Effects of AST-120 on muscle health and quality of life in chronic kidney disease patients: results of RECOVERY study

Ran-Hui Cha, Seok Hui Kang, Mi Yeun Han, Won Suk An, Su-Hyun Kim, Jun Chul Kim, Ran-Hui Cha, Seok Hui Kang, Mi Yeun Han, Won Suk An, Su-Hyun Kim, Jun Chul Kim

Abstract

Background: The prevalence of sarcopenia is increased with declining renal function. Elevated serum indoxyl sulfate levels are associated with poor skeletal muscle conditions. We aimed to determine the effects of AST-120, the oral adsorbent of indoxyl sulfate, on sarcopenia and sarcopenia-associated factors in chronic kidney disease patients.

Methods: This was a 48 week, randomized controlled, parallel group, open-label, multicentre trial (n = 150). The participants were randomly assigned in a 1:1 ratio to the control (CON) and AST-120 (Renamezin®, REN) groups. Outcome measurements were performed at baseline and every 24 weeks for 48 weeks. The primary outcome was gait speed difference ≥0.1 m/s between the two groups, and secondary outcomes included hand grip strength, muscle mass, and health-related quality of life.

Results: A difference of gait speed ≥0.1 m/s was not observed during the study period. The mean dynamic-start gait speed in the REN group increased from baseline to 48 weeks (1.04 ± 0.31 to 1.08 ± 0.32 m/s, P = 0.019). The static-start gait speed changed by -0.024 and 0.04 m/s (P = 0.049) in the CON and REN groups over 48 weeks, respectively. Hand grip strength decreased during the first 24 weeks and did not significantly change over the next 24 weeks in either group. The proportion of low muscle mass or sarcopenia at baseline was larger in the REN group than in the CON group, but the difference attenuated over the study period [low muscle mass and sarcopenia in the CON and REN groups at baseline, 4.0% vs. 18.9% (P = 0.004) and 2.7% vs. 13.5% (P = 0.017); at 24 weeks, 2.9% vs. 13.6% (P = 0.021) and 1.4% vs. 10.5% (P = 0.029); and at 48 weeks, 7.6% vs. 12.9% (P = 0.319) and 4.5% vs. 8.1% (P = 0.482), respectively]. Bodily pain, vitality, symptoms/problems, and cognitive function in the REN group improved, while the quality of social interactions and the kidney disease effects in the CON group aggravated from baseline to 48 weeks. Interaction between time and group was evident only in symptoms/problems, cognitive function, and kidney disease effects.

Conclusions: The addition of AST-120 to standard treatment in chronic kidney disease patients did not make a significant difference in gait speed, although AST-120 modestly had beneficial effects on gait speed change and quality of life and showed the potential to improve sarcopenia. (clinicaltrials.gov: NCT03788252).

Keywords: AST-120; Chronic kidney disease; Gait speed; Handgrip strength; Quality of life; Sarcopenia.

Conflict of interest statement

The authors have no conflicts of interest to disclose.

© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.

Figures

Figure 1
Figure 1
Flow chart of study participant enrolment, randomization, and analysis.
Figure 2
Figure 2
Changes of indoxyl sulfate level (A), gait speed (B), and standing handgrip strength (C) from baseline to 24 and 48 weeks.Data were expressed as mean and standard error. *P < 0.05 vs. baseline, ¶P < 0.01 vs. baseline, #P < 0.05 vs. 24 weeks. ITT, intention‐to‐treat; PP, per‐protocol.
Figure 3
Figure 3
The proportions of low muscle mass (SMI), slow gait speed, weak handgrip strength, and sarcopenia according to 2019 AWGS in the ITT (a) and PP (B) groups. *P < 0.05. AWGS, Asian working group for sarcopenia; GS, gait speed; HGS, handgrip strength; ITT, intention‐to‐treat; PP, per‐protocol; MM, muscle mass; SP, sarcopenia.

