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Original Investigation |

Decline in Estimated Glomerular Filtration Rate and Subsequent Risk of End-Stage Renal Disease and Mortality

Josef Coresh, MD, PhD1; Tanvir Chowdhury Turin, MD, PhD2; Kunihiro Matsushita, MD, PhD1; Yingying Sang, MSc1; Shoshana H. Ballew, PhD1; Lawrence J. Appel, MD3; Hisatomi Arima, MD4; Steven J. Chadban, PhD5,6; Massimo Cirillo, MD7; Ognjenka Djurdjev, MSc8; Jamie A. Green, MD9; Gunnar H. Heine, MD10; Lesley A. Inker, MD11; Fujiko Irie, MD, PhD12; Areef Ishani, MD, MS13; Joachim H. Ix, MD, MAS14; Csaba P. Kovesdy, MD15,16; Angharad Marks, MBBCh17; Takayoshi Ohkubo, MD, PhD18,19,20; Varda Shalev, MD21; Anoop Shankar, MD22; Chi Pang Wen, MD, DrPH23,24; Paul E. de Jong, MD, PhD25; Kunitoshi Iseki, MD, PhD26; Benedicte Stengel, MD, PhD27; Ron T. Gansevoort, MD, PhD25; Andrew S. Levey, MD11 ; for the CKD Prognosis Consortium
[+] Author Affiliations
1Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
2Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
3Johns Hopkins Medical Institutions, Baltimore, Maryland
4George Institute for Global Health, University of Sydney, Sydney, Australia
5Department of Nephrology and Transplantation, Royal Prince Alfred Hospital, Sydney, Australia
6Sydney Medical School, University of Sydney, Sydney, Australia
7Department of Medicine, University of Salerno, Salerno, Italy
8BC Provincial Renal Agency, Vancouver, British Columbia, Canada
9Nephrology Department, Geisinger Medical Center, Danville, Pennsylvania
10Department of Internal Medicine IV, Nephrology, and Hypertension, Saarland University Medical Center, Hamburg, Germany
11Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
12Department of Health and Welfare, Ibaraki Prefectural Office, Mito, Japan
13Minneapolis VA Health Care System and Department of Medicine, University of Minnesota, Minneapolis
14University of California, San Diego
15Memphis Veterans Affairs Medical Center, Memphis, Tennessee
16University of Tennessee Health Science Center, Memphis
17Division of Applied Health Sciences, University of Aberdeen, and NHS Grampian, Aberdeen, Scotland
18Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan
19Department of Planning for Drug Development and Clinical Evaluation, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan
20Department of Health Science, Shiga University of Medical Science, Shiga, Japan
21Medical Informatics Department, Maccabi Healthcare Services, and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
22Department of Family Medicine and Population Health, Virginia Commonwealth University School of Medicine, Richmond
23China Medical University Hospital, Taichung, Taiwan
24Institute of Population Health Science, National Health Research Institutes, Zhunan, Taiwan
25Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
26Dialysis Unit, University Hospital of the Ryukyus, Okinawa, Japan
27Inserm U1018, CESP Center for Research in Epidemiology and Population Health and UMRS 1018, Paris-Sud University, Villejuif, France
JAMA. 2014;311(24):2518-2531. doi:10.1001/jama.2014.6634.
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Importance  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.

Objective  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.

Data Sources and Study Selection  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.

Data Extraction and Synthesis  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.

Main Outcomes and Measures  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.

Results  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.

Conclusions and Relevance  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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Figure 1.
End-Stage Renal Disease (ESRD) Associated With Percentage Change in Estimated GFR During a 2-Year Baseline Period

Values trimmed at less than −70% change (0.22% and 0.055% of the study population for estimated GFR <60 mL/min/1.73 m2 and ≥60 mL/min/1.73 m2, respectively) and greater than 40% change (5.9% and 0.51% of the population for estimated GFR <60 mL/min/1.73 m2 and ≥60 mL/min/1.73 m2, respectively). In the top 2 panels, the diamonds indicate the reference point of 0% change in estimated GFR.

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Figure 2.
Risk of End-Stage Renal Disease by Change in Estimated Glomerular Filtration Rate (GFR) During a 2-Year Baseline Period, First Estimated GFR, and Subsequent Follow-up

Baseline risk is calculated for participants with 0% change in estimated GFR, estimated GFR of 50 mL/min/1.73 m2, age of 60 years, male sex, nonblack race, systolic blood pressure of 130 mm Hg, total cholesterol level of 5 mmol/L, and without diabetes or a history of cardiovascular disease.

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Figure 3.
All-Cause Mortality Associated With Percentage Change in Estimated GFR During a 2-Year Baseline Period

Values trimmed at less than −70% change (0.30% and 0.050% of the study population for estimated GFR <60 mL/min/1.73 m2 and ≥60 mL/min/1.73 m2, respectively) and greater than 40% change (5.8% and 0.46% of the population for estimated GFR <60 mL/min/1.73 m2 and ≥60 mL/min/1.73 m2, respectively). In the top 2 panels, the diamonds indicate the reference point of 0% change in estimated GFR.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.
Risk of All-Cause Mortality by Change in Estimated Glomerular Filtration Rate (GFR) During a 2-Year Baseline Period, First Estimated GFR, and Subsequent Follow-up

Baseline risk is calculated for participants with 0% change in estimated GFR, estimated GFR of 50 mL/min/1.73 m2, age of 60 years, male sex, nonblack race, systolic blood pressure of 130 mm Hg, total cholesterol level of 5 mmol/L, and without diabetes or a history of cardiovascular disease.

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