Childhood diabetes mellitus and early-onset kidney diseases later in life: a nationwide population-based matched cohort study

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 significant 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].

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 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 tubulo-interstitial 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 tubulo-interstitial diseases, renal failure, urolithiasis, injury of kidney, and other disorders of kidney and ureter, taking into consideration sex, age at diagnosis of DM, and duration of DM.

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.

Our study showed that children with T1DM or T2DM had an increased risk of overall and type-specific early-onset kidney diseases than those without DM. Older children who received a diagnosis of DM at 6–17 years (vs. younger children with DM diagnosed at 0–5 years) and children with longer DM duration (vs. shorter DM duration) were more likely to have overall and type-specific early-onset kidney diseases later in life. Females with DM were more likely to have urolithiasis, whereas males were not.

Several previous studies have reported that the overall risks of kidney diseases increased in young people with DM [15, 17, 31]. However, little is known about the association of DM with type-specific kidney diseases later in life. A cohort study based on 342 Canadian youths showed that DM was associated with an increased risk of renal failure compared with non-DM [15]. However, only a small number of individuals (365 with T1DM and 56 with T2DM) were followed up for more than 10 years. Although several previous studies in Norway, Sweden, and Finland showed that children or young people with DM had an increased risk of end-stage renal disease [19, 23‐25], evidence is scarce on the cumulative risks of other kidney diseases for young people with DM. In this study, we used nationwide data in Denmark and confirmed that children with DM had an increased overall risk of kidney diseases, and we firstly reported that children with either type of DM had an increased risk of type-specific kidney diseases including glomerular disease, renal tubulo-interstitial disease, renal failure, and urolithiasis. Exposure to hyperglycemia could drive the loss of kidney function, influencing both renal tubulointerstitial and glomerular filtration barriers through increased oxidative stress, cell apoptosis, tissue fibrosis, and inflammation [32]. Our findings support that it is imperative to achieve and maintain glycemic control in youths [33] to prevent overall and type-specific early-onset kidney outcomes later in life. It is documented that improved glucose control may be useful for delaying the onset and progression of early complications of DM (including T1DM and T2DM) [34, 35]. Parental involvement in school and social settings, anticipation of poorer adherence and glucose control in youth with DM, a concern of depression symptoms, and appropriate health care services may help manage glucose more optimally [36].

The study based on 4555 children and adolescents from a young diabetes registry showed that the incidence rate of nephropathy per 1000 person-years increased with the duration of T1DM and T2DM [31]. However, this study was only based on a tertiary care private DM center in India, which might not be generalized to other populations [31]. Moreover, the effects of youth-onset DM on type-specific kidney diseases were not investigated. Two previous studies showed that both young and old people with a longer duration of DM had an increased risk of end-stage kidney disease [19, 27], but data on other type-specific kidney diseases are lacking. In this study, we found that the risks of kidney diseases overall and specific types (including renal failure, glomerular diseases, renal tubulo-interstitial disease, and urolithiasis) increased with the DM duration. Besides, we found that renal tubulo-interstitial disease and renal failure may occur with a short DM duration of fewer than 10 years, which suggest that it is important to keep healthy blood glucose level earlier to prevent these kidney diseases later in life.

Interestingly, similar to previous studies on the association between T2DM and long-term end-stage kidney disease in Canadian and Australian young adults [27, 37], we found that DM diagnosed at 0–5 years afforded lower cumulative incidence of all kidney diseases than DM diagnosed at 6–12 years and 13–17 years, independent of types of DM. Data from the Swedish Childhood Diabetes Register showed that the cumulative incidence of end-stage kidney disease for T1DM diagnosed at 0–9 years was lower than that diagnosed at 10–19 years [19]. However, this study did not compare the rate of end-stage kidney disease between T1DM diagnosed at 0–5 years and that at 5–9 years. In Norwegian children, the cumulative incidence of end-stage kidney disease for T1DM diagnosed at 0–5 years and 5–9 years was lower than that diagnosed at 10–14 years [24], whereas in Finnish children, the cumulative incidence of end-stage kidney disease for T1DM diagnosed at 0–4 years was lower than that diagnosed at 5–9 years and 10–14 years [23]. Our findings on the age of diagnosis of DM and cumulative incidence of all kidney diseases were similar to the latter one. The higher cumulative incidence of kidney diseases for diagnosed DM at 6–17 years compared with diagnosis at 0–5 years might be due to that sexual maturation caused by psychological and endocrine factors at puberty appears to accelerate the progress of DM, reflux nephropathy, and posterior urethral valves [38]. Moreover, the large psychological changes in puberty might influence the adherence to DM treatment [39], which poses a challenge to achieving good DM care for youths with DM. Besides, other risk factors including a rapid increase in body weight and blood pressure and altered endocrine during the puberty period also influence the development of chronic kidney disease [38]. In general, detecting DM in early childhood might be important for physicians helping them improve glycemic control, increase monitoring intensity, and delay long-term DM complications. It has been demonstrated that DM diagnosed at a young age might contribute to a delay in the development of end-stage kidney disease [23, 24].

Although several studies reported a higher or similar incidence of renal complications in T1DM than that in T2DM [12, 40, 41], a large number of emerging studies have shown that youths with T2DM had a higher burden of renal complications (especially end-stage kidney diseases or renal failure) and poor prognosis than those with T1DM [15, 17, 31, 40, 42]. The discrepancy of previous studies might be due to the differences in age and ethnicity/race of study participants, study sample size, the definition of DM, duration of follow-up years, and various renal complications (such as kidney risk profile, renal failure, and diabetic kidney diseases). In this study, we found that children with T1DM or T2DM had a similar increased overall risk of kidney disease, renal tubulo-interstitial disease, and urolithiasis compared with those without DM. The similarity in the risks of type-specific kidney diseases due to T1DM and T2DM implies shared pathological mechanisms between both types of DM in the development of kidney diseases [32]. However, the odds of glomerular disease and kidney failure among children with T2DM were nearly twice the odds among those with T1DM. Our findings might partly explain the discrepancy of previous findings. Although the potential mechanisms have not been elucidated, obesity, which causes T2DM, might play an important role in the formation of these kidney diseases [43, 44]. Besides, it might be driven by other major risk factors such as hypertension and dyslipidemia [45].

We found a similar risk of glomerular disease for youth-onset DM among both males and females, which was in line with the finding on the association between childhood-onset T1DM and end-stage kidney disease in a nationwide study in Sweden [25], but inconsistent with the finding of a markedly higher risk of end-stage kidney disease for the onset of DM among Australian males at 10–29 years vs. females and among Swedish males at 20–34 years vs. females [25, 27]. We additionally observed that females with DM were more likely to have urolithiasis, whereas males were not. Previous evidence has indicated that pediatric nephrolithiasis was more common in females than in males [46]. These findings might be explained by the fact that females had more acquisition of bone mineralization driven by estrogen, which might cause the formation of urine chemistry and stone [47]. At the start of puberty, females had higher levels of urinary citrate than males [48]. These findings imply that sex plays a vital role in the development of urolithiasis among children with DM, and further studies are warranted to understand the mechanism. However, we could not assess the sex effect on the association between childhood DM types and type-specific kidney diseases due to limited cases when stratified by sex, which needs further exploration.

To our knowledge, this was the first nationwide prospective study that offered new insights into the incidence of type-specific kidney diseases later in life for children with T1DM or T2DM. Additionally, we performed sibling design to assess the influence of unmeasured genetic and environmental characteristics, which are difficult to adjust using a conventional cohort study design. Several limitations deserved consideration. First, the small numbers of some type-specific kidney outcomes precluded us from performing subgroup analyses. Second, although several confounders have been adjusted in this study, confounding effects of some unadjusted factors cannot be ruled out, such as obesity status and lifestyles in childhood or adulthood. Third, the same code (ICD-8, 205) of T1DM and T2DM before 1986 might cause potential misclassification bias because children with T2DM who required insulin treatment might be misclassified as T1DM. However, our subgroup analyses stratified by calendar periods yielded a similar association between DM and the overall risk of kidney diseases between 1977–1985 and 1986–2016. Fourth, the use of ICD codes might underestimate the incidence of chronic kidney disease in administrative data because of inadequate documentation in discharge summaries and/or inaccurate coding practice [49]. However, we used both Danish-modified ICD-10 codes, ICD-8 codes, and ATC codes to capture kidney diseases. Fifth, we only examined the risk of kidney diseases in childhood and early adulthood because of the short follow-up duration (median: 13 years), and limited follow-up duration in our study might omit young children born in 1996–2016 who had a high risk of T2DM in adolescence. Future well-designed cohort studies with longer follow-up duration are warranted.

In conclusion, we found that childhood DM (both T1DM and T2DM) could lead to an increased risk of early-onset kidney diseases overall and a number of specific types, such as glomerular disease, renal tubulo-interstitial disease, and renal failure later in life. Older children who received a diagnosis of DM during later childhood were at a higher risk of developing kidney diseases compared with those during early childhood. Youth-onset DM with a longer duration was associated with a higher increased risk of overall and type-specific early-onset kidney diseases later in life. These findings highlight the significance of early detection and prevention of T1DM and T2DM among children at high risk because of prolonged exposure and stress and the importance of strict control of DM in the life course to reduce the high burden of kidney disease later in life.