Non-traditional Risk Factors for Progression through Chronic Kidney Disease Risk Categories: the Coronary Artery Risk Development in Young Adults Study

  • Author Footnotes
    ⁎ Yuni Choi and David R Jacobs Jr contributed equally as co-first authors of this paper.
    Yuni Choi
    ⁎ Yuni Choi and David R Jacobs Jr contributed equally as co-first authors of this paper.
    Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA
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  • Author Footnotes
    ⁎ Yuni Choi and David R Jacobs Jr contributed equally as co-first authors of this paper.
    David R Jacobs Jr
    ⁎ Yuni Choi and David R Jacobs Jr contributed equally as co-first authors of this paper.
    Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA
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  • Holly J. Kramer
    Departments of Public Health Sciences and Medicine, Loyola University Chicago, Maywood, Illinois, USA
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  • Gautam R. Shroff
    Division of Cardiology and Department of Medicine, Hennepin Healthcare, University of Minnesota Medical School, Minneapolis, MN, USA
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  • Alexander R. Chang
    Department of Population of Health Sciences; Kidney Health Research Institute; Department of Nephrology, Geisinger, Danville, PA
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  • Daniel A Duprez
    Corresponding author: Professor Daniel Duprez, University of Minnesota, Cardiovascular Division, Department of Medicine, Medical School Twin Cities, 420 Delaware Street SE, MMC 508, Minneapolis, MN 55455, United States, Phone: 612-624-4948, Fax: 612-626-4411
    Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
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  • Author Footnotes
    ⁎ Yuni Choi and David R Jacobs Jr contributed equally as co-first authors of this paper.
Published:December 21, 2022DOI:


      • About 29% of the Black and White participants progressed to a higher chronic kidney disease risk category. Beyond hypertension, diabetes, triglycerides, and obesity, forced vital capacity, and serum inflammatory markers, urate, and carotenoids were strongly associated with chronic kidney disease progression.
      • Transition into early stages of chronic kidney disease is common over 20 years starting in early middle age. The existence of several risk markers enables timely beginning of prevention and treatment activities.



      There may be non-traditional pathways of chronic kidney disease (CKD) progression that are complementary to classical pathways. Therefore, we aimed to examine non-traditional risk factors for incident CKD and its progression.


      Generally healthy population (n=4,382) starting at age 27-41 years in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort which is an observational longitudinal study. Non-traditional risk factors included forced vital capacity (FVC), inflammation, serum urate, and serum carotenoids. CKD risk category was classified using the estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) measured in 1995-96 and repeated 5-yearly for 20 years: No CKD, Low Risk, Moderate Risk, High Risk, and Very High Risk.


      At baseline, 84.8% had no CKD (eGFR ≥60 ml/min/1.73 m2 and UACR <10 mg/g), 10.3% were in the Low Risk (eGFR ≥60 and UACR 10−29), and 4.9% had CKD, (eGFR <60 and/or UACR ≥ 30). Non-traditional risk factors were significantly associated with the progression of CKD to higher categories. Hazard ratios per standard deviation of the predictor for incident CKD and its progression from the No CKD and Low and Moderate Risk into CKD were inverse for FVC and serum carotenoids and positive for serum urate, GlycA, and C-reactive protein, the first 3 even after adjustment for conventional risk factors.


      Several non-traditional markers were significantly associated with an increased risk of progression to higher CKD categories in generally healthy young to middle-aged adults.

      Graphical Abstract


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      1. Centers for Disease Control and Prevention. Chronic Kidney Disease in the United States, 2021. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2021.

