Evaluation and risk factors of microalbuminuria in children with type 1 diabetes in Aswan University Hospital: a hospital-based study

Magda F Gabri; Ashraf A Meabed; Treza S Abdelshahid; Hanan M Ali; Eslam M Fathy; Edrees H Zaki

doi:10.4103/jesnt.jesnt_8_22

ORIGINAL ARTICLE

Year : 2022 | Volume : 22 | Issue : 4 | Page : 200-208

Evaluation and risk factors of microalbuminuria in children with type 1 diabetes in Aswan University Hospital: a hospital-based study

Magda F Gabri¹, Ashraf A Meabed¹, Treza S Abdelshahid¹, Hanan M Ali¹, Eslam M Fathy², Edrees H Zaki³
¹ Department of Paediatric, Faculty of Medicine, Aswan University, Aswan, Egypt
² Department of Clinical Pathology, Faculty of Medicine, Aswan University, Aswan, Egypt
³ Department of Paediatric, Faculty of Medicine, Assiut University, Assiut, Egypt

Date of Submission	17-Feb-2022
Date of Acceptance	09-Jun-2022
Date of Web Publication	22-Sep-2022

Correspondence Address:
Dr. Magda F Gabri
Department of Pediatrics, Faculty of Medicine, Aswan University, Aswan, New Aswan City 81528
Egypt

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jesnt.jesnt_8_22

Abstract

Background Diabetic nephropathy is the major complication of diabetes and is one of the leading causes of end-stage renal disease. Early identification of nephropathy is crucial to slow down this process. Assessment of albuminuria is used as an early clinical marker for impaired kidney function. The aim of this study is to evaluate the magnitude of microalbuminuria (MA) in children with type 1 diabetes and determine the factors correlated to it. Patients and methods A cohort study that was carried out on diabetic children attained the endocrinology clinic in our hospital from August 2019 to October 2020. Children aged 6–18 years old with a history of 2 years of diabetes were subjected to history, examination, and investigation, including urea, creatinine, lipid profile, hemoglobin A1c, and 24-h urinary albumin were done twice. Statistical analysis used χ², Fisher exact, and independent Wilcoxon t test for comparison between groups. Spearman and Pearson’s for correlations. Results The median (interquartile range) of MA in the first visit was 10 mg/24 h (6.15–20 mg/24 h) in the first visit versus 9.5 mg/24 h (4.9–23.55 mg/24 h) in the second visit, with an insignificant P value. The abnormal numbers of hemoglobin A1c in the first visit were 85.7 and 79.3% in the second visit; P value is 0.350. Children with abnormal MA were 13.2% in the first visit versus 20% in the second visit with only four patients having persistent MA. MA was positively correlated to the Tanner stage in the first visit to blood pressure, serum triglyceride, and Tanner stage in the second visit, and negatively correlated to high-density lipoprotein. Conclusion Most of our patients had uncontrolled diabetes with an increasing prevalence of MA over time.

Keywords: microalbuminuria, nephropathy, type 1 diabetes mellitus

How to cite this article:
Gabri MF, Meabed AA, Abdelshahid TS, Ali HM, Fathy EM, Zaki EH. Evaluation and risk factors of microalbuminuria in children with type 1 diabetes in Aswan University Hospital: a hospital-based study. J Egypt Soc Nephrol Transplant 2022;22:200-8

How to cite this URL:
Gabri MF, Meabed AA, Abdelshahid TS, Ali HM, Fathy EM, Zaki EH. Evaluation and risk factors of microalbuminuria in children with type 1 diabetes in Aswan University Hospital: a hospital-based study. J Egypt Soc Nephrol Transplant [serial online] 2022 [cited 2023 Jun 8];22:200-8. Available from: http://www.jesnt.eg.net/text.asp?2022/22/4/200/356692

Introduction

Diabetes mellitus (DM) is a serious, long-term condition in which blood glucose levels rise due to the body’s inability to produce enough insulin or to use it effectively [1]. Over the long term, damage to many of the body’s organs leads to disabling and life-threatening health complications. However, if proper management of diabetes is achieved, these serious complications can be delayed or prevented altogether [2].

Diabetic nephropathy is the major complication of diabetes and is one of the leading causes of end-stage renal disease (ESRD) worldwide. Early identification of nephropathy in diabetic patients is crucial to slowing down this process or preventing the occurrence of diabetic nephropathy [3]. Assessment of albuminuria is used as an early clinical marker for impaired kidney function that occurs in most glomerulopathies. It is very well known that the presence of albuminuria is associated with a poor prognosis for ESRD [4].

