Physical Function in Adults With Metabolic Acidosis and Advanced CKD: Patient Reported Versus Assessed Physical Function

Chronic kidney disease (CKD) is characterized by a progressive reduction in kidney function. In this condition, acid accumulates and is buffered by bone and muscle, leading to bone demineralization and protein catabolism.1Walker S.R. Gill K. Macdonald K. et al.Association of frailty and physical function in patients with non-dialysis CKD: a systematic review.BMC Nephrol. 2013; 14: 228Crossref PubMed Scopus (79) Google Scholar Eventually, the increased protein catabolism results in disturbances in skeletal muscle, with reduction in muscle mass and muscle strength, and worsening of physical function. Reduction in physical function begins early in the disease process and is associated with increased mortality risk.2Kraut J.A. Madias N.E. Adverse effects of the metabolic acidosis of chronic kidney disease.Adv Chronic Kidney Dis. 2017; 24: 289-297Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar,3Mitch W.E. Price S.R. May R.C. Jurkovitz C. England B.K. Metabolic consequences of uremia: extending the concept of adaptive responses to protein metabolism.Am J Kidney Dis. 1994; 23: 224-228Abstract Full Text PDF PubMed Scopus (28) Google ScholarIn a recent prospective cohort study, we observed that the time necessary to complete a 5 time sit-to-stand (STS-5) test was associated with all-cause mortality in patients with CKD, and chair stand time declined immediately after dialysis initiation.4Rampersad C. Darcel J. Harasemiw O. et al.Change in physical activity and function in patients with baseline advanced nondialysis CKD.Clin J Am Soc Nephrol. 2021; 16: 1805-1812Crossref Scopus (1) Google Scholar However, measurement of physical function using chair stand time is not part of routine clinical assessment or workflow for patients with CKD. As such, the purpose of this study was to assess the correlation between easily obtained survey questions from the 10-item Kidney Disease and Quality of Life Physical Function Domain (KDQOL-PFD) instrument and objectively measured physical performance from the STS-5 to establish the validity of the KDQOL-PFD in assessment of physical function.Using data from a 1-year phase 3 randomized, placebo-controlled trial in patients with CKD and metabolic acidosis (n = 196), we evaluated the correlation between patient-reported limitation on daily activities as measured by the 10-item KDQOL-PFD scale (also known as the Short Form-36 physical function or SF-36 PF-10 scale) and the STS-5.5Wesson D.E. Mathur V. Tangri N. et al.Long-term safety and efficacy of veverimer in patients with metabolic acidosis in chronic kidney disease: a multicentre, randomised, blinded, placebo-controlled, 40-week extension.Lancet. 2019; 394: 396-406Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar,6Hays R.D. Kallich J.D. Mapes D.L. Coons S.J. Carter W.B. Development of the kidney disease quality of life (KDQOL) instrument.Qual Life Res. 1994; 3: 329-338Crossref PubMed Scopus (832) Google Scholar,7Bohannon R.W. Reference values for the five-repetition sit-to-stand test: a descriptive meta-analysis of data from elders.Percept Mot Skills. 2006; 103: 215-222Crossref PubMed Google Scholar Individual items of the KDQOL-PFD are provided in Table S1, and instructions for performing the STS-5 are provided in Item S1. Baseline characteristics of the patients are reported in Table S2. This trial examined the efficacy and safety of veverimer, a nonabsorbed hydrochloric acid binder, as a treatment for metabolic acidosis in patients with estimated glomerular filtration rate 20-40 mL/min/1.73 m2 and metabolic acidosis (serum bicarbonate 12-20 mEq/L). In this study, both the STS-5 and the KDQOL-PFD were significantly improved in patients who received veverimer compared to placebo.5Wesson D.E. Mathur V. Tangri N. et al.Long-term safety and efficacy of veverimer in patients with metabolic acidosis in chronic kidney disease: a multicentre, randomised, blinded, placebo-controlled, 40-week extension.Lancet. 2019; 394: 396-406Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Both the STS-5 and KDQOL-PFD were assessed at the same study visits. This multi-site study was conducted across 29 sites with institutional review board or ethics committee approval received at each site. All patients provided written consent before participation in the study, and full results of the trial including patient demographics and clinical characteristics have been previously published.5Wesson D.E. Mathur V. Tangri N. et al.Long-term safety and efficacy of veverimer in patients with metabolic acidosis in chronic kidney disease: a multicentre, randomised, blinded, placebo-controlled, 40-week extension.Lancet. 