Plasma levels of carboxylic acids are markers of early kidney dysfunction in young people with type 1 diabetes.

BACKGROUND: We compared plasma metabolites of amino acid oxidation and the tricarboxylic acid (TCA) cycle in youth with and without type 1 diabetes mellitus (T1DM) and related the metabolites to glomerular filtration rate (GFR), renal plasma flow (RPF), and albuminuria. Metabolites associated with impaired kidney function may warrant future study as potential biomarkers or even future interventions to improve kidney bioenergetics. METHODS: Metabolomic profiling of fasting plasma samples using a targeted panel of 644 metabolites and an untargeted panel of 19,777 metabolites was performed in 50 youth with T1DM ≤ 10 years and 20 controls. GFR and RPF were ascertained by iohexol and p-aminohippurate clearance, and albuminuria calculated as urine albumin to creatinine ratio. Sparse partial least squares discriminant analysis and moderated t tests were used to identify metabolites associated with GFR and RPF. RESULTS: Adolescents with and without T1DM were similar in age (16.1 ± 3.0 vs. 16.1 ± 2.9 years) and BMI (23.4 ± 5.1 vs. 22.7 ± 3.7 kg/m2), but those with T1DM had higher GFR (189 ± 40 vs. 136 ± 22 ml/min) and RPF (820 ± 125 vs. 615 ± 65 ml/min). Metabolites of amino acid oxidation and the TCA cycle were significantly lower in adolescents with T1DM vs. controls, and the measured metabolites were able to discriminate diabetes status with an AUC of 0.82 (95% CI: 0.71, 0.93) and error rate of 0.21. Lower glycine (r:-0.33, q = 0.01), histidine (r:-0.45, q < 0.001), methionine (r: -0.29, q = 0.02), phenylalanine (r: -0.29, q = 0.01), serine (r: -0.42, q < 0.001), threonine (r: -0.28, q = 0.02), citrate (r: -0.35, q = 0.003), fumarate (r: -0.24, q = 0.04), and malate (r: -0.29, q = 0.02) correlated with higher GFR. Lower glycine (r: -0.28, q = 0.04), phenylalanine (r:-0.3, q = 0.03), fumarate (r: -0.29, q = 0.04), and malate (r: -0.5, q < 0.001) correlated with higher RPF. Lower histidine (r: -0.28, q = 0.02) was correlated with higher mean ACR. CONCLUSIONS: In conclusion, adolescents with relatively short T1DM duration exhibited lower plasma levels of carboxylic acids that associated with hyperfiltration and hyperperfusion. TRIAL REGISTRATION: ClinicalTrials.gov NCT03618420 and NCT03584217 A higher resolution version of the Graphical abstract is available as Supplementary information.

Trends in all-cause mortality among people with diagnosed diabetes in high-income settings: a multicountry analysis of aggregate data.

BACKGROUND: Population-level trends in mortality among people with diabetes are inadequately described. We aimed to examine the magnitude and trends in excess all-cause mortality in people with diabetes. METHODS: In this retrospective, multicountry analysis, we collected aggregate data from 19 data sources in 16 high-income countries or jurisdictions (in six data sources in Asia, eight in Europe, one from Australia, and four from North America) for the period from Jan 1, 1995, to Dec 31, 2016, (or a subset of this period) on all-cause mortality in people with diagnosed total or type 2 diabetes. We collected data from administrative sources, health insurance records, registries, and a health survey. We estimated excess mortality using the standardised mortality ratio (SMR). FINDINGS: In our dataset, there were approximately 21 million deaths during 0·5 billion person-years of follow-up among people with diagnosed diabetes. 17 of 19 data sources showed decreases in the age-standardised and sex-standardised mortality in people with diabetes, among which the annual percentage change in mortality ranged from -0·5% (95% CI -0·7 to -0·3) in Hungary to -4·2% (-4·3 to -4·1) in Hong Kong. The largest decreases in mortality were observed in east and southeast Asia, with a change of -4·2% (95% CI -4·3 to -4·1) in Hong Kong, -4·0% (-4·8 to -3·2) in South Korea, -3·5% (-4·0 to -3·0) in Taiwan, and -3·6% (-4·2 to -2·9) in Singapore. The annual estimated change in SMR between people with and without diabetes ranged from -3·0% (95% CI -3·0 to -2·9; US Medicare) to 1·6% (1·4 to 1·7; Lombardy, Italy). Among the 17 data sources with decreasing mortality among people with diabetes, we found a significant SMR increase in five data sources, no significant SMR change in four data sources, and a significant SMR decrease in eight data sources. INTERPRETATION: All-cause mortality in diabetes has decreased in most of the high-income countries we assessed. In eight of 19 data sources analysed, mortality decreased more rapidly in people with diabetes than in those without diabetes. Further longevity gains will require continued improvement in prevention and management of diabetes. FUNDING: US Centers for Disease Control and Prevention, Diabetes Australia Research Program, and Victoria State Government Operational Infrastructure Support Program.

The Cost-Effectiveness of Anemia Treatment for Persons with Chronic Kidney Disease.

BACKGROUND: Although major guidelines uniformly recommend iron supplementation and erythropoietin stimulating agents (ESAs) for managing chronic anemia in persons with chronic kidney disease (CKD), there are differences in the recommended hemoglobin (Hb) treatment target and no guidelines consider the costs or cost-effectiveness of treatment. In this study, we explored the most cost-effective Hb target for anemia treatment in persons with CKD stages 3-4. METHODS AND FINDINGS: The CKD Health Policy Model was populated with a synthetic cohort of persons over age 30 with prevalent CKD stages 3-4 (i.e., not on dialysis) and anemia created from the 1999-2010 National Health and Nutrition Examination Survey. Incremental cost-effectiveness ratios (ICERs), computed as incremental cost divided by incremental quality adjusted life years (QALYs), were assessed for Hb targets of 10 g/dl to 13 g/dl at 0.5 g/dl increments. Targeting a Hb of 10 g/dl resulted in an ICER of $32,111 compared with no treatment and targeting a Hb of 10.5 g/dl resulted in an ICER of $32,475 compared with a Hb target of 10 g/dl. QALYs increased to 4.63 for a Hb target of 10 g/dl and to 4.75 for a target of 10.5 g/dl or 11 g/dl. Any treatment target above 11 g/dl increased medical costs and decreased QALYs. CONCLUSIONS: In persons over age 30 with CKD stages 3-4, anemia treatment is most cost-effective when targeting a Hb level of 10.5 g/dl. This study provides important information for framing guidelines related to treatment of anemia in persons with CKD.