, 30 vs 38 to 40 minutes, in university hospitals compared with non-university hospitals and private clinics. CONCLUSION: The significant gap between received and recommended care reflects human resources and organizational limits in chronic kidney disease management in the nephrology setting. Improvements with bundled payment are expected.

Nine-year incident diabetes is predicted by fatty liver indices: the French D.E.S.I.R. study.

BACKGROUND: Fatty liver is known to be linked with insulin resistance, alcohol intake, diabetes and obesity. Biopsy and even scan-assessed fatty liver are not always feasible in clinical practice. This report evaluates the predictive ability of two recently published markers of fatty liver: the Fatty Liver Index (FLI) and the NAFLD fatty liver score (NAFLD-FLS), for 9-year incident diabetes, in the French general-population cohort: Data from an Epidemiological Study on the Insulin Resistance syndrome (D.E.S.I.R). METHODS: At baseline, there were 1861 men and 1950 women, non-diabetic, aged 30 to 65 years. Over the follow-up, 203 incident diabetes cases (140 men, 63 women) were identified by diabetes-treatment or fasting plasma glucose > or = 7.0 mmol/l. The FLI includes: BMI, waist circumference, triglycerides and gamma glutamyl transferase, and the NAFLD-FLS: the metabolic syndrome, diabetes, insulin, alanine aminotransferase, and asparate aminotransferase. Logistic regression was used to determine the odds ratios for incident diabetes associated with categories of the fatty liver indices. RESULTS: In comparison to those with a FLI < 20, the age-adjusted odds ratio (95% confidence interval) for diabetes for a FLI > or = 70 was 9.33 (5.05-17.25) for men and 36.72 (17.12-78.76) for women; these were attenuated to 3.43 (1.61-7.28) and 11.05 (4.09 29.81), after adjusting on baseline glucose, insulin, hypertension, alcohol intake, physical activity, smoking and family antecedents of diabetes; odds ratios increased to 4.71 (1.68-13.16) and 22.77 (6.78-76.44) in those without an excessive alcohol intake. The NAFLD-FLS also predicted incident diabetes, but with odds ratios much lower in women, similar in men. CONCLUSIONS: These fatty liver indexes are simple clinical tools for evaluating the extent of liver fat and they are predictive of incident diabetes. Physicians should screen for diabetes in patients with fatty liver.

Urinary Sodium-to-Potassium Ratio and Blood Pressure in CKD.

INTRODUCTION: In the general population, urinary sodium-to-potassium (uNa/K) ratio associates more strongly with high blood pressure (BP) than either urinary sodium or potassium alone. Whether this is also the case among patients with chronic kidney disease (CKD) is unknown. METHODS: We studied the associations of spot urine sodium-to-creatinine (uNa/Cr), potassium-to-creatinine (uK/Cr), and uNa/K ratios with a single office BP reading in 1660 patients with moderate to severe CKD at inclusion in the CKD-REIN cohort. RESULTS: Patients' median age was 68 (interquartile range [IQR], 59-76) years; most were men (65%), had moderate CKD (57%), and albuminuria (72%). Mean systolic and diastolic BP was 142/78 mm Hg. Spot uNa/Cr and uNa/K ratios were positively associated with systolic, mean arterial, and pulse pressures. The mean adjusted difference in systolic BP between the highest and the lowest quartile (Q4 vs. Q1) was 4.24 (95% confidence interval [CI], 1.53-6.96) mm Hg for uNa/Cr and 4.79 (95% CI, 2.18-7.39) mm Hg for uNa/K. Quartiles of spot uK/Cr were not associated with any BP index. The higher the quartile of uNa/K, the higher the prevalence ratio of uncontrolled (Q4 vs. Q1, 1.43; 95% CI, 1.19-1.72) or apparently treatment-resistant hypertension (Q4 vs. Q1, 1.35; 95% CI, 1.14-1.60). Findings were consistent in a subset of 803 individuals with 2 BP readings. CONCLUSION: In patients with CKD, higher urinary sodium excretion is associated with higher BP, but unlike in general population, lower potassium excretion is not. Urinary Na/K does not add significant value in assessing high BP risk, except perhaps for hypertension control assessment.

Achievement of Low-Density Lipoprotein Cholesterol Targets in CKD.

