Abstract

Background:

This study aimed to evaluate the relationship between quadriceps muscle thickness and functional performance on the 60s sit-to-stand test (60s-STS), the six-minute walk test (6MWT), and handgrip strength in non-dialytic stage 4 and 5 chronic kidney disease (CKD) patients.

Methods:

This was a cross-sectional study that evaluated 40 CKD patients aged between 30-70 years. Participants were submitted to an assessment that included quadriceps muscle thickness evaluated by a portable ultrasound. Functional performance tests included the 60s-STS, distance walked in the 6MWT, and handgrip strength. Also, body composition evaluated using electrical bioimpedance analysis and physical activity level through the short version of International Physical Activity were measured. Multiple linear regression was used to investigate the relationship between the quadriceps thickness and functional performance.

Results:

Quadriceps muscle thickness was correlated to 60s-STS (R2 = 43.6%; 95% CI = 0.022 - 0.665; β = 0.34; p = 0.037). Also, a moderate correlation between this muscle thickness and appendicular skeletal muscle (ALM) was found in CKD patients (r = 0.603, p <0.001). No relationship was found between quadriceps muscle thickness with the 6MWT and handgrip strength.

Conclusion:

Quadriceps muscle thickness is associated to 60s-STS, thus our results demonstrate the repercussions of the disease on the musculoskeletal system.

Keywords:
Musculoskeletal System; Ultrasonics; Body Composition; Physical Functional Performance

Resumo

Antecedentes:

Este estudo teve como objetivo avaliar a relação entre espessura muscular do quadríceps e desempenho funcional no teste sit-to-stand de 60s (STS-60s), no teste de caminhada de seis minutos (TC6M), e na força de preensão manual em pacientes não dialíticos com doença renal crônica (DRC) estágios 4 e 5.

Métodos:

Este foi um estudo transversal que avaliou 40 pacientes com DRC com idades entre 30-70 anos. Os participantes foram submetidos a uma avaliação que incluiu a espessura muscular do quadríceps avaliada por um ultrassom portátil. Os testes de desempenho funcional incluíram o STS-60s, a distância percorrida no TC6M e a força de preensão manual. Além disso, foram medidos a composição corporal, avaliada usando a análise de bioimpedância elétrica e o nível de atividade física por meio da versão curta do International Physical Activity. A regressão linear múltipla foi usada para investigar a relação entre a espessura do quadríceps e o desempenho funcional.

Resultados:

A espessura muscular do quadríceps foi correlacionada com o STS-60s (R2 = 43,6%; IC 95% = 0,022 - 0,665; β = 0,34; p = 0,037). Também foi encontrada uma correlação moderada entre esta espessura muscular e a massa muscular esquelética apendicular (MEA) em pacientes com DRC. (r = 0,603, p <0,001). Nenhuma relação foi encontrada entre a espessura muscular do quadríceps com o TC6M e a força de preensão manual.

Conclusão:

A espessura muscular do quadríceps está associada ao STS-60s, assim nossos resultados demonstram as repercussões da doença sobre o sistema músculo-esquelético.

Descritores:
Sistema Musculoesquelético; Ultrassom; Composição Corporal; Desempenho Físico Funcional

Introduction

Dysfunction in the musculoskeletal system is frequent in chronic kidney disease (CKD) as a result of systemic changes caused by decreased glomerular filtration rate (GFR), inflammatory process, metabolic acidosis, reduced protein intake, insulin resistance, and physical inactivity¹1 Medeiros AIC, Fuzari HKB, Rattes C, Brandão DC, Marinho PEM. Inspiratory muscle training improves respiratory muscle strength , functional capacity and quality of life in patients with chronic kidney disease: a systematic review. J Physiother. 2017 Apr;63(2):76-83.

2 Gollie JM, Harris-love MO, Patel SS, Argani S. Chronic kidney disease: considerations for monitoring skeletal muscle health and prescribing resistance exercise. Clin Kidney J. 2018 Dec;11(6):822-31.

3 Chukwuonye II, Ogah OS, Anyabolu EN, Ojagwu KA, Nwabuko OC, Onwuchekwa U, et al. Prevalence of chronic kidney disease in Nigeria: systematic review of population-based studies. Int J Nephrol Renovasc Dis. 2018 May;11:165-72.

