Sunil Sethi

National University Health System, Singapore

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Publications (48)147.96 Total impact

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    ABSTRACT: The relationship between glycated hemoglobin A1c (HbA1c) and average glucose has been described by the empirically derived estimated average glucose (eAG) equation in the A1c-derived Average Glucose (ADAG) study, with extensive calibration efforts in four secondary reference HbA1c methods. It is not known if this relationship is preserved when HbA1c is measured by routine laboratory methods under routine conditions. We measured average glucose (mAG) by six days of continuous glucose monitoring in 45 adults with stable HbA1c (<1% HbA1c change in the preceding two months). Subjects with medical conditions that may confound HbA1c measurement, including anemia and hemoglobinopathy, were excluded. HbA1c were measured using Bio-Rad Variant II (cation-exchange HPLC), Bio-Rad in2it (boronate affinity HPLC) and Roche Tina-quant (immunoassay) methods. The average differences between eAG derived from the routine HbA1c methods and mAG were 10.4% (Variant II), 6.0% (Tina-quant) and 1.0% (in2it). The regression coefficients between the mAG and HbA1c are different between in2it (mAG, mmol/L = 0.58×%HbA1c + 2.3), Tina-quant and Variant II (both mAG, mmol/L = 0.66×%HbA1c + 1.9). However, the 95% confidence intervals of the slope and bias of these methods overlap. The correlation between mAG and HbA1c was greatest when measured using the Variant II (r(2)=0.84), followed by Tina-quant (r(2)=0.82) and in2it (r(2)=0.71). The relationship between HbA1c and measured average glucose is method-dependent despite improved HbA1c standardization. The differences in relationship may reflect as discrepant eAG and home glucose monitoring results. Copyright © 2015. Published by Elsevier Inc.
    Clinical Biochemistry 03/2015; DOI:10.1016/j.clinbiochem.2015.02.012 · 2.23 Impact Factor
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    ABSTRACT: Purpose:Leptin, a 167-aminoacid protein secreted by adipocytes has been shown to reduce beta-amyloid deposition and intracellular lipid concentration in animal models, two key pathogenic mechanisms underlying aging. We examined the association between serum leptin levels and age-related macular degeneration (AMD). Methods: We conducted a population-based case-control study including Chinese and Indian adults aged 40-80 years who participated in the Singapore Epidemiology of Eye Diseases Study (2007-2011). AMD was assessed from retinal photographs graded using a modified Wisconsin Age-Related Maculopathy Grading System (n=423, early = 387, late=36). Controls (n=927) without AMD were frequency matched for age, gender and ethnicity. Serum leptin levels were measured using direct sandwich ELISA. Results:Participants with AMD had lower levels of leptin compared to those without (mean (SD) = 10.0 (11.5) vs. 12.9 (16.4) ng/mL; p=0.001). Mean levels of leptin among those with late, early and without AMD were 8.8, 10.1 and 12.9 (p-trend= 0.005). In multivariable models adjusting for potential confounders including smoking, body mass index, blood pressure and HDL cholesterol, increasing quartiles of leptin were associated with lower odds of AMD, odds ratio (95% confidence interval) of AMD was 0.56 (0.34-0.92) comparing highest to lowest quartile of serum leptin. In subgroup analyses, the inverse association between leptin and AMD was significant in women, Indian ethnicity and ex-smokers (all P-interaction>0.05). Conclusions:Higher serum leptin levels were inversely associated with AMD. These findings, if confirmed in prospective studies, may provide insights into new pathogenic pathways and possibly therapeutic targets in AMD. Copyright © 2015 by Association for Research in Vision and Ophthalmology.
