Aerobic exercise capacity is maintained over a 5-year period in mild-to-moderate chronic kidney disease: A longitudinal study

Aerobic exercise capacity is maintained over a 5-year period in mild-to-moderate chronic kidney disease: A longitudinal study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Aerobic exercise capacity is maintained over a 5-year period in mild-to-moderate chronic kidney disease: A longitudinal study Helena Wallin, Eva Jansson, Carin Wallquist, Britta Hylander Rössner, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.18456/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Nov, 2020 Read the published version in BMC Nephrology → Version 2 posted 11 You are reading this latest preprint version Show more versions Abstract Background: Aerobic exercise capacity is reduced in non-dialysis chronic kidney disease (CKD), but little is known about the magnitude of changes in exercise capacity over time. Our main hypothesis was that aerobic ExCap would decline over 5 years in individuals with mild-to-moderate CKD along with a decline in renal function. A secondary hypothesis was that such a decline in ExCap would be associated with a decline in muscle strength, cardiovascular function and physical activity. Methods: We performed a 5-year-prospective study on individuals with mild-to-moderate CKD, who were closely monitored at a nephrology clinic. Fiftytwo individuals with CKD stage 2–3 and 54 age- and sex-matched healthy controls were included. Peak workload was assessed through a maximal cycle exercise test. Muscle strength and lean body mass, cardiac function, vascular stiffness, self-reported physical activity level, renal function and haemoglobin level were evaluated. Tests were repeated after 5 years. Statistical analysis of longitudinal data was performed using linear mixed models. Results: Exercise capacity did not change significantly over time in either the CKD group or controls, although the absolute workloads were significantly lower in the CKD group. Only in a CKD subgroup reporting low physical activity at baseline, exercise capacity declined. Renal function decreased in both groups, with a faster decline in CKD ( p = 0.05 between groups). Peak heart rate, haemoglobin level, handgrip strength, lean body mass and cardiovascular function did not decrease significantly over time in CKD individuals. Conclusions: On a group level, aerobic exercise capacity and peak heart rate were maintained over 5 years in patients with well-controlled mild-to-moderate CKD, despite a slight reduction in glomerular filtration rate, mirroring the lack of progression of cardiovascular and muscular dysfunction in this group. In patients with mild-to-moderate CKD, physical activity level at baseline seems to have a predictive value for exercise capacity at follow-up. Urology & Nephrology Exercise capacity Non-dialysis chronic kidney disease Grip strength Peak heart rate Figures Figure 1 Background We and others have previously shown that aerobic exercise capacity (ExCap), measured as peak oxygen uptake (VO 2 peak) or peak ExCap, is already reduced in the early stages of non-dialysis chronic kidney disease (CKD) [ 1 – 3 ]. Reduced VO 2 peak is associated with increased mortality in CKD and reduced physical capacity has a negative impact on daily-life activities [ 4 , 5 ]. Aerobic ExCap is influenced by the function of most organ systems, particularly the cardiovascular and muscular systems. The cause of the reduced ExCap in CKD is likely multifactorial and may differ between different stages of CKD. Anaemia, autonomic dysfunction, vascular dysfunction, cardiac and skeletal muscle abnormalities may all contribute to exercise intolerance in non-dialysis CKD [ 1 , 3 , 6 – 10 ]. We recently showed that aerobic ExCap in patients with mild to severe CKD stages 2–5 was mainly associated with systemic oxygen delivery factors, in particular peak heart rate (HR) [ 1 ]. Although renal function declines over time in most individuals with CKD, the rate of progression differs, and some individuals do not show any progression at all [ 11 , 12 ]. Surprisingly little is known about how aerobic ExCap and muscle strength and mass change over time in individuals with non-dialysis CKD and how this correlates with changes in renal function. Leikis et al. found that in patients with CKD stages 3–4, both leg strength and VO 2 peak declined over a two-year period as glomerular filtration rate (GFR) declined, despite stable haemoglobin levels [ 13 ]. The progression of muscle wasting in CKD seems to be highly variable, although few data are available [ 14 ]. Physical activity levels of individuals with CKD are generally low and are increasingly reduced in the later stages of CKD [ 15 , 16 ]. A sedentary lifestyle most likely contributes to a further reduction in aerobic ExCap in patients with CKD, and vice versa. Given the high incidence of cardiovascular disease in CKD [ 17 ] and the higher mortality associated with reduced aerobic ExCap [ 4 , 18 ], it is of interest to monitor aerobic ExCap. The main aim of this study was to investigate the change in aerobic ExCap over 5 years in individuals with CKD stages 2–3 who were closely monitored at a nephrology clinic. Furthermore, we wanted to study the changes in possible determinants of ExCap in CKD, such as cardiovascular function, muscle strength, lean body mass (LBM), physical activity level and kidney function during the same period of time. Methods The current analyses are part of a larger, prospective, single-centre cohort study, PROGRESS 2002, investigating factors impacting the progress of renal insufficiency. The details of this study have been described previously [8]. Study protocol We included 52 patients with non-dialysis CKD stage 2–3 (CKD; aged 18–65 years) and 54 healthy controls who had completed an exercise test at baseline. The cohort has been monitored over a follow-up of 5 years. GFR was measured by iohexol plasma clearance [19]. During follow-up, GFR measurement by iohexol was repeated in the CKD group. In both CKD and controls, estimated GFR (eGFR) was calculated using the Chronic Kidney Disease–Epidemiology Collaboration (CKD–EPI) equation. This equation was chosen because it has been shown to provide a the most precise estimate of filtration capacity in the range of mild CKD [20]. The methodological considerations have been described in detail elsewhere [21]. Patients were recruited consecutively from the outpatient clinic at the Department of Renal Medicine at the Karolinska University Hospital during 2002–2009 if they had renal function corresponding to CKD stage 2–3a as defined by the National Kidney Foundation [22]. The controls, matched for age and sex with the CKD 2–3 group, were randomly selected from the Swedish Total Population Register or recruited through the website of the regional University Hospital. The exclusion criteria for all participants were current malignancy, kidney transplantation or kidney donation, or blood-transmitted disease. The inclusion criteria for the controls were absence of kidney disease, cardiovascular disease, diabetes or any chronic medication. After inclusion, all participants underwent clinical investigation, anthropometric measurement, an exercise stress test, a handgrip strength test, laboratory testing, carotid ultrasound, transthoracic echocardiography and a body composition scan. The participants with CKD were closely monitored and treated aggressively for hypertension, hyperlipidaemia and proteinuria at the Department of Renal Medicine. The study population and the excluded individuals are presented in Figure 1. Two participants in the CKD group died from cancer before the end of the follow-up period. No patient in the CKD group progressed to renal replacement therapy within the follow-up period. However, several patients were lost to follow-up. At year 5, 49 participants in the CKD group and 43 in the control group participated in the examinations. Forty-six participants in the CKD group and 40 in the control group performed an exercise test; however, one participant with CKD was excluded from the follow-up exercise test analysis because the exercise test was terminated early owing to the occurrence of atrial fibrillation with a high HR. Two other participants with CKD had atrial fibrillation before and during the exercise test; therefore, these individuals were not included in the peak HR analyses. Fig. 1 . Study population at baseline and 5-year-follow up. The study protocol was reviewed and approved by the Local Ethics Committee and Institutional Review Board of the Karolinska Institutet at the Karolinska University Hospital. All participants gave their written informed consent. Measurements Aerobic exercise capacity . A symptom-limited incremental cycle ergometer test on an electronically braked cycle ergometer (RE990; Rodby Innovation AB, Uppsala, Sweden) was administered according to clinical standards. The initial workload and workload increase/minute (10, 15 or 20 W) were individualized with the goal of achieving symptom limitation within 6 to 10 minutes. Participants were instructed to cycle at a speed of 60 rpm and were encouraged to continue cycling until exhaustion. Perceived exertion was reported as the highest rating on the Borg CR10 scale for either leg fatigue, dyspnoea or general exhaustion as a limiting symptom [23]. Aerobic ExCap was defined as the peak workload in W. Continuous 12-lead electrocardiography was used to measure HR and for ST–T-segment monitoring and safety purposes. Resting HR was measured in the supine position before the exercise test. Predicted peak HR was calculated as 220 minus age. HR reserve was defined as the difference between peak and resting HR. Muscular function . A handheld dynamometer (Grip-A; Takei Scientific Instruments Co., Ltd, Tokyo, Japan) was used to measure maximum voluntary isometric contraction as a measure of handgrip strength. The test was performed with the participant in a standing position. The measurement was repeated three times using the dominant arm, and the highest value was recorded as handgrip strength. Cardiac and vascular function. Echocardiography was performed with the participant in the supine left decubitus position and according to current guidelines [24]. The images were acquired using an ultrasound scanner (Sequoia 512; Siemens Medical Solutions, Mountain View, CA, USA) with an appropriate transducer. Cardiac function was evaluated and expressed for systolic left-ventricular (LV) function as ejection fraction (EF), for right-ventricular systolic function as tricuspid annular plane systolic excursion (TAPSE) and for diastolic LV function as an E/é ratio (mitral flow velocity E, divided by tissue LV velocity é). Carotid artery ultrasound was performed to assess arterial stiffness. Measurements of the diameter of the right common carotid artery and calculations of the pressure strain elastic modulus (Ep) were performed according to a standardized protocol [8]. Ambulatory blood pressure monitoring was performed over 24 hours from morning to morning using Spacelab 90217 (Spacelab Healthcare, Issaquah, Washington, USA) and a cuff of appropriate size on the non-dominant arm. Blood pressure was measured three times per hour day and night. Body composition. Body composition was measured with a whole-body dual-energy X-ray absorptiometry scan to determine LBM (QDR 4500 Discovery A, software version 12.3; Hologic, Bedford, MA, USA). Only the CKD group were examined at follow-up. Physical activity level. Physical activity level was rated by the participants using a four-point scale modified from the Saltin–Grimby Physical Activity Level Scale as follows [25]: Level 1 = Regular exercise : running, swimming, tennis, badminton, gymnastics or similar activity on three or more occasions per week; every session should last at least 30 min and cause sweating. Level 2 = Moderate amount of regular exercise : running, swimming, tennis, badminton, gymnastics or similar