| Abstract|| |
Microalbuminuria (MA) is an early marker of various diseases affecting the renal system. Its relevance in children with sickle cell anemia (SCA), who are known to be prone to renal complications, has not been fully explored, particularly in the study locale. Besides, its occurrence in this group of patients remains under-reported in locations where the burden of SCA is enormous. To assess its prevalence in this cohort, 69 children with sickle cell anemia (in their steady state), aged 1-16 years, were consecutively enrolled and evaluated. The study, spanning from November 2006 to February 2007, was cross-sectional and descriptive. Employing a semiquantitative method, MA in an early morning spot urine sample was determined in each subject. Also evaluated were the anthropometry, blood pressure (BP) and packed cell volume. Prevalence of MA in the study subjects was 20.3%. Though not significant, prevalence of MA was more in females (25.9%) than in males (16.7%). Prevalence of MA increased with increasing age and was also significantly associated with weight (P = 0.033), but was independent of family history of hypertension. BP recordings, both systolic and diastolic, in the study subjects were within normal range. MA occurs significantly enough in children with SCA to warrant routine screening for it. Such a measure could assist in the early detection of ensuing renal complications and can pave way for improved management of a sickler who is particularly prone to such problems. In addition, interventional measures, known to retard rate of deterioration of kidney function due to prolonged proteinuria, could also be instituted early.
|How to cite this article:|
Imuetinyan BA, Okoeguale MI, Egberue GO. Microalbuminuria in children with sickle cell anemia. Saudi J Kidney Dis Transpl 2011;22:733-8
|How to cite this URL:|
Imuetinyan BA, Okoeguale MI, Egberue GO. Microalbuminuria in children with sickle cell anemia. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2020 Jun 6];22:733-8. Available from: http://www.sjkdt.org/text.asp?2011/22/4/733/82663
| Introduction|| |
Dipstick urinalysis is a valuable tool in the screening for urinary abnormalities ,, as it detects proteinuria, hematuria, urinary specific gravity, leukocyturia, among others. It, however, cannot detect proteinuria below the value of 300 mg/dL,  defined as microalbuminuria (MA) that heralds early renal involvement. In recent years, therefore, interest has shifted to testing for MA in a variety of clinical diseases, renal and non-renal, such as diabetes mellitus,  hypertension  and sickle cell disease (SCD). , MA is the excretion in urine of very small amounts of albumin, slightly in excess of 20 μg/min,  in the range of 30-300 mg/24 hours  , levels that require sensitive radioimmunoassay for detection.  MA has also been found to be an important marker of glomerular injury in patients with sickle cell anemia (SCA).  MA detection using the Micral-test strip (commercial test strips that detect MA in spot urine) has now become useful in this regard.
The term sickle cell nephropathy (SCN)encompasses all the structural and functional abnormalities of the kidneys seen in SCD.  SCN manifests with various glomerular and tubular abnormalities such as proteinuria with or without nephritic or nephrotic syndrome.  These manifestations are as a result of chronic renal microvascular occlusion by sickled erythrocytes, the effect of which is accentuated during crises. ,,
Although MA has been found to be useful in early detection of renal impairment, and hence, the early detection of SCN as well, studies on this aspect are scanty in Nigeria.  This study, therefore, was designed to explore the presence of MA in children with SCA, as a possible marker of early renal impairment. Patients with SCA who have impaired renal function could benefit from enhanced care through interventional measures aimed at minimizing progression of proteinuria, such as with the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone, etc. 
The relevance of the findings of the study would be better appreciated when one realizes that Africa and most parts of the Third World will be better off practicing preventive nephrology, as the cost of specialized health care for chronic renal failure patients is beyond the reach of the majority of their populace.
| Patients and Methods|| |
The study, a prospective and cross-sectional one, was carried out at the Consultant Outpatient Clinic (COPC) of the University of Benin Teaching Hospital (UBTH) and the Sickle Cell Centre (SCC), both in Benin City, Edo State, Nigeria. The period of study was from November 2006 to February 2007. The study was carried out on working days and during working hours. Samples were collected on working days.
Study subjects were children with SCA (as confirmed by electrophoresis using cellulose acetate paper) in their steady state, who were 1-16 years of age and were being followed up at the Pediatric Hematology, COPC in UBTH and the SCC, both in Benin City.
Excluded from the study were the children who had been involved in competitive sports/ exercise in the 12 hours preceding sample collection, children with fever at presentation or a history of febrile illness within the preceding week of presentation and children with ongoing menstruation or vaginal/penile discharge. Others excluded were children with symptoms and signs suggestive of urinary tract infection (UTI) or a pre-existing renal disease and history of use of drugs such as oxytetracycline.
Patients who came for routine follow-up and had satisfied the inclusion criteria were recruited consecutively in the study. A minimum of two clinical contacts were made with the subjects, with the second contact being a week after the first. For each child, a detailed history was obtained including patient's age, gender and relevant medical history of recurrent admissions, blood transfusions, cigarette smoking, and family history of hypertension and drug use within 72 hours antedating sample collection.