INTRODUCTION: We describe the characteristics of patients with moderate/advanced chronic kidney disease (CKD) according to receipt of lipid-lowering therapy (LLT), and whether they achieved low-density lipoprotein cholesterol (LDL-C) targets for high- and very high-risk patients. METHODS: CKD-REIN (NCT03381950), a prospective cohort study conducted in 40 nephrology clinics in France, enrolled 3033 patients with moderate (stage G3) or advanced (stage G4/G5) CKD (2013-2016) who had not been on chronic dialysis or undergone kidney transplantation. Data were collected from patients' interviews and medical records. Patients were followed up at 1 year. RESULTS: Among 2542 patients (mean [SD] age 67 [13] years, 34% women) with LDL-C measurements at baseline (mean [SD] LDL-C 2.7 [1.1] mmol/l; cholesterol 4.8 [1.3] mmol/l), 63% were on LLT; 24% were at high (CKD stage G3, no cardiovascular disease [CVD] or diabetes) and 74% at very high (CKD stage G3 with diabetes or CVD, or CKD stage G4/5) cardiovascular risk. Among high-risk patients, 45% of those on statin and/or ezetimibe achieved the LDL-C treatment target (<2.6 mmol/l). Among very high-risk patients, the percentage at goal (<1.8 mmol/l) was 38% for CKD stage G3 and 29% for stage G4/5. There was a trend toward higher achievement of LDL-C targets with increasing LLT intensity (adjusted odds ratios for moderate vs. low intensity 1.20; 95% confidence interval 0.92-1.56; high vs. low intensity 1.46; 1.02-2.09; Ptrend = 0.036). CONCLUSION: Many patients with CKD stage G3-G5 who are eligible for LLT are not treated, and those on LLT rarely achieve LDL-C targets.

Urinary albumin excretion is a risk factor for diabetes mellitus in men, independently of initial metabolic profile and development of insulin resistance. The DESIR Study.

BACKGROUND: Elevated urinary albumin excretion (UAE) is more frequent in patients with the metabolic syndrome or insulin resistance. Whether UAE predicts the development of diabetes mellitus, independently of the presence or the development of the metabolic syndrome, is unclear, in particular, in women. OBJECTIVE: We prospectively assessed the association between baseline UAE and subsequent diabetes mellitus in participants selected from the general population. PARTICIPANTS AND METHODS: Four thousand and seventy-four nondiabetic patients (aged 30-64 years) included in the Data from an Epidemiological Study on the Insulin Resistance syndrome Study had a baseline UAE. Among them, 3851 patients had complete data regarding diabetes mellitus. RESULTS: Diabetes mellitus occurred in 171 out of 3851 patients during the 9-year follow-up (132/2056 men and 39/1795 women). UAE was associated with diabetes mellitus in a dose-dependent manner in men [as compared to men with UAE<9 mg/l, hazard ratios were 1.81 (P=0.0160), 1.83 (P=0.0134), 2.31 (P=0.0008) and 4.43 (P=0.0005) for men with UAE: 9-12 mg/l, 12-19 mg/l, 20-200 mg/l and >200 mg/l, respectively] but not in women; the association was more marked after exclusion of men with baseline impaired fasting glucose [hazard ratios were 3.28 (P=0.0007), 3.08 (P=0.0012), 3.27 (P=0.0022), 9.23 (P<0.0001), respectively]. The association remained significant after adjustments on BMI, sporting activity, diet, smoking, waist circumference, insulin and homeostasis model assessment of insulin resistance, lipids, C-reactive protein and family of history of diabetes mellitus. Adjustment on the first 3-year change in weight, glucose, insulin and homeostasis model assessment of insulin resistance did not modify the results. CONCLUSION: Elevated UAE predicts the 9-year risk of diabetes mellitus in men, independent of baseline or early development of metabolic abnormalities or insulin resistance.

The Data from an Epidemiologic Study on the Insulin Resistance Syndrome Study: the change and the rate of change of the age-blood pressure relationship.

OBJECTIVE: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) increase significantly until around 55 years, when SBP increases, DBP decreases. Whether the rates of change of SBP and DBP with age exhibit a similar dissociation has never been investigated. DESIGN AND PARTICIPANTS: The Data from an Epidemiologic Study on the Insulin Resistance Syndrome Study (D.E.S.I.R.), a 9-year longitudinal study included 2278 men and 2314 women, 30-65 years and SBP, DBP, and other cardiometabolic risk factors were determined every 3 years. RESULTS: Both SBP and DBP increased with age, more rapidly in women than in men. SBP and DBP were higher in the presence of risk factors (except smoking) but the increases with age were similar. For the rates of change, whereas DeltaSBP increased linearly with age, DeltaDBP declined as early as 45 years. This finding was not influenced by sex, menopause or other risk factors but was significantly attenuated in the presence of hypertension at baseline, whether treated or not, and mainly in men. CONCLUSION: DBP increases with age between 30 and 60 years, DeltaDBP tends to be markedly reduced as early as 45 years, in contrast with DeltaSBP. Consequences for the understanding of vascular aging and antihypertensive therapy remain to be explored.

Waist circumference and the metabolic syndrome predict the development of elevated albuminuria in non-diabetic subjects: the DESIR Study.

