Borschmann K.,University of Vic |
Borschmann K.,University of Melbourne |
Pang M.Y.C.,Hong Kong Polytechnic University |
Iuliano S.,University of Melbourne |
And 7 more authors.
International Journal of Stroke | Year: 2015
Stroke survivors experience accelerated bone loss and increased fracture risk, particularly in paretic weight bearing limbs. Understanding how these changes unfold and their relationship to stroke severity and physical activity could help in the development of targeted interventions to prevent or reduce the severity of these outcomes. The primary aim of this study is to investigate the time course and magnitude of changes in volumetric bone mineral density within the first year after stroke, and to examine relationships with physical activity and motor recovery. Design: This is a prospective, observational study of 43 nondiabetic, nonambulant adults with first ever hemispheric stroke. Primary outcome: The primary outcome was the difference in six-month change of total volumetric bone mineral density between paretic and nonparetic distal tibiae, measured at 7% of bone length site using high-resolution peripheral quantitative computed tomography. Secondary outcomes: The secondary outcomes are cortical and trabecular volumetric bone mineral density, cortical thickness, and total and cross-sectional areas of distal tibiae and radii of paretic and nonparetic limbs. Also included are total body and regional bone mineral density derived using dual-energy X-ray absorptiometry, physical activity measured using accelerometry, and motor recovery (Chedoke McMaster Stroke Assessment). Discussion: Measuring the timing and magnitude of changes to volumetric bone mineral density and bone structure from immediately after stroke, and relationships between these changes with physical activity and motor recovery will provide the basis for targeted interventions to reduce fracture risk in stroke survivors. © 2013 World Stroke Organization.
Ekinci E.I.,Endocrine Center |
Ekinci E.I.,University of Melbourne |
Jerums G.,Endocrine Center |
Jerums G.,University of Melbourne |
And 11 more authors.
Diabetes Care | Year: 2013
OBJECTIVE-The structural basis of normoalbuminuric renal insufficiency in patients with type 2 diabetes remains to be elucidated. We compared renal biopsy findings in patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) and measured GFR of <60 mL/min/1.73 m2, associated with either normo-, micro-, or macroalbuminuria. RESEARCH DESIGN AND METHODS-In patients with normo- (n = 8) ormicroalbuminuria (n = 6), renal biopsies were performed according to a research protocol. In patients with macroalbuminuria (n = 17), biopsies were performed according to clinical indication. Findings were categorized according to the Fioretto classification: category 1 (C1), normal/near normal; category 2 (C2), typical diabetic nephropathy (DN)with predominantly glomerular changes; and category 3 (C3), atypical with disproportionately severe interstitial/tubular/vascular damage and with no/mild diabetic glomerular changes. RESULTS-In our study population (mean eGFR 35 mL/min/1.73 m2), typical glomerular changes (C2) of DN were observed in 22 of 23 subjects with micro- or macroalbuminuria compared with 3 of 8 subjects with normoalbuminuria (P = 0.002). By contrast, predominantly interstitial or vascular changes (C3) were seen in only 1 of 23 subjects with micro- or macroalbuminuria compared with 3 of 8 normoalbuminuric subjects (P = 0.08). Mesangial area increased progressively fromnormal controls to patients with type 2 diabetes and normo-, micro-, and macroalbuminuria. Varying degrees of arteriosclerosis, although not necessarily the predominant pattern, were seen in seven of eight subjects with normoalbuminuria. CONCLUSIONS-Typical renal structural changes of DN were observed in patients with type 2 diabetes and elevated albuminuria. By contrast, in normoalbuminuric renal insufficiency, these changes were seen less frequently, likely reflecting greater contributions from aging, hypertension, and arteriosclerosis. © 2013 by the American Diabetes Association.
PubMed | Baker IDI Heart and Diabetes Institute, Monash University, Murdoch Childrens Research Institute, La Trobe University and 8 more.