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    ABSTRACT: Vitamin D levels are linked to susceptibility to infections, but its relevance in candidaemia is unknown. We aimed to investigate the in-vivo sequelae of vitamin D3 supplementation in systemic Candida infection. Implicating the role of vitamin D in Candida infections, we showed that candidemia patients had significantly lower 25-OHD concentrations. Candida-infected mice treated with low dose 1,25(OH)2D3 had reduced fungal burden and better survival relative to untreated mice. Conversely, higher 1,25(OH)2D3 doses led to poor outcomes. Mechanistically, low dose 1,25(OH)2D3 induced proinflammatory immune responses. This was mediated through suppression of SOCS3 and induction of VDR binding with the vitamin D response elements in the IFN-γ promoter. These beneficial effects were negated with higher vitamin D(3) doses. While the anti-inflammatory effects of vitamin D3 are well-described, we found that lower doses conversely conferred proinflammatory benefits in Candida infection. Our study highlights caution against extreme deviations of vitamin D levels in infections. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    The Journal of Infectious Diseases 01/2015; DOI:10.1093/infdis/jiv033 · 5.78 Impact Factor
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    ABSTRACT: Background. The use of spot urine protein to creatinine ratios in estimating 24 hr urine protein excretion rates for diagnosing and managing chronic kidney disease (CKD) predated the standardization of creatinine assays. The comparative predictive performance of spot urine ratios and 24 hr urine collections (of albumin or protein) for the clinical outcomes of CKD progression, end-stage renal disease (ESRD), and mortality in Asians is unclear. We compared 4 methods of assessing urine protein excretion in a multiethnic population of CKD patients. Methods. Patients with CKD (n = 232) provided 24 hr urine collections followed by spot urine samples the next morning. We created multiple linear regression models to assess the factors associated with GFR decline (median follow-up: 37 months, IQR 26-41) and constructed Cox proportional-hazards models for predicting the combined outcome of ESRD and death. Results. The linear regression models showed that 24 hr urine protein excretion was most predictive of GFR decline but all other methods were similar. For the combined outcomes of ESRD and death, the proportional hazards models had similar predictive performance. Conclusions. We showed that all methods of assessments were comparable for clinical end-points, and any method can be used in clinical practice or research.
    01/2015; 2015:156484. DOI:10.1155/2015/156484
  • Clinical Chemistry and Laboratory Medicine 12/2014; DOI:10.1515/cclm-2014-0862 · 2.96 Impact Factor
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    ABSTRACT: Clinical practice guidelines recommend using creatinine-based equations to estimate glomerular filtration rates (GFRs). While these equations were formulated for Caucasian-American populations and have adjustment coefficients for African-American populations, they are not validated for other ethnicities. The Chronic Kidney Disease-Epidemiology Collaborative Group (CKD-EPI) recently developed a new equation that uses both creatinine and cystatin C. We aimed to assess the accuracy of this equation in estimating the GFRs of participants (healthy and with chronic kidney disease [CKD]) from a multiethnic Asian population. Serum samples from the Asian Kidney Disease Study and the Singapore Kidney Function Study were used. GFR was measured using plasma clearance of 99mTc-DTPA. GFR was estimated using the CKD-EPI equations. The performance of GFR estimation equations were examined using median and interquartile range values, and the percentage difference from the measured GFR. The study comprised 335 participants (69.3% with CKD; 38.5% Chinese, 29.6% Malays, 23.6% Indians, 8.3% others), with a mean age of 53.5 ± 15.1 years. Mean standardised serum creatinine was 127 ± 86 μmol/L, while mean standardised serum cystatin C and mean measured GFR were 1.43 ± 0.74 mg/L and 67 ± 33 mL/min/1.73 m2, respectively. The creatinine-cystatin C CKD-EPI equation performed the best, with an estimated GFR of 67 ± 35 mL/min/1.73 m2. The new creatinine-cystatin C equation estimated GFR with little bias, and had increased precision and accuracy in our multiethnic Asian population. This two-biomarker equation may increase the accuracy of population studies on CKD, without the need to consider ethnicity.
    Singapore medical journal 12/2014; 55(12):656-9. · 0.63 Impact Factor
  • Tze Ping Loh, Weng Kung Peng, Lan Chen, Sunil Kumar Sethi
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    ABSTRACT: Aims We aim to develop smoothed continuous 2.5th and 97.5th percentile values for labile glycated haemoglobin A(1c) to glycated haemoglobin A(1c) (LHbA(1c): HbA(1c)) ratio against HbA(1c), and apply them on our patient population for identification of potentially spurious HbA(1c) measurements. Methods The LHbA(1c) and HbA(1c) were measured using Bio-rad Variant II high-performance liquid chromatography system. We recorded the LHbA(1c) and HbA(1c) values of 1555 patients who had normal chromatograms. Using these results, the 2.5th and 97.5th percentile reference limits of the LHbA(1c): HbA(1c) ratio were described by LHbA(1c): HbA(1c)=-0.0072xHbA(1c) +0.2925 and LHbA(1c): HbA(1c)=-0.0132xHbA(1c) +0.5327, respectively. Results When the reference intervals were applied on a separate 1000 patients, 34 and 29 of them had abnormally high and low LHbA(1c): HbA(1c) ratios, respectively. Most of the observed high ratios were associated concurrently with elevated plasma glucose, anaemia, chronic liver and kidney diseases. A suppressed ratio was mostly associated with haemoglobin variants. Patients with heterozygous HbE or HbS variants tend to have lower LHbA(1c): HbA(1c) ratios while the converse is true for heterozygous HbJ. Conclusions The continuous LHbA(1c): HbA(1c) ratio may be used to detect confounding factors or spurious HbA(1c) results, but its performance is confounded and reduced by the ambient plasma glucose.