        • Chronic Kidney Disease Collaboration GBD
        Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.
        Lancet. 2020; 395: 709-733
        • Disease Kidney
        Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
        Kidney Int Suppl. 2013; 3: 1-150
        • Arnett DK
        • Blumenthal RS
        • Albert MA
        • et al.
        2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
        J Am Coll Cardiol. 2019; 74: 1376-1414
        • Choi Y
        • Jacobs Jr DR
        • Shroff GR
        • Kramer H
        • Chang AR
        • Duprez DA
        Progression of Chronic Kidney Disease Risk Categories and Risk of Cardiovascular Disease and Total Mortality: Coronary Artery Risk Development in Young Adults Cohort.
        J Am Heart Assoc. 2022; 11 (2022)e026685
        • Ortiz A
        • Wanner C
        • Gansevoort R
        • Council E.
        Chronic kidney disease as cardiovascular risk factor in routine clinical practice: a position statement by the Council of the European Renal Association.
        Nephrol Dial Transplant. 2022; : gfac257
        • Rossing P
        • Epstein M.
        Microalbuminuria Constitutes a Clinical Action Item for Clinicians in 2021.
        Am J Med. 2022; 135: 576-580
        • Kalantar-Zadeh K
        • Jafar TH
        • Nitsch D
        • Neuen BL
        • Perkovic V.
        Chronic kidney disease.
        Lancet. 2021; 398: 786-802
        • Ku E
        • Lee BJ
        • Wei J
        • Weir MR.
        Hypertension in CKD: Core Curriculum 2019.
        Am J Kidney Dis. 2019; 74: 120-131
        • Nichols GA
        • Déruaz-Luyet A
        • Brodovicz KG
        • Kimes TM
        • Rosales AG
        • Hauske SJ.
        Kidney disease progression and all-cause mortality across estimated glomerular filtration rate and albuminuria categories among patients with vs. without type 2 diabetes.
        BMC Nephrol. 2020; 21: 167
        • Baigent C
        • Landray MJ
        • Reith C
        • et al.
        The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial.
        Lancet. 2011; 377: 2181-2192
        • Husain-Syed F
        • Slutsky AS
        • Ronco C.
        Lung-Kidney Cross-Talk in the Critically Ill Patient.
        Am J Respir Crit Care Med. 2016; 194: 402-414
        • Sorino C
        • Scichilone N
        • Pedone C
        • Negri S
        • Visca D
        • Spanevello A.
        When kidneys and lungs suffer together.
        J Nephrol. 2019; 32: 699-707
        • Harris B
        • Klein R
        • Jerosch-Herold M
        • et al.
        The association of systemic microvascular changes with lung function and lung density: a cross-sectional study.
        PLoS One. 2012; 7: e50224
        • Jourde-Chiche N
        • Fakhouri F
        • Dou L
        • et al.
        Endothelium structure and function in kidney health and disease.
        Nat Rev Nephrol. 2019; 15: 87-108
        • Kumagai T
        • Ota T
        • Tamura Y
        • Chang WX
        • Shibata S
        • Uchida S.
        Time to target uric acid to retard CKD progression.
        Clin Exp Nephrol. 2017; 21: 182-192
        • Pan J
        • Shi M
        • Ma L
        • Fu P.
        Mechanistic Insights of Soluble Uric Acid-related Kidney Disease.
        Curr Med Chem. 2020; 27: 5056-5066
        • Ejaz AA
        • Nakagawa T
        • Kanbay M
        • et al.
        Hyperuricemia in Kidney Disease: A Major Risk Factor for Cardiovascular Events, Vascular Calcification, and Renal Damage.
        Semin Nephrol. 2020; 40: 574-585
        • Hozawa A
        • Jacobs DR
        • Steffes MW
        • Gross MD
        • Steffen LM
        • Lee DH.
        Relationships of circulating carotenoid concentrations with several markers of inflammation, oxidative stress, and endothelial dysfunction: the Coronary Artery Risk Development in Young Adults (CARDIA)/Young Adult Longitudinal Trends in Antioxidants (YALTA) study.
        Clin Chem. 2007; 53: 447-455
        • Friedman GD
        • Cutter GR
        • Donahue RP
        • et al.
        CARDIA: study design, recruitment, and some characteristics of the examined subjects.
        J Clin Epidemiol. 1988; 41: 1105-1116
        • Levey AS
        • Stevens LA
        • Schmid CH
        • et al.
        A new equation to estimate glomerular filtration rate.
        Ann Intern Med. 2009; 150: 604-612
        • Delgado C
        • Baweja M
        • Crews DC
        • et al.
        A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease.
        Am J Kidney Dis. 2022; 79 (e1): 268-288
        • Hozawa A
        • Jacobs DR
        • Steffes MW
        • Gross MD
        • Steffen LM
        • Lee DH.
        Circulating carotenoid concentrations and incident hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) study.
        J Hypertens. 2009; 27: 237-242
        • Hozawa A
        • Jacobs DR
        • Steffes MW
        • Gross MD
        • Steffen LM
        • Lee DH.
        Associations of serum carotenoid concentrations with the development of diabetes and with insulin concentration: interaction with smoking: the Coronary Artery Risk Development in Young Adults (CARDIA) Study.
        Am J Epidemiol. 2006; 163: 929-937
        • Fox ER
        • Benjamin EJ
        • Sarpong DF
        • et al.
        The relation of C–reactive protein to chronic kidney disease in African Americans: the Jackson Heart Study.
        BMC Nephrol. 2010; 11: 1
        • Amdur RL
        • Feldman HI
        • Gupta J
        • et al.