Type: Journal Article | Journal: Diabetes | Year: 2016
Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein with dual roles in redox signaling and programmed cell death. Deficiency in AIF is known to result in defective oxidative phosphorylation (OXPHOS), via loss of complex I activity and assembly in other tissues. Because the kidney relies on OXPHOS for metabolic homeostasis, we hypothesized that a decrease in AIF would result in chronic kidney disease (CKD). Here, we report that partial knockdown of Aif in mice recapitulates many features of CKD, in association with a compensatory increase in the mitochondrial ATP pool via a shift toward mitochondrial fusion, excess mitochondrial reactive oxygen species production, and Nox4 upregulation. However, despite a 50% lower AIF protein content in the kidney cortex, there was no loss of complex I activity or assembly. When diabetes was superimposed onto Aif knockdown, there were extensive changes in mitochondrial function and networking, which augmented the renal lesion. Studies in patients with diabetic nephropathy showed a decrease in AIF within the renal tubular compartment and lower AIFM1 renal cortical gene expression, which correlated with declining glomerular filtration rate. Lentiviral overexpression of Aif1m rescued glucose-induced disruption of mitochondrial respiration in human primary proximal tubule cells. These studies demonstrate that AIF deficiency is a risk factor for the development of diabetic kidney disease.
Penfold S.A.,Baker IDI Heart and Diabetes Institute |
Coughlan M.T.,Baker IDI Heart and Diabetes Institute |
Patel S.K.,University of Melbourne |
Srivastava P.M.,University of Melbourne |
And 13 more authors.
Kidney International | Year: 2010
The accumulation of advanced glycation end products is thought to be a key factor in the initiation and progression of diabetic nephropathy. Here we determined whether the size of the ligands for the receptor for advanced glycation end products (RAGEs) that were present in the serum of patients with type 2 diabetes modulates their pathogenic potential. Serum was collected from control subjects and patients with type 2 diabetes with varying degrees of renal disease (normo-, micro-, or macroalbuminuria). The titers of the RAGE ligands N-carboxymethyllysine (CML), S100A, S100B, and high-mobility group box 1 (HMGB1) were measured by enzyme-linked immunosorbent assay in serum as well as in pooled size-fractionated serum. We also measured cellular binding of serum fractions to mesangial cells transfected with RAGE and examined the downstream signaling pathways. Circulating CML was increased in patients with type 2 diabetes, whereas HMGB1 was decreased. S100A8, S100BA9, and soluble RAGE were unchanged. The high-molecular-weight (over 50 kDa) serum fraction contained the greatest proportion of RAGE ligands, with all immunoreactivity and cellular binding observed only with serum fractions over 30 kDa. High-molecular-weight serum from macroalbuminuric patients showed greater RAGE binding capacity, modulation of cell-surface RAGE expression, increased phospho-protein kinase C-α, and p65 nuclear factor B DNA-binding activity, which were competitively inhibited by soluble RAGE or CML neutralizing antibodies. These data show that ligands that activate RAGE present in the circulation of patients with type 2 diabetes and nephropathy are predominantly of high molecular weight. © 2010 International Society of Nephrology.
Uma Jyothi K.,Indian Statistical Institute |
Jayaraj M.,Indian Statistical Institute |
Subburaj K.S.,Indian Statistical Institute |
Prasad K.J.,Endocrine Center |
And 3 more authors.
PLoS ONE | Year: 2013
We attempt to evaluate the nature of association of TCF7L2 gene variants with T2DM, for the first time in the population of Hyderabad, which is considered to be diabetic capital of India. It is a case-control study of the three SNPs of TCF7L2, rs7903146, rs12255372 and rs11196205, genotyped on Sequenom Massarray platform, in a sample of 758 patients and 621 controls. The risk allele frequency of the three SNPs was found to be significantly higher in the T2DM cases than controls, implicating susceptibility for diabetes (p<0.01). The greatest risk of developing the disease was conferred by rs7903146. Further, the logistic regression of genotypes of each SNP under log additive model, and the haplotypes constituted by at least one of the three risk alleles also show significantly greater risk of developing T2DM when compared to the wild type haplotype. Further, BMI and WHR emerge as significant covariates with confounding effects. The strong association of the TCF7L2 SNPs with T2DM is consistent with the findings among other Indian and Non-Indian populations, suggesting universal phenomena of its association across ethnic groups globally, both within and outside the Indian subcontinent, albeit the functional relevance of these SNPs needs yet to be established. © 2013 Uma Jyothi et al.
Teng J.,St Vincents Hospital |
Dwyer K.M.,St Vincents Hospital |
Hill P.,University of Melbourne |
See E.,St Vincents Hospital |
And 6 more authors.