activity on 1–2 occasions per week; every session should last at least 30 minutes and cause sweating. Level 3 = Light exercise : walking or cycling or other physical activity during at least 2 h per week, usually without sweating; this includes walking or cycling to/from work, Sunday walks, gardening, fishing, table tennis and bowling or similar activity. Level 4 = Sedentary : mostly reading, watching television, movies or other sedentary activities, or walking, cycling or light exercise for less than 2 h per week. Blood samples. Haemoglobin, creatinine and high-sensitivity C-reactive protein (hs-CRP) concentration were measured in venous blood obtained using routine laboratory methods at the Karolinska University Laboratory at the inclusion visit before the exercise test. Statistical analysis Continuous variables are presented as mean and standard deviation, and categorical variables as number and percentage of the study sample. Variables with a skewed distribution are presented as median and interquartile range. The normality assumption was assessed graphically using histograms. Potential outliers were examined graphically by box plots and their validity were assessed. Logarithmic transformation was performed for variables with a skewed distribution when they were analysed in mixed models. Group comparisons at baseline were performed using Student’s t -test or Mann–Whitney U -test when the assumptions of normality and homogeneity were not fulfilled. For categorical variables, a chi-square test was used. Wilcoxon’s signed-rank test for related samples was used to assess the change over time for ordinal data. Statistical significance was defined as a p -value < 0.05 for a two-tailed test. Linear mixed models were considered to be the most suitable method for the analysis of longitudinal data because this method provides effect estimates from the whole study sample provided that the values missing at follow-up are random. Changes over time were analysed in CKD and controls and the changes were compared between the groups by the interaction factor group ´ time in the mixed model. The analyses were adjusted for different background factors (depending on the chosen outcome variable), including age at baseline, sex, height and beta-blocker use. To analyse longitudinal data where the outcome variables were ordered categoricals, generalized estimating equations (GEE) model were used. The model was set up with the same factors as in the mixed linear model mentioned above. The parameter estimates from the GEE model are presented as odds ratios (OR) and 95% confidence intervals (CI). Pearson (r) or Spearman (r s ) correlation coefficients were used to analyse the relationship between two variables. Statistical analyses were performed using IBM SPSS Statistics (version 23.0; IBM, Armonk, NY, USA) and SAS (version 9.3; SAS Institute, Cary, NC, USA) software. Results The baseline characteristics of the study participants are summarized in Table 1 . The mean age of the whole cohort at entry was 47 years and there were no significant differences between the CKD group and controls in age, sex or body size. Based on their GFR, 31 individuals in the CKD group were in CKD stage 2 and 21 in CKD stage 3 at baseline. At follow-up, two individuals in the CKD group were in stage 1; nine in stage 2; 27 in stage 3; five in stage 4; and one was in stage 5. Ten individuals in the CKD group had diabetes at inclusion and follow-up and two in the control group had developed diabetes at follow-up. At baseline, 10 individuals in the CKD group were on beta-blocker treatment. At follow-up, this number had increased to 15 and four of the controls had started beta-blocker treatment. Table 1 Baseline characteristics. Variable Controls CKD p -value Subjects (n) 54 52 Age (years) 48 ± 11 47 ± 11 0.7 Male, n (%) 33 (61) 32 (61) 0.8 Height (cm) 176 ± 9 174 ± 9 0.4 Weight (kg) 77 ± 12 76 ± 16 1 BMI (kg/m 2 ) 24.9 ± 3.4 25.1 ± 4.0 0.2 Lean body mass (kg) 54 ± 11 52 ± 11 0.5 GFR (mL/min/1.73 m 2 ) 99 ± 12 60.3 ± 5.2 < 0.001 eGFR (mL/min/1.73 m 2 ) 96 ± 13.2 59 ± 13 < 0.001 Haemoglobin (g/dL) 14.2 ± 1.2 13.5 ± 1.4 0.02 Hs-CRP (mg/L) 0.89 (0.47–2.1) 1.60 (0.86–3.5) 0.04 Diabetes, n (%) 10 (22) NA 24-h SBP (mmHg) 124 ± 11 122 ± 14 0.4 24-h DBP (mmHg) 78 ± 8 76 ± 7 0.4 Aetiology of CKD, n (%) Familial/hereditary/congenital disease 14 (27) NA Primary glomerulonephritis 17 (33) NA Secondary glomerular/systemic disease 9 (17) NA Miscellaneous/unknown 12 (23) NA Medication, n (%) Beta blocker 10 (19) NA Diuretics 12 (23) NA ACE inhibitors 22 (42) NA Angiotensin II blockers 21 (39) NA Calcium-channel blockers 10 (19) NA ESA 1 (2) NA Oral cortisone 2 (4) NA Iron supplementation 4 (8) NA Functional measurements Peak workload (W) 238 ± 60 193 ± 63 < 0.001 Peak HR (bpm) 177 ± 11 161 ± 24 < 0.001 Peak RPE 8.6 ± 1.3 9 ± 1.3 0.2 Handgrip strength (kg) 44 ± 12 40 ± 11 0.08 BMI body mass index; bpm beats per minute; CKD chronic kidney disease; eGFR glomerular filtration rate estimated by CKD–EPI; ESA erythropoiesis-stimulating agents; GFR glomerular filtration rate measured by iohexol clearance; HR heart rate; hs-CRP high-sensitivity C-reactive protein; n number; 24-h SBP / DBP average 24-h systolic/diastolic blood pressure Values reported as number (percentage), mean ± standard deviation or median (interquartile range). P -value: t -test, Mann–Whitney U -test (continuous variables) or chi-square (categorical values). Renal function and blood analyses At baseline, GFR measured by iohexol clearance was 60.3 ± 5.2 mL/min/1.73 m 2 in CKD and 99.5 ± 12.5 mL/min/1.73 m 2 in the controls ( p < 0.001). At follow-up, measured GFR in the CKD group was 50.2 ± 16.9 mL/min/1.73 m 2 , a mean decline of 17% over 5 years. eGFR values at baseline and follow-up were calculated by CKD–EPI for both CKD and controls. A significant decrease in eGFR was seen between baseline and year 5 for both groups; the difference in the change in eGFR over time between the groups was borderline significant (interaction group ⋅ time, p = 0.05) (Table 2). The annual rate of decline in eGFR was 1.8 mL/min/1.73 m 2 in the CKD group and 0.8 mL/min/1.73 m 2 in the control group. Haemoglobin was significantly lower in the CKD group than in controls at both time points, but increased significantly over time in both groups. This change did not differ significantly over time between the groups (Table 2). However, separate analyses in men and women using the paired samples t -test showed that haemoglobin increased significantly in women ( p = 0.001) but not in men ( p = 0.2). Hs-CRP was higher in the CKD group than in controls at each time point, but no significant change over time was seen in either CKD or controls. Table 2 . Functional measurements at baseline and 5-year follow-up. Exercise test results Aerobic ExCap and peak HR were both significantly lower in CKD than in controls at both time points, and did not change significantly over time in neither CKD nor controls (Table 2, mixed model with values adjusted for covariates). In CKD, there was a non-significant average decline in ExCap of 2.6%. The non-significant decline in peak HR in the CKD group was 0.6%. In controls, the mean values of ExCap showed a non-significant decrease of 1.7% and peak HR significantly decreased by an average of 2.3%. There was no significant difference in the rating of perceived exertion (RPE) between the groups at baseline. At follow-up, the mean ratings were 8.3 for CKD and 8.5 for controls ( p = 0.7 between groups). Muscle strength and lean body mass Handgrip strength was significantly lower in CKD than in controls at baseline, but not at follow-up (Table 2, mixed model). The difference in the change over time between the two groups was borderline significant ( p = 0.06), with a significant reduction in the control group. LBM did not differ significantly between groups at baseline (CKD 52.8 kg; controls 53.5 kg, p = 0.3, analysed by linear mixed model) and increased from 52.8 kg to 54.5 kg ( p = 0.02) at follow-up in the CKD group. Mean values were adjusted for the covariates of age at baseline, sex, height and weight at baseline. Weight increased from 75.7 kg to 78.3 kg (p = 0.006, paired samples t-test) in the CKD group. Cardiovascular function At baseline, LV diastolic function (E/é ratio), was significantly lower in the CKD group compared with controls, although within normal values; while LV systolic function (EF), right ventricular systolic function (TAPSE) and vascular stiffness (Ep) did not differ significantly between groups (Table 2, mixed model). E/é, EF, TAPSE and Ep did not change significantly over 5 years in the CKD group, nor was the change over time significantly different from that in controls (Table 2). E/é increased and EF decreased in controls from baseline to follow-up with values remaining within the normal range. Self-reported physical activity The results of this analysis are presented in Table 3. Self-reported physical activity levels differed between groups at baseline with controls being physically more active than CKD patients. At follow-up, there was no significant difference in physical activity level between groups. Individuals with CKD reported higher physical activity levels at follow-up compared with baseline while controls reported lower physical activity levels at follow-up compared with baseline. The interaction group x time was statistically significant ( p = 0.0002), indicating that the two groups differed regarding their change in physical activity level over time. Table 3. Change in physical activity (PA) level between baseline and 5-year follow-up. Odds ratio Confidence interval P -value a CKD: Follow-up vs. baseline 2.12 1.26–3.56 0.0047 b Controls: Follow-up vs. baseline 0.54 0.35–0.84 0.0057 c CKD vs. controls at baseline 0.42 0.21–0.86 0.0169 d CKD vs. controls at follow-up 1.66 0.77–3.63 0.2008 CKD chronic kidney disease. a CKD: Odds for increased PA at follow-up compared with baseline. b Controls: Odds for increased PA at follow-up compared with baseline. c Odds for higher PA in CKD group compared with controls at baseline. d Odds for higher PA in CKD group compared with controls at follow-up. Results are analysed using a generalized estimation equation. The results are based on 188 observations from 106 subjects. P -value: chi-square test. Correlations between the change in ExCap and physiological measurements Correlations between the change in aerobic ExCap and changes in selected physiological and biochemical measurements were analysed for the CKD group. There were significant correlations between the change in ExCap and changes in peak HR and handgrip strength (r = 0.5 and 0.3 respectively, p = 0.001 and 0.03 respectively, n = 43 and 45 respectively). The change in measured GFR was significantly correlated with the change in aerobic ExCap in CKD (r = 0.3, p = 0.03, n = 42). However, when eGFR was used, the correlation between the change in eGFR and the change in ExCap was not significant (r = 0.06 and p = 0.7, n = 44). The change in physical activity level did not correlate to the change in ExCap (r s = − 0.05 and p = 0.7, n = 45), nor did the change in haemoglobin level, Hs-CRP level, E/é or EP (r = 0.1, 0.03, − 0.08 and − 0.01 respectively, p = 0.4; 0.9, 0.6 and 0.9, respectively, n = 45, 42, 43 and 43, respectively). For controls, there were no significant correlations between the change in ExCap and changes in peak HR, handgrip strength and eGFR (r = 0.1, 0.1 and − 0.3 respectively, p = 0.5, 0.5 and 0.06, respectively, n = 40, 40 and 39, respectively). Discussion In this study we analysed changes in aerobic ExCap and known determinants over a 5-year period in individuals with mild-to-moderate CKD compared with healthy individuals. Individuals with CKD were recruited from a dedicated nephrology clinic and closely monitored. In these patients, aerobic ExCap, peak HR, handgrip strength, LBM, haemoglobin level and cardiovascular function were all maintained over 5 years, despite a 17% reduction in