Childhood Diabetes Mellitus And Early-onset Kidney Diseases Later in Life: A Nationwide Population-based Matched Cohort Study

Abstract Background: The empirical evidence remains inconclusive for an association between diabetes mellitus (DM) in children and early-onset kidney disease later in life, and little is known about the effects of DM types (i.e., type 1 diabetes [T1DM] and type 2 diabetes [T2DM]) in childhood on type-specific kidney diseases. We aimed to evaluate the association of childhood DM with overall and type-specific early-onset kidney diseases later in life.

Methods: The population-based matched cohort study included 9356 individuals with DM (T1DM: 8470, T2DM: 886) diagnosed in childhood (<18 years) who were born between 1977 and 2016, and 93,560 individuals without DM matched on sex and year of birth in Denmark. The main outcomes were overall and type-specific early-onset kidney diseases. The follow-up period of all included participants was from the date of DM diagnosis in the exposure group until the first diagnosis of kidney disease, emigration, or 31 December 2018, whichever came first. 

Results: During a median follow-up of 13 years, children with DM had a 154% increased risk of early-onset kidney diseases than children without DM (adjusted hazard ratios 2.54, 95% confidence intervals 2.38–2.72), and T1DM (2.48, 2.31–2.67) and T2DM (2.75, 2.28–3.31) showed similar results. Children with DM also had a higher risk of multiple specific kidney diseases including glomerular diseases, renal tubulointerstitial diseases, renal failure, and urolithiasis. The risks of type-specific kidney diseases including glomerular diseases and renal failure tended to be higher for children with T2DM (glomerular diseases: 5.84, 3.69–9.24; renal failure: 14.77, 8.53–25.59) than those with T1DM (glomerular diseases: 3.14, 2.57–3.83; renal failure: 8.24, 6.66–10.20). 

Conclusions: Children with DM had a higher increased risk of early-onset overall and specific kidney diseases later in life. Early prevention and treatment of both T1DM and T2DM in childhood may significantly reduce the risk of kidney diseases later in life. 

Keywords: Diabetes mellitus, Kidney disease, Childhood, Adulthood

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Background

Diabetes mellitus (DM) is one of the leading chronic medical disorders among children and adolescents [1]. The prevalence of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) during childhood has been increasing worldwide [2–4]. An annual increase of 3.4% in the prevalence of T1DM between 1989 and 2013 was reported among European children under 14  years [3]. In the USA, the prevalence of T2DM among those aged<19  years increased from 1.48 per 1000 youths in 2001 to 2.15 in 2017 [5]. In Denmark, the prevalence of T1DM has been increasing in childhood from 0.20 per 1000 person-years in 1996 to 0.35 per 1000 person-years in 2016 [6]. Although the prevalence of T2DM among Danish youth in 2014 was 0.6 per 100,000 inhabitants, T2DM was highly associated with overweight and obesity which has a signifcant increase in Danish youth [7, 8]. DM in children and adolescents poses a major public health burden and clinical challenges to pediatric and adult DM services [1, 9].

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Youth-onset T2DM may cause longer exposure to the adverse effects of hyperglycemia than DM diagnosed in adulthood, thus leading to higher odds of progression to short-term and long-term detrimental complications, such as kidney lesions and cardiovascular diseases [10, 11]. Although several studies have suggested an association between DM (T1DM or T2DM) in children and early-onset kidney disease later in life, the empirical evidence remains inconclusive due to a relatively small number of DM cases, the representation of participants only recruited from diabetes centers, cross-sectional study design, and crude definition of nephropathy defined only according to the presence of microalbuminuria [12–20]. Besides, limited research on type-specific kidney diseases mainly focused on renal failure [15] and several studies have addressed end-stage renal disease in particular [19, 21–27]. However, the findings on the association between the ages of diagnosis of DM (5–9 years vs. 10–14 years) and rate of end-stage renal disease were inconsistent [19, 23, 24]. Moreover, little is known about the effects of DM types in childhood on other type-specific kidney diseases, such as glomerular diseases and renal tubulointerstitial diseases later in life, particularly taking into consideration the age of DM diagnosis, sex, and duration of DM. A better understanding of such association is imperative to prevent and control subsequent adverse kidney complications.