Nephrology | Year: 2014
The spectrum of renal disease in patients with diabetes encompasses both diabetic kidney disease (including albuminuric and non-albuminuric phenotypes) and non-diabetic kidney disease. Diabetic kidney disease can manifest as varying degrees of renal insufficiency and albuminuria, with heterogeneity in histology reported on renal biopsy. For patients with diabetes and proteinuria, the finding of non-diabetic kidney disease alone or superimposed on the changes of diabetic nephropathy is increasingly reported. It is important to identify non-diabetic kidney disease as some forms are treatable, sometimes leading to remission. Clinical indications for a heightened suspicion of non-diabetic kidney disease and hence consideration for renal biopsy in patients with diabetes and nephropathy include absence of diabetic retinopathy, short duration of diabetes, atypical chronology, presence of haematuria or other systemic disease, and the nephrotic syndrome. Summary at a Glance This review article highlights the heterogeneity of renal disease in patients with diabetes. The spectrum of renal disease in patients with diabetes encompasses both diabetic kidney disease (including albuminuric and non-albuminuric phenotypes) and non-diabetic kidney disease which can be independent or superimposed on albuminuric diabetic kidney disease. It is important to identifying non-diabetic kidney disease because it is potentially reversible. The clinical features suggestive of non-diabetic kidney disease, which should prompt consideration of renal biopsy, are discussed. © 2014 Asian Pacific Society of Nephrology.
MacIsaac R.J.,Victoria University of Melbourne |
Ekinci E.I.,Victoria University of Melbourne |
Premaratne E.,Endocrine Center |
Lu Z.X.,Melbourne Pathology |
And 5 more authors.
BMC Nephrology | Year: 2015
Background: Our hypothesis was that both the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations would underestimate directly measured GFR (mGFR) to a similar extent in people with diabetes and preserved renal function. Methods: In a cross-sectional study, bias (eGFR - mGFR) was compared for the CKD-EPI and MDRD equations, after stratification for mGFR levels. We also examined the ability of the CKD-EPI compared with the MDRD equation to correctly classify subjects to various CKD stages. In a longitudinal study of subjects with an early decline in GFR i.e., initial mGFR >60 ml/min/1.73 m2 and rate of decline in GFR ((increment)mGFR) > 3.3 ml/min/1.73 m2 per year, (increment)mGFR (based on initial and final values) was compared with (increment)eGFR by the CKD-EPI and MDRD equations over a mean of 9 years. Results: In the cross-sectional study, mGFR for the whole group was 80 ± 2.2 ml/min/1.73 m2 (n = 199, 75 % type 2 diabetes). For subjects with mGFR >90 ml/min/1.73 m2 (mGFR: 112 ± 2.0, n = 76), both equations significantly underestimated mGFR to a similar extent: bias for CKD-EPI: -12 ± 1.4 ml/min/1.73 m2 (p < 0.001) and for MDRD: -11 ± 2.1 ml/min/1.73 m2 (p < 0.001). Using the CKD-EPI compared with the MDRD equation did not improve the number of subjects that were correctly classified to a CKD-stage. No biochemical or clinical patient characteristics were identified to account for the under estimation of mGFR values in the normal to high range by the CKD-EPI equation. In the longitudinal study (n = 30, 66 % type 1 diabetes), initial and final mGFR values were 102.8 ± 6 and 54.6 ± 6.0 ml/min/1.73 m2, respectively. Mean (increment)GFR (ml/min/1.73 m2 per year) was 6.0 by mGFR compared with only 3.0 by MDRD and 3.2 by CKD-EPI (both p < 0.05 vs mGFR) Conclusions: Both the CKD-EPI and MDRD equations underestimate reference GFR values >90 ml/min/1.73 m2 as well as an early decline in GFR to a similar extent in people with diabetes. There is scope to improve methods for estimating an early decline in GFR. © 2015 MacIsaac et al.
Bala Y.,INSA Lyon |
Bala Y.,University of Lyon |
Zebaze R.,Endocrine Center |
Zebaze R.,University of Melbourne |
And 2 more authors.
Current Opinion in Rheumatology | Year: 2015
Purpose of review Trabecular bone loss and vertebral fractures are historical hallmarks of osteoporosis. During the past 70 years, this view has dominated research aiming to understand the structural basis of bone fragility. We suggest this notion needs to be revised to recognize and include the role of cortical bone deterioration as an important determinant of bone strength throughout life. Recent findings About 80% of the fragility fractures involve the appendicular skeleton, at regions comprising large amounts of cortical bone. Up to 70% of the age-related bone loss at these locations is the result of intracortical remodeling that cavitates cortical bone producing porosity. It is now possible to accurately quantify cortical porosity in vivo and use this information to understand the pathogenesis of bone fragility throughout life, assist in identifying patients at risk for fracture, and use this as a potential marker to monitor the effects of treatment on bone structure and strength. Summary Cortical bone has an important role in determining bone strength. The loss of strength is the result of intracortical and endocortical remodeling imbalance that produces cortical porosity and thinning. Studies are needed to determine whether porosity is an independent predictor of fracture risk and whether a reduction in porosity serves as a surrogate of antifracture efficacy. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Kommoju U.J.,Indian Statistical Institute |
Maruda J.,Indian Statistical Institute |
Kadarkarai Samy S.,Indian Statistical Institute |
Irgam K.,Indian Statistical Institute |
And 2 more authors.
