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      Longitudinal Study of the Decline in Renal Function in Healthy Subjects

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          Abstract

          Background

          Chronic kidney disease is an important concern in preventive medicine, but the rate of decline in renal function in healthy population is not well defined. The purpose of this study was to determine reference values for the estimated glomerular filtration rate (eGFR) and rate of decline of eGFR in healthy subjects and to evaluate factors associated with this decline using a large cohort in Japan.

          Methods

          Retrospective cross-sectional and longitudinal studies were performed with healthy subjects aged ≥18 years old who received a medical checkup. Reference values for eGFR were obtained using a nonparametric method and those for decline of eGFR were calculated by mixed model analysis. Relationships of eGFR decline rate with baseline variables were examined using a linear least-squares method.

          Results

          In the cross-sectional study, reference values for eGFR were obtained by gender and age in 72,521 healthy subjects. The mean (±SD) eGFR was 83.7±14.7ml/min/1.73m 2. In the longitudinal study, reference values for eGFR decline rate were obtained by gender, age, and renal stage in 45,586 healthy subjects. In the same renal stage, there was little difference in the rate of decline regardless of age. The decline in eGFR depended on the renal stage and was strongly related to baseline eGFR, with a faster decline with a higher baseline eGFR and a slower decline with a lower baseline eGFR. The mean (±SD) eGFR decline rate was ‒1.07±0.42ml/min/1.73m 2/year (‒1.29±0.41%/year) in subjects with a mean eGFR of 81.5±11.6ml/min/1.73m 2.

          Conclusions

          The present study clarified for the first time the reference values for the rate of eGFR decline stratified by gender, age, and renal stage in healthy subjects. The rate of eGFR decline depended mainly on baseline eGFR, but not on age, with a slower decline with a lower baseline eGFR.

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          Most cited references 16

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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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            Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study.

            The Modification of Diet in Renal Disease (MDRD) Study examined the effects of dietary protein restriction and strict blood pressure control on the decline in glomerular filtration rate (GFR) in 840 patients with diverse renal diseases. We describe a systematic analysis to determine baseline factors that predict the decline in GFR, or which alter the efficacy of the diet or blood pressure interventions. Univariate analysis identified 18 of 41 investigated baseline factors as significant (P < 0.05) predictors of GFR decline. In multivariate analysis, six factors--greater urine protein excretion, diagnosis of polycystic kidney disease (PKD), lower serum transferrin, higher mean arterial pressure, black race, and lower serum HDL cholesterol--independently predicted a faster decline in GFR. Together with the study interventions, these six factors accounted for 34.5% and 33.9% of the variance between patients in GFR slopes in Studies A and B, respectively, with proteinuria and PKD playing the predominant role. The mean rate of GFR decline was not significantly related to baseline GFR, suggesting an approximately linear mean GFR decline as renal disease progresses. The 41 baseline predictors were also assessed for their interactions with the diet and blood pressure interventions. A greater benefit of the low blood pressure intervention was found in patients with higher baseline urine protein. None of the 41 baseline factors were shown to predict a greater or lesser effect of dietary protein restriction.
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              Mild renal insufficiency is associated with increased cardiovascular mortality: The Hoorn Study.

              Cardiovascular mortality is extremely high in end-stage renal disease. Cardiovascular mortality risk also is increased in selected (high-risk) individuals with mild to moderate impairment of renal function. It is not clear whether a similar association exists in the general population and, if so, through what mechanisms. We investigated the association of renal function with all-cause and cardiovascular mortality in a population-based cohort and explored potential mechanisms underlying any such relationship. An age-, sex-, and glucose-tolerance-stratified sample (N = 631) of a population-based cohort aged 50 to 75 years was followed prospectively. After up to 10.2 years of follow-up, 117 subjects had died (50 of cardiovascular causes). At baseline, renal function was estimated by the serum creatinine level, the Cockcroft-Gault formula and Levey's equation. At baseline, the mean age was 64 +/- 7 years, 48% were men, 55% had hypertension, and 27% (by design) had type 2 diabetes. Serum creatinine was 91.7 +/- 19.0 micromol/L; creatinine clearance as estimated by the Cockroft-Gault formula was 72.5 +/- 13.7 mL/min/1.73 m(2), and the glomerular filtration rate (GFR) estimated by Levey's equation was 67.8 +/- 12.1 mL/min/1.73 m(2). Renal function was inversely associated with all-cause and with cardiovascular mortality. Relative risks (95% confidence intervals) were 1.08 (1.04 to 1.13) and 1.11 (1.07 to 1.16) per 5 micromol/L increase of serum creatinine; 1.07 (0.98 to 1.17) and 1.15 (1.01 to 1.31) for each decrease of 5 mL/min/1.73 m(2) creatinine clearance; and 1.15 (1.05 to 1.26) and 1.26 (1.12 to 1.42) for each decrease of 5 mL/min/1.73 m(2) of GFR. These associations remained after adjusting for age, sex, glucose tolerance status, hypertension, prior cardiovascular disease, low-density lipoprotein cholesterol, homocysteine, (micro)albuminuria, von Willebrand factor, soluble vascular adhesion molecule-1 and C-reactive protein. Analyses in diabetic and hypertensive subjects gave similar results. Mild to moderate loss of renal function is strongly associated with an increased risk of cardiovascular mortality. The mechanism behind this association is unclear but does not appear to involve common risk factors such as hypertension, diabetes or hyperhomocysteinemia. Estimation of renal function by relatively simple methods therefore may be a valuable tool for cardiovascular risk assessment over and above that provided by conventional risk factors. Our results were obtained in a general middle-aged to elderly population, and thus have broad applicability.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                10 June 2015
                2015
                : 10
                : 6
                Affiliations
                [1 ]Center for Preventive Medicine, St. Luke’s Affiliated Clinic, St. Luke’s International University, Tokyo, Japan
                [2 ]Ohta Nishinouchi Hospital, Koriyama, Japan
                [3 ]Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
                [4 ]Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
                [5 ]Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
                [6 ]Division of Nephrology, Department of Medicine, St. Luke’s Hospital, St. Luke’s International University, Tokyo, Japan
                Tokushima University Graduate School, JAPAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MB TS YY YK S. Mar. Analyzed the data: MB TS MH S. Mar. Wrote the paper: MB TS MA YY YK KM S. Mat S. Mar.

                Article
                PONE-D-14-50705
                10.1371/journal.pone.0129036
                4464887
                26061083

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Page count
                Figures: 4, Tables: 5, Pages: 18
                Product
                Funding
                This study was funded by a grant from St. Luke’s Life Science Institute, St. Luke’s International University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
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                All relevant data are within the paper and its Supporting Information files.

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