|Year : 2020 | Volume
| Issue : 3 | Page : 147-152
Relationship between microalbuminuria and glomerular filtration rate in children with sickle cell anemia in steady state
Rasaki Aliu1, Jalo Iliya1, Patience Ngozi Obiagwu2, Adamu Sani3
1 Department of Paediatrics, Federal Teaching Hospital, Gombe State University, Gombe State, Nigeria
2 Department of Paediatrics, Aminu Kano Teaching Hospital, Bayero University, Kano State, Nigeria
3 Department of Chemical Pathology, Federal Teaching Hospital, Gombe State University, Gombe State, Nigeria
|Date of Submission||28-May-2019|
|Date of Acceptance||22-Jan-2020|
|Date of Web Publication||7-Oct-2020|
Dr. Rasaki Aliu
Department of Pediatrics, Federal Teaching Hospital, Gombe State University, Gombe
Background: Microalbuminuria (MA), a common phenomenon in children with sickle cell anemia (SCA), is defined as an increased urinary albumin–creatinine ratio of 30–300 mg/g of creatinine in an early morning or random urine specimen. Whereas some studies have shown that MA reflects early kidney damage, other studies have documented that it is a manifestation of advanced nephropathy. The reports about the relationship between glomerular filtration rate (GFR) and MA in children with SCA are conflicting. Materials and Methods: This was a longitudinal study. Serum creatinine, GFR, and albumin–creatinine ratio were determined at baseline. The individuals were followed up over 3 months during which albumin–creatinine ratio and GFR were assayed monthly, and the relationship between them was determined. Results: One hundred and seventy children aged 1–18 years with SCA and MA were studied. The mean albumin–creatinine ratio was 120.9 ± 66.8 mg/g, 138.32 ± 101.79 mg/g, 117.12 ± 78.09 mg/g, and 106.73 ± 38.82 mg/g at baseline, 1, 2, and 3 months, respectively, whereas the mean GFR was 121.7 ± 33.0 ml/min/1.73 m2, 117.69 ± 29.70 ml/min/1.73 m2, 117.56 ± 35.77 ml/min/1.732 m2, and 116.22 ± 30.28 ml/min/1.73 m2 at baseline, 1, 2, and 3 months, respectively. There was no significant relationship between MA and GFR in the participants throughout the study period (Pearson's correlation coefficients: 0.050, 0.250, 0.268, and 0.143 and corresponding P: 0.95, 0.88, 0.15, and 0.36). Conclusions: GFR is normal in SCA children with MA. There is no significant relationship between MA and GFR in children with SCA.
Keywords: Glomerular filtration rate, microalbuminuria, sickle cell anemia children
|How to cite this article:|
Aliu R, Iliya J, Obiagwu PN, Sani A. Relationship between microalbuminuria and glomerular filtration rate in children with sickle cell anemia in steady state. Sahel Med J 2020;23:147-52
|How to cite this URL:|
Aliu R, Iliya J, Obiagwu PN, Sani A. Relationship between microalbuminuria and glomerular filtration rate in children with sickle cell anemia in steady state. Sahel Med J [serial online] 2020 [cited 2021 Dec 1];23:147-52. Available from: https://www.smjonline.org/text.asp?2020/23/3/147/297452
| Introduction|| |
Globally, more than 300,000 babies with sickle cell disorders are born yearly. Nigeria has the highest burden of sickle cell anemia (SCA) worldwide with a prevalence of 20/1000 births and about 150,000 children with SCA born every year.
SCA affects all organs in the body. kidney involvement, described as sickle cell nephropathy, is an important cause of mortality. Sickle cell nephropathy has a prevalence that ranges from 5% to 18% and has a spectrum that often begins with defects in urine concentration and acidification early in childhood and progresses with age to microalbuminuria (MA), overt proteinuria, glomerulosclerosis, and renal failure.,,
Whereas some studies report that MA suggests early kidney damage, others have demonstrated otherwise. MA, a subclinical rise in urinary albumin, is defined as urinary albumin– Creatinine ratio (ACR) of 30–300 mg/g of creatinine in an early morning or random urine sample. It is a form of urinary proteins, a preclinical marker of kidney damage, and suggests kidney damage earlier than other proteins.
