PREDICTORS OF RENAL INVOLVEMENT IN SICKLE CELL ANEMIA

Sickle cell anemia (SCA) is the most common hereditary hemoglobinopathy, affecting more than 300,000 newborns annually worldwide. It is a genetic, autosomal recessive disease, homozygous for hemoglobin S (HbS), a hemoglobin mutated by replacing valine with glutamic acid in position 6 of the beta (β) globin chain. Due to the abnormal structure, HbS polymerizes and precipitates inside the erythrocyte in environments with low oxygen concentration, which make her rigid and distorted, giving it a sickle shape. This abnormal form predisposes to the vaso-occlusive phenomenon and its cascade of secondary processes including inflammation, hemolysis, anemia, vasculopathy and oxidative stress in various organs. Furthermore, increased adherence to the vascular endothelium and changes in the structure and function of the red blood cell membrane. It is a multisystemic disease associated with acute events and progressive organic damage in which practically all organs could be affected with multiple complications. Common manifestations include pain crises, acute chest syndrome (ACS), infections (mainly caused by encapsulated bacteria), retinopathy, stroke and nephropathy. Sickle cell nephropathy (SCN) is one of the most frequent complications. It affects all the main pathophysiological processes of the kidney, being an important and non-negligible cause of morbidity and mortality. Early manifestations include hyperfiltration and loss of urinary concentration capacity, followed by proteinuria and defects in urinary acidification, all with the possibility of progressing to chronic kidney disease (CKD) and, finally, end-stage kidney disease (EEKD). Given the related morbidity and mortality, with consequences including on patients' quality of life, the present study aimed to estimate the incidence, as well as determine the factors associated with the emergence of SCN in patients diagnosed with SCA regularly monitored at the benign hematology outpatient clinic of the University Hospital (UH) linked to the Federal University of Sergipe -UFS.

IIt was a retrospective cohort study with patients of both sexes, aged 12 years and over, with a confirmed diagnosis of SCA, regularly monitored at the sickle cell disease outpatient clinic of the Sergipe University Hospital linked to the Federal University of Sergipe – HU-UFS. The inclusion criteria were patients with SCA who reached the minimum age of 12 years and underwent regular follow-up at the sickle cell disease clinic at HU-UFS. Regular follow-up is understood to mean having at least two consultations per year. Were excluded patients with kidney disease of another etiology and without specific evaluation of renal markers. The following predictor variables were dichotomized: Sex: female or male; Age: ≤ 20 years or > 20 years; Age at which Hydrea started to be used: ≤ 15 years or > 15 years; Time of use of Hydrea: ≤ 5 years or > 5 years; Number of transfusions (< 5x or ≥ 5x); Diagnosis of heart disease: yes or no; Use of angiotensin-converting enzyme inhibitors (ACEIs): yes or no. 4.5 Statistical analysis The variables associated with nephropathy with a significance level of p< 0.20 in the univariate analysis were included in a multiple regression model with backward selection to finally determine the predictors of the outcome of interest. The variables that were independently associated with nephropathy were maintained in the final model at a significance level of 5%. The odds ratio (OR) with a 95% confidence interval (95%CI) was used as a measure of association. The analyzes were carried out using the JASP program (JASP Team, Amsterdam, Netherlands), version 0.13. 4.6 Ethical aspects The present study was approved by the Ethics Committee of the Federal University of Sergipe under CAAE number 53021621.4.0000.5546.

134 patients were eligible for the present study, 38 were excluded due to lack of data on potential predictors of nephropathy. The final sample consisted of 96 patients, of which 48 (50%) were men and 48 (50%) women. The median age was 23 years old. All patients were using Hydrea and the medians regarding the age at which they started using this medication and the length of time they had been using this medication were 15.8 years (Q1 = 11.4; Q3 = 21.2) and 6.2 years (Q1 = 4.6; Q3 = 7.9). A total of 51 (53.1%) patients had received 5 or more blood transfusions throughout their lives and had some type of heart disease, and 35 (36.5%) were using ACE inhibitors. Sixty (62.5%) patients with sickle cell anemia were diagnosed with nephropathy. Age over 20 years (OR = 3.91; 95% CI 1.58 – 9.71; p = 0.003) and time using Hydrea for more than 5 years (OR = 2.45; 95% CI 1.00 – 6.10; p = 0.050) were associated with nephropathy among patients with sickle cell anemia (Table 1)

Table 1: Univariate and multivariate analyses of potential predictors associated with nephropathy in patients with sickle cell anemia.

The study identified a high prevalence of sickle cell nephropathy through the presence of hyperfiltration and/or proteinuria. The current age showed statistical significance in relation to the onset of sickle cell nephropathy. There was a high percentage of patients with SCN, including proteinuria, without ACE inhibitors.

Due to the extreme relevance attributed to SCN, an important contributing factor in the morbidity and mortality of patients with SCA, it is imperative to adopt screening and follow-up protocols for renal involvement. This serial approach contributes to the early approach and, consequently, to the identification of its complications.