References

    1. Moon SJ, Kim TH, Yoon SY, Chung JH, Hwang HJ. Relationship between stage of chronic kidney disease and sarcopenia in Korean aged 40 years and older using the Korea National Health and Nutrition Examination Surveys (KNHANES IV‐2, 3, and V‐1, 2), 2008–2011. PLoS One 2015;10:e0130740.
    1. Foley RN, Wang C, Ishani A, Collins AJ, Murray AM. Kidney function and sarcopenia in the United States general population: NHANES III. Am J Nephrol 2007;27:279–286.
    1. Lenk K, Schuler G, Adams V. Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training. J Cachexia Sarcopenia Muscle 2010;1:9–21.
    1. Wang XH, Mitch WE. Mechanisms of muscle wasting in chronic kidney disease. Nat Rev Nephrol 2014;10:504–516.
    1. Adey D, Kumar R, McCarthy JT, Nair KS. Reduced synthesis of muscle proteins in chronic renal failure. Am J Physiol Endocrinol Metab 2000;278:E219–E225.
    1. Yazdi PG, Moradi H, Yang JY, Wang PH, Vaziri ND. Skeletal muscle mitochondrial depletion and dysfunction in chronic kidney disease. Int J Clin Exp Med 2013;6:532–539.
    1. Tamaki M, Miyashita K, Wakino S, Mitsuishi M, Hayashi K, Itoh H. Chronic kidney disease reduces muscle mitochondria and exercise endurance and its exacerbation by dietary protein through inactivation of pyruvate dehydrogenase. Kidney Int 2014;85:1330–1339.
    1. Deguchi T, Kouno Y, Terasaki T, Takadate A, Otagiri M. Differential contributions of rOat1 (Slc22a6) and rOat3 (Slc22a8) to the in vivo renal uptake of uremic toxins in rats. Pharm Res 2005;22:619–627.
    1. Miyamoto Y, Watanabe H, Noguchi T, Kotani S, Nakajima M, Kadowaki D, et al. Organic anion transporters play an important role in the uptake of p‐cresyl sulfate, a uremic toxin, in the kidney. Nephrol Dial Transplant 2011;26:2498–2502.
    1. Deguchi T, Kusuhara H, Takadate A, Endou H, Otagiri M, Sugiyama Y. Characterization of uremic toxin transport by organic anion transporters in the kidney. Kidney Int 2004;65:162–174.
    1. Deguchi T, Ohtsuki S, Otagiri M, Takanaga H, Asaba H, Mori S, et al. Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney. Kidney Int 2002;61:1760–1768.
    1. Motojima M, Hosokawa A, Yamato H, Muraki T, Yoshioka T. Uremic toxins of organic anions up‐regulate PAI‐1 expression by induction of NF‐kappaB and free radical in proximal tubular cells. Kidney Int 2003;63:1671–1680.
    1. Enoki Y, Watanabe H, Arake R, Sugimoto R, Imafuku T, Tominaga Y, et al. Indoxyl sulfate potentiates skeletal muscle atrophy by inducing the oxidative stress‐mediated expression of myostatin and atrogin‐1. Sci Rep 2016;6:32084.
    1. Niwa T. Role of indoxyl sulfate in the progression of chronic kidney disease and cardiovascular disease: experimental and clinical effects of oral sorbent AST‐120. Ther Apher Dial 2011;15:120–124.
    1. Watanabe H, Miyamoto Y, Honda D, Tanaka H, Wu Q, Endo M, et al. p‐Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidase. Kidney Int 2013;83:582–592.
    1. Sato E, Mori T, Mishima E, Suzuki A, Sugawara S, Kurasawa N, et al. Metabolic alterations by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease. Sci Rep 2016;6:36618.
    1. Shimizu H, Bolati D, Adijiang A, Adelibieke Y, Muteliefu G, Enomoto A, et al. Indoxyl sulfate downregulates renal expression of Klotho through production of ROS and activation of nuclear factor‐kB. Am J Nephrol 2011;33:319–324.
    1. Adijiang A, Shimizu H, Higuchi Y, Nishijima F, Niwa T. Indoxyl sulfate reduces klotho expression and promotes senescence in the kidneys of hypertensive rats. J Ren Nutr 2011;21:105–109.
    1. Avin KG, Coen PM, Huang W, Stolz DB, Sowa GA, Dubé JJ, et al. Skeletal muscle as a regulator of the longevity protein, Klotho. Front Physiol 2014;5:10.3389/fphys.2014.00189
    1. Semba RD, Ferrucci L, Sun K, Simonsick E, Turner R, Milijkovic I, et al. Low plasma Klotho concentrations and decline of knee strength in older aAdults. J Gerontol A Biol Sci Med Sci 2016;71:103–108.
    1. Sato E, Saigusa D, Mishima E, Uchida T, Miura D, Morikawa‐Ichinose T, et al. Impact of the oral adsorbent AST‐120 on organ‐specific accumulation of uremic toxins: LC–MS/MS and MS imaging techniques. Toxins (Basel) 2017;10:10.3390/toxins10010019
    1. Adijiang A, Niwa T. An oral sorbent, AST‐120, increases Klotho expression and inhibits cell senescence in the kidney of uremic rats. Am J Nephrol 2010;31:160–164.
    1. Enoki Y, Watanabbe H, Arake R, Fujimura R, Ishiodori K, Imafuku T, et al. Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction. J Cachexia Sarcopenia Muscle 2017;8:735–747.
    1. Peel NM, Kuys SS, Klein K. Gait speed as a measure in geriatric assessment in clinical settings: a systematic review. J Gerontol A Biol Sci Med Sci 2013;68:39–46.
    1. Lin YL, Liu CH, Lai YH, Wang CH, Kuo CH, Liou HH, 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 2020;107:257–265.
    1. Lau LK, Wee SL, Pang WJB, Chen KK, Abdul Jabbar K, Yap PLK, et al. Reference values of gait sped and gait spatiotemporal parameters for a South East Asian population: The Yishun Study. Clin Interv Aging 2020;15:1753–1765.
    1. Lustgarten MS. The kidney‐gut‐muscle axis in end‐stage renal disease is similarly represented in older adults. Nutrients 2020;12:10.3390/nu12010106
    1. Lin CN, Wu IW, Huang YF, Peng SY, Huang YC, Ning HC. Measuring serum total and free indoxyl sulfate and p‐cresyl sulfate in chronic kidney disease using UPLC‐MS/MS. J Food Drug Anal 2019;27:502–509.
    1. Takkavatakarn K, Wuttiputinun T, Phannajit J, Praditpornsilpa K, Eiam‐Ong S, Susantitaphong P. Protein‐bound uremic toxin lowering strategies in chronic kidney disease: a systematic review and meta‐analysis. J Nephrol 2021;10.1007/s40620-020-00955-2
    1. Baczek J, Silkiewicz M, Wojszel ZB. Myostatin as a biopmarker of muscle wasting and other pathologies‐State of the art and knowledge gaps. Nutrients 2020;10.3390/nu12082401
    1. Naud J, Michaud J, Beauchemin S, Hébert MJ, Roger M, Lefrancois S, et al. Effects of chronic renal failure on kidney drug transporters and cytochrome P450 in rats. Drug Metab Dispos 2011;39:1363–1369.
    1. Patel KP, Luo FH, Plummer NS, Hostetter TH, Meyer TW. The production of p‐cresol sulfate and indoxyl sulfate in vegetarians versus omnivores. Clin J Am Soc Nephrol 2012;7:982–988.
    1. Frassetto LA, Todd KM, Morris RC Jr, Sebastian A. Estimation of net endogenous noncarbonic acid production in humans from diet potassium and protein contents. Am J Clin Nutr 1998;68:576–583.
    1. Remer T, Manz F. Potential renal acid load of foods and its influence on urine pH. J Am Diet Assoc 1995;95:791–797.
    1. Lamonte G, Tang X, Chen JL, Wu J, Ding CK, Keenan MM, et al. Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress. Cancer Metab 2013;1:10.1186/2049-3002-1-23
    1. Kalantar‐Zadeh K, Mehrotra R, Fouque D, Kopple JD. Metabolic acidosis and malnutrition‐inflammation complex syndrome. Semin Dial 2004;17:455–465.
    1. Kalantar‐Zadeh K, Fouque D. Nutritional management of chronic kidney disease. N Engl J Med 2017;377:1765–1776.
    1. Bailey JL, Zheng B, Hu Z, Price SR, Mitch WE. Chronic kidney disease causes defects in signaling through the insulin receptor substrate/phosphatidylinositol‐e‐kinase/Akt pathway: implications for muscle atrophy. J Am Soc Nephrol 2006;17:1388–1394.
    1. Yeh YC, Huang MF, Liang SS, Hwang SJ, Tsai JC, Liu TL, et al. Indoxyl sulfate, not p‐cresyl sulfate, is associated with cognitive impairment in early‐stage chronic kidney disease. Neurotoxicology 2016;53:148–152.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever