Diabetes Cardio-Renal Intervention Trial Research Articles

Socioeconomic representativeness of Australian, Canadian and British cohorts from the paediatric diabetes AdDIT study: comparisons to regional and national data

BackgroundGiven limited data regarding the involvement of disadvantaged groups in paediatric diabetes clinical trials, this study aimed to evaluate the socioeconomic representativeness of participants recruited into a multinational clinical trial in relation to regional and national type 1 diabetes reference populations.MethodsRetrospective, cross-sectional evaluation of a subset of adolescent type 1 diabetes cardiorenal intervention trial (AdDIT) participants from Australia (n = 144), Canada (n = 312) and the UK (n = 173). Validated national measures of deprivation were used: the Index of Relative Socioeconomic Disadvantage (IRSD) 2016 (Australia), the Material Resources (MR) dimension of the Canadian Marginalisation index 2016 (Canada) and the Index of Multiple Deprivation (IMD) 2015 (UK). Representativeness was assessed by comparing the AdDIT cohort’s distribution of deprivation quintiles with that of the local paediatric type 1 diabetes population (regional), and the broader type 1 diabetes population for which the trial’s intervention was targeted (national).ResultsRecruited study cohorts from each country had higher proportions of participants with higher SES, and significant underrepresentation of lower SES, in relation to their national references. The socioeconomic make-up in Australia mirrored that of the regional population (p = 0.99). For Canada, the 2nd least deprived (p = 0.001) and the most deprived quintiles (p < 0.001) were over- and under-represented relative to the regional reference, while the UK featured higher regional and national SES bias with over-representation and under-representation from the least-deprived and most-deprived quintiles (p < 0.0001).ConclusionsSignificant national differences in trial participation of low SES participants were observed, highlighting limitations in access to clinical research and the importance of reporting sociodemographic representation in diabetes clinical trials.Trial registrationNCT01581476. Registered on 20 April 2012.

Biomarkers associated with early stages of kidney disease in adolescents with type 1 diabetes.

To identify biomarkers of renal disease in adolescents with type 1 diabetes (T1D) and to compare findings in adults with T1D. Twenty-five serum biomarkers were measured, using a Luminex platform, in 553 adolescents (median [interquartile range] age: 13.9 [12.6, 15.2] years), recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Associations with baseline and final estimated glomerular filtration rate (eGFR), rapid decliner and rapid increaser phenotypes (eGFR slopes <-3 and > 3 mL/min/1.73m2 /year, respectively), and albumin-creatinine ratio (ACR) were assessed. Results were also compared with those obtained in 859 adults (age: 55.5 [46.1, 64.4) years) from the Scottish Diabetes Research Network Type 1 Bioresource. In the adolescent cohort, baseline eGFR was negatively associated with trefoil factor-3, cystatin C, and beta-2 microglobulin (B2M) (B coefficient[95%CI]: -0.19 [-0.27, -0.12], P = 7.0 × 10-7 ; -0.18 [-0.26, -0.11], P = 5.1 × 10-6 ; -0.12 [-0.20, -0.05], P = 1.6 × 10-3 ), in addition to clinical covariates. Final eGFR was negatively associated with osteopontin (-0.21 [-0.28, -0.14], P = 2.3 × 10-8 ) and cystatin C (-0.16 [-0.22, -0.09], P = 1.6 × 10-6 ). Rapid decliner phenotype was associated with osteopontin (OR: 1.83 [1.42, 2.41], P = 7.3 × 10-6 ), whereas rapid increaser phenotype was associated with fibroblast growth factor-23 (FGF-23) (1.59 [1.23, 2.04], P = 2.6 × 10-4 ). ACR was not associated with any of the biomarkers. In the adult cohort similar associations with eGFR were found; however, several additional biomarkers were associated with eGFR and ACR. In this young population with T1D and high rates of hyperfiltration, osteopontin was the most consistent biomarker associated with prospective changes in eGFR. FGF-23 was associated with eGFR increases, whereas trefoil factor-3, cystatin C, and B2M were associated with baseline eGFR.

