© Springer International Publishing Switzerland 2017
Andrea Scaramuzza, Carine de Beaufort and Ragnar Hanas (eds.)Research into Childhood-Onset Diabetes10.1007/978-3-319-40242-0_44. Adolescent Prevention of Complications
(1)
Department of Paediatrics, University of Cambridge, Cambridge, UK
(2)
Department of Pediatrics, University of Cambridge Metabolic Research Laboratories Wellcome Trust-Medical Research Council Institute of Metabolic Science, National Institute of Human Research Cambridge Comprehensive Biomedical Research Center, Level 8, Box 116, Addenbrooke’s Hospital Hills Road, Cambridge, CB2 0QQ, UK
4.1 Introduction
The incidence of type 1 diabetes (T1D) is increasing worldwide by 2–5 % per year, and it accounts for 90 % of all cases of childhood and adolescent diabetes [1, 2]. Based on recent data from the International Diabetes Federation, the overall number of children (age 0–14 years) with T1D worldwide is around 497,000, with around 79,000 newly diagnosed cases per year [3].
T1D is associated with increased morbidity and mortality due to the development of long-term microvascular and macrovascular complications [4, 5]. Diabetic nephropathy (DN) and cardiovascular disease (CVD) are among the most common vascular complications of T1D, which negatively influence the long-term prognosis of young people with that condition [6]. Several studies have shown that premature atherosclerosis represents the main cause of morbidity and mortality in patients with T1D [7], and individuals with T1D have a risk of myocardial infarction equivalent to that of a nondiabetic individual with previous history of myocardial infarction [7]. In longitudinal cohorts of adults with T1D from the USA and Europe, the incidence of coronary events was 16 % after 10 years of diabetes duration, significantly contributing to mortality [7]. In patients with T1D, the risk for CVD is strongly associated with the presence of DN, being tenfold greater for patients with DN compared to those without this complication [8]. This is also highlighted by recent studies reporting that, in the absence of renal complications, mortality in patients with T1D is similar to that in the general population, whereas it significantly increases in the presence of microalbuminuria (MA) or more advanced stages of DN [9, 10].
4.2 Childhood-Onset T1D and Risk of Vascular Complications
An early onset of T1D during childhood and adolescence determines a longer exposure to the metabolic derangements of the disease when compared to an onset during adulthood, therefore increasing the risk of micro- and macrovascular complications [13]. The natural history of T1D vascular complications appears to be more aggressive in youth-onset compared to adult-onset T1D, particularly in youth with poor glycaemic control, who often show a faster progression than adults [5]. Recent data from a large cohort of adults with T1D have shown a remarkable effect of age at T1D diagnosis on CVD mortality. In particular, when comparing subjects with an onset of T1D before the age of 15 years with those with later onset of T1D, the standardised mortality ratio was substantially higher in the earlier-onset group (16.9 [95 % CI = 13.5–20.9] vs 5.9 [95 % CI = 5.2–6.8]) [14]. This age at onset-related risk for CVD is in line with previous data reporting a higher risk for retinopathy and MA in people diagnosed with T1D during childhood compared to those with an onset after puberty or during early adult life [15, 16].
Adolescence is a critical period for the lifetime risk of complications in individuals with childhood-onset T1D, and it is during this period of life that the first signs of micro- and macrovascular disease appear [4, 5, 17]. During adolescence, the typical pubertal hormonal and metabolic changes, as well as lifestyle, environmental exposures and genetic factors, may interact with poor glycaemic control and contribute to the overall complication risk [17, 18]. Although hard endpoints, such as overt proteinuria, end-stage renal disease, advanced stages of retinopathy or CVD events (stroke, myocardial infarction), are rare, several subclinical manifestations of micro- and macrovascular complications manifest during puberty. These include early increases in albumin excretion rates up to the stage of MA, early changes in the retinal microvasculature as well as subclinical changes in big vessels, including arterial stiffness, endothelial dysfunction, arterial calcification and increased aortic and carotid intima-media thickness, representing early stages of the atherosclerotic process [19].