In this large-scale population-based cohort study, we aimed to assess the associations of childhood T1DM and T2DM with subsequent overall and type-specific early-onset kidney diseases including glomerular diseases, renal tubulointerstitial diseases, renal failure, urolithiasis, injury of the kidney, and other disorders of kidney and ureter, taking into consideration sex, age at diagnosis of DM, and duration of DM.

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Methods Study population and procedures 

The unique personal identification number in the Danish Civil Registration System was used to accurately merge individual data from all national registers in Denmark [28]. A total of 102,916 participants aged 0–17 years born between January 1977 and December 2016 were included in this study, i.e., 9356 children with DM (8470 for T1DM and 886 for T2DM) from the Danish National Patient Register and 93,560 randomly selected children without DM (a ratio of 1:10 individually matched by sex and birth year) from the general population. Additional file 1: Fig. S1 shows the flow chart of inclusion and exclusion of study participants. The study was approved by the Data Protection Agency (record number 2013–41-2569). By Danish law, no informed consent is required for a research-based study of anonymized data.

We performed sibling comparison analyses to control for the influence of unmeasured familial and shared genetic characteristics [29, 30]. A sub-sample of 6908 families including 17,315 siblings born to the same mother discordant for both DM and subsequent kidney diseases contributed to the effect estimate. The date of diagnosis of siblings in the DM exposure group was used as the start date for both groups. Te follow-up period of all included participants was from the date of DM diagnosis in the exposure group until the first diagnosis of kidney disease, emigration, or 31 December 2018, whichever came first.

Exposure

Data on DM were from the Danish National Patient Registry, the Danish National Diabetes Register, and the Danish National Prescription Registry. We defined T1DM and T2DM as any first inpatient or outpatient visit with the diagnosis based on the International Classification of Disease (ICD) codes and prescription of anti-diabetic medicine by Anatomical Therapeutic Chemical (ATC) classification codes (T1DM: ICD-10 E10-E10.9, O24.0; ICD-8 249, ATC A10A; T2DM: ICD-10 E11- E119, O24.1; ICD-8 250, ATC A10B) (Additional fle  1: Table  S1). If one was diagnosed with both T1DM and T2DM, he/she was classified as the first type diagnosed DM. It should be noted that 91.0% of children with diabetes (T1DM or T2DM) had been mainly treated with insulin and its analogs, biguanides, and other drugs. Among all treated pediatric patients with T1DM, the proportions were 99.0% for the use of insulin and its analogs, 0.4% for biguanides, and 0.6% for other drugs. Among all treated pediatric patients with T2DM, the proportions were 43.6% for the use of insulin and its analogs, 50.4% for biguanides, and 6.0% for other drugs.

Outcome of interest

Early-onset kidney disease in childhood or adulthood was identified at the first hospital diagnosis of glomerular diseases, renal tubulointerstitial diseases, renal failure, urolithiasis, injury of the kidney, and other disorders of the kidney and ureter based on the Danish National Patient Register by using ICD-8 and ICD-10 codes (Additional file 1: Table S1).

Covariates

Potential covariates used for adjustment included birthweight category (low, high, normal, or unknown), preterm birth (yes vs. no), parity (1, 2, or≥3), singleton status (yes vs. no), residence (Copenhagen, cities with 100,000 or more inhabitants, or others), maternal marital status (unmarried, married, or unknown), maternal and paternal education levels (0–9  years, 10–14 years,≥15 years, or unknown), and maternal and paternal history of DM (yes vs. no).

Statistical analyses 

Continuous variables were presented as mean deviation (SD) or median with interquartile range (P25–P75) and mean rank, and categorical variables were presented as frequency (percentage). Considering non-kidney disease deaths as the competing event, competing risk analysis was used to calculate the cumulative incidence between children with and without DM. Stratified Cox proportional regression analysis with inverse probability of treatment weighting was used to estimate the associations of childhood TIDM/T2DM with kidney diseases later in life after adjustment for the aforementioned covariates. We performed subgroup analyses stratified by sex, child age at diagnosis of DM (0–5, 6–12, and 13–17  years), diabetic duration (0–10, 11–20, and≥21 years), calendar periods (1977–1985 vs. 1986–2016), and DM complications (≥1 complication vs. 0 complications). We performed sensitivity analyses to examine these associations including (1) the use of sibling sub-cohort design with stratified Cox proportional regression analyses to take into account the influence of unmeasured genetic and environmental characteristics [29], (2) the exclusion of 1-year, 3-year, and 5-year duration of DM from exposed the group to examine the potential detection bias of DM [18]; (3) the exclusion of DM patients in childhood without the use of hypoglycemic drugs (9.0%) to examine whether this therapy influenced the association; and (4) further adjustment for the use of nephroprotective therapy to examine whether this variable influenced the association. We used multiple imputation procedures to impute missing values of all covariates of interest for final data analyses. All analyses were performed using SAS version 9.4. A two-sided p-value<0.05 was considered statistically signifcant.

Results

Table 1 shows the baseline characteristics of participants by DM type. Children with DM were more likely to have low and high birth weight, preterm birth, lower maternal and paternal educational level, and parental history of DM before childbirth compared with children without DM. Similar results were found for most of these variables in children with T2DM compared with those with T1DM.

Associations of childhood DM with overall and type‑specific early‑onset kidney diseases 

During a median follow-up of 13 years, 340 children with DM (T1DM: 283, T2DM: 57) and 1376 children without DM were diagnosed with kidney disease. The cumulative incidence of any kidney diseases among individuals with DM was higher than those without DM, and the cumulative incidence seemed slightly higher in T2DM than in T1DM (Fig. 1). Children with DM had a 154% increased risk of early-onset kidney diseases, compared with children without DM (adjusted hazard ratios [aHR] 2.54, 95% confidence intervals 2.38–2.72). Both T1DM (2.48, 2.31– 2.67) and T2DM (2.75, 2.28–3.31) were associated with an increased risk of overall kidney diseases. The risks for type-specific kidney diseases, in particular for glomerular disease (aHR=3.56, 95% CI=2.97–4.27), renal tubulointerstitial diseases (aHR=2.74, 95% CI=2.48–3.02), renal failure (aHR=9.13, 95% CI=7.49–11.14), and urolithiasis (aHR=1.39, 95% CI=1.20–1.61) among children with DM, were also increased (Table  2). Similar patterns were found for T1DM and T2DM while the magnitude of associations seemed slightly stronger in children with T2DM than in those with T1DM (Table 2). Analyses stratified by sex showed similar results for any kidney diseases, glomerular disease, renal tubulointerstitial disease, and renal failure. We observed an increased risk of urolithiasis among females with DM (1.93, 1.61–2.31) but not among males with DM (0.92, 0.71–1.19) (Additional file 1: Table S2).

Associations of childhood DM with early‑onset kidney diseases by calendar years, age of DM diagnosis, DM types, DM duration, and DM complications 

The results for DM and overall and specific types of early-onset kidney diseases were stable during different calendar periods (1977–1985 vs. 1986–2016) (Additional file 1: Table  S3). When we stratified the age of DM diagnosis, older exposed children at 6–12 years or 13–17 years were more likely to have a higher rate of kidney disease than younger children at 0–5 years (Fig. 2 and Additional fle 1: Table  S4). Similar results were found according to DM types (Additional file 1: Fig. S2 and Fig. S3). We found that children with longer DM duration (10–20  years and≥21 years vs. 0–10 years) were at a higher increased risk of kidney diseases (Additional file 1: Table S5). Children with DM in combination with more than one diabetic complication (vs. without diabetic complication)tended to have a higher risk of kidney diseases later in life (Additional fle 1: Table S6).

Sensitivity analyses

The results from the sibling cohort were similar to the main results from the general population cohort (Additional file 1: Table S7). After excluding children with follow-up after a diagnosis of DM less than 1  year, 3 years, and 5 years, the results also remained stable (Additional file 1: Table S8). Further excluding DM patients in childhood without the use of hypoglycemic drugs also did not substantially change the findings (Additional file 1: Table S9). After further adjustment for the use of nephroprotective therapy, the results also remained consistent (Additional file 1: Table S10).