Journal of Diabetes | Year: 2014
Background: We attempted to validate earlier findings on the nature of the association of the IRS1, CAPN10, and PPARG genes with type 2 diabetes mellitus (T2DM) in the high-risk population of Hyderabad, India. Methods: A sample of 1379 subjects (758 T2DM patients, 621 controls) was genotyped for single nucleotide polymorphisms (SNPs) of the IRS1 (rs1801278), CAPN10 (rs3792267, rs5030952), and PPARG (rs1801282) genes. Results: The allele and genotype frequencies of IRS1 (rs1801278) and CAPN10 (rs3792267) SNPs differed significantly between the patient and control groups. Logistic regression analysis suggested a significant association of these two SNPs (P≤0.007) with T2DM and the strength of association did not alter when adjusted for age, gender, body mass index, and the waist:hip ratio as covariates. The same two SNPs showed significant association in multivariate logistic regression analyses, even after Bonferroni correction for multiple testing, suggesting an independent nature of the role of these genes in the manifestation of T2DM in our population. Conclusions: We replicated the significant association of rs1801278 and rs3792267 SNPs of the IRS1 and CAPN10 genes with T2DM in the population of Hyderabad. Despite the known biological significance of the PPARG gene and a sufficient statistical power of the present study, we could not replicate the association of PPARG with T2DM in our high-risk population. Given the vast ethnic, geographic, and genetic heterogeneity of the Indian population, many more studies are needed covering the ethnic and geographic heterogeneity of India to enable identification of an Indian-specific profile of genes associated with T2DM. © 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.
PubMed | Endocrine Center, St Vincents Hospital Melbourne and Melbourne Pathology
Type: | Journal: BMC nephrology | Year: 2015
Our hypothesis was that both the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations would underestimate directly measured GFR (mGFR) to a similar extent in people with diabetes and preserved renal function.In a cross-sectional study, bias (eGFR - mGFR) was compared for the CKD-EPI and MDRD equations, after stratification for mGFR levels. We also examined the ability of the CKD-EPI compared with the MDRD equation to correctly classify subjects to various CKD stages. In a longitudinal study of subjects with an early decline in GFR i.e., initial mGFR > 60 ml/min/1.73 m(2) and rate of decline in GFR (mGFR)> 3.3 ml/min/1.73 m(2) per year, mGFR (based on initial and final values) was compared with eGFR by the CKD-EPI and MDRD equations over a mean of 9 years.In the cross-sectional study, mGFR for the whole group was 80 2.2 ml/min/1.73 m(2) (n = 199, 75 % type 2 diabetes). For subjects with mGFR >90 ml/min/1.73 m(2) (mGFR: 112 2.0, n = 76), both equations significantly underestimated mGFR to a similar extent: bias for CKD-EPI: -12 1.4 ml/min/1.73 m(2) (p < 0.001) and for MDRD: -11 2.1 ml/min/1.73 m(2) (p < 0.001). Using the CKD-EPI compared with the MDRD equation did not improve the number of subjects that were correctly classified to a CKD-stage. No biochemical or clinical patient characteristics were identified to account for the under estimation of mGFR values in the normal to high range by the CKD-EPI equation. In the longitudinal study (n = 30, 66 % type 1 diabetes), initial and final mGFR values were 102.8 6 and 54.6 6.0 ml/min/1.73 m(2), respectively. Mean GFR (ml/min/1.73 m(2) per year) was 6.0 by mGFR compared with only 3.0 by MDRD and 3.2 by CKD-EPI (both p < 0.05 vs mGFR) CONCLUSIONS: Both the CKD-EPI and MDRD equations underestimate reference GFR values > 90 ml/min/1.73 m(2) as well as an early decline in GFR to a similar extent in people with diabetes. There is scope to improve methods for estimating an early decline in GFR.