4.3 Renal Involvement in Children and Adolescents with T1D
DN is one of the most common microvascular complications of T1D, reflecting structural and functional changes occurring in the kidney and leading to the development of albuminuria and hypertension and a progressive decline in renal function [20]. The changes occurring in the kidney in patients with T1D are generally classified into five stages, reflecting specific and progressive alterations in renal morphology and function [20]. The earliest stage is characterised by glomerular hypertrophy, hyperfiltration and hyperperfusion. This is followed by a stage of subclinical morphological changes and increases in albumin excretion rates (AER) within the normal range [20]. Further increases in albumin excretion, with an AER between 30 and 300 mg/24 h or 20–200 μg/min in a 24-h or timed urine collection, indicate the development of MA (stage 3), which may further progress to overt proteinuria (macroalbuminuria) (AER >200 μg/min or >300 mg/24 h) (stage 4) and, without any treatment, to end-stage renal disease (ESRD) (stage 5) [20].
Although advanced DN stages, such as macroalbuminuria or ESRD, are rare in children and adolescents with T1D [21], early structural and functional renal alterations develop soon after the diagnosis of diabetes and often progress during puberty [22–25]. Biopsy studies have shown that renal lesions, such as basement membrane thickening and mesangial expansion, can be detected in young normoalbuminuric subjects, and these changes are predictive of subsequent patterns in AER [22].
Hyperfiltration is often detected in young people with T1D and precedes the onset of MA [25, 26]. In some, although not all studies, increased glomerular filtration rate has emerged as an independent predictor of MA, and a meta-analysis published in 2009 reported a 2.7 increased risk of developing MA associated with hyperfiltration [27].
MA is a frequent finding among adolescents with T1D, and cross-sectional studies have reported a prevalence between 4 and 20 % [28–37]. This variability is largely related to differences in T1D duration across studies, variations in glycaemic control and criteria used to define MA. Based on longitudinal studies, the cumulative prevalence of MA is 10–26 % during the first 10–15 years of T1D [15, 23, 38–44], and it becomes as high as 51 % after 19 years of diabetes duration, as emerged by the analysis of longitudinal data collected in the Oxford Regional Prospective Study (ORPS) [15]. This prevalence is significantly higher than that reported in adult cohorts (34 %) after 18-year diabetes duration and exposure to similar levels of glycaemic control [45], thus suggesting that a diagnosis of T1D during childhood is associated with different risk factors for the development of MA when compared to a later diagnosis during adult life [15, 45].
The rate of progression of MA to macroalbuminuria appears to be similar between adults and children with T1D, but in children macroalbuminuria occurs at an earlier age (18.5 vs 41 years) [15, 45]. In the ORPS cohort, the cumulative prevalence of macroalbuminuria was 13.9 % [15], and this was similar to the 14.6 % prevalence reported in a similar inception cohort in adults [45], suggesting that progression is related to the duration of diabetes regardless of the age at onset. Interestingly, both persistent and intermittent MA during adolescence predicted progression to macroalbuminuria [15]. Recent studies have introduced the concept of ‘regression to normoalbuminuria’, and this phenomenon has been reported in around 40–50 % adolescents with T1D [15, 46] and occurs mainly after puberty. These rates of regression are similar to those reported in adults with T1D [45, 47]. Recent updated results from the Diabetes Control and Complication Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) studies have reported a cumulative incidence of regression to normoalbuminuria of 40 % after 10 years from the onset of MA [11]. However, even though MA regresses, the morphological changes occurring in the kidney can persist and increase the risk of its recurrence and progression to macroalbuminuria during follow-up [22]. This is supported by the ORPS data indicating an increasing number of ‘intermittent’ subjects originally described as transient, with continued follow-up [15].
4.3.1 Risk Factors Associated with MA in Adolescents with T1D
During adolescence, several factors, both genetic and environmental, contribute to the development of MA and other vascular complications of diabetes. The characteristic hormonal and metabolic milieu of puberty makes this population particularly vulnerable to the effect of the metabolic derangement of diabetes.
Poor glycaemic control is a common finding among adolescents with T1D [48–50], and it is closely linked to the development of MA and progression to macroalbuminuria [15]. Puberty is associated with a decrease in insulin sensitivity [51], and adolescents with T1D are more insulin resistant when compared with healthy controls [52]. Insulin omission to control weight gain can be a common finding among adolescent girls, and this can be another contributing factor to poor glycaemic control. High HbA1c levels are also independently associated to the risk of progression to macroalbuminuria, whereas a better glycaemic control appears to characterise subjects who regress to normoalbuminuria [15].
During pubertal years several factors other than glycaemic control can promote the development of MA. Of note is the sexual dimorphism for complication risk, with a higher percentage of girls developing MA, in contrast with the higher male risk during adulthood [15]. The higher testosterone levels found in adolescent girls with MA when compared with matched controls without MA [53] could contribute to renal disease and to the female predominance of this complication during puberty [15, 23, 53].