Medication Adherence During Adjunct Therapy With Statins and ACE Inhibitors in Adolescents With Type 1 Diabetes.

Suboptimal adherence to insulin treatment is a main issue in adolescents with type 1 diabetes. However, to date, there are no available data on adherence to adjunct noninsulin medications in this population. Our aim was to assess adherence to ACE inhibitors and statins and explore potential determinants in adolescents with type 1 diabetes. There were 443 adolescents with type 1 diabetes recruited into the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) and exposed to treatment with two oral drugs-an ACE inhibitor and a statin-as well as combinations of both or placebo for 2-4 years. Adherence was assessed every 3 months with the Medication Event Monitoring System (MEMS) and pill count. Median adherence during the trial was 80.2% (interquartile range 63.6-91.8) based on MEMS and 85.7% (72.4-92.9) for pill count. Adherence based on MEMS and pill count dropped from 92.9% and 96.3%, respectively, at the first visit to 76.3% and 79.0% at the end of the trial. The percentage of study participants with adherence ≥75% declined from 84% to 53%. A good correlation was found between adherence based on MEMS and pill count (r = 0.82, P < 0.001). Factors associated with adherence were age, glycemic control, and country. We report an overall good adherence to ACE inhibitors and statins during a clinical trial, although there was a clear decline in adherence over time. Older age and suboptimal glycemic control at baseline predicted lower adherence during the trial, and, predictably, reduced adherence was more prevalent in subjects who subsequently dropped out.

Renal and Cardiovascular Risk According to Tertiles of Urinary Albumin-to-Creatinine Ratio: The Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT).

Baseline data from the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) indicated that tertiles of urinary albumin-to-creatinine ratios (ACRs) in the normal range at age 10-16 years are associated with risk markers for diabetic nephropathy (DN) and cardiovascular disease (CVD). We aimed to determine whether the top ACR tertile remained associated with DN and CVD risk over the 2-4-year AdDIT study. One hundred fifty adolescents (mean age 14.1 years [SD 1.6]) with baseline ACR in the upper tertile (high-ACR group) recruited to the AdDIT trial, who remained untreated, and 396 (age 14.3 years [1.6]) with ACR in the middle and lower tertiles (low-ACR group), who completed the parallel AdDIT observational study, were evaluated prospectively with assessments of ACR and renal and CVD markers, combined with carotid intima-media thickness (cIMT) at baseline and end of study. After a median follow-up of 3.9 years, the cumulative incidence of microalbuminuria was 16.3% in the high-ACR versus 5.5% in the low-ACR group (log-rank P < 0.001). Cox models showed independent contributions of the high-ACR group (hazard ratio 4.29 [95% CI 2.08-8.85]) and HbA1c (1.37 [1.10-1.72]) to microalbuminuria risk. cIMT change from baseline was significantly greater in the high- versus low-ACR group (mean difference 0.010 mm [0.079], P = 0.006). Changes in estimated glomerular filtration rate, systolic blood pressure, and hs-CRP were also significantly greater in the high-ACR group (P < 0.05). ACR at the higher end of the normal range at the age of 10-16 years is associated with an increased risk of progression to microalbuminuria and future CVD risk, independently of HbA1c.

Banting Memorial Lecture 2016 Reducing lifetime risk of complications in adolescents with Type 1 diabetes.

Adolescence is a challenging period of life for any young person, and for those with Type 1 diabetes, physiological and psychological factors can result in a deterioration in glycaemic control. In young people with Type 1 diabetes, puberty may be an additional risk factor impacting on the lifetime risk for renal and cardiovascular complications. Our longitudinal studies have identified that increases in urinary albumin excretion through childhood are associated with the development of microalbuminuria and a generalized endotheliopathy linked to cardiovascular risk. Screening of participants recruited to the Adolescent type 1 Diabetes cardio-renal Intervention Trial (AdDIT) confirms that these early changes in albumin excretion are related to both diabetic nephropathy and cardiovascular risk; in part, independent of glycaemic control. Thus, as well as current attempts to improve glycaemic control through enhanced targeted insulin delivery, pumps, sensors and closed loop, we have explored the role of angiotensin-converting enzyme inhibitors and statins in providing cardio-renal protection during adolescence.

