Reference values for plasma and urine trace elements in a Swiss population-based cohort.

OBJECTIVES: Trace elements (TEs) are ubiquitous. TE concentrations vary among individuals and countries, depending on factors such as living area, workplaces and diet. Deficit or excessive TEs concentrations have consequences on the proper functioning of human organism so their biomonitoring is important. The aim of this project was to provide reference values for TEs concentrations in the Swiss population. METHODS: The 1,078 participants to the SKiPOGH cohort included in this study were aged 18-90 years. Their 24-h urine and/or plasma samples were analyzed by inductively coupled plasma mass spectrometry (ICP-MS) to determine 24 TEs concentrations: Ag, Al, As, Be, Bi, Cd, Co, Cr, Cu, Hg, I, Li, Mn, Mo, Ni, Pb, Pd, Pt, Sb, Se, Sn, Tl, V and Zn. Statistical tests were performed to evaluate the influence of covariates (sex, age, BMI, smoking) on these results. Reference intervals for the Swiss adult population were also defined. RESULTS: TEs concentrations were obtained for respectively 994 and 903 persons in plasma and urine matrices. It was possible to define percentiles of interest (P50 and P95) for almost all the TEs. Differences in TEs distribution between men and women were noticed in both matrices; age was also a cofactor. CONCLUSIONS: This first Swiss biomonitoring of a large TEs-panel offers reference values in plasma and in urine for the Swiss population. The results obtained in this study were generally in line with clinical recommendations and comparable to levels reported in other population-based surveys.

Relationship between renal function and blood pressure dipping status in renal transplant recipients: a longitudinal study.

BACKGROUND: Hypertension (HT) is associated with adverse outcomes in kidney transplant (KTX) recipients. Blunting of physiological decrease in nighttime compared to daytime blood pressure (non-dipping status) is frequent in this setting. However, weather non-dipping is independently associated with renal function decline in KTX patients is unknown. METHODS: We retrospectively screened KTX outpatients attending for a routine ambulatory blood pressure monitoring (ABPM) (T1) at a single tertiary hospital. Patients had two successive follow-up visits, 1 (T2) and 2 (T3) years later respectively. Routine clinical and laboratory data were collected at each visit. Mixed linear regression models were used with estimated glomerular filtration rate (eGFR) as the dependent variable. RESULTS: A total of 123 patients were included with a mean follow-up of 2.12 ± 0.45 years after ABPM. Mean age and eGFR at T1 were 56.0 ± 15.1 and 54.9 ± 20.0 mL/min/1.73m2 respectively. 61 patients (50.4%) had sustained HT and 81 (65.8%) were non-dippers. In multivariate analysis, systolic dipping status was positively associated with eGFR (p = 0.009) and compared to non-dippers, dippers had a 10.4 mL/min/1.73m2 higher eGFR. HT was negatively associated with eGFR (p = 0.003). CONCLUSIONS: We confirm a high prevalence of non-dippers in KTX recipients. We suggest that preserved systolic dipping is associated with improved renal function in this setting independently of potential confounders, including HT and proteinuria. Whether modification of dipping status by chronotherapy would preserve renal function remains to be tested in clinical trials.

Combining the advantages of multilevel and orthogonal partial least squares data analysis for longitudinal metabolomics: Application to kidney transplantation.

Kidney transplantation is one of the renal replacement options in patients suffering from end-stage renal disease (ESRD). After a transplant, patient follow-up is essential and is mostly based on immunosuppressive drug levels control, creatinine measurement and kidney biopsy in case of a rejection suspicion. The extensive analysis of metabolite levels offered by metabolomics might improve patient monitoring, help in the surveillance of the restoration of a "normal" renal function and possibly also predict rejection. The longitudinal follow-up of those patients with repeated measurements is useful to understand changes and decide whether an intervention is necessary. The time modality, therefore, constitutes a specific dimension in the data structure, requiring dedicated consideration for proper statistical analysis. The handling of specific data structures in metabolomics has received strong interest in recent years. In this work, we demonstrated the recently developed ANOVA multiblock OPLS (AMOPLS) to efficiently analyse longitudinal metabolomic data by considering the intrinsic experimental design. Indeed, AMOPLS combines the advantages of multilevel approaches and OPLS by separating between and within individual variations using dedicated predictive components, while removing most uncorrelated variations in the orthogonal component(s), thus facilitating interpretation. This modelling approach was applied to a clinical cohort study aiming to evaluate the impact of kidney transplantation over time on the plasma metabolic profile of graft patients and donor volunteers. A dataset of 266 plasma metabolites was identified using an LC-MS multiplatform analytical setup. Two separate AMOPLS models were computed: one for the recipient group and one for the donor group. The results highlighted the benefits of transplantation for recipients and the relatively low impacts on blood metabolites of donor volunteers.

