Degree of anemia, indirect markers of hemolysis, and vascular complications of sickle cell disease in Africa.

The hyperhemolysis paradigm that describes overlapping "hyperhemolytic-endothelial dysfunction" and "high hemoglobin-hyperviscous" subphenotypes of sickle cell disease (SCD) patients is based on North American studies. We performed a transversal study nested in the CADRE cohort to analyze the association between steady-state hemolysis and vascular complications of SCD among sub-Saharan African patients. In Mali, Cameroon, and Ivory Coast, 2407 SCD patients (1751 SS or sickle ß-zero-thalassemia [Sß0], 495 SC, and 161 sickle ß+-thalassemia [Sß+]), aged 3 years old and over, were included at steady state. Relative hemolytic intensity was estimated from a composite index derived from principal component analysis, which included bilirubin levels or clinical icterus, and lactate dehydrogenase levels. We assessed vascular complications (elevated tricuspid regurgitant jet velocity [TRV], microalbuminuria, leg ulcers, priapism, stroke, and osteonecrosis) by clinical examination, laboratory tests, and echocardiography. After adjustment for age, sex, country, and SCD phenotype, a low hemoglobin level was significantly associated with TRV and microalbuminuria in the whole population and with leg ulcers in SS-Sß0 adults. A high hemolysis index was associated with microalbuminuria in the whole population and with elevated TRV, microalbuminuria, and leg ulcers in SS-Sß0 adults, but these associations were no longer significant after adjustment for hemoglobin level. In conclusion, severe anemia at steady state in SCD patients living in West and Central Africa is associated with elevated TRV, microalbuminuria, and leg ulcers, but these vascular complications are not independently associated with indirect markers of increased hemolysis. Other mechanisms leading to anemia, including malnutrition and infectious diseases, may also play a role in the development of SCD vasculopathy.

Arterial Stiffness Impairment in Sickle Cell Disease Associated With Chronic Vascular Complications: The Multinational African CADRE Study.

BACKGROUND: Although a blood genetic disease, sickle cell disease (SCD) leads to a chronic vasculopathy with multiple organ involvement. We assessed arterial stiffness in SCD patients and looked for associations between arterial stiffness and SCD-related vascular complications. METHODS: The CADRE (Coeur Artères et Drepanocytose, ie, Heart Arteries and Sickle Cell Disease) study prospectively recruited pediatric and adult SCD patients and healthy controls in Cameroon, Ivory Coast, Gabon, Mali, and Senegal. Patients underwent clinical examination, routine laboratory tests (complete blood count, serum creatinine level), urine albumin/creatinine ratio measure, and a measure of carotid-femoral pulse wave velocity (cf-PWV) and augmentation index (AI) at a steady state. The clinical and biological correlates of cf-PWV and AI were investigated by using a multivariable multilevel linear regression analysis with individuals nested in families further nested in countries. RESULTS: Included were 3627 patients with SCD and 943 controls. Mean cf-PWV was lower in SCD patients (7.5±2.0 m/s) than in controls (9.1±2.4 m/s, P<0.0001), and lower in SS-Sß(0) than in SC-Sß(+) phenotypes. AI, corrected for heart rate, increased more rapidly with age in SCD patients and was higher in SCD than in control adults. cf-PWV and AI were independently associated with age, sex, height, heart rate, mean blood pressure, hemoglobin level, country, and hemoglobin phenotype. After adjustment for these correlates, cf-PWV and AI were associated with the glomerular filtration rate and osteonecrosis. AI was also associated with stroke, pulmonary hypertension, and priapism, and cf-PWV was associated with microalbuminuria. CONCLUSIONS: PWV and AI are deeply modified in SCD patients in comparison with healthy controls. These changes are independently associated with a lower blood pressure and a higher heart rate but also with the hemoglobin phenotype. Moreover, PWV and AI are associated with several SCD clinical complications. Their prognostic value will be assessed at follow-up of the patients.

Subclinical Cardiac Dysfunction Is Associated With Extracardiac Organ Damages.