The relationship between urinary renin-angiotensin system markers, renal function, and blood pressure in adolescents with type 1 diabetes.

The relationship between the renal renin-angiotensin aldosterone system (RAAS) and cardiorenal pathophysiology is unclear. Our aims were to assess 1) levels of urinary RAAS components and 2) the association between RAAS components and HbA1c, the urine albumin/creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), and blood pressure (BP) in otherwise healthy adolescents with type 1 diabetes mellitus (TID) vs. healthy controls (HC). Urinary angiotensinogen and angtionsin-converting enzyme (ACE) 2 levels, activity of ACE and ACE2, BP, HbA1c, ACR, and eGFR were measured in 65 HC and 194 T1D from the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT). Urinary levels of all RAAS components were higher in T1D vs. HC (P < 0.0001). Higher HbA1c was associated with higher urinary angiotensinogen, ACE2, and higher activity of ACE and ACE2 (P < 0.0001, P = 0.0003, P = 0.003, and P = 0.007 respectively) in T1D. Higher ACR (within the normal range) was associated with higher urinary angiotensinogen (P < 0.0001) and ACE activity (P = 0.007), but not with urinary ACE2 activity or ACE2 levels. These observations were absent in HC. Urinary RAAS components were not associated with BP or eGFR in T1D or HC. Otherwise healthy adolescents with T1D exhibit higher levels of urinary RAAS components compared with HC. While levels of all urinary RAAS components correlate with HbA1c in T1D, only urinary angiotensinogen and ACE activity correlate with ACR, suggesting that these factors reflect an intermediary pathogenic link between hyperglycemia and albuminuria within the normal range.

Social Determinants of Health Are Associated with Modifiable Risk Factors for Cardiovascular Disease and Vascular Function in Pediatric Type 1 Diabetes

To evaluate the relationship between social determinants of health (SDH) and cardiovascular disease (CVD) risk factors as well as a measure of arterial stiffness in adolescents with type 1 diabetes (T1D). SDH were measured with the validated Ontario Marginalization Index, derived from deidentified postal code data and stratified by quintile (first = least deprived; fifth = most deprived). SDH dimensions included material deprivation; ethnic concentration; and measures of dependency and residential instability. Metabolic control (hemoglobin A1c), cardiovascular risk metrics, and pulse wave velocity, as a measure of arterial stiffness, were related to SDH. Data were evaluated from a cohort of Canadian adolescents within the Adolescent Diabetes Cardiorenal Intervention Trial, a T1D clinical trial A total of 704 participants were evaluated, and significant differences in hemoglobin A1c were evident at the extremes of material deprivation (8.4% vs 9.1% for least vs most deprived, P < .01). CVD risk factors were analyzed in 199 participants, with the most deprived reporting significantly less exercise (P = .004) and increased rates of smoking (P = .008). Increased material deprivation was associated with fewer metrics of "ideal" cardiovascular health attained. Arterial stiffness, as measured by pulse wave velocity, was associated positively with age, body mass index z score, and material deprivation. Increased material deprivation was associated with poorer glycemic control. Modifiable, lifestyle-related risk factors for CVD and early arterial wall change are associated with SDH and represent a target for clinical intervention to reduce future CVD burden in adolescents with T1D.

Association Between Plasma Uric Acid Levels and Cardiorenal Function in Adolescents With Type 1 Diabetes.

