| Abstract|| |
Microalbuminuria (MA) has been recognized as a sensitive marker of early glomerular injury and a predictor of kidney dysfunction in patients with sickle cell disease (SCD). Limited data are available about MA in SCD children in the Arab countries and none from Yemen. The aim of this study is to determine the prevalence and correlates of MA among 101 children aged 1–16 years, with SCD at their steady state. Children were recruited during their routine health-care visits to the pediatric outpatient clinic in Al-Sadaqa general teaching hospital, Aden, Yemen, between September 2014 and February 2015. A random spot urine sample for each child was screened for MA using Micral-Test strips method. Data on clinical history, anthropometry, blood pressure (BP), and laboratory investigations were obtained. The overall prevalence of MA in this sample was 30.7%, with male predominance (80.6%) (P <0.05). The mean age of children with MA was 7.5 ± 3.2 years, and 10% of them were under five years of age. MA was correlated to both hemoglobin and hematocrit levels, which found to have protective effect against MA (Odds ratio = 0.17 and 0.59, respectively, P <0.05). No correlations were found between MA with age, height, weight, body mass index, recurrent clinical events (painful crises, blood transfusions, and hospitalizations), or fetal hemoglobin levels. BP measurements for all individuals were within the normal ranges, but systolic and diastolic BP were significantly higher in those with MA than without. This study demonstrated a high prevalence of MA in Yemeni children with SCD, and affecting young children as early as 2.5 years of age. Screening for MA as one of the early renal injury markers in children with SCD may help in the prevention of permanent loss of renal function and subsequent renal insufficiency in adulthood.
|How to cite this article:|
Al-Musawa FE, Al-Saqladi AWM. Prevalence and correlates of microalbuminuria in Yemeni children with sickle cell disease. Saudi J Kidney Dis Transpl 2019;30:832-42
|How to cite this URL:|
Al-Musawa FE, Al-Saqladi AWM. Prevalence and correlates of microalbuminuria in Yemeni children with sickle cell disease. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2020 Jun 6];30:832-42. Available from: http://www.sjkdt.org/text.asp?2019/30/4/832/265459
| Introduction|| |
Sickle cell disease (SCD) is a common hereditary blood disorder which adversely affects all body systems leading to multiple organ damage including the kidneys. Renal involvement in SCD patient is known as sickle cell nephropathy (SCN), which encompasses numerous structural and functional alterations with widely variable manifestations., SCN involves tubule-medullary function defects, hematuria, glomerular hyperfiltration, and proteinuria, that subsequently progress into renal insufficiency and end-stage renal disease., The exact mechanism of SCN is not completely understood; however, it is assumed to be a result of recurrent renal vaso-occlusion, ischemic-reperfusion injury, and gradual loss of nephron mass.,, In patients with SCD, renal damage begins in childhood and may progress with increasing age to a degree in which renal replacement therapy become an urgent need. Due to improvement of health care and prolong of life, renal failure in SCD adults becomes a major cause of death. SCN is heralded by the development of microalbuminuria (MA), which is the leakage of small amount of albumin into urine that indicates dysfunction of glomerular filtration barrier, with less severe pore size and charge selectivity damage., MA is proved to be a sensitive marker of early glomerulopathy, and it can significantly predict the progression toward chronic kidney disease (CKD). Previous studies have reported variable prevalence of MA in children with SCD ranged between 11.3% and 51.3%;, this figure increases up to 68% in adult patients. Proteinuria progresses with age to macroalbuminuria in about 20%–40%, and to a nephrotic range in 4% of adult SCD patients., Therefore, it becomes evident that early recognition of SCN is critical for successful intervention and for long-term management as well, and this might lead to reduction in morbidity and mortality with improvement of patients’ quality of life. The occurrence of nephropathy among SCD children remains underreported particularly in places where the burden of this disease is high and the importance of practicing nephrology is a demand. Most reports described MA in adult patients, and limited information are available about children, particularly from the Arab countries and none from Yemen. The primary aim of this study is to determine the prevalence of MA and to analyze its correlates in a group of Yemeni children affected by SCD, and the results are compared with other reports.
| Materials and Methods|| |
This is a cross-sectional study conducted in the outpatient clinic in Al-Sadaqa general teaching hospital, Pediatric Department during a time period of six months (September 2014 to February 2015). The study included consequently all SCD children (as confirmed by Hb electrophoresis) who were ≤16 years, while in their steady state and attended for routine clinical care. A child was considered in steady state if he/she is symptom free without fever, acute illness, or crisis and received no blood transfusion at least in the previous two weeks. Exclusion criteria include children who had been involved in competitive/exercise in the 12 h preceding sample collection, those with fever at time of presentation or history of febrile illness, hospitalization, blood transfusion, and painful crises within the preceding two weeks. Adolescent with ongoing menses or vaginal or penile discharge, findings suggestive urinary tract infection, history of preexisting renal disease, diabetes mellitus, hypertension, or history of drug intake like angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers were also excluded.
