Benefits of Exercise in Chronic Kidney Disease Progression: Comparison
Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Jamie Hugo Macdonald.

Chronic Kidney Disease (CKD) is a progressive condition characterised by declining eGFR and associated, particularly in advanced stages, with increased morbidity and cardiovascular mortality. Current treatment options for delaying disease progression are limited to a small number of pharmacological agents. Considering that rates of kidney function decline are greater in patients with lower levels of habitual physical activity, there is interest in the potential benefits of structured exercise training in delaying CKD progression. 

  • aerobic
  • Chronic Kidney Disease
  • disease progression
  • eGFR
  • exercise
  • kidney function

1. Introduction

Chronic Kidney Disease (CKD) is a progressive condition characterised by variable, but usually inevitable, annual rates of estimated glomerular filtration rate (eGFR) decline [1]. Even before progressing to end-stage kidney disease (ESKD), CKD is associated with increased mortality, particularly cardiovascular death [2]. Furthermore, CKD is an independent risk factor for cardiovascular disease with an increased risk of death, cardiovascular events and hospitalisation as eGFR falls [3]. Current treatment options for delaying the progression of CKD are limited to a small handful of therapeutic options, namely renin-angiotensin-aldosterone (RAS) system inhibitors, sodium bicarbonate supplementation and sodium-glucose transporter 2 (SGLT-2) inhibitors [4,5][4][5]. In the hunt for additional strategies, exercise training has been considered a possible therapy for delaying disease progression.
Despite evidence of exercise-induced acute kidney injury (AKI) in endurance athletes and increased proteinuria post-exercise, concerns that exercise may have a detrimental effect on kidney function have been allayed by a wealth of studies showing exercise training to be safe [6,7,8,9][6][7][8][9]. Indeed, structured exercise training has been shown to have multiple beneficial effects in the non-dialysis-dependent CKD (ND-CKD) population, including improved aerobic capacity [10,11[10][11][12][13],12,13], physical function [9,14[9][14][15],15], muscle strength [14,15,16][14][15][16] and health-related quality of life (HRQoL) [9,17][9][17]. Increased habitual physical activity is associated with better survival in both ESKD [18] and ND-CKD patients [19,20][19][20] (though there is a possible influence of selection bias and other factors not adjusted for in these observational studies).

2. Exercise Training to Delay CKD Progression

Exercise training in CKD patients produces physiological adaptations that produce improved cardiorespiratory fitness and muscle strength. It is reasonable to consider whether similar training may induce adaptations in the kidney.

Whilst the precise mechanisms have not been elucidated, the stimulants for exercise-induced physiological adaptations occur primarily due to muscle stretching. Muscle activity results in changes including intra-muscular energy consumption, intracellular pH and Ca2+ concentration, as well as the generation of mechanical forces by muscle contraction [158][21]. These stimulants have all been linked to changes in protein and enzyme transcription, which result in metabolic, hormonal and vascular changes, which then produce beneficial adaptations to exercise training. There are also stimulants that occur outside of the contracting muscles, including increased shear stress driven by increased cardiac output and blood flow and altered sympathetic nervous activity [159][22]. Clearly, physical stretching is not relevant to kidney tissue. Furthermore, during exercise, renal blood flow diminishes rather than increases. Hence, mechanisms specific to muscles (related to mechanical stretching and increased shear stress) are not replicated in the kidney. However, whilst these stimulants derive from active muscle tissue, the downstream effectors are not necessarily limited to muscles, and some are of relevance to renal pathophysiology. For example, skeletal muscle capillary growth is stimulated by mechanical influences, such as shear stress induced by increased blood flow, and stretching of the muscle tissue, with VEGF mediating the effect [160,161][23][24]. VEGF may have systemic and beneficial effects on maintaining the renal vasculature, particularly the glomerular and tubular capillaries, which are so relevant to the pathogenesis of CKD progression. There are a number of lines of evidence to suggest that the physiological changes that occur during exercise not only occur in the active skeletal muscle but also take place elsewhere in the body. Examples include an improvement in endothelial-dependent dilation in the brachial artery as a result of leg cycling training [162][25]. Distal vascular changes have also been demonstrated in studies where there is no increased cardiac load: in a four-week passive leg movement programme, there was an increased capillary density and VEGF concentration in the muscle of the untrained leg [163][26].