The relationship between plasma uric acid (PUA) and renal and cardiovascular parameters in adolescents with type 1 diabetes (T1D) is not well understood. Our aims in this exploratory analysis were to study the association between PUA and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (ACR), blood pressure, endothelial function, and arterial stiffness in T1D adolescents. These associations were also studied in healthy control (HC) subjects. We studied 188 T1D subjects recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) and 65 HC subjects. Baseline PUA, eGFRcystatin C, ACR, blood pressure, flow-mediated dilation (FMD), and carotid-femoral pulse wave velocity (PWV) were measured. PUA was lower in T1D vs. HC subjects (242 ± 55 vs. 306 ± 74 μmol/L, respectively; P < 0.0001). Higher PUA was inversely associated with eGFR in T1D subjects (r = -0.48, P < 0.0001) even after correction for baseline clinical demographic characteristics. PUA was not associated with ACR in T1D after adjustment for potential confounders such as eGFR. For cardiovascular parameters, PUA levels did not associate with systolic blood pressure, FMD, or PWV in T1D or HC subjects. Even within the physiological range, PUA levels were significantly lower in T1D adolescent patients compared with HC subjects. There was an inverse relationship between PUA and eGFR in T1D, likely reflecting an increase in clearance. There were no associations observed with ACR, blood pressure, arterial stiffness, or endothelial function. Thus, in contrast with adults, PUA may not yet be associated with cardiorenal abnormalities in adolescents with T1D.

Early atherosclerosis relates to urinary albumin excretion and cardiovascular risk factors in adolescents with type 1 diabetes: Adolescent type 1 Diabetes cardio-renal Intervention Trial (AdDIT).

The origins of cardiovascular and renal disease in type 1 diabetes begin during childhood. We aimed to evaluate carotid (cIMT) and aortic intima-media thickness (aIMT) and their relationship with cardiovascular risk factors and urinary albumin excretion in adolescents with type 1 diabetes in the Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT). A total of 406 adolescents with type 1 diabetes, who were 14.1 ± 1.9 years old with type 1 diabetes duration of 6.7 ± 3.7 years, and 57 age-matched control subjects provided clinical and biochemical data and ultrasound measurements of vascular structure (cIMT and aIMT). Vascular endothelial and smooth muscle function was also measured in 123 of 406 with type 1 diabetes and all control subjects. In type 1 diabetic subjects, mean/maximal aIMT (P < 0.006; <0.008), but not mean/maximal cIMT, was greater than in control subjects. Mean/maximal aIMT related to urinary albumin-to-creatinine ratio (multiple regression coefficient [SE], 0.013 [0.006], P = 0.03; 0.023 [0.007], P = 0.002), LDL cholesterol (0.019 [0.008], P = 0.02; 0.025 [0.011], P = 0.02), and age (0.010 [0.004], P = 0.004; 0.012 [0.005], P = 0.01), independent of other variables. Mean/maximal cIMT was greater in males (0.023 [0.006], P = 0.02; 0.029 [0.007], P < 0.0001), and mean cIMT related independently to systolic blood pressure (0.001 [0.001], P = 0.04). Vascular smooth muscle function related to aIMT and cIMT but not to urinary albumin excretion. aIMT may be a more sensitive marker of atherosclerosis than cIMT in type 1 diabetes during mid-adolescence. Higher urinary albumin excretion, even within the normal range, is associated with early atherosclerosis and should direct clinical attention to modifiable cardiovascular risk factors.

THE EFFECT OF ALBUMIN:CREATININE RATIO ON STANDARD ECHOCARDIOGRAPHIC PARAMETERS IN ADOLESCENT TYPE 1 DIABETES

Study Design Single center prospective cross-sectional study Patient Population The AdDIT study is a multi-centre, randomized, double-blind, placebo-controlled, 2x2 factorial design trial of angiotensinconverting enzyme inhibitor and statin therapy vs. placebo in 500 high-risk (>1.2 mg⁄mmol) T1D adolescents, defined on the basis of albumin excretion.1 It also includes a parallel observational study based on longitudinal follow-up of 400 low-risk (<0.8 mg⁄mmol) and medium-risk (0.8-1.2 mg⁄mmol) T1D adolescents who were screened but did not qualify for randomization. Subjects recruited in the current study were lowand mediumrisk from the parallel observational study and high-risk T1D adolescents that declined participation in the randomized controlled trial. All 199 T1D were compared with 178 adolescents recruited as healthy volunteers, who were not on any vasoactive medications, had no previous history of familial hyperlipidemia, diabetes, obesity, hypertension, or any other significant cardiac, renal or systemic disease and normal cardiac anatomy and function by screening echocardiogram. In subgroup analysis, 68 low-, 78 medium-and 53 high-risk were compared with 65 controls that underwent the same baseline clinical assessment. Anthropometric Assessment Height was measured by stadiometer to the nearest 0.1 cm and weight by electronic balance to the nearest 0.1 kg. Resting heart rate and right brachial blood pressure was measured using an age-appropriate cuff and averaging 3 readings with an automated DINAMAP® sphygmomanometer (Critikon, Tampa, Florida, USA). Echocardiographic Assessment Using a Vivid 7 ultrasound system (GE, General Electric Corp., Wisconsin, USA) with appropriate transducers ranging from frequencies 4-12 MHz depending on subject age and size, a standardized functional imaging protocol, including subcostal, parasternal, apical and suprasternal views, was performed according to published guidelines.2 Modalities employed in this study included M-mode, 2D and pulse Doppler blood flow measurements. Laboratory Assessment Glycemic control was measured by fasting blood glucose and haemoglobin A1c. Serum lipids including total, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were measured. Serum creatinine was used to estimate glomerular filtration rate.3 Statistical Analysis Between groups comparisons were performed using Student’s ttests. Relationships were tested using Pearson’s correlations. Statistical significance was considered at p<0.05.

EXPLORING MYOCARDIAL FUNCTION IN ADOLESCENT TYPE 1 DIABETES

Preclinical detection of myocardial dysfunction in adolescents with type 1 diabetes (T1D) may help identify individuals at increased risk of adult-onset cardiovascular disease, who would most benefit from early intervention strategies. This study compared echocardiographic assessment of myocardial function in patients screened for the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) with healthy controls. Myocardial function assessment included tissue Doppler, strain and strain rate imaging. In subgroup analysis, T1D separated into tertiles according to urinary albumin:creatinine ratio as per the AdDIT protocol, were compared with the subgroup of healthy controls that underwent the same baseline clinical assessment including glycemic measures and serum lipids. Between groups comparisons were performed using Student’s t-tests, with p-values <0.05 considered significant. We studied 188 T1D patients (M:F 93:95; age 14.4±2.1 years; disease duration 7.0 [1.7-15.0] years) and compared to 178 controls (M:F 84:94; age 14.5±1.6 years). Sex, age and height were similar. T1D were heavier with increased systolic and diastolic blood pressures, but decreased resting heart rates. Lateral mitral valve annulus myocardial velocities, E’ (17.5±2.6 vs. 18.6±2.6 cm/s; p=0.0001), A’ (5.4±1.1 vs. 5.9±1.1 cm/s; p<0.0001) and S (10.5±1.8 vs. 11.1±2.0 cm/s; p=0.0017) were decreased and mitral valve E/E’ (5.8±1.1 vs. 5.4±1.0; p=0.0002) increased. Global left ventricular (LV) circumferential strain (-20.4±2.3 vs. -19.5±1.7 %; p=0.0002) and longitudinal strain (-19.6±1.7 vs. -18.9±1.9 %; p=0.0003) were different, but systolic and diastolic global longitudinal strain rates were similar. Basal rotation was similar, but apical rotation (6.26±2.97 vs. 5.28±2.45 degrees; p=0.0012) and LV twist (10.35±3.58 vs. 9.33±3.05 degrees; p=0.0065) were increased. In sub-group analysis, we compared 59 controls vs. 53 high-risk, 71 medium-risk and 64 low-risk T1D. As expected all the T1D sub-groups had increased fasting blood glucose and HbA1c, and also HDL cholesterol. Total and LDL cholesterol and triglycerides were similar. Only global LV circumferential strain in the medium-risk tertile remained different when comparing the smaller T1D subgroups vs. controls (-19.4±1.6 vs. -18.8±1.7 %; p=0.0312). Significant changes in myocardial function are evident in adolescent T1D of short to intermediate disease duration, suggesting these may be clinically useful preclinical markers of deterioration in cardiac performance to guide early intervention.

Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT): urinary screening and baseline biochemical and cardiovascular assessments.

We assessed the association between early increases in albumin excretion and cardiovascular (CV) and renal markers in a large cohort of young people with type 1 diabetes. As part of preliminary screening for a multicenter, randomized controlled trial of statins/ACE inhibitors, we measured albumin-creatinine ratio (ACR) in six early morning urine samples from 3,353 adolescents (10-16 years of age) and calculated tertiles based on an established algorithm. From those subjects deemed to be at higher risk (upper ACR tertile), we recruited 400 into the intervention study (trial cohort). From those subjects deemed to be at lower risk (middle-lower ACR tertiles), we recruited 329 to the observation cohort. At baseline, vascular measurements (carotid intima-media thickness, pulse wave velocity [PWV], flow-mediated dilatation, digital pulse amplitude tonometry), renal markers (symmetric dimethylarginine, cystatin C, creatinine), and CV disease markers (lipids and apolipoproteins [Apo] A-1 and B, C-reactive protein, asymmetric dimethylarginine) were assessed. Age- and sex-adjusted PWV was higher in the trial than in the observational cohort (5.00 ± 0.84 vs. 4.86 ± 0.70 m/s; P = 0.021). Similarly, non-HDL cholesterol (2.95 ± 0.83 vs. 2.81 ± 0.78 mmol/L; P = 0.02) and ApoB-ApoA-1 ratio (0.50 ± 0.14 vs. 0.47 ± 0.11; P = 0.04) were higher in the trial cohort. Cystatin C and creatinine were decreased (0.88 ± 0.13 vs. 0.90 ± 0.13 mg/L, P = 0.04; 51.81 ± 10.45 vs. 55.35 ± 11.05 μmol/L, P < 0.001; respectively) and estimated glomerular filtration rate (137.05 ± 23.89 vs. 129.31 ± 22.41 mL/min/1.73 m(2); P < 0.001) increased in the trial compared with the observational cohort. Our data demonstrate that in adolescents with type 1 diabetes, the group with the highest tertile of albumin excretion showed more evidence of early renal and CV disease than those in the lower tertiles.

Albumin excretion in adolescents with diabetes

If you would like to express interest in reviewing or writing papers for the Journal of Renal Nursing, please contact the journal’s editor via email (natasha.devan@markallengroup.com) Albumin excretion in adolescents with diabetes O ver the last 20 years, two longitudinal studies—the Oxford Regional Prospective Study (ORPS) and Nephropathy Family Study (NFS), facilitated by UK research nurses—have improved our understanding of the natural history of microalbuminuria in young people with type 1 diabetes. Microalbuminuria, a marker of early-stage renal damage and an independent risk factor for nephropathy and cardiovascular disease, has been found in around 26% of adolescents with type 1 diabetes 10–20 years after diagnosis. Early increases in urinary albumin excretion predict progression to microalbuminuria and more severe renal disease. In adults with type 1 diabetes, such early increases in albumin excretion have also been associated with risk for cardiovascular disease, but data from adolescents with type 1 diabetes has been lacking. The Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT), designed to explore the effects of lipid-lowering drugs (statins) and blood pressure lowering drugs (angiotensin-converting-enzyme (ACE) inhibitors) on risk for diabetic nephropathy and cardiovascular disease, has allowed exploration of the relationship between cardiovascular risk and urinary albumin excretion in adolescents with type 1 diabetes. Research nurses in the UK, Australia and Canada screened over 3000 people aged 10–16 years with type 1 diabetes to identify those with higher than average albumin excretion. Participants were found to have renal hyperfiltration and an increase in both risk markers and direct measures of cardiovascular disease. Around 850 participants have now been recruited to a clinical trial of ACE inhibitors and/or statins, which has the potential to change diabetes management during adolescence and improve the long-term prognosis of young patients with type 1 diabetes.

