| Abstract|| |
The prevalence of suboptimal Vitamin D levels is higher in patients with chronic kidney disease (CKD) than in the general population. Recent findings suggest that progression of CKD is linked to a suboptimal Vitamin D level. A high percentage of CKD patients have severe Vitamin D deficiency. These patients also have a low level of 25-hydroxy-vitamin D [25(OH)D] and consequently, a reduced ability to form active 1,25-dihydroxyvitamin D. Various factors underlie the low level of 25(OH)D, including a sedentary lifestyle, decreased intake of Vitamin D due to CKD-related dietary restrictions, and decreased synthesis of Vitamin D in skin due to uremia. All these factors may be particularly influential in patients with progressively worsening CKD, including those receiving chronic dialysis. The objective of our study is to determine the prevalence of Vitamin D deficiency in children with CKD stages three to five and those receiving chronic dialysis, to ascertain whether there is a relationship between Vitamin D deficiency and the stage of CKD, and to identify any clinical correlates associated with the Vitamin D status. A single-center, retrospective review was conducted of 46 children (younger than 18 years) with CKD stages 3–5D who attended the renal clinic of the Red Cross Children’s Hospital between October 2013 and November 2014. In total, 73.9% of the study population had suboptimal Vitamin D levels (43.5% and 30.4% had Vitamin D deficiency and insufficiency, respectively). The prevalence of Vitamin D deficiency was significantly higher in older children (≥10 years of age) than in younger children (P = 0.000) but did not significantly differ between males and females (P = 0.693). In total, 12 of 15 black children (80%), 19 of 26 colored children (73.1%), two of four white children (50%), and one Asian child (100%) had suboptimal Vitamin D levels.
Neither white nor Asian child had Vitamin D deficiency. In addition, 90% of patients undergoing chronic dialysis, 80% of whom were receiving peritoneal dialysis, had suboptimal Vitamin D levels. Age, weight, height, and the albumin concentration were significantly associated with the Vitamin D level. There was a positive linear relationship between the Vitamin D level and the serum albumin concentration (Spearman’s rho correlation coefficient = 0.397, P = 0.007). In total, 87.5% of patients with nephrotic-range proteinuria had suboptimal Vitamin D levels, and 80% were Vitamin D deficient (P = 0.004). A higher percentage of Vitamin D deficiency/insufficiency cases was documented during the winter (24/34, 70.6%) than during the summer (10/34, 29.4%); however, this difference was not statistically significant (P = 0.685). Sub-optimal Vitamin D is high among children with moderate to severe CKD and significantly higher in those undergoing chronic dialysis. The emerging evidence of the role of Vitamin D in slowing progression of CKD highlights the need for monitoring and correction of Vitamin D levels in predialysis children.
|How to cite this article:|
Solarin AU, Nourse P, Gajjar P. Vitamin D status of children with moderate to severe chronic Kidney Disease at a Tertiary Pediatric Center in Cape Town. Saudi J Kidney Dis Transpl 2019;30:781-94
|How to cite this URL:|
Solarin AU, Nourse P, Gajjar P. Vitamin D status of children with moderate to severe chronic Kidney Disease at a Tertiary Pediatric Center in Cape Town. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2020 Aug 10];30:781-94. Available from: http://www.sjkdt.org/text.asp?2019/30/4/781/265453
| Introduction|| |
Vitamin D deficiency is a global health problem affecting almost one billion people, particularly children,, with Vitamin D deficiency prevalence in infants, children, and adolescents remaining high globally. Vitamin D deficiency prevalence rates were 12.1% among healthy infants and toddlers at a clinic in an urban primary care and 24.1% among adolescents in an urban setting; another study reported rates of 0%–42%, noting the impact of season, latitude, and race. Vitamin D deficiency and insufficiency prevalence rates were 7% and 19%, respectively, in a study on Vitamin D levels among healthy 10-year olds in Johannesburg, South Africa.
Recent studies showed that Vitamin D deficiency was highly prevalent among adults and children with chronic kidney disease (CKD)., Furthermore, Vitamin D deficiency prevalence was high among children (20%–75%). Vitamin D deficiency incidence among adults on dialysis was approximately 97%, whereas that in adults not yet on dialysis (CKD stages three and four) was approximately 86%. In children with CKD, abnormalities in bone metabolism and structure are universal findings with progressing kidney failure.