Puberty is characterised by rapid renal growth and the development of glomerular hyperfiltration [25], and these two factors can affect MA risk, independently of glycaemic control [25, 26]. These may be linked to abnormalities in the growth hormone (GH) insulin-like growth hormone (IGF)-I axis, characterised by increased circulating GH levels and decreased IGF-I concentrations, which have been related to an increased risk of developing MA, particularly in girls [53, 54]. Short adult stature has also been associated with a higher prevalence of MA, probably reflecting childhood exposure to diabetes or common pathogenic factors between short stature and risk for vascular complications [55].
In addition, the development of MA during adolescence is associated with the presence of subclinical inflammation and markers of subclinical atherosclerosis, supporting the concept that MA is a marker not only of renal disease but of a more generalised endothelial dysfunction [56]. Abnormalities in blood pressure, either high diastolic blood pressure or alterations in its circadian rhythm, are associated with the risk of MA in adolescents with T1D [57]. Similarly, dyslipidaemia, often detected in this population, may be associated with MA [58].
Clinical markers of insulin resistance, such as overweight, have also been associated with the development of MA in adolescents with T1D [59].
Environmental and dietary factors may also contribute to the risk of developing MA during puberty. Smoking is a common finding among adolescents, and it has been reported in up to 48 % of those with T1D [60]. A high protein intake has been suggested as a potential risk factor for the development of DN, with a normalisation of glomerular filtration rate associated with a reduction in protein intake [61, 62].
Another factor that has been related to MA is low birth weight [63]. Intrauterine growth retardation might lead to reduced nephron number and decreased renal functional reserve, with increased susceptibility to renal disease in response to other environmental factors [63]. This theory might also explain the association between short stature, low IGF-1 and risk of DN [63, 64] as well as the relationship between impaired growth during puberty and risk of MA [65]. However, no association has been found between birth weight or gestational age and MA in young people with T1D [66].
There is accumulating evidence that the risk of developing MA and DN is partly genetic [67], and therefore, during puberty, genetic factors could interact with hormonal, metabolic and other environmental factors and contribute to the onset of MA. The role of genetic factors is supported by the familial clustering of nephropathy as well as by the observation that a subset of patients can develop MA independently of glycaemic control [68]. In addition, a family history of hypertension, dyslipidaemia and insulin resistance appears to be more common among adolescents developing MA, compared to those who remain free of this complication [56]. Although they are the subject of extensive research activity, as yet, these genes have not been identified.
4.3.2 Screening for Renal Complications During Adolescence
Given that MA is the first clinical sign of DN and it is an important predictor for progression towards more advanced renal damage, it should be carefully evaluated during adolescence. The basis of screening of MA, as well as for other vascular complications of T1D, is that early markers/signs of complications should be identified as early as possible in order to implement appropriate and effective interventions.
Based on the International Society for Paediatric and Adolescent Diabetes (ISPAD) guidelines, screening for MA should start from 10 years of age or at the onset of puberty if this is earlier, with 2–5-year diabetes duration [4]. Annual screening for albuminuria should be undertaken by any of these methods: first morning urine samples for urinary albumin/creatinine ratio (ACR) or timed urine collections for AER. The definition of MA differs depending on the method used for screening. If a 24-h or a timed urine collection is performed, the standard definition is based on values between 20 and 200 ug/min or 30–300 mg/l. Values above the upper limit for MA are diagnostic of macroalbuminuria/proteinuria. However, 24-h or timed urine collections are often difficult to obtain, particularly in young people, and lack of accuracy may be questioned. Assessing ACR in a spot urinary sample is the easiest method to carry out in an office setting, and it generally provides accurate information. First-voided urine in the morning is preferable because of the known diurnal variation in albumin excretion and postural effects, but if this timing cannot be used, uniformity of timing for different collections in the same individual should be employed [4]. Factors, such as exercise, infections, fever and marked hyperglycaemia, can influence albumin excretion, as well as kidney diseases, such as IgA nephropathy or systemic inflammatory diseases, and therefore all these factors need to be considered when interpreting elevated albumin excretion. Storage of urines at −20 °C can also affect albumin concentrations, therefore storage at −70 °C or early measurement of fresh samples is preferable [69].
