Identifying high-risk hospitalised chronic kidney disease patient using electronic health records for serious illness conversation.

INTRODUCTION: This study aimed to identify risk factors that are associated with increased mortality that could prompt a serious illness conversation (SIC) among patients with chronic kidney disease (CKD). METHODS: The electronic health records of adult CKD patients admitted between August 2018 and February 2020 were retrospectively reviewed to identify CKD patients with >1 hospitalisation and length of hospital stay ≥4 days. Outcome measures were mortality and the duration of hospitalisation. We also assessed the utility of the Cohen's model to predict 6-month mortality among CKD patients. RESULTS: A total of 442 patients (mean age 68.6 years) with median follow-up of 15.3 months were identified. The mean (standard deviation) Charlson Comorbidity Index [CCI] was 6.8±2.0 with 48.4% on chronic dialysis. The overall mortality rate until August 2020 was 36.7%. Mortality was associated with age (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.29-1.77), CCI≥7 (1.58, 1.08-2.30), lower serum albumin (1.09, 1.06-1.11), readmission within 30-day (1.96, 1.43-2.68) and CKD non-dialysis (1.52, 1.04-2.17). Subgroup analysis of the patients within first 6-month from index admission revealed longer hospitalisation stay for those who died (CKD-non dialysis: 5.5; CKD-dialysis: 8.0 versus 4 days for those survived, P<0.001). The Cohen's model demonstrated reasonable predictive ability to discriminate 6-month mortality (area under the curve 0.81, 95% CI 0.75-0.87). Only 24 (5.4%) CKD patients completed advanced care planning. CONCLUSION: CCI, serum albumin and recent hospital readmission could identify CKD patients at higher risk of mortality who could benefit from a serious illness conversation.

Optimizing Vancomycin Dosing in Chronic Kidney Disease by Deriving and Implementing a Web-Based Tool Using a Population Pharmacokinetics Analysis.

Background: Chronic kidney disease (CKD) patients requiring intravenous vancomycin bear considerable risks of adverse outcomes both from the infection and vancomycin therapy itself, necessitating especially precise dosing to avoid sub- and supratherapeutic vancomycin exposure. Methods: In this retrospective study, we performed a population pharmacokinetic analysis to construct a vancomycin dose prediction model for CKD patients who do not require renal replacement therapy. The model was externally validated on an independent cohort of patients to assess its prediction accuracy. The pharmacokinetic parameter estimates and the equations were productized into a Web application (VancApp) subsequently implemented in routine care. The association between VancApp-based dosing and time-to-target concentration attainment, 30-day mortality, and nephrotoxicity were assessed postimplementation. Results: The model constructed from an initial cohort (n = 80) revealed a population clearance and volume of distribution of 1.30 L/h and 1.23 L/kg, respectively. External model validation (n = 112) demonstrated a mean absolute prediction error of 1.25 mg/L. Following 4 months of clinical implementation of VancApp as an optional alternative to usual care [VancApp (n = 22) vs. usual care (n = 21)], patients who had received VancApp-based dosing took a shorter time to reach target concentrations (median: 66 vs. 102 h, p = 0.187) and had fewer 30-day mortalities (14% vs. 24%, p = 0.457) compared to usual care. While statistical significance was not achieved, the clinical significance of these findings appear promising. Conclusion: Clinical implementation of a population pharmacokinetic model for vancomycin in CKD can potentially improve dosing precision in CKD and could serve as a practical means to improve vital clinical outcomes.

Association of central arterial stiffness with the presence and severity of diabetic retinopathy in Asians with type 2 diabetes.

