Continuous glucose monitoring has an increasing role in pre-symptomatic type 1 diabetes: advantages, limitations, and comparisons with laboratory-based testing.

Type 1 diabetes (T1D) is well-recognised as a continuum heralded by the development of islet autoantibodies, progression to islet autoimmunity causing beta cell destruction, culminating in insulin deficiency and clinical disease. Abnormalities of glucose homeostasis are known to exist well before the onset of typical symptoms. Laboratory-based tests such as the oral glucose tolerance test (OGTT) and glycated haemoglobin (HbA1c) have been used to stage T1D and assess the risk of progression to clinical T1D. Continuous glucose monitoring (CGM) can detect early glycaemic abnormalities and can therefore be used to monitor for metabolic deterioration in pre-symptomatic, islet autoantibody positive, at-risk individuals. Early identification of these children can not only reduce the risk of presentation with diabetic ketoacidosis (DKA), but also determine eligibility for prevention trials, which aim to prevent or delay progression to clinical T1D. Here, we describe the current state with regard to the use of the OGTT, HbA1c, fructosamine and glycated albumin in pre-symptomatic T1D. Using illustrative cases, we present our clinical experience with the use of CGM, and advocate for an increased role of this diabetes technology, for monitoring metabolic deterioration and disease progression in children with pre-symptomatic T1D.

Urinary albumin/creatinine ratio tertiles predict risk of diabetic retinopathy progression: a natural history study from the Adolescent Cardio-Renal Intervention Trial (AdDIT) observational cohort.

AIMS/HYPOTHESIS: We hypothesised that adolescents with type 1 diabetes with a urinary albumin/creatinine ratio (ACR) in the upper tertile of the normal range (high ACR) are at greater risk of three-step diabetic retinopathy progression (3DR) independent of glycaemic control. METHODS: This was a prospective observational study in 710 normoalbuminuric adolescents with type 1 diabetes from the non-intervention cohorts of the Adolescent Cardio-Renal Intervention Trial (AdDIT). Participants were classified as 'high ACR' or 'low ACR' (lowest and middle ACR tertiles) using baseline standardised log10 ACR. The primary outcome, 3DR, was determined from centrally graded, standardised two-field retinal photographs. 3DR risk was determined using multivariable Cox regression for the effect of high ACR, with HbA1c, BP, LDL-cholesterol and BMI as covariates; diabetes duration was the time-dependent variable. RESULTS: At baseline mean ± SD age was 14.3 ± 1.6 years and mean ± SD diabetes duration was 7.2 ± 3.3 years. After a median of 3.2 years, 83/710 (12%) had developed 3DR. In multivariable analysis, high ACR (HR 2.1 [1.3, 3.3], p=0.001), higher mean IFCC HbA1c (HR 1.03 [1.01, 1.04], p=0.001) and higher baseline diastolic BP SD score (HR 1.43 [1.08, 1.89], p=0.01) were independently associated with 3DR risk. CONCLUSIONS/INTERPRETATION: High ACR is associated with greater risk of 3DR in adolescents, providing a target for future intervention studies. TRIAL REGISTRATION: isrctn.org ISRCTN91419926.

Worldwide differences in childhood type 1 diabetes: The SWEET experience.