Dialysis initiation improves calcification propensity.

BACKGROUND: Cardiovascular morbidity and mortality is high in patients starting dialysis and could be related to modifications of calcification inducers and inhibitors by dialysis, promoting cardiovascular events. The impact of dialysis initiation on serum calcification propensity evolution and arterial stiffness is unknown. We therefore prospectively determined the evolution of the one-half maximal transition time (T50) value and its main determinants as well as pulse wave velocity over the first 3 months of dialysis initiation. METHODS: We analysed the evolution of T50, fetuin-A and mineral metabolism parameters before dialysis initiation (M0) and monthly until Month 3 (M3) in incident patients starting haemodialysis (HD) or peritoneal dialysis (PD) in two tertiary Swiss university hospitals. Arterial stiffness was assessed by pulse tonometry at M0 and M3 and biological parameters were compared between M0 and M3 and before/after HD. Linear mixed models were used to assess parameter evolution over time, taking into account repeated measures and other influencing variables. RESULTS: Forty-six patients on HD and 12 on PD were followed. Among them, 45 were male (78%) with a median age of 67 years (25th-75th quartile range 54-77). T50 significantly increased between M0 and M3 from 183 (120-266) to 246 min (175-330) (P < 0.001). Fetuin-A, calcium and magnesium also increased while phosphate decreased. Factors associated with T50 changes over time were fetuin-A, phosphate and magnesium (P < 0.001). Fetuin-A changes were associated with inflammation-related factors (albumin, C-reactive protein) but not calcium and phosphate levels. Arterial stiffness was not significantly modified over 3 months. PD and HD initiation showed similar trends. CONCLUSIONS: Dialysis initiation significantly improves calcification propensity and fetuin-A levels. These modifications do not explain the high mortality related to dialysis initiation. The clinical relevance of using T50 values to initiate dialysis awaits further studies.

Tumor necrosis factor stimulates fibroblast growth factor 23 levels in chronic kidney disease and non-renal inflammation.

Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis, and its early rise in patients with chronic kidney disease is independently associated with all-cause mortality. Since inflammation is characteristic of chronic kidney disease and associates with increased plasma FGF23 we examined whether inflammation directly stimulates FGF23. In a population-based cohort, plasma tumor necrosis factor (TNF) was the only inflammatory cytokine that independently and positively correlated with plasma FGF23. Mouse models of chronic kidney disease showed signs of renal inflammation, renal FGF23 expression and elevated systemic FGF23 levels. Renal FGF23 expression coincided with expression of the orphan nuclear receptor Nurr1 regulating FGF23 in other organs. Antibody-mediated neutralization of TNF normalized plasma FGF23 and suppressed ectopic renal Fgf23 expression. Conversely, TNF administration to control mice increased plasma FGF23 without altering plasma phosphate. Moreover, in Il10-deficient mice with inflammatory bowel disease and normal kidney function, plasma FGF23 was elevated and normalized upon TNF neutralization. Thus, the inflammatory cytokine TNF contributes to elevated systemic FGF23 levels and also triggers ectopic renal Fgf23 expression in animal models of chronic kidney disease.

Use of day and night urinary iodine excretion to estimate the prevalence of inadequate iodine intakes via the estimated average requirement cut-point method.