OBJECTIVE: Arterial stiffness has been associated with diabetic retinopathy; however, the information is limited in Asians. We aim to examine the association of central arterial stiffness with the presence and severity of diabetic retinopathy in type 2 diabetes mellitus patients in Singapore. METHODS: Arterial stiffness was estimated by carotid-femoral pulse wave velocity and augmentation index using applanation tonometry method. Digital colour fundus photographs from 1,203 patients were assessed for diabetic retinopathy. Diabetic retinopathy severity was categorized into non-proliferative diabetic retinopathy and proliferative diabetic retinopathy. Logistic regression model was used to evaluate the associations of diabetic retinopathy with pulse wave velocity and augmentation index. RESULTS: Diabetic retinopathy was diagnosed in 391 (32.5%) patients, including 271 non-proliferative diabetic retinopathy and 108 proliferative diabetic retinopathy. Diabetic retinopathy have higher pulse wave velocity (11.2 ± 3.3 vs 9.5 ± 2.6 m/s, p < 0.001) and augmentation index (28.4 ± 9.4 vs 26.1 ± 10.6%, p < 0.001) than non-diabetic retinopathy. After multivariable adjustment, pulse wave velocity [odds ratio = 1.11 (95% confidence interval = 1.05-1.17), p < 0.001] and augmentation index [odds ratio = 1.03 (95% confidence interval = 1.01-1.04), p = 0.009] was associated with diabetic retinopathy. In severity analyses, pulse wave velocity was associated with non-proliferative diabetic retinopathy [odds ratio = 1.10 (95% confidence interval = 1.03-1.17), p = 0.002] and proliferative diabetic retinopathy [odds ratio = 1.15 (95% confidence interval = 1.06-1.25), p = 0.001] (p-trend < 0.001). Augmentation index showed significant associations with non-proliferative diabetic retinopathy [odds ratio = 1.02 (95% confidence interval = 1.01-1.04), p = 0.008], but not with proliferative diabetic retinopathy [odds ratio = 1.01 (95% confidence interval = 0.98-1.04), p = 0.36] (p-trend = 0.03). CONCLUSION: Central arterial stiffness was associated with the presence and severity of diabetic retinopathy in type 2 diabetes mellitus patients, suggesting its etiologic implication in diabetic retinopathy.

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 (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.

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 rate ⩾ 120 mL/min/1.73 m2) and rapid renal decline (annual estimated glomerular filtration rate loss ⩾ 3 mL/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 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.

Low, rather than High, Body Mass Index Is a Risk Factor for Acute Kidney Injury in Multiethnic Asian Patients: A Retrospective Observational Study.

BACKGROUND: Acute kidney injury (AKI) is common in hospitalised patients. The relationship between body mass index (BMI) and the risk of having AKI for patients in the acute hospital setting is not known, particularly in the Asian population. METHODS: This was a retrospective, single-centre, observational study conducted in Singapore, a multiethnic population. All patients aged ≥21 years and hospitalised from January to December 2013 were recruited. RESULTS: A total of 12,555 patients were eligible for the analysis. A BMI of <18.5 kg/m2 was independently associated with the development of AKI in hospitalised patients (odds ratio (OR): 1.23 [95% confidence interval [CI]: 1.04-1.44, P = 0.01]) but not for overweight and obesity. Subgroup analysis further revealed that underweight patients aged ≥75 and repeated hospitalisation posed a higher risk of AKI (OR: 1.25 [CI: 1.01-1.56], P = 0.04; OR: 1.23 [CI: 1.04-1.44], P = 0.01, resp.). Analyses by interactions between different age groups and BMI using continuous or categorised variables did not affect the overall probability of developing AKI. CONCLUSIONS: Underweight Asian patients are susceptible to AKI in acute hospital settings. Identification of this novel risk factor for AKI allows us to optimise patient care by prevention, early detection, and timely intervention.

