Su Chi Lim

Discovery and validation of serum creatinine variability as novel biomarker for predicting onset of albuminuria in Type 2 diabetes mellitus

AIMnWe aim to study association serum creatinine(cr) variability and albuminuria progression.nnnMETHODSnWe conducted a retrospective cohort study on patients with Type 2 Diabetes Mellitus at a Diabetes Centre in Singapore (discovery cohort). Outcome is worsening of urinary albumin-to-creatinine(ACR) across stages. Cr variability was expressed as adjusted cr-intrapersonal standard deviation(SD) and coefficient-of-variation(cr-CV). A separate cohort was used for validating association between cr variability and albuminuria progression (validation cohort).nnnRESULTSnOver median follow-up of 4.2u202fyears, 38.4% of 636 patients had albuminuria progression in the discovery cohort. Increasing log-transformed adjusted cr-intrapersonal SD and cr-CV were significantly associated with albuminuria progression: HRs 1.43 (95%CI 1.11-1.85) and 1.44 (1.11-1.87) respectively in the discovery cohort, and HRs 1.94 (1.09-3.45) and 1.91 (1.05-3.45) respectively in the validation cohort. When stratified by baseline urinary ACR, higher cr variability was significantly associated with albuminuria progression in patients with normoalbuminuria but not microalbuminuria.nnnCONCLUSIONSnCr variability independently predicts albuminuria onset. This is evident in patients with normoalbuminuria, suggesting that higher cr variability could herald albuminuria onset.

Urine tricarboxylic acid (TCA) cycle metabolites predict progressive chronic kidney disease in type 2 diabetes.

ContextnMetabolites in the tricarboxylic acid (TCA) cycle are not only involved in energy metabolism but also play important roles in non-energy production activities.nnnObjectivenTo study whether baseline urine key TCA cycle metabolites (lactate, pyruvate, citrate, α-ketoglutaric acid, succinate, fumarate, and malate) independently predict risk of chronic kidney disease (CKD) progression [fast estimated glomerular filtration rate (eGFR) decline] in individuals with type 2 diabetes mellitus (T2DM).nnnDesignnOne discovery and one validation nested case-control studies in two independent T2DM cohorts.nnnSetting and ParticipantsnSubjects with T2DM were recruited and followed in a regional hospital and at a primary care facility.nnnMain Outcome MeasuresneGFR trajectory (slope) was estimated by linear regression. Progressive CKD was defined as eGFR decline of ≥5 mL/min/1.73 m2 per year.nnnResultsnAs compared with those with stable renal function (n = 271), participants who experienced progressive CKD (n = 116) had a lower level of urine citrate but significantly higher levels of lactate, fumarate, and malate levels at baseline. Both fumarate and malate predicted progressive CKD independent of traditional cardio-renal risk factors, including eGFR and albuminuria. Fumarate interacted with sex (P for interaction = 0.03) and independently predicted progressive CKD in male but not female participants. All these findings were reproducible in a validation study (case n = 96, control n = 402). Exploratory analysis suggested that fumarate might partially mediate the effect of oxidative stress on CKD progression.nnnConclusionsnKey TCA cycle metabolites, especially fumarate, may be involved in the pathophysiologic pathway independent of traditional cardio-renal risk factors, leading to CKD progression in patients with T2DM.

Ethnic disparities in relationship of obesity indices and telomere length in Asians with type 2 diabetes

Obesity and shorter telomeres increase the risk for diabetes complications and mortality. However, the relationship between obesity and telomere length in diverse Asian populations with type 2 diabetes (T2D) is not well understood. This study examined the association of baseline and changes in obesity indices with telomere length in multiethnic Asian populations with T2D.

Risk of progressive chronic kidney disease in individuals with early-onset type 2 diabetes: a prospective cohort study

BackgroundnThe 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.nnnMethodsnIn 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 ≥5u2009mL/min/1.73u2009m2 per year. Early-onset T2DM was defined as age at T2DM diagnosis between 18 and 30u2009years.nnnResultsnCompared with later-onset counterparts (Nu2009=u20091032), participants with early-onset T2DM (Nu2009=u2009157) 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 (Pu2009=u20090.007). 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 ≥60u2009mL/min/1.73u2009m2, odds ratio (OR) 2.85, 95% CI 1.50-5.42] and was more pronounced in those with diabetes duration <10u2009years (OR 3.67, 95% CI 1.51-8.90).nnnConclusionsnIndividuals 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.

Microvascular endothelial function is an independent predictor for albuminuria progression among Asians with type 2 diabetes-A prospective cohort study

We aim to investigate whether microvascular endothelial dysfunction is an independent predictor for future albuminuria progression in T2DM cohort.

The association of serum creatinine and estimated glomerular filtration rate variability with diabetic retinopathy in Asians with type 2 diabetes: A nested case–control study

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 (medianu2009=u20093.2u2009years). 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/(nu2009–u20091). 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)u2009µM, pu2009<u20090.001]. After multivariable adjustment, adjusted-serum creatinine-standard deviation was associated with diabetic retinopathy [odds ratiou2009=u20091.47, 95% confidence interval (1.02–2.10), pu2009=u20090.04]. 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), pu2009<u20090.03]. 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)u2009µM, pu2009<u20090.001]. After adjustment, adjusted-serum creatinine-standard deviation remained associated with non-proliferative diabetic retinopathy [1.48 (1.04–2.12), pu2009=u20090.03] and proliferative diabetic retinopathy [2.43 (1.34–4.39), pu2009=u20090.003; p-trendu2009=u20090.002]. 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.

Long-term prospective observation suggests that glomerular hyperfiltration is associated with rapid decline in renal filtration function: A multiethnic study

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 rateu2009⩾u2009120u2009mL/min/1.73 m2) and rapid renal decline (annual estimated glomerular filtration rate lossu2009⩾u20093u2009mL/min/1.73 m2). 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 6u2009years, 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.

The role of triglyceride glucose index in development of Type 2 diabetes mellitus

AIMSnTriglyceride-Glucose (TyG) is an emerging surrogate indicator of insulin resistance. We explored the role of TyG in development of Type 2 Diabetes Mellitus (T2DM) and elucidated the mechanism for the relationship.nnnMETHODSn4109 subjects without baseline T2DM participated in a community screening programme in 2013-2016. TyG was calculated as Ln[fasting triglyceride level (mg/dl)u202f×u202ffasting plasma glucose (FPG) (mg/dl)/2]. Outcome was T2DM defined as FPGu202f≥u202f7.0u202fmmol/l; current treatment with anti-diabetes medication; and/or self-reported diabetes on follow-up screening. We used Cox proportion-hazard model to assess risk of T2DM by TyG quartiles at baseline. Binary mediation analysis was performed to examine extent of mediation by TyG between Body Mass Index (BMI) and T2DM development.nnnRESULTSnAfter 5734.23 person-years of follow-up, T2DM developed in 117 subjects with an incidence of 20.40/1000 person-years. Risk of T2DM incidence was increased with quartiles 2, 3 and 4 versus quartile 1 of TyG (adjusted HR 1.79(95%CI 0.80-3.99), 2.54 (1.18-5.49) and 4.68(2.19-10.01), Ptrendu202f<u202f0.001) across TyG quartiles. TyG accounted for 35.1% of association between BMI and T2DM development, having adjusted for potential cofounders (pu202f<u202f0.001).nnnCONCLUSIONSnTyG is potentially useful for predicting T2DM in clinical practice. It is a potential mediator of association between BMI and T2DM development.