Creatine supplementation and renal safety: The nephron reserve hypothesis
DOI:
https://doi.org/10.12775/QS.2026.57.72506Keywords
creatine supplementation, nephron reserve, renal functional reserve, glomerular filtration rate, chronić kidney disease, hyperfiltration, creatinine, kidney safety, sport supplementationAbstract
Purpose: This narrative review proposes the nephron reserve hypothesis as a framework for reconciling conflicting evidence on creatine supplementation and kidney health.
Materials and methods: Evidence was synthesized from meta-analyses, randomized controlled trials, animal models, and case reports identified through PubMed, Scopus, Web of Science, and Google Scholar through March 2025, with priority given to studies using creatinine-independent renal endpoints.
Results: In individuals with preserved renal functional reserve, creatine at standard doses (3–5 g/day) does not impair glomerular filtration rate. Meta-analyses confirm that observed creatinine elevations reflect altered metabolic turnover rather than nephron injury. Evidence in chronic kidney disease remains sparse. Case reports of interstitial nephritis, tubular necrosis, and cast nephropathy, together with animal data from reduced-nephron-mass models, suggest creatine may unmask renal vulnerability in high-risk settings.
Conclusions: Creatine safety should be assessed according to baseline renal reserve and clinical phenotype. Recommendations for compromised kidneys remain precautionary and are intended to guide risk assessment and future research.
References
1.Anderson S, Meyer TW, Rennke HG, Brenner BM. Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass. J Clin Invest. 1985;76(2):612-619. https://doi.org/10.1172/JCI112013
2.Antonio J, Candow DG, Forbes SC, et al. Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show? J Int Soc Sports Nutr. 2021;18(1):13. https://doi.org/10.1186/s12970-021-00412-w
3.Ardalan MR, S Samadifar Z, Vahedi A. Creatine monohydrate supplement induced interstitial nephritis. J Nephropathol. 2012;1(2):117-120. https://doi.org/10.5812/nephropathol.7530
4.Armenta A, Madero M, Rodriguez-Iturbe B. Functional reserve of the kidney. Clin J Am Soc Nephrol. 2022;17(3):458-466. https://doi.org/10.2215/CJN.11070821
5.Balsom PD, Söderlund K, Ekblom B. Creatine in humans with special reference to creatine supplementation. Sports Med. 1994;18(4):268-280. https://doi.org/10.2165/00007256-199418040-00005
6.Bernales-Delmon W, Basualto-Alarcón C. Creatine supplementation in hemodialysis patients: an open-label pilot clinical trial. PLoS One. 2025;20(7):e0328757. https://doi.org/10.1371/journal.pone.0328757
7.Bonfá E, Gualano B, Roschel H, et al. Effect of creatine supplementation on measured glomerular filtration rate in postmenopausal women. Appl Physiol Nutr Metab. 2011;36(3):419-422. https://doi.org/10.1139/h11-014
8.Bosch JP, Saccaggi A, Lauer A, et al. Renal functional reserve in humans: effect of protein intake on glomerular filtration rate. Am J Med. 1983;75(6):943-950. https://doi.org/10.1016/0002-9343(83)90873-2
9.Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med. 1982;307(11):652-659. https://doi.org/10.1056/NEJM198209093071104
10.Brenner BM, Lawler EV, Mackenzie HS. The hyperfiltration theory: a paradigm shift in nephrology. Kidney Int. 1996;49(6):1774-1777. https://doi.org/10.1038/ki.1996.265
11.Brenner BM, Mackenzie HS. Nephron mass as a risk factor for progression of renal disease. Kidney Int Suppl. 1997;63:S124-S127. Academic Journal available at link
12.Brosnan ME, Brosnan JT. Renal arginine metabolism. J Nutr. 2004;134(10 Suppl):2791S-2795S. https://doi.org/10.1093/jn/134.10.2791S
13.Chen Z, Taubert M, et al. A joint pharmacometric model of iohexol and creatinine administered through a meat meal to assess GFR and renal OCT2/MATE activity. Clin Pharmacol Ther. 2025;117(5):1388-1400. https://doi.org/10.1002/cpt.3591
14.Cortinovis M, Perico N, Ruggenenti P, Remuzzi A, Remuzzi G. Glomerular hyperfiltration. Nat Rev Nephrol. 2022;18(7):435-451. https://doi.org/10.1038/s41581-022-00559-y
15.da Silva RP, Brosnan JT, et al. Sy ~~nthesis of guanidinoacetate and creatine from amino acids by rat pancreas. Br J Nutr. 2014;111(3):571-577. https://doi.org/10.1017/S0007114513002535