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

OBJECTIVE: We aim to investigate whether microvascular endothelial dysfunction is an independent predictor for future albuminuria progression in T2DM cohort. METHODS: A total of 1098 patients with T2DM were clinically assessed at baseline and 3.2-year follow-up. Progression was defined as transition from normoalbuminuria (ACR <30 mg/g) to microalbuminuria (ACR = 30-299 mg/g) or macroalbuminuria (ACR >300 mg/g), or microalbuminuria to macroalbuminuria. Microvascular endothelial vasodilation at baseline was quantified using LDF. The increase in perfusion in response to ACh and NaNP was calculated. Logistic regression model was used to estimate the OR for albuminuria progression. RESULTS: Albuminuria progression occurred in 226 (20.6%) patients. Baseline ACh was significantly higher in nonprogression than progression group (80.0 ± 53.2% vs 72.0 ± 49.7%, P = .04). There is no significant difference in NaNP between the two groups (111.1 ± 80.3% vs 121.1 ± 87.4%, P = .12). After multivariable adjustment, 1-SD increase in ACh was marginally associated with albuminuria progression (OR = 0.87, 95% CI, 0.72-1.02, P = .08) in all patients. When stratified by baseline albuminuria, 1-SD increase in ACh was significantly associated with albuminuria progression in normoalbuminuria (OR = 0.76, 95% CI, 0.59-0.97, P = .03), but not in microalbuminuria patients (OR = 1.18, 95% CI, 0.81-1.70, P = .39). CONCLUSIONS: Impaired endothelial-dependent microvascular reactivity predicts the onset of albuminuria progression among T2DM patients with normoalbuminuria.

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

AIM: We aim to study association serum creatinine(cr) variability and albuminuria progression. METHODS: We 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"). RESULTS: Over median follow-up of 4.2 years, 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. CONCLUSIONS: Cr variability independently predicts albuminuria onset. This is evident in patients with normoalbuminuria, suggesting that higher cr variability could herald albuminuria onset.

Efficacy of self-monitoring of blood glucose versus retrospective continuous glucose monitoring in improving glycaemic control in diabetic kidney disease patients.

AIMS: Patients with diabetic kidney disease (DKD) on anti-diabetic agents, are at greater risk of glycemic variations, both hypoglycemia and hyperglycemia. We aimed to compare glycemic control (using HbA1c) and hypoglycemia incidence in patients with Stage 3 DKD (eGFR 30-60 mL/min per 1.73 m2 ), receiving retrospective CGM-guided anti-diabetic therapy versus self-monitoring of blood glucose (SMBG) over 3 months. METHODS: Thirty patients with HbA1c >8% were randomized to 6-day retrospective CGM or SMBG. In the CGM group, CGM was worn at the beginning and 6 weeks. HbA1c, assessment of hypoglycaemia events (self-reported and BG < 4 mmol/L from CGM/SMBG data) and medication adjustment were performed at baseline and 3 months. All patients received education on hypoglycaemia avoidance. RESULTS: Fourteen patients were allocated to CGM and 16 to SMBG. Mean (±SD) eGFR was 42.9 ± 10.3 mL/min. Majority (86.7%) of patients had diabetes duration >10 years and on insulin therapy (90%). HbA1c improved significantly from baseline 9.9 ± 1.2 to 9.0 ± 1.5% (P < 0.001) at 3 months, with no difference between CGM (9.8 ± 1.2 to 8.8 ± 1.8%, P = 0.009) or SMBG (9.9 ± 1.3 to 9.1 ± 1.1%, P = 0.007) groups (P = 0.869 between groups). In the CGM group, percentage duration in hyperglycaemia (BG > 10 mmol/L) reduced from baseline 65.4 ± 22.4% to 54.6 ± 23.6% (P = 0.033) at 6 weeks, with a non-significant rise in percentage duration in hypoglycaemia from 1.2 ± 2.2% to 4.0 ± 7.0% (P = 0.176). There was no difference in self-reported and documented hypoglycaemia events. CONCLUSION: In a pilot study of DKD patients, short-term episodic use of CGM reduced time spent in hyperglycaemia range without significantly increasing time-exposure to hypoglycaemia. However, both CGM and SMBG were equally effective in improving glycaemic control.

Short-term outcomes of patients with Type 2 diabetes mellitus treated with canagliflozin compared with sitagliptin in a real-world setting.