So, our study aimed to evaluate the magnitude of microalbuminuria (MA) in children with type 1 diabetes mellitus (T1DM) to prevent the conversion of MA to ESRD and determine factors correlated to it, such as anthropometric measurements, Tanner stage (TS), blood pressure (BP), glycemic control, kidney function, and lipid profile.

Patients and methods

This prospective cohort study was conducted on diabetic children who attended the endocrinology outpatient clinic in our hospital for regular follow-up from August 2019 to October 2020. 98 diabetic children were enrolled in the first visit. Only 80 of them came in the second visit for follow up.

Methods

All diabetic children were subjected to history taking, physical examination including anthropometric measurements and TS, and laboratory investigation including urea, creatinine, low-density lipoprotein (LDL), high-density lipoprotein (HDL), cholesterol, hemoglobin A1c (HbA1c), and 24-h urinary albumin. These measures were taken twice; the first time they attained follow-up and the second time after 6 months.

Measurement of blood pressure

Arterial BP was measured on the right arm with a standard clinical sphygmomanometer after the patient had been sitting for 10 min. For children between 1 and 13 years of age, elevated BP (previously referred to as prehypertension) is defined as systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) more than or equal to 90th percentile or 120/80 mmHg but less than 95th percentile. Stage 1 hypertension is defined as SBP and/or DBP ranging from the 95th percentile to the 95th percentile+12 mmHg, or 130/80–139/89 mmHg (whichever is lower). In children under 13 years old, elevated BP is defined as an SBP of between 120 and 129 with a DBP of 80 mmHg, and stage 1 hypertension is defined as a BP of 130/80–139/89 mmHg [5].

TS, also known as sexual maturity rating, is an objective classification system that providers use to document and track the development and sequence of secondary sex characteristics of children during puberty. It was developed by Marshall and Tanner while conducting a longitudinal study from the 1940s to the 1960s in England. TS1 is pre-pubertal in males, with testicular volumes of less than 4 ml, a thick and corrugated scrotum, and an immature penis. By TS2, coarse, sex-steroid-dependent hair has appeared on the pubis, but it is sparse and does not typically meet in the midline. The penis remains immature, but scrotal thinning and testicular enlargement have begun. TS3 is characterized by pubic hair meeting at the midline and beginning penis growth, predominantly in length. At TS4, the pubic hair growth is dense and continuous but has not yet reached a full adult pattern, and the penis has enlarged in both length and circumference. TS5 is that of full adult development. For females, the descriptions are like those for male pubic hair growth, but normal breast development progression follows. Stage 1 is the normal prepubertal state. Tender ‘buds’ are felt and seen at stage 2, and stage 3 is characterized by further development of the breast tissue well beyond the areolar diameter and incomplete nipple development. Stage 4 is easily recognized by the secondary elevation of the areola above the contour of the breast, and by stage 5, this areolar elevation recedes to the plane of the surrounding breast [6].

Blood sample

Two blood samples were drawn from the cases; the first was a fasting blood sample (3 ml) collected between 7 and 9 a.m. by a trained pediatric nurse. HbA1c was measured by high-performance liquid chromatography (Bio-Rad, Munchen, Germany). The second blood sample (3 ml) was drawn from the child for urea, creatinine, and lipid profile, and the analyses were performed with the BT3500 biochemistry autoanalyzer [7]. The reference ranges for HbA1c levels are as follows: HbA1c (4–5.7%) is normal in adults and children who do not have diabetes. HbA1c less than 7% indicates good diabetic control; HbA1c 8–9% indicates fair diabetic control; and HbA1c greater than 9% indicates poor diabetic control. Abnormal values were as follows: blood urea nitrogen greater than 20 mg/dl, serum creatinine greater than 1.06 mg/dl, serum cholesterol greater than 200 mg/dl, HDL less than 30 mg/dl, LDL greater than 135 mg/dl, and triglycerides greater than 150 mg/dl.

The method of microalbuminuria

Patients were asked to collect two 24-h urine samples. They received oral and written instructions on how to collect 24-h urine samples. They then asked that urine samples to be stored in the refrigerator, that urine collections be postponed in the event of a urinary tract infection or menstruation, and that heavy exercise be avoided as much as possible during collection. We assessed urinary albumin concentrations by nephelometry and by high-performance liquid chromatography (BT3500 Biochemistry Autoanalyzer). According to the ADA, in the 24-h collection technique, albumin excretion less than 30 mg/24 h is considered normal; 30–299 mg/24 h indicates MA; and 300 mg or higher indicates macroalbuminuria [8].

Statistical analysis

Statistical analysis was performed with IBM SPSS Statistics, version 26 for Windows (IBM Inc, Chicago, IL, USA). A summary of measures was reported as mean±SD for quantitative variables such as age and weight, while categorical variables such as sex and TS were represented as percentages. An independent Wilcoxon t test analyzed a comparison between two quantitative data sets. The χ² test and Fisher’s exact test were used to compare between categorical variables. For nonparametric and parametric data, Spearman’s and Pearson’s correlations were used to analyze the correlation between different parameters within the combined groups. A two-tailed P value of 0.05 was considered statistically significant.

Results

Sociodemographic data (as shown in [Table 1]) of the studied cases revealed that the mean age of them was 14.17 ± 3.514 years on the first visit and 14.65 ± 3.89 years on the second visit; 45.9 and 45.1% of children were males on the first and second visit, respectively. There was a positive family history in 27.5 and 30.5% of cases in the first and second visit, and disease duration was 6.482 ± 2.8751 years in the first visit versus 6.77 ± 3.11 years in the second visit. Of our patients, 62.2% were from Aswan city, while 37.8% were from Aswan cities and villages as shown in [Fig. 1]. The type of insulin treatment used in the studied cases as shown in [Fig. 2] revealed that most children use the basal-bolus regimen as 60.2% use Humulin R/Glargine, while the remaining children use another combination except seven (7.1%) children used Mixtard and only one child use glargine alone. TS of a studied group ([Fig. 3]) showed that 37.1% of cases were stage 0 and 41.2% were stage 5.

Table 1: Sociodemographic data of studied cases

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Figure 1: Distribution of diabetic children in Aswan government.

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Figure 2: Type of insulin treatment used in studied cases.

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Figure 3: Tanner stage of studied cases.

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Most of our patients had abnormal urine analysis ([Fig. 4]) in which 47% of patients had glucose in urine analysis. Only 44% of patients had normal urine analysis on the first visit, compared with 30% on the second visit.

Figure 4: Urine analysis results of studied cases.

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Regarding the comparison of anthropometric measurements and BP of studied cases between the first and second visit ([Table 2]), there was a significant increase in weight and height but not in BMI after 6 months of follow-up. Laboratory investigations of the studied cases revealed that the mean±SD of HbA1c in the first visit was 10.9 ± 2.27% and 10.56 ± 2.29% in the second visit, with an insignificant P value. The median (interquartile range) of MA in the first visit was 10 mg/24 h (6.15–20 mg/24 h) in the first visit versus 9.5 mg/24 h (4.9–23.55 mg/24 h) in the second visit, with an insignificant P value.

Table 2: Comparison between first visit and second visit of anthropometric measurement and blood pressure of studied cases

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The abnormal numbers of HbA1c in the first visit were 85.7 and 79.3% in the second visit. The P value was 0.350. Children with abnormal blood urea were 57.1% in the first visit in contrast to 31.7% in the second visit, with a highly significant P value of 0.001. Children with abnormal serum creatinine were 7.1% in the first visit, in contrast to 3.7% in the second visit, with an insignificant P value. Children with abnormal serum cholesterol were 18.4% in the first visit in contrast to 22% in the second visit, with an insignificant P value. Children with abnormal serum triglycerides were 14.3% in the first visit, in contrast to 22% in the second visit, with an insignificant P value. Children with abnormal LDL were 11.2% in the first visit, in contrast to 18.3% in the second visit, with an insignificant P value. None of the children had abnormal HDL in the first visit, in contrast to 4.9% in the second visit, with an insignificant P value. Children with abnormal MA were 13.26% in the first visit versus 20% in the second visit, with only four patients having persistent MA. Two of them had macroalbuminuria and an insignificant P value ([Table 3]).

Table 3: Comparison between first visit and second visit of laboratory investigations of studied cases

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In the first visit, MA was positively correlated to TS, while in the second visit, it was negatively correlated to HDL and positively correlated to BP (systolic and diastolic), serum triglyceride, and TS ([Table 4]).

Table 4: Correlation of microalbuminuria and all studied parameters of studied cases in both visits

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Discussion

T1DM is a chronic disease that must be managed properly to avoid short-term and long-term complications [9]. In some areas, diabetic nephropathy is the most common cause of end-stage renal failure worldwide, accounting for more than half of all patients on renal replacement therapy. The condition is common in people with both type 1 and type 2 diabetes, although the incidence seems to be declining, especially in type 1 diabetes. Advances in our understanding of the pathogenesis and natural history of the condition have enabled us to consider earlier therapy aimed at renal preservation and reduction in cardiovascular morbidity.

