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Karim Y.,St. Thomas Hospital | Turner C.,Wellchild Laboratory | Dalton N.,Wellchild Laboratory | Roplekar R.,St. Thomas Hospital | And 6 more authors.
International Immunopharmacology | Year: 2013

Inflammatory/pro-resorptive cytokines and chemokines form part of a complex inter-dependent network and may be influenced by vitamin D. We investigated their inter-relationship and the effect of a loading dose of vitamin D. We measured plasma concentrations of an array of cytokines including tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, IL-17, IL-8, granulocyte macrophage colony stimulating factor (GM-CSF), and the chemokine monocyte chemoattractant protein-1 (MCP-1). Cytokines, 25 (OH) vitamin D, 1,25 (OH)2 vitamin D, the Wnt inhibitor, DKK1 concentrations and bone turnover markers were measured at baseline and 3 months following a bolus dose (300,000 IU) of vitamin D2 in 39 subjects with vitamin D insufficiency. We observed strong correlations between TNF-α with GM-CSF (r = 0.628, p < 0.001), IL-17 (r = 0.7, p < 0.001) and MCP-1 (r = 0.5, p = 0.001), between IL-1β with IL-17 (r = 0.45, p = 0.004) and between the 2 chemokines, IL-8 and MCP-1 (r = 0.45, p = 0.004). A positive correlation was seen between DKK1 and IL-1β (r = 0.35, p = - 0.029). Following vitamin D loading at 3 months, the relationships between some of the cytokines changed (TNF-α and MCP-1: r = 0.38, p = 0.017, IL-1β and IL-17: r = 0.3, p = 0.06). 1,25 (OH)2 vitamin D increased markedly following supplementation. Significant correlations were seen between 25 (OH) vitamin D (r = 0.4 p = 0.016) and 1,25 (OH)2 vitamin D (r = 0.39 p = 0.02) with plasma CTX (marker of bone resorption) at 3 months. TNF-α and IL-1β increased significantly at 3 months (p < 0.05). The close association between several cytokines is influenced by vitamin D status. Acute increases in 1,25 (OH)2 vitamin D, achieved with loading doses of vitamin D, lead to increases in pro-resorptive cytokines. © 2013 Elsevier B.V. Source

Cherney D.Z.I.,University of Toronto | Scholey J.W.,University of Toronto | Daneman D.,University of Toronto | Dunger D.B.,University of Cambridge | And 7 more authors.
Diabetic Medicine | Year: 2012

Aims 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 Type1 diabetes to determine whether higher range normoalbuminuria is associated with evidence of renal inflammation. Methods Forty-two urinary cytokines/chemokines were measured in subjects who were screened for the Adolescent Type1 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. Results 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 interleukin6, interleukin8, 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). Conclusions 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 Type1 diabetes. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK. Source

Maftei O.,Medical Imaging | Pena A.S.,Medical Imaging | Pena A.S.,University of Adelaide | Sullivan T.,University of Adelaide | And 17 more authors.
Diabetes Care | Year: 2014

OBJECTIVE: 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). RESEARCH DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. © 2014 by the American Diabetes Association. Source

Kilbride H.S.,University of Canterbury | Stevens P.E.,University of Canterbury | Eaglestone G.,University of Canterbury | Knight S.,University of Canterbury | And 7 more authors.
American Journal of Kidney Diseases | Year: 2013

Background: Glomerular filtration rate (GFR) is a measure of kidney function, commonly estimated using equations that adjust serum creatinine concentration for age, race, and sex. The Modification of Diet in Renal Disease (MDRD) Study equation is widely used, but underestimates GFR at higher levels. The serum creatinine-based Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPIcr) equation generally provides more accurate estimation at GFR >60 mL/min/1.73 m2. Newer equations have been reported using cystatin C concentration either alone (CKD-EPIcys) or in combination with creatinine concentration (CKD-EPIcr-cys). None of these equations has been well validated in older people. We tested the accuracy of these equations in people 74 years or older compared with GFR measured by a reference method. Study Design: Diagnostic test evaluation in a prospective cohort. Setting & Participants: Participants (n = 394; median age, 80 [range, 74-97] years) recruited from nephrology clinics and the community. Index Test: GFR estimated using the MDRD Study, CKD-EPIcr, CKD-EPI cys and CKD-EPIcr-cys equations. Reference Test: GFR measured using an iohexol clearance method. Results: Median measured GFR was 53.4 (range, 7.2-100.9) mL/min/1.73 m2. MDRD Study-, CKD-EPI cr-, and CKD-EPIcr-cys-estimated GFRs overestimated GFR (median differences of 3.5 [P< 0.001], 1.7 [P < 0.001], and 0.8 [P = 0.02] mL/min/1.73 m2, respectively); the CKD-EPIcys equation was unbiased. Accuracy (percentage of estimates within 30% of measured GFR [P30]) was 81%, 83%, 86%, and 86% for the MDRD Study, CKD-EPI cr, CKD-EPIcys, and CKD-EPIcr-cys equations, respectively. Accuracy of the MDRD Study equation was inferior (P = 0.004) to the CKD-EPIcr equation at GFR >60 mL/min/1.73 m2. Limitations: Those of non-European ancestry were not included. For practical reasons, only a 4-hour sampling protocol was used for iohexol clearance. Conclusions: The CKD-EPIcr equation appeared less biased and was more accurate than the MDRD Study equation. No equation achieved an ideal P 30 in the overall population. Our data suggest that GFR estimation is as satisfactory in older people of European ancestry as it has been reported to be in younger individuals. © 2012 National Kidney Foundation, Inc. Source

Har R.L.H.,University of Toronto | Reich H.N.,A+ Network | Scholey J.W.,A+ Network | Daneman D.,University of Toronto | And 10 more authors.
PLoS ONE | Year: 2014

Objective: Urinary cytokine/chemokine levels are elevated in adults with type 1 diabetes (T1D) exhibiting renal hyperfiltration. Whether this observation extends to adolescents with T1D remains unknown. Our first objective was to determine the relationship between hyperfiltration and urinary cytokines/chemokines in normotensive, normoalbuminuric adolescents with T1D using GFRcystatin. Our second aim was to determine the relationship between urine and plasma levels of inflammatory biomarkers, to clarify the origin of these factors.Methods: Urine and serum cytokines/chemokines (Luminex platform) and GFRcystatin were measured in normofiltering (n=111, T1D-N, GFR,135 ml/min/1.73 m2) and hyperfiltering (n= 31, T1D-H, GFR ≥135 ml/min/1.73 m2) adolescents with T1D (ages 10-16), and in age and sex matched healthy control subjects (HC, n=59).Results:We noted significant step-wise increases in urinary cytokine/chemokine excretion according to filtration status with highest levels in T1D-H, with parallel trends in serum analyte concentrations. After adjusting for serum glucose at the time of sampling, differences in urinary cytokine excretion were not statistically significant. Only serum IL-2 significantly differed between HC and T1D (p=0.0076).Conclusions: Hyperfiltration is associated with increased urinary cytokine/chemokine excretion in T1D adolescents, and parallel trends in serum cytokine concentration. The GFR-associated trends in cytokine excretion may be driven by the effects of ambient hyperglycemia. The relationship between hyperfiltration, glycemia, and variations in serum and urine cytokine expression and their impact on future renal and systemic vascular complications requires further study. © 2014 Har et al. Source

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