INTRODUCTION: We aimed to evaluate the effectiveness and safety of canagliflozin as compared to sitagliptin in a real-world setting among multiethnic patients with Type 2 diabetes mellitus (T2DM) in Singapore. METHODS: This was a new-user, active-comparator, single-centre retrospective cohort study. Patients aged 18-69 years with T2DM and estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 were eligible for inclusion if they were initiated and maintained on a steady daily dose of canagliflozin 300 mg or sitagliptin 100 mg between 1 May and 31 December 2014, and followed up for 24 weeks. RESULTS: In total, 57 patients (canagliflozin 300 mg, n = 22; sitagliptin 100 mg, n = 35) were included. The baseline patient characteristics in the two groups were similar, with overall mean glycated haemoglobin (HbA1c) of 9.4% ± 1.4%. The use of canagliflozin 300 mg was associated with greater reductions in HbA1c (least squares [LS] mean change -1.6% vs. -0.4%; p < 0.001), body weight (LS mean change -3.0 kg vs. 0.2 kg; p < 0.001) and systolic blood pressure (LS mean change: -9.7 mmHg vs. 0.4 mmHg; p < 0.001), as compared with sitagliptin 100 mg. About half of the patients on canagliflozin 300 mg reported mild osmotic diuresis-related side effects that did not lead to drug discontinuation. CONCLUSION: Our findings suggest that canagliflozin was more effective than sitagliptin in reducing HbA1c, body weight and systolic blood pressure in patients with T2DM, although its use was associated with an increased incidence of mild osmotic diuresis-related side effects.

Long-term outcomes of patients with type 2 diabetes attending a multidisciplinary diabetes kidney disease clinic.

BACKGROUND: The best model of care to retard diabetic kidney disease (DKD) in the clinic is underexplored. In this study we investigated the long-term renal outcomes of a joint endocrinologist-nephrologist clinic. METHODS: The present study was a nested case-control study derived from a cohort of patients with type 2 diabetes mellitus (T2DM) seen prospectively at a secondary care diabetes center (DC). Cases ("DKD clinic group") were patients seen at the CKD clinic after being referred by physicians in DCs for management of DKD. Controls ("non-DKD clinic group") were patients from the same DC (i.e. same source population) with the same inclusion criteria of Stages 3-4 chronic kidney disease (CKD) at baseline but not seen at the DKD clinic. The outcome was Stage 5 CKD, defined as an estimated glomerular filtration rate <15 mL/min per 1.73 m2 . RESULTS: During the median follow-up period of 3.0 years (interquartile range 1.2-5.1 years), 240 patients (28.7%) reached Stage 5 CKD, with 45.8% and 54.2% of those reaching Stage 5 CKD in the DKD and non-DKD clinic groups, respectively. Multivariable Cox regression revealed that the DKD clinic group had a lower risk of progressing to Stage 5 CKD (hazard ratio 0.55; 95% confidence interval 0.36-0.83; P = 0.004) compared with the non-DKD clinic group. CONCLUSIONS: Multidisciplinary endocrinology and nephrology care in the DKD clinic is associated with a lower risk of end-stage renal disease. These findings may inform future management strategies targeted at patients with T2DM and CKD, especially with regard to joint specialist management involving endocrinologists and nephrologists.

Outcomes of a nephrologist-driven tunnelled dialysis catheter insertion service in South East Asia.

