ED Sociétés, Politique, Santé Publique
Anemia, iron deficiency and major adverse cardiovascular events in chronic kidney disease
by Lisa LE GALL (Bordeaux Population Health Research Center)
The defense will take place at 14h00 - Amphithéatre Louis ISPED (Institut de Santé Publique d'épidémiologie et de développement) 146 rue Léo Saignat 33076 Bordeaux CEDEX
in front of the jury composed of
- KAREN LEFFONDRE - Professeure des universités - Université de Bordeaux - Directeur de these
- Bénédicte SAUTENET - Professeure des universités - praticienne hospitalière - CHU Tours - Rapporteur
- Sahar BAYAT-MAKOEI - Professeure - EHESP - Rapporteur
- Anne-Laure FAUCON - Chercheur post-doctorant / médecin - Karolinska Institutet - Examinateur
- Mathilde PREZELIN-REYDIT - Praticien attaché - Néphrologue - Chercheur - AURAD Aquitaine - CoDirecteur de these
- Hélène JACQMIN-GADDA - Directrice de recherche - Inserm - Examinateur
Chronic kidney disease (CKD) involves a progressive decline of kidney function and is defined by the presence of kidney damage or reduced estimated glomerular filtration rate (eGFR). As CKD progresses, many patients ultimately require renal replacement therapy (dialysis or renal transplantation). Cardiovascular disease is the leading cause of death in patients with CKD. Improving the cardiovascular prognosis of CKD patients requires identification and a well understanding of its determinants. Anemia, defined as a hemoglobin level below 12 g/dL in women and 13 g/L in men, is a common complication of CKD. The main causes of anemia in CKD are relative erythropoietin deficiency and iron deficiency defined according to the levels of two biomarkers: transferrin saturation coefficient (TSAT) and ferritin. Over the past two decades, numerous epidemiological studies have highlighted associations between anemia, iron deficiency, and poor outcomes—including an increased risk of cardiovascular events, premature mortality, kidney failure, and reduced quality of life. Many of those were based on a single measurement of the biomarkers often the value at cohort entry. However, the levels of these biomarkers vary over time. The general objective of this thesis was to study the association between longitudinal biomarkers of anemia and iron deficiency in the one hand and major adverse cardiovascular events (MACE) in the second hand. We specifically 1) identified distinct profiles of hemoglobin trajectories over time, 2) estimated the association between current level of hemoglobin and the hazard of MACE in males and females separately, 3) estimated the effect of iron deficiency without concomitant anemia on MACE, and 4) described the management practices for anemia and iron deficiency as self-reported by nephrologists in France. We used data from the CKD-REIN cohort which included 3 033 patients with moderate to severe CKD enrolled from 40 nationally nephrology clinics in France. Over 5 years of follow-up, many clinical and biological data were recorded including repeated measurement of hemoglobin, TSAT, ferritin and eGFR. The main outcome was MACE defined as cardiovascular death, myocardial infarction, stroke or hospitalization for acute heart failure, occurring during follow-up before any renal replacement therapy. We used statistical methods which allowed the joint modeling of longitudinal and time-to-event data. The results indicated (i) a predominant profile showing an overall stable trajectory and low risk of MACE and 4 profiles with non-linear declining hemoglobin trajectories associated with gradual increase risks of MACE (ii) an association between anemia and MACE which persists when accounting for repeated measurements of hemoglobin and was stronger in females than in males, and (iii) a trend toward an increase in the risk of MACE in patients with iron deficiency but no concomitant anemia. We also found a strong heterogeneity in the management of iron deficiency, as opposed to the management of anemia. This thesis highlights the importance of taking account of the biomarkers dynamics and of considering the value of biomarkers within clinical context and according the patients characteristics.