16.de Souza e Silva A, Pertille A, Reis Barbosa CG, et al . Effects of creatine supplementation on renal function: a systematic review and meta-analysis. J Ren Nutr. 2019;29(6):480-489. https://doi.org/10.1053/j.jrn.2019.05.004
17.Edmunds JW, Jayapalan S, DiMarco NM, Saboorian MH, Aukema HM. Creatine supplementation increases renal disease progression in Han:SPRD-cy rats. Am J Kidney Dis. 2001;37(1):73-78. https://doi.org/10.1053/ajkd.2001.20590
18.Filler G, Maung E, Diaz Gonzales de Ferris ME, et al. Acute kidney injury with cast nephropathy following creatine loading in a 17-year-old: a pediatric case report. Pediatr Nephrol. 2025. https://doi.org/10.21203/rs.3.rs-6264415/v1
19.Garcia MP, Longobardi I, Saito T, et al. Safety of long-term creatine supplementation in women's football players: a real-world in-season study. J Int Soc Sports Nutr. 2025;22(1). https://doi.org/10.1080/15502783.2025.2591782
20.Gualano B, Ugrinowitsch C, Novaes RB, et al. Effects of creatine supplementation on renal function: a randomized, double-blind, placebo-controlled clinical trial. Eur J Appl Physiol.2008;103(1):33-40. https://doi.org/10.1007/s00421-007-0669-3
21.Gualano B, Ugrinowitsch C, Seguro AC, Lancha AH Jr. Effect of short-term high dose creatine supplementation on measured GFR in a young man with a single kidney: case report. Am J Kidney Dis. 2010;55(3):e7-e9. https://doi.org/10.1053/j.ajkd.2009.10.053
22.Gualano B, de Salles Painelli V, Roschel H, et al. Creatine supplementation does not impair kidney function in type 2 diabetic patients: a randomized, double-blind, placebo-controlled, clinical trial. Eur J Appl Physiol. 2011;111(5):749-756. https://doi.org/10.1007/s00421-010-1676-
23.Gualano B, Roschel H, Lancha AH Jr, Brightbill CE, Rawson ES. In sickness and in health: the widespread application of creatine supplementation. Amino Acids. 2012;43(2):519-529. https://doi.org/10.1007/s00726-011-1132-7
24.Hultman E, Söderlund K, Timmons JA, Cederblad G, Greenhaff PL. Muscle creatine loading in men. J Appl Physiol. 1996;81(1):232-237. https://doi.org/10.1152/jappl.1996.81.1.232
25.Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367(1):20-29. https://doi.org/10.1056/NEJMoa1114248
26.Inker LA, Eneanya ND, Coresh J, et al. New creatinine- and cystatin C-based equations to estimate GFR without race. N Engl J Med. 2021;385(19):1737-1749. https://doi.org/10.1056/NEJMoa2102953
27.Kabiri Naeini E, Eskandari M, Mortazavi M, Ghola minejad A, Karevan N. Effect of creatine supplementation on kidney function: a systematic review and meta-analysis. BMC Nephrol. 2025;26:622. https://doi.org/10.1186/s12882-025-04558-6
28.Kim HJ, Kim CK, Carpentier A, Poortmans JR. Studies on the safety of creatine supplementation. Amino Acids. 2011;40(5):1409-1418. https://doi.org/10.1007/s00726-011-0878-2
29.Kishi S, et al. Redefining glomerular hyperfiltration: pathophysiology, clinical implications, and novel perspectives. Hypertens Res. 2025. https://doi.org/10.1038/s41440-024-02092-w
30.Koshy KM, Griswold E, Schneeberger EE. Interstitial nephritis in a patient taking creatine. N Engl J Med. 1999;340(10):814-815. https://doi.org/10.1056/NEJM199903113401017
31.Kreider RB, Melton C, Rasmussen CJ, et al. Long-term creatine supplementation does not significantly affect clinical markers of health in athletes. Mol Cell Biochem. 2003;244(1-2):95-104. https://doi.org/10.1023/A:1022469320296
32.Kreider RB, Kalman DS, Antonio J, et al. International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. J Int Soc Sports Nutr. 2017;14:18. https://doi.org/10.1186/s12970-017-0173-z
33.Kreider RB, Bonilla DA. Safety of creatine supplementation: analysis of the prevalence of reported side effects in clinical trials and adverse event reports. J Int Soc Sports Nutr. 2025;22(1). https://doi.org/10.1080/15502783.2025.2488937
34.Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-612. https://doi.org/10.7326/0003-4819-150-9-
35.Longobardi I, Gualano B, Seguro AC, Roschel H. Is it time for a requiem for creatine supplementation-induced kidney failure? A narrative review. Nutrients. 2023;15(6):1466. https://doi.org/10.3390/nu15061466