4 As'habi A, Najafi I, Tabibi H, Hedayati M. Prevalence of sarcopenia and dynapenia and their determinants in iranian peritoneal dialysis patients. Iran J Kidney Dis. 2018 Jan;12(1):53-60.^-55 Fahal IH. Uraemic sarcopenia: aetiology and implications. Nephrol Dial Transplant. 2014;29(9):1655-65.. This condition contributes to the development of uremic sarcopenia, characterized by reduced strength and muscle mass⁵5 Fahal IH. Uraemic sarcopenia: aetiology and implications. Nephrol Dial Transplant. 2014;29(9):1655-65.^,66 Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, et al. Sarcopenia: revised European consensus on de finition and diagnosis. Age Ageing. 2019 Jan;48(1):16-31.. Previous studies have shown that the prevalence of sarcopenia in non-dialytic (non-D) CKD patients may range from 5 to 60%⁴4 As'habi A, Najafi I, Tabibi H, Hedayati M. Prevalence of sarcopenia and dynapenia and their determinants in iranian peritoneal dialysis patients. Iran J Kidney Dis. 2018 Jan;12(1):53-60.^,77 Souza VA, Oliveira D, Barbosa SR, Corrêa JOA, Colugnati FAB, Mansur HN, et al. Sarcopenia in patients with chronic kidney disease not yet on dialysis: analysis of the prevalence and associated factors. PLoS One. 2017 Apr;12(4):1-13.^,88 Lai S, Muscaritoli M, Andreozzi P, Sgreccia A, De Leo S, Mazzaferro S, et al. Sarcopenia and cardiovascular risk indices in patients with chronic kidney disease on conservative and replacement therapy. Nutrition. 2019 Jun;62:108-14., and is associated with physical limitations, reduced quality of life, and increased morbidity and mortality⁴4 As'habi A, Najafi I, Tabibi H, Hedayati M. Prevalence of sarcopenia and dynapenia and their determinants in iranian peritoneal dialysis patients. Iran J Kidney Dis. 2018 Jan;12(1):53-60.^,88 Lai S, Muscaritoli M, Andreozzi P, Sgreccia A, De Leo S, Mazzaferro S, et al. Sarcopenia and cardiovascular risk indices in patients with chronic kidney disease on conservative and replacement therapy. Nutrition. 2019 Jun;62:108-14..

The reduction in muscle mass in patients with CKD becomes apparent in the beginning of the course of this disease and it is multifactorial, since the disease itself contributes to the catabolic state due to increased muscle proteolysis and reduced protein synthesis⁵5 Fahal IH. Uraemic sarcopenia: aetiology and implications. Nephrol Dial Transplant. 2014;29(9):1655-65.^,99 Gould DW, Watson EL, Wilkinson TJ, Wormleighton J, Xenophontos S, Viana JL, et al. Ultrasound assessment of muscle mass in response to exercise training in chronic kidney disease: a comparison with MRI. J Cachexia Sarcopenia Muscle. 2019 Aug;10(4):748-55.. This reduction in muscle mass leads to sedentary lifestyle, exercise intolerance, and poor cardiorespiratory fitness⁵5 Fahal IH. Uraemic sarcopenia: aetiology and implications. Nephrol Dial Transplant. 2014;29(9):1655-65.^,99 Gould DW, Watson EL, Wilkinson TJ, Wormleighton J, Xenophontos S, Viana JL, et al. Ultrasound assessment of muscle mass in response to exercise training in chronic kidney disease: a comparison with MRI. J Cachexia Sarcopenia Muscle. 2019 Aug;10(4):748-55.

10 Zelle DM, Klaassen G, Van Adrichem E, Bakker SJL, Corpeleijin E, Navis G. Physical inactivity: a risk factor and target for intervention in renal care. Nat Rev Nephrol. 2017 Mar;13(3):152-68.^-1111 Glavinovic T, Ferguson T, Komenda P, Rigatto C, Duhamel TA, Tangri N, et al. CKD and sedentary time: results from the canadian health measures survey. Am J Kidney Dis. 2018 Oct;72(4):529-537. being in turn associated with functional limitation and increased mortality⁹9 Gould DW, Watson EL, Wilkinson TJ, Wormleighton J, Xenophontos S, Viana JL, et al. Ultrasound assessment of muscle mass in response to exercise training in chronic kidney disease: a comparison with MRI. J Cachexia Sarcopenia Muscle. 2019 Aug;10(4):748-55.^,1212 Souza VA, Oliveira D, Cupolilo EN, Miranda CS, Colugnati FAB, Mansur HN, et al. Rectus femoris muscle mass evaluation by ultrasound: facilitating sarcopenia diagnosis in pre-dialysis chronic kidney disease stages. Clinics. 2018;73:1-5..