    Journal of Clinical Pathology 06/2014; 67(8). DOI:10.1136/jclinpath-2014-202346 · 2.55 Impact Factor
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    ABSTRACT: Background. Chronic kidney disease (CKD) is identified in the general population using estimated glomerular filtration rates (eGFR) calculated from a serum creatinine-based equation, the chronic kidney disease-epidemiology collaboration (CKD-EPI) equation. Using serum cystatin C in combination may improve eGFR accuracy. We evaluated the new CKD-EPI equations incorporating cystatin C in a population of Asian Indians in classifying CKD across body mass index, diabetes, and hypertension status. Methods. We retrieved standardized serum creatinine and serum cystatin C data from a cohort of 2877 Asian Indians aged 40-80 years from the Singapore Indian Eye Study and calculated eGFR (in mL/min/1.73 m(2)) with the new CKD-EPI equations and serum creatinine only equation. Results. The creatinine only equation mean eGFR (88 ± 17) was similar to using spline Log cystatin C (88 ± 22). The lowest mean eGFR (81 ± 21) was obtained with the spline Log cystatin C-age, sex, and weight equation. The creatinine only equation had the fewest participants (7.1%) with eGFR <60 and spline Log cystatin C-age, sex, and weight equation had the most (16.1%). Conclusions. Using serum cystatin C resulted in widely varying eGFR which significantly affected the classification of chronic kidney disease.
    04/2014; 2014:746497. DOI:10.1155/2014/746497
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    Karen Tan, Sunil K Sethi
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    ABSTRACT: Cardiac and renal diseases often coexist and patients with cardiac and renal failure have high morbidity and mortality. Cardiorenal syndromes (CRSs) are disorders of the heart and kidneys whereby dysfunction in one organ may induce dysfunction in the other organ. Five subtypes of CRSs have been defined by the Acute Dialysis Quality Initiative Consensus Group. There is a need for early detection and monitoring of patients with CRSs. Biomarkers play a key role in the diagnosis and monitoring of acute myocardial infarction, chronic heart failure, and chronic kidney disease. In recent years, new biomarkers have been identified that may play a role in the early diagnosis of acute kidney injury. Herein, we review the use of serum and urine biomarkers in the diagnosis and management of CRSs. The established cardiac and renal biomarkers such as the cardiac troponins, natriuretic peptides, urine albumin, and creatinine, as well as the new renal biomarkers cystatin C and neutrophil gelatinase-associated lipocalin are reviewed in detail. The recent advances in assay methods, clinical studies, and recommendations in clinical guidelines are discussed. With advances in biomarker research, in future, perhaps a multimarker approach will become feasible to stratify the diagnosis of CRS for individualized treatment and prognosis.
    04/2014; DOI:10.1016/j.trsl.2014.04.011
  • Pathology 03/2014; DOI:10.1097/PAT.0000000000000087 · 2.62 Impact Factor
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    ABSTRACT: Obesity is associated with diabetes and hypertension, two major risk factors for chronic kidney disease (CKD). Recently, it has been shown that obesity is associated with preclinical kidney disease defined by elevated levels of cystatin C among those without CKD in US adults. However, the association of obesity with cystatin C is not known in industrialized Asian populations. We examined 2,052 Indian adults aged 40-80 years in Singapore who were free of CKD defined as a serum creatinine-based estimated glomerular filtration rate (eGFRcr) <60 mL/min/1.73 m(2) and/or the presence of microalbuminuria. Body mass index (BMI) values were categorized into normal (18.5-24.9), overweight (25-29.9) and obese (≥30 kg/m(2)). Elevated serum cystatin C was defined as cystatin C ≥1 mg/L. Overweight and obesity were significantly associated with elevated levels of cystatin C after adjusting for potential confounders including diabetes and hypertension and eGFRcr. Compared to those with normal weight, the odds ratio (95 % confidence interval) of elevated cystatin C was 1.49 (1.17-1.88) for overweight and 3.20 (2.33-4.39) for obese. This association was consistently present when BMI was analyzed as a continuous variable and also in subgroups of men, women and in those without diabetes mellitus or hypertension. Higher BMI levels are associated with preclinical kidney disease in Indian adults aged 40 years and above without CKD.