A thorough physical examination was carried out on each child, checking for pulse rate, blood pressure (BP), pallor (anemia), jaundice, peripheral edema, leg ulcers, and organomegaly.
Weight and height were recorded and body surface area was (BSA) estimated using standard normogram. The weight of each subject was measured using a bathroom weighing scale made by U-MEC Model 98114. It had a sensitivity of 0.5 kg. The standing height was measured using a standiometer, well calibrated up to 2 meters, which could measure to the nearest 1 cm, and using the technique as described by Paynter and Parkin. The lower of two BP readings taken on arrival and on departure was recorded with the patient in sitting position and using the Accoson mercury sphygmomanometer. Values obtained were compared to the established standards for age to determine those who were hypertensive, normotensive or hypotensive.
Findings of the study on the subjects were recorded in the study proforma designed for the purpose. Informed consent was obtained from parents/caregivers of subjects. Ethical approvals were obtained from both the UBTH and the SCC Ethical Committees.
All enrolled subjects were provided with pre-labeled universal bottles for the collection of early morning urine. Subjects were instructed on how to collect early morning mid-stream/ clean catch urine. They were encouraged to return the samples as early as possible after collection, that is, between 7 a.m. and 8 a.m.
About 2 mL of venous blood was collected from each patient by venepuncture (using aseptic precautions) during the second visit, into an ethylenediaminetetraacetic acid (EDTA) bottle to confirm the patient's hemoglobin genotype. Urine sample was tested first for albuminuria within an hour of collection, using the Combi-10 multi-strips. Samples negative for albuminuria were subsequently tested for MA using the Micral test strips and employing the methods as described by the manufacturers (Roche Diagnostics, Quebec, Canada). MA was defined by varying shades of pink in the test strip that corresponded to a range of 20-250 mg/L of urinary albumin.
The data collected were entered into Microsoft Excel 2003 and cross-checked for accuracy. The data were then sorted. Means and standard deviation were calculated for continuous variables. Where appropriate, data were uploaded into Statistical Package for Social Sciences (SPSS) 11.0 for the calculation of frequencies and association between variables. Inferential statistics to explore the relationship between MA and demographic factors was done with the aid of Graph Pad Instat, which reports exact P-values. Student's t-test, one-way analysis of variance (ANOVA) and chi-square analysis were used where appropriate. Values of P ≤ 0.05 were interpreted as significant.
| Results|| |
Sixty-nine children made up the study group. Of these, 42 (60.9%) were males and 27 (39.1%) were females, giving an M:F ratio of 1.6:1. The distribution of subjects in the various age cohorts for both males and females is as shown in [Table 1]. The table reveals that there were more males than females in all age cohorts.
The mean age of the study population was 8.8 ± 4.7 years (range 1-16 years) and that for male subjects was 8.7 ± 4.8 years which did not vary significantly from the 9.0 ± 4.7 years obtained for females (P = 0.799).
As shown in [Table 2], the mean weight of the study subjects was 28.0 ± 5.8 kg. Males had a mean weight of 27.4 ± 6.1 kg and females had a mean weight of 28.6 ± 5.4 kg. The mean height for all subjects was 131.5 ± 10.1 cm. Males had a mean height of 130.3 ± 11.4 cm as against 132.6 ± 8.7 cm for females. The mean body surface area for (all) subjects was 1.00 ± 0.2 m 2 , while it was 0.99 ± 0.2 m 2 and 1.01 ± 0.1 m 2 for the males and females, respectively. Generally, the females had comparable anthropometry with their male counterparts.
Fourteen (20.3%) of the 69 subjects had MA in their early morning urine [Table 3]. The gender-specific prevalence was in favor of females, that is a prevalence of 25.9% as against 16.7% for the males. The difference was, however, not statistically significant (P = 0.374). Thirty-four (49.3%) of the subjects were less than nine years of age, while 35 (50.7%) were nine years and above. In the age group ≥9 years, the prevalence of MA was 22.9% as against 17.6% in those <9 years [Table 4] The two broad age groups, (i.e. <9 and ≥9 years) were used because in previous literatures, presence of MA in children who were 10 years and below was compared with that in children who were above 10 years of age. The modal age group for children with MA was ≥15 years. However, there was another peak between 6 and 8 years of age. Among children aged less than 5 years also, only two (14.3%) had MA.
|Table 3: Age distribution of children with and without microalbuminuria.|
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The mean age of subjects with MA (10.9 ± 4.9 years) did not differ significantly from that obtained in those without MA (8.3 ± 4.6 years). Similarly, no significant relationship existed between MA, height and family history of hypertension. Twelve of the 69 subjects had family history of hypertension. Of the 12, only four had MA while the remaining eight did not have MA. Ten of 57 children without family history of hypertension had MA (χ2 = 1.53; P = 0.245). However, a significant relationship existed between weight and presence of MA (t = 2.184; P = 0.33).