OBJECTIVE: Metabolic determinants of microalbuminuria remain poorly understood in non-diabetic individuals and particularly in women. We investigated in both sexes whether an elevated waist circumference (WC) or the presence of the metabolic syndrome (MetS) predict the development of elevated albuminuria at 6 years. DESIGN AND PATIENTS: We studied 2738 subjects from the DESIR cohort without microalbuminuria or diabetes at baseline and who were followed up for 6 years. RESULTS: At 6 years, 254 individuals [9.3%; 95% confidence interval (CI) 8.2-10.4%] had developed elevated albuminuria (> or = 20 mg/l), which was significantly and positively associated with WC and blood pressure, but not with fasting glucose, lipids or body mass index in either sex. In both sexes, subjects with a high WC or with MetS at baseline were more likely to develop elevated albuminuria at 6 years compared with those with a normal WC or absence of MetS. In multivariate logistic analysis, WC as a continuous variable or a WC of 94 cm or greater for men and a WC greater than 88 cm for women were predictive of the development of elevated albuminuria, after adjusting for age, hypertension, the use of angiotensin-converting enzyme inhibitors, fibrinogen and glycaemia. MetS was a risk factor for elevated albuminuria in men (odds ratio 1.87; 95% CI 1.25-2.81), with differences according to the MetS definition. CONCLUSION: Abdominal adiposity is related to the development of elevated albuminuria in both sexes, suggesting that the measurement of WC may improve the identification of non-diabetic individuals at risk of developing microalbuminuria and emphasizing the interest of screening for albuminuria among those with MetS.

Blood microbiota dysbiosis is associated with the onset of cardiovascular events in a large general population: the D.E.S.I.R. study.

AIM: We recently described a human blood microbiome and a connection between this microbiome and the onset of diabetes. The aim of the current study was to assess the association between blood microbiota and incident cardiovascular disease. METHODS AND RESULTS: D.E.S.I.R. is a longitudinal study with the primary aim of describing the natural history of the metabolic syndrome and its complications. Participants were evaluated at inclusion and at 3-, 6-, and 9-yearly follow-up visits. The 16S ribosomal DNA bacterial gene sequence, that is common to the vast majority of bacteria (Eubac) and a sequence that mostly represents Proteobacteria (Pbac), were measured in blood collected at baseline from 3936 participants. 73 incident cases of acute cardiovascular events, including 30 myocardial infarctions were recorded. Eubac was positively correlated with Pbac (r = 0.59; P<0.0001). In those destined to have cardiovascular complications, Eubac was lower (0.14±0.26 vs 0.12±0.29 ng/µl; P = 0.02) whereas a non significant increase in Pbac was observed. In multivariate Cox analysis, Eubac was inversely correlated with the onset of cardiovascular complications, (hazards ratio 0.50 95% CI 0.35-0.70) whereas Pbac (1.56, 95%CI 1.12-2.15) was directly correlated. CONCLUSION: Pbac and Eubac were shown to be independent markers of the risk of cardiovascular disease. This finding is evidence for the new concept of the role played by blood microbiota dysbiosis on atherothrombotic disease. This concept may help to elucidate the relation between bacteria and cardiovascular disease.

Hypertension and vascular dynamics in men and women with metabolic syndrome.

Metabolic syndrome (MetS), an important component of insulin resistance and cardiovascular (CV) risk, is defined by 3 or more of the following characteristics: abdominal obesity, hyperglycemia, hypertension, hypertriglyceridemia, and hypo-high-density lipoprotein cholesterolemia. Based on the previously published age- and sex-mediated DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) cohort and parallel central hemodynamic measurements, our goal was to evaluate the effects of MetS on brachial central pulse pressure (PP), PP amplification, aortic stiffness, and wave reflections. These data were then compared with those of patients with essential hypertension but without MetS for the same mean arterial pressure. Increased aortic stiffness, a major mechanical factor predicting CV risk, has been well identified as playing a role in MetS. Its age progression is proportional to the number of risk factors involved in MetS and is responsible for increased systolic blood pressure and decreased diastolic blood pressure with increasing age, the principal hallmarks of hypertension in the elderly. Beyond brachial pressure measurements, central hemodynamic parameters involve increased aortic stiffness, reduced wave reflections, and increased PP amplification, a parameter commonly associated with increased heart rate. With the exception of arterial stiffness, all these findings are opposite in direction to those observed in essential hypertension, in which MetS is absent. A divergent behavior of wave reflections and PP amplification, but not of arterial stiffness, is observed when hypertension is studied alone or when compared with MetS for the same mean arterial pressure. This pulsatile hemodynamic abnormality contributes independently to increase age- and sex-mediated CV risk, justifying new research regarding Framingham scores and drug treatment.