GFR over time. To the best of our knowledge, this is the first study to evaluate the change in aerobic ExCap over time in CKD patients compared with healthy controls. As expected, eGFR decreased more in CKD patients than in controls ( p = 0.05). Aerobic ExCap is expected to decline with age, with an average 5–20% decline per decade in cross-sectional studies of healthy individuals, while longitudinal studies show a greater decline in older individuals compared with younger people [ 26 , 27 ]. The mean change in ExCap in our study was almost 3% over 5 years in the CKD group and a little less in the control group. Our study included some younger individuals (< 35 years old), which could explain the modest decline compared with those seen in previous studies of healthy individuals. An important finding from our study is that ExCap did not decline more rapidly in the CKD group attending a nephrology clinic than in the controls. Reductions in peak HR and peripheral oxygen utilization but not stroke volume appear to mediate the normal age-associated decline in aerobic ExCap [ 26 – 28 ]. The expected decline in peak HR with normal aging is not as pronounced as the decline in aerobic ExCap of 4–6% per decade that was reported by Fleg et al. [ 28 ], which is similar to our data for the controls. The reduction in peak HR in the CKD group was only 0.6%. For the CKD group, there was a significant correlation between the change in ExCap over 5 years and the change in peak HR, which was not seen in the control group. This suggests that peak HR, or the possibility of achieving a high peak HR, could be an important factor influencing ExCap in this CKD group. Peripheral oxygen utilization and maximal stroke volume were not measured in our study, however a measure of diastolic function, E/é, decreased in controls but not in CKD patients over 5 years. Diastolic dysfunction may lead to an inability to increase stroke volume at exercise through the Frank–Starling mechanism and a preserved diastolic function at rest might indicate that maximal stroke volume was also preserved. While both aerobic ExCap and peak HR are known to be more reduced in the later stages of CKD than in the earlier stages [ 1 , 3 , 29 ], only one small study has reported the changes in aerobic ExCap over time in non-dialysis CKD patients [ 13 ]. That study found a reduction in VO 2 peak of 9% over two years, a stable haemoglobin level and a fall of 28% in the calculated creatinine clearance. As a decline in leg strength paralleled the reduction in VO 2 peak, the authors speculated that the reduction in VO 2 peak was likely related to intrinsic muscle changes. However, peak HR decreased with a mean value of 9 over only two years, which may also have influenced aerobic ExCap in that study. The difference between the results of our study compared with that study may in part be explained by the higher mean GFR in our study (at baseline, 60 versus 31 mL/min/1.73 m 2 ) and the smaller decline in GFR over time. Furthermore, handgrip strength and LBM did not decrease over 5 years in the CKD group in our study. Grip strength is known to be reduced in non-dialysis CKD patients [ 1 , 30 , 31 ] and to further decrease in conjunction with the progression of CKD [ 31 ]. Muscle wasting seems to be more pronounced in patients with dialysis-dependent CKD than in those with non-dialysis CKD [ 32 ]. However, John et al. [ 14 ] showed a highly variable course of the change in muscle cross-sectional area over two years, and the rate of muscle loss was actually more pronounced in non-dialysis CKD patients than in patients on dialysis. Compared with the non-dialysis CKD group in our study, the non-dialysis CKD group in the study by John et al. had more advanced CKD with a substantially lower eGFR (16 mL/min/1.73 m 2 ), which might explain the discrepancy between the results. Overall, at the group level, the individuals with CKD in our study were very stable in all measured parameters: i.e., cardiovascular, muscular and haematological. Cardiac function and vascular stiffness showed no significant change over time in the CKD group, while the controls significantly decreased their cardiac diastolic and systolic function and their peak HR. The changes in the control group can be considered to be the result of normal aging. Data from our group show that in the same cohort, daytime systolic blood pressure did not increase over 5 years in the CKD group, while a small but significant increase was seen in the controls [ 33 ]. According to the Fick principle, aerobic ExCap is the result of oxygen delivery and oxygen extraction mechanisms, which are highly dependent on the function of the cardiovascular system and skeletal musculature. Given the lack of progression in outcomes representing the function of these systems, it is not surprising that aerobic ExCap did not decrease significantly in the CKD group. A reduced level of physical activity may contribute to a decline in ExCap, but physical activity actually increased in the CKD group, perhaps further contributing to the maintenance of their ExCap. The opposite was seen in the control group, who significantly decreased their physical activity over 5 years. The participants with mild-to-moderate CKD in our study were recruited from a dedicated nephrology clinic and showed well-controlled blood pressure over time [ 33 ]. The CKD group was monitored more closely than the controls, with aggressive treatment of hypertension, hyperlipidaemia and proteinuria. These factors may explain the fact that this group could maintain their cardiovascular and muscular function and thereby their aerobic ExCap. The mean decline in GFR over time was comparable to or a little lower than values reported in other studies [ 12 , 34 , 35 ]. Interestingly, Jones et al. reported that GFR decline slowed significantly following referral to a nephrology clinic, indicating that interventions to slow progression of CKD are important and beneficial. The decline of GFR in the control group was not more pronounced than expected in healthy individuals [ 36 ]. There are some important limitations of our study. The study groups were relatively small at baseline and were further reduced at follow-up. To overcome the problem with subjects lost to follow-up, statistical analyses were performed using linear mixed models to compensate for missing values. We measured aerobic ExCap as peak workload and not VO 2 peak during exercise. However, given the linear relationship between exercise load and oxygen uptake during cycle ergometry [ 37 ], and the fact that the tests were performed according to the same protocol at both time-points with similar high RPEs, we believe our results are a valid measurement of the true changes in aerobic ExCap and peak HR over time. Conclusions Individuals with mild-to-moderate CKD maintained their aerobic ExCap over a 5-year-period. Known determinants of aerobic ExCap such as peak HR, haemoglobin level, muscle strength and cardiac diastolic function were also preserved over the 5 years. Possible explanations for this include attendance at a specialist nephrology clinic with tight monitoring and an increase in self-reported physical activity level over 5 years. Abbreviations CI, confidence interval; CKD: Chronic kidney disease; CKD–EPI, Chronic Kidney Disease–Epidemiology Collaboration; E/é: Mitral flow velocity E divided by tissue LV velocity é; EF: Ejection fraction; eGFR: Estimated GFR; Ep: Pressure strain elastic modulus in the carotid artery; ExCap: Exercise capacity; GEE, Generalized estimating equations; GFR: Glomerular filtration rate; Hs-CRP: high-sensitivity C-reactive protein; HR: Heart rate; LBM: Lean body mass; LV: Left ventricular; OR, odds ratio; RPE: Rating of perceived exertion; TAPSE: tricuspid annular plane systolic excursion; VO 2 peak: Peak oxygen uptake Declarations Ethics approval and consent to participate The study protocol was reviewed and approved by the Local Ethics Committee and Institutional Review Board of the Karolinska Institutet at the Karolinska University Hospital. All participants gave their written informed consent. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding The study was supported by grants from the Stockholm County Council, grant numbers 20150555 and 20120628 received by MJE and grants from the Swedish Kidney Foundation, grant number F2017-0048 received by AR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Authors’ contributions HW performed all statistical analyses and prepared the original draft of the manuscript. HW, AR, ME and EJ interpreted the data and contributed to substantial revision of the manuscript. SJ, CW, BHR and ME designed the study and contributed to data acquisition. All authors read and approved the final manuscript. Acknowledgements We thank the staff and participants of the PROGRESS study, especially Research Nurse/PhL Agneta Aspegren-Pagels for her important contributions. The authors acknowledge Elisabeth Berg for assistance with statistical analysis of data. References Wallin H, Asp AM, Wallquist C, Jansson E, Caidahl K, Hylander Rossner B, Jacobson SH, Rickenlund A, Eriksson MJ: Gradual reduction in exercise capacity in chronic kidney disease is associated with systemic oxygen delivery factors . PLoS One 2018, 13 (12):e0209325. Chinnappa S, White E, Lewis N, Baldo O, Tu YK, Glorieux G, Vanholder R, El Nahas M, Mooney A: Early and asymptomatic cardiac dysfunction in chronic kidney disease . Nephrol Dial Transplant 2018, 33 (3):450-458. Van Craenenbroeck AH, Van Craenenbroeck EM, Van Ackeren K, Hoymans VY, Verpooten GA, Vrints CJ, Couttenye MM: Impaired vascular function contributes to exercise intolerance in chronic kidney disease . Nephrol Dial Transplant 2016, 31 (12):2064-2072. Sietsema KE, Amato A, Adler SG, Brass EP: Exercise capacity as a predictor of survival among ambulatory patients with end-stage renal disease . Kidney Int 2004, 65 (2):719-724. Heiwe S, Clyne N, Dahlgren MA: Living with chronic renal failure: patients' experiences of their physical and functional capacity . Physiother Res Int 2003, 8 (4):167-177. Odden MC, Whooley MA, Shlipak MG: Association of chronic kidney disease and anemia with physical capacity: the heart and soul study . J Am Soc Nephrol 2004, 15 (11):2908-2915. Clyne N, Hellberg M, Kouidi E, Deligiannis A, Hoglund P: Relationship between declining glomerular filtration rate and measures of cardiac and vascular autonomic neuropathy . Nephrology (Carlton) 2016, 21 (12):1047-1055. Asp AM, Wallquist C, Rickenlund A, Hylander B, Jacobson SH, Caidahl K, Eriksson MJ: Cardiac remodelling and functional alterations in mild-to-moderate renal dysfunction: comparison with healthy subjects . Clin Physiol Funct Imaging 2015, 35 (3):223-230. Otsuka T, Suzuki M, Yoshikawa H, Sugi K: Left ventricular diastolic dysfunction in the early stage of chronic kidney disease . J Cardiol 2009, 54 (2):199-204. Conjard A, Ferrier B, Martin M, Caillette A, Carrier H, Baverel G: Effects of chronic renal failure on enzymes of energy metabolism in individual human muscle fibers . J Am Soc Nephrol 1995, 6 (1):68-74. Al-Aly Z, Zeringue A, Fu J, Rauchman MI, McDonald JR, El-Achkar TM, Balasubramanian S, Nurutdinova D, Xian H, Stroupe K et al : Rate of kidney function decline associates with mortality . J Am Soc Nephrol 2010, 21 (11):1961-1969. Jones C, Roderick P, Harris S, Rogerson M: Decline in kidney function before and after nephrology referral and the effect on survival in moderate to advanced chronic kidney disease . Nephrol Dial Transplant 2006, 21 (8):2133-2143. Leikis MJ, McKenna MJ, Petersen AC, Kent AB, Murphy KT, Leppik JA, Gong X, McMahon LP: Exercise performance falls over time in patients with chronic kidney disease despite maintenance of hemoglobin concentration . Clin J Am Soc Nephrol 2006, 1 (3):488-495. John SG, Sigrist MK, Taal MW, McIntyre CW: Natural history of skeletal muscle mass changes in chronic kidney disease stage 4 and 5 patients: an observational study . PLoS One 2013, 8 (5):e65372. Johansen KL, Chertow GM, Ng AV, Mulligan K, Carey S, Schoenfeld PY, Kent-Braun JA: Physical activity levels in patients on hemodialysis and healthy sedentary controls . Kidney Int 2000, 57 (6):2564-2570. Hawkins MS, Sevick MA, Richardson CR, Fried LF, Arena VC, Kriska AM: Association between physical activity and kidney function: National Health and Nutrition Examination Survey . Med Sci Sports Exerc 2011, 43 (8):1457-1464. Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, McCullough PA, Kasiske BL, Kelepouris E, Klag MJ et al : Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention . Circulation 2003, 108 (17):2154-2169. Ting SM, Iqbal H, Kanji H, Hamborg T, Aldridge N, Krishnan N, Imray CH, Banerjee P, Bland R, Higgins R et al : Functional cardiovascular reserve predicts survival pre-kidney and post-kidney transplantation . J Am Soc Nephrol 2014, 25 (1):187-195. Krutzen E, Back SE, Nilsson-Ehle I, Nilsson-Ehle P: Plasma clearance of a new contrast agent, iohexol: a method for the assessment of glomerular filtration rate . J Lab Clin Med 1984, 104 (6):955-961. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T et al : A new equation to estimate glomerular filtration rate . Ann Intern Med 2009, 150 (9):604-612. Wallquist C, Mansouri L, Norrback M, Hylander B, Jacobson SH, Lundahl J: Early Changes in Monocyte Adhesion Molecule Expression and Tumor Necrosis Factor-alpha Levels in Chronic Kidney Disease - A 5-Year Prospective Study . Am J Nephrol 2016, 44 (4):268-275. National Kidney F: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification . Am J Kidney Dis 2002, 39 (2 Suppl 1):S1-266. Borg G: Perceived exertion as an indicator of somatic stress . Scand J Rehabil Med 1970, 2 (2):92-98. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS et al : Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology . J Am Soc Echocardiogr 2005, 18 (12):1440-1463. Saltin B, Grimby G: Physiological analysis of middle-aged and old former athletes. Comparison with still active athletes of the same ages . Circulation 1968, 38 (6):1104-1115. Fleg JL, Strait J: Age-associated changes in cardiovascular structure and function: a fertile milieu for future disease . Heart Fail Rev 2012, 17 (4-5):545-554. Carrick-Ranson G, Hastings JL, Bhella PS, Shibata S, Fujimoto N, Palmer D, Boyd K, Levine BD: The effect of age-related differences in body size and composition on cardiovascular determinants of VO2max . J Gerontol A Biol Sci Med Sci 2013, 68 (5):608-616. Fleg JL, Morrell CH, Bos AG, Brant LJ, Talbot LA, Wright JG, Lakatta EG: Accelerated longitudinal decline of aerobic capacity in healthy older adults . Circulation 2005, 112 (5):674-682. Chinnappa S, White E, Lewis N, Baldo O, Tu YK, Glorieux G, Vanholder R, El Nahas M, Mooney A: Early and asymptomatic cardiac dysfunction in chronic kidney disease . Nephrol Dial Transplant 2017. Pagels A, Heiwe S, Hylander B: [Nutritional status of pre-dialysis patients] . J Ren Care 2006, 32 (3):162-166. Hiraki K, Yasuda T, Hotta C, Izawa KP, Morio Y, Watanabe S, Sakurada T, Shibagaki Y, Kimura K: Decreased physical function in pre-dialysis patients with chronic kidney disease . Clin Exp Nephrol 2013, 17 (2):225-231. 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, 21 (8):2210-2216. Asp AM, Wallquist C, Rickenlund A, Hylander B, Jacobson SH, Caidahl K, Eriksson MJ: Cardiovascular changes in patients with mild-to-moderate chronic kidney disease compared with healthy subjects: a 5-year follow-up study . Clin Physiol Funct Imaging 2019. Tsai CW, Ting IW, Yeh HC, Kuo CC: Longitudinal change in estimated GFR among CKD patients: A 10-year follow-up study of an integrated kidney disease care program in Taiwan . PLoS One 2017, 12 (4):e0173843. Baek SD, Baek CH, Kim JS, Kim SM, Kim JH, Kim SB: Does stage III chronic kidney disease always progress to end-stage renal disease? A ten-year follow-up study . Scand J Urol Nephrol 2012, 46 (3):232-238. Weinstein JR, Anderson S: The aging kidney: physiological changes . Adv Chronic Kidney Dis 2010, 17 (4):302-307. Åstrand P-O., Rodahl K., Dahl H. A., Strømme S. B. : Textbook of Work Physiology: Physiological Bases of Exercise. , 4th edn. Leeds, UK: Human Kinetics; 2003. Table Table 2. Functional measurements at baseline and 5-year follow-up. Controls CKD Baseline (n = 54) Year 5 P -value time a Baseline (n = 52) Year 5 P -value time a P -value group b P -value group*time c Covariates d Peak workload (W) 237 (225–249) 233 (221–245) 0.3 195 (184–207) 190 (178–202) 0.2 < 0.001/< 0.001 0.8 Age, sex, height n = 40 n = 45 Peak heart rate (bpm) 175 (171–179) 171 (167–176) 0.04 161 (157–165) 160 (155–164) 0.3 < 0.001/0.001 0.4 Age, BB medication n = 40 n = 43 HR reserve (bpm) 99 (94–104) 102 (96–107) 0.4 91 (86–96) 89 (84–95) 0.5 0.03/0.002 0.2 Age, BB medication n = 40 n = 43 Handgrip strength (kg) 44(43–46) 43 (41–44) 0.006 41 (39–42) 41 (39–42) 0.8 < 0.001/0.07 0.06 Age, sex, height n = 40 n = 48 LV systolic function LVEF (%) 65 (63–68) 61 (59–64) <0.001 62 (60–65) 61 (58–63) 0.1 0.06/0.7 0.1 * n = 41 n = 45 LV diastolic function E/é 5.0 (4.7–5.4) 5.7 (5.3–6.1) <0.001 5.6 (5.3–6.0) 5.9 (5.6–6.3) 0.06 0.01/0.3 0.1 Age n = 43 n = 46 RV systolic function TAPSE (cm) 2.5 (2.4–2.6) 2.5 (2.4–2.6) 0.4 2.3 (2.2–2.4) 2.4 (2.3–2.5) 0.09 0.06/0.2 0.6 * n = 43 n = 45 Vascular function Ep ((N/m 2 ) ´ 10 4 ) e 5.8 (5.4–6.3) 6.0 (5.5–6.6) 0.5 6.5 (5.8–7.1) 6.8 (6.2–7.4) 0.4 0.06/0.08 1 Age n = 43 n = 47 eGFR (mL/min/1.73 m 2 ) 96 (92–100) 92 (87–96) 0.03 59 (55–62) 50 (46–54) <0.001 < 0.001/< 0.001 0.05 n = 43 n = 47 Haemoglobin (g/dL) 14.2 (13.8–14.5) 14.7 (14.3–15.0) 0.002 13.6 (13.3–13.9) 13.9 (13.6–14.2) 0.04 0.01/0.001 1 Sex n = 40 n = 49 Hs-CRP (mg/L) e 1.0 (0.7–1.3) 1.0 (0.8–1.3) 0.9 1.9 (1.4–2.6) 1.8 (1.4–2.4) 0.8 0.002/0.006 0.8 n = 43 n = 49 BB beta-blocker; bpm beats per minute; CKD chronic kidney disease; E/é left-ventricular early filling velocity/early diastolic myocardial velocity (a variable of left-ventricular diastolic function); eGFR glomerular filtration rate estimated by CKD–EPI; Ep pressure strain elastic modulus in the carotid artery; HR heart rate; hs-CRP high-sensitivity C-reactive protein; LV left ventricular; LVEF left-ventricular ejection fraction; n number; RV right ventricular; TAPSE tricuspid annular plane systolic excursion (a variable of right-ventricular systolic function). Values reported as mean (95% confidence interval). P -value: linear mixed models. Mean values are adjusted for covariates. a Significance of the change over time in the control group and the CKD group, respectively. b Significance of the difference between the control group and the CKD group at baseline/year 5. c Significance of the difference in change over time between the CKD group and the control group. d Baseline values are used as fixed covariates. e Values presented in the table are the calculated anti-logs of the log-scale estimates that were used in linear mixed models analyses. * Age was tested as a covariate but was not significant. Supplementary Files STROBEchecklistcombined200817.doc Cite Share Download PDF Status: Published Journal Publication published 11 Nov, 2020 Read the published version in BMC Nephrology → Version 2 posted Editorial decision: Minor revision 16 Sep, 2020 Review # 3 received at journal 15 Sep, 2020 Review # 2 received at journal 11 Sep, 2020 Reviewer # 3 agreed at journal 28 Aug, 2020 Review # 1 received at journal 25 Aug, 2020 Reviewers invited by journal 21 Aug, 2020 Reviewer # 1 agreed at journal 21 Aug, 2020 Reviewer # 2 agreed at journal 21 Aug, 2020 Editor assigned by journal 20 Aug, 2020 Submission checks completed at journal 19 Aug, 2020 Editor invited by journal 19 Aug, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9076","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":1617808,"identity":"97a76366-e290-4491-8867-52cb54095706","order_by":0,"name":"Helena Wallin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYBACAwbmBgiLnbnhAENFAg8RWhihWpgZgVrOkKqFgbEtgbDDzNkbGx8X1DAk9jczNh4unJcmw8B/+ABeLZY9B5uNZxxjSJxxmLHh8MxtOTwMEmn4rTK4kdgmzcPGkNsA0sK7rQKohccAv5b7D9t/8/xjyJ0P1jIHqIX//AcCtjC2MfO2MeRuAGtpADqMIQevDgaDM4nN0rx9EvUbQVp4jqXxsEmkEXDY8cMHP/N8szGWO958+DNPTbI9P//hB/itgQAJBJONGPWjYBSMglEwCvADAHymRSaOpjXrAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-9187-2426","institution":"Karolinska Institutet","correspondingAuthor":true,"prefix":"","firstName":"Helena","middleName":"","lastName":"Wallin","suffix":""},{"id":1617809,"identity":"cad0fba1-d3c0-48e5-987e-a82bf1c9bc49","order_by":1,"name":"Eva Jansson","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Eva","middleName":"","lastName":"Jansson","suffix":""},{"id":1617810,"identity":"db754294-db6e-4c6a-840c-f10415858f78","order_by":2,"name":"Carin Wallquist","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Carin","middleName":"","lastName":"Wallquist","suffix":""},{"id":1617811,"identity":"124a1d50-a007-4af5-8d79-83cb6b2f99d7","order_by":3,"name":"Britta Hylander Rössner","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Britta","middleName":"Hylander","lastName":"Rössner","suffix":""},{"id":1617812,"identity":"65f4f7f7-209a-4c76-bb22-25f9c377316d","order_by":4,"name":"Stefan H Jacobson","email":"","orcid":"","institution":"Karolinska Institutet Institute of Environmental Medicine","correspondingAuthor":false,"prefix":"","firstName":"Stefan","middleName":"H","lastName":"Jacobson","suffix":""},{"id":1617813,"identity":"c7a2257d-729e-48d3-883a-8f890a7ba36f","order_by":5,"name":"Anette Rickenlund","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Anette","middleName":"","lastName":"Rickenlund","suffix":""},{"id":1617814,"identity":"77288c5e-eccb-4356-95bb-04faddfc0ca6","order_by":6,"name":"Maria J Eriksson","email":"","orcid":"","institution":"Karolinska Institutet Institute of Environmental Medicine","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"J","lastName":"Eriksson","suffix":""}],"badges":[],"createdAt":"2019-12-05 14:26:55","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.2.18456/v2","doiUrl":"https://doi.org/10.21203/rs.2.18456/v2","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12882-020-02110-2","type":"published","date":"2020-11-11T15:02:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":2035469,"identity":"f739a248-98c5-4c9b-b5ca-68e3bd17fd9a","added_by":"auto","created_at":"2020-08-22 00:45:10","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":132561,"visible":true,"origin":"","legend":"Study population at baseline and 5-year-follow up.","description":"","filename":"studypop.