The objectives were to determine urinary iodine concentration (UIC) in day and night samples collected over a 24-hour period and evaluate the usual dietary iodine intake distribution from this collection. We propose a method by which the prevalence of inadequacy can be calculated from a single 24-hour collection, reducing the burden on participants and the study costs. The samples from 1128 participants were collected between 2009 and 2013 within the framework of the Swiss Kidney Project on Genes observational cohort study; 1024 samples were suitable for statistical evaluation of iodine analysis. Participants were over 18, resident in Switzerland and of European ancestry. Over 24 hours, urine was collected as night-time (bedtime until and including first morning urine) and day-time (the remainder) samples. Associations with variables, in particular to estimated glomerular filtration rate (eGFR), were investigated using mixed models. The 24-hour median UICs were 73 and 96 µg/l for women (n = 542) and men (n = 482), respectively; 24-hour median intakes (derived from the corresponding excretion) were 127 and 156 µg/d, respectively. Day and night excretions were normalised to 24-hour excretion values and the usual intake distribution calculated by the US National Cancer Institute method. The Estimated Average Requirement cut-point method was used to calculate the prevalence of inadequacy, estimated at 14% for women and 4% for men; above the target of 2-3%. We conclude that segregating 24-hour urine into day and night collections is sufficient to determine the prevalence of iodine inadequacy in the population and reduces the burden on participants by sparing a second 24-hour collection. No association between iodine intake and eGFR was found.

Biomarkers for acute kidney injury in decompensated cirrhosis: A prospective study.

AIM: Acute kidney injury (AKI) is a frequent complication in cirrhotic patients. As serum creatinine is a poor marker of renal function in this population, we aimed to study the utility of several biomarkers in this context. METHODS: A prospective study was conducted in hospitalized patients with decompensated cirrhosis. Serum creatinine (SCr), Cystatin C (CystC), NGAL and urinary NGAL, KIM-1, protein, albumin and sodium were measured on three separate occasions. Renal resistive index (RRI) was obtained. We analyzed the value of these biomarkers to determine the presence of AKI, its aetiology [prerenal, acute tubular necrosis (ATN), or hepatorenal (HRS)], its severity and a composite clinical outcome at 30 days (death, dialysis and intensive care admission). RESULTS: We included 105 patients, of which 55 had AKI. SCr, CystC, NGAL (plasma and urinary), urinary sodium and RRI at inclusion were independently associated with the presence of AKI. SCr, CystC and plasma NGAL were able to predict the subsequent development of AKI. Pre-renal state showed lower levels of SCr, NGAL (plasma and urinary) and RRI. ATN patients had high levels of NGAL (plasma and urinary) as well as urinary protein and sodium. HRS patients presented an intermediate pattern. All biomarkers paralleled the severity of AKI. SCr, CystC and plasma NGAL predicted the development of the composite clinical outcome with the same performance as the MELD score. CONCLUSIONS: In patients with decompensated cirrhosis, early measurement of renal biomarkers provides valuable information on AKI aetiology. It could also improve AKI diagnosis and prognosis.

Urinary steroid profiling in women hints at a diagnostic signature of the polycystic ovary syndrome: A pilot study considering neglected steroid metabolites.

BACKGROUND: Although the polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women with vast metabolic consequences, its etiology remains unknown and its diagnosis is still made by exclusion. This study aimed at characterizing a large number of urinary steroid hormone metabolites and enzyme activities in women with and without PCOS in order to test their value for diagnosing PCOS. METHODS: Comparative steroid profiling of 24h urine collections using an established in-house gas-chromatography mass spectrometry method. Data were collected mostly prospectively. Patients were recruited in university hospitals in Switzerland. Participants were 41 women diagnosed with PCOS according to the current criteria of the Androgen Excess and PCOS Society Task Force and 66 healthy controls. Steroid profiles of women with PCOS were compared to healthy controls for absolute metabolite excretion and for substrate to product conversion ratios. The AUC for over 1.5 million combinations of metabolites was calculated in order to maximize the diagnostic accuracy in patients with PCOS. Sensitivity, specificity, PPV, and NPV were indicated for the best combinations containing 2, 3 or 4 steroid metabolites. RESULTS: The best single discriminating steroid was androstanediol. The best combination to diagnose PCOS contained four of the forty measured metabolites, namely androstanediol, estriol, cortisol and 20ßDHcortisone with AUC 0.961 (95% CI 0.926 to 0.995), sensitivity 90.2% (95% CI 76.9 to 97.3), specificity 90.8% (95% CI 81.0 to 96.5), PPV 86.0% (95% CI 72.1 to 94.7), and NPV 93.7% (95% CI 84.5 to 98.2). CONCLUSION: PCOS shows a specific 24h urinary steroid profile, if neglected metabolites are included in the analysis and non-conventional data analysis applied. PCOS does not share a profile with hyperandrogenic forms of congenital adrenal hyperplasias due to single steroid enzyme deficiencies. Thus PCOS diagnosis by exclusion may no longer be warranted. Whether these findings also apply to spot urine and serum, remains to be tested as a next step towards routine clinical applicability.

