Screening, genetic determinants and management of kidney disease in sickle cell anemia children living in a resource-limited setting

Sickle cell anemia (SCA) is the most prevalent inherited hemoglobin disorder and poses a significant public health problem in the Democratic Republic of Congo (DRC). Despite the contribution of SCA to the high morbidity and mortality in the DRC, SCA-associated chronic complications, particularly sickle cell nephropathy (SCN), are poorly recognized in the pediatric population. Importantly, children with SCA who develop kidney complications experience poor survival and outcomes. Therefore, understanding the progression and identifying risk factors of SCN are crucial to allow early interventions in this resource-limited country. The final goal of this research was to promote the early screening and prevention of SCA-associated kidney complications in children living in the DRC.

In the first chapter of this thesis, we aimed to evaluate the kidney function of Congolese children with SCA using a gold standard method of glomerular filtration rate (GFR) measurement (iohexol clearance). Indeed, GFR is the best indicator for assessing kidney function in adults and children. In routine, GFR is estimated using equations based on serum creatinine (SCr) concentration, the commonly used endogenous marker to evaluate kidney function.  However, all these equations have yet to be validated in African children, especially those with SCA. Given the lack of data in the general African pediatric population, the first section of this chapter evaluates the applicability of commonly used estimated GFR equations in apparently healthy Congolese children. Next, in the second section, we evaluated the applicability of these equations in comparison with the iohexol clearance (a gold standard method of GFR measurement) in Congolese children with SCA. Of all the equations studied in healthy children, FAS-Age appears to be the most appropriate equation when SCr is measured using the enzymatic calibrated method. More so, establishing specific SCr-references values for the widespread Jaffe-measured creatinine in Africa can further broaden the applicability of this equation. However, all SCr-based eGFR-equations poorly predicted the measured GFR in children with SCA.  Thus, a direct GFR measurement will be of interest in case a more accurate determination of GFR is required in this specific population.

In the second chapter, we described the burden of persistent kidney abnormalities (hyperfiltration, albuminuria, or decreased GFR) and their associated risk factors in a large cohort of 600 steady-state Congolese children with SCA. This study reveals that a one-time kidney disease screening can overestimate the rate of kidney abnormalities in children with SCA and could lead to over-treatment. Indeed, a significant proportion (almost 70.0%) of SCA children found with kidney abnormalities at the first analysis presented regression of these abnormalities without any reno-protective treatment. On the other hand, hemoglobinuria (p = 0.017) and male gender (p = 0.047) were significantly associated with persistent albuminuria and persistent hyperfiltration, respectively. Regarding genetic risk factors, individuals carrying the APOL1 high-risk genotype (HRG) tended to have an increased risk of persistent albuminuria compared to those with the low-risk genotype (LRG).

In the third chapter, we aimed to assess the effect of HU alone or HU combined with an angiotensin-converting enzyme inhibitor (ACEi) in Congolese children with SCA who presented with persistent kidney abnormalities (albuminuria and hyperfiltration) in the study mentioned above. In these patients, HU alone or HU combined with ACEi appears to be effective on the reduction of persistent albuminuria, although the reduction was significantly higher within HU + ACEi group. However, none of these therapies had an effect on persistent hyperfiltration. This is the first study to report the effect of current recommended therapies (HU and ACEi) on persistent kidney abnormalities in children with SCA. More prospective studies, including a significant number of participants, are needed to better assess the effects of these therapy modalities. Such studies could allow to formulate adequate recommendations regarding the treatment of persistent kidney abnormalities in children with SCA.

In conclusion, this thesis provided critical evidence on the importance of early screening and management of kidney complications in children with SCA. These results could help the development of national evidence-based guidelines for the follow-up and management of kidney complications in children with SCA living in the DRC.