    Clinical and Experimental Nephrology 02/2014; 18(6). DOI:10.1007/s10157-014-0945-6 · 1.71 Impact Factor
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    Karen Tan, Sunil K. Sethi
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    ABSTRACT: Cardiac and renal diseases often co-exist and patients with cardiac and renal failure have high morbidity and mortality. Cardiorenal syndromes (CRS) are disorders of the heart and kidneys whereby dysfunction in one organ may induce dysfunction in the other. Five subtypes of CRS have been defined by the Acute Dialysis Quality Initiative Consensus Group. There is a need for early detection and monitoring of patients with CRS. Biomarkers play a key role in the diagnosis and monitoring of acute myocardial infarction, chronic heart failure and chronic kidney disease. In recent years, new biomarkers have been identified that may play a role in the early diagnosis of acute kidney injury (AKI). Herein, we review the use of serum and urine biomarkers in the diagnosis and management of CRS. The established cardiac and renal biomarkers such as the cardiac troponins, natriuretic peptides, urine albumin and creatinine, as well as the new renal biomarkers cystatin C and neutrophil gelatinase associated lipocalin (NGAL) are reviewed in detail. The recent advances in assay methods, clinical studies, and recommendations in clinical guidelines are discussed. With advances in biomarker research, in future, perhaps a multi-marker approach will become feasible to stratify the diagnosis of CRS for individualized treatment and prognosis.
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    ABSTRACT: The Chronic Kidney Disease Collaboration - Epidemiology (CKD-EPI) GFR estimation equation is believed to estimate GFR more accurately in healthy people but this has not been validated in Asians. We studied the distribution of GFR in a multi-ethnic Asian population without CKD, and compared the performance of measures of GFR estimation, including the CKD-EPI equation, Cockroft-Gault equation, and 24-hour urine creatinine clearances. 103 healthy volunteers without a history of kidney disease, hypertension, or diabetes underwent GFR measurement using 3-sample plasma clearance of (99m) Tc-DTPA. Cockroft-Gault estimated GFR and 24-hour urine creatinine clearances were normalized to body surface area. The mean measured GFR was 101 ±15.8 mL/min/1.73m(2) and was lowest in Indians (93 ±12.3 mL/min/1.73m(2) ; p <0.001). The CKD-EPI equation appears to be more accurate for healthy participants. Estimated GFR correlated with measured GFR (r = 0.57, p <0.001), and the mean difference is 3.72 ±14.43 mL/min/1.73m(2) (p <0.001). However, estimating GFR using self-directed 24-hour urine creatinine clearances is poorer than using the CKD-EPI equation. GFR estimation using self-directed 24-hour urine collection for creatinine clearance is less accurate than using the CKD-EPI equation. A larger study is required to clarify GFR in healthy Asians, and the association of health outcomes of Asian kidney donors with lower GFR thresholds.
    Nephrology 11/2013; 19(2). DOI:10.1111/nep.12182 · 1.86 Impact Factor
  • Pathology 08/2013; 45(5):527-9. DOI:10.1097/PAT.0b013e32836359e1 · 2.62 Impact Factor
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    Karen M L Tan, Sharon Saw, Sunil K Sethi
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    ABSTRACT: In this study, we aimed to determine the normal ranges of 25-hydroxy-vitamin D3 (25-OHD3 ), parathyroid hormone (PTH), and the markers of bone turnover, procollagen type 1 N propeptide (P1NP) and C-terminal cross-linked telopeptide of type 1 collagen (CTX), in normal healthy women in Singapore, and to explore the relationship between vitamin D, PTH, and these markers of bone turnover in the women. One hundred and ninety-seven healthy women, aged 25 to 60, were selected from a hospital staff health screening program; 68% were Chinese, 18% Malay, and 14% Indian. P1NP, CTX, and 25-OHD3 were measured using the Roche Cobas® electrochemiluminescence immunoassay. Serum PTH was measured using the Siemens ADVIA Centaur® immunoassay. Sixty-five percent had 25-OHD3 concentrations <50 nmol/l. Vitamin D insufficiency (25-OHD3 < 50 nmol/l) was more prevalent in Malays (89%) and Indians (82%) compared to Chinese (56%). There was no correlation between vitamin D and age. PTH positively correlated with age, and Malays and Indians had higher PTH concentrations than Chinese. There was an inverse correlation between PTH and 25-OHD3 , but no threshold of 25-OHD3 concentrations at which PTH plateaued. The bone turnover markers P1NP and CTX inversely correlated with age but were not different between ethnic groups. CTX and P1NP exhibited good correlation, however, there was no significant correlation between 25-OHD3 or PTH concentrations and the bone turnover markers P1NP and CTX. Healthy women in Singapore have a high prevalence of vitamin D insufficiency. Vitamin D insufficiency was more prevalent in Malays and Indians compared to Chinese.