BP was evaluated as a possible confounding factor for the presence of MA. For the entire cohort, the mean systolic BP and diastolic BP were 98.97 ± 11.5 and 59.9 ± 9.8 mmHg, respectively [Table 5]. Both systolic BP and diastolic BP were found to be higher with increasing age in both the sexes. In the MA positive group, mean systolic BP and diastolic BP were 101.8 ± 11.0 and 62.1 ± 8.0 mmHg, respectively, whereas the corresponding values were 98.3 ± 11.6 and 59.3 ± 10.2 mmHg, respectively, in the MA negative group. No child actually had an abnormal BP, and the differences in systolic BP and diastolic BP between the groups with and without MA were also not statistically significant. However, the differences in mean systolic BP and diastolic BP amongst the different age groups were statistically significant.
|Table 5: Distribution of systolic BP, diastolic BP and packed cell volume (PCV) among the various age groups.|
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The mean PCV for all subjects was 22.7 ± 4.0%, while the mean PCV for the subjects with and without MA were 22.5 ± 3.9% and 22.7 ± 4.1%, respectively (P = 0.870).
| Discussion|| |
In this study, the overall prevalence of MA in children with HbSS was 20.3%. Prevalence figures were low among pre-school aged children and rose to 22.9% in those aged ≥9 years. In consonance with the findings in this study, Datta et al  in 2003 reported a 19.2% prevalence of MA among Indian children with SCD. Similarly, Alvarex et al  in 2006 recorded a prevalence of 16.8% amongst HbSS children and 18.0% amongst the SC group. They worked on 120 children and young adults between the ages of 4 and 20 years. In the United States, McBurney et al  in 2002 found the prevalence of MA in 142 children with SCD to be 19.0%. In yet another American study, Dharnidharka et al  in 1998 reported on 102 children aged 2-18 years with SCA. They found a higher prevalence of 26.5% in their study subjects. However, in children aged 10-18 years, the prevalence was 46%. The slight difference between their overall prevalence and that found in this study is most likely due to the increased number of older subjects (between 17 and 18 years) recruited for their study compared to our study, as prevalence of MA increases with increasing age.
In the current study, the oldest child was 16 years of age (although the study had been set out to include children 17 and 18 years of age, none presented during the period of the study). A Brazilian study found 40% prevalence of MA in their adult SCD population,  corroborating the observation that incidence of MA increases with increasing age. Furthermore, in 1998, Sesso et al  recorded a prevalence of 30% in Brazil. Their subjects were both children and adults with SCA and sickle cell trait. The higher figure may therefore be ascribed to the fact that older subjects known to have higher rate of MA were recruited for the study.
Unlike what was found by Dharnidharka et al  where MA was not seen in any child less than 7 years of age, in the current study MA was seen in pre-school children. MA in this locale may be an indicator of severity of the disease (i.e. the number and severity of crises which the child may have encountered) rather than just age. The older the child, the more crises he/she is likely to have had, particularly in resource-poor countries including Nigeria. This may explain why younger patients in the study location had MA.
In this study, gender-specific prevalence was higher in females. This observation is similar to that reported by Dharnidharka et al  who noted a gender-specific prevalence of 20.7% in males as against 32.7% in females. It is uncertain why the higher prevalence is found in females. However, factors known to confound proteinuria (UTI, hematuria, leukocyturia) are common in females, as evidenced by the increased rate of macroalbuminuria found in females. Female children in general are prone to higher incidence of UTI and this holds true also for individuals with HbSS. Increased incidence of UTI was advanced by Dharnidharka et al  as the reason for the gender variation in the prevalence. This reason alone may not suffice to explain the gender disparity because as much as possible, measures were taken to exclude children with UTI in this study, as perhaps was also done in other studies.
However, it is uncertain how many SCD patients with MA progress to more established renal disease including chronic renal failure (CRF). Since patients may present with fullblown renal disease early in adulthood, it might be important to commence monitoring early in childhood. , Such a measure would provide the opportunities for detecting early those who could progress to chronic kidney disease and thus permitting the implementation of inter-ventional measures meant at decelerating rapid deterioration delaying the eventual need for renal replacement therapy.
The BP in all subjects was normal. The children with MA did not vary in their mean BP when compared to their counterparts without MA. The findings of normal BP in individuals with SCD have also alluded other authors. , In SCD patients, BP fails to show the age-related rise seen in normal adult populations. According to the authors, the exact mechanism for the trend among patients with SCD is unclear. However, Denenberg et al  recorded that in SCA patients, cardiac dilatation, increased preload and decreased peripheral resistance reduce the after load. This could account for the normal BP recorded in them.
In conclusion, the prevalence of MA in children (1-16 years) with SCA in the steady state in our study was 20.3%. Prevalence of MA was influenced by age, gender and weight. MA was also found in pre-school aged children with SCA.
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Michael Ibadin Okoeguale
Department of Child Health, University of Benin Teaching Hospital, Benin City
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]