Another key adaptation to exercise training is mitochondrial biogenesis [164][27]. This is an important development, in response to Ca2+ cycling and ROS production etc., for improving the energy supply to active muscle. It would also be a useful adaptation in metabolically active kidney tissue, helping to optimise the use of oxygen to produce energy, potentially alleviating the effects of hypoxia in CKD pathophysiology. In animal models of diabetic and hypertensive nephropathy, aerobic exercise training produced beneficial effects on renal mitochondria, including inducing key enzymes and transcription factors for mitochondrial biogenesis, increasing mitochondrial ATP and reducing mitochondrial ROS production. These changes were associated with reduced renal disease progression compared with untrained animals [165,166,167][28][29][30]. Studies in humans have demonstrated reduced concentrations of some of the key molecules implicated in renal pathophysiology (discussed above) in response to exercise. These include MCP-1 [168[31][32],169], RANTES [170][33], NF-κB [171][34] and TNFα [172][35]. Exercise also increases anti-oxidants and decreases pro-oxidants in a variety of healthy and chronic disease populations [173][36]. Alterations to levels of myokines, i.e., cytokines produced by active skeletal muscle tissue, may also be relevant because of their anti-inflammatory and metabolic effects. These include the effects of IL-6 on increasing fatty acid oxidation, thus increasing energy availability, and reducing TNFα production from macrophages, amongst other anti-inflammatory effects [174][37]. Another example is the myokine irisin, serum levels of which are decreased in patients with CKD [175,176][38][39] and can be increased with exercise training, e.g., in older adults [177][40]. Interestingly, a mouse model of CKD (interstitial fibrosis) demonstrated improved kidney mitochondrial energy metabolism and reduced fibrosis after irisin induction [178][41]. Whilst some of these changes have not yet been demonstrated in patients with CKD, exercise may help readjust the imbalance of these important mediators in this population. Benefits on other inflammatory and oxidative stress molecules have been seen in patients with CKD: 12 weeks of exercise in CKD 3–4 ameliorated cutaneous microvascular endothelial dysfunction by reducing oxidative stress. This suggests systemic anti-oxidant and endothelial function benefits of exercise [141][42]. Similarly, exercise training in CKD has been shown to reduce serum markers of oxidative stress, including F2-isoprostane [12] and reduce lipid peroxidation and glutathione oxidation after 12 weeks of aquatic exercise in participants with mild-to-moderate CKD [142][43]. There is reduced (sodium oxide dismutase) SOD and Nrf2, important anti-oxidant/anti-inflammatory molecules in moderate CKD, compared with healthy controls; this was improved after acute exercise [179][44]. Likewise, resistance exercise in haemodialysis patients increases Nrf2 [180][45]. These are systemic anti-oxidant effects that may benefit ROS imbalance present in the diseased kidney.
Finally, whilst a bout of exercise leads to increased SNS activity [181][46], exercise training is known to dampen this response and may even reduce resting sympathetic tone [182][47]. Indeed, exercise training in healthy adults has been shown to result in reduced resting renal sympathetic activity, specifically [183][48]. As discussed, CKD patients have SNS overactivity, which may contribute to the pathophysiology of the disease. Thus, reduced SNS activity may be another way in which exercise training may affect CKD progression. In summary, there are a number of potential ways in which exercise may reduce CKD progression. Prominent risk factors for CKD—BP and BMI—are improved by exercise, both in CKD patients and other populations. It is also plausible that exercise may affect the mediators of kidney disease pathophysiology themselves, with human exercise studies showing modification of many of the relevant molecules and pathways.