Mean and yearly changes in blood pressure with age in the metabolic syndrome: the DESIR study.

Systolic and diastolic blood pressure (SBP; DBP) increase with age, but after 45 years of age, the yearly change in DBP (ΔDBP) tends to be smaller in comparison with the yearly change in SBP (ΔSBP), which increases with age. The effect of the metabolic syndrome (MetS) on this yearly change has never been explored. In a 9-year longitudinal cohort Data from an Epidemiologic Study on the Insulin Resistance syndrome (DESIR) study, we examined 1308 men and 1325 women, aged 30-65 years, who had never been treated for hypertension. SBP and DBP were measured at four examinations 3 years apart, and pulse pressure (PP) and yearly changes (ΔSBP, ΔDBP and ΔPP) were calculated. SBP and PP increased with age to a higher degree in patients with the MetS. In men and women with the MetS, DBP remained nearly constant, but in those without the MetS, DBP increased. After adjusting for baseline values, ΔSBP and ΔPP increased by 0.5 mm Hg per year for every additional 10 years from baseline. These correlations with age were similar for men and women, and the yearly change was always higher than in those with the MetS. In contrast, ΔDBP increased very slowly until 50 years of age and then decreased similarly for those with and without the MetS. The increase in PP with age, a marker of vascular aging, was determined to begin earlier in the present study than has been shown in the past, and the MetS amplified this effect. This new aspect of the MetS might modify clinical management leading to earlier drug treatment, particularly in regard to both endothelial dysfunction and increased arterial stiffness.

Are the same clinical risk factors relevant for incident diabetes defined by treatment, fasting plasma glucose, and HbA1c?

OBJECTIVE: To compare incidences and risk factors for diabetes using seven definitions, with combinations of pharmacological treatment, fasting plasma glucose (FPG) ≥7.0 mmol/L, and HbA(1c) ≥6.5%. RESEARCH DESIGN AND METHODS: Participants aged 30-65 years from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort were followed for 9 years. RESULTS: More men had incident diabetes as defined by FPG ≥7.0 mmol/L and/or treatment than by HbA(1c) ≥6.5% and/or treatment: 7.5% (140/1,867) and 5.3% (99/1,874), respectively (P < 0.009); for women incidences were similar: 3.2% (63/1,958) and 3.4% (66/1,954). Known risk factors predicted diabetes for almost all definitions. Among those with incident diabetes by FPG alone versus HbA(1c) alone, there were more men (78 vs. 35%), case patients were 8 years younger, and fewer were alcohol abstainers (12 vs. 35%) (all P < 0.005). A diabetes risk score discriminated well between those with and without incident diabetes for all definitions. CONCLUSIONS: In men, FPG definitions yielded more incident cases of diabetes than HbA(1c) definitions, in contrast with women. An FPG-derived risk score remained relevant for HbA(1c)-defined diabetes.

Hemoglobin A1c and fasting plasma glucose levels as predictors of retinopathy at 10 years: the French DESIR study.

OBJECTIVE: To evaluate the predictive values of hemoglobin A(1c) (HbA(1c)) and fasting plasma glucose (FPG) for retinopathy 10 years after the baseline examination. METHODS: Seven hundred men and women from the DESIR (Data From an Epidemiological Study on the Insulin Resistance Syndrome) Study underwent evaluation for retinopathy using a nonmydriatic digital camera. During the preceding 9 years, 235 had diabetes mellitus (treated or FPG level of ≥126 mg/dL at least once), 227 had an impaired FPG level (110-125 mg/dL) at least once, and 238 always had glucose levels within reference limits (<110 mg/dL). RESULTS: Compared with those without retinopathy, the 44 participants with retinopathy at 10 years had higher baseline mean (SD) levels of FPG (130 [49] vs 106 [22] mg/dL) and HbA(1c) (6.4% [1.6%] vs 5.7% [0.7%]) (both, P < .001). The frequency of retinopathy at 10 years, standardized according to the distribution of glycemia across the entire DESIR population, was 3.6%. In our population, FPG levels of 108 and 116 mg/dL had positive predictive values of 8.4% and 14.0%, respectively, for retinopathy at 10 years; HbA(1c) levels of 6.0% and 6.5% had positive predictive values of 6.0% and 14.8%, respectively. After 10 years of follow-up, retinopathy was equally frequent in participants with impaired FPG levels and in those who became diabetic during the study (8.6% and 6.7%, respectively), lower than in those with diabetes at baseline (13.9%). CONCLUSION: Because the positive predictive values for retinopathy increase sharply from 108 mg/dL for FPG and from 6.0% for HbA(1c) levels, these thresholds are proposed to identify those at risk of retinopathy 10 years later.