OBJECTIVE: To study worldwide differences in childhood diabetes, comparing relevant indicators among five regions within the SWEET initiative. SUBJECTS: We investigated 26 726 individuals with type 1 diabetes (T1D) from 54 centers in the European region; 7768 individuals from 30 centers in the Asia/Middle East/Africa region; 2642 people from five centers in Australia/New Zealand; 10 839 individuals from seven centers in North America, and 1114 patients from five centers in South America. METHODS: The SWEET database was analyzed based on the following inclusion criteria: T1D, time period 2015-2019, and age < 21 years, with analysis of the most recent documented year of therapy. For the statistical analysis, we used multivariable linear and logistic regression models to adjust for age (<6 years, 6- < 12 years, 12- < 18 years, 18- < 21 years), gender, and duration of diabetes (<2 years, 2- < 5 years, 5- < 10 years, ≥10 years). RESULTS: Adjusted HbA1c means ranged from 7.8% (95%-confidence interval: 7.6-8.1) in Europe to 9.5% (9.2-9.8) in Asia/Middle East/Africa. Mean daily insulin dose ranged from 0.8 units/kg in Europe (0.7-0.8) and Australia/New Zealand (0.6-0.9) to 1.0 unit/kg 0.9-1.1) in Asia/Middle East/Africa. Percentage of pump use was highest in North America (80.7% [79.8-81.6]) and lowest in South America (4.2% [3.2-5.6]). Significant differences between the five regions were also observed with regards to body mass index SD scores, frequency of blood glucose monitoring and presence of severe hypoglycaemia. CONCLUSIONS: We found significant heterogeneity in diabetes care and outcomes across the five regions. The aim of optimal care for each child remains a challenge.

Higher frequency of vertebrate-infecting viruses in the gut of infants born to mothers with type 1 diabetes.

BACKGROUND: Microbial exposures in utero and early life shape the infant microbiome, which can profoundly impact on health. Compared to the bacterial microbiome, very little is known about the virome. We set out to characterize longitudinal changes in the gut virome of healthy infants born to mothers with or without type 1 diabetes using comprehensive virome capture sequencing. METHODS: Healthy infants were selected from Environmental Determinants of Islet Autoimmunity (ENDIA), a prospective cohort of Australian children with a first-degree relative with type 1 diabetes, followed from pregnancy. Fecal specimens were collected three-monthly in the first year of life. RESULTS: Among 25 infants (44% born to mothers with type 1 diabetes) at least one virus was detected in 65% (65/100) of samples and 96% (24/25) of infants during the first year of life. In total, 26 genera of viruses were identified and >150 viruses were differentially abundant between the gut of infants with a mother with type 1 diabetes vs without. Positivity for any virus was associated with maternal type 1 diabetes and older infant age. Enterovirus was associated with older infant age and maternal smoking. CONCLUSIONS: We demonstrate a distinct gut virome profile in infants of mothers with type 1 diabetes, which may influence health outcomes later in life. Higher prevalence and greater number of viruses observed compared to previous studies suggests significant underrepresentation in existing virome datasets, arising most likely from less sensitive techniques used in data acquisition.

An improved clinical model to predict stimulated C-peptide in children with recent-onset type 1 diabetes.

BACKGROUND: Stimulated C-peptide measurement after a mixed meal tolerance test (MMTT) is the accepted gold standard for assessing residual beta-cell function in type 1 diabetes (T1D); however, this approach is impractical outside of clinical trials. OBJECTIVE: To develop an improved estimate of residual beta-cell function in children with T1D using commonly measured clinical variables. SUBJECTS/METHODS: A clinical model to predict 90-minute MMTT stimulated C-peptide in children with recent-onset T1D was developed from the combined AbATE, START, and TIDAL placebo subjects (n = 46) 6 months post-recruitment using multiple linear regression. This model was then validated in a clinical cohort (Hvidoere study group, n = 262). RESULTS: A model of estimated C-peptide at 6 months post-diagnosis, which included age, gender, body mass index (BMI), hemoglobin A1c (HbA1c), and insulin dose predicted 90-minute stimulated C-peptide measurements (adjusted R2 = 0.63, P < 0.0001). The predictive value of insulin dose and HbA1c alone (IDAA1c) for 90-minute stimulated C-peptide was significantly lower (R2 = 0.37, P < 0.0001). The slopes of linear regression lines of the estimated and stimulated 90-minute C-peptide levels obtained at 6 and 12 months post diagnosis in the Hvidoere clinical cohort were R2 = 0.36, P < 0.0001 at 6 months and R2 = 0.37, P < 0.0001 at 12 months. CONCLUSIONS: A clinical model including age, gender, BMI, HbA1c, and insulin dose predicts stimulated C-peptide levels in children with recent-onset T1D. Estimated C-peptide is an improved surrogate to monitor residual beta-cell function outside clinical trial settings.

