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Context: Elevated levels of plasma leucine-rich α-2-glycoprotein 1 (LRG1), a component of transforming growth factor beta signaling, are associated with development and progression of chronic kidney disease in patients with type 2 diabetes (T2D). However, whether this relationship is causal is uncertain., Objectives: To identify genetic variants associated with plasma LRG1 levels and determine whether genetically predicted plasma LRG1 contributes to a rapid decline in kidney function (RDKF) in patients with T2D., Design and Participants: We performed a genome-wide association study of plasma LRG1 among 3694 T2D individuals [1881 (983 Chinese, 420 Malay, and 478 Indian) discovery from Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes cohort and 1813 (Chinese) validation from Diabetic Nephropathy cohort]. One- sample Mendelian randomization analysis was performed among 1337 T2D Chinese participants with preserved glomerular filtration function [baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2)]. RDKF was defined as an eGFR decline of 3 mL/min/1.73 m2/year or greater., Results: We identified rs4806985 variant near LRG1 locus robustly associated with plasma LRG1 levels (meta P = 6.66 × 10-16). Among 1337 participants, 344 (26%) developed RDKF, and the rs4806985 variant was associated with higher odds of RDKF (meta odds ratio = 1.23, P = 0.030 adjusted for age and sex). Mendelian randomization analysis provided evidence for a potential causal effect of plasma LRG1 on kidney function decline in T2D (P < 0.05)., Conclusion: We demonstrate that genetically influenced plasma LRG1 increases the risk of RDKF in T2D patients, suggesting plasma LRG1 as a potential treatment target. However, further studies are warranted to elucidate underlying pathways to provide insight into diabetic kidney disease prevention., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: Little is known about whether overhydration (OH), measured using bioimpedance assay (BIA), is associated with CKD progression in patients with type 2 diabetes mellitus (T2DM). We hypothesised that OH was a predictor, and pigment epithelium-derived factor (PEDF) was a modifiable risk factor of CKD progression., Methods: We conducted a prospective cohort study of 1,065 patients with clinically euvolemic T2DM who attended the diabetes centre in a tertiary hospital or primary care clinic. CKD progression was defined as a combination of the worsening of the KDIGO defined CKD category by eGFR and a ≥25% decline in eGFR compared to baseline., Results: Patients with T2DM in the highest tertile of OH and relative OH (OH/ extracellular water > 7%) were positively associated with CKD progression (hazard ratio [HR] 1.45 [95% confidence interval (CI) 1.14-1.85; p = 0.003 and HR 1.29 [95%CI 1.05-1.59; p = 0.017]). There were positive associations between PEDF and CKD progression (β = 1.10; p = 0.001) and between OH and CKD progression (β = 0.21; p = 0.036). OH remained positively associated with CKD progression mediated by PEDF., Conclusions: OH is an independent risk factor for CKD progression in patients with T2DM. Our study supports the novel definition of PEDF as a positive mediator between OH and CKD progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: The diabetic cohort (DC) was set up to study the determinants of complications in individuals with type 2 diabetes and examine the role of genetic, physiological and lifestyle factors in the development of complications in these individuals., Participants: A total of 14 033 adult participants with type 2 diabetes were recruited from multiple public sector polyclinics and hospital outpatient clinics in Singapore between November 2004 and November 2010. The first round of follow-up was conducted for 4131 participants between 2012 and 2016; the second round of follow-up started in 2016 and is expected to end in 2021. A questionnaire survey, physical assessments, blood and urine sample collection were conducted at recruitment and each follow-up visit. The data set also includes genetic data and linkage to medical and administrative records for recruited participants., Findings to Date: Data from the cohort have been used to identify determinants of diabetes and related complications. The longitudinal data of medical records have been used to analyse diabetes control over time and its related outcomes. The cohort has also contributed to the identification of genetic loci associated with type 2 diabetes and diabetic kidney disease in collaboration with other large cohort studies. About 25 scientific papers based on the DC data have been published up to May 2019., Future Plans: The rich data in DC can be used for various types of research to study disease-related complications in patients with type 2 diabetes. We plan to further investigate disease progression and new biomarkers for common diabetic complications, including diabetic kidney disease and diabetic neuropathy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Poor glycaemic control elevates the risk for vascular complications. Biomarkers for predicting susceptibility