Patients and Methods
The study was approved by the Institutional Review Board of the KAUH. This cross-sectional prevalence study retrospectively reviewed all medical records of children aged 2–18 years diagnosed with SCD in the KAUH Pediatric Sickle Cell Clinic between June 2010 and April 2019. We excluded all patients without urine analysis testing.
Data obtained from the recent outpatient follow-up visit included: sex, age, nationality, weight, height, ABO blood group system, sickle cell genotype, the number of hospitalizations, blood transfusion (BT) status, and the number of transfusions (NOH). The frequency of the vaso-occlusive events and SCD complications were collected.
Hydroxyurea (HU) therapy and its associations with the number of BTs and NOH were studied. In urine analysis, microalbuminuria was defined as >1+ protein, and red blood cells (RBCs) were counted and defined as hematuria if >5.
Descriptive statistics are used to describe study participants’ demographic characteristics. Mean±standard deviations and median values are used to describe continuous variables. Frequencies with proportions are used to report categorical variables. A comparison of numerical variables between the groups was performed using the independent t-test, whereas a comparison of categorical variables was performed using the chi-square and Fisher’s exact tests. Statistical significance was set at P<.05. All statistical analyses were performed using IBM SPSS statistics, version 23 (IBM, Armonk, NY, USA).
Renal failure secondary to SCD can affect 5-–20% of the adult population. The progressive process starts from childhood and eventually leads to renal failure.19 Microalbuminuria is one of the earliest manifestations of SCN. Hence, many studies have been concerned with determining the prevalence of microalbuminuriaamong SCD patients to assess the severity of the condition.20,21 We determined the prevalence of microalbuminuria to be 9.6% among pediatric patients with a mean age of 12.4 years, starting from a very young age (2 years) and continuously progressing to its highest percentage in the young adult group (15–18 years), reaching a prevalence of 51.6% in this group. Patients’ mean age and the average percentage of microalbuminuria among older patients were consistent with a prevalence of 46% reported by Dharnidharka et al20 and a prevalence of 39–43% in adults with SCD reported by McBurney et al.16 However, the overall prevalence of microalbuminuriaamong all patients (9.6%) was lower than the average prevalence reported by those previous studies. Additionally, Alkhunaizi et al22 determined that the prevalence of microalbuminuria among adult Saudi Arabian patients (>18 years) was 25%, which was very similar to our findings with respect to the same age group.
Dharnidharka et al20 and McBurney et al16 reported that no microalbuminuria was detected in children <7 years old. Conversely, we found that 9.7% of microalbuminuria patients were aged 2–5 years. These findings were supported by Aloni et al23 who confirmed the presence of microalbuminuria among their patients aged <7 years. This early deterioration of glomerular function could be explained by the presence of certain factors including a genetic predisposition, the level of fetal hemoglobin (HbF), environmental factors, efficacy of medical care, and lifestyle in the developing countries.24 Another reasonable explanation for these contradictory results is our study’s small sample size. However, 104 and 151 patients were enrolled in the studies by Dharnidharka et al20 and by McBurney et al,16 respectively.
Interestingly, when compared the microalbuminuria and non- microalbuminuria groups, there was no statistical difference in terms of age (P =.432), which indicated that age was not a defining variable for both groups. However, age was a defining variable in the progression of microalbuminuria in the affected group.
A female predominance of microalbuminuria has been reported in the literature. Jones et al reported a prevalence of 9.7% of microalbuminuria among female patients and 6.1% among male patients.8 Further, Okpere ET al25 reported consistent results of female predominance (45.3%) compared to male predominance (20.4%). However, no significant difference in sex was detected between the microalbuminuria and non-microalbuminuria groups in our study or the studies of McBurney et al16 and Dharnidharka et al.20 Consequently, additional study is necessary to provide further evidence regarding these contrary results.
Our findings demonstrated that microalbuminuria occurs in most of the hemoglobin genotypes, with the highest percentage in the Hb-ss genotype (74.2%) in the microalbuminuriagroup, which is similar to that reported in previous studies conducted by Wigfall et al.26 However, no microalbuminuriawas detected in the HB-Sβ0 (Beta-Zero) thalassemia sub-group. In most previous studies, patients with Sβ-thalassemia were few in number, and there have been limited studies with mixed results about this patient group. Becton et al21 reported that only one patient with Sβ-thalassemia had microalbuminuria.
We further examined the percentage of several clinical complications that may be associated with microalbuminuria (Table 3). Next, we compared the microalbuminuriaand non-microalbuminuria groups to identify definitive variables that significantly varied between the groups. Interestingly, we found that most patients in the microalbuminuriagroup experienced acute chest syndromes, gallbladder stones, osteomyelitis, pneumonia, and spleen sequestration, but none reported priapism, avascular necrosis, aplasia, stroke, acute coronary syndrome (ACS), or dactylitis. These findings were consistent with those reported by Dharnidharka et al20 and McBurney et al,16 who found no significant correlation between microalbuminuriaand stroke. McBurney et al16 and Kalpathi et al21 reported no significant correlation between microalbuminuriaand ACS. We found a significant association between acute chest syndrome and the microalbuminuria group (P =.005), which was consistent with other findings reported by Alvarez et al.27
In contrast Bodas et al28 reported that the glomerular filtration rate was not correlated to episodes of stroke or acute chest syndrome, which suggests that the etiologies of these complications may differ from the etiologies of the development of SCN. However, only 48 patients were enrolled in their study and the small sample size, compared to our sample, may have likely influenced the significant correlation between the two conditions.
Furthermore, we found a significant correlation between the microalbuminuriagroup and development of gallbladder stones (P =.014%). Our findings were consistent with those of Alexander-Reindorf et al29 and Bond et al,30 who reported a significantly higher morbidity and more hospital admissions for SCD patients with gallbladder stones. Additionally, the mean age of the microalbuminuriagroup was 13.74 years, which was consistent with Martins et al’s31 11- and 29-year-old study cohort with a higher prevalence of cholelithiasis and gallbladder stones.
HU is an effective drug associated with an increasing hemoglobin concentration, MCV, and HbF level in adults and children. High levels of HbF reduces sickling of RBCs and glomerular damage of the kidney.32
We attempted to identify a correlation between the administration of HU and the NOH or BTs in SCD patients. However, we found no significant effect of administrating the drug and NOH or BT in both groups (P =.7). This finding could suggest that the effect of HU as a renoprotective agent is effective when treatment starts during infancy.27
We found that the number of BTs was significantly associated with a decreased level of microalbuminuria. This finding suggests that BTs are a renoprotective process in the management of SCD. Alvarez et al.27 reported similar results when they indicated that starting transfusion at an early age could help the kidney and hinders the deterioration of SCN. However, the side effects of transfusion, iron overload, must be considered before starting the process. Aloni et al23 reported that BT is not a significant factor when comparing bothgroups.
Kalpathi et al21 stated that 36% of SCD patients presented with hematuria. However, they reported no significant difference in the level of hematuria between the microalbuminuriaand non- microalbuminuria groups. We determined the percentage of hematuria among SCD patients and found a statistically significant difference in the percentage of hematuria between the two groups (P =.007). These results were consistent with the findings of Sesso et al,34 who reported a higher level of hematuria among Hb-ss and Hb-as groups. They stated that hematuria is caused by increased sickling of RBCs in the renal medulla, resulting in extravasation and ischemia.
We also determined that most SCD patients have O RhD+ blood, which was significantly different between the two groups (P =.022). This result is consistent with that of Alagwu et al,35 who reported a percentage of 63% for blood group O among Hb-ss patients. This finding could be explained by the fact that blood group O Rh+ is the most prevalent group among all humans.
In conclusion, our findings highlight the importance of early investigations, e.g., urine analysis for assessment of microalbuminuria and hematuria, and determination of the degree SCN. The fact that average mean BT was significantly higher in the non-microalbuminuria group than in the microalbuminuria group could suggest a protective role of transfusion in the development of microalbuminuria. However, further investigations need to be conducted to confirm our results. Besides, we reported significantly higher rates of acute chest syndrome and gallbladder stones in microalbuminuria patients, which must be considered, and special care needs to be provided to them. We recommend routine screening of microalbuminuria and hematuria for SCD patients.