In stage one and two CKD, serum 25- hydroxy-vitamin D [25(OH)D] levels start declining. The levels of enzyme 1-a hydroxylase, involved in 1,25-dihydroxyvitamin D [1,25 (OH)2D] synthesis from 25(OH)D in kidneys decrease with decreasing renal mass. This enzyme is highly dependent on 25(OH)D in patients with CKD, in whom reduced 25(OH)D substrate levels have an important role in 1,25 (OH) 2D deficiency., Studies have not elucidated on consistent associations of 25(OH)D with elevated parathyroid hormone (PTH) and decreased calcium levels despite the biologic role of 25(OH)D in CKD-associated mineral bone disorder.,,,
Vitamin D was recently reported to exert functions beyond its normal role in calcium and phosphate maintenance,,, including cell differentiation and proliferation in various settings.,,
In patients with CKD, 25(OH)D is involved in renin–angiotensin system (RAS) and nuclear factor (NF)-kB pathway regulation., RAS involves sequential activation of angio-tensin II, with a deleterious effect on blood pressure and vasculature, and contributes to renal parenchymal damage. Conversely, the NF-kB pathway is involved in immune response, inflammation, and fibrosis. Vitamin D inhibits NF-kB activation; studies have shown an indirect relationship between serum Vitamin D levels and tissue inflammation severity in different kidney diseases., These findings led to a shift in the management of patients with Vitamin D deficiency and CKD and contributed to a paradigm shift in Vitamin D replacement in patients with CKD, in whom Vitamin D therapy goes beyond secondary hyperparathyroidism treatment.,
Secondary hyperparathyroidism is associated with a moderate decrease in plasma 25(OH)D, whereas a severe decrease in 25(OH)D is associated with osteomalacia and increased osteoporosis risk, particularly in patients on hemo-dialysis (HD)., Secondary hyperparathyroidism severity increases with plasma 25(OH)D levels <15 ng/mL (37 nmol/L), particularly in patients on dialysis., Recent reviews also support secondary hyperparathyroidism in Vitamin D deficiency., Further evidence comes from a randomized control trial on ergocalciferol supplementation in children with CKD by Shroff et al, who found that this treatment delayed secondary hyperparathyroi-dism onset by effectively increasing 25(OH)D and decreasing PTH levels. Lack of an effect with ergocalciferol use in other randomized control trials led to a debate on the role of Vitamin D in secondary hyperparathyroidism and the effect of Vitamin D supplementation with ergocalciferol on PTH, which remains inconclusive.
The best indicator of Vitamin D levels is circulating 25(OH)D levels because there is no negative feedback required for the conversion of pre-Vitamin D metabolites into 25(OH)D. Furthermore, 25(OH)D is not stored in the liver and circulates in the plasma with a half-life of approximately three weeks. Vitamin D deficiency is widely defined as 25(OH)D levels <20 ng/mL., At levels lower than this, body stores are predicted to decline, with a concurrent increase in PTH levels to maintain normal calcium levels. Seasonal changes influence Vitamin D levels; significantly lower levels were documented during winter because of minimal ultraviolet-B radiation from sunlight in higher latitudes., In patients with CKD, 25(OH)D can be reduced due to several reasons including decreased sunlight exposure, reduced Vitamin D-rich food intake, increased Vitamin D-binding protein (VDBP) loss in patients with proteinuria, and 25(OH)D and VDBP loss in patients on dialysis., Furthermore, low-calcium diets can lead to reduced Vitamin D stores, and the resultant high PTH levels cause a rapid breakdown of 25(OH)D to unusable forms. When glomerular filtration rate of the patient falls to <50 mL/min/1.73 m2, the kidneys have reduced ability of converting 25(OH)D to 1,25(OH)2D.