2019; 394: 396-406Abstract Full Text Full Text PDF PubMed Scopus (45) Google ScholarCorrelations between the 2 measures of physical function were calculated using the Pearson product-moment correlation coefficient. In addition, a linear model was fit to determine the association of each category of decline related to activities of daily living (Table S1) in the KDQOL-PFD with the change (measured in seconds) in the STS-5. A clinically important difference in the STS-5 was 1.7 seconds, based on applications in cohorts for other chronic conditions.8Jones S.E. Kon S.S. Canavan J.L. et al.The five-repetition sit-to-stand test as a functional outcome measure in COPD.Thorax. 2013; 68: 1015-1020Crossref PubMed Scopus (195) Google ScholarIn the linear model, each category of decline in the KDQOL-PFD was associated with a statistically significant deterioration in the times from the STS-5 (ranging between 3.29 to 3.80 seconds for each category), all of which were greater than the clinically important difference of 1.7 seconds (Table 1).8Jones S.E. Kon S.S. Canavan J.L. et al.The five-repetition sit-to-stand test as a functional outcome measure in COPD.Thorax. 2013; 68: 1015-1020Crossref PubMed Scopus (195) Google Scholar There were significant, direct correlations between improvement in the STS-5 time (defined as a short time to complete the test) and the improvement in the KDQOL-PFD (defined as a higher score) over 1 year, with a Pearson product-moment correlation of +0.223, P = 0.002). A visual representation of this relationship is provided in Fig 1. In addition, 5 of the 10 KDQOL-PFD items were significantly correlated with improvement in the repeated chair stand time: lifting or carrying groceries; bending, kneeling, or stooping; walking several blocks; walking 1 block; and bathing or dressing oneself (Table 2).Table 1Linear Models of Change in Repeated Chair Stand Test Time Versus Change in KDQOL-PFD2.1 Model of Change in Repeated Chair Stand Test Time Vs Change in KDQOL-PFD Total ScoreEstimateStd. Errort-valuePIntercept−2.398550.90961−2.6370.00907KDQOL change−0.122330.03912−3.1270.002052.2 Model of Change in Repeated Chair Stand Test Time Vs Change in KDQOL-PFD Item C Lifting or Carrying GroceriesEstimateStd. Errort-valuePIntercept−2.45990.9046−2.7190.00716KDQOL C change−3.82821.2254−3.1240.002072.3 Model of Change in Repeated Chair Stand Test Time Vs Change in KDQOL-PFD Item F Bending, Kneeling, or StoopingEstimateStd. Errort-valuePIntercept−2.26330.9363−2.4170.01660KDQOL F change−3.29101.1654−2.8240.005262.4 Model of Change in Repeated Chair Stand Test Time Vs Change in KDQOL-PFD Item H Walking Several BlocksEstimateStd. Errort-valuePIntercept−2.37680.9221−2.5780.01072KDQOL H change−3.18471.1161−2.8530.004812.5 Model of Change in Repeated Chair Stand Test Time Vs Change in KDQOL-PFD Item I Walking One BlockEstimateStd. Errort-valuePIntercept−3.00340.8879−3.3830.000874KDQOL I change−3.47261.4695−2.3630.0191472.6 Model of Change in Repeated Chair Stand Test Time Vs Change in KDQOL-PFD Item J Bathing or Dressing YourselfEstimateStd. Errort-valuePIntercept−2.86120.8977−3.1870.00168KDQOL J change−3.63321.6492−2.2030.02882Abbreviations: KDQOL, Kidney Disease and Quality of Life; KDQOL-PFD, Kidney Disease and Quality of Life Physical Function Domain. Open table in a new tab Table 2Improvement (ie, Higher Score) on the KDQOL-PFD Total and Individual Scores Correlated Significantly with Improvement (ie, Faster Time) on the Repeated Chair Stand TestVariablesCorrelation Coefficient (r)95% CIPChange in KDQOL-PFD total score+0.2230.083-0.3540.002Change in Individual KDQOL-PFD Item Scores Lifting or carrying groceries+0.2230.083-0.3540.002 Bending, kneeling, or stooping+0.2020.061-0.3350.005 Walking several blocks+0.2040.063-0.3370.005 Walking one block+0.1700.028-0.3060.02 Bathing or dressing yourself+0.1590.017-0.2950.03Abbreviations: CI, confidence interval; KDQOL-PFD, Kidney Disease and Quality of Life Physical Function Domain. Open table in a new tab These findings suggest that incorporating the KDQOL-PFD physical function questionnaire as part of the clinical visit workflow for patients with CKD can identify patients with objective impairment in physical function. This short questionnaire that comprises 10 items and requires less than 5 minutes to complete may be particularly useful for patients unable to do the STS-5 and in situations where incorporation of the physical performance measure (chair stand) is infeasible in a particular clinic setting. Integration of this questionnaire in the clinic may provide a rapid and practical mechanism for both identifying at-risk patients as well as quantifying changes in physical function over time. A 3-5 point decrease in the total score of the KDQOL-PFD (score range 0-100) represents a clinically meaningful decline.9Leaf D.E. Goldfarb D.S. Interpretation and review of health-related quality of life data in CKD patients receiving treatment for anemia.Kidney Int. 2009; 75: 15-24Abstract Full Text Full Text PDF PubMed Scopus (112) Google ScholarPhysical performance has important implications for overall health outcomes.10Perlman R.L. Finkelstein F.O. Liu L. et al.Quality of life in chronic kidney disease (CKD): a