Information was collected using a prestruc-tured questionnaire, through direct interview with the closet caretaker of the child, the mother in most instances. Each child was evaluated thoroughly, and data were obtained on demographic characteristics, drug therapy, disease complications, and frequency of clinical events during the previous year including number of hospital admission, blood transfusion, painful crisis, acute chest syndrome, acute anemic episodes, and cerebrovascular event. Data were cross-checked with hospital records for those with previous hospital admission.
All children were subjected to full clinical examination. Blood pressure (BP) was measured by auscultatory method using mercury sphygmomanometer according to standard method. Two different readings were obtained, on arrival and on departure, and the average was taken as actual BP. The result was interpreted based on the currently published SCD-specific BP tables as normal, prehypertension, or hypertension., Data on weight, length/ height, and midupper arm circumference (MUAC) were recorded for every participant, while in light clothing and in correct position during anthropometric measurements. Body mass index (BMI) was calculated by dividing body weight in kg over length/height in m2.
Five milliliters of venous blood sample was collected from each patient by venipuncture using aseptic procedure in the same clinic visit as the urine sample obtained. This blood sample was used for determination of hemoglobin levels, leukocytes’ count [white blood cells (WBC)], platelets, hematocrit, and blood urea nitrogen (BUN) using standard methods. For serum creatinine (SCr) evaluation, colorimetric Jaffe’s method was used. Each participant was issued with a well-labeled universal urine bottle for the collection of 10 mL of a random midstream clean catch urine sample on the day of appointment. Urinalysis for specific gravity and PH were done using Self-Stik multistrips (Chungdo, Pharm Co., Ltd., Korea). For red blood cells and WBC, specimen was screened under microscopic examination of urine sediment. Urine sample was tested first for macroalbuminuria within an hour of collection using the Self-Stik multistrips. Samples negative for macroalbuminuria were subsequently tested for MA using the Micral-Test urine dipsticks, which reported sensitivity and specificity of 96.7% and 71%, respectively. Method employed as described by the manufacturers (Roche Diagnostic GmbH, Mannheim, Germany). Any albumin present in the urine binds specifically with a monoclonal antibody (anti-human albumin IgG) present on a zone on the Micral-Test strip; the reaction color on the strip was then compared visually with an interval scale on the dipstick container. Positive results then classified at concentrations of 20, 50, and 100 mg/L.
The study protocol was approved by the institution ethical committee, and verbal consent from parents or close caregiver was obtained, and confidentiality of information was maintained.
Data analysis was performed using Statistical Package for Social Sciences version 20 (IBM Corp., Armonk, NY, USA). Categorical data were expressed as frequencies (numbers and percentages) and numerical data as mean ± standard deviation for normally distributed data or median and interquartile range for nonnormal data. Chi-square test, Fisher’s exact test, Student’s t-test, and Mann–Whitney U- test were used where appropriate. Logistic regression models were used to describe the association between urine microalbumin and clinical, hematological, and biochemical variables. P <0.05 was considered as statistically significant.
| Results|| |
A total of 101 children with SCD were recruited in this study, 65 males and 36 females, giving a male:female ratio of 1.8:1. The mean age at enrollment was 7.2 ± 3.9 years, range: 6 months–16 years. Majority of children 64 (63.4%) were above five years. Mean age of males were 7.6 ± 4.0 years versus 6.5 ± 3.7 years for females, P= 0.18 [Table 1].
|Table 1: Age and sex distribution of sickle cell disease children (,n=101).|
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Thirty-one (30.7%) of individuals had positive MA test, the gender-specific prevalence was in favor of males 25 (24.8%) against six (5.9%) for females, and the difference was statistically significant (P = 0.023). The mean age of patients with MA (7.5 ± 3.2 years) did not differ significantly from those without MA (7.1 ± 4.2 years) (P = 0.60). Among children with MA, 9.9% were under five years of age and the youngest child with positive MA was 2.5 years of age [Table 2].