The Adolescent Cardio-Renal Intervention Trial (AdDIT): retinal vascular geometry and renal function in adolescents with type 1 diabetes.

AIMS/HYPOTHESIS: We examined the hypothesis that elevation in urinary albumin creatinine ratio (ACR) in adolescents with type 1 diabetes is associated with abnormal retinal vascular geometry (RVG) phenotypes. METHODS: A cross-sectional study at baseline of the relationship between ACR within the normoalbuminuric range and RVG in 963 adolescents aged 14.4 ± 1.6 years with type 1 diabetes (median duration 6.5 years) screened for participation in AdDIT. A validated algorithm was used to categorise log10 ACR into tertiles: upper tertile ACR was defined as 'high-risk' for future albuminuria and the lower two tertiles were deemed 'low-risk'. RVG analysis, using a semi-automated computer program, determined retinal vascular calibres (standard and extended zones) and tortuosity. RVG measures were analysed continuously and categorically (in quintiles: Q1-Q5) for associations with log10 ACR and ACR risk groups. RESULTS: Greater log10 ACR was associated with narrower vessel calibres and greater tortuosity. The high-risk group was more likely to have extended zone vessel calibres in the lowest quintile (arteriolar Q1 vs Q2-Q5: OR 1.67 [95% CI 1.17, 2.38] and venular OR 1.39 [0.98, 1.99]) and tortuosity in the highest quintile (Q5 vs Q1-Q4: arteriolar OR 2.05 [1.44, 2.92] and venular OR 2.38 [1.67, 3.40]). The effects of retinal vascular calibres and tortuosity were additive such that the participants with the narrowest and most tortuous vessels were more likely to be in the high-risk group (OR 3.32 [1.84, 5.96]). These effects were independent of duration, blood pressure, BMI and blood glucose control. CONCLUSIONS/INTERPRETATION: Higher ACR in adolescents is associated with narrower and more tortuous retinal vessels. Therefore, RVG phenotypes may serve to identify populations at high risk of diabetes complications during adolescence and well before onset of clinical diabetes complications.

The Australasian Diabetes Data Network: first national audit of children and adolescents with type 1 diabetes.

OBJECTIVES: To assess glycaemic control, anthropometry and insulin regimens in a national sample of Australian children and adolescents with type 1 diabetes. DESIGN: Cross-sectional analysis of de-identified, prospectively collected data from the Australasian Diabetes Data Network (ADDN) registry. SETTING: Five paediatric diabetes centres in New South Wales, Queensland, South Australia, Victoria and Western Australia. PARTICIPANTS: Children and adolescents (aged 18 years or under) with type 1 diabetes of at least 12 months' duration for whom data were added to the ADDN registry during 2015. MAIN OUTCOME MEASURES: Glycaemic control was assessed by measuring haemoglobin A1c (HbA1c) levels. Body mass index standard deviation scores (BMI-SDS) were calculated according to the CDC-2000 reference; overweight and obesity were defined by International Obesity Task Force guidelines. Insulin regimens were classified as twice-daily injections (BD), multiple daily injections (MDI; at least three injection times per day), or continuous subcutaneous insulin infusion (CSII). RESULTS: The mean age of the 3279 participants was 12.8 years (SD, 3.7), mean diabetes duration was 5.7 years (SD, 3.7), and mean HbA1c level 67 mmol/mol (SD, 15); only 27% achieved the national HbA1c target of less than 58 mmol/mol. The mean HbA1c level was lower in children under 6 (63 mmol/mol) than in adolescents (14-18 years; 69 mmol/mol). Mean BMI-SDS for all participants was 0.6 (SD, 0.9); 33% of the participants were overweight or obese. 44% were treated with CSII, 38% with MDI, 18% with BD. CONCLUSIONS: Most Australian children and adolescents with type 1 diabetes are not meeting the recognised HbA1c target. The prevalence of overweight and obesity is high. There is an urgent need to identify barriers to achieving optimal glycaemic control in this population.