to glycaemic worsening are lacking. This 3-year prospective analysis assessed the utility of several circulating diabetes-related biomarkers for predicting loss of glycaemic control, and their contribution to albuminuria progression in type 2 diabetes mellitus (T2DM)., Methods: T2DM subjects with adequately-controlled diabetes (HbA1c < 8%) at initial recruitment were analysed (N = 859). Baseline plasma levels of osteoprotegerin (OPG), C-reactive protein (CRP), adiponectin, intercellular-cell adhesion molecule-1, and vascular-cell adhesion molecule-1 were quantified using immunoassay. Definitions for development of uncontrolled diabetes and albuminuria progression were HbA1c ≥ 8.0% and increase in albuminuria category at follow-up, respectively., Results: At follow-up, 185 subjects developed uncontrolled diabetes. Higher baseline CRP and OPG levels were observed in the high-risk individuals, and predicted increased risk for developing uncontrolled diabetes. OPG, but not CRP, was associated with albuminuria progression after multivariable adjustment. The relationship was attenuated following adjustment for development of uncontrolled diabetes, which emerged as a significant associate. Mediation analysis revealed that loss of glycaemic control explained 64.5% of the relationship between OPG and albuminuria progression., Conclusions: OPG outperformed other diabetes-related biomarkers to be a potentially useful biomarker for predicting loss of glycaemic control and its associated albuminuria deterioration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The progression trajectory of renal filtration function has not been well characterized in patients with early-onset type 2 diabetes mellitus (T2DM) although albuminuria is often reported in this population. We aim to study the risk of progressive chronic kidney disease (CKD) in individuals with early-onset T2DM., Methods: In total, 1189 T2DM participants were followed for 3.9 (interquartile range 3.2-4.7) years. Progressive CKD was defined as estimated glomerular filtration rate (eGFR) decline of ≥5 mL/min/1.73 m2 per year. Early-onset T2DM was defined as age at T2DM diagnosis between 18 and 30 years., Results: Compared with later-onset counterparts (N = 1032), participants with early-onset T2DM (N = 157) were more obese and had poorer glycaemic control at baseline. In the follow-up, 24.2% and 15.6% experienced progressive CKD in early-onset and later-onset participants, respectively (P = 0.007). Logistic regression suggested that participants with early-onset T2DM had 2.63-fold [95% confidence interval (CI) 1.46-4.75] higher risk of progressive CKD after accounting for multiple traditional risk factors. Furthermore, the excess risk of progressive CKD associated with early-onset T2DM mainly occurred in participants with preserved renal function [eGFR ≥60 mL/min/1.73 m2, odds ratio (OR) 2.85, 95% CI 1.50-5.42] and was more pronounced in those with diabetes duration <10 years (OR 3.67, 95% CI 1.51-8.90)., Conclusions: Individuals with early-onset T2DM have a higher risk of progressive CKD. The excess risk mainly exhibits in early stage of CKD and cannot be solely attributed to traditional risk factors and a longer diabetes duration., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Aims: Increased adiposity confers elevated risk for diabetic kidney disease (DKD) progression in type 2 diabetes mellitus (T2DM). This 3-year prospective study examined whether worsening of metabolic control e.g. development of uncontrolled diabetes mediated the relationship between increased adiposity and DKD deterioration., Methods: T2DM subjects who had adequately controlled diabetes (HbA1c < 8%) at initial recruitment were analysed (N = 853). HbA1c ≥ 8% at follow-up was classified as development of uncontrolled T2DM. Absolute changes in body weight (ΔWeight), body mass index (ΔBMI), and body fat mass (ΔBFM) were calculated by subtracting baseline from follow-up values. DKD deterioration (outcome) was defined as an increase in the composite ranking of relative risk by glomerular filtration rate and albuminuria levels (Kidney Disease: Improving Global Outcomes 2009)., Results: Subjects with deteriorated DKD displayed lower reduction in body composition at follow-up than those who remained stable or/improved (all P < 0.05). In separate regression models, ΔWeight (risk ratio (RR):1.04, 95% CI:1.01-1.06), ΔBMI (RR:1.07, 95% CI:1.01-1.13), and ΔBFM (RR:1.03, 95% CI:1.01-1.06) were independently associated with worsened DKD. The associations were attenuated after accounting for the loss of glycaemic control. Binary mediation analysis revealed that the development of uncontrolled diabetes explained 41.7%, 45.4% and 39.7%, respectively, of the effects of ΔWeight, ΔBMI and ΔBFM on the outcome., Conclusions: Among T2DM individuals who had adequately-controlled T2DM at initial recruitment, the relationship between gain in adiposity and DKD deterioration is mediated by the development of poor glycaemic control over time. Therefore, preventing worsening adiposity and hyperglycaemia is pivotal to impede DKD progression., (Copyright © 2019. Published by Elsevier B.V.)

