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      Sudomotor dysfunction independently predicts incident cardiovascular–renal events and all-cause death in type 2 diabetes: the Joint Asia Diabetes Evaluation register

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          Abstract

          Background

          Early detection and risk factor control prevent chronic kidney disease (CKD) progression. Evaluation of peripheral autonomic dysfunction may detect incident cardiovascular–renal events in type 2 diabetes (T2D).

          Methods

          SUDOSCAN, a non-invasive tool, provides an age-adjusted electrochemical skin conductance (ESC) composite score incorporating hands/feet ESC measurements, with a score ≤53 indicating sudomotor dysfunction. A consecutive cohort of 2833 Chinese adults underwent structured diabetes assessment in 2012–13; 2028 participants without preexisting cardiovascular disease (CVD) and CKD were monitored for incident cardiovascular–renal events until 2015.

          Results

          In this prospective cohort {mean age 57.0 [standard deviation (SD) 10.0] years; median T2D duration 7.0 [interquartile range (IQR) 3.0–13.0] years; 56.1% men; 72.5% never-smokers; baseline ESC composite score 60.7 (SD 14.5)}, 163 (8.0%) and 25 (1.2%) participants developed incident CKD and CVD, respectively, after 2.3 years of follow-up. The adjusted hazard ratios (aHRs) per 1-unit decrease in the ESC composite score for incident CKD, CVD and all-cause death were 1.02 [95% confidence interval (CI) 1.01–1.04], 1.04 (1.00–1.07) and 1.04 (1.00–1.08), respectively. Compared with participants with an ESC composite score >53, those with a score ≤53 had an aHR of 1.56 (95% CI 1.09–2.23) for CKD and 3.11 (95% CI 1.27–7.62) for CVD, independent of common risk markers. When added to clinical variables (sex and duration of diabetes), the ESC composite score improved discrimination of all outcomes with appropriate reclassification of CKD risk.

          Conclusions

          A low ESC composite score independently predicts incident cardiovascular–renal events and death in T2D, which may improve the screening strategy for early intervention.

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          Most cited references18

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          Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis.

          Chronic kidney disease is characterised by low estimated glomerular filtration rate (eGFR) and high albuminuria, and is associated with adverse outcomes. Whether these risks are modified by diabetes is unknown. We did a meta-analysis of studies selected according to Chronic Kidney Disease Prognosis Consortium criteria. Data transfer and analyses were done between March, 2011, and June, 2012. We used Cox proportional hazards models to estimate the hazard ratios (HR) of mortality and end-stage renal disease (ESRD) associated with eGFR and albuminuria in individuals with and without diabetes. We analysed data for 1,024,977 participants (128,505 with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 chronic kidney disease cohorts. In the combined general population and high-risk cohorts with data for all-cause mortality, 75,306 deaths occurred during a mean follow-up of 8·5 years (SD 5·0). In the 23 studies with data for cardiovascular mortality, 21,237 deaths occurred from cardiovascular disease during a mean follow-up of 9·2 years (SD 4·9). In the general and high-risk cohorts, mortality risks were 1·2-1·9 times higher for participants with diabetes than for those without diabetes across the ranges of eGFR and albumin-to-creatinine ratio (ACR). With fixed eGFR and ACR reference points in the diabetes and no diabetes groups, HR of mortality outcomes according to lower eGFR and higher ACR were much the same in participants with and without diabetes (eg, for all-cause mortality at eGFR 45 mL/min per 1·73 m(2) [vs 95 mL/min per 1·73 m(2)], HR 1·35; 95% CI 1·18-1·55; vs 1·33; 1·19-1·48 and at ACR 30 mg/g [vs 5 mg/g], 1·50; 1·35-1·65 vs 1·52; 1·38-1·67). The overall interactions were not significant. We identified much the same findings for ESRD in the chronic kidney disease cohorts. Despite higher risks for mortality and ESRD in diabetes, the relative risks of these outcomes by eGFR and ACR are much the same irrespective of the presence or absence of diabetes, emphasising the importance of kidney disease as a predictor of clinical outcomes. US National Kidney Foundation. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality.