    Journal of Clinical Laboratory Analysis 07/2013; 27(4):301-4. DOI:10.1002/jcla.21602 · 1.14 Impact Factor
  • Tze Ping Loh, Chin Meng Khoo, Pin Lim, Sunil Kumar Sethi
    Clinical Chemistry and Laboratory Medicine 06/2013; 51(11):1-3. DOI:10.1515/cclm-2013-0319 · 2.96 Impact Factor
  • Tze Ping Loh, Sai Mun Leong, Sunil Kumar Sethi
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    ABSTRACT: No abstract available.
    Clinical Chemistry and Laboratory Medicine 04/2013; 51(9):1-3. DOI:10.1515/cclm-2013-0160 · 2.96 Impact Factor
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    Clinical Chemistry 02/2013; 59(5). DOI:10.1373/clinchem.2012.195321 · 7.77 Impact Factor
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    ABSTRACT: OBJECTIVE: The control of hypertension is often suboptimal, and it is frequently due to excessive sodium intake. Monitoring sodium intake is cumbersome and involves 24-hour collection of urine. We hypothesize that a spot urine test can accurately predict 24-hour urine sodium excretion in an Asian population. DESIGN: This is a prospective, observational study. We used stored urine specimens (n = 333) from the Asian Kidney Disease Study and Singapore Kidney Function Study Phase I. We measured spot urine tests and correlated these variables to the previously measured 24-hour urine sodium measurements. RESULTS: Age, gender, ethnicity, diastolic blood pressure, height, weight, body mass index, serum creatinine, spot urine sodium, spot urine chloride, and spot urine osmolality were associated with 24-hour urine sodium excretion. The final model for predicting 24-hour urine sodium less than 100 mmol included age, gender, ethnicity, weight, and spot urine sodium. CONCLUSION: Spot urine sodium can help monitor a patient's sodium intake when used in the derived 5-variable equation.
    Journal of Renal Nutrition 02/2013; DOI:10.1053/j.jrn.2012.12.004 · 2.55 Impact Factor
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    Karen Tan, Lizhen Ong, Sunil K Sethi, Sharon Saw
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    ABSTRACT: OBJECTIVES: The COBAS Elecsys PTH(1-84) assay is a novel, electro-chemiluminescence immunoassay that exclusively measures full-length parathyroid hormone (PTH). The aim of this study is to compare the automated biointact Elecsys PTH(1-84) assay with four contemporary, iPTH assays in chronic kidney disease (CKD) patients. Design and Methods We compared the Elecsys PTH(1-84) assay with four iPTH assays (Siemens ADVIA Centaur, Ortho Clinical Diagnostics (OCD) VITROS, Beckman Access2, Abbott ARCHITECT) in the measurement of PTH in 83 local CKD patients. Majority of the patients (44) had CKD but were not on dialysis, 15 were on hemodialysis, 15 were on peritoneal dialysis, and 9 were post-renal transplant. The precision performance and correlation of the assays were determined. PTH(1-84) concentrations were correlated with calcium, phosphate, alkaline phosphatase, hemoglobin, HbA1c and lipid concentrations. RESULTS: The Elecsys PTH(1-84) assay showed comparable precision and good correlation with the iPTH assays. Although the four different iPTH assays correlated well with each other, there was significant discrepancy among assays. The discrepancy among assays increased with increasing PTH concentrations. The ADVIA Centaur and ARCHITECT assays measured significantly higher PTH concentrations than the VITROS and Access2 assays. PTH(1-84) showed a positive association with phosphate and alkaline phosphatase and an inverse association with HbA1c. There was no significant association with lipid concentrations. CONCLUSIONS: The third generation Elecsys PTH(1-84) assay had comparable precision performance and correlated well with second generation iPTH assays. However, significant discrepancy was found among the four iPTH assays in measuring iPTH in CKD patients.
    Clinical biochemistry 02/2013; DOI:10.1016/j.clinbiochem.2013.01.016 · 2.23 Impact Factor