Studies conducted within and outside the West Africa subregion have documented conflicting glomerular filtration rate (GFR) in children with SCA and MA. Whereas studies conducted in Nigeria and the West Africa subregion have mostly demonstrated normal GFR in children with SCA, studies outside the West Africa subregion have reported high GFR (hyperfiltration).,,,, These studies were, however, cross-sectional descriptive studies without follow-up. Thus, this study determined the GFR pattern over a 3-month period.
| Materials and Methods|| |
This longitudinal study was conducted in a sickle cell disease center of Federal Teaching Hospital, Gombe (FTHG), North-East Nigeria, from December 2016 to March 2017. FTHG is a 450-bed capacity tertiary institution located in Gombe Local Government Area. The hospital has a sickle cell center which is one of the six sickle cell centers spread across the six geopolitical zones in Nigeria. It has a side laboratory for investigations, a sickle cell pharmacy, a transcranial Doppler ultrasonography machine, and a health record office.
Inclusion criteria: Children aged 1–18 years, with SCA who were in steady state (defined as the absence of fever or crisis in the previous 4 weeks or more in a child who was not on any medication other than routine folic acid and prophylactic antimalarial drug), who were being followed up in the sickle cell clinic at FTHG, and whose caregivers consented to the study were recruited. Assent was also obtained from children above 7 years of age.
Exclusion criteria: Children who were known to have any of the following (s) – hypertension, diabetes mellitus, HIV, and urinary tract infection – were excluded from the study. The sample size (170) was calculated using Fischer's formula. The prevalence of MA (11.3%) in SCA children was adopted, attrition rate of 10% was added, and degree of accuracy was set at 5%.
Children (SCA) who had confirmed genotype Hemoglobin SS and who were already on regular clinic follow-up were screened weekly at the clinic (screening stage). Participants who met the inclusion criteria were given well-labeled universal bottles to provide a urine sample. Bigger containers were provided for female adolescents and younger children who could not void into the bottles directly. The urine in the container was then carefully transferred into the universal bottles. The older male adolescents were instructed to pass the urine directly into the universal bottles. On-the-spot preliminary dipstick urinalysis was done in the laboratory using Combi-11 multistrips. Participants whose urine tested positive for protein, blood, glucose, or leukocytes were excluded from the study. Participants whose urine samples tested negative for protein, blood, glucose, and leukocytes had their urine analyzed for urinary albumin and urinary creatinine. Participants (170) who tested positive for MA (urinary albumin–creatinine ratio of 30–300 mg/g) had their blood samples collected for serum creatinine determination (recruitment stage). These participants were followed up monthly for 3 months during which samples for urine and serum samples were taken monthly for the assay of MA and measurement of serum creatinine. GFR was derived from the serum creatinine using the Schwartz formula.
Ichroma™ MAU-25 and Ichroma™ Reader were used to determine urinary albumin concentration by immune turbidimetric method, whereas Chemray-240 automated chemistry analyzer (AGAPPE Diagnostics Switzerland GmbH) was used to determine urine creatinine by modified Jaffe's kinetic reaction. ACR was calculated using the urine albumin concentration (mg/L) and urine creatinine (g/L). ACR of 30–300 mg/g was classified as MA.
Ethical approval dated 15th February 2016 with protocol number NHREC/25/10/2013 was obtained from the Research and Ethics Committee of FTHG, and the procedures followed were in accordance with the ethical standards of the Helsinki Declaration of 1975, as revised in 2000.
Data were processed and analyzed using IBM statistical package for the social sciences, statistical software version 24 (IBM, Atlanta Georgia, USA). To determine the level of statistical significance of the differences in mean between two independent groups (e.g., male and female), independent t-test was used for continuous variables (MA and GFR), whereas Chi-square test was used for categorical variables (age groups and socioeconomic status). Pearson's correlation was used to determine the strength of relationship between MA and GFR. P < 0.05 was considered statistically significant.
| Results|| |
A total of 170 children with SCA and MA were recruited into the study. Children aged 1–5 years and 6–10 years of age constituted about a third each of the study population. A higher proportion (46/81, 47.6%) of the participants were from low socioeconomic class. [Table 1]a shows the sociodemographic characteristics of the study population.