Nondipping pattern on 24-h ambulatory blood pressure monitoring is associated with left ventricular hypertrophy in chronic kidney disease.

BACKGROUND: Few studies have assessed the role of 24-h ambulatory blood pressure monitoring (ABPM) in adults with nondialysis chronic kidney disease (CKD). We examined the potential determinants of left ventricular hypertrophy (LVH) and mass index (LVMI) in this population. PARTICIPANTS AND METHODS: We carried out a cross-sectional study on 69 stage 3b-5 CKD adults who had ABPM and transthoracic echocardiography performed simultaneously. Hypertension (HT) was defined as 24 h blood pressure (BP) of at least 130/80 mmHg. ABPM parameters considered were BP dipping status, BP load, and the BP night-time/daytime ratio. We performed stepwise backward multivariate linear and logistic regression to assess the determinants of LVH and LVMI. ABPM parameters were considered the main independent variables, whereas HT, angiotensin-converting enzyme inhibitor/angiotensin II receptor antagonist use, glomerular filtration rate of less than 30 ml/min/1.72 m, diabetes, smoking, age, sex, hemoglobin, and parathyroid hormone levels were considered covariates. RESULTS: LVH was present in 22 (31.8%) patients. In linear regression analysis, systolic [ß=-13.8, 95% confidence interval (CI)=-26.3 to -1.3, P=0.031] and mean (ß=-13.5, 95% CI=-25.7 to -1.2, P=0.031) nondipping status was associated with increased LVMI. BP load and night-time/daytime ABPM ratio were not associated with LVMI. In logistic regression analysis, systolic nondipping status (odds ratio=0.27, 95% CI=0.08-0.91, P=0.036) was associated with LVH. Among covariates, estimated glomerular filtration rate of less than 30 ml/min/1.72 m and HT were associated with LVH and increased LVMI. At 1-year follow-up, mean nondipping status on the initial ABPM remained associated significantly with increased LVMI (ß=-19.8, 95% CI=-36.6 to -3.0, P=0.022). CONCLUSION: These data confirm the high incidence of LVH among nonrenal replacement therapy CKD patients and suggest that the nondipping phenomenon on ABPM is associated independently with LVH and increased LVMI in this population.

Urinary Cadmium Excretion Is Associated With Increased Synthesis of Cortico- and Sex Steroids in a Population Study.

Context: Urinary cadmium (Cd) excretion is associated with cancer and cardiovascular morbidity. A potential mechanism could be disturbance of steroidogenesis in gonads and adrenal glands. Objective: We tested whether urinary excretion of Cd is correlated with that of cortico- and sex steroid metabolites in the general adult population. Setting: The Swiss Kidney Project on Genes in Hypertension is a multicentric, family-based population study. Measures: Urinary excretions of steroid hormone metabolites and Cd were measured with separate day and night collections. Associations were analyzed by mixed linear models. Results: Urinary Cd and testosterone excretions in men were significantly correlated (respective day and night ß values [standard error (SE)], 1.378 [0.242], P < 0.0005; and 1.440 [0.333], P < 0.0005), but not in women [0.333(0.257), P = 0.2; and 0.674 (0.361), P = 0.06]. Urinary Cd and cortisol excretions were positively associated in both sexes [day: ß = 0.475 (SE, 0.157), P = 0.0025, and 0.877 (SE, 0.194), P < 0.0005, respectively; night: ß = 0.875 (SE, 0.253), P < 0.0005 and 1.183 (SE, 0.277), P = 0.00002, respectively]. Cd excretion was correlated with mineralocorticoid metabolites excretion, except tetrahydroaldosterone, in both sexes (P < 0.01). There was an independent effect of Cd on sex hormone and corticosteroid synthesis and an interdependent effect on gluco- and mineralcorticoid production. Conclusion: Our findings provide evidence for a global stimulating effect on steroid synthesis already at low-dose Cd exposure. These findings might explain the association of Cd with diseases such as steroid-sensitive cancers or metabolic disorders.