Magnetic nuclear resonance (MRI) and computed tomography (CT) have been considered the gold standard for evaluating muscle mass quantification. However, lack of portability, high cost, and radiation exposure limit its use in clinical practice⁶6 Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, et al. Sarcopenia: revised European consensus on de finition and diagnosis. Age Ageing. 2019 Jan;48(1):16-31.^,1212 Souza VA, Oliveira D, Cupolilo EN, Miranda CS, Colugnati FAB, Mansur HN, et al. Rectus femoris muscle mass evaluation by ultrasound: facilitating sarcopenia diagnosis in pre-dialysis chronic kidney disease stages. Clinics. 2018;73:1-5.^,1313 Perkisas S, Baudry S, Bauer J, Beckwée D, Cock AM, Hobbelen H, et al. Application of ultrasound for muscle assessment in sarcopenia: towards standardized measurements. Eur Geriatr Med. 2018 Sep;9(6):739-757.. In this way, ultrasonography (US) has been proposed as an alternative means for evaluation because it is valid, reliable, and a low cost imaging method with good intra and inter-evaluator reliability, and is feasible in clinical practice¹²12 Souza VA, Oliveira D, Cupolilo EN, Miranda CS, Colugnati FAB, Mansur HN, et al. Rectus femoris muscle mass evaluation by ultrasound: facilitating sarcopenia diagnosis in pre-dialysis chronic kidney disease stages. Clinics. 2018;73:1-5.^,1313 Perkisas S, Baudry S, Bauer J, Beckwée D, Cock AM, Hobbelen H, et al. Application of ultrasound for muscle assessment in sarcopenia: towards standardized measurements. Eur Geriatr Med. 2018 Sep;9(6):739-757..

Considering the existence of muscle mass loss during CKD and its clinical repercussions on inactivity and functionality, assessing quadriceps muscle thickness in relation to the functional performance of these patients may provide information on the course of muscle mass loss and functional decline throughout kidney disease. Previous studies have demonstrated positive correlation and good reliability and validity among US with DEXA, CT, and RMI to quantify muscle mass in elderly and young people and patients with CKD¹²12 Souza VA, Oliveira D, Cupolilo EN, Miranda CS, Colugnati FAB, Mansur HN, et al. Rectus femoris muscle mass evaluation by ultrasound: facilitating sarcopenia diagnosis in pre-dialysis chronic kidney disease stages. Clinics. 2018;73:1-5.^,1313 Perkisas S, Baudry S, Bauer J, Beckwée D, Cock AM, Hobbelen H, et al. Application of ultrasound for muscle assessment in sarcopenia: towards standardized measurements. Eur Geriatr Med. 2018 Sep;9(6):739-757.. However, investigating the association between quadriceps muscle thickness by US and physical function in non-dialytic CKD patients will provide more information about how muscle impairment impacts functional performance in patients at the conservative treatment. Thus, the present study aimed to evaluate the relationship between quadriceps muscle thickness and functional performance on the 60s sit-to-stand test (60s-STS), six-minute walk test (6MWT), and handgrip strength in CKD patients non-dialytic stage.

Methods

Study design and setting

This was a cross-sectional study conducted from April 2018 to June 2019, where CKD patients from the Nephrology Service of the Clinical Hospital of the Universidade Federal de Pernambuco were recruited by convenience. All procedures were carried out at the Cardiopulmonary Physical Therapy Laboratory of the Universidade Federal de Pernambuco in Recife-PE, Brazil. This study was approved by the ethics and research committee of this institution (CAAE: 84135518.3.0000.5208 and opinion number: 3,366,668) and followed the norms of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)¹⁴14 Cuschieri S. The STROBE guidelines. Saudi J Anaesth. 2019;13(Suppl 1):S31-S34..

Participants

Participants with CKD, non-dialytic, at stage 4 and 5 according to the criteria proposed by the Kidney Disease Improving Global Outcomes¹⁵15 Kidney Disease - Improving Global Outcomes (KDIGO). KDIGO 2012 Clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2013;(Suppl 1):1-150., aged between 30 and 70 years and of both genders were included in the study. Patients who were on a dialysis program, who had been transplanted, and who were unable to perform the functional or clinical tests or answer the questionnaires were excluded.

Outcome measures

Participants were submitted to an initial assessment that included sociodemographic data (age, gender), anthropometric measures (weight and height), self-reported number of comorbidities and time in months and cause of CKD. After, physical activity level, body composition quadriceps muscle thickness and functional performance tests were measured as described below.

Level of physical activity

The level of physical activity was assessed using the International Physical Activity Questionnaire (IPAQ - short version), validated for the Brazilian population. The questionnaire consisted of eight open questions that assessed time and frequency of performing walking and activities of moderate and vigorous intensity in the last week in order to evaluate the time spent per week in physical activities. For the purposes of this study we have categorized physical activity levels as follow: sedentary when participants reported frequency of activities being less than 5 days/week or less than 150 min/week and active, when participants were above those limits¹⁶16 Matsudo S, Araújo T, Matsudo V, Andrade D, Andrade E, Oliveira LC, et al. Questionário internacional de atividade física (Ipaq): estudo de validade e reprodutibilidade no Brasil. Rev Bras Atividade Física Saúde [Internet]. 2012 Oct; [ 6(2):5-18. Available from: https://periodicos.ufpel.edu.br/ojs2/index.php/RBAFS/article/view/931
https://periodicos.ufpel.edu.br/ojs2/ind... .