Because of the biological variability, two of three consecutive collections should be used as evidence of MA [4]. Regular follow-up is important to identify rapid or slow progression to microalbuminuria, as well as cases of regression to normoalbuminuria. Regular longitudinal follow-up of albumin excretion is also important to identify patients with progressive small increases of urinary albumin excretion within the normal range, which might be a prelude to the development of microalbuminuria [70].
4.3.3 Reno-protective Strategies During Adolescence
4.3.3.1 Glycaemic Control
Achieving a tight glycaemic control is the primary goal of any intervention aiming at preventing the development and progression of MA and other micro- and macrovascular complications of T1D.
The DCCT/EDIC studies have provided strong evidence for the important role of strict glycaemic control in reducing risk of microvascular and macrovascular complications in subjects with T1D [49, 71]. In the adolescent cohort of the DCCT, a positive effect of improved glycaemic control on complication risk was obtained, even though mean HbA1c levels were significantly higher when compared to the adult cohort [49]. Remarkably, the DCCT follow-up study, EDIC, highlighted the important phenomenon of ‘metabolic memory’; that is, patients who benefited in the past from a better metabolic control continued to be protected from the development of vascular complications many years later. Recently, the 10-year EDIC follow-up data have also shown that in the DCCT adolescent cohort, this metabolic memory wore off in the long term, and this is mainly due to a worse glycaemic control during the earlier DCCT [72]. The DCCT/EDIC data underline the importance of a good glycaemic control during puberty, but psychological issues, together with the effect of the physiological pubertal insulin resistance [51] and other changes in the hormonal milieu, may provide challenges [73]. These difficulties in achieving a good glycaemic control were identified in the DCCT, where weight gain and hypoglycaemia were limiting factors in gaining good compliance [48]. The issue of weight gain is of particular relevance for adolescent girls, who often omit their insulin injections in order to avoid overweight [74]. Taken together, these data suggest that other strategies may need to be implemented to reduce complication risk during adolescence.
4.3.3.2 Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers and Statins
In adults with T1D, the presence of MA is a general indication for intervention with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) [75] and also for consideration of statin therapy [76]. These recommendations are based on the evidence of a beneficial effect of these drugs on renal complications as well as on cardiovascular risk.
Adult studies have shown that treatment with ACEIs reduces the rate of progression and can even promote regression of MA [77], independently from the effect on blood pressure control. Furthermore, in patients with diabetes but with albumin excretion within the normal range, ACEIs have been proven to be effective in reducing the risk of developing MA [75]. ACEIs can also have a significant effect on other diabetic microvascular complications, such as retinopathy [78] and potentially CVD [79].
Many large-scale interventional trials in adults have demonstrated that treatment with statins significantly reduces the risk of CVD events and total mortality [80]. People with diabetes often exhibit dyslipidaemia, and statin therapy has been associated with a significant reduction in the risk of macrovascular complications [76]. Clinical and experimental studies have also highlighted the role of dyslipidaemia in the development of MA and DN [81] and the potential of statins to reduce proteinuria and retard the progression of chronic kidney disease [81, 82].
4.3.3.3 ACEIs and Statins in Children and Adolescents
In children and adolescents, the efficacy and safety of ACEIs and statins have been shown in the context of hypertension and familial hypercholesterolaemia, respectively [83, 84]. However, there is a lack of data on the long-term use of these drugs in those with T1D, and, in particular, there is no clear indication for their use in patients with MA.
Although screening for MA is strongly recommended in youth with T1D, there is no definitive consensus on the use of ACEIs and/or statins when this complication is detected.
The recent ISPAD guidelines suggest considering treatment with an ACEI, when elevated urinary ACR (30 mg/g) is documented with at least two of three urine samples. This should be obtained over a 6-month interval following efforts to improve glycaemic control and normalise blood pressure [4].
Although there is clear evidence that adolescents with T1D represent a particular vulnerable category at risk for vascular complications [15], the lack of a general consensus for the management of early DN with specific reno-protective drugs is related, in part, to the natural course of albumin excretion, which presents a high probability of reversal at the end of puberty. An additional reservation for the early use of these drugs in young people with T1D is that they may be taking them for a long time, with the potential risk of adverse effects. The use of ACEIs has been associated with several side effects, including hypotension, cough and hyperkalaemia [85]. Statin treatment is associated with the risk of myopathy and altered liver function, mainly when used in combination with other drugs [84]. However, as emerged by several meta-analyses of studies performed in children with familial hypercholesterolaemia [86, 87], the reported incidence of these events is low. However, for both classes of drugs, there have been issues related to the potential risk of congenital malformation when used during pregnancy [84, 88].