Comparison of weight- vs body surface area-based growth hormone dosing for children: implications for response.

OBJECTIVE: To compare weight (per kg)- vs body surface area (BSA, per m(2) )-based growth hormone (GH) dosing formats in children and to derive a useful conversion formula between the two formats. PATIENTS AND DESIGN: Growth hormone doses (>33,000) from 1874 children were obtained from the national Australian database (OZGROW) and used to derive conversion formulae and to confirm the accuracy of a conversion formula based on a weight-only BSA estimate. A further 27,000 doses were used to test the accuracy of all formulae. The best conversion formula was used to compare weight- and surface area-based GH dosing, which included an analysis of first year response (∆SDS height or growth velocity, GV). MEASUREMENTS: Growth hormone doses in mg/m(2) /wk and mg/kg/wk, dose estimates, residuals, first year ∆SDS, first year GV. RESULTS: The formula, [Formula: see text] based on a weight-only BSA estimate, provides accurate dose conversion (mean residual, 0·005 mg/kg/week). A constant mg/m(2) /week dose expressed in terms of mg/kg/week declines quickly with increasing body weight to approximately 15 kg after which the decline continues although less dramatically. For Australian patients, despite an increase in mean per m(2) dose with increased starting weight/age, the per kg dose decreased. This was associated with a greater decline in first year GV than estimated if a per kg dose had been maintained. CONCLUSIONS: Growth hormone doses can be accurately converted between formats. Surface area-based GH dosing is likely to result in a reduced height response as children become heavier when compared with weight-based GH dosing.

Comparison of Centers for Disease Control and Prevention and World Health Organization references/standards for height in contemporary Australian children: analyses of the Raine Study and Australian National Children's Nutrition and Physical Activity cohorts.

AIM: (i) To compare the Centers for Disease Control and Prevention (CDC) reference and World Health Organization (WHO) standard/reference for height, particularly with respect to short stature and eligibility for growth hormone (GH) treatment by applying them to contemporary Australian children; (ii) To examine the implications for identifying short stature and eligibility for GH treatment. METHODS: Children from the longitudinal Raine Study were serially measured for height from 1991 to 2005 (2-15-year-old girls (660) and boys (702) from Western Australia). In the cross-sectional Australian National Children's Nutrition and Physical Activity survey (2-16-year-old boys (2415) and girls (2379) from all states), height was measured in 2007. Heights were converted to standard deviation scores (SDSs) based on CDC and WHO. RESULTS: Means and standard deviations of height-SDS varied between CDC and WHO definitions and with age and gender within each definition. However, both identified similar frequencies of short stature (<1st centile for GH eligibility), although these were very significantly less than the anticipated 1% (0.1-0.7%) of the Australian cohorts. Mean heights in the Australian cohorts were greater than both the WHO and CDC means. CONCLUSIONS: Neither CDC nor WHO height standardisations accurately reflect the contemporary Australian child population. Australian children are taller than the CDC or WHO height means, and significantly less than 1% of Australian children are defined as being short using either CDC or WHO. This study suggests there may be a case for an Australian-specific standard/reference for height.

A novel NR5A1 variant in an infant with elevated testosterone from an Australasian cohort of 46,XY patients with disorders of sex development.