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9076/v2/studypop.jpg"},{"id":13584613,"identity":"8b42ea07-30c7-494a-9b29-9aaec3948883","added_by":"auto","created_at":"2021-09-17 04:40:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1273853,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9076/v2/24b82c27-4138-4059-9281-6299418fc139.pdf"},{"id":2035471,"identity":"6a756b22-7d2e-4e2d-a0d3-ee900a82494c","added_by":"auto","created_at":"2020-08-22 00:45:10","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":92672,"visible":true,"origin":"","legend":"","description":"","filename":"STROBEchecklistcombined200817.doc","url":"https://assets-eu.researchsquare.com/files/rs-9076/v2/STROBEchecklistcombined200817.doc"}],"financialInterests":"","formattedTitle":"Aerobic exercise capacity is maintained over a 5-year period in mild-to-moderate chronic kidney disease: A longitudinal study","fulltext":[{"header":"Background","content":" \u003cp\u003eWe and others have previously shown that aerobic exercise capacity (ExCap), measured as peak oxygen uptake (VO\u003csub\u003e2\u003c/sub\u003epeak) or peak ExCap, is already reduced in the early stages of non-dialysis chronic kidney disease (CKD) [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Reduced VO\u003csub\u003e2\u003c/sub\u003epeak is associated with increased mortality in CKD and reduced physical capacity has a negative impact on daily-life activities [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Aerobic ExCap is influenced by the function of most organ systems, particularly the cardiovascular and muscular systems. The cause of the reduced ExCap in CKD is likely multifactorial and may differ between different stages of CKD. Anaemia, autonomic dysfunction, vascular dysfunction, cardiac and skeletal muscle abnormalities may all contribute to exercise intolerance in non-dialysis CKD [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. We recently showed that aerobic ExCap in patients with mild to severe CKD stages 2\u0026ndash;5 was mainly associated with systemic oxygen delivery factors, in particular peak heart rate (HR) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough renal function declines over time in most individuals with CKD, the rate of progression differs, and some individuals do not show any progression at all [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Surprisingly little is known about how aerobic ExCap and muscle strength and mass change over time in individuals with non-dialysis CKD and how this correlates with changes in renal function. Leikis et al. found that in patients with CKD stages 3\u0026ndash;4, both leg strength and VO\u003csub\u003e2\u003c/sub\u003epeak declined over a two-year period as glomerular filtration rate (GFR) declined, despite stable haemoglobin levels [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The progression of muscle wasting in CKD seems to be highly variable, although few data are available [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Physical activity levels of individuals with CKD are generally low and are increasingly reduced in the later stages of CKD [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. A sedentary lifestyle most likely contributes to a further reduction in aerobic ExCap in patients with CKD, and vice versa.\u003c/p\u003e \u003cp\u003eGiven the high incidence of cardiovascular disease in CKD [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and the higher mortality associated with reduced aerobic ExCap [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], it is of interest to monitor aerobic ExCap. The main aim of this study was to investigate the change in aerobic ExCap over 5\u0026nbsp;years in individuals with CKD stages 2\u0026ndash;3 who were closely monitored at a nephrology clinic. Furthermore, we wanted to study the changes in possible determinants of ExCap in CKD, such as cardiovascular function, muscle strength, lean body mass (LBM), physical activity level and kidney function during the same period of time.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003eThe current analyses are part of a larger, prospective, single-centre cohort study, PROGRESS 2002, investigating factors impacting the progress of renal insufficiency. The details of this study have been described previously [8].\u003c/p\u003e\n\u003ch2\u003eStudy protocol\u003c/h2\u003e\n\u003cp\u003eWe included 52 patients with non-dialysis CKD stage 2\u0026ndash;3 (CKD; aged 18\u0026ndash;65 years) and 54 healthy controls who had completed an exercise test at baseline. The cohort has been monitored over a follow-up of 5 years. GFR was measured by iohexol plasma clearance [19]. During follow-up, GFR measurement by iohexol was repeated in the CKD group. In both CKD and controls, estimated GFR (eGFR) was calculated using the Chronic Kidney Disease\u0026ndash;Epidemiology Collaboration (CKD\u0026ndash;EPI) equation. This equation was chosen because it has been shown to provide a the most precise estimate of filtration capacity in the range of mild CKD [20]. The methodological considerations have been described in detail elsewhere [21].\u003c/p\u003e\n\u003cp\u003ePatients were recruited consecutively from the outpatient clinic at the Department of Renal Medicine at the Karolinska University Hospital during 2002\u0026ndash;2009 if they had renal function corresponding to CKD stage 2\u0026ndash;3a as defined by the National Kidney Foundation [22]. The controls, matched for age and sex with the CKD 2\u0026ndash;3 group, were randomly selected from the Swedish Total Population Register or recruited through the website of the regional University Hospital. The exclusion criteria for all participants were current malignancy, kidney transplantation or kidney donation, or blood-transmitted disease. The inclusion criteria for the controls were absence of kidney disease, cardiovascular disease, diabetes or any chronic medication. After inclusion, all participants underwent clinical investigation, anthropometric measurement, an exercise stress test, a handgrip strength test, laboratory testing, carotid ultrasound, transthoracic echocardiography and a body composition scan. The participants with CKD were closely monitored and treated aggressively for hypertension, hyperlipidaemia and proteinuria at the Department of Renal Medicine.\u003c/p\u003e\n\u003cp\u003eThe study population and the excluded individuals are presented in Figure 1. Two participants in the CKD group died from cancer before the end of the follow-up period. No patient in the CKD group progressed to renal replacement therapy within the follow-up period. However, several patients were lost to follow-up. At year 5, 49 participants in the CKD group and 43 in the control group participated in the examinations. Forty-six participants in the CKD group and 40 in the control group performed an exercise test; however, one participant with CKD was excluded from the follow-up exercise test analysis because the exercise test was terminated early owing to the occurrence of atrial fibrillation with a high HR. Two other participants with CKD had atrial fibrillation before and during the exercise test; therefore, these individuals were not included in the peak HR analyses.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig. 1\u003c/strong\u003e\u003cem\u003e. \u003c/em\u003eStudy population at baseline and 5-year-follow up.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study protocol was reviewed and approved by the Local Ethics Committee and Institutional Review Board of the Karolinska Institutet at the Karolinska University Hospital. All participants gave their written informed consent.\u003c/p\u003e\n\u003ch2\u003eMeasurements\u003c/h2\u003e\n\u003cp\u003e\u003cem\u003eAerobic exercise capacity\u003c/em\u003e. A symptom-limited incremental cycle ergometer test on an electronically braked cycle ergometer (RE990; Rodby Innovation AB, Uppsala, Sweden) was administered according to clinical standards. The initial workload and workload increase/minute (10, 15 or 20 W) were individualized with the goal of achieving symptom limitation within 6 to 10 minutes. Participants were instructed to cycle at a speed of 60 rpm and were encouraged to continue cycling until exhaustion. Perceived exertion was reported as the highest rating on the Borg CR10 scale for either leg fatigue, dyspnoea or general exhaustion as a limiting symptom [23]. Aerobic ExCap was defined as the peak workload in W. Continuous 12-lead electrocardiography was used to measure HR and for ST\u0026ndash;T-segment monitoring and safety purposes. Resting HR was measured in the supine position before the exercise test. Predicted peak HR was calculated as 220 minus age. HR reserve was defined as the difference between peak and resting HR.\u003c/p\u003e\n\u003cp\u003eMuscular function\u003cem\u003e. \u003c/em\u003eA handheld dynamometer (Grip-A; Takei Scientific Instruments Co., Ltd, Tokyo, Japan) was used to measure maximum voluntary isometric contraction as a measure of handgrip strength. The test was performed with the participant in a standing position. The measurement was repeated three times using the dominant arm, and the highest value was recorded as handgrip strength.\u003c/p\u003e\n\u003cp\u003eCardiac and vascular function. Echocardiography was performed with the participant in the supine left decubitus position and according to current guidelines [24]. The images were acquired using an ultrasound scanner (Sequoia 512; Siemens Medical Solutions, Mountain View, CA, USA) with an appropriate transducer. Cardiac function was evaluated and expressed for systolic left-ventricular (LV) function as ejection fraction (EF), for right-ventricular systolic function as tricuspid annular plane systolic excursion (TAPSE) and for diastolic LV function as an E/\u0026eacute; ratio (mitral flow velocity E, divided by tissue LV velocity \u0026eacute;). Carotid artery ultrasound was performed to assess arterial stiffness. Measurements of the diameter of the right common carotid artery and calculations of the pressure strain elastic modulus (Ep) were performed according to a standardized protocol [8].\u003c/p\u003e\n\u003cp\u003eAmbulatory blood pressure monitoring was performed over 24 hours from morning to morning using Spacelab 90217 (Spacelab Healthcare, Issaquah, Washington, USA) and a cuff of appropriate size on the non-dominant arm. Blood pressure was measured three times per hour day and night.\u003c/p\u003e\n\u003cp\u003eBody composition. Body composition was measured with a whole-body dual-energy X-ray absorptiometry scan to determine LBM (QDR 4500 Discovery A, software version 12.3; Hologic, Bedford, MA, USA). Only the CKD group were examined at follow-up.\u003c/p\u003e\n\u003cp\u003ePhysical activity level. Physical activity level was rated by the participants using a four-point scale modified from the Saltin\u0026ndash;Grimby Physical Activity Level Scale as follows [25]:\u003c/p\u003e\n\u003cp\u003eLevel 1 = \u003cem\u003eRegular exercise\u003c/em\u003e: running, swimming, tennis, badminton, gymnastics or similar activity on three or more occasions per week; every session should last at least 30 min and cause sweating.\u003c/p\u003e\n\u003cp\u003eLevel 2 = \u003cem\u003eModerate amount of regular exercise\u003c/em\u003e: running, swimming, tennis, badminton, gymnastics or similar activity on 1\u0026ndash;2 occasions per week; every session should last at least 30 minutes and cause sweating.\u003c/p\u003e\n\u003cp\u003eLevel 3 = \u003cem\u003eLight exercise\u003c/em\u003e: walking or cycling or other physical activity during at least 2 h per week, usually without sweating; this includes walking or cycling to/from work, Sunday walks, gardening, fishing, table tennis and bowling or similar activity.\u003c/p\u003e\n\u003cp\u003eLevel 4 = \u003cem\u003eSedentary\u003c/em\u003e: mostly reading, watching television, movies or other sedentary activities, or walking, cycling or light exercise for less than 2 h per week.\u003c/p\u003e\n\u003cp\u003eBlood samples. Haemoglobin, creatinine and high-sensitivity C-reactive protein (hs-CRP) concentration were measured in venous blood obtained using routine laboratory methods at the Karolinska University Laboratory at the inclusion visit before the exercise test.\u003c/p\u003e\n\u003ch2\u003eStatistical analysis\u003c/h2\u003e\n\u003cp\u003eContinuous variables are presented as mean and standard deviation, and categorical variables as number and percentage of the study sample. Variables with a skewed distribution are presented as median and interquartile range. The normality assumption was assessed graphically using histograms. Potential outliers were examined graphically by box plots and their validity were assessed. Logarithmic transformation was performed for variables with a skewed distribution when they were analysed in mixed models. Group comparisons at baseline were performed using Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test or Mann\u0026ndash;Whitney \u003cem\u003eU\u003c/em\u003e-test when the assumptions of normality and homogeneity were not fulfilled. For categorical variables, a chi-square test was used. Wilcoxon\u0026rsquo;s signed-rank test for related samples was used to assess the change over time for ordinal data. Statistical significance was defined as a \u003cem\u003ep\u003c/em\u003e-value \u0026lt; 0.05 for a two-tailed test.