MA is an early sign of diabetic renal disease. It occurs before persistent proteinuria and is a stage of diabetic nephropathy that may be reversible [10]. It has been identified as the initial risk factor for nephropathy in people with type 1 diabetes [11]. In adolescents with MA, careful monitoring and adequate intervention should be emphasized to prevent rapid progression toward diabetic nephropathy [12].

Most of our patients had poor glycemic control, as more than 85% had HbA1c more than 9% in the first visit versus 79.3% in the second one, and the level reached up to 17% in some patients. This agreed with Omar et al. [13]. They said that 67.5% of their cases had poor glycemic control, and Zurita Cruz et al. [14] reported that HbA1c levels of 8% occurred in 56% of their patients in the first year after diagnosis, and this increased to 64% in the second year. This was higher than previously reported from Egypt. Mohammad et al. [15] reported that children with poor glycemic control made up 45.8% of their cases, and Aljuhani et al. [16] reported 43.2% of their patients had poor metabolic control, with HbA1c levels averaging 9.15% in their patients. In an Iranian study, it was shown that poor glycemic control was seen in 82.7% of the patients [17].

The prevalence of early nephropathy, as shown by elevated 24-h protein in urine among children and adolescents with T1DM, varies widely between different studies. Our study showed that 13.26% of children had MA in the first visit and increased to 20% in the second visit. This was higher than the average reported by the ADA [18]. Many other studies have shown a higher degree of MA than our results. Omar et al. [13] said that 77.5% of their cases had early nephropathy. In an Iranian study, MA occurred in 34.6% of 81 diabetic children and adolescents [17]. Cobas et al. [19] stated in their prospective study that 41% of their patients with T1DM developed MA after an 11-year duration of diabetes and 5.9 years of follow-up. In the United Kingdom, Cizmecioğlu et al. [20] showed that MA occurred in 9% of the population; however, less developed countries reported higher figures. In a study in Iraq, MA occurred in 41.4% of patients [21]. In a Danish study, the prevalence was 13% [22]. As the earlier figures showed, the variation is wide and may be related mainly to the degree of diabetes control as it is affected by education, socioeconomic status, and the influence of race and ethnicity. Diabetic nephropathy due to T1DM is still a disease involving a heavy burden of morbidity and mortality and is difficult to manage in a developing country because of the low socioeconomic level of patients and the lack of reliable epidemiological data [23].

In our study, we measured the frequency of persistent MA as we measured MA in two consecutive urine samples at a 6-month interval, which therefore excluded the transient form of MA, whereas in other studies, like Atiya et al. [21], they measured the MA in a spot urine sample, and this cannot differentiate between transient and persistent forms of MA.

Most of our patients were adolescents, with a wide range of 2–15 years of disease duration. More than half of our patients were female (54%), which is similar to Zurita Cruz et al. [14] and Lee et al. [24] who reported that 54 and 51.5% of their patients were female, respectively. In contrast, Hassan et al. [25] and Aljuhani et al. [16] reported a slight male predominance (50.1 and 56.8%, respectively) among diabetic children. In our study, family history was positive in 27.6 and 30.5% of cases in the first and second visits, respectively, which is like Lee et al. [24], who reported a positive family history in 28.8% of their cases.

Most of our patients were at Tanner stage 5 (full mature sexual development), but more than one-third of our patients had immature sexual development (at Tanner stage 0). This may be due to most of our patients being adolescents. Zurita Cruz et al. [14] reported that 50% of their patients were prepubertal, and only 5% had reached TS4.

Hypertension is an adaptable risk factor that hastens the onset of microvascular and macrovascular problems [18]. According to Gross et al. [26], the development and progression of MA is closely linked to hypertension. In our study, there was a significant positive correlation between MA and BP (systolic and diastolic). Omar et al. [13] found that SBP and DBP did not significantly differ between cases with and without MA.

Numerous studies have revealed conflicting results; some of these studies did not show any significant role of BP on MA [27], while others have revealed that high BP, especially diastolic pressure, is one of the important predictors of developing MA. BP may only rise in conjunction with the development of MA, either immediately before or after, and hence is only a short-term risk factor. Another theory is that the early changes in BP are so minor that they are undetectable with baseline office measures, necessitating 24-h ambulatory BP monitoring to prove their presence [28]. The link between MA and BP, on the other hand, is still debatable. It might be argued that in children with type 1 diabetes, BP is not a significant initiating factor for MA [29]. The varied methods used to measure BP, especially in children, may possibly be a factor in contradictory results.