            The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in estimated glomerular filtration rate [GFR] of −57% or greater) is a late event. To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated. Individual meta-analysis of 1.7 million participants with 12,344 ESRD events and 223,944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data. Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012. End-stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR. The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m2, the adjusted HRs for ESRD were 32.1 (95% CI, 22.3-46.3) for changes of −57% in estimated GFR and 5.4 (95% CI, 4.5-6.4) for changes of −30%. However, changes of −30% or greater (6.9% [95% CI, 6.4%-7.4%] of the entire consortium) were more common than changes of −57% (0.79% [95% CI, 0.52%-1.06%]). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD (in patients with a baseline estimated GFR of 35 mL/min/1.73 m2) was 99% (95% CI, 95%-100%) for estimated GFR change of −57%, was 83% (95% CI, 71%-93%) for estimated GFR change of −40%, and was 64% (95% CI, 52%-77%) for estimated GFR change of −30% vs 18% (95% CI, 15%-22%) for estimated GFR change of 0%. Corresponding mortality risks were 77% (95% CI, 71%-82%), 60% (95% CI, 56%-63%), and 50% (95% CI, 47%-52%) vs 32% (95% CI, 31%-33%), showing a similar but weaker pattern. Declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in estimated GFR (such as a 30% reduction over 2 years) as an alternative end point for CKD progression.
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              Non-proteinuric pathways in loss of renal function in patients with type 2 diabetes.

              Largely on the basis of data from patients with type 1 diabetes, the natural history of diabetic renal disease has been classified as a sequence of three stages: normoalbuminuria, microalbuminuria, and macroalbuminuria. Progressive decline of glomerular filtration rate (GFR) was thought to parallel the onset of macroalbuminuria (overt nephropathy), whereas glomerular hyperfiltration was deemed a hallmark of early disease. However, researchers have since shown that albuminuria is a continuum and that GFR can start to decline before progression to overt nephropathy. In addition to proteinuria, other risk factors might contribute to GFR deterioration including female sex, obesity, dyslipidaemia (in particular hypertriglyceridaemia), hypertension, and glomerular hyperfiltration, at least in a subgroup of patients. This phenomenon could explain why patients with type 2 diabetes can have renal insufficiency even before the onset of overt nephropathy, and might also suggest why the heterogeneous phenotype of type 2 diabetic renal disease does not necessarily associate with typical histological lesions of diabetic renal disease, unlike in type 1 diabetic renal disease. Patients with renal insufficiency but without albuminuria are usually excluded from randomised clinical trials in overt nephropathy, thus optimum treatment for this group of patients is unknown. The wide inter-patient variability of the disease probably needs individually tailored intervention.
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                Author and article information

                Journal
                Nephrol Dial Transplant
                Nephrol. Dial. Transplant
                ndt
                Nephrology Dialysis Transplantation
                Oxford University Press
                0931-0509
                1460-2385
                August 2019
                22 June 2018
                22 June 2018
                : 34
                : 8
                : 1320-1328
                Affiliations
                [1 ]Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
                [2 ]Asia Diabetes Foundation, Prince of Wales Hospital, Shatin, Hong Kong
                [3 ]Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
                [4 ]Hong Kong Institute of Diabetes and Obesity, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
                Author notes
                Correspondence and offprint requests to: Juliana C.N. Chan, E-mail: jchan@ 123456cuhk.edu.hk
                Author information
                http://orcid.org/0000-0002-6214-6924
                Article
                gfy154
                10.1093/ndt/gfy154
                6680097
                29939305
                a3a0d340-f623-435b-a4c3-f4769613df9f
                © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 22 November 2017
                : 18 April 2018
                Page count
                Pages: 9
                Funding
                Funded by: Impeto Medical to the Asia Diabetes Foundation (ADF)
                Funded by: Chinese University of Hong Kong Foundation
                Funded by: AstraZeneca 10.13039/100004325
                Funded by: Bayer 10.13039/100004326
                Funded by: Boehringer Ingelheim 10.13039/100001003
                Funded by: Eli Lilly
                Funded by: Merck Sharp & Dohme and Takeda
                Categories
                ORIGINAL ARTICLES
                Clinical Research

                Nephrology
                autonomic dysfunction,chronic kidney disease,cohort study,mortality
                Nephrology
                autonomic dysfunction, chronic kidney disease, cohort study, mortality

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