cross-sectional analysis in the Renal Research Institute-CKD study.Am J Kidney Dis. 2005; 45: 658-666Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar Moreover, the KDQOL-PFD specifically evaluates limitations in activities that affect independent living and risk of injury, if impaired, such as walking, climbing stairs, and bending or stooping. The routine assessment of physical function in this manner can complement the STS-5 and would allow for appropriate interventions to help prevent further impairment and downstream disability and hospitalizations. Chronic kidney disease (CKD) is characterized by a progressive reduction in kidney function. In this condition, acid accumulates and is buffered by bone and muscle, leading to bone demineralization and protein catabolism.1Walker S.R. Gill K. Macdonald K. et al.Association of frailty and physical function in patients with non-dialysis CKD: a systematic review.BMC Nephrol. 2013; 14: 228Crossref PubMed Scopus (79) Google Scholar Eventually, the increased protein catabolism results in disturbances in skeletal muscle, with reduction in muscle mass and muscle strength, and worsening of physical function. Reduction in physical function begins early in the disease process and is associated with increased mortality risk.2Kraut J.A. Madias N.E. Adverse effects of the metabolic acidosis of chronic kidney disease.Adv Chronic Kidney Dis. 2017; 24: 289-297Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar,3Mitch W.E. Price S.R. May R.C. Jurkovitz C. England B.K. Metabolic consequences of uremia: extending the concept of adaptive responses to protein metabolism.Am J Kidney Dis. 1994; 23: 224-228Abstract Full Text PDF PubMed Scopus (28) Google Scholar In a recent prospective cohort study, we observed that the time necessary to complete a 5 time sit-to-stand (STS-5) test was associated with all-cause mortality in patients with CKD, and chair stand time declined immediately after dialysis initiation.4Rampersad C. Darcel J. Harasemiw O. et al.Change in physical activity and function in patients with baseline advanced nondialysis CKD.Clin J Am Soc Nephrol. 2021; 16: 1805-1812Crossref Scopus (1) Google Scholar However, measurement of physical function using chair stand time is not part of routine clinical assessment or workflow for patients with CKD. As such, the purpose of this study was to assess the correlation between easily obtained survey questions from the 10-item Kidney Disease and Quality of Life Physical Function Domain (KDQOL-PFD) instrument and objectively measured physical performance from the STS-5 to establish the validity of the KDQOL-PFD in assessment of physical function. Using data from a 1-year phase 3 randomized, placebo-controlled trial in patients with CKD and metabolic acidosis (n = 196), we evaluated the correlation between patient-reported limitation on daily activities as measured by the 10-item KDQOL-PFD scale (also known as the Short Form-36 physical function or SF-36 PF-10 scale) and the STS-5.5Wesson D.E. Mathur V. Tangri N. et al.Long-term safety and efficacy of veverimer in patients with metabolic acidosis in chronic kidney disease: a multicentre, randomised, blinded, placebo-controlled, 40-week extension.Lancet. 2019; 394: 396-406Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar,6Hays R.D. Kallich J.D. Mapes D.L. Coons S.J. Carter W.B. Development of the kidney disease quality of life (KDQOL) instrument.Qual Life Res. 1994; 3: 329-338Crossref PubMed Scopus (832) Google Scholar,7Bohannon R.W. Reference values for the five-repetition sit-to-stand test: a descriptive meta-analysis of data from elders.Percept Mot Skills. 2006; 103: 215-222Crossref PubMed Google Scholar Individual items of the KDQOL-PFD are provided in Table S1, and instructions for performing the STS-5 are provided in Item S1. Baseline characteristics of the patients are reported in Table S2. This trial examined the efficacy and safety of veverimer, a nonabsorbed hydrochloric acid binder, as a treatment for metabolic acidosis in patients with estimated glomerular filtration rate 20-40 mL/min/1.73 m2 and metabolic acidosis (serum bicarbonate 12-20 mEq/L). In this study, both the STS-5 and the KDQOL-PFD were significantly improved in patients who received veverimer compared to placebo.5Wesson D.E. Mathur V. Tangri N. et al.Long-term safety and efficacy of veverimer in patients with metabolic acidosis in chronic kidney disease: a multicentre, randomised, blinded, placebo-controlled, 40-week extension.Lancet. 2019; 394: 396-406Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Both the STS-5 and KDQOL-PFD were assessed at the same study visits. This multi-site study was conducted across 29 sites with institutional review board or ethics committee approval received at each site. All patients provided written consent before participation in the study, and full results of the trial including patient demographics and clinical characteristics have been previously published.5Wesson D.E. Mathur V. Tangri N. et al.Long-term safety and efficacy of veverimer in patients with metabolic acidosis in chronic kidney disease: a multicentre, randomised, blinded, placebo-controlled, 40-week extension.Lancet. 