Background: This study evaluated the association between gain in adiposity and renal decline in a large prospective multiethnic South-east Asian cohort with type 2 diabetes mellitus (T2DM)., Methods: Three years after the baseline visit, 2057 T2DM subjects were recalled for reassessment. The final cohort comprised 1014 subjects and was categorized into tertiles based on changes in body weight (ΔWt), body mass index (ΔBMI), visceral fat area (ΔVFA), and BMI-adjusted VFA (ΔVFA BMI ). Outcomes included annual and rapid (≥3 mL/min per 1.73 m 2 per year) decline in estimated glomerular filtration rate (eGFR) and progression of albuminuria., Results: Participants (mean [±SD] age 57 ± 11 years, 48.8% women, BMI 27.7 ± 5.4 kg/m 2 ) exhibited a median annual decline in eGFR of 1.0 mL/min per 1.73 m 2 . Compared with the lower tertiles, Tertile 3 of ΔWt, ΔBMI, ΔVFA, and ΔVFA BMI had the highest anthropometric increase, albeit of modest magnitude, and this was accompanied by the worst renal outcomes (all P < 0.05). The relationship between annual eGFR decline and Tertile 3 of ΔWt, ΔBMI, and ΔVFA BMI persisted after multivariate adjustment in men but not in women. In addition, Tertile 3 of ΔWt, ΔBMI, ΔVFA, and ΔVFA BMI predicted rapid eGFR decline. Anthropometric gains were also associated with progression of albuminuria., Conclusions: Modest longitudinal gain in adiposity was associated with progressive renal decline in T2DM patients, suggesting that increased adiposity over time adversely affects renal outcomes. Therefore, a carefully designed weight-neutral or -loss antidiabetic treatment regimen is important when managing T2DM in the clinic., (© 2018 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Fluctuation of kidney function may signify intra-glomerular microvascular hemodynamic instability. We aim to examine the association of long-term serum creatinine and estimated glomerular filtration rate variability with diabetic retinopathy., Methods: We included type 2 diabetes mellitus patients who attended the Diabetes Centre in 2011-2014 and were followed up (median = 3.2 years). Digital colour fundus photographs were assessed for diabetic retinopathy at follow-up. Diabetic retinopathy severity was categorized into non-proliferative diabetic retinopathy and proliferative diabetic retinopathy. We conducted a nested case-control study involving 177 diabetic retinopathy (118 non-proliferative diabetic retinopathy, 50 proliferative diabetic retinopathy) and 327 age- and gender-matched non-diabetic retinopathy. Serum creatinine measured before follow-up visit was obtained (⩾3 readings/patient). Variability was calculated as intra-individual standard deviation/√ n/( n - 1)., Results: Diabetic retinopathy have higher adjusted-serum creatinine-standard deviation than non-diabetic retinopathy [9.1 (4.9-21.6) vs 5.4 (3.4-10.1) µM, p < 0.001]. After multivariable adjustment, adjusted-serum creatinine-standard deviation was associated with diabetic retinopathy [odds ratio = 1.47, 95% confidence interval (1.02-2.10), p = 0.04]. The area under the curve increased significantly after adding adjusted-serum creatinine-standard deviation [0.70 (0.65-0.75) vs 0.72 (0.68-0.77), p < 0.03]. Proliferative diabetic retinopathy have higher adjusted-serum creatinine-standard deviation than non-proliferative diabetic retinopathy [15.5 (6.6-39.7) vs 7.47 (4.52-17.8) µM, p < 0.001]. After adjustment, adjusted-serum creatinine-standard deviation remained associated with non-proliferative diabetic retinopathy [1.48 (1.04-2.12), p = 0.03] and proliferative diabetic retinopathy [2.43 (1.34-4.39), p = 0.003; p-trend = 0.002]. Similar findings were observed for estimated glomerular filtration rate variability., Conclusion: Serum creatinine and estimated glomerular filtration rate variability is associated with the presence and severity of diabetic retinopathy independent of intra-individual means. This may inform novel therapeutic strategies aiming to achieve stable renal function in type 2 diabetes mellitus.