Risk factors for community-acquired acute kidney injury in patients with and without chronic kidney injury and impact of its initial management on prognosis: a prospective observational study.

BACKGROUND: We aimed to describe clinical characteristics of patients with community-acquired acute kidney injury (CA-AKI), the effectiveness of initial management of CA-AKI, its prognosis and the impact of medication on its occurrence in patients with previous chronic kidney injury (CKI). METHODS: We undertook a prospective observational study within the Emergency Department (ED) of a University Hospital, screening for any patient >16 years admitted with an eGFR <60 ml/mn/1.73 m2 and a rise in serum creatinine as compared to previous values. Patients' medical files were reviewed by a panel of nephrologists in the subsequent days and at one and three-years follow-up. RESULTS: From May 1st to June 21st 2013, there were 8464 admissions in the ED, of which 653 had an eGFR <60 ml/mn/1.73 m2. Of these, 352 had previous CKI, 341 had CA-AKI, and 104 had CA-ACKI (community-acquired acute on chronic kidney injury). Occurrence of superimposed CA-AKI in CKI patients was associated with male gender and with use of diuretics, but not with use of ARBs or ACEIs. Adequate management of CA-AKI defined as identification, diagnostic procedures and therapeutic intervention within 24 h, was recorded in 45% of the cases and was not associated with improved outcomes. Three-year mortality was 21 and 48% in CKI and CA-ACKI patients respectively, and 40% in patients with only CA-AKI (p < 0.001). Mortality was significantly associated with age, hypertension, ischemic heart disease and CA-AKI. Progression of renal insufficiency was associated with male gender and age. CONCLUSIONS: CA-AKI is more frequently encountered in male patients and those treated with diuretics and is an independent risk factor for long-term mortality. Its initial adequate management failed to improve outcomes.

Phosphocalcic Markers and Calcification Propensity for Assessment of Interstitial Fibrosis and Vascular Lesions in Kidney Allograft Recipients.

Renal interstitial fibrosis and arterial lesions predict loss of function in chronic kidney disease. Noninvasive estimation of interstitial fibrosis and vascular lesions is currently not available. The aim of the study was to determine whether phosphocalcic markers are associated with, and can predict, renal chronic histological changes. We included 129 kidney allograft recipients with an available transplant biopsy in a retrospective study. We analyzed the associations and predictive values of phosphocalcic markers and serum calcification propensity (T50) for chronic histological changes (interstitial fibrosis and vascular lesions). PTH, T50 and vitamin D levels were independently associated to interstitial fibrosis. PTH elevation was associated with increasing interstitial fibrosis severity (r = 0.29, p = 0.001), while T50 and vitamin D were protective (r = -0.20, p = 0.025 and r = -0.23, p = 0.009 respectively). On the contrary, fibroblast growth factor 23 (FGF23) and Klotho correlated only modestly with interstitial fibrosis (p = 0.045) whereas calcium and phosphate did not. PTH, vitamin D and T50 were predictors of extensive fibrosis (AUC: 0.73, 0.72 and 0.68 respectively), but did not add to renal function prediction. PTH, FGF23 and T50 were modestly predictive of low fibrosis (AUC: 0.63, 0.63 and 0.61) but did not add to renal function prediction. T50 decreased with increasing arterial lesions (r = -0.21, p = 0.038). The discriminative performance of T50 in predicting significant vascular lesions was modest (AUC 0.61). In summary, we demonstrated that PTH, vitamin D and T50 are associated to interstitial fibrosis and vascular lesions in kidney allograft recipients independently of renal function. Despite these associations, mineral metabolism indices do not show superiority or additive value to fibrosis prediction by eGFR and proteinuria in kidney allograft recipients, except for vascular lesions where T50 could be of relevance.

Sociodemographic, behavioral and genetic determinants of allostatic load in a Swiss population-based study.