INTRODUCTION: Tunnelled dialysis catheters (TDCs) are being increasingly inserted by nephrologists globally but there is limited experience and paucity of published outcomes data from South-East Asia (SEA). This study was conducted to analyse the outcomes of TDC insertion by nephrologists from a single centre in SEA. METHODS: All patients who underwent TDC insertion by nephrologists from October 2013 to June 2016 were included. TDC survival was calculated using Kaplan-Meier survival method. Impact of variables was assessed using Cox proportional hazards model. RESULTS: A total of 344 TDCs were inserted in 274 patients. The most common indication was haemodialysis initiation (60.2%) followed by existing catheter dysfunction (CD) (12.2%), failed vascular access (10.2%) and catheter-related bacteraemia (CRB) (9.9%). Insertion was successful in 97% patients. The most common location was the right internal jugular vein (87%). The cumulative survival for all TDCs inserted, as defined by the time to non-elective removal of a TDC, at 3, 6 and 9 months was 83%, 61%, and 44%, respectively. Median catheter survival was 231 days. Common indications for removal were CD (13.4%) and CRB or suspected infection (12.5%). Common complications were bleeding (8.72%), infection (13.7%) and CD (16.5%). Median time to infection was 103 days. In multivariate analysis, male gender was associated with poor catheter survival, for primary insertions (p = 0.015, HR 0.62) and diabetes was associated with TDC infection (p = 0.024, OR 1.1). CONCLUSIONS: This is one of the first reports of TDC insertion by nephrologists from SEA. Our outcomes compare favourably with those reported in the literature.

Association of apolipoprotein-CIII (apoC-III), endothelium-dependent vasodilation and peripheral neuropathy in a multi-ethnic population with type 2 diabetes.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a common complication of Type 2 diabetes (T2D). Apart from hyperglycemia, its pathogenesis is poorly understood. Apolipoprotein-CIII (apoC-III) associated with triglyceride metabolism, is a risk factor for cardiovascular disease. Its role in DPN is not well-established. We studied the associations of apoC-III, endothelial function and DPN. METHODS: In patients with T2D, anthropometric data, fasting blood, and urine were collected for biochemistry and urine albumin/creatinine measurements (uACR). Endothelial function assessments were performed by laser Doppler flowmetry/imaging. DPN was considered present if there was an abnormal finding in monofilament (≤8 of 10 points) or neurothesiometer testing≥25V on either foot. Plasma apoC-III was assessed by ELISA. RESULTS: Monofilament and neurothesiometer readings were measured in 1981 patients, mean age 57.4±10.8 years old. DPN prevalence was 10.8% (n=214). Patients with DPN compared to those without, were significantly older (p<0.0001), with longer duration of T2D (p<0.0001), had higher BMI (p=0.006), higher glucose (p=0.015) and HbA1c (p<0.0001), Systolic blood pressure (SBP) (p<0.0001), lower eGFR (p<0.0001), higher urine ACR (p<0.0001), poorer endothelium-dependent and endothelium-independent vasodilation (both p<0.0001), higher VCAM-1 (p<0.0001) and higher apoC-III [285.3 (195.2-405.6) vs 242.9(165.0-344.0) µg/ml]. After adjustment, log transformed apoC-III, remained independently associated with the presence of DPN (B=0.965, SE=0.397, p=0.015). CONCLUSION: Plasma apoC-III is higher in patients with DPN. Apart from its known association with lipids and macrovascular complications, this study suggests its association with DPN. Whether regulating apoC-III metabolism may be an important new therapeutic approach to managing dyslipidemia and microvascular complications in T2D remains to be proven in future mechanistic and clinical studies.

Association of the anti-angiogenic factor secreted protein and rich in cysteine (SPARC) with vascular complications among Chinese type 2 diabetic patients in Singapore.

