Association Between Caffeine Intake and Mortality Among Patients with Chronic Kidney Disease: A Population-Based Study

Abstract

Objective

The benefits of caffeine to human health have been widely reported, but the association between caffeine intake and mortality among patients with chronic kidney disease (CKD) has been rarely reported in large epidemiologic studies. This study aimed to investigate the association between caffeine intake and mortality among CKD patients.

Methods

Our study was conducted among non-dialysis CKD patients in the 2003–2016 National Health and Nutrition Examination Survey (NHANES). Weighted COX regression analysis was used to explore the linear relationship between caffeine intake and mortality among CKD patients (including all-cause mortality, as well as mortality due to cardiovascular disease, cancer, cerebrovascular disease, nephropathy, and influenza or pneumonia). Restricted cubic spline analysis was performed to explore the nonlinear relationship. Finally, threshold effects were analyzed through fitting a two-piecewise linear regression model.

Results

In a fully adjusted model, no significant linear association was found between caffeine intake and mortality. However, there was a U-shaped association between caffeine intake and all-cause mortality (inflection point: 277 mg). Moreover, there was a J-shaped association between caffeine intake and cardiovascular mortality (inflection point: 252 mg) and cancer mortality (inflection point: 79 mg).

Conclusion

All-cause mortality was reduced in CKD patients when caffeine intake was less than 277 mg (about 1.85 cups of Americano). However, excessive caffeine intake was associated with increased all-cause mortality, cardiovascular mortality and cancer mortality in this population.

Keywords

Chronic kidney disease / Caffeine / Mortality / NHANES / Population-based study / Nonlinear association / Threshold effect / U-shaped relationship

References

[1] 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(10225):709–733.

[2] Thompson S, James M, Wiebe N, et al.. Cause of Death in Patients with Reduced Kidney Function. J Am Soc Nephrol., 2015, 26(10): 2504-2511

[3] Ziemba R, Campbell KN, Yang TH, et al.. Excess Death Estimates in Patients with End-Stage Renal Disease - United States, February-August 2020. MMWR Morb Mortal Wkly Rep., 2021, 70(22): 825-829

[4] Keith DS, Nichols GA, Gullion CM, et al.. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med., 2004, 164(6): 659-663

[5] Foreman KJ, Marquez N, Dolgert A, et al.. Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016–40 for 195 countries and territories. Lancet., 2018, 392(10159): 2052-2090

[6] Gonzalez de Mejia E, Ramirez-Mares MV. Impact of caffeine and coffee on our health. Trends Endocrinol Metab. 2014;25(10):489–492.

[7] Fredholm BB, Bättig K, Holmén J, et al.. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev., 1999, 51(1): 83-133

[8] Cornelis MC. Coffee intake. Prog Mol Biol Transl Sci., 2012, 108: 293-322

[9] Voskoboinik A, Koh Y, Kistler PM. Cardiovascular effects of caffeinated beverages. Trends Cardiovasc Med., 2019, 29(6): 345-350

[10] Tellone E, Galtieri A, Russo A, et al.. Protective Effects of the Caffeine Against Neurodegenerative Diseases. Curr Med Chem., 2019, 26(27): 5137-5151

[11] Bigotte Vieira M, Magriço R, Viegas Dias C, et al.. Caffeine consumption and mortality in chronic kidney disease: a nationally representative analysis. Nephrol Dial Transplant., 2019, 34(6): 974-980

[12] Kennedy OJ, Pirastu N, Poole R, et al.. Coffee Consumption and Kidney Function: A Mendelian Randomization Study. Am J Kidney Dis., 2020, 75(5): 753-761

[13] Jhee JH, Nam KH, An SY, et al.. Effects of Coffee Intake on Incident Chronic Kidney Disease: A Community-Based Prospective Cohort Study. Am J Med., 2018, 131(12): 1482-1490.e1483