  1. Li, L.; Astor, B.C.; Lewis, J.; Hu, B.; Appel, L.J.; Lipkowitz, M.S.; Toto, R.D.; Wang, X.; Wright, J.T.; Greene, T.H. Longitudinal progression trajectory of GFR among patients with CKD. Am. J. Kidney Dis. 2012, 59, 504–512.
  2. Tonelli, M.; Wiebe, N.; Culleton, B.; House, A.; Rabbat, C.; Fok, M.; McAlister, F.; Garg, A.X. Chronic Kidney Disease and mortality risk: A systematic review. J. Am. Soc. Nephrol. 2006, 17, 2034–2047.
  3. Go, A.S.; Chertow, G.M.; Fan, D.; McCulloch, C.E.; Hsu, C.Y. Chronic Kidney Disease and the Risks of Death, Cardiovascular Events, and Hospitalization. N. Engl. J. Med. 2004, 351, 1296–1305.
  4. Mende, C.W. Chronic Kidney Disease and SGLT2 Inhibitors: A Review of the Evolving Treatment Landscape. Adv. Ther. 2022, 39, 148–164.
  5. Shabaka, A.; Cases-Corona, C.; Fernandez-Juarez, G. Therapeutic Insights in Chronic Kidney Disease Progression. Front. Med. 2021, 8, 645187.
  6. Yang, L.; Wu, X.; Wang, Y.; Wang, C.; Hu, R.; Wu, Y. Effects of exercise training on proteinuria in adult patients with Chronic Kidney Disease: A systematic review and meta-analysis. BMC Nephrol. 2020, 21, 172.
  7. Beetham, K.S.; Howden, E.J.; Fassett, R.G.; Petersen, A.; Trewin, A.J.; Isbel, N.M.; Coombes, J.S. High-intensity interval training in Chronic Kidney Disease: A randomized pilot study. Scand. J. Med. Sci. Sports 2019, 29, 1197–1204.
  8. Howden, E.J.; Coombes, J.S.; Strand, H.; Douglas, B.; Campbell, K.L.; Isbel, N.M. Exercise training in CKD: Efficacy, adherence, and safety. Am. J. Kidney Dis. 2015, 65, 583–591.
  9. Rossi, A.P.; Burris, D.D.; Lucas, F.L.; Crocker, G.A.; Wasserman, J.C. Effects of a renal rehabilitation exercise program in patients with CKD: A randomized, controlled trial. Clin. J. Am. Soc. Nephrol. 2014, 9, 2052–2058.
  10. Greenwood, S.A.; Koufaki, P.; Mercer, T.H.; MacLaughlin, H.L.; Rush, R.; Lindup, H.; O’Connor, E.; Jones, C.; Hendry, B.M.; Macdougall, I.C.; et al. Effect of Exercise Training on Estimated GFR, Vascular Health, and Cardiorespiratory Fitness in Patients With CKD: A Pilot Randomized Controlled Trial. Am. J. Kidney Dis. 2015, 65, 425–434.
  11. Van Craenenbroeck, A.H.; Van Craenenbroeck, E.M.; Van Ackeren, K.; Vrints, C.J.; Conraads, V.M.; Verpooten, G.A.; Kouidi, E.; Couttenye, M.M. Effect of Moderate Aerobic Exercise Training on Endothelial Function and Arterial Stiffness in CKD Stages 3–4: A Randomized Controlled Trial. Am. J. Kidney Dis. 2015, 66, 285–296.
  12. Ikizler, T.A.; Robinson-Cohen, C.; Ellis, C.; Headley, S.A.; Tuttle, K.; Wood, R.J.; Evans, E.E.; Milch, C.M.; Moody, K.A.; Germain, M.; et al. Metabolic effects of diet and exercise in patients with moderate to severe CKD: A randomized clinical trial. J. Am. Soc. Nephrol. 2018, 29, 250–259.
  13. Headley, S.A.; Germain, M.; Milch, C.; Pescatello, L.; Coughlin, M.A.; Nindl, B.C.; Cornelius, A.; Sullivan, S.; Gregory, S.; Wood, R. Exercise training improves HR responses and VO2peak in predialysis kidney patients. Med. Sci. Sports Exerc. 2012, 44, 2392–2399.
  14. Watson, E.L.; Gould, D.W.; Wilkinson, T.J.; Xenophontos, S.; Clarke, A.L.; Vogt, B.P.; Viana, J.L.; Smith, A.C. Twelve-week combined resistance and aerobic training confers greater benefits than aerobic training alone in nondialysis CKD. Am. J. Physiol. Ren. Physiol. 2018, 314, F1188–F1196.
  15. Hellberg, M.; Höglund, P.; Svensson, P.; Clyne, N. Randomized Controlled Trial of Exercise in CKD-The RENEXC Study. Kidney Int. Rep. 2019, 4, 963–976.
  16. Heiwe, S.; Jacobson, S.H. Exercise training in adults with CKD: A systematic review and meta-analysis. Am. J. Kidney Dis. 2014, 64, 383–393.
  17. Villanego, F.; Naranjo, J.; Vigara, L.A.; Cazorla, J.M.; Montero, M.E.; García, T.; Torrado, J.; Mazuecos, A. Impact of physical exercise in patients with Chronic Kidney Disease: Sistematic review and meta-analysis. Nefrologia 2020, 40, 237–252.
  18. Martins, P.; Marques, E.A.; Leal, D.V.; Ferreira, A.; Wilund, K.R.; Viana, J.L. Association between physical activity and mortality in end-stage kidney disease: A systematic review of observational studies. BMC Nephrol. 2021, 22, 227.
  19. Clarke, A.L.; Zaccardi, F.; Gould, D.W.; Hull, K.L.; Smith, A.C.; Burton, J.O.; Yates, T. Association of self-reported physical function with survival in patients with Chronic Kidney Disease. Clin. Kidney J. 2019, 12, 122–128.
  20. MacKinnon, H.J.; Wilkinson, T.J.; Clarke, A.L.; Gould, D.W.; O’Sullivan, T.F.; Xenophontos, S.; Watson, E.L.; Singh, S.J.; Smith, A.C. The association of physical function and physical activity with all-cause mortality and adverse clinical outcomes in nondialysis Chronic Kidney Disease: A systematic review. Ther. Adv. Chronic Dis. 2018, 9, 209.
  21. Sakamoto, K.; Goodyear, L.J. Invited review: Intracellular signaling in contracting skeletal muscle. J. Appl. Physiol. 2002, 93, 369–383.
  22. Hellsten, Y.; Nyberg, M. Cardiovascular adaptations to exercise training. Compr. Physiol. 2016, 6, 1–32.
  23. Rivilis, I.; Milkiewicz, M.; Boyd, P.; Goldstein, J.; Brown, M.D.; Egginton, S.; Hansen, F.M.; Hudlicka, O.; Haas, T.L. Differential involvement of MMP-2 and VEGF during muscle stretch- versus shear stress-induced angiogenesis. Am. J. Physiol. Heart Circ. Physiol. 2002, 283, H1430–H1438.
  24. Brown, M.D.; Hudlicka, O. Modulation of physiological angiogenesis in skeletal muscle by mechanical forces: Involvement of VEGF and metalloproteinases. Angiogenesis 2003, 6, 1–14.
  25. Linke, A.; Schoene, N.; Gielen, S.; Hofer, J.; Erbs, S.; Schuler, G.; Hambrecht, R. Endothelial dysfunction in patients with Chronic Heart Failure: Systemic effects of lower-limb exercise training. J. Am. Coll. Cardiol. 2001, 37, 392–397.
  26. Høier, B.; Rufener, N.; Bojsen-Møller, J.; Bangsbo, J.; Hellsten, Y. The effect of passive movement training on angiogenic factors and capillary growth in human skeletal muscle. J. Physiol. 2010, 588, 3833–3845.
  27. Hood, D.A. Mechanisms of exercise-induced mitochondrial biogenesis in skeletal muscle. Appl. Physiol. Nutr. Metab. Physiol. Appl. Nutr. Metab. 2009, 34, 465–472.
  28. Tang, L.X.; Wang, B.; Wu, Z.K. Aerobic Exercise Training Alleviates Renal Injury by Interfering with Mitochondrial Function in Type-1 Diabetic Mice. Med. Sci. Monit. Int. Med. J. Exp. Clin. Res. 2018, 24, 9081–9089.
  29. Gu, Q.; Zhao, L.; Ma, Y.P.; Liu, J.D. Contribution of mitochondrial function to exercise-induced attenuation of renal dysfunction in spontaneously hypertensive rats. Mol. Cell. Biochem. 2015, 406, 217–225.
  30. Jorge, L.; Reinecke, N.; Da Silva, W.; Jorge, M.L.S.; Schor, N. Impact of different exercise training on mitochondrial in diabetic nephropathy. J. Diabetes Metab. Disord. Control 2021, 8, 79–85.
  31. Trøseid, M.; Lappegård, K.T.; Claudi, T.; Damås, J.K.; Mørkrid, L.; Brendberg, R.; Mollnes, T.E. Exercise reduces plasma levels of the chemokines MCP-1 and IL-8 in subjects with the metabolic syndrome. Eur. Heart J. 2004, 25, 349–355.
  32. Balan, E.; Diman, A.; Everard, A.; Nielens, H.; Decottignies, A.; Deldicque, L. Endurance training alleviates MCP-1 and TERRA accumulation at old age in human skeletal muscle. Exp. Gerontol. 2021, 153, 111510.