Allostatic load (AL) is a marker of physiological dysregulation which reflects exposure to chronic stress. High AL has been related to poorer health outcomes including mortality. We examine here the association of socioeconomic and lifestyle factors with AL. Additionally, we investigate the extent to which AL is genetically determined. We included 803 participants (52% women, mean age 48±16years) from a population and family-based Swiss study. We computed an AL index aggregating 14 markers from cardiovascular, metabolic, lipidic, oxidative, hypothalamus-pituitary-adrenal and inflammatory homeostatic axes. Education and occupational position were used as indicators of socioeconomic status. Marital status, stress, alcohol intake, smoking, dietary patterns and physical activity were considered as lifestyle factors. Heritability of AL was estimated by maximum likelihood. Women with a low occupational position had higher AL (low vs. high OR=3.99, 95%CI [1.22;13.05]), while the opposite was observed for men (middle vs. high OR=0.48, 95%CI [0.23;0.99]). Education tended to be inversely associated with AL in both sexes(low vs. high OR=3.54, 95%CI [1.69;7.4]/OR=1.59, 95%CI [0.88;2.90] in women/men). Heavy drinking men as well as women abstaining from alcohol had higher AL than moderate drinkers. Physical activity was protective against AL while high salt intake was related to increased AL risk. The heritability of AL was estimated to be 29.5% ±7.9%. Our results suggest that generalized physiological dysregulation, as measured by AL, is determined by both environmental and genetic factors. The genetic contribution to AL remains modest when compared to the environmental component, which explains approximately 70% of the phenotypic variance.

A Pilot Study Identifying a Set of microRNAs As Precise Diagnostic Biomarkers of Acute Kidney Injury.

In the last decade, Acute Kidney Injury (AKI) diagnosis and therapy have not notably improved probably due to delay in the diagnosis, among other issues. Precocity and accuracy should be critical parameters in novel AKI biomarker discovery. microRNAs are key regulators of cell responses to many stimuli and they can be secreted to the extracellular environment. Therefore, they can be detected in body fluids and are emerging as novel disease biomarkers. We aimed to identify and validate serum miRNAs useful for AKI diagnosis and management. Using qRT-PCR arrays in serum samples, we determined miRNAs differentially expressed between AKI patients and healthy controls. Statistical and target prediction analysis allowed us to identify a panel of 10 serum miRNAs. This set was further validated, by qRT-PCR, in two independent cohorts of patients with relevant morbi-mortality related to AKI: Intensive Care Units (ICU) and Cardiac Surgery (CS). Statistical correlations with patient clinical parameter were performed. Our results demonstrated that the 10 selected miRNAs (miR-101-3p, miR-127-3p, miR-210-3p, miR-126-3p, miR-26b-5p, miR-29a-3p, miR-146a-5p, miR-27a-3p, miR-93-3p and miR-10a-5p) were diagnostic biomarkers of AKI in ICU patients, exhibiting areas under the curve close to 1 in ROC analysis. Outstandingly, serum miRNAs estimated before CS predicted AKI development later on, thus becoming biomarkers to predict AKI predisposition. Moreover, after surgery, the expression of the miRNAs was modulated days before serum creatinine increased, demonstrating early diagnostic value. In summary, we have identified a set of serum miRNAs as AKI biomarkers useful in clinical practice, since they demonstrate early detection and high diagnostic value and they recognize patients at risk.

Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population-Based Study.

Increased pulse wave velocity (PWV) is a marker of aortic stiffness and an independent predictor of mortality. Matrix Gla-protein (MGP) is a vascular calcification inhibitor that needs vitamin K to be activated. Inactive MGP, known as desphospho-uncarboxylated MGP (dp-ucMGP), can be measured in plasma and has been associated with various cardiovascular markers, cardiovascular outcomes, and mortality. In this study, we hypothesized that high levels of dp-ucMGP are associated with increased PWV. We recruited participants via a multicenter family-based cross-sectional study in Switzerland. Dp-ucMGP was quantified in plasma by sandwich ELISA. Aortic PWV was determined by applanation tonometry using carotid and femoral pulse waveforms. Multiple regression analysis was performed to estimate associations between PWV and dp-ucMGP adjusting for age, renal function, and other cardiovascular risk factors. We included 1001 participants in our analyses (475 men and 526 women). Mean values were 7.87±2.10 m/s for PWV and 0.43±0.20 nmol/L for dp-ucMGP. PWV was positively associated with dp-ucMGP both before and after adjustment for sex, age, body mass index, height, systolic and diastolic blood pressure (BP), heart rate, renal function, low- and high-density lipoprotein, glucose, smoking status, diabetes mellitus, BP and cholesterol lowering drugs, and history of cardiovascular disease (P≤0.01). In conclusion, high levels of dp-ucMGP are independently and positively associated with arterial stiffness after adjustment for common cardiovascular risk factors, renal function, and age. Experimental studies are needed to determine whether vitamin K supplementation slows arterial stiffening by increasing MGP carboxylation.

Efficacy and safety of citrate-based anticoagulation compared to heparin in patients with acute kidney injury requiring continuous renal replacement therapy: a randomized controlled trial.

INTRODUCTION: A systemic anticoagulation is often required to prevent circuit and filter clotting in ICU patients undergoing continuous renal replacement therapy (CRRT). A regional citrate-based anticoagulation (RCA) does not induce a systemic anticoagulation and prolongs the filter lifespan, but metabolic side-effects have been associated with this therapy. We conducted a randomized controlled trial with patients requiring CRRT to determine whether RCA using a balanced predilution replacement fluid is more effective than heparin in terms of renal replacement delivered dose and safety profile. METHODS: One hundred and three patients with AKI requiring CRRT were included. The patients were randomized to either CRRT with RCA or heparin anticoagulation. Primary endpoints were effective daily delivered RRT dose during the first 3 days of CRRT and filter lifespan. Secondary endpoints were 28-day and 90-day survival and severe metabolic complications and bleeding disorders. RESULTS: Median CRRT duration was 3.0 (2-6) days. Effective delivered daily RRT doses were 29 ± 3 and 27 ± 5 mL/kg/hr in the RCA and heparin groups, respectively (p = 0.005). Filter lifespans were 49 ± 29 versus 28 ± 23 hrs in the RCA and heparin groups (p = 0.004). Survival rates at 28 and 90 days were 80-74% in the RCA and 74-73% in the heparin group. Electrolytes and acid-base disturbances were uncommon and transient in patients treated with RCA. CONCLUSIONS: These results show that RCA is superior to heparin-based anticoagulation in terms of delivered RRT dose and filter life span and is a safe and feasible method. This does not translate into an improvement in short term survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT01269112 . Registered 3rd January 2011.

Living kidney donation does not adversely affect serum calcification propensity and markers of vascular stiffness.

Living kidney donors (LKDs) experience a decline in glomerular filtration rate (GFR) after donation. Calcification propensity (T50 ) can be determined by a blood test predicting all-cause mortality in patients with chronic kidney disease. We studied the impact of kidney donation on T50 and markers of arterial stiffness. We analyzed T50 prospectively before and 1 year after kidney donation in 21 LKDs along with fetuin-A, mineral metabolism markers, kidney length, pulse wave velocity (PWV), augmentation index (AI), and renal resistive index (RRI) as markers of arterial stiffness. We studied the impact of kidney donation on these parameters. LKDs were 54 ± 10 years old and had a GFR of 101 ± 18 ml/min/1.73 m(2) before donation, decreasing to 67 ± 8 ml/min/1.73 m(2) after donation (P < 0.001). Despite this, T50 improved after donation (290 ± 53 to 312 ± 38 min, P = 0.049). This change was inversely related to plasma phosphate (P = 0.03), which declined after donation (P = 0.002). Fetuin-A levels increased after donation (P = 0.01). Upon donation, the length of the remaining kidney increased (P < 0.001) while PWV, AI, and RRI remained unchanged. Calcification propensity was not adversely affected by kidney donation. This indicates that T50 is independent from GFR in LKDs and that kidney donation does neither worsen calcification propensity nor markers of vascular stiffness at 1 year.

New anthropometry-based age- and sex-specific reference values for urinary 24-hour creatinine excretion based on the adult Swiss population.

BACKGROUND: Urinary creatinine excretion is used as a marker of completeness of timed urine collections, which are a keystone of several metabolic evaluations in clinical investigations and epidemiological surveys. METHODS: We used data from two independent Swiss cross-sectional population-based studies with standardised 24-hour urinary collection and measured anthropometric variables. Only data from adults of European descent, with estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2 and reported completeness of the urinary collection were retained. A linear regression model was developed to predict centiles of the 24-hour urinary creatinine excretion in 1,137 participants from the Swiss Survey on Salt and validated in 994 participants from the Swiss Kidney Project on Genes in Hypertension. RESULTS: The mean urinary creatinine excretion was 193 ± 41 µmol/kg/24 hours in men and 151 ± 38 µmol/kg/24 hours in women in the Swiss Survey on Salt. The values were inversely correlated with age and body mass index (BMI). CONCLUSIONS: We propose a validated prediction equation for 24-hour urinary creatinine excretion in the general European population, based on readily available variables such as age, sex and BMI, and a few derived normograms to ease its clinical application. This should help healthcare providers to interpret the completeness of a 24-hour urine collection in daily clinical practice and in epidemiological population studies.

Copeptin is associated with kidney length, renal function, and prevalence of simple cysts in a population-based study.

Arginine vasopressin (AVP) has a key role in osmoregulation by facilitating water transport in the collecting duct. Recent evidence suggests that AVP may have additional effects on renal function and favor cyst growth in polycystic kidney disease. Whether AVP also affects kidney structure in the general population is unknown. We analyzed the association of copeptin, an established surrogate for AVP, with parameters of renal function and morphology in a multicentric population-based cohort. Participants from families of European ancestry were randomly selected in three Swiss cities. We used linear multilevel regression analysis to explore the association of copeptin with renal function parameters as well as kidney length and the presence of simple renal cysts assessed by ultrasound examination. Copeptin levels were log-transformed. The 529 women and 481 men had median copeptin levels of 3.0 and 5.2 pmol/L, respectively (P<0.001). In multivariable analyses, the copeptin level was associated inversely with eGFR (ß=-2.1; 95% confidence interval [95% CI], -3.3 to -0.8; P=0.002) and kidney length (ß=-1.2; 95% CI, -1.9 to -0.4; P=0.003) but positively with 24-hour urinary albumin excretion (ß=0.11; 95% CI, 0.01 to 0.20; P=0.03) and urine osmolality (ß=0.08; 95% CI, 0.05 to 0.10; P<0.001). A positive association was found between the copeptin level and the presence of renal cysts (odds ratio, 1.6; 95% CI, 1.1 to 2.4; P=0.02). These results suggest that AVP has a pleiotropic role in renal function and may favor the development of simple renal cysts.

Reference values and factors associated with renal resistive index in a family-based population study.

Increased renal resistive index (RRI) has been recently associated with target organ damage and cardiovascular or renal outcomes in patients with hypertension and diabetes mellitus. However, reference values in the general population and information on familial aggregation are largely lacking. We determined the distribution of RRI, associated factors, and heritability in a population-based study. Families of European ancestry were randomly selected in 3 Swiss cities. Anthropometric parameters and cardiovascular risk factors were assessed. A renal Doppler ultrasound was performed, and RRI was measured in 3 segmental arteries of both kidneys. We used multilevel linear regression analysis to explore the factors associated with RRI, adjusting for center and family relationships. Sex-specific reference values for RRI were generated according to age. Heritability was estimated by variance components using the ASSOC program (SAGE software). Four hundred women (mean age±SD, 44.9±16.7 years) and 326 men (42.1±16.8 years) with normal renal ultrasound had mean RRI of 0.64±0.05 and 0.62±0.05, respectively (P<0.001). In multivariable analyses, RRI was positively associated with female sex, age, systolic blood pressure, and body mass index. We observed an inverse correlation with diastolic blood pressure and heart rate. Age had a nonlinear association with RRI. We found no independent association of RRI with diabetes mellitus, hypertension treatment, smoking, cholesterol levels, or estimated glomerular filtration rate. The adjusted heritability estimate was 42±8% (P<0.001). In a population-based sample with normal renal ultrasound, RRI normal values depend on sex, age, blood pressure, heart rate, and body mass index. The significant heritability of RRI suggests that genes influence this phenotype.