|Table 2: Distribution of children with and without microalbuminuria by age and sex.|
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Mean age of males with MA (8 ± 3.2 years) was comparatively higher than females with MA (5.2 ± 2.7 years), but the difference did not reach statically significant (P = 0.09). The mean Hb level was not significantly different between those with positive and negative MA (Hb 7± 1 g/dL vs. 7.4 ± 1 g/dL compared to 7.4 ± 1 g/dL, P = 0.061), while mean platelets count was significantly lower in MA group (P = 0.038) [Table 3].
|Table 3: Hematological and laboratory data in children with and without microalbuminuria.|
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The mean systolic and diastolic BP were 92.6 ± 6.7 and 51.5 ± 5.2 mm Hg respectively, and based on SCD-specific BP tables, they were all normotensive for both systolic and diastolic BP (<90th percentile for age and gender). No child actually had an elevated BP either in prehypertension or hypertension grades. In the MA-positive group, mean systolic BP and diastolic BP were 87.1 ± 10.5 mm Hg and 51 ± 7.4 mm Hg, respectively, whereas the corresponding values in the MA-negative group were 81.9 ± 10.8 and 47.8 ± 7.2 mm Hg, respectively. The differences in BP were significantly higher in MA group for both systolic (P = 0.025) and diastolic (P = 0.045).
Univariate analysis showed that significant predictors of MA were being Hb and Hct levels. Patients with higher Hb were less likely to have MA at odds ratio of 0.31. The same for Hct, where patients with higher Hct were 0.58 times less likely to have MA. There was no association between urine MA excretions with age, frequency of blood transfusions, painful crisis, hospitalizations, or HbF. In multivariate regression analysis, both Hb and Hct levels remain in the final model as statistically significant predictors [Table 4].
|Table 4: Univariate and multivariate logistic regression for predictors of microalbuminuria.|
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| Discussion|| |
To the best of our knowledge, this is the first report about the prevalence of MA and associated factors in children with SCD from Yemen. The prevalence of MA in this sample was 30.7%, which is comparable to 38.8% in Nigerian children, but higher than 18% and 19% reported from Congo and USA.
However, other studies reported widely variable results summarized in [Table 5].,,,,,,,,,,,,,,,,,,, The wide variation in the prevalence of MA across studies maybe attributed to sampling method and testing analysis for microalbumin in urine. Solarin et al used two different methods to measure MA for the same sample: the Micral-Test, which was used in our study, and the quantitative method of albumin/crea-tinine ratio (ACR). The prevalence of MA was markedly different between the two methods, with 38.8% by Micral-Test versus 11.3% by ACR, which is nearly two-thirds lower. Similar observations have been noted by other researches who reported MA rates of 63.3% for Micral-Test and 24% for ACR by assessment of 165 SCD adult patients from Saudi Arabia. It is worth mentioning that the prevalence of MA was also varied in the same country evaluated by different investi-gators.,,, The reason for this wide variation within the same country is not clear, even for studies using the same analytic method. One probable explanation is related to variation in the sample size and patient selection. Other possibilities are the diversity of βs haplotypes and other genetic determinants of SCD severity, alongside some specific genetic predisposition for the development of SCD nephropathy.
In our study, the mean age of patients with MA was 7.5 ± 3.2 years, and it does not differ significantly from those without MA (7.1 ±4.2 years, P = 0.61). This result is comparable to the mean age of 7.8 years reported in Jamaican SCD children, which did not differ significantly from the mean age of non-MA group (7.1 years). Similar observation was reported by two American studies., However, other researchers found higher mean age in MA-positive children., Age was not correlated with MA in our study, which is consistent with previous studies from Brazil and USA, but contrasted to other reports that showed positive correlation between increasing age and the development of MA.,,
In the current report, MA was detected in preschool children with the youngest child affected at 2.5 years of age, and the highest prevalence of MA (58.1%) was seen at age group 6–11 years. This result is similar to that reported from Jamaican study, where MA detected as early as 2.8 years of age and the highest prevalence (55.6%) detected in children aged 5–9 years. Likewise, MA was identified in 14.3% of preschool SCD children in Nigerian study, and in 6.9% of American children with SCD. Furthermore, Marsenic et al found total proteinuria in a significant portion of young children, starting at age of three years and 25% of patients with MA were ≤6 years. On the contrary, some researchers found no MA in children younger than seven years of age.,,
The presence of MA among younger age in the current sample indicates potential early development of renal damage in this group of patients, which could be attributed to the higher proportion of younger children in our sample than the previously mentioned studies. The overall mean age in our sample was lower than 9.5 ± 4.6 years, 11.3 years and 10.6 ± 4.5 years reported in other studies which could not found MA in children younger than seven years of age.,, Hence, the prevalence of MA in pediatrics population seems to be influenced in part by the mean age of the included participants. Another possibility might be related to environmental factors which modify the occurrence of MA in preschool age children living at different circumstances, but these factors remain to be elucidated.