Aim: Glomerular hyperfiltration usually occurs early in development of kidney complications in diabetes. To understand hyperfiltration as a marker of renal disease progression in type 2 diabetes mellitus, we aimed to examine association between glomerular hyperfiltration (estimated glomerular filtration rate ⩾ 120 mL/min/1.73 m 2 ) and rapid renal decline (annual estimated glomerular filtration rate loss ⩾ 3 mL/min/1.73 m 2 )., Methods: This was a prospective cohort comprising 1014 patients with type 2 diabetes mellitus attending a Diabetes Centre of a regional hospital in 2002-2014. A separate prospective cohort, comprising 491 patients who attended Diabetes Centre or primary-care polyclinics, was used for validation. We performed binary mediation analysis to examine role of hyperfiltration on relationship between baseline haemoglobin A1c and rapid renal decline., Results: Among patients in discovery cohort, 5.2% had baseline hyperfiltration. Over mean follow-up of 6 years, 22.9% had rapid glomerular filtration rate decline. Baseline hyperfiltration was significantly associated with greater odds of rapid renal decline after adjusting for demographics, diabetes duration and clinical covariates (odds ratio: 2.57; 95% confidence interval: 1.21-5.46; p = 0.014). Similar finding was found in validation cohort (odds ratio: 2.98; 95% confidence interval: 1.06-8.42; p = 0.034). Hyperfiltration significantly accounted for 35.3% of association between increasing baseline haemoglobin A1c and rapid renal decline., Conclusion: Glomerular hyperfiltration is an independent risk factor of rapid renal decline. It mediates the association between increasing haemoglobin A1c and rapid renal decline.

Background: The soluble receptor for advanced glycation end products (sRAGE) has been shown to play an important role in diabetic complications. We conducted genome-wide association study (GWAS) of sRAGE in Asian type 2 diabetes mellitus (T2DM) patient and validated the association in an independent cohort of T2DM., Methods: GWAS for sRAGE was performed in 2058 T2DM patients. Associations between single-nucleotide polymorphisms (SNPs) and plasma sRAGE level were analyzed in an additive model using a linear mixed model. To validate the associations, we performed de novo genotyping in an independent cohort (n = 1984). We selected the top SNP for assessment with diabetic kidney disease (DKD)., Results: The strongest SNP, rs2070600C>T (P = 1.21 × 10-52), was a genotyped, missense SNP located on chromosome 6, corresponding to the RAGE (AGER) gene locus, the gene encoding RAGE. Conditioning analysis on rs2070600 revealed that rs2071288C>T was the top genotyped independent SNP (P = 8.36 × 10-10). Both SNPs were strongly and dose-dependently correlated with sRAGE level (TT = 399.6 pg/mL, CT = 737.0 pg/mL and CC = 967.0 pg/mL, P < 0.001 for rs2070600; TT = 687.9 pg/mL, CT = 737.6 pg/mL and CC = 904.7 pg/mL, P < 0.001 for rs2072188). Both SNPs were robustly replicated in the independent cohort, especially among Chinese patients (P = 9.02 × 10-72 for rs2070600; P = 1.13 × 10-9 for rs2071288). Log-transformed sRAGE was associated with DKD after adjustment for age, gender and ethnicity in pooled cohorts [odds ratio 2.536 (95% confidence interval 1.864-3.450), P < 0.001]. However, we did not observe any significant association between rs2070600 and DKD., Conclusions: Common variants in RAGE are strongly associated with plasma sRAGE level, which is associated with DKD. However, we did not find a causal link between sRAGE and renal function by Mendelian randomization., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Aim: Albuminuria progression has been associated with renal deterioration in type 2 diabetes (T2DM). Central arterial stiffness can aggravate systemic vasculopathy by propagating elevated systolic and pulse pressures forward, thereby accentuating global vascular injury. We aim to investigate whether central arterial stiffness is an independent predictor for albuminuria progression in a multi-ethnic T2DM Asian cohort in Singapore., Methods: In a prospective cohort, 1012 T2DM patients were assessed at baseline and after a median follow-up of 3.1years. 880 patients with baseline normo- (urinary albumin-to-creatinine ratio (ACR)<30mg/g, n=579) and microalbuminuria (ACR=30-299mg/g, n=301) were divided into progression and non-progression groups according to ACR changes. Progression was defined as transition from normo- to microalbuminuria, micro- to macroalbuminuria, or normo- to macroalbuminuria. Central arterial stiffness was estimated by carotid-femoral pulse wave velocity (PWV) using applanation tonometry method. Stepwise multiple regression analysis was used to determine the predictor(s) for albuminuria progression., Results: Albuminuria progression occurred in 178 patients (20.2%). Baseline PWV was higher in progression (10.1±2.9m/s) than non-progression group (9.2±2.4m/s, p<0.001). 1-SD increase in baseline PWV was associated with albuminuria progression (OR=1.457, 95% CI, 1.236-1.718, p<0.001). Stepwise regression analysis identified that baseline PWV (OR=1.241, 95% CI, 1.033-1.490, p=0.021), BMI (OR=1.046, 95% CI, 1.012-1.080, p=0.008), nature log-transformed estimated glomerular filtration rate (LneGFR) (OR=0.320, 95% CI, 0.192-0.530, p=0.010) and LnACR (OR=1.344, 95% CI, 1.187-1.522, p=0.008) are predictors for albuminuria progression., Conclusion: Increased central arterial stiffness at baseline predicted future progression of albuminuria. Our results suggest the potential benefit of ameliorating central arterial stiffness to retard albuminuria progression in T2DM., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Aims: The association of adhesion molecules ICAM-1 and VCAM-1 with cardiovascular diseases has been well-studied. However, their roles in diabetic kidney disease (DKD) are incompletely understood. We aim to study the association of plasma ICAM-1 and VCAM-1 with DKD in Asians with type 2 diabetes (T2DM)., Subjects and Methods: A total of 1950 Asians with T2DM were included in this cross-sectional study. Plasma ICAM-1 and VCAM-1 were measured by immunoassays., Results: Renal filtration function (eGFR) declined and urinary albumin-to-creatinine ratio (ACR) levels increased progressively with the increase in plasma VCAM-1 levels. In contrast, no significant changes in eGFR and ACR were observed in subjects across different plasma ICAM-1 levels. Both ICAM-1 and VCAM-1 were correlated with ACR (rho = 0.153, p < 0.001 for VCAM-1 and ACR; rho = 0.053, p = 0.020 for ICAM-1 and ACR) in bivariate correlation analysis. However, only VCAM-1 was correlated with eGFR (rho = -0.228, p < 0.001). Multivariable linear regression models revealed that VCAM-1, but not ICAM-1, was independently associated with eGFR and albuminuria. Backward linear regression suggested that plasma VCAM-1 variability was mainly determined by eGFR whereas plasma ICAM-1 level was mainly determined by C-reactive protein in patients with T2DM., Conclusions: Plasma VCAM-1 level, but not ICAM-1 level, was independently associated with prevalent DKD in Asians with T2DM. High level of ICAM-1 may be indicative of systemic inflammation and portends increase risk of incipient DKD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background Chronic kidney disease (CKD) is common among people with type 2 diabetes (T2D), and increases the risk of kidney failure and cardiovascular diseases. Shorter leukocyte telomere length (LTL) is associated with CKD in patients with T2D. We previously reported single-nucleotide polymorphisms (SNPs) associated with LTL in an Asian population. In this study, we elucidated the association of these SNPs with CKD in patients with T2D using the Mendelian randomization (MR) approach. Methods The cross-sectional association of 16 LTL SNPs with CKD, defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m2, was assessed among 4768 (1628 cases and 3140 controls) participants in the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in T2D and Diabetic Nephropathy cohorts. MR analysis was performed using the random-effect inverse-variance weighted (IVW) method, the weighted median, MR-Egger and Radial MR adjusted for age and sex-stratified by cohorts and ethnicity (Chinese and Malays), then meta-analyzed. Results Genetically determined shorter LTL was associated with increased risk of CKD in patients with T2D (meta-IVW adjusted odds ratio   = 1.51, 95% confidence interval 1.12–2.12, P   =   0.007, Phet   =   0.547). Similar results were obtained following sensitivity analysis. MR-Egger analysis (intercept) suggested no evidence of horizontal pleiotropy (β  = 0.010, P   =   0.751). Conclusions Our findings suggest that genetically determined LTL is associated with CKD in patients with T2D. Further studies are warranted to elucidate the causal role of telomere length in CKD progression. [ABSTRACT FROM AUTHOR]