BACKGROUND: NR5A1 loss-of-function mutations are increasingly found to be the cause of 46,XY disorders of sex development (DSD). OBJECTIVE: To determine the presence of NR5A1 mutations in an Australasian cohort of 17 46,XY DSD patients with presumed androgen insensitivity syndrome (AIS) who were negative for androgen receptor gene (AR) mutation. DESIGN: Exons 2-7 of NR5A1 were PCR amplified and sequenced. Gene expression and cellular localization studies were performed on a novel NR5A1 variant c.74A>G (p.Y25C) identified in this study. RESULTS: We identified one novel mutation, c.74A>G (p.Y25C) in a patient characterized by penoscrotal hypospadias with bifid scrotum. He had elevated testosterone and gonadotropins in early infancy. Functional analysis of p.Y25C in vitro demonstrated reduced transcriptional activation by SF-1 and partially impaired nuclear localization in a proportion of transfected human adrenal NCI-H295R cells. CONCLUSION: This is the first reported case of a DSD patient with a NR5A1 mutation and elevated testosterone levels. Our finding supports evaluation of NR5A1 mutations in 46,XY DSD patients with a range of testosterone levels.

Environmental determinants of islet autoimmunity (ENDIA): a pregnancy to early life cohort study in children at-risk of type 1 diabetes.

BACKGROUND: The incidence of type 1 diabetes has increased worldwide, particularly in younger children and those with lower genetic susceptibility. These observations suggest factors in the modern environment promote pancreatic islet autoimmunity and destruction of insulin-producing beta cells. The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is investigating candidate environmental exposures and gene-environment interactions that may contribute to the development of islet autoimmunity and type 1 diabetes. METHODS/DESIGN: ENDIA is the only prospective pregnancy/birth cohort study in the Southern Hemisphere investigating the determinants of type 1 diabetes in at-risk children. The study will recruit 1,400 unborn infants or infants less than six months of age with a first-degree relative (i.e. mother, father or sibling) with type 1 diabetes, across five Australian states. Pregnant mothers/infants will be followed prospectively from early pregnancy through childhood to investigate relationships between genotype, the development of islet autoimmunity (and subsequently type 1 diabetes), and prenatal and postnatal environmental factors. ENDIA will evaluate the microbiome, nutrition, bodyweight/composition, metabolome-lipidome, insulin resistance, innate and adaptive immune function and viral infections. A systems biology approach will be used to integrate these data. Investigation will be by 3-monthly assessments of the mother during pregnancy, then 3-monthly assessments of the child until 24 months of age and 6-monthly thereafter. The primary outcome measure is persistent islet autoimmunity, defined as the presence of autoantibodies to one or more islet autoantigens on consecutive tests. DISCUSSION: Defining gene-environment interactions that initiate and/or promote destruction of the insulin-producing beta cells in early life will inform approaches to primary prevention of type 1 diabetes. The strength of ENDIA is the prospective, comprehensive and frequent systems-wide profiling from early pregnancy through to early childhood, to capture dynamic environmental exposures that may shape the development of islet autoimmunity. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12613000794707.

Disturbed eating behaviours and thoughts in Australian adolescents with type 1 diabetes.

AIM: To describe the presence and type of disturbed eating behaviours and thoughts in a combined male/female Australian sample of adolescents with type 1 diabetes, and examine the association of eating behaviours and thoughts with glycaemic control as evidenced by high glycosylated haemoglobin levels (HbA1c). METHODS: In this cross-sectional descriptive study, 124 adolescents aged 13-18 years were invited to complete three self-administered questionnaires. The Youth Eating Disorder Examination Questionnaire (YEDE-Q) and the Eating Disorder Inventory -3 Risk Composite (EDI-3RC) assessed risk for an eating disorder. The third questionnaire, the Strengths and Difficulties Questionnaire (SDQ) assessed emotional and behavioural concerns. Clinical data were collected from the medical records, routine clinic appointments and the adolescent. RESULTS: Any disturbed eating behaviour was reported by approximately one-third of participants (32.3%) and was common in females and males (37.9% vs. 25.9%). Binge eating (17.7%), driven exercise (13.0%) and dietary restraint (8.9%) were the most common disturbed eating behaviours, although restraint was not evident in males. Insulin manipulation/omission (5.6%), vomiting (3.3%), laxative (0.8%) or diuretic use (0.8%) were less common. Regression analysis showed a significant association between HbA1c and more disturbed eating behaviours and thoughts which remained significant when adjusted for confounders. CONCLUSIONS: High rates of disturbed eating behaviours and thoughts were seen in this Australian sample of adolescents with type 1 diabetes. High scores on both eating disorder measures were associated with poorer glycaemic control. These results highlight the need to screen for disordered eating in adolescents with type 1 diabetes.

Growth hormone regimens in Australia: analysis of the first 3 years of treatment for idiopathic growth hormone deficiency and idiopathic short stature.

OBJECTIVE: To investigate response to growth hormone (GH) in the first, second and third years of treatment for all idiopathic GH-deficient (GHD) and idiopathic short stature (ISS) patients in Australia. CONTEXT: Eligibility for subsidized GH treatment in Australia is determined on auxological criteria for the indication of Short Stature and Slow Growth (SSSG), which includes ISS (SSSG-ISS). The biochemical GHD (BGHD, peak GH < 10 mU/l) and SSSG indications are treated similarly: starting dose of 4·5 mg/m(2)/week with provision for incremental dosing. Some ISS patients were specifically diagnosed with familial short stature (SSSG-FSS). DESIGN: Responses for each year of treatment for BGHD, SSSG-ISS and SSSG-FSS cohorts were compared in relation to influencing variables and with international benchmarks. The effect of incremental dosing was assessed. PATIENTS: Australian BGHD, SSSG-ISS and SSSG-FSS patients who had completed 1, 2, or 3 years of treatment and were currently receiving GH. MEASUREMENTS: Growth hormone dose, change in height-standard deviation score (ΔSDS) and growth velocity (GV). RESULTS: First-year response was 2-3 times greater than that in subsequent years: ΔSDS(1st year) = 0·92, 0·50 and 0·46 for BGHD, SSSG-ISS and SSSG-FSS, respectively. Responses were similar to international reports and inversely related to age at commencement of GH. First-year GV-for-age for BGHD patients was similar to international standards for idiopathic GHD. However, girls had an inferior response to boys when treatment commenced at <6 years of age. First-year GV-for-age for SSSG-ISS/FSS patients was less than ISS standards. Dose increments attenuated the first- to second-year decline in response to BGHD but marginally improved the responses for SSSG-ISS/FSS. CONCLUSIONS: The Australian auxology-based GH programme produces comparable responses to international programmes. A lower starting dose is offset by the initiation of treatment at younger ages. Incremental dosing does not appear optimal. A first-year dose of 6·4-6·9 mg/m(2)/week for GHD and 8·9 mg/m(2)/week for ISS with early commencement of GH treatment may be most efficacious.

Concurrent validity of self-report measures of eating disorders in adolescents with type 1 diabetes.

AIM: Eating disorder screening tools have not been adequately validated for use with adolescents with type 1 diabetes. This study compared the Youth Eating Disorder Examination-Questionnaire (YEDE-Q) and the Eating Disorder Inventory-3 Risk Composite (EDI-3RC) against the child Eating Disorder Examination (chEDE). These screening tools were chosen because they broadly assess eating disorder psychopathology and have subscales helpful for clinical management. METHODS: In this cross-sectional study, 124 adolescents with type 1 diabetes aged 13-18 years completed two self-administered questionnaires, the YEDE-Q and the EDI-3RC. Cronbach's alpha was used to assess internal consistency of the tools. Fifty-one adolescents, randomly selected, participated in the chEDE. Intraclass correlations and Spearman's correlations were used to measure concordance of the chEDE with the YEDE-Q and EDI-3RC. RESULTS: The YEDE-Q and EDI-3RC demonstrated good subscale internal consistency; Cronbach's alpha for YEDE-Q (0.78-0.95) and EDI-3RC (0.79-0.94). High levels of concurrent validity with the chEDE were seen with both tools. CONCLUSION: Preliminary evidence is provided for the validation of the YEDE-Q and EDI-3RC for use in adolescents with type 1 diabetes. The YEDE-Q also defines individual disturbed eating behaviours with frequency ratings which can be helpful for tailoring early intervention.