\u003c/p\u003e\n\u003cp\u003eLinear mixed models were considered to be the most suitable method for the analysis of longitudinal data because this method provides effect estimates from the whole study sample provided that the values missing at follow-up are random. Changes over time were analysed in CKD and controls and the changes were compared between the groups by the interaction factor group \u0026acute; time in the mixed model. The analyses were adjusted for different background factors (depending on the chosen outcome variable), including age at baseline, sex, height and beta-blocker use.\u003c/p\u003e\n\u003cp\u003eTo analyse longitudinal data where the outcome variables were ordered categoricals, generalized estimating equations (GEE) model were used. The model was set up with the same factors as in the mixed linear model mentioned above. The parameter estimates from the GEE model are presented as odds ratios (OR) and 95% confidence intervals (CI).\u003c/p\u003e\n\u003cp\u003ePearson (r) or Spearman (r\u003csub\u003es\u003c/sub\u003e) correlation coefficients were used to analyse the relationship between two variables.\u003c/p\u003e\n\u003cp\u003eStatistical analyses were performed using IBM SPSS Statistics (version 23.0; IBM, Armonk, NY, USA) and SAS (version 9.3; SAS Institute, Cary, NC, USA) software.\u003c/p\u003e"},{"header":"Results","content":" \u003cp\u003eThe baseline characteristics of the study participants are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The mean age of the whole cohort at entry was 47\u0026nbsp;years and there were no significant differences between the CKD group and controls in age, sex or body size.\u003c/p\u003e \u003cp\u003eBased on their GFR, 31 individuals in the CKD group were in CKD stage 2 and 21 in CKD stage 3\u0026nbsp;at baseline. At follow-up, two individuals in the CKD group were in stage 1; nine in stage 2; 27 in stage 3; five in stage 4; and one was in stage 5. Ten individuals in the CKD group had diabetes at inclusion and follow-up and two in the control group had developed diabetes at follow-up. At baseline, 10 individuals in the CKD group were on beta-blocker treatment. At follow-up, this number had increased to 15 and four of the controls had started beta-blocker treatment.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cdiv class=\"SimplePara\"\u003eBaseline characteristics.\u003c/div\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eVariable\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eControls\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003eCKD\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e-value\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSubjects (n)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e54\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e52\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eAge (years)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e48\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e47\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.7\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale, n (%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e33 (61)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e32 (61)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.8\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eHeight (cm)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e176\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e174\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.4\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eWeight (kg)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e77\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e76\u0026thinsp;\u0026plusmn;\u0026thinsp;16\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e24.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e25.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.2\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eLean body mass (kg)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e54\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e52\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.5\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eGFR (mL/min/1.73\u0026nbsp;m\u003csup\u003e2\u003c/sup\u003e)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e99\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e60.3\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u0026lt;\u0026thinsp;0.001\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eeGFR (mL/min/1.73\u0026nbsp;m\u003csup\u003e2\u003c/sup\u003e)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e96\u0026thinsp;\u0026plusmn;\u0026thinsp;13.2\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e59\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u0026lt;\u0026thinsp;0.001\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eHaemoglobin (g/dL)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e14.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e13.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.02\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eHs-CRP (mg/L)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.89 (0.47\u0026ndash;2.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.60 (0.86\u0026ndash;3.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.04\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eDiabetes, n (%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e10 (22)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003eNA\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e24-h SBP (mmHg)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e124\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e122\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.4\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e24-h DBP (mmHg)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e78\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e76\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.4\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eAetiology of CKD, n (%)\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eFamilial/hereditary/congenital disease\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e14 (27)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003eNA\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePrimary glomerulonephritis\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e17 (33)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003eNA\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSecondary glomerular/systemic disease\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e9 (17)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003eNA\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eMiscellaneous/unknown\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e12 (23)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003eNA\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eMedication, n (%)\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eBeta blocker\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e10 (19)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003eNA\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eDiuretics\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e12 (23)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003eNA\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eACE inhibitors\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e22 (42)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003eNA\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eAngiotensin II blockers\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e21 (39)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003eNA\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eCalcium-channel blockers\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e10 (19)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003eNA\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eESA\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e1 (2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003eNA\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eOral cortisone\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e2 (4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003eNA\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eIron supplementation\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e4 (8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003eNA\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eFunctional measurements\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePeak workload (W)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e238\u0026thinsp;\u0026plusmn;\u0026thinsp;60\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e193\u0026thinsp;\u0026plusmn;\u0026thinsp;63\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u0026lt;\u0026thinsp;0.001\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePeak HR (bpm)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e177\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e161\u0026thinsp;\u0026plusmn;\u0026thinsp;24\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u0026lt;\u0026thinsp;0.001\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePeak RPE\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e8.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.2\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eHandgrip strength (kg)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e44\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e40\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.08\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eBMI\u003c/span\u003e body mass index; \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ebpm\u003c/span\u003e beats per minute; \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eCKD\u003c/span\u003e chronic kidney disease; \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eeGFR\u003c/span\u003e glomerular filtration rate estimated by CKD\u0026ndash;EPI; \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eESA\u003c/span\u003e erythropoiesis-stimulating agents; \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eGFR\u003c/span\u003e glomerular filtration rate measured by iohexol clearance; \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eHR\u003c/span\u003e heart rate; \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ehs-CRP\u003c/span\u003e high-sensitivity C-reactive protein; \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003en\u003c/span\u003e number; \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003e24-h SBP\u003c/span\u003e/\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eDBP\u003c/span\u003e average 24-h systolic/diastolic blood pressure\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eValues reported as number (percentage), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median (interquartile range). \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eP\u003c/span\u003e-value: \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003et\u003c/span\u003e-test, Mann\u0026ndash;Whitney \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eU\u003c/span\u003e-test (continuous variables) or chi-square (categorical values).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRenal function and blood analyses\u003c/p\u003e \u003cp\u003eAt baseline, GFR measured by iohexol clearance was 60.3\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2\u0026nbsp;mL/min/1.73\u0026nbsp;m\u003csup\u003e2\u003c/sup\u003e in CKD and 99.5\u0026thinsp;\u0026plusmn;\u0026thinsp;12.5\u0026nbsp;mL/min/1.73\u0026nbsp;m\u003csup\u003e2\u003c/sup\u003e in the controls (\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). At follow-up, measured GFR in the CKD group was 50.2\u0026thinsp;\u0026plusmn;\u0026thinsp;16.9\u0026nbsp;mL/min/1.73\u0026nbsp;m\u003csup\u003e2\u003c/sup\u003e, a mean decline of 17% over 5\u0026nbsp;years. eGFR values at baseline and follow-up were calculated by CKD\u0026ndash;EPI for both CKD and controls. A significant decrease in eGFR was seen between baseline and year 5 for both groups; the difference in the change in eGFR over time between the groups was borderline significant (interaction group \u0026sdot; time, \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.05) (Table\u0026nbsp;2). The annual rate of decline in eGFR was 1.8\u0026nbsp;mL/min/1.73\u0026nbsp;m\u003csup\u003e2\u003c/sup\u003e in the CKD group and 0.8\u0026nbsp;mL/min/1.73\u0026nbsp;m\u003csup\u003e2\u003c/sup\u003e in the control group.