Body composition

Body composition was assessed by electrical bioimpedance analysis (InBody R20^® - Dogok 2-Dong, Gangnam-gu, Seoul, Korea). The patient was previously instructed to eat at least two hours before the evaluation, wear light clothing, avoid physical activity, and empty their bladder prior to the evaluation. The patient remained in an orthostatic position during the test with their feet positioned over the electrodes on the digital scale surface and the other electrodes attached to a bar supported by the patient's hands. The bioimpedance lasted 30 seconds and was repeated in case of reading error¹⁷17 Sales A. Prevalência de doença arterial obstrutiva periférica (DAOP) e alterações sensoriais em pacientes diabéticos tipo 2: impacto da DAOP sobre a qualidade de vida, nível de atividade física e composição corporal [tese] [Internet]. Natal: Universidade Federal do Rio Grande do Norte; 2012; . Available from: https://repositorio.ufrn.br/jspui/handle/123456789/16716
https://repositorio.ufrn.br/jspui/handle... . Body weight (kg), body mass index (BMI, kg/m²), and appendicular skeletal muscle (ASM, kg) were obtained.

Quadriceps muscle thickness

Quadriceps muscle thickness was measured using a portable high-definition ultrasound (Sonoace R3^®, Samsung Medison - South Korea) with the transducer positioned perpendicular on the anterior thigh. The assessment of muscle thickness was performed in the dominant segment, which was identified from a question about which leg the patient usually kicks with and performed with the patient in supine position, with a foam roller below the popliteal region of this limb. The transducer was positioned midway between the anterior superior iliac spine and the knee joint line, from which the cross-sectional image of the quadriceps muscle was obtained¹⁸18 Seymour JM, Ward K, Sidhu PS, Putchucheary Z, Steier J, Jolley CJ, et al. Ultrasound measurement of rectus femoris cross-sectional area and the relationship with quadriceps strength in COPD. Thorax. 2009 May;64(5):418-23.^,1919 Gruther W, Benesch T, Zorn C, Paternostro-Sluga T, Quittan M, Fialka-Moser V, et al. Muscle wasting in intensive care patients: Ultrasound observation of the M. quadriceps femoris muscle layer. J Rehabil Med. 2008 Mar;40(3):185-9.. Three femoral quadriceps thickness (mm) measurements were performed from the frozen image of the muscle on the equipment monitor. For recording purposes, the average of the three values obtained was considered as long as the difference between them was less than 10%¹⁸18 Seymour JM, Ward K, Sidhu PS, Putchucheary Z, Steier J, Jolley CJ, et al. Ultrasound measurement of rectus femoris cross-sectional area and the relationship with quadriceps strength in COPD. Thorax. 2009 May;64(5):418-23.^,2020 Souza H, Rocha T, Pessoa M, Rattes C, Brandão D, Fregonezi G, et al. Effects of inspiratory muscle training in elderly women on respiratory muscle strength, diaphragm thickness and mobility. J Gerontol Ser A Biol Sci Med Sci. 2014 Dec;69(12):1545-53..

Functional performance tests

Lower limb resistance (60s-STS)

The 60s sit-to-stand test (60s-STS) was performed to evaluate lower limb resistance. The patient was instructed to stand and sit in a 46-cm-high chair without arm support and with their hands positioned on the contralateral shoulder for 60 seconds. Patients were instructed to complete as many repetitions as possible within the standardization of the correct test execution movement²¹21 Greenwood SA, Koufaki P, Mercer TH, Rush R, O'Connor E, Tuffnel R, et al. Aerobic or resistance training and pulse wave velocity in kidney transplant recipients: a 12-week pilot randomized controlled trial (the Exercise in Renal Transplant [ExeRT] Trial). Am J Kidney Dis. 2015 Oct;66(4):689-98.^,2222 Segura-Ortí E, Martínez-Olmos FJ. Test-retest reliability and minimal detectable change scores for sit-to-stand-to-sit tests, the six-minute walk test, the one-leg heel-rise test, and handgrip strength in people undergoing hemodialysis. Phys Ther. 2011 Aug;91(8):1244-52..

Submaximal functional capacity

The six-minute walk test (6MWT) was performed according to the guidelines established by the American Thoracic Society²³23 ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul;166(1):111-7.. The distance traveled was recorded in meters at the end of the test. The reference equation for the Brazilian population was used to estimate the predicted percentage²⁴24 Britto R, Probst V, Andrade A, Sasmora GAR, Hernandes NA, Marinho PEM, et al. Reference equations for the six-minute walk distance based on a Brazilian multicenter study. Braz J Phys Ther. 2013 Dec;17(6):556-63..

