Proteomic biomarkers of cardiovascular complications in chronic kidney disease – PROTEOMARK_CKD

CKD is common affecting 10-12% of the adult population, and 30% or more over 70 years of age. Cardiovascular disease (CVD) is the leading cause of death in CKD patients with steadily increased risk as kidney function declines up to 10-20 times higher in end-stage renal disease (ESRD) than in the general population. CKD is mainly associated with two types of CVD: accelerated atherosclerosis and specific CKD-related CVD including arteriosclerosis and cardiac abnormalities (i.e. left ventricular hypertrophy and diastolic dysfunction). CVD risk assessment is currently based upon the Framingham risk score and traditional risk factors (i.e. diabetes, hypertension, dyslipidemia, and smoking), which underestimate CKD-related CV complications. Additional CKD-related factors called uremic toxins may ameliorate this prediction in CKD patients. However, in front of the multiplicity of known and unknown uremic toxins, global methods such as proteomic are necessary to confirm and to explore this issue. Therefore, we propose to build on those observations and to validate and develop molecular profiles predicting CV complications (i.e. the main objective of PROTEOMARK_CKD) and CKD progression (i.e. the secondary objective) in the large-scale CKD-REIN prospective cohort. Indeed, CKD-REIN (Chronic Kidney Disease-Renal Epidemiology and Information Network) is a large prospective cohort study carried out in 40 nephrology outpatient facilities, nationally representative with respect to geography and public or private legal status. From July 2013 through March 2016, 3033 adult patients (> 18 years) with moderate (stage 3, eGFR within 45-59 mL/min/1.73 m2) or advanced (stage 4, eGFR 15-44 mL/min/1.73 m2) CKD, without prior chronic dialysis or kidney transplantation, gave informed consent to participate in the study and were included during a routine nephrology visit. In these patients, clinical events and deaths will be collected from baseline through December 31, 2018. At this time, almost all patients will have completed 3-year follow-up. For each cardiovascular event, whether fatal or non-fatal, clinical research associates are trained to document events by up-loading medical or death reports in the CKD-REIN information system. Primary coding of clinical events and deaths considered in this project will be performed by a physician who will ensure that CV events are sufficiently documented for adjudication. Baseline biological sampling for urinary proteome analyses will be available at the biobank .We will use a case-cohort design to select participants for the urinary proteome analysis. In such a design, all incident cases as defined above over the period from baseline through December 31, 2018 and a random sample of the overall population at baseline are included. The PROTEOMARK-CKD consortium is composed of two highly complementary teams providing clinical (Ziad Massy, INSERM-U1018), epidemiologic and statistical (Bénédicte Stengel, and Marie Metzger INSERM-U1018), clinical proteomics (Joost Schanstra, Inserm U1048) and bioinformatic (Julie Klein, Inserm U1048) expertise and operational capacity which form the pillars of the project. PROTEOMARK_CKD will identify and validate molecular signatures that allow stratifying CKD patients at risk for CV complications by combining established clinical characteristics with proteomic profiles derived from plasma and urine, reflecting the underlying pathogenic processes. Once validated, these biomarkers will be introduced in clinical practice. The present program will significantly improve our understanding of the mechanisms of CKD associated CVD and CKD progression. The validation of CKD related factors may lead to the discovery of new pathophysiological pathways and allow a "pharmacophenomics" approach, associating biomarker-guided treatment strategies and individually targeted pharmacological treatments, then to be tested in patients with CVD or progression in RCTs.