\u003c/p\u003e \u003cp\u003eHaemoglobin was significantly lower in the CKD group than in controls at both time points, but increased significantly over time in both groups. This change did not differ significantly over time between the groups (Table\u0026nbsp;2). However, separate analyses in men and women using the paired samples \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003et\u003c/span\u003e-test showed that haemoglobin increased significantly in women (\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.001) but not in men (\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.2).\u003c/p\u003e \u003cp\u003eHs-CRP was higher in the CKD group than in controls at each time point, but no significant change over time was seen in either CKD or controls.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eTable\u0026nbsp;2\u003c/span\u003e. Functional measurements at baseline and 5-year follow-up.\u003c/p\u003e \u003cp\u003eExercise test results\u003c/p\u003e \u003cp\u003eAerobic ExCap and peak HR were both significantly lower in CKD than in controls at both time points, and did not change significantly over time in neither CKD nor controls (Table\u0026nbsp;2, mixed model with values adjusted for covariates). In CKD, there was a non-significant average decline in ExCap of 2.6%. The non-significant decline in peak HR in the CKD group was 0.6%. In controls, the mean values of ExCap showed a non-significant decrease of 1.7% and peak HR significantly decreased by an average of 2.3%. There was no significant difference in the rating of perceived exertion (RPE) between the groups at baseline. At follow-up, the mean ratings were 8.3 for CKD and 8.5 for controls (\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.7 between groups).\u003c/p\u003e \u003cp\u003eMuscle strength and lean body mass\u003c/p\u003e \u003cp\u003eHandgrip strength was significantly lower in CKD than in controls at baseline, but not at follow-up (Table\u0026nbsp;2, mixed model). The difference in the change over time between the two groups was borderline significant (\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.06), with a significant reduction in the control group. LBM did not differ significantly between groups at baseline (CKD 52.8\u0026nbsp;kg; controls 53.5\u0026nbsp;kg, \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.3, analysed by linear mixed model) and increased from 52.8\u0026nbsp;kg to 54.5\u0026nbsp;kg (\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.02) at follow-up in the CKD group. Mean values were adjusted for the covariates of age at baseline, sex, height and weight at baseline. Weight increased from 75.7\u0026nbsp;kg to 78.3\u0026nbsp;kg (p\u0026thinsp;=\u0026thinsp;0.006, paired samples t-test) in the CKD group.\u003c/p\u003e \u003cp\u003eCardiovascular function\u003c/p\u003e \u003cp\u003eAt baseline, LV diastolic function (E/\u0026eacute; ratio), was significantly lower in the CKD group compared with controls, although within normal values; while LV systolic function (EF), right ventricular systolic function (TAPSE) and vascular stiffness (Ep) did not differ significantly between groups (Table\u0026nbsp;2, mixed model). E/\u0026eacute;, EF, TAPSE and Ep did not change significantly over 5\u0026nbsp;years in the CKD group, nor was the change over time significantly different from that in controls (Table\u0026nbsp;2). E/\u0026eacute; increased and EF decreased in controls from baseline to follow-up with values remaining within the normal range.\u003c/p\u003e \u003cp\u003eSelf-reported physical activity\u003c/p\u003e \u003cp\u003eThe results of this analysis are presented in Table\u0026nbsp;3. Self-reported physical activity levels differed between groups at baseline with controls being physically more active than CKD patients. At follow-up, there was no significant difference in physical activity level between groups. Individuals with CKD reported higher physical activity levels at follow-up compared with baseline while controls reported lower physical activity levels at follow-up compared with baseline. The interaction group x time was statistically significant (\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.0002), indicating that the two groups differed regarding their change in physical activity level over time.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eTable\u0026nbsp;3. Change in physical activity (PA) level between baseline and 5-year follow-up.\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eOdds ratio\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eConfidence interval\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003e-value\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003csup\u003ea\u003c/sup\u003eCKD: Follow-up vs. baseline\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e2.12\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.26\u0026ndash;3.56\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.0047\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003csup\u003eb\u003c/sup\u003eControls: Follow-up vs. baseline\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.54\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.35\u0026ndash;0.84\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.0057\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003csup\u003ec\u003c/sup\u003eCKD vs. controls at baseline\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.42\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.21\u0026ndash;0.86\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.0169\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003csup\u003ed\u003c/sup\u003eCKD vs. controls at follow-up\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.66\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.77\u0026ndash;3.63\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.2008\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eCKD\u003c/span\u003e chronic kidney disease.\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e\u003csup\u003ea\u003c/sup\u003e CKD: Odds for increased PA at follow-up compared with baseline.\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e\u003csup\u003eb\u003c/sup\u003e Controls: Odds for increased PA at follow-up compared with baseline.\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e\u003csup\u003ec\u003c/sup\u003e Odds for higher PA in CKD group compared with controls at baseline.\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e\u003csup\u003ed\u003c/sup\u003e Odds for higher PA in CKD group compared with controls at follow-up. Results are analysed using a generalized estimation equation. The results are based on 188 observations from 106 subjects. \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eP\u003c/span\u003e-value: chi-square test.\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCorrelations between the change in ExCap and physiological measurements\u003c/p\u003e \u003cp\u003eCorrelations between the change in aerobic ExCap and changes in selected physiological and biochemical measurements were analysed for the CKD group. There were significant correlations between the change in ExCap and changes in peak HR and handgrip strength (r\u0026thinsp;=\u0026thinsp;0.5 and 0.3 respectively, \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.001 and 0.03 respectively, n\u0026thinsp;=\u0026thinsp;43 and 45 respectively). The change in measured GFR was significantly correlated with the change in aerobic ExCap in CKD (r\u0026thinsp;=\u0026thinsp;0.3, \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.03, n\u0026thinsp;=\u0026thinsp;42). However, when eGFR was used, the correlation between the change in eGFR and the change in ExCap was not significant (r\u0026thinsp;=\u0026thinsp;0.06 and \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.7, n\u0026thinsp;=\u0026thinsp;44). The change in physical activity level did not correlate to the change in ExCap (r\u003csub\u003es\u003c/sub\u003e = \u0026minus;\u0026thinsp;0.05 and \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.7, n\u0026thinsp;=\u0026thinsp;45), nor did the change in haemoglobin level, Hs-CRP level, E/\u0026eacute; or EP (r\u0026thinsp;=\u0026thinsp;0.1, 0.03, \u0026minus;\u0026thinsp;0.08 and \u0026minus;\u0026thinsp;0.01 respectively, \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.4; 0.9, 0.6 and 0.9, respectively, n\u0026thinsp;=\u0026thinsp;45, 42, 43 and 43, respectively). For controls, there were no significant correlations between the change in ExCap and changes in peak HR, handgrip strength and eGFR (r\u0026thinsp;=\u0026thinsp;0.1, 0.1 and \u0026minus;\u0026thinsp;0.3 respectively, \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.5, 0.5 and 0.06, respectively, n\u0026thinsp;=\u0026thinsp;40, 40 and 39, respectively).\u003c/p\u003e "},{"header":"Discussion","content":" \u003cp\u003eIn this study we analysed changes in aerobic ExCap and known determinants over a 5-year period in individuals with mild-to-moderate CKD compared with healthy individuals. Individuals with CKD were recruited from a dedicated nephrology clinic and closely monitored. In these patients, aerobic ExCap, peak HR, handgrip strength, LBM, haemoglobin level and cardiovascular function were all maintained over 5 years, despite a 17% reduction in GFR over time.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, this is the first study to evaluate the change in aerobic ExCap over time in CKD patients compared with healthy controls. As expected, eGFR decreased more in CKD patients than in controls (\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e\u0026thinsp;=\u0026thinsp;0.05). Aerobic ExCap is expected to decline with age, with an average 5\u0026ndash;20% decline per decade in cross-sectional studies of healthy individuals, while longitudinal studies show a greater decline in older individuals compared with younger people [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The mean change in ExCap in our study was almost 3% over 5\u0026nbsp;years in the CKD group and a little less in the control group. Our study included some younger individuals (\u0026lt;\u0026thinsp;35\u0026nbsp;years old), which could explain the modest decline compared with those seen in previous studies of healthy individuals. An important finding from our study is that ExCap did not decline more rapidly in the CKD group attending a nephrology clinic than in the controls. Reductions in peak HR and peripheral oxygen utilization but not stroke volume appear to mediate the normal age-associated decline in aerobic ExCap [\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The expected decline in peak HR with normal aging is not as pronounced as the decline in aerobic ExCap of 4\u0026ndash;6% per decade that was reported by Fleg et al. [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], which is similar to our data for the controls. The reduction in peak HR in the CKD group was only 0.6%. For the CKD group, there was a significant correlation between the change in ExCap over 5\u0026nbsp;years and the change in peak HR, which was not seen in the control group. This suggests that peak HR, or the possibility of achieving a high peak HR, could be an important factor influencing ExCap in this CKD group. Peripheral oxygen utilization and maximal stroke volume were not measured in our study, however a measure of diastolic function, E/\u0026eacute;, decreased in controls but not in CKD patients over 5\u0026nbsp;years. Diastolic dysfunction may lead to an inability to increase stroke volume at exercise through the Frank\u0026ndash;Starling mechanism and a preserved diastolic function at rest might indicate that maximal stroke volume was also preserved.