A few small studies have assessed the effect of ACEIs on albumin excretion in young people with T1D and persistent MA [89–92]. Overall these studies have confirmed adult findings of a positive effect on urinary albumin excretion. However, these results are based on a small number of subjects, short follow-up and lack of a placebo arm in the majority of studies, therefore limiting the possibility of drawing clear conclusions. In addition, there are no data on the potential effect of ACEI in subjects with high normal albumin excretion rates, who are at high risk for later development of nephropathy and potentially cardiovascular disease [70].
Abnormal lipid profiles are often detected in adolescents with T1D [93–95], and they appear to contribute to the increased risk of endothelial dysfunction as well as of MA [81]. However, there is no clear guidance on the role of statin treatment in children and adolescents with T1D and increased albumin excretion, and thus their use has been limited [93, 94]. The management of dyslipidaemia in paediatric patients relies on the results of trials conducted in adults [80] and in children with familial hypercholesterolaemia [86, 87, 96]. However, it is of utmost importance to assess the long-term efficacy and safety of statins in young people with T1D.
A recent pilot study assessed the safety and efficacy of atorvastatin in improving lipid profiles in 60 adolescents with T1D and elevated LDL-C [97]. This study confirmed the efficacy of atorvastatin in reducing LDL-C, apoB and atherogenic lipoprotein subparticles and also confirmed that the drug was well tolerated and safe.
4.3.3.4 The Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT)
The efficacy of ACEIs and statins in high-risk adolescents with T1D is being investigated by the Adolescent type 1 Diabetes Intervention Trial (AdDIT), a multicentre multinational study, involving centres in the UK, Canada and Australia [98].
High-risk adolescents were defined as those with an albumin excretion rate, as assessed by measurement of ACR in two sets of three early-morning urine samples, in the upper tertile of the normal range, after adjustment for potential confounders, such as age, gender, age at diagnosis and duration of disease [70]. Subjects were recruited from a prescreened population of 3000 young people with T1D aged 10–16 years. Around 400 subjects (100 for each arm of the study) were randomised to a 2 × 2 factorial design contrasting the effects of ACEIs, statins alone or in combination to placebo over a 2–4-year treatment period.
The primary aim of the study was to determine whether intervention will (1) reduce albumin excretion as assessed by six monthly measurements of ACR, (2) reduce the incidence of MA at the end of the study period, and (3) reduce the incidence of MA during the 6-month run-out period following the completion of the intervention phase. The secondary objective of the study was to determine the effect of the intervention on changes in cIMT, arterial blood pressure, plasma lipids and lipoproteins, glomerular filtration rate and plasma markers of CVD risk. In addition, the effect of treatment is assessed in relation to quality of life, risk benefit, compliance and impact on health economics as well as long-term outcomes with regard to incidence of DN and CVD.
AdDIT will therefore provide important data on the potential renal and cardiovascular protective effects of ACEIs and statins in high-risk adolescents and will allow clarifying whether these drugs should be associated to the standard insulin treatment in adolescents with T1D at risk of vascular complications. Long-term follow-up of the randomised subjects will supplement the effects on early surrogate measures of DN and CVD with direct evidence of disease outcomes. In addition, this study will provide valuable data on tolerance and safety of treatment with ACEIs and statins as well as data on compliance and on potential health economic benefits.
As part of AdDIT, an additional group of 400 non-randomised adolescents deemed to be at low risk on the basis of their albumin excretion (in the middle and lower tertiles) is being followed up, with the aim of assessing the relationship between urinary albumin excretion and cardiovascular measures during pubertal years and its modification by CVD risk factors, renal function and diabetes control [98]. It will also provide an indication of the population effect of the intervention.
The recent published analysis of the baseline data from AdDIT has confirmed that early increases in urinary albumin excretion, even within the normal range, are associated with increased CVD risk. In this baseline cohort of around 700 AdDIT participants, urinary albumin excretion levels in the top 30 % of the observed distribution were associated with increased glomerular filtration rates, higher lipid levels, increased arterial stiffness, higher aortic intima-media thickness, and signs of early cardiac autonomic dysfunction, indicative of CVD risk, when compared to adolescents with T1D and lower ACR [98–100].
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