Handgrip strength

Handgrip strength was verified using a dynamometer (Dinamometer Smedley^® - hand type, Saehan - Korea) according to the guidelines established by The American Society of Hand Therapists²⁵25 Fess E. Grip strength. In: Casanova JS, ed. Clinical assessment recommendations. 2nd ed. Chicago: American Society of Hand Therapists; 1992. p. 41-5.. The test was performed 3 times in the dominant limb, with a 30-second rest interval between each maneuver, and the highest value among the measurements was adopted provided that the difference between them was less than 10%²⁶26 Bohannon RW, Peolsson A, Massy-Westropp N, Desrosiers J, Bear-Lehman J. Reference values for adult grip strength measured with a Jamar dynamometer: a descriptive meta-analysis. Physiotherapy. 2006 Mar;92(1):11-5.. The predicted value for each patient was determined from prediction equations proposed by the study by Novaes et al. (2009)²⁷27 Novaes RD, Miranda AS, Silva JO, Tavares BVF, Dourado VZ. Equações de referência para a predição da força de preensão manual em brasileiros de meia idade e idosos. Fisioter Pesqui [Internet]. 2009 Sep; 16(3):217-22. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1809-29502009000300005&lng=pt&nrm=iso&tlng=en
http://www.scielo.br/scielo.php?script=s... . Muscle strength was classified as low if values less than 32 kg for men and less than 17 kg for women were obtained, based on the 20^th percentile of the sample.

Statistical analysis

The Kolmogorov-Smirnov test was initially used to verify the normality distribution of continuous variables. Data were expressed as mean and 95% confidence interval for continuous variables and as means of distribution of absolute and percentage frequency for dichotomous variables. Pearson's correlation test was used to assess the relationship between quadriceps thickness and appendicular skeletal muscle. Multiple linear regression was used to investigate the relationship between the quadriceps thickness and functional performance (60s-STS, 6MWT, and handgrip strength)²⁸28 Hsiao S, Tsai Y, Chen H, Lin MY, Chiu YM, Chen TH, et al. Association of fluid status and body composition with physical function in patients with chronic kidney disease. PLoS One. 2016 Oct;11(10):e0165400.^,2929 Gordon PL, Doyle JW, Johansen KL. Association of 1,25-dihydroxyvitamin d levels with physical performance and thigh muscle cross-sectional area in chronic kidney disease stage 3 and 4. J Ren Nutr. 2012 Jul;22(4):423-33.. Each functional performance variable was analyzed separately with quadriceps thickness in order to avoid multicollinearity. All models were adjusted for gender, age, and height. Data were processed using the Statistical Package for Social Science (SPSS) software, Chicago, IL, USA, version 20.0 for Windows. The tests were considered significant at the 5% level.

Results

After screening for study participation, 192 of the 312 patients did not meet the inclusion criteria. Of the 120 eligible patients, 40 did not agree to participate because they lived in the country side of the state, 17 gave up due to financial difficulties, and 23 did not accept to commute to the evaluation location, thus a total of 40 patients were evaluated.

The general characteristics of the patients are described in Table 1. Mean age of the participants was 51.45 years, most participants were male (52.5%), sedentary (57.5%), and with disease time of 77.63 months.

Table 2 shows the descriptive values of quadriceps thickness, functional performance tests and its predicted values. CKD patients walked 82.64% of the predicted 6MWT and 81.13% of them showed low values of handgrip strength.

The quadriceps thickness was 26.60 (25.03-28.15) mm for men and 20.98 (19.01-22.94) mm for women. The performance on the 60s-STS was 24.81 (23.11-26.50) repetitions for men and 20.84 (19.19-22.50) repetitions for women. Regarding the 6MWT, 16 patients (40%) presented performance below 80% of the predicted value, with 28.6% men (6) and 52.6% women (10). The frequency of muscle weakness among men and women was 28.6% (6) and 21% (4), respectively.

According to the result of the multiple linear regression analysis, a relationship was observed between quadriceps thickness and number of repetitions on the 60s-STS, where the increase by one repetition was related to a 0.34 mm increase in quadriceps thickness (R² = 0.436; 95% CI: 0.022-0.665; p=0.03), as shown in Table 3. Moreover, quadriceps thickness was moderately correlated with ASM (r = 0.603, p < 0.001).

Discussion

A relationship between quadriceps muscle thickness with 60s-STS was observed in the study patients. To date, the only study with similar results was that of Wilkinson et al. (2019)³⁰30 Wilkinson TJ, Gould DW, Nixon DGD, Watson EL, Smith AC. Quality over quantity? Association of skeletal muscle myosteatosis and myofibrosis on physical function in chronic kidney disease. Nephrol Dial Transplant. 2019 Aug;34(8):1344-53., who found a negative relationship between the low echogenicity of the rectus femoris measured by ultrasound and the 60s-STS in CKD patients under conservative treatment; however, according to these authors, the cross-sectional area of this muscle was considered the best predictor of physical performance in these patients, relative to echogenicity, as found in the present study.