2019; 394: 396-406Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Correlations between the 2 measures of physical function were calculated using the Pearson product-moment correlation coefficient. In addition, a linear model was fit to determine the association of each category of decline related to activities of daily living (Table S1) in the KDQOL-PFD with the change (measured in seconds) in the STS-5. A clinically important difference in the STS-5 was 1.7 seconds, based on applications in cohorts for other chronic conditions.8Jones S.E. Kon S.S. Canavan J.L. et al.The five-repetition sit-to-stand test as a functional outcome measure in COPD.Thorax. 2013; 68: 1015-1020Crossref PubMed Scopus (195) Google Scholar In the linear model, each category of decline in the KDQOL-PFD was associated with a statistically significant deterioration in the times from the STS-5 (ranging between 3.29 to 3.80 seconds for each category), all of which were greater than the clinically important difference of 1.7 seconds (Table 1).8Jones S.E. Kon S.S. Canavan J.L. et al.The five-repetition sit-to-stand test as a functional outcome measure in COPD.Thorax. 2013; 68: 1015-1020Crossref PubMed Scopus (195) Google Scholar There were significant, direct correlations between improvement in the STS-5 time (defined as a short time to complete the test) and the improvement in the KDQOL-PFD (defined as a higher score) over 1 year, with a Pearson product-moment correlation of +0.223, P = 0.002). A visual representation of this relationship is provided in Fig 1. In addition, 5 of the 10 KDQOL-PFD items were significantly correlated with improvement in the repeated chair stand time: lifting or carrying groceries; bending, kneeling, or stooping; walking several blocks; walking 1 block; and bathing or dressing oneself (Table 2). Abbreviations: KDQOL, Kidney Disease and Quality of Life; KDQOL-PFD, Kidney Disease and Quality of Life Physical Function Domain. Abbreviations: CI, confidence interval; KDQOL-PFD, Kidney Disease and Quality of Life Physical Function Domain. These findings suggest that incorporating the KDQOL-PFD physical function questionnaire as part of the clinical visit workflow for patients with CKD can identify patients with objective impairment in physical function. This short questionnaire that comprises 10 items and requires less than 5 minutes to complete may be particularly useful for patients unable to do the STS-5 and in situations where incorporation of the physical performance measure (chair stand) is infeasible in a particular clinic setting. Integration of this questionnaire in the clinic may provide a rapid and practical mechanism for both identifying at-risk patients as well as quantifying changes in physical function over time. A 3-5 point decrease in the total score of the KDQOL-PFD (score range 0-100) represents a clinically meaningful decline.9Leaf D.E. Goldfarb D.S. Interpretation and review of health-related quality of life data in CKD patients receiving treatment for anemia.Kidney Int. 2009; 75: 15-24Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar Physical performance has important implications for overall health outcomes.10Perlman R.L. Finkelstein F.O. Liu L. et al.Quality of life in chronic kidney disease (CKD): a cross-sectional analysis in the Renal Research Institute-CKD study.Am J Kidney Dis. 2005; 45: 658-666Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar Moreover, the KDQOL-PFD specifically evaluates limitations in activities that affect independent living and risk of injury, if impaired, such as walking, climbing stairs, and bending or stooping. The routine assessment of physical function in this manner can complement the STS-5 and would allow for appropriate interventions to help prevent further impairment and downstream disability and hospitalizations. Research idea and study design: NT, VM; data acquisition: N/A; data analysis/interpretation: NT, MW, TWF, VM; statistical analysis: MW. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. This study was funded by Tricida, Inc. NT, MW, TFW, and VM were paid consultants to Tricida, Inc. in connection with the development of this manuscript. NT and VM report consultancy, personal fees, and equity ownership from Tricida, Inc. MW and TWF report consultancy and personal fees from Tricida, Inc Received January 22, 2022. Evaluated by 2 external peer reviewers, with direct editorial input from the Statistical Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form May 28, 2022. Supplementary Material Download .pdf (.32 MB) Help with pdf files Supplementary File (PDF)Item S1, Tables S1-S2. Download .pdf (.32 MB) Help with pdf files Supplementary File (PDF)Item S1, Tables S1-S2.

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