Growth hormone treatment for Turner syndrome in Australia reveals that younger age and increased dose interact to improve response.

OBJECTIVE: To investigate response to growth hormone (GH) in the first, second and third years of treatment in the total clinical cohort of Turner syndrome (TS) patients in Australia. CONTEXT: Short stature is the most common clinical manifestation of TS. GH treatment improves growth. DESIGN: Response was measured for each year of treatment. Stepwise multiple regression analyses were used to identify factors that significantly influenced response. PATIENTS: Prepubertal TS patients who completed 1 year (n=176), 2 years (n=148), or 3 years (n=117) of treatment and were currently receiving GH. MEASUREMENTS: Change in TS specific Height Standard Deviation Score (ΔTSZ) was the main response variable used. Major influencing variables considered included dose, starting age and height, BMI, bone age delay, karyotype, parental height, and interactions between dose and starting age or height. RESULTS: Response was greatest in first year and declined thereafter (median ΔTSZ: 1st year= +0·705, 2nd year= +0·439, 3rd year= +0·377) despite the median dose increasing [1st year= 5·5 mg/m(2) /week (0·23 mg/kg/week), 2nd year= 6·4(0·24), 3rd year= 7·2(0·26)]. An Age*Dose interaction was identified influencing first, second year, and total ΔTSZ. The ΔTSZ over 3 years was significantly influenced by first-year dose. Dose increments only attenuated the general decline in response. An acceptable first-year response (ΔTSZ>1·01) was achieved by only 17·6% of patients. CONCLUSIONS: Growth response is greatest and most influenced by dose in the first year. Dose in first year is a major factor contributing to total response. A starting Age*Dose interaction effect was observed such that young girls on a high dose respond disproportionately better. Optimal GH treatment of short stature in TS thus requires early initiation with the highest safe dose in the first year.

Is it time to commence newborn screening for congenital adrenal hyperplasia in Australia?

21-Hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia, with an incidence of 1:14000 live births and equal prevalence among males and females. Newborns with the most severe "salt-wasting" form of 21-OHD are susceptible to salt-wasting crises in the first few weeks of life. This is associated with morbidity and mortality. 21-OHD newborn screening (NBS) is currently performed in many countries. Despite several prominent medical societies recommending 21-OHD NBS, no state in Australia currently screens for this condition. We report a case that illustrates the need to reconsider including 21-OHD in NBS. 21-OHD NBS can be reliable, sensitive and effective in reducing morbidity and mortality.

T-Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes.

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of diabetic kidney disease (DKD). In type 1 diabetes, increased urinary albumin-to-creatinine ratio (uACR) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule-1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. DKD risk was assigned in youth with type 1 diabetes (n = 100; 20.0 ± 2.8 years; males/females, 54:46; HbA1c 66.1 [12.3] mmol/mol; diabetes duration 10.7 ± 5.2 years; and BMI 24.5 [5.3] kg/m2) and 10-year historical uACR, HbA1c, and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared with streptozotocin diabetes in apolipoprotein E -/- mice. Kidney biopsies were used to examine infiltration of KIM-1-expressing T cells in DKD and compared with other chronic kidney disease. Individuals at high risk for DKD had persistent elevations in uACR defined by area under the curve (AUC; uACRAUC0-10yrs, 29.7 ± 8.8 vs. 4.5 ± 0.5; P < 0.01 vs. low risk) and early kidney dysfunction, including ∼8.3 mL/min/1.73 m2 higher estimated glomerular filtration rates (modified Schwartz equation; Padj < 0.031 vs. low risk) and plasma KIM-1 concentrations (∼15% higher vs. low risk; P < 0.034). High-risk individuals had greater glycemic variability and increased peripheral blood T-cell KIM-1 expression, particularly on CD8+ T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1+ T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high-risk youth with diabetes showed elevated collagen IV and sodium-glucose cotransporter 2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8+ T-cell production of KIM-1.