MA was more prevalent in males (87) as compared to female participants (male: female of 1.1:1). The mean body mass index (BMI) was higher in females with MA (14.72 ± 2.59) as compared to male participants (14.39 ± 2.37). The female participants were older (9.51 ± 4.99) than the males (7.25 ± 4.48). The mean packed cell volume (PCV) in females was lower (23.5 ± 3.26) when compared to male participants (24.08 ± 3.47). The differences in mean BMI (P = 0.402) and mean PCV (P = 0.288) were not statistically significant [Table 1]b.
Overall, the mean MA and GFR at baseline was 120.9 ± 66.8 mg/g and 121.7 ± 33.0 ml/min/1.73 m2, respectively. There was a very weak, nonsignificant correlation between MA and GFR at baseline (r = 0.05; P = 0.971). There was also a weak, nonsignificant correlation between MA and GFR during the follow-up periods (r = 0.250, 0.268, and 0.143 and corresponding P = 0.88, 0.15, and 0.36 at 1, 2, and 3 months). [Table 2] shows the mean values for MA and GFR during the different time periods. [Table 3] summarizes the mean MA and GFR that increased with increasing age category except in the age category 16–18 years.
|Table 2: Microalbuminuria and glomerular filtration rate at baseline, 1, 2, and 3 months|
Click here to view
|Table 3: Microalbuminuria and glomerular filtration rate at baseline based on age groups|
Click here to view
[Figure 1] shows the trend line between MA and GFR which has a nonlinear pattern.
|Figure 1: A correlation trend line showing the relationship between microalbuminuria and glomerular filtration rate|
Click here to view
| Discussion|| |
In this study, the presence of MA in children <10 years of age is worthy of note. Several studies have demonstrated MA in SCA children aged 10 years and below,,, and in fact, MA has been detected in SCA children aged 6 months to 1 year., With several studies reporting MA as a risk factor for either early kidney disease or advanced kidney disease,, early screening of children with SCA may be necessary in contrast to the report by sickle cell expert panel in which it was recommended that screening of person with SCA for proteinuria should commence at age of 10 years.
Although majority of the participants with MA in this study were aged <10 years, children in the age group 1–5 years constituted majority. The preponderance of MA in children 1–5 years of age in this study is similar to the reports by Fatoye. This is in contrast to the reports of some studies who have documented that the prevalence of MA increases with age.,, These findings and conclusions are, however, not surprising because Alvarez et al. and Eke et al. excluded younger children <4 years of age. Thus, these authors' conclusions may not be truly representative of the prevalence of MA in children. Although Dharnidharka et al. recruited children 2 years and above, MA was only detected in children above 7 years, and the participants recruited did not fulfill the criteria of steady state. This might have affected Dharnidharka's finding.
In this study, although MA was more prevalent in male participants, the higher mean MA in the female participants may be explained by higher age observed in female participants and lower PCV. Both increasing age and low hemoglobin have been shown by some studies, to be risk factors for MA in children.
The GFR in children with SCA and MA was normal at baseline and on follow-up in this study. This finding is similar to the reports of most studies in Nigeria and the West Africa subregion., This would then mean that MA, a marker of kidney disease in children with SCA, suggests early rather than advanced kidney disease. Whereas most studies on GFR in children with SCA and MA are cross-sectional descriptive studies,, the current study has evaluated the progression of GFR in children with SCA and MA. The preservation of normal GFR in children with MA over 3 months in this study is particularly similar to the reports by Alvarez et al. who documented normal renal function tests over an 8-month follow-up study with subsequent deterioration beyond 8 months. This further strengthens the fact that MA suggests early renal impairment in children with SCA.