36.Longobardi I, et al. A short review of the most common safety concerns regarding creatine ingestion. Front Nutr. 2025;12:1234567. https://doi.org/10.3389/fnut.2025.1682746
37.Luyckx VA, Brenner BM. Low birth weight, nephron number, and kidney disease. Kidney IntSuppl. 2005;(97):S68-S77. https://doi.org/10.1111/j.1523-1755.2005.09712.x
38.Luyckx VA, Shukha K, Brenner BM. Low nephron number and its clinical consequences. Rambam Maimonides Med J. 2011;2(4):e0061. https://doi.org/10.5041/RMMJ.10061
39.Martin WF, Armstrong LE, Rodriguez NR. Dietary protein intake and renal function. Nutr Metab (Lond). 2005;2:25.https://doi.org/10.1186/1743-7075-2-25
40.Persky AM, Brazeau GA. Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacol Rev. 2001;53(2):161-176. Academic Journal available at link
41.Poortmans JR, Francaux M. Renal dysfunction accompanying oral creatine supplements [letter]. Lancet. 1998;352(9123):234. https://doi.org/10.1016/S0140-6736(05)77836-3
42.Poortmans JR, Francaux M. Long-term oral creatine supplementation does not impair renal function in healthy athletes. Med Sci Sports Exerc. 1999;31(8):1108-1110. https://doi.org/10.1097/00005768-199908000-00005
43.Poortmans JR, Francaux M. Adverse effects of creatine supplementation: fact or fiction? Sports Med. 2000;30(3):155-170. https://doi.org/10.2165/00007256-200030030-00002
44.Post A, et al. Creatine homeostasis and the kidney: comparison between kidney transplant recipients and healthy controls. Amino Acids. 2024;56(1):44. https://doi.org/10.1007/s00726-024-03401-w
45.Pritchard NR, Kalra PA. Renal dysfunction accompanying oral creatine supplements. Lancet. 1998;351(9111):1252-1253. https://doi.org/10.1016/s0140-6736(05)79319-3
46.Ronco C, Bellomo R, Kellum JA. Understanding renal functional reserve. Intensive Care Med. 2017;43(6):917-920.https://doi.org/10.1007/s00134-017-4691-6
47.Roschel H, Gualano B, Ostojic SM, Rawson ES. Creatine supplementation and brain health. [Nutrients. 2021;13(2):586. https://doi.org/10.3390/nu13020586
48.Taes YEC, Delanghe JR, Wuyts B, van de Voorde J, Lameire NH. Creatine supplementation does not affect kidney function in an animal model with pre-existing renal failure. Nephrol Dial Transplant. 2003;18(2):258-264. https://doi.org/10.1093/ndt/18.2.258
49.Taner B, Aysim O, Abdulkadir U. The effects of the recommended dose of creatine monohydrate on kidney function. NDT Plus. 2011;4(1):23-24. https://doi.org/10.1093/ndtplus/sfq177
50.ter Wee PM, Tegzess AM, Donker AJ. Renal reserve filtration capacity before and after kidney donation. J Intern Med. 1994;236(5):559-563. https://doi.org/10.1111/j.1365-2796.1990.tb00251.x
51.Thorsteinsdottir B, Grande JP, Garovic VD. Acute renal failure in a young weight lifter taking multiple food supplements, including creatine monohydrate. J Ren Nutr. 2006;16(4):341-345. https://doi.org/10.1053/j.jrn.2006.04.025
52.Tonneijck L, Muskiet MHA, Smits MM, et al. Glom~erular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment. J Am Soc Nephrol. 2017;28(4):1023-1039. https://doi.org/10.1681/ASN.2016060666
53.Williamson L, New D. How the use of creatine supplements can elevate serum creatinine in the absence of underlying kidney pathology. BMJ Case Rep. 2014;2014:bcr2014204754. https://doi.org/10.1136/bcr-2014-204754
54.Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev. 2000;80(3):11071213. https://doi.org/10.1152/physrev.2000.80.3.1107
55.Zandi-Nejad K, Luyckx VA, Brenner BM. Adult hypertension and kidney disease: the role of fetal programming. Hypertension. 2006;47(3):502-508. https://doi.org/10.1161/01.HYP.0000198544.09909.1a
56.Zatz R, Dunn BR, Meyer TW, Anderson S, Rennke HG, Brenner BM. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest. 1986;77(6):1925-1930. https://doi.org/10.1172/JCI112521
57.Zhou B, et al. Exploring the relationship between creatine supplementation and renal function. Ren Fail. 2024;46(1):2364762. https://doi.org/10.1080/0886022X.2024.2364762
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Michał Kasznicki, Mikołaj Kamela, Alicja Rogozińska, Emilia Skrzypek, Małgorzata Czechowska, Jakub Łącki, Karol Jackowiak, Michał Kalisiak, Natalia Micek, Wiktor Beśka

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Stats
Number of views and downloads: 19
Number of citations: 0