Urinary markers of renal inflammation in adolescents with Type 1 diabetes mellitus and normoalbuminuria.

Patients with the highest albumin:creatinine ratio within the normal range are at an increased risk for developing microalbuminuria. The mechanistic basis for this is unknown, but may be related to renal inflammation. Our goal was to characterize the urinary excretion of cytokines/chemokines in normoalbuminuric adolescents with Type 1 diabetes to determine whether higher range normoalbuminuria is associated with evidence of renal inflammation. Forty-two urinary cytokines/chemokines were measured in subjects who were screened for the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Urinary cytokines/chemokines were compared across low (n = 50), middle (n = 50) or high (n = 50) albumin:creatinine ratio tertile groups. At baseline, participants in the upper tertile were younger and had shorter diabetes duration compared with the other groups. Other clinical characteristics were similar. Urinary levels of interleukin 6, interleukin 8, platelet-derived growth factor-AA and RANTES differed across albumin:creatinine ratio tertiles, with higher values in patients in the middle and high tertiles compared with the lower tertile (ANCOVA P ≤ 0.01). Within the normal albumin:creatinine ratio range, higher urinary albumin excretion is associated with elevated urinary levels of inflammatory markers. Ultimately, this may provide mechanistic insights into disease pathophysiology and stratify the risk of nephropathy in Type 1 diabetes.

Adolescent type 1 Diabetes Cardio-renal Intervention Trial (AdDIT).

BackgroundThe prognosis for young people diagnosed with diabetes during childhood remains poor and this is mainly related to the long-term risk of developing vascular complications.Microalbuminuria identifies subjects at risk for diabetic nephropathy (DN) and cardiovascular disease (CVD). It is often detected in adolescence but is rarely treated before the age of 18 years, as at the end of puberty albumin excretion may decline and in some subjects will return into the normal range. However, evidence indicates that subjects with both transient and persistent microalbuminuria have experienced renal damage during puberty and thus reno-protection to prevent long-term complications is warranted. In adults with diabetes and microalbuminuria, the use of angiotensin converting enzyme inhibitors (ACEI) and Statins is increasing, and in order to determine whether these agents are of value in the adolescent population a large randomized controlled clinical trial is needed.Methods/DesignThe Adolescent type 1 Diabetes cardio-renal Intervention Trial (AdDIT) is a multi-center, randomized, double-blind, placebo-controlled trial of ACEI and Statin therapy in adolescents with type 1 diabetes. 500 high-risk adolescents, defined on the basis of their albumin excretion, are randomized to receive either ACEI (Quinapril) or Statins (Atorvastatin) or combination therapy or placebo for 3-4 years. There will also be a parallel open observational study, based on the follow-up of 400 low-risk non-randomized adolescents. The major endpoint of the study is the change in albumin excretion; secondary endpoints include markers of CVD, renal function, retinopathy, quality of life combined with assessment of compliance and potential health economic benefits.DiscussionAdDIT will provide important data on the potential renal and cardiovascular protective effects of ACEI and Statins in high-risk adolescents. Long-term follow-up of the randomized subjects will provide direct evidence of disease outcomes, in addition to the data on early surrogate measures of DN and CVD. Follow-up of non-randomized low-risk subjects will determine the potential impact of intervention on DN and CVD. AdDIT will help to determine whether, in addition to encouraging young people to achieve good glycaemic control, pharmacological cardio-renal protection should also be implemented.EudraCT Number2007-001039-72Trial Registration NumberISRCTN91419926