The impetus for this study was based on the paucity of data on Vitamin D levels among patients with CKD in South Africa. Interestingly, most studies investigating Vitamin D and kidney disease included adults in temperate regions, whereas studies in our region did not focus on children with CKD. Cape Town is the third largest city in South Africa with three major ethnic groups: mixed race (colored), Black African, and Whites constituting 42.4%, 28.6%, and 15.7% of the population, respectively, with Asians and Indians constituting the remaining 1.4%. In this study, we determined the prevalence of vitamin D deficiency in children with stage 3–5 CKD and those on chronic dialysis and explored the relationship of Vitamin D deficiency with CKD stage to identify clinical correlates associated with Vitamin D status.
| Methods|| |
This study was done in children and adolescents <18 years of age who access our pediatric nephrology services at the Red Cross Children’s Hospital in Cape Town. Cape Town is located at latitude 33.55° South like Los Angeles in the north. Significant sunshine occurs between the months of November to April and was regarded as summer for this study while May to October was regarded as winter time because of the reduced sunshine during that period.
The study involved a retrospective folder review of all renal patients with an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 in CKD three to five and those on chronic dialysis between November 2013 and October 2014 and was approved by the Human Research Ethics Committee of the Faculty of Health Sciences of the University of Cape Town (HREC REF 180/2015). The requirement for consent was waived by the research ethics committee, and all data were deidentified before access and analysis. The criteria for exclusion in this study include absence of 25(OH)D result documented in the patient’s record and history of renal transplantation or renal cancer.
Anthropometric and other clinical parameters such as the blood pressure, urine protein or spot urine protein/creatinine ratio, information on primary and secondary causes of renal disease, medications, mode of dialysis as well as duration on dialysis were retrieved from the patient’s record. Laboratory investigation including calcium, phosphate, 25(OH)D, PTH, albumin, electrolytes, urea, and creatinine were retrieved from the electronic data system and documented in the study pro forma. In this study, 25(OH)D was documented as “Vitamin D”
Vitamin D levels were analyzed by the National Health Laboratory Services by chemiluminescent immunoassay. Vitamin D status was categorized as deficiency for levels <50 nmol/L, insufficiency for levels between 50 and 72.5 nmol/L, and sufficiency for levels >72.5 nmol/L. This classification is in accordance with the KDOQI guidelines. CKD staging was defined in accordance with the KDOQI Clinical Practice Guidelines for CKD, and GFR was estimated using the modified Schwartz formula. Creatinine at our hospital is determined by the enzymatic method. Proteinuria was defined as protein: creatinine ratio >0.02 g/mmol and nephrotic range proteinuria >0.2 g/mmol. Body mass index (BMI) z-scores were calculated using the Centers for Disease Control and Prevention (2000) Clinical Growth Charts.
None of the studied population were on ergocalciferol or cholecalciferol replacement at the time of review. However, most of our patients including all peritoneal dialysis (PD) patients were on multivitamins which contains 400 IU Vitamin D per 5 mL. All the patients on dialysis except one were on 1α Vitamin D. Forty-six patients who met the inclusion criteria over the period of the study (November 2013 to October 2014) were the study participants.
| Statistical Analysis|| |
Data were entered and analyzed using Statistical Package for Social Sciences (SPSS) version 20 (IBM Corp., Armonk, NY, USA). Percentages and frequency were used to represent categorical data while mean and standard deviations were determined for numerical variables. Independent Students’ test and one-way analysis of variance were used to compare means of two or more independent numerical variables. Chi-squared test (Fisher exact) was used to compare categorical variables. P <0.05 was considered significant. Charts including pie, bar, box pot, and scatter plot were used for data representation where appropriate.
| Results|| |
We evaluated forty-six pediatric patients in CKD stage 3 to 5D (22 boys, 24 girls; mean age of 9.0 ± 2.5 years); 14 of the 46 (30.4%) were on chronic dialysis (71.4% on PD, 28.6% on HD). All patients were of South African origin: blacks - 15 (32.6%), mixed race - 26 (56.5%), white - four (8.7%), and Asian - one (2.2%). The demographic characteristics of the studied population are shown in [Table 1]. Thirty of the 46 patients (65.2%) had a normal BMI (z score between -2 and 1). Wasting (z score below -3) and obesity (z score above 3) were documented in five (10.9%) and five (10.9%), respectively. Spectrum of renal disease of studied population include congenital anomalies of kidney and urinary tract in 57.8%, glomerular diseases such as nephrotic syndrome (17.8%), hemolytic uremic syndrome (13.3%), rapidly progressing glomerulonephritis (2.4%), and cystinosis (6.7%).