AIMS: This study evaluated the association of the anti-angiogenic SPARC with known angiogenesis-associated factors and diabetes-related micro- and macro-vascular complications in a Singapore Chinese cohort with type 2 diabetes (T2DM). METHODS: Plasma SPARC was measured by immunoassay in 438 T2DM adults (mean age:58±11years). RESULTS: Higher SPARC levels in subjects stratified by SPARC tertiles displayed decreased pro-angiogenic adiponectin, osteopontin, vascular cell adhesion molecule (VCAM)-1 and matrix metalloproteinase (MMP)-2 concentrations (all p<0.05). The anti-angiogenic pigment epithelium-derived factor (PEDF) level was not statistically different among the SPARC tertiles. Age-adjusted partial correlation revealed significant associations of SPARC with adiponectin, osteopontin, VCAM-1, MMP-2, and PEDF (all p<0.05). Lower SPARC was accompanied by less favorable estimated glomerular filtration rate (eGFR) and carotid-femoral pulse wave velocity (PWV) readings (all p<0.05). Conversely, ankle-brachial index (ABI) reduced with increasing SPARC (p=0.048). The eGFR (B=0.834, p=0.019), PWV (B=-7.925, p=0.009), and ABI (B=-142.160, p=0.010) remained as determinants of SPARC after confounder adjustment. Moreover, individuals in the lowest SPARC tertile had increased odds of aortic stiffness (OR=1.900, 95% CI=1.103-3.274) but reduced odds of peripheral arterial disease (OR=0.400, 95% CI=0.175-0.919). However, SPARC was not independently associated with chronic kidney disease. CONCLUSIONS: The anti-angiogenic SPARC may be associated with the pathophysiology of diabetes-related macrovascular complications.

Arterial stiffness is an independent predictor for albuminuria progression among Asians with type 2 diabetes-A prospective cohort study.

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.

Genetic variants in the receptor for advanced glycation end products (RAGE) gene were associated with circulating soluble RAGE level but not with renal function among Asians with type 2 diabetes: a genome-wide association study.

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.

Development and validation of a predictive model for Chronic Kidney Disease progression in Type 2 Diabetes Mellitus based on a 13-year study in Singapore.

AIMS: This study aims to develop and validate a predictive model for Chronic Kidney Disease (CKD) progression in Type 2 Diabetes Mellitus (T2DM). METHODS: We conducted a prospective study on 1582 patients with T2DM from a Diabetes Centre in regional hospital in 2002-2014. CKD progression was defined as deterioration across eGFR categories with ⩾25% drop from baseline. The dataset was randomly split into development (70%) and validation (30%) datasets. Stepwise multivariable logistic regression was used to identify baseline predictors for model development. Model performance in the two datasets was assessed. RESULTS: During median follow-up of 5.5years, 679 (42.9%) had CKD progression. Progression occurred in 467 (42.2%) and 212 patients (44.6%) in development and validation datasets respectively. Systolic blood pressure, HbA1c, estimated glomerular filtration rate and urinary albumin-to-creatinine ratio were associated with progression. Areas under receiving-operating-characteristics curve for the training and test datasets were 0.80 (95%CI, 0.77-0.83) and 0.83 (95%CI, 0.79-0.87). Observed and predicted probabilities by quintiles were not statistically different with Hosmer-Lemeshow χ2 0.65 (p=0.986) and 1.36 (p=0.928) in the two datasets. Sensitivity and specificity were 71.4% and 72.2% in development dataset, and 75.6% and 72.3% in the validation dataset. CONCLUSIONS: A model using routinely available clinical measurements can accurately predict CKD progression in T2DM.

Onset and progression of kidney disease in type 2 diabetes among multi-ethnic Asian population.

AIM: To elucidate the natural history of chronic kidney disease(CKD), which is defined as estimated glomerular filtration rate(eGFR)<60ml/min/1.73m(2) and/or increase of urinary albumin-to-creatinine ratio (uACR)≥30mg/g), and to identify factors associated with its onset and progression. METHODS: Prospective cohort study on individuals with T2DM attending Diabetes Centre in a regional hospital in Singapore from 2002. There were 553 patients with no pre-existing CKD for "onset" analysis and 967 patients with pre-existing CKD for "progression" analysis. Multivariable logistic regression was performed to determine risk factors of the outcomes. RESULTS: The mean follow-up period was 5.8years (4.5-7.1) and 5.3years (3.9-6.9) for the onset and progression cohorts respectively. About 45% of individuals developed CKD and 41% had progression. Among subjects with CKD onset, albuminuria-only occurred in 75% of them. Majority of the patients remained in the same CKD risk-category during follow-up. Progression and regression occurred across all CKD-categories. Transitions to adjacent risk-category were much more likely than transitions bypassing adjacent state. Risk factors for CKD onset included baseline albuminuria, eGFR, HbA1c variability, body mass index, triglycerides and age (all P<0.05). The predictors for CKD progression or rapid-progression included HbA1c variability, baseline albuminuria, systolic blood pressure, LDL-cholesterol, eGFR, HbA1c and ethnicity (all P<0.05). CONCLUSIONS: Albuminuria was the first manifestation of CKD in most T2DM patients. Transition across CKD-category occurred bi-directionally, but evolved largely in a stepwise fashion. The onset and progression of CKD were predicted by multiple risk factors, some of which were modifiable.