Our study found a positive relationship between quadriceps thickness and 60s-STS, similar to that found in studies by Mateos-Angulo et al. (2019)³¹31 Mateos-Angulo A, Galán-Mercant A, Cuesta-Vargas AI. Muscle thickness contribution to sit-to-stand ability in institutionalized older adults. Aging Clin Exp Res. 2019;32:1477-83. DOI: https://doi.org/10.1007/s40520-019-01328-x
https://doi.org/10.1007/s40520-019-01328... , Lopez et al. (2017)³²32 Lopez P, Wilhelm E, Rech A, Minozzo F, Radaelli R, Pinto RS. Echo intensity independently predicts functionality in sedentary older men. Muscle Nerve. 2017 Jan;55(1):9-15., and McIntyre et al. (2006)³³33 McIntyre CW, Selby NM, Sigrist M, Pearce LE, Mercer TH, Naish PF. Patients receiving maintenance dialysis have more severe functionally significant skeletal muscle wasting than patients with dialysis-independent chronic kidney disease. Nephrol Dial Transplant. 2006 Aug;21(8):2210-6.. Mateos-Angulo et al. (2019)³¹31 Mateos-Angulo A, Galán-Mercant A, Cuesta-Vargas AI. Muscle thickness contribution to sit-to-stand ability in institutionalized older adults. Aging Clin Exp Res. 2019;32:1477-83. DOI: https://doi.org/10.1007/s40520-019-01328-x
https://doi.org/10.1007/s40520-019-01328... and Lopez et al. (2017)³²32 Lopez P, Wilhelm E, Rech A, Minozzo F, Radaelli R, Pinto RS. Echo intensity independently predicts functionality in sedentary older men. Muscle Nerve. 2017 Jan;55(1):9-15. evaluated muscle thickness by ultrasound and functional tests (5R-CST and 30R-CST, respectively) in older adults. McIntyre et al. (2006)³³33 McIntyre CW, Selby NM, Sigrist M, Pearce LE, Mercer TH, Naish PF. Patients receiving maintenance dialysis have more severe functionally significant skeletal muscle wasting than patients with dialysis-independent chronic kidney disease. Nephrol Dial Transplant. 2006 Aug;21(8):2210-6. used CT to verify the quadriceps cross-sectional area, relating it to the 60s-STS and also found similar results when comparing CKD patients under conservative treatment with those undergoing dialysis therapy. However, Segura-Ortí et al. (2018)³⁴34 Segura-Ortí E, Gordon PL, Doyle JW, Johansen KL. Correlates of physical functioning and performance across the spectrum of kidney function. Clin Nurs Res. 2018 Jun;27(5):579-96. found no relationship between quadriceps cross-sectional area and 5-repetition sit-to-stand test using MRI in conservative, hemodialysis, and CKD subjects, but found a strong relationship between isokinetic and isometric strength of this muscle. Changes occur in physical and functional performance of patients with CKD and are due to muscle protein degradation³⁵35 Tamaki M, Miyashita K, Wakino S, Mituishi 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 Jun;85(6):1330-9., which can be observed by imaging exams³¹31 Mateos-Angulo A, Galán-Mercant A, Cuesta-Vargas AI. Muscle thickness contribution to sit-to-stand ability in institutionalized older adults. Aging Clin Exp Res. 2019;32:1477-83. DOI: https://doi.org/10.1007/s40520-019-01328-x
https://doi.org/10.1007/s40520-019-01328...

32 Lopez P, Wilhelm E, Rech A, Minozzo F, Radaelli R, Pinto RS. Echo intensity independently predicts functionality in sedentary older men. Muscle Nerve. 2017 Jan;55(1):9-15.

33 McIntyre CW, Selby NM, Sigrist M, Pearce LE, Mercer TH, Naish PF. Patients receiving maintenance dialysis have more severe functionally significant skeletal muscle wasting than patients with dialysis-independent chronic kidney disease. Nephrol Dial Transplant. 2006 Aug;21(8):2210-6.^-3434 Segura-Ortí E, Gordon PL, Doyle JW, Johansen KL. Correlates of physical functioning and performance across the spectrum of kidney function. Clin Nurs Res. 2018 Jun;27(5):579-96.. The association found in our study reinforces the importance of periodic measurement of both tests since US is a low cost, portable method, and has good reliability that can complement functional tests to monitor the repercussions of the disease on the musculoskeletal system.

Our study found no relationship between quadriceps thickness and 6MWT. Wilkinson et al. (2019)³⁰30 Wilkinson TJ, Gould DW, Nixon DGD, Watson EL, Smith AC. Quality over quantity? Association of skeletal muscle myosteatosis and myofibrosis on physical function in chronic kidney disease. Nephrol Dial Transplant. 2019 Aug;34(8):1344-53. evaluated the cross-sectional area of rectus femoris muscle of CKD patients under conservative treatment by ultrasound and found a moderate association with the incremental shuttle walking test, which is opposite to our findings. In CKD patients, factors linked to muscle quality (infiltration of fat and collagen into the muscle of these patients) and muscle size could result in muscle impairment contributing for structural changes in contractile properties in these patients³⁰30 Wilkinson TJ, Gould DW, Nixon DGD, Watson EL, Smith AC. Quality over quantity? Association of skeletal muscle myosteatosis and myofibrosis on physical function in chronic kidney disease. Nephrol Dial Transplant. 2019 Aug;34(8):1344-53. leading to muscle loss, inability to exercise, and immobility³⁶36 Abramowitz M, Paredes W, Zhang K, Brightwell CR, Newsom JN, Kwon HJ, et al. Skeletal muscle fibrosis is associated with decreased muscle inflammation and weakness in patients with chronic kidney disease. Am J Physiol Physiol. 2018 Dec;315(1):F1658-69..

The 6MWT assesses patients' health status and involves an integrative analysis among cardiovascular, pulmonary, neuromuscular, and metabolic systems²³23 ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul;166(1):111-7.. Functional disability in patients with CKD is multifactorial³⁷37 Wilkinson TJ, Watson EL, Xenophontos S, Gould DW, Smith AC. The "minimum clinically important difference" in frequently reported objective physical function tests after a 12-week renal rehabilitation exercise intervention in nondialysis chronic kidney disease. Am J Phys Med Rehabil. 2019;98(6):431-7., associated with cardiovascular disease³⁸38 Lima MC, Cicotoste CL, Cardoso KS, Forgiarini Junior LA, Monteiro MB, Dias AS. Effect of exercise performed during hemodialysis: strength versus aerobic. Ren Fail. 2013;35(5):697-704.^,3939 Roshanravan B, Robinson-Cohen C, Patel KV, Ayers E, Littman AJ, Boer IH, et al. Association between physical performance and all-cause mortality in CKD. J Am Soc Nephrol. 2013 Apr;24(5):822-30., sedentary behavior⁴⁰40 Robinson-Cohen C, Katz R, Mozaffarian D, Dalrymple LS, Boer I, Sarnak M, et al. Physical activity and rapid decline in kidney function among older adults. Arch Intern Med. 2009;169(22):2116-23.^,4141 Robinson-Cohen C, Littman AJ, Duncan GE, Weiss NS, Sachs MC, Ruzinski J, et al. Physical activity and change in estimated GFR among persons with CKD. J Am Soc Nephrol. 2014 Feb;25(2):399-406., muscle weakness, and reduced glomerular filtration rate⁵5 Fahal IH. Uraemic sarcopenia: aetiology and implications. Nephrol Dial Transplant. 2014;29(9):1655-65.^,4242 Kaltsatou A, Sakkas GK, Poulianiti KP, Koutedakis Y, Tepetes K, Christodoulidis G, et al. Uremic myopathy: is oxidative stress implicated in muscle dysfunction in uremia?. Front Physiol. 2015;30(6):102.^,4343 Stenvinkel P, Carrero JJ, Von Walden F, Ikizler TA, Nader GA. Muscle wasting in end-stage renal disease promulgates premature death: established, emerging and potential novel treatment strategies. Nephrol Dial Transplant. 2016 Jul;31(7):1070-7.. In this way, quadriceps muscle thickness, which represents only the amount of muscle mass, might not be related to the distance covered in the 6MWT.

Our study also found no relationship between quadriceps thickness and handgrip strength. These results suggest that upper limb strength measurements are not comparable to measurements of quadriceps thickness, although both reflect on patient functionality. CKD patients have reduced strength and muscle mass, characterizing sarcopenia⁶6 Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, et al. Sarcopenia: revised European consensus on de finition and diagnosis. Age Ageing. 2019 Jan;48(1):16-31.^,4444 Isoyama N, Qureshi AR, Avesani CM, Lindholm B, Bàràny P, Heimbürger O, et al. Comparative associations of muscle mass and muscle strength with mortality in dialysis patients. Clin J Am Soc Nephrol. 2014 Oct;9(10):1720-8., although we only observed 5% of sarcopenia in our sample (data not shown). According to the current European Consensus on Older Adult Sarcopenia⁶6 Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, et al. Sarcopenia: revised European consensus on de finition and diagnosis. Age Ageing. 2019 Jan;48(1):16-31., muscle strength is the best predictor of adverse outcomes (falls, fractures, physical dysfunction, and mortality) for patients when compared to only reduction/loss in muscle mass, and its periodic evaluation in CKD is necessary.

A moderate correlation was found between muscle thickness and the ASM in our patients, which could explain the relationship between the thickness of the muscle and its functional performance. Changes in body composition are present in early stages of CKD as a consequence of uremic syndrome, and these lead to increased muscle proteolysis and reduced protein synthesis⁵5 Fahal IH. Uraemic sarcopenia: aetiology and implications. Nephrol Dial Transplant. 2014;29(9):1655-65.^,3333 McIntyre CW, Selby NM, Sigrist M, Pearce LE, Mercer TH, Naish PF. Patients receiving maintenance dialysis have more severe functionally significant skeletal muscle wasting than patients with dialysis-independent chronic kidney disease. Nephrol Dial Transplant. 2006 Aug;21(8):2210-6.^,4545 Zhou Y, Hellberg M, Svensson P, Höglund P, Clyne N. Sarcopenia and relationships between muscle mass, measured glomerular filtration rate and physical function in patients with chronic kidney disease stages 3-5. Nephrol Dial Transplant. 2018 Feb;33(2):342-8.. The reduction in muscle mass and muscle strength may cause impairment in physical and functional performance of these patients as GFR decreases⁵5 Fahal IH. Uraemic sarcopenia: aetiology and implications. Nephrol Dial Transplant. 2014;29(9):1655-65.^,3434 Segura-Ortí E, Gordon PL, Doyle JW, Johansen KL. Correlates of physical functioning and performance across the spectrum of kidney function. Clin Nurs Res. 2018 Jun;27(5):579-96.^,3535 Tamaki M, Miyashita K, Wakino S, Mituishi 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 Jun;85(6):1330-9..

Muscle weakness was observed in 25% of our patients under conservative treatment. A relatively recent study found that muscle mass and strength reduction in dialysis patients were predictors of mortality in this population but muscle strength reduction was more strongly associated with mortality⁴⁴44 Isoyama N, Qureshi AR, Avesani CM, Lindholm B, Bàràny P, Heimbürger O, et al. Comparative associations of muscle mass and muscle strength with mortality in dialysis patients. Clin J Am Soc Nephrol. 2014 Oct;9(10):1720-8.. However, we highlight the fact that the patients evaluated in our study were under conservative treatment and had already presented muscle weakness. Considering that these patients will progress to the final stages of CKD, a marked reduction in muscle mass and strength is expected, which may result in decreased functional performance³⁵35 Tamaki M, Miyashita K, Wakino S, Mituishi 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 Jun;85(6):1330-9..

Regarding functional performance on the 6MWT of our patients, we observed that 40% of them were below 80% of the predicted distance traveled. In evaluating patients on peritoneal dialysis and hemodialysis program, Painter et al⁴⁶46 Painter P, Agarwal A, Drummond M. Physical function and physical activity in peritoneal dialysis patients. Perit Dial Int. 2017 Nov/Dec;37(6):598-604. identified 62.2 and 52.8% of the predicted 6MWT, respectively. Faria et al. (2013)⁴⁷47 Faria R, Fernandes N, Lovisi J, Reboredo MM, Marta MSM, Pinheiro BV, et al. Pulmonary function and exercise tolerance are related to disease severity in pre-dialytic patients with chronic kidney disease: a cross-sectional study. BMC Nephrol. 2013 Sep;14:184. observed a progressive decline in the distance covered on the 6MWT by patients with CKD as they advanced in disease staging. Segura-Ortí et al. (2018)³⁴34 Segura-Ortí E, Gordon PL, Doyle JW, Johansen KL. Correlates of physical functioning and performance across the spectrum of kidney function. Clin Nurs Res. 2018 Jun;27(5):579-96. also found a shorter distance traveled on this test between patients on conservative and dialytic treatment when compared to healthy individuals. The reduction in the functional capacity of our patients in the conservative stage calls for preventive measures to be instituted in order to prevent functional decline in later stages of the disease, when patients may progress to terminal CKD. For clinical implications, considering that almost 60% of our sample was sedentary, exercise programs for this population need to be implemented as a strategy to maintain physical activity level.

Conclusion

In the present study, we found a correlation between quadriceps muscle thickness assessed by ultrasonography and functional performance on the 60s-STS and between this muscle thickness and ASM in CKD patients under non-dialytic treatment. As a future perspective, imaging evaluation and functional tests may be considered in clinical practice, as their results could be used for physical therapy monitoring to improve functional status in exercise programs developed to minimize the deleterious effects of CKD.

Limitations of the study

The present study had as limitation the lack of echogenicity quadriceps assessment. Another possible limitation was that we did not include patients at all CKD stages, which could provide additional information about which stage of the disease occurs the greatest impairment in physical function. Finally, we have not performed a prior sample size calculation. However, a post-hoc power analysis using four predictors and the probability level of 0.05, resulted in a power of 0.99, 0.97, and 0.97, respectively⁴⁸48 Soper DS. Post-hoc statistical power calculator for multiple regression [software]. California: STATCALC; 2021; . Available from: https://www.danielsoper.com/statcalc
https://www.danielsoper.com/statcalc... .

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