Vitamin D status
In this study population, 34 (73.9%) children had a serum 25(OH)D concentration below 72.5 nmol/L (29 ng/mL). In 20 of these patients (43.5%), 25(OH)D was <50 nmol/L (deficient), and in the other 14 (30.4%), it was between 50 and 72.5 nmol/L (insufficient). Twelve (26.1%) children were sufficient for Vitamin D [Figure 1]. The prevalence of Vitamin D deficiency was analyzed according to the CKD stages as shown in [Table 2]. Eight (40%) of patients in CKD 5D were Vitamin D deficient while five (35.7%) in CKD 3 were Vitamin D insufficient each accounting for the highest proportion, respectively. [Figure 2] is the boxplot of Vitamin D levels at the various stages of CKD. The lowest median was in CKD stage 5D. There was no significant sex effect on Vitamin D levels. In this study, nine (40.9%) male patients were deficient, and eight (36.4%) were insufficient for Vitamin D whereas 11 (45.8%) female patients were deficient and six (25.0%) were insufficient of Vitamin D (P = 0.693). When assessing Vitamin D level according to race, it was found that suboptimal Vitamin D levels occurred in 12 (80%) black patients, 19 (73.1%) mixed race patients, two (50%) white patients, and one (100%) Asian patient. There was no deficiency in any white or Asian patients whereas 46.7% of black and 50% of mixed race patients were deficient for Vitamin D.
|Figure 1: Pie chart showing proportion of patients with Vitamin D deficiency.|
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|Table 2: Prevalence of Vitamin D deficiency among the various stages of CKD.|
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The demographic and laboratory characteristics of the study population according to the CKD stage are as shown in [Table 3]. Systolic blood pressure, albumin, creatinine, urea, eGFR, PTH, calcium, magnesium, phosphate, transferrin, and ferritin were significantly different between the CKD groups (P <0.05). Age, weight, height, diastolic BP, and albumin were significantly different between patients with deficiency, insufficiency, and sufficiency of Vitamin D (P <0.05) [Table 4].
|Table 3: Demographic and laboratory characteristics according to CKD stages.|
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Among patients on chronic dialysis, eight out of the 10 (80%) patients on peritoneal dialysis had Vitamin D deficiency. One patient on peritoneal dialysis had Vitamin D insufficiency and another had Vitamin D sufficiency while two patients each on HD had Vitamin D insufficiency and sufficiency, respectively, and none had Vitamin D deficiency (P = 0.021). Eighteen out of the 46 patients had proteinuria, and of the 18, 14 (77.8%) had subnormal Vitamin D levels compared to four (22.2%) with normal Vitamin D levels (P = 0.047). Ten patients with proteinuria had Vitamin D deficiency; eight of them (80%) were in the nephrotic range. In addition, all the patients with proteinuria with Vitamin D insufficiency were in the nephrotic range four (100%), and of the four patients with Vitamin D sufficiency, two (50%) were in the nephrotic range (P = 0.228). Eleven (78.6%) of 14 patients on chronic dialysis had Vitamin D deficiency/ insufficiency compared to 22 (68.7%) of 32 children in the predialysis group (P = 0.446).
The patients were categorized into two age groups – <10 years of age and greater than 10 years of age [Figure 3]. Ten out of 26 (38.46%) of those <10 years of age were Vitamin D insufficient compared to four out of 20 (20%) of those >10 years of age. 13 (65%) of those >10 years had Vitamin D deficiency compared to seven (26.92%) of those <10 years (P = 0.035).
|Figure 3: Bar chart showing Vitamin D status according to age group.|
χ2 = 6.703, P = 0.035
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Patients were further categorized based on their PTH. 8.3% of patients with normal Vitamin D had a PTH level appropriate for the CKD stage, 66.7% of patients with normal Vitamin D had PTH above CKD stage while 25% had PTH below the CKD stage. Among patients with subnormal Vitamin D level, 17.6% of patients had a PTH level appropriate for the stage of CKD whereas 58.8% of these patients had a PTH level higher than expected for the stage of CKD and 23.6% had a PTH level below the expected for the stage of CKD.