[14] Cai Q, van Westing AC, Cao Y, et al.. Coffee consumption and risk of kidney function decline in a Dutch population-based cohort. Nutr Metab Cardiovasc Dis., 2024, 34(2): 455-465

[15] Srithongkul T, Ungprasert P. Coffee Consumption is Associated with a Decreased Risk of Incident Chronic Kidney Disease: A Systematic Review and Meta-analysis of Cohort Studies. Eur J Intern Med., 2020, 77: 111-116

[16] Curtin LR, Mohadjer LK, Dohrmann SM, et al. National Health and Nutrition Examination Survey: sample design, 2007–2010. Vital Health Stat 2. 2013(160):1–23.

[17] Levey AS, Stevens LA, Schmid CH, et al.. A new equation to estimate glomerular filtration rate. Ann Intern Med., 2009, 150(9): 604-612

[18] Zipf G, Chiappa M, Porter KS, et al. National health and nutrition examination survey: plan and operations, 1999–2010. Vital Health Stat 1. 2013(56):1–37.

[19] Feng L, Li S, Li C. Association between folate intake and suicidal ideation: NHANES 2005–2018 and Mendelian randomization. J Affect Disord., 2025, 389: 119730

[20] Liu M, Zhu W, Xie L, et al. Dietary fiber intake and rheumatoid arthritis among U.S. adults: Evidence from a cross-sectional analysis of NHANES with inflammatory markers as mediators. Exp Gerontol. 2025;212:112947.

[21] Hu N, Qin J, Dong H, et al.. Association between daily calcium intake and the prevalence of chronic diarrhea: an analysis of NHANES 2005–2010 data. BMC Gastroenterol., 2025, 25(1): 694

[22] Saimaiti A, Zhou DD, Li J, et al.. Dietary sources, health benefits, and risks of caffeine. Crit Rev Food Sci Nutr., 2023, 63(299648-9666

[23] MacLaughlin HL, Friedman AN, Ikizler TA. Nutrition in Kidney Disease: Core Curriculum 2022. Am J Kidney Dis., 2022, 79(3437-449

[24] Nawrot P, Jordan S, Eastwood J, et al.. Effects of caffeine on human health. Food Addit Contam., 2003, 20(1): 1-30

[25] Kanbay M, Siriopol D, Copur S, et al.. Effect of Coffee Consumption on Renal Outcome: A Systematic Review and Meta-Analysis of Clinical Studies. J Ren Nutr., 2021, 31(1): 5-20

[26] Wijarnpreecha K, Thongprayoon C, Thamcharoen N, et al. Association of coffee consumption and chronic kidney disease: A meta-analysis. Int J Clin Pract. 2017;71(1). https://doi.org/10.1111/ijcp.12919.

[27] Irazabal MV, Torres VE. Reactive Oxygen Species and Redox Signaling in Chronic Kidney Disease. Cells. 2020;9(6):1342.

[28] Ősz BE, Jîtcă G, Ștefănescu RE, et al. Caffeine and Its Antioxidant Properties-It Is All about Dose and Source. Int J Mol Sci. 2022;23(21):13074.

[29] Tofovic SP, Salah EM, Jackson EK, et al.. Early renal injury induced by caffeine consumption in obese, diabetic ZSF1 rats. Ren Fail., 2007, 29(7): 891-902

[30] Tofovic SP, Rominski BR, Bastacky S, et al.. Caffeine augments proteinuria in puromycin-aminonucleoside nephrotic rats. Ren Fail., 2000, 22(2): 159-179

[31] Tofovic SP, Jackson EK. Effects of long-term caffeine consumption on renal function in spontaneously hypertensive heart failure prone rats. J Cardiovasc Pharmacol., 1999, 33(3): 360-366

[32] Tofovic SP, Kusaka H, Jackson EK, et al.. Renal and metabolic effects of caffeine in obese (fa/fa(cp)), diabetic, hypertensive ZSF1 rats. Ren Fail., 2001, 23(2): 159-173

[33] Tofovic SP, Kost CKJr, Jackson EK, et al.. Long-term caffeine consumption exacerbates renal failure in obese, diabetic, ZSF1 (fa-fa(cp)) rats. Kidney Int., 2002, 61(4): 1433-1444

[34] Said MA, van de Vegte YJ, Verweij N, et al.. Associations of Observational and Genetically Determined Caffeine Intake With Coronary Artery Disease and Diabetes Mellitus. J Am Heart Assoc., 2020, 9(24): e016808

[35] Lebeau PF, Byun JH, Platko K, et al.. Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance. Nat Commun., 2022, 13(1770

[36] Noordzij M, Uiterwaal CS, Arends LR, et al.. Blood pressure response to chronic intake of coffee and caffeine: a meta-analysis of randomized controlled trials. J Hypertens., 2005, 23(5921-928

[37] Cadoná FC, Dantas RF, de Mello GH, et al.. Natural products targeting into cancer hallmarks: An update on caffeine, theobromine, and (+)-catechin. Crit Rev Food Sci Nutr., 2022, 62(26): 7222-7241

[38] Liu H, Zhou Y, Tang L. Caffeine induces sustained apoptosis of human gastric cancer cells by activating the caspase-9/caspase-3 signalling pathway. Mol Med Rep., 2017, 16(3): 2445-2454

[39] Wrześniok D, Rzepka Z, Respondek M, et al.. Caffeine modulates growth and vitality of human melanotic COLO829 and amelanotic C32 melanoma cells: Preliminary findings. Food Chem Toxicol., 2018, 120: 566-570

[40] Tonkaboni A, Lotfibakhshaiesh N, Danesh P, et al.. Evaluation of Inhibitory Effects of Caffeine on Human Carcinoma Cells. Nutr Cancer., 2021, 73(10): 1998-2002

[41] Meisaprow P, Aksorn N, Vinayanuwattikun C, et al. Caffeine Induces G0/G1 Cell Cycle Arrest and Inhibits Migration through Integrin αv, β3, and FAK/Akt/c-Myc Signaling Pathway. Molecules. 2021;26(24):7659.

[42] Venkata Charan Tej GN, Neogi K, Verma SS, et al. Caffeine-enhanced anti-tumor immune response through decreased expression of PD1 on infiltrated cytotoxic T lymphocytes. Eur J Pharmacol. 2019;859:172538.

[43] Mok Y, Surapaneni A, Sang Y, et al.. Chronic kidney disease and incident cancer risk: an individual participant data meta-analysis. Br J Cancer., 2025, 133(10): 1535-1543

[44] Liabeuf S, Berdougo-Tritz J, Augey L, et al.. Drug Exposure in Chronic Kidney Disease: It Is Not Just About the Glomerular Filtration Rate. Fundam Clin Pharmacol., 2025, 39(4): e70037

[45] Nowak KL, Jovanovich A, Farmer-Bailey H, et al. Vascular Dysfunction, Oxidative Stress, and Inflammation in Chronic Kidney Disease. Kidney360. 2020;1(6):501–509.

[46] Moradi H, Sica DA, Kalantar-Zadeh K. Cardiovascular burden associated with uremic toxins in patients with chronic kidney disease. Am J Nephrol., 2013, 38(2136-148

Funding

Chinese Cardiovascular Association-Natural lipid-lowering drugs fund(No. 2023-CCA-NLD-742)

RIGHTS & PERMISSIONS

The Author(s), under exclusive licence to the Huazhong University of Science and Technology

Just Accepted

This article has successfully passed peer review and final editorial review, and will soon enter typesetting, proofreading and other publishing processes. The currently displayed version is the accepted final manuscript. The officially published version will be updated with format, DOI and citation information upon launch. We recommend that you pay attention to subsequent journal notifications and preferentially cite the officially published version. Thank you for your support and cooperation.