Long-term diabetes outcomes in multi-ethnic Asians living in Singapore.

AIMS: This study aims to assess ethnic and gender disparities on long-term complications among multi-ethnic Asians with Diabetes Mellitus (DM) living in Singapore. METHODS: We conducted a retrospective cohort study involving 3006 patients who attended a diabetes centre in a hospital from 2003 to 2011. Demographics and clinical data were obtained from standardised questionnaire and patient's case records. Age at onset of diabetes was calculated as current age minus duration of DM in years. Outcomes on Acute Myocardial Infarction (AMI), End-Stage Renal Failure (ESRF) and all-cause death were ascertained by data linkage with national registries. RESULTS: The mean duration of diabetes exposure was 15.6 ± 9.1 years for AMI, 15.4 ± 9.0 years for ESRF and 17.0 ± 9.0 years for death. After adjusting for traditional cardiovascular risk factors, Malay and Indian with diabetes remained significantly associated with AMI with HRs 2.81(95%CI, 1.81-4.37) and 2.03 (95%CI, 1.15-3.59), respectively. The effect of Malays on ESRF and death became attenuated post-adjustment. Besides mortality, there was preponderance for other adverse outcomes associated with male. CONCLUSIONS: Ethnic (Malay worse) and gender (male worse) disparities were observed in DM-related outcomes. The results may inform allocation of finite resources and to organize care targeted at high-risk groups.

Ethnic disparity in inter-arm systolic blood pressure difference and its determinants among Asians with type 2 diabetes: A cross-sectional study / Journal of the ASEAN Federation of Endocrine Societies

@#<p><strong>OBJECTIVES:</strong> An inter-arm difference in systolic blood pressure (IADSBP) of 10 mmHg or more has been associated with cardiovascular disease (CVD) and increased mortality in T2DM patients. We aim to study ethnic disparity in IADSBP and its determinants in a multi-ethnic T2DM Asian cohort.<br /><strong>METHODOLOGY:</strong> Bilateral blood pressures were collected sequentially in Chinese (n=654), Malays (n=266) and Indians (n=313). IADSBP was analyzed as categories (<br /><strong>RESULTS:</strong> Malays (27.4%) and Indians (22.4%) had higher prevalence of IADSBP ?10 mmHg than Chinese (17.4%) (p=0.002). After adjustment for age, gender, duration of diabetes, hemoglobin A1c, body mass index (BMI), heart rate, pulse wave velocity (PWV), estimated glomerular filtration rate (eGFR), albumin-to-creatinine ratio (ACR), smoking, hypertension, soluble receptor for advanced glycation end products (sRAGE), and usage of hypertension medications, ethnicity remained associated with IADSBP. While Malays were more likely to have IADSBP ?10 mmHg than Chinese (OR=1.648, 95%CI: 1.138-2.400, p=0.009), Indians had comparable odds with the Chinese. BMI (OR=1.054, 95%CI: 1.022-1.087, p=0.001) and hypertension (OR=2.529, 95%CI: 1.811-3.533, p<0.001) were also associated with IADSBP ?10 mmHg.<br /><strong>CONCLUSION:</strong> IADSBP in Malays were more likely to be ?10 mmHg than the Chinese which may explain their higher risk for CVD and mortality. Measuring bilateral blood pressures may identify high-risk T2DM individuals for intensive risk factor-management.</p>