Among patients with PTH above the expected value for CKD level, the percentage with low Vitamin D, i.e., 20 (71.4%) was significantly higher than those with normal Vitamin D, i.e., eight (28.6%) (P = 0.040).
1α Vitamin D was used by patients in all the stages of CKD. Five out of 14 (35.7%) in stage 3, eight out of 10 (80%) for CKD stage 4, eight out of eight (100%) in CKD stage 5, and 13 out of 14 (92.9%) in CKD stage 5D. When patients on 1α Vitamin D were compared to those who were not on 1 a Vitamin D for the CKD staging, there was significant difference (χ2 = 17.343, P = 0.001).
We compared whether the season during which the Vitamin D level was taken had an influence on the result. Of the 20 patients who were Vitamin D deficient, 14 (70%) of these were in the winter months and six (30%) in the summer months. Of the 14 patients who were insufficient for Vitamin D, 10 (41.7%) of these were during the winter months and four (40%) were during the summer months (P = 0.685). Twenty-four (70.6%) had suboptimal Vitamin D levels during the winter season and 10 (83.3%) during the summer, and this was not statistically significant (P = 0.387) [Figure 4].
Albumin had a weak positive or direct correlation with Vitamin D level and was statistically significant [Figure 5] (r = 0.400, P <0.05). Protein/creatinine ratio, calcium and phosphate product in CKD 5 and 5D, and duration of dialysis had a weak negative correlation. These were not statistically significant.
|Figure 5: Relationship between Vitamin D and albumin.|
Spearman rho correlation coefficient = 0.400, P = 0.007.
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| Discussion|| |
Our findings demonstrate a high prevalence of suboptimal Vitamin D levels among pediatric patients with moderate to severe CKD including those on chronic dialysis. In addition, low Vitamin D levels were more prevalent in the older children as well as those on peritoneal dialysis.
The prevalence rates of Vitamin D deficiency and insufficiency found in this study are comparable with other hospital-based studies in Michigan, Miami, New Delhi, and Saudi Arabia. Higher Vitamin D deficiency was noted in the CKD stage 4-5D (severe) compared to stage 3 (moderate). This was similar to Seeherunvong et al but in contrast to another study. Kumar et al studied a cohort population of children in CKD stage 1 to 3 longitudinally over a six year period and found 28% deficient at recruitment, 23% deficient two and four years after, and 28% six years after enrollment. Seeherunvong et al showed that 60% of patients had reduced (<75 nmol/L) 25(OH)D concentrations, and 28% of patients had a 25(OH) D level<50 nmol/L. Patients with CKD stages 3 to 5D had a higher prevalence (42%) of Vitamin D deficiency compared to those patients with a mild/moderately reduced or normal eGFR (26%).
In our patients on chronic dialysis, prevalence of Vitamin D deficiency/insufficiency was noted to be high, similar to other pediatric,, as well as in adults., Among our patients on PD, we documented that 90% had subnormal levels of Vitamin D with 80% of them being deficient for Vitamin D. This rate of deficiency is similar to other studies done in children and adults on dialysis.,
The Vitamin D status was not affected by gender which is different from previous studies. Many previous studies have noted lower Vitamin D levels in non-white patients.,,, In our study, the black and mixed race (colored) patients also had lower Vitamin D levels than in the white patients. Because of the low number of white patients in our study, it is not possible to be sure about the veracity of this finding. Circulating Vitamin D is bound to vitamin D binding protein (DBP) (80%–90%) and albumin (10–15%), with <1% existing in a free, unbound form; free and albumin bound Vitamin D constitute the bioavailable 25(OH)D. In healthy black adults as well as black children with CKD, total 25(OH)D and DBP levels were reported to be lower than in whites, but the bioavailability was similar between the groups., In the CKiD study which is a registry that collects data on children in North America with mild to moderate renal failure, it was found that non-white children had a higher prevalence of Vitamin D deficiency than the white children. The conclusion in this study, however, was that this may not correspond to lower bioavailable Vitamin D.
Reports of age-related Vitamin D deficiency vary, with some studies showing a decreased level in older children, and some not., In our study, low Vitamin D levels were significantly more common in the older age group. It is unclear what the reasons for this are as there are no clear differences in severity of renal disease or other factors such as dietary restrictions or the time spent outdoors between the older and younger children.