\u003c/p\u003e \u003cp\u003eWhile both aerobic ExCap and peak HR are known to be more reduced in the later stages of CKD than in the earlier stages [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], only one small study has reported the changes in aerobic ExCap over time in non-dialysis CKD patients [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. That study found a reduction in VO\u003csub\u003e2\u003c/sub\u003epeak of 9% over two years, a stable haemoglobin level and a fall of 28% in the calculated creatinine clearance. As a decline in leg strength paralleled the reduction in VO\u003csub\u003e2\u003c/sub\u003epeak, the authors speculated that the reduction in VO\u003csub\u003e2\u003c/sub\u003epeak was likely related to intrinsic muscle changes. However, peak HR decreased with a mean value of 9 over only two years, which may also have influenced aerobic ExCap in that study. The difference between the results of our study compared with that study may in part be explained by the higher mean GFR in our study (at baseline, 60 versus 31\u0026nbsp;mL/min/1.73\u0026nbsp;m\u003csup\u003e2\u003c/sup\u003e) and the smaller decline in GFR over time. Furthermore, handgrip strength and LBM did not decrease over 5\u0026nbsp;years in the CKD group in our study. Grip strength is known to be reduced in non-dialysis CKD patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] and to further decrease in conjunction with the progression of CKD [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Muscle wasting seems to be more pronounced in patients with dialysis-dependent CKD than in those with non-dialysis CKD [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. However, John et al. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] showed a highly variable course of the change in muscle cross-sectional area over two years, and the rate of muscle loss was actually more pronounced in non-dialysis CKD patients than in patients on dialysis. Compared with the non-dialysis CKD group in our study, the non-dialysis CKD group in the study by John et al. had more advanced CKD with a substantially lower eGFR (16\u0026nbsp;mL/min/1.73\u0026nbsp;m\u003csup\u003e2\u003c/sup\u003e), which might explain the discrepancy between the results.\u003c/p\u003e \u003cp\u003eOverall, at the group level, the individuals with CKD in our study were very stable in all measured parameters: i.e., cardiovascular, muscular and haematological. Cardiac function and vascular stiffness showed no significant change over time in the CKD group, while the controls significantly decreased their cardiac diastolic and systolic function and their peak HR. The changes in the control group can be considered to be the result of normal aging. Data from our group show that in the same cohort, daytime systolic blood pressure did not increase over 5\u0026nbsp;years in the CKD group, while a small but significant increase was seen in the controls [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. According to the Fick principle, aerobic ExCap is the result of oxygen delivery and oxygen extraction mechanisms, which are highly dependent on the function of the cardiovascular system and skeletal musculature. Given the lack of progression in outcomes representing the function of these systems, it is not surprising that aerobic ExCap did not decrease significantly in the CKD group. A reduced level of physical activity may contribute to a decline in ExCap, but physical activity actually increased in the CKD group, perhaps further contributing to the maintenance of their ExCap. The opposite was seen in the control group, who significantly decreased their physical activity over 5\u0026nbsp;years.\u003c/p\u003e \u003cp\u003eThe participants with mild-to-moderate CKD in our study were recruited from a dedicated nephrology clinic and showed well-controlled blood pressure over time [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The CKD group was monitored more closely than the controls, with aggressive treatment of hypertension, hyperlipidaemia and proteinuria. These factors may explain the fact that this group could maintain their cardiovascular and muscular function and thereby their aerobic ExCap. The mean decline in GFR over time was comparable to or a little lower than values reported in other studies [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Interestingly, Jones et al. reported that GFR decline slowed significantly following referral to a nephrology clinic, indicating that interventions to slow progression of CKD are important and beneficial. The decline of GFR in the control group was not more pronounced than expected in healthy individuals [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere are some important limitations of our study. The study groups were relatively small at baseline and were further reduced at follow-up. To overcome the problem with subjects lost to follow-up, statistical analyses were performed using linear mixed models to compensate for missing values. We measured aerobic ExCap as peak workload and not VO\u003csub\u003e2\u003c/sub\u003epeak during exercise. However, given the linear relationship between exercise load and oxygen uptake during cycle ergometry [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], and the fact that the tests were performed according to the same protocol at both time-points with similar high RPEs, we believe our results are a valid measurement of the true changes in aerobic ExCap and peak HR over time.\u003c/p\u003e "},{"header":"Conclusions","content":" \u003cp\u003eIndividuals with mild-to-moderate CKD maintained their aerobic ExCap over a 5-year-period. Known determinants of aerobic ExCap such as peak HR, haemoglobin level, muscle strength and cardiac diastolic function were also preserved over the 5\u0026nbsp;years. Possible explanations for this include attendance at a specialist nephrology clinic with tight monitoring and an increase in self-reported physical activity level over 5\u0026nbsp;years.\u003c/p\u003e "},{"header":"Abbreviations","content":" \u003cp\u003eCI, confidence interval; CKD: Chronic kidney disease; CKD\u0026ndash;EPI, Chronic Kidney Disease\u0026ndash;Epidemiology Collaboration; E/\u0026eacute;: Mitral flow velocity E divided by tissue LV velocity \u0026eacute;; EF: Ejection fraction; eGFR: Estimated GFR; Ep: Pressure strain elastic modulus in the carotid artery; ExCap: Exercise capacity; GEE, Generalized estimating equations; GFR: Glomerular filtration rate; Hs-CRP: high-sensitivity C-reactive protein; HR: Heart rate; LBM: Lean body mass; LV: Left ventricular; OR, odds ratio; RPE: Rating of perceived exertion; TAPSE: tricuspid annular plane systolic excursion; VO\u003csub\u003e2\u003c/sub\u003epeak: Peak oxygen uptake\u003c/p\u003e "},{"header":"Declarations","content":" \u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eThe study protocol was reviewed and approved by the Local Ethics Committee and Institutional Review Board of the Karolinska Institutet at the Karolinska University Hospital. All participants gave their written informed consent.\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThe study was supported by grants from the Stockholm County Council, grant numbers 20150555 and 20120628 received by MJE and grants from the Swedish Kidney Foundation, grant number F2017-0048 received by AR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026rsquo; contributions\u003c/h2\u003e\n\u003cp\u003eHW performed all statistical analyses and prepared the original draft of the manuscript. HW, AR, ME and EJ interpreted the data and contributed to substantial revision of the manuscript. SJ, CW, BHR and ME designed the study and contributed to data acquisition. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eWe thank the staff and participants of the PROGRESS study, especially Research Nurse/PhL Agneta Aspegren-Pagels for her important contributions. The authors acknowledge Elisabeth Berg for assistance with statistical analysis of data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWallin H, Asp AM, Wallquist C, Jansson E, Caidahl K, Hylander Rossner B, Jacobson SH, Rickenlund A, Eriksson MJ: \u003cstrong\u003eGradual reduction in exercise capacity in chronic kidney disease is associated with systemic oxygen delivery factors\u003c/strong\u003e. \u003cem\u003ePLoS One \u003c/em\u003e2018, \u003cstrong\u003e13\u003c/strong\u003e(12):e0209325.\u003c/li\u003e\n\u003cli\u003eChinnappa S, White E, Lewis N, Baldo O, Tu YK, Glorieux G, Vanholder R, El Nahas M, Mooney A: \u003cstrong\u003eEarly and asymptomatic cardiac dysfunction in chronic kidney disease\u003c/strong\u003e. \u003cem\u003eNephrol Dial Transplant \u003c/em\u003e2018, \u003cstrong\u003e33\u003c/strong\u003e(3):450-458.\u003c/li\u003e\n\u003cli\u003eVan Craenenbroeck AH, Van Craenenbroeck EM, Van Ackeren K, Hoymans VY, Verpooten GA, Vrints CJ, Couttenye MM: \u003cstrong\u003eImpaired vascular function contributes to exercise intolerance in chronic kidney disease\u003c/strong\u003e. \u003cem\u003eNephrol Dial Transplant \u003c/em\u003e2016, \u003cstrong\u003e31\u003c/strong\u003e(12):2064-2072.\u003c/li\u003e\n\u003cli\u003eSietsema KE, Amato A, Adler SG, Brass EP: \u003cstrong\u003eExercise capacity as a predictor of survival among ambulatory patients with end-stage renal disease\u003c/strong\u003e. \u003cem\u003eKidney Int \u003c/em\u003e2004, \u003cstrong\u003e65\u003c/strong\u003e(2):719-724.\u003c/li\u003e\n\u003cli\u003eHeiwe S, Clyne N, Dahlgren MA: \u003cstrong\u003eLiving with chronic renal failure: patients' experiences of their physical and functional capacity\u003c/strong\u003e. \u003cem\u003ePhysiother Res Int \u003c/em\u003e2003, \u003cstrong\u003e8\u003c/strong\u003e(4):167-177.\u003c/li\u003e\n\u003cli\u003eOdden MC, Whooley MA, Shlipak MG: \u003cstrong\u003eAssociation of chronic kidney disease and anemia with physical capacity: the heart and soul study\u003c/strong\u003e. \u003cem\u003eJ Am Soc Nephrol \u003c/em\u003e2004, \u003cstrong\u003e15\u003c/strong\u003e(11):2908-2915.\u003c/li\u003e\n\u003cli\u003eClyne N, Hellberg M, Kouidi E, Deligiannis A, Hoglund P: \u003cstrong\u003eRelationship between declining glomerular filtration rate and measures of cardiac and vascular autonomic neuropathy\u003c/strong\u003e. \u003cem\u003eNephrology (Carlton) \u003c/em\u003e2016, \u003cstrong\u003e21\u003c/strong\u003e(12):1047-1055.\u003c/li\u003e\n\u003cli\u003eAsp AM, Wallquist C, Rickenlund A, Hylander B, Jacobson SH, Caidahl K, Eriksson MJ: \u003cstrong\u003eCardiac remodelling and functional alterations in mild-to-moderate renal dysfunction: comparison with healthy subjects\u003c/strong\u003e. \u003cem\u003eClin Physiol Funct Imaging \u003c/em\u003e2015, \u003cstrong\u003e35\u003c/strong\u003e(3):223-230.\u003c/li\u003e\n\u003cli\u003eOtsuka T, Suzuki M, Yoshikawa H, Sugi K: \u003cstrong\u003eLeft ventricular diastolic dysfunction in the early stage of chronic kidney disease\u003c/strong\u003e. \u003cem\u003eJ Cardiol \u003c/em\u003e2009, \u003cstrong\u003e54\u003c/strong\u003e(2):199-204.\u003c/li\u003e\n\u003cli\u003eConjard A, Ferrier B, Martin M, Caillette A, Carrier H, Baverel G: \u003cstrong\u003eEffects of chronic renal failure on enzymes of energy metabolism in individual human muscle fibers\u003c/strong\u003e. \u003cem\u003eJ Am Soc Nephrol \u003c/em\u003e1995, \u003cstrong\u003e6\u003c/strong\u003e(1):68-74.\u003c/li\u003e\n\u003cli\u003eAl-Aly Z, Zeringue A, Fu J, Rauchman MI, McDonald JR, El-Achkar TM, Balasubramanian S, Nurutdinova D, Xian H, Stroupe K\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eRate of kidney function decline associates with mortality\u003c/strong\u003e. \u003cem\u003eