Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits.

Genetic studies of the metabolome can uncover enzymatic and transport processes shaping human metabolism. Using rare variant aggregation testing based on whole-exome sequencing data to detect genes associated with levels of 1,294 plasma and 1,396 urine metabolites, we discovered 235 gene-metabolite associations, many previously unreported. Complementary approaches (genetic, computational (in silico gene knockouts in whole-body models of human metabolism) and one experimental proof of principle) provided orthogonal evidence that studies of rare, damaging variants in the heterozygous state permit inferences concordant with those from inborn errors of metabolism.

Association of Serum Afamin Concentrations With Kidney Failure in Patients With CKD: Findings From the German CKD Cohort Study.

Rationale & Objective: Afamin is a vitamin E-binding glycoprotein primarily expressed in liver and kidney. This study investigated whether serum afamin concentrations are associated with kidney function and incident kidney failure.

Study Design: Prospective cohort study with 6.

Interactive exploration of adverse events and multimorbidity in CKD.

Background: Persons with chronic kidney disease (CKD) are at increased risk of adverse events, early mortality and multimorbidity. A detailed overview of adverse event types and rates from a large CKD cohort under regular nephrological care is missing. We generated an interactive tool to enable exploration of adverse events and their combinations in the prospective, observational German CKD (GCKD) study.

Apolipoprotein A-IV concentrations and cancer in a large cohort of chronic kidney disease patients: results from the GCKD study.

Background: Chronic kidney disease (CKD) is highly connected to inflammation and oxidative stress. Both favour the development of cancer in CKD patients. Serum apolipoprotein A-IV (apoA-IV) concentrations are influenced by kidney function and are an early marker of kidney impairment.

Copeptin, Natriuretic Peptides, and Cardiovascular Outcomes in Patients With CKD: The German Chronic Kidney Disease (GCKD) Study.

Rationale & Objective: Copeptin and Midrange pro-atrial natriuretic peptide (MR-pro-ANP) are associated with outcomes independently of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in patients with heart failure (HF). The value of these markers in patients with chronic kidney disease (CKD) has not been studied.

Study Design: Prospective cohort study.

Cardiovascular risk due to diabetes mellitus in patients with chronic kidney disease-prospective data from the German Chronic Kidney Disease cohort.

Background: Diabetes mellitus (DM) and chronic kidney disease (CKD) are well-known cardiovascular and mortality risk factors. To what extent they act in an additive manner and whether the etiology of CKD modifies the risk is uncertain.

Methods: The multicenter, prospective, observational German Chronic Kidney Disease study comprises 5217 participants (1868 with DM) with a baseline mean estimated glomerular filtration rate of 30-60 mL/min/1.

Expectation of clinical decision support systems: a survey study among nephrologist end-users.

Background: Chronic kidney disease (CKD), a major public health problem with differing disease etiologies, leads to complications, comorbidities, polypharmacy, and mortality. Monitoring disease progression and personalized treatment efforts are crucial for long-term patient outcomes. Physicians need to integrate different data levels, e.

Association of mineral and bone biomarkers with adverse cardiovascular outcomes and mortality in the German Chronic Kidney Disease (GCKD) cohort.

Mineral and bone disorder (MBD) in chronic kidney disease (CKD) is tightly linked to cardiovascular disease (CVD). In this study, we aimed to compare the prognostic value of nine MBD biomarkers to determine those associated best with adverse cardiovascular (CV) outcomes and mortality. In 5 217 participants of the German CKD (GCKD) study enrolled with an estimated glomerular filtration rate (eGFR) between 30-60 mL·min per 1.

Differential Prognostic Utility of Adiposity Measures in Chronic Kidney Disease.

Objective: Adipose tissue contributes to adverse outcomes in chronic kidney disease (CKD), but there is uncertainty regarding the prognostic relevance of different adiposity measures. We analyzed the associations of neck circumference (NC), waist circumference (WC), and body mass index (BMI) with clinical outcomes in patients with mild to severe CKD.

Methods: The German Chronic Kidney Disease study is a prospective cohort study, which enrolled Caucasian adults with mild to severe CKD, defined as estimated glomerular filtration rate : 30-60 mL/min/1.

Development and Validation of a Prediction Model for Future Estimated Glomerular Filtration Rate in People With Type 2 Diabetes and Chronic Kidney Disease.

Importance: Type 2 diabetes increases the risk of progressive diabetic kidney disease, but reliable prediction tools that can be used in clinical practice and aid in patients' understanding of disease progression are currently lacking.

Objective: To develop and externally validate a model to predict future trajectories in estimated glomerular filtration rate (eGFR) in adults with type 2 diabetes and chronic kidney disease using data from 3 European multinational cohorts.

Design, Setting, And Participants: This prognostic study used baseline and follow-up information collected between February 2010 and December 2019 from 3 prospective multinational cohort studies: PROVALID (Prospective Cohort Study in Patients with Type 2 Diabetes Mellitus for Validation of Biomarkers), GCKD (German Chronic Kidney Disease), and DIACORE (Diabetes Cohorte).

Different roles of protein biomarkers predicting eGFR trajectories in people with chronic kidney disease and diabetes mellitus: a nationwide retrospective cohort study.

Background: Chronic kidney disease (CKD) is a common comorbidity in people with diabetes mellitus, and a key risk factor for further life-threatening conditions such as cardiovascular disease. The early prediction of progression of CKD therefore is an important clinical goal, but remains difficult due to the multifaceted nature of the condition. We validated a set of established protein biomarkers for the prediction of trajectories of estimated glomerular filtration rate (eGFR) in people with moderately advanced chronic kidney disease and diabetes mellitus.

KLKB1 and CLSTN2 are associated with HDL-mediated cholesterol efflux capacity in a genome-wide association study.

Background And Aims: HDL-mediated cholesterol efflux capacity (CEC) may protect from cardiovascular disease. Thus, we aimed to identify its genetic and non-genetic determinants.

Methods: We measured CEC to 2% apolipoprotein B-depleted serum using BODIPY-cholesterol and cAMP-stimulated J774A.

Prevalence of hereditary tubulointerstitial kidney diseases in the German Chronic Kidney Disease study.

Hereditary chronic kidney disease (CKD) appears to be more frequent than the clinical perception. Exome sequencing (ES) studies in CKD cohorts could identify pathogenic variants in ~10% of individuals. Tubulointerstitial kidney diseases, showing no typical clinical/histologic finding but tubulointerstitial fibrosis, are particularly difficult to diagnose.

The Cardiovascular Literature-Based Risk Algorithm (CALIBRA): Predicting Cardiovascular Events in Patients With Non-Dialysis Dependent Chronic Kidney Disease.

Background And Objectives: Cardiovascular (CV) disease is the main cause of morbidity and mortality in patients suffering from chronic kidney disease (CKD). Although it is widely recognized that CV risk assessment represents an essential prerequisite for clinical management, existing prognostic models appear not to be entirely adequate for CKD patients. We derived a literature-based, naïve-bayes model predicting the yearly risk of CV hospitalizations among patients suffering from CKD, referred as the CArdiovascular, LIterature-Based, Risk Algorithm (CALIBRA).

Uromodulin and its association with urinary metabolites: the German Chronic Kidney Disease Study.

Background: The progression of chronic kidney disease (CKD), a global public health burden, is accompanied by a declining number of functional nephrons. Estimation of remaining nephron mass may improve assessment of CKD progression. Uromodulin has been suggested as a marker of tubular mass.

Educational Attainment Is Associated With Kidney and Cardiovascular Outcomes in the German CKD (GCKD) Cohort.

Introduction: Prospective data on impact of educational attainment on prognosis in patients with chronic kidney disease (CKD) are scarce. We investigated the association between educational attainment and all-cause mortality, major adverse cardiovascular (CV) events (MACEs), kidney failure requiring dialysis, and CKD etiology.

Methods: Participants ( = 5095, aged 18-74 years) of the ongoing multicenter German Chronic Kidney Disease (GCKD) cohort, enrolled on the basis of an estimated glomerular filtration rate (eGFR) of 30 to 60 ml/min (stages G3, A1-A3) or overt proteinuria (stages G1-G2, A3), were divided into 3 categories according to their educational attainment and were followed for 6.

Heart-Type Fatty Acid Binding Protein, Cardiovascular Outcomes, and Death: Findings From the German CKD Cohort Study.

Rationale & Objective: Heart-type fatty acid binding protein (H-FABP) is a biomarker that has been shown to provide long-term prognostic information in patients with coronary artery disease independently of high-sensitivity troponin T (hs-TNT). We examined the independent associations of H-FABP with cardiovascular outcomes in patients with chronic kidney disease (CKD).

Study Design: Prospective cohort study.

Validation of a Novel Predictive Algorithm for Kidney Failure in Patients Suffering from Chronic Kidney Disease: The Prognostic Reasoning System for Chronic Kidney Disease (PROGRES-CKD).

Current equation-based risk stratification algorithms for kidney failure (KF) may have limited applicability in real world settings, where missing information may impede their computation for a large share of patients, hampering one from taking full advantage of the wealth of information collected in electronic health records. To overcome such limitations, we trained and validated the Prognostic Reasoning System for Chronic Kidney Disease (PROGRES-CKD), a novel algorithm predicting end-stage kidney disease (ESKD). PROGRES-CKD is a naïve Bayes classifier predicting ESKD onset within 6 and 24 months in adult, stage 3-to-5 CKD patients.

A prediction model for the decline in renal function in people with type 2 diabetes mellitus: study protocol.

Background: Chronic kidney disease (CKD) is a well-established complication in people with diabetes mellitus. Roughly one quarter of prevalent patients with diabetes exhibit a CKD stage of 3 or higher and the individual course of progression is highly variable. Therefore, there is a clear need to identify patients at high risk for fast progression and the implementation of preventative strategies.

Association of the metabolic syndrome with mortality and major adverse cardiac events: A large chronic kidney disease cohort.

Background: Metabolic syndrome with its key components insulin resistance, central obesity, dyslipidaemia, and hypertension is associated with a high risk for cardiovascular events and all-cause mortality in the general population. However, evidence that these findings apply to patients with chronic kidney disease (CKD) with moderately reduced estimated glomerular filtration rate and/or albuminuria is limited.

Objectives: We aimed to investigate the association between metabolic syndrome and its components with all-cause mortality and cardiovascular outcomes in CKD patients.

Association of mitochondrial DNA copy number with metabolic syndrome and type 2 diabetes in 14 176 individuals.

Background: Mitochondria play an important role in cellular metabolism, and their dysfunction is postulated to be involved in metabolic disturbances. Mitochondrial DNA is present in multiple copies per cell. The quantification of mitochondrial DNA copy number (mtDNA-CN) might be used to assess mitochondrial dysfunction.

Results from the German Chronic Kidney Disease (GCKD) study support association of relative telomere length with mortality in a large cohort of patients with moderate chronic kidney disease.

Telomere length is known to be inversely associated with aging and has been proposed as a marker for aging-related diseases. Telomere attrition can be accelerated by oxidative stress and inflammation, both commonly present in patients with chronic kidney disease. Here, we investigated whether relative telomere length is associated with mortality in a large cohort of patients with chronic kidney disease stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment.

Association of Serum Uromodulin with Death, Cardiovascular Events, and Kidney Failure in CKD.

Background And Objectives: Uromodulin is exclusively produced by tubular epithelial cells and released into urine and serum. Higher serum uromodulin has been associated with lower risk for kidney failure in Chinese patients with CKD and with lower risk for mortality in the elderly and in patients undergoing coronary angiography. We hypothesized that lower serum uromodulin is associated with mortality, cardiovascular events, and kidney failure in white patients with CKD.