Abstract
Sarcopenia is highly prevalent in patients undergoing chronic hemodialysis (HD). This study investigated the relationship among serum indoxyl sulfate (IS) levels, muscle mass, and strength in HD patients. A total of 108 HD patients were enrolled. Skeletal muscle mass and handgrip strength (HGS) were assessed, using bioimpedance analysis and a hand-held dynamometer, respectively. Skeletal muscle index (SMI) was defined as skeletal muscle mass/height2 (kg/m2). Serum IS, p-cresol sulfate (PCS), and trimethylamine N-oxide (TMAO) levels were determined using liquid chromatography–mass spectrometry. Patients were classified into two groups based on median serum IS values. HGS measurement was repeated after 2 years. Patients in the high IS group had longer HD duration and higher serum TMAO levels than those in the low IS group. Log-normalized IS level was negatively correlated with SMI (r = − 0.227; p = 0.018), but PCS and TMAO levels were not. Among 78 patients who completed 2-year follow-up, those in the high IS group (n = 41) showed greater absolute (− 2.48 kg versus − 0.25 kg, p = 0.035) and relative HGS loss (− 9.1% versus 1.4%, p = 0.036) than those in the low IS group, after adjustment for potential confounders. Indoxyl sulfate (IS) may play a significant role in uremic sarcopenia. Further large-scale studies are needed to confirm our preliminary findings.
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Mak RH, Ikizler AT, Kovesdy CP, Raj DS, Stenvinkel P, Kalantar-Zadeh K (2011) Wasting in chronic kidney disease. J Cachexia Sarcopenia Muscle 2:9–25
Bonanni A, Mannucci I, Verzola D, Sofia A, Saffioti S, Gianetta E et al (2011) Protein-energy wasting and mortality in chronic kidney disease. Int J Environ Res Public Health 8:1631–1654
Stenvinkel P, Carrero JJ, von Walden F, Ikizler TA, Nader GA (2016) Muscle wasting in end-stage renal disease promulgates premature death: established, emerging and potential novel treatment strategies. Nephrol Dial Transplant 31:1070–1077
Kittiskulnam P, Chertow GM, Carrero JJ, Delgado C, Kaysen GA, Johansen KL (2017) Clinical investigation: sarcopenia and its individual criteria are associated, in part, with mortality among patients on hemodialysis. Kidney Int 92:238–247
Fahal IH (2014) Uraemic sarcopenia: aetiology and implications. Nephrol Dial Transplant 29:1655–1665
Wang XH, Mitch WE (2014) Mechanisms of muscle wasting in chronic kidney disease. Nat Rev Nephrol 10:504–516
Rodriguez J, Vernus B, Chelh I, Cassar-Malek I, Gabillard JC, Hadj Sassi A et al (2014) Myostatin and the skeletal muscle atrophy and hypertrophy signaling pathways. Cell Mol Life Sci 71:4361–4371
van Tongeren SP, Slaets JP, Harmsen HJ, Welling GW (2005) Fecal microbiota composition and frailty. Appl Environ Microbiol 71:6438–6442
Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S et al (2012) Gut microbiota composition correlates with diet and health in the elderly. Nature 488:178–184
Buigues C, Fernandez-Garrido J, Pruimboom L, Hoogland AJ, Navarro-Martinez R, Martinez-Martinez M et al (2016) Effect of a prebiotic formulation on frailty syndrome: a randomized, double-blind clinical trial. Int J Mol Sci 17:E932
Grosicki GJ, Fielding RA, Lustgarten MS (2018) Gut microbiota contribute to age-related changes in skeletal muscle size, composition, and function: biological basis for a gut-muscle axis. Calcif Tissue Int 102:433–442
Nallu A, Sharma S, Ramezani A, Muralidharan J, Raj D (2017) Gut microbiome in chronic kidney disease: challenges and opportunities. Transl Res 179:24–37
Leong SC, Sirich TL (2016) Indoxyl sulfate-review of toxicity and therapeutic strategies. Toxins (Basel) 8:E358
Vanholder R, Schepers E, Pletinck A, Nagler EV, Glorieux G (2014) The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. J Am Soc Nephrol 25:1897–1907
Barreto FC, Barreto DV, Liabeuf S, Meert N, Glorieux G, Temmar M et al (2009) Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol 4:1551–1558
Sun CY, Tsai CJ, Lee CC, Hsu HJ, Wu MS, Wang YC et al (2010) p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease. Nephrol Dial Transplant 26:938–947
Sato E, Mori T, Mishima E, Suzuki A, Sugawara S, Kurasawa N et al (2016) Metabolic alterations by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease. Sci Rep 6:36618
Enoki Y, Watanabe H, Arake R, Sugimoto R, Imafuku T, Tominaga Y et al (2016) Indoxyl sulfate potentiates skeletal muscle atrophy by inducing the oxidative stress-mediated expression of myostatin and atrogin-1. Sci Rep 6:32084