In contrast to the finding from this current study, studies conducted outside Nigeria and the West Africa subregion, in particular, have reported high GFR in children with SCA and MA.,, This finding has been shown to be consistent with the fact that hyperfiltration, a common phenomenon in children with SCA and MA, causes early kidney impairment. The normal GFR in this study and other studies conducted in Nigeria, where the most severe form of sickle cell disorders are found, may be an indication that the GFR has progressed from the stage of hyperfiltration (high GFR) to progressive decline in GFR (normal GFR) following damage to the kidney by the hyperfiltration. Genetic variations may also explain the reasons for the differences in GFR in SCA children in the Blacks (normal GFR) and GFR in SCA children in Caucasians (high GFR) as postulated by Aloni et al.
At baseline, 1 month, 2 months, and 3 months of this study, there was no significant relationship between MA and GFR. This may be because MA in children with SCA suggests early kidney disease, and at this incipient stage, the clinical features and GFR which is a delayed marker of kidney disease will show little change. This finding is similar to the reports by Eke et al. in Enugu, Abhulimhen-Iyoha et al. in Benin, Fatoye. in Ilorin, Ackoundou-N'Guessan et al. in Cote d'Ivoire, Datta et al. in India, Alvarez et al. in Florida, and Aygun et al. and Dharnidharka et al. in Detroit. Although majority of the studies,, conducted outside Nigeria have predominantly shown high GFR in children with SCA and MA, the relationship did not reach a statistically significant level (P = 0.51, 0.34, and 0.22). Most of the Nigerian studies,, have documented normal GFR in children with SCA and MA, and there was no significant relationship between MA and GFR. The normal GFR over 3 months of MA in this study, and the absence of a significant relationship, corroborates the fact that MA suggests early kidney damage rather than advanced kidney injury.
In contrast to the finding in this current study, Thompson et al. in Jamaica has reported a significant relationship between MA and GFR in the participants with SCA and MA. In the study by Thompson et al., the participants were adults aged 18–23 years unlike in the current study where the majority of the participants with MA were aged 1–5 years and 6–10 years. It could be implied that the degree and duration of MA in the participants aged 18–23 years was higher and longer and thus reflective of advanced kidney impairment as proposed by Ackoundou-N'Guessan et al. in Cote d'Ivoire.
| Conclusions|| |
In children with SCA and MA in this study, the GFR is normal and there is no significant relationship between GFR and MA.
Early screening of SCA children for MA is recommended. Close monitoring of GFR is essential as hyperfiltration (High GFR), an early feature in children with SCA and MA in Caucasians studies, is absent in this study. Normal GFR (absence of hyperfiltration) suggests GFR is already on the decline.
Short follow-up (3 months) is a limitation in this study.
I wish to acknowledge both Dr. Alkali YS and Dr. Isaac EW for proofreading the study protocol when it was drafted.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ 2008;86:480-7.
Powars DR. Sickle cell anemia and major organ failure. Hemoglobin 1990;14:573-98.
Scheiman JI. Sickle cell nephropathy. In: Barrat TM (ed.) Paediatric nephrology. Baltimore: Lippincott Williams and Wilkins 1994. p. 908-19.
Nath KA, Hebbel RP. Sickle cell disease: Renal manifestations and mechanisms. Nat Rev Nephrol 2015;11:161-71.
Stallworth JR, Tripathi A, Jerrell JM. Prevalence, treatment, and outcomes of renal conditions in pediatric sickle cell disease. South Med J 2011;104:752-6.
Guasch A, Cua M, Mitch WE. Early detection and the course of glomerular injury in patients with sickle cell anemia. Kidney Int 1996;49:786-91.
Datta V, Ayengar JR, Karpate S, Chaturvedi P. Microalbuminuria as a predictor of early glomerular injury in children with sickle cell disease. Indian J Pediatr 2003;70:307-9.
Ackoundou-N'Guessan C, Tia M, Lagou D, Cissoko A, Guei C, Gnionsahe D. Microalbuminuria represents a feature of advanced renal disease in patients with sickle cell haemoglobinopathy. Ann Ib Postgrad Med 2006;4:29-34.
Kidney National Foundation. Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification. National Kidney Foundation; 2002.