  33. Baturcam, E.; Abubaker, J.; Tiss, A.; Abu-Farha, M.; Khadir, A.; Al-Ghimlas, F.; Al-Khairi, I.; Cherian, P.; Elkum, N.; Hammad, M.; et al. Physical exercise reduces the expression of RANTES and its CCR5 receptor in the adipose tissue of obese humans. Mediat. Inflamm. 2014, 2014, 627150.
  34. Soltani, N.; Esmaeil, N.; Marandi, S.M.; Hovsepian, V.; Momen, T.; Shahsanai, A.; Kelishadi, R. Assessment of the Effect of Short-Term Combined High-Intensity Interval Training on TLR4, NF-κB and IRF3 Expression in Young Overweight and Obese Girls. Public Health Genom. 2020, 23, 26–36.
  35. Petersen, A.M.W.; Pedersen, B.K. The anti-inflammatory effect of exercise. J. Appl. Physiol. 2005, 98, 1154–1162.
  36. de Sousa, C.V.; Sales, M.M.; Rosa, T.S.; Lewis, J.E.; de Andrade, R.V.; Simões, H.G. The Antioxidant Effect of Exercise: A Systematic Review and Meta-Analysis. Sports Med. 2017, 47, 277–293.
  37. Benatti, F.B.; Pedersen, B.K. Exercise as an anti-inflammatory therapy for rheumatic diseases—Myokine regulation. Nat. Rev. Rheumatol. 2015, 11, 86–97.
  38. Wen, M.S.; Wang, C.Y.; Lin, S.L.; Hung, K.C. Decrease in irisin in patients with Chronic Kidney Disease. PLoS ONE 2013, 8, e64025.
  39. Ebert, T.; Focke, D.; Petroff, D.; Wurst, U.; Richter, J.; Bachmann, A.; Lössner, U.; Kralisch, S.; Kratzsch, J.; Beige, J.; et al. Serum levels of the myokine irisin in relation to metabolic and renal function. Eur. J. Endocrinol. 2014, 170, 501–506.
  40. Miyamoto-Mikami, E.; Sato, K.; Kurihara, T.; Hasegawa, N.; Fujie, S.; Fujita, S.; Sanada, K.; Hamaoka, T.; Tabata, I.; Iemitsu, M. Endurance Training-Induced Increase in Circulating Irisin Levels Is Associated with Reduction of Abdominal Visceral Fat in Middle-Aged and Older Adults. PLoS ONE 2015, 10, e0120354.
  41. Peng, H.; Wang, Q.; Lou, T.; Qin, J.; Jung, S.; Shetty, V.; Li, F.; Wang, Y.; Feng, X.H.; Mitch, W.E.; et al. Myokine mediated muscle-kidney crosstalk suppresses metabolic reprogramming and fibrosis in damaged kidneys. Nat. Commun. 2017, 8, 1493.
  42. Kirkman, D.L.; Ramick, M.G.; Muth, B.J.; Stock, J.M.; Pohlig, R.T.; Townsend, R.R.; Edwards, D.G. Effects of aerobic exercise on vascular function in nondialysis Chronic Kidney Disease: A randomized controlled trial. Am. J. Physiol. Ren. Physiol. 2019, 316, F898–F905.
  43. Pechter, U.; Maaroos, J.; Mesikepp, S.; Veraksits, A.; Ots, M. Regular low-intensity aquatic exercise improves cardio-respiratory functional capacity and reduces proteinuria in chronic renal failure patients. Nephrol. Dial. Transplant. 2003, 18, 624–625.
  44. Watson, E.L.; Baker, L.A.; Wilkinson, T.J.; Gould, D.W.; Graham-Brown, M.P.; Major, R.W.; Ashford, R.U.; Philp, A.; Smith, A.C. Reductions in skeletal muscle mitochondrial mass are not restored following exercise training in patients with Chronic Kidney Disease. FASEB J. 2020, 34, 1755–1767.
  45. Abreu, C.C.; Cardozo, L.F.M.F.; Stockler-Pinto, M.B.; Esgalhado, M.; Barboza, J.E.; Frauches, R.; Mafra, D. Does resistance exercise performed during dialysis modulate Nrf2 and NF-κB in patients with Chronic Kidney Disease? Life Sci. 2017, 188, 192–197.
  46. White, D.W.; Raven, P.B. Autonomic neural control of heart rate during dynamic exercise: Revisited. J. Physiol. 2014, 592, 2491–2500.
  47. Mueller, P.J. Exercise training and sympathetic nervous system activity: Evidence for physical activity dependent neural plasticity. Clin. Exp. Pharmacol. Physiol. 2007, 34, 377–384.
  48. Meredith, I.T.; Friberg, P.; Jennings, G.L.; Dewar, E.M.; Fazio, V.A.; Lambert, G.W.; Esler, M.D. Exercise training lowers resting renal but not cardiac sympathetic activity in humans. Hypertension 1991, 18, 575–582.