Background: Several studies conducted in America or Europe have described major cardiac remodeling and diastolic dysfunction in patients with sickle cell disease (SCD). We aimed at assessing cardiac involvement in SCD in sub-Saharan Africa where SCD is the most prevalent. Methods: In Cameroon, Mali and Senegal, SCD patients and healthy controls of the CADRE study underwent transthoracic echocardiography if aged ≥10 years. The comparison of clinical and echocardiographic features between patients and controls, and the associations between echocardiographic features and the vascular complications of SCD were assessed. Results: 612 SCD patients (483 SS or Sß0, 99 SC, and 19 Sß+) and 149 controls were included. The prevalence of dyspnea and congestive heart failure was low and did not differ significantly between patients and controls. While left ventricular ejection fraction did not differ between controls and patients, left and right cardiac chambers were homogeneously more dilated and hypertrophic in patients compared to controls and systemic vascular resistances were lower (p < 0.001 for all comparisons). Three hundred and forty nine SCD patients had extra-cardiac organ damages (stroke, leg ulcer, priapism, microalbuminuria or osteonecrosis). Increased left ventricular mass index, cardiac dilatation, cardiac output, and decreased systemic vascular resistances were associated with a history of at least one SCD-related organ damage after adjustment for confounders. Conclusions: Cardiac dilatation, cardiac output, left ventricular hypertrophy, and systemic vascular resistance are associated with extracardiac SCD complications in patients from sub-Saharan Africa despite a low prevalence of clinical heart failure. The prognostic value of cardiac subclinical involvement in SCD patients deserves further studies.

Early renal damage in patients with sickle cell disease in sub-Saharan Africa: a multinational, prospective, cross-sectional study.

BACKGROUND: Chronic kidney disease is one of the leading causes of mortality in patients with sickle cell disease. However, it has been almost exclusively studied in patients with the SS phenotype and in high-income countries, despite more than 80% of patients living in Africa. We looked for the determinants of glomerulopathy in a multinational cohort of patients with sickle cell disease of different phenotypes in sub-Saharan Africa. METHODS: In the CADRE cohort, we prospectively included patients 3 years and older with sickle cell disease of all haemoglobin phenotypes in Cameroon, Côte d'Ivoire, Mali, and Senegal. All individuals were assessed at steady state. The main outcome of interest was albuminuria defined as a urine albumin-to-creatinine ratio of greater than 30 mg/g. We investigated the clinical and biological determinants (including haemolysis markers) of albuminuria in two main phenotype groups (SS and Sß(0); SC and Sß(+)) with further stratification by age and country. FINDINGS: The study is ongoing because of follow-up. 2582 patients with sickle cell disease were included (1776 SS, 136 Sß(0), 511 SC, and 159 Sß(+)). 644 patients with the SS and Sß(0) phenotypes (33·7%, 95% CI 31·6-35·8) and 110 with the SC and Sß(+) phenotypes (16·4%, 13·6-19·2) had albuminuria. In the SS and Sß(0) group, albuminuria was detected in 144 (27%) of 527 children younger than 10 years and its frequency increased with age (29 [48%] of 60 patients aged >40 years). Multivariable analysis showed that albuminuria was associated with age (odds ratio 1·43, 95% CI 1·20-1·71; p<0·0001), female sex (1·35, 1·02-1·82; p=0·045), low haemoglobin (0·79, 0·66-0·93; p=0·006), high lactate dehydrogenase concentrations (1·33, 1·14-1·58; p=0·0009), and, using Côte d'Ivoire as the reference, Mali (2·49, 1·64-3·79; p=0·042) and Cameroon (1·59, 1·01-2·51; p=0·0007) in patients with the SS and Sß(0) phenotypes. The magnitude of the association of albuminuria with haemoglobin and lactate dehydrogenase concentrations increased with age. In the SC and Sß(+) patients, only low haemoglobin (0·69, 0·48-0·97; p=0·029), high blood pressure (1·63, 1·17-2·27; p=0·0017), and Mali (3·75, 1·75-8·04; p<0·0001) were associated with albuminuria. INTERPRETATION: Hyperhaemolysis is associated with albuminuria, with an age-dependent effect, in the SS and Sß(0) phenotypes only, suggesting a different pathological mechanism for glomerular disease in the patients with SC and Sß(+) phenotypes. However, both phenotypes are associated with a high prevalence of albuminuria in childhood. Therefore, screening for albuminuria is advised in African children with sickle cell disease to detect early renal damage. FUNDING: Paris Cité Sorbonne University (GrEX project) and Cardiology and Development.