Enoki Y, Watanabe H, Arake R, Fujimura R, Ishiodori K, Imafuku T et al (2017) Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunction. J Cachexia Sarcopenia Muscle 8:735–747
Nishikawa M, Ishimori N, Takada S, Saito A, Kadoguchi T, Furihata T et al (2015) AST-120 ameliorates lowered exercise capacity and mitochondrial biogenesis in the skeletal muscle from mice with chronic kidney disease via reducing oxidative stress. Nephrol Dial Transplant 30:934–942
Lin YL, Liou HH, Lai YH, Wang CH, Kuo CH, Chen SY et al (2018) Decreased serum fatty acid binding protein 4 concentrations are associated with sarcopenia in chronic hemodialysis patients. Clin Chim Acta 485:113–118
Kalantar-Zadeh K, Kopple JD, Block G, Humphreys MH (2001) A malnutrition-inflammation score is correlated with morbidity and mortality in maintenance hemodialysis patients. Am J Kidney Dis 38(6):1251–1263
Iseki K, Tozawa M, Yoshi S, Fukiyama K (1999) Serum c-reactive protein (CRP) and risk of death in chronic dialysis patients. Nephrol Dial Transplant 14:1956–1960
Bazeley J, Bieber B, Li Y, Morgenstern H, de Sequera P, Combe C et al (2011) C-reactive protein and prediction of 1-year mortality in prevalent hemodialysis patients. Clin J Am Soc Nephrol 6:2452–2461
Fouque D, Kalantar-Zadeh K, Kopple J, Cano N, Chauveau P, Cuppari L et al (2008) A proposed nomenclature and diagnostic criteria for protein–energy wasting in acute and chronic kidney disease. Kidney Int 73:391–398
Panzetta G, Tessitore N, Faccini G, Maschio G (1990) The protein catabolic rate as a measure of protein intake in dialysis patients: usefulness and limits. Nephrol Dial Transplant 5:125–127
Steuer C, Schutz P, Bernasconi L, Huber AR (2016) Simultaneous determination of phosphatidylcholine-derived quaternary ammonium compounds by a lc-ms/ms method in human blood plasma, serum and urine samples. J Chromatogr B Analyt Technol Biomed Life Sci 1008:206–211
Shu C, Chen X, Xia T, Zhang F, Gao S, Chen W (2016) LC-MS/MS method for simultaneous determination of serum p-cresyl sulfate and indoxyl sulfate in patients undergoing peritoneal dialysis. Biomed Chromatogr 30:1782–1788
Ng DP, Salim A, Liu Y, Zou L, Xu FG, Huang S et al (2012) A metabolomic study of low estimated GFR in non-proteinuric type 2 diabetes mellitus. Diabetologia 55:499–508
Krieter DH, Kerwagen S, Ruth M, Lemke HD, Wanner C (2019) Differences in dialysis efficacy have limited effects on protein-bound uremic toxins plasma levels over time. Toxins (Basel) 11:E47
Yazdi PG, Moradi H, Yang JY, Wang PH, Vaziri ND (2013) Skeletal muscle mitochondrial depletion and dysfunction in chronic kidney disease. Int J Clin Exp Med 6:532–539
Tamaki M, Miyashita K, Wakino S, Mitsuishi M, Hayashi K, Itoh H (2014) Chronic kidney disease reduces muscle mitochondria and exercise endurance and its exacerbation by dietary protein through inactivation of pyruvate dehydrogenase. Kidney Int 85:1330–1339
Jheng JR, Chen YS, Ao UI, Chan DC, Huang JW, Hung KY et al (2018) The double-edged sword of endoplasmic reticulum stress in uremic sarcopenia through myogenesis perturbation. J Cachexia Sarcopenia Muscle 9:570–584
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This study was supported by a Grant from Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taiwan (TCRD107-56).
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Conceptualization, Y-LL and B-GH; methodology, Y-LL and B-GH; formal analysis, Y-LL and C-HL; investigation, Y-HL, C-HW, and C-HK; data curation, Y-HL, C-HW, and C-HK; funding acquisition, C-HL and Y-HL; writing—original draft preparation, Y-LL; writing—review and editing, Y-LL, C-HL, H-HL and B-GH; supervision, H-HL and B-GH.
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Yu-Li Lin, Chin-Hung Liu, Yu-Hsien Lai, Chih-Hsien Wang, Chiu-Huang Kuo, Hung-Hsiang Liou and Bang-Gee Su declare no conflict of interest.
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This study was approved by the Institutional Review Board of Tzu Chi Hospital (IRB104-84-B), and all patients gave written informed consent in accordance with the general recommendations of the Declaration of Helsinki.
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Lin, YL., Liu, CH., Lai, YH. et al. Association of Serum Indoxyl Sulfate Levels with Skeletal Muscle Mass and Strength in Chronic Hemodialysis Patients: A 2-year Longitudinal Analysis. Calcif Tissue Int 107, 257–265 (2020). https://doi.org/10.1007/s00223-020-00719-x
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DOI: https://doi.org/10.1007/s00223-020-00719-x