Our results revealed higher prevalence of MA in males, which is comparable to other previous studies in children as well as adults. However, some researchers found no sex difference, and some others even found females more likely to have higher prevalence of MA than males., It is uncertain why males showed higher prevalence of MA; the overrepresentation of males in our sample could be a probable explanation. Other possibility is that the higher MA prevalence in males could be attributed to hormonal differences as androgens assumed to permit and accelerate renal damage, in contrast to estrogen which may have a renal protective effect. However, further studies are needed to ascertain the true possibility.
Analysis of disease-related events mainly pain episodes, blood transfusions, hospitalizations, acute anemic episodes, and acute chest syndrome failed to reveal any significant correlation with MA, similar to findings reported by other researchers.,,,,,,
Lower Hb and hematocrit levels were associated with MA and were identified as predictors for MA development, as have been reported by others.,,,, HbF is another important determinant of SCD severity; but in our sample, it did not differ significantly between those with and without MA, which is consistent with other reports., Furthermore, total leukocytes’ count (WBC) did not differ significantly between MA-positive and MA-negative patients, incorporating observations by other investigators.,,, Failure to find a relationship between clinical events as markers of disease severity and the prevalence of MA, suggesting that additional pathogenic mechanisms along with vaso-occlusion and hemolysis-induced vasculopathy, may play a role in the development of SCN; moreover, there is increasing evidence for the contribution of inflammation and podocytes dysfunction in the pathogenesis of proteinuria in SCN patients.
The mean SCr and BUN were within normal range for age and sex in our sample. In addition, when SCr and BUN levels were compared between group with and without MA, there were no significant differences. Screening for MA among 69 Nigerian SCD children aged 1–16 years (mean age 8.8 ± 4.7 years), using Micral test, with assessment of SCr and BUN showed none of the studied individuals had elevated SCr or BUN, and measurements did not differ significantly between patients with and without MA. The absence of SCr abnormalities pointed that renal function was preserved in these patients despite the presence of MA and support the idea that MA heralds the early renal involvement before any alteration of SCr levels occurs, which is considered a late marker of kidney dysfunction.
Both systolic and diastolic BP differ significantly between patients with and without MA in our study, being slightly higher in MA-positive group, similar to a Congolese study but contrasted to findings reported from Nigeria and USA where systolic and diastolic BP did not differ between MA positive and negative groups., Increased BP in SCD patients even in the upper normal limits is considered as relative hypertension and has been associated with risk of CKD. Furthermore, decreased baseline ACR was found to be strongly associated with decreases in systolic BP in one follow-up study.
Other clinical correlates such as weight, height, MUAC, and BMI showed no significant association with MA, similar to that reported by others. Imuetinyan et al failed to find relationship between MA and height, but a significant relation existed with weight. In a Jamaican study, BMI was inversely related to MA although the relation was not statistically significant. Others did not find any significant correlation between MA and BMI in American, or Tanzanian children.
Prolonged period of MA may progress to persistent proteinuria. There are very limited longitudinal studies to examine the evolution of MA in children with SCD. In a large SCD cohort study of 373 children and young adults with a mean follow-up time of 3.12 ± 1.16 years, analysis showed one half of the patients developed worsening urinary MA/Cr level, while one-third revealed improved levels but did not normalize during the study period, suggesting that MA in SCD children may increase or decrease overtime but the rate of progression remains unknown.
This study was a cross-sectional design, which limits the true predictability of pediatric MA in SCD; the best way to determine fate and significance of MA in the development of CKD is to follow the affected children in a well-designed large cohort study taking in consideration the widely variable environmental and genetic risk factors. MA was screened using randomly spot urine sample instead of 24-h urine collection which is more accurate for MA measurement, even though such method is less convenient and less practical in small children.
| Conclusion|| |
The present study has revealed a relatively high prevalence of MA in children with SCD living in Yemen. MA has been detected in preschool-aged children as youngest as 2.5 years, signifying an early onset of renal damage in this group of patients. MA was significantly associated with low Hb, low hematocrit, and increased BP levels. These findings highlight the importance of regular monitoring of urine albumin excretion as one of the early renal injury markers in children with SCD and might help in timely intervention to prevent permanent loss of renal function and subsequent renal insufficiency in adulthood.
Conflict of interest: None declared.
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Abdul-Wahab M Al-Saqladi
Department of Pediatrics, Faculty of Medicine and Health Sciences, University of Aden, Aden
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]