In our study, the percentage of children with abnormal blood urea in the first visit was higher than that in the second visit, with a highly significant P value of 0.001. This may be explained on the basis of time of visit. The first visit was in summer, and the very high temperature in our city at that time resulted in dehydration for many people, and children are more susceptible to this, especially in the presence of chronic diseases like DM, but the second visit was in winter and spring, where the temperature returned to its normal value.

This study discovered a substantial positive connection between MA and TS. Earlier studies have yielded inconsistent findings as to whether nephropathy in T1DM progresses more slowly before puberty than thereafter, but these studies have generally been limited to later stages of progression (i.e. after the development of albuminuria) and have suffered from several important methodologic limitations. Drummond et al. [30] in their results suggest that it is the total duration of disease, rather than the duration before or after puberty, which affects the rate of progression of the glomerular basement membrane and mesangial lesions characteristic of diabetic nephropathy.

A small proportion of our patients had abnormal lipid profiles, and there was a significant negative correlation between MA and HDL and a significant positive correlation between MA and serum triglyceride. According to Cobas et al. [19], the only independent indicators related to the development of MA were BMI and the cholesterol/HDL ratio in their patients. Higher levels of HDL have been shown to protect against the development of albuminuria in long-term type 1 diabetic patients [31]. Type 1 diabetic patients were sometimes predisposed to the early development of atherosclerosis even when their plasma HDL cholesterol levels were normal or slightly elevated due to the loss of HDL’s ability to protect arteries from the inhibition of endothelium-dependent relaxation induced by oxidized-LDL [32] total cholesterol, and LDL cholesterol [33].

Diabetic nephropathy is linked to cardiovascular disease, and dyslipidemia is thought to be a risk factor for both. Furthermore, cholesterol levels rise as diabetic nephropathy progresses and are directly correlated with the rate of glomerular filtration rate decline [34]. Low-grade inflammation and oxidative stress, the hallmarks of metabolic syndrome linked with insulin resistance, which tend to increase with disease progression [35], have been demonstrated to be risk factors for overt nephropathy and renal injury [36]. In vitro, patients with T1DM are more vulnerable to LDL oxidation and have higher levels of acute-phase proteins than nondiabetic patients [37].

This study found an insignificant positive correlation in the first visit and an insignificant negative correlation in the second visit between MA and HbA1c. In an Iranian study, there was no correlation between MA and HbA1c [17]. Chae et al. [38] showed that the mean HbA1c levels were significantly higher in the MA group than in the normal albuminuria group, suggesting that the incidence of diabetic nephropathy increases according to the degree of glycemic control. Omar et al. [13] showed that poor glycemic control was associated with a higher proportion of nephropathy, and it was more evident in the adolescent age group as 93.3% of those with poor glycemic control had an abnormal albumin/creatinine ratio compared with 20% of those with good glycemic control (P=0.001).

In this study, there was an insignificant correlation between MA and disease duration; this is the same as Basiratnia et al. [17], while Chae et al. [38] observed that the duration of diabetes was significantly higher in the MA group. Omar et al. [13] showed that the highest proportion of cases with nephropathy was found when the duration of diabetes was more than 10 years. However, the differences among the groups were not statistically significant. This insignificant correlation between MA and the duration of DM in our study may be explained by the fact that the mean duration of DM in this study was 6.91 ± 3.12 years, which may be considered a short time to develop nephropathy. Alleyn et al. [39] found 23% of their patients had MA in one urine sample in a disease duration of 5.6 ± 3 years and 40% of them had persistent MA in the 2-year period. They concluded that there were no significant differences in the rates of persistent MA across the diabetes duration groups when all young people aged 8–18 years were analyzed together. However, the duration of T1DM was significantly related to persistent MA in older individuals but not in the younger children. According to Lampropoulou et al. [40], age and diabetes duration of more than 10 years are well-known risk factors for diabetic nephropathy development.

Our study has shown no correlation between MA and sex or family history. In univariate analysis, Kiconco et al. [41] discovered an association between sex and family history of DM and MA; however, only the family history of DM remained statistically significant in multivariate analysis. According to Lin et al. [42], it was shown to be common in males.

Conclusion

Our study found that the incidence of MA in children with T1DM was 13.26%, which increased to 20% in the second visit with an insignificant P value. MA was positively correlated to TS, BP (systolic and diastolic), and serum triglycerides, while there was a significant negative correlation between MA and HDL.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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