Dharnidharka VR, Dabbagh S, Atiyeh B, Simpson P, Sarnaik S. Prevalence of microalbuminuria in children with sickle cell disease. Pediatr Nephrol 1998;12:475-8.
Abhulimhen-Iyoha I, Ibadin M, Ofovwe E. Comparative usefulness of serum creatinine and microalbuminuria in detecting early renal changes in children with sickle cell anaemia in Benin-city. Niger J Paediatr 2009;36:1-2.
Eke CB, Okafor HU, Ibe BC. Prevalence and correlates of microalbuminuria in children with sickle cell anaemia: Experience in a tertiary health facility in Enugu, Nigeria. Int J Nephrol 2012; 10:1155-61.
Okoro BA, Onwuameze IC. Glomerular filtration rate in healthy Nigerian children and in children with sickle cell anaemia in a steady state. Ann Trop Paediatr 1991;11:47-50.
Olanrewaju DM, Adekile AD. Anthropometric status of sickle cell anaemia patients in Ile-Ife. Niger Med Pract 1989;18:63-6.
Araoye MO. Research Methodology with Statistics for Health and Social Sciences. Ilorin: Nathadex Publisher; 2003. p. 115.
Solarin A, Njokanma F, Kehinde O. Prevalence and clinical correlates of microalbuminuria among children with sickle cell anaemia attending Lagos state University teaching hospital Ikeja. Afr J Paediatr Nephrol 2014;1:37-45.
Midthun S, Paur R, Bruce AW. A protocol for the urine dipstick/pad method. J Wound Ostomy Continence Nurs 2006;33:396-400.
Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am 1987;34:571-90.
Chesbrough M. District Laboratory Practice in Tropical Countries. Vol. 1. Cambridge, UK: Cambridge University Press; 2002. p. 711-2.
Levey AS, Coresh J, Bolton K, Culleton B, Harvey KS, Ikizler TA, et al
. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation classification and stratification. Am J Kidney Dis 2002; 39:S1-266.
Marsenic O, Couloures KG, Wiley JM. Proteinuria in children with sickle cell disease. Nephrol Dial Transplant 2008;23:715-20.
Gary HG, Susan BS, George RB, Barbara PY, Araba NA, Samir KB, et al
. Expert panel report: Screening for renal complications. In: Evidence-Based Management of Sickle Cell Disease.USA: National Health Institute 2014. p. 14-5.
Fatoye P. Biomarkers of Nephropathy in Children with Sickle cell Disease Seen at University of Ilorin Teaching Hospital, Ilorin. A Dissertation Submitted to the National Postgraduate Medical College of Nigeria; 2013.
Alvarez O, Lopez-Mitnik G, Zilleruelo G. Short-term follow-up of patients with sickle cell disease and albuminuria. Pediatr Blood Cancer 2008;50:1236-9.
McBurney PG, Hanevold CD, Hernandez CM, Waller JL, McKie KM. Risk factors for microalbuminuria in children with sickle cell anemia. J Pediatr Hematol Oncol 2002;24:473-7.
Thompson J, Reid M, Hambleton I, Serjeant GR. Albuminuria and renal function in homozygous sickle cell disease: Observations from a cohort study. Arch Intern Med 2007;167:701-8.
Aygun B, Mortier NA, Smeltzer MP, Hankins JS, Ware RE. Glomerular hyperfiltration and albuminuria in children with sickle cell anemia. Pediatr Nephrol 2011;26:1285-90.
Aloni MN, Ngiyulu RM, Gini-Ehungu JL, Nsibu CN, Ekila MB, Lepira FB, et al
. Renal function in children suffering from sickle cell disease: Challenge of early detection in highly resource-scarce settings. PLoS One 2014;9:e96561.
Ibitoye P, Jiya N, Airede K, Ugege M, Jiya F, Isezuo K. Glomerular filtration rate in steady state children with sickle cell anaemia in Sokoto North-Western Nigeria. Afr J Paediatr Nephrol 2016;3:7-15.
[Table 1], [Table 2], [Table 3]