We observed that the form of dialysis may be contributory to low levels of Vitamin D. Our patients on PD had significantly lower levels of Vitamin D compared to those on HD. A plausible reason is the loss of VDBP through the peritoneal fluid in patients on PD. A recent study in children on chronic PD demonstrated that losses of VDBP were reflective of both dialysate albumin and urinary albumin losses (in those who were proteinuric) and were associated with longer dialysis vintage. In contrary, Prytula et al observed that peritoneal VDBP losses do not contribute to Vitamin D deficiency in children on PD.
In our patients, low Vitamin D levels were associated with time on dialysis. This is probably due to the known association with time on dialysis and poor nutrition.
We found a significant positive correlation between Vitamin D and albumin. This was noted by Cho et al in their study of pediatric patients on dialysis as well as other studies., A possible explanation for this is that poor nutrition may cause a low albumin level as well as poor Vitamin D intake. Patients with poor nutrition may also have low levels of VDBP, further contributing to low serum Vitamin D levels.,,,, The low serum albumin can readily be explained by the contributory effect of inflammation on protein energy wasting in the face of protein calorie restriction. Low levels of Vitamin D enhance the process of inflammation through the NF- kB pathway.
The inverse relationship between Vitamin D and proteinuria observed in our study is similar to findings from another study. In one study, proteinuria correlated with both serum VDBP and loss of VDBP in the urine supporting the suggestion of a possible link between low Vitamin D and proteinuria.
We observed that patients who had PTH above expected for their CKD levels were more Vitamin D deficient. The mean PTH values increased with increasing CKD stage. We did not however observe any significant inverse correlation between Vitamin D and PTH, similar to findings of Alonso et al. Many studies have documented significant inverse relationship between PTH with Vitamin D levels.,,, There are many factors affecting PTH, and it could be that in our study, the numbers were too low to detect a signal.
Our patients routinely are on multivitamin which contains 400 IU of Vitamin D. Regardless of this, we still had significantly high rate of suboptimal Vitamin D levels, especially those on dialysis. Our finding was in contrast with the findings in another study. The study noted Vitamin D supplementation rate was low at 8% and further noted an association between lack of supplementation and low 25(OH)D.
In our study, the prevalence of Vitamin D deficiency was high in both seasons (winter and summer). However, the prevalence was higher in summer than in winter, but this was not statistically significant. This may be because the population studied in summer were fewer and better clustered around the interquartile range than the winter group. Pettifor et al in their study assessed the effect of season and latitude on Vitamin D formation by sunlight in two South African cities – Cape Town and Johannesburg and documented a significant difference in season for Vitamin D3 production in Cape Town with very little Vitamin D formed during winter. The CKiD cohort study also reported that the season during which blood samples were taken predicted Vitamin D deficiency. 25(OH)D levels measured in winter were fivefold more likely to be deficient than those measured in summer. This has been a consistent finding in studies of healthy controls as well as in those with CKD.,,
We had limitations to this study. It was a single-center study; although the center is a major referral place for specialized pediatric renal care, our sample size was small, and it may be difficult to generalize our findings to the whole South African population. The study focus was on CKD 3–5D. Those in CKD 1 and 2 were not included, and they may well have subnormal Vitamin D levels. A longitudinal study assessing Vitamin D levels and the effect of replacement is warranted.
In summary, suboptimal Vitamin D levels are prevalent in children with CKD, especially those on chronic dialysis. It was significantly associated with older age and albumin. An inverse relationship exists with duration of dialysis and proteinuria.
In view of the recent study by Shroff et al that have shown that Vitamin D supplementation may slow the progression of CKD, and our documented low levels of Vitamin D, it is advisable that all patients with CKD have Vitamin D levels measured yearly, and all with suboptimal levels should be corrected.
| Acknowledgment|| |
We acknowledge the nurses and doctors in E2 ward of the Red Cross Children’s Hospital for their support and love during the training programme, especially Dr. Lynn for her help in data collection. The training would not have been possible in the first place (during which this study was conducted) without the support of International Society of Nephrology and International Pediatric Nephrology Association.
Conflict of interest: None declared.
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Adaobi Uzoamaka Solarin
Department of Pediatrics, Lagos State University Teaching Hospital, Ikeja Lagos, Lagos
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4]