        Inflammation and Progression of CKD: The CRIC Study.
        Clin J Am Soc Nephrol. 2016; 11: 1546-1556
        • Medenwald D
        • Girndt M
        • Loppnow H
        • et al.
        Inflammation and renal function after a four-year follow-up in subjects with unimpaired glomerular filtration rate: results from the observational, population-based CARLA cohort.
        PLoS One. 2014; 9e108427
        • Benson EA
        • Tibuakuu M
        • Zhao D
        • et al.
        Associations of ideal cardiovascular health with GlycA, a novel inflammatory marker: The Multi-Ethnic Study of Atherosclerosis.
        Clin Cardiol. 2018; 41: 1439-1445
        • Duprez DA
        • Otvos J
        • Sanchez OA
        • Mackey RH
        • Tracy R
        • Jacobs DR.
        Comparison of the Predictive Value of GlycA and Other Biomarkers of Inflammation for Total Death, Incident Cardiovascular Events, Noncardiovascular and Noncancer Inflammatory-Related Events, and Total Cancer Events.
        Clin Chem. 2016; 62: 1020-1031
        • Ford ES
        • Giles WH
        • Mokdad AH
        • Ajani UA.
        Microalbuminuria and concentrations of antioxidants among US adults.
        Am J Kidney Dis. 2005; 45: 248-255
        • Hirahatake KM
        • Jacobs DR
        • Gross MD
        • et al.
        The Association of Serum Carotenoids, Tocopherols, and Ascorbic Acid With Rapid Kidney Function Decline: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.
        J Ren Nutr. 2019; 29: 65-73
        • Dounousi E
        • Papavasiliou E
        • Makedou A
        • et al.
        Oxidative stress is progressively enhanced with advancing stages of CKD.
        Am J Kidney Dis. 2006; 48: 752-760
        • Annuk M
        • Zilmer M
        • Lind L
        • Linde T
        • Fellström B.
        Oxidative stress and endothelial function in chronic renal failure.
        J Am Soc Nephrol. 2001; 12: 2747-2752
        • Rowley K
        • O'Dea K
        • Su Q
        • Jenkins AJ
        • Best JD.
        Low plasma concentrations of diet-derived antioxidants in association with microalbuminuria in Indigenous Australian populations.
        Clin Sci (Lond). 2003; 105: 569-575
        • Oluwo O
        • Scialla JJ.
        Uric Acid and CKD Progression Matures with Lessons for CKD Risk Factor Discovery.
        Clin J Am Soc Nephrol. 2021; 16: 476-478
        • Sumida K
        • Kwak L
        • Grams ME
        • et al.
        Lung Function and Incident Kidney Disease: The Atherosclerosis Risk in Communities (ARIC) Study.
        Am J Kidney Dis. 2017; 70: 675-685
        • Kastarinen M
        • Juutilainen A
        • Kastarinen H
        • et al.
        Risk factors for end-stage renal disease in a community-based population: 26-year follow-up of 25,821 men and women in eastern Finland.
        J Intern Med. 2010; 267: 612-620
        • Anderson AH
        • Yang W
        • Townsend RR
        • et al.
        Time-updated systolic blood pressure and the progression of chronic kidney disease: a cohort study.
        Ann Intern Med. 2015; 162: 258-265
        • Hsu CY
        • McCulloch CE
        • Darbinian J
        • Go AS
        • Iribarren C.
        Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease.
        Arch Intern Med. 2005; 165: 923-928
        • Shen Y
        • Cai R
        • Sun J
        • et al.
        Diabetes mellitus as a risk factor for incident chronic kidney disease and end-stage renal disease in women compared with men: a systematic review and meta-analysis.
        Endocrine. 2017; 55: 66-76
        • Jo W
        • Lee S
        • Joo YS
        • et al.
        Association of smoking with incident CKD risk in the general population: A community-based cohort study.
        PLoS One. 2020; 15e0238111
        • Chang Y
        • Ryu S
        • Choi Y
        • et al.
        Metabolically Healthy Obesity and Development of Chronic Kidney Disease: A Cohort Study.
        Ann Intern Med. 2016; 164: 305-312
        • Herrington WG
        • Smith M
        • Bankhead C
        • et al.
        Body-mass index and risk of advanced chronic kidney disease: Prospective analyses from a primary care cohort of 1.4 million adults in England.
        PLoS One. 2017; 12e0173515
      2. Tonelli M, Wanner C, Members KDIGOLGDWG. Lipid management in chronic kidney disease: synopsis of the Kidney Disease: Improving Global Outcomes 2013 clinical practice guideline. Ann Intern.2014;160:182. doi:10.7326/M13-2453

        • Shimizu M
        • Furusyo N
        • Mitsumoto F
        • et al.
        Subclinical carotid atherosclerosis and triglycerides predict the incidence of chronic kidney disease in the Japanese general population: results from the Kyushu and Okinawa Population Study (KOPS).
        Atherosclerosis. 2015; 238: 207-212
        • Tsuruya K
        • Yoshida H
        • Nagata M
        • et al.
        Association of Hypertriglyceridemia With the Incidence and Progression of Chronic Kidney Disease and Modification of the Association by Daily Alcohol Consumption.
        J Ren Nutr. 2017; 27: 381-394
        • Muntner P
        • Coresh J
        • Smith JC
        • Eckfeldt J
        • Klag MJ.
        Plasma lipids and risk of developing renal dysfunction: the atherosclerosis risk in communities study.
        Kidney Int. 2000; 58: 293-301
        • Schaeffner ES
        • Kurth T
        • Curhan GC
        • et al.
        Cholesterol and the risk of renal dysfunction in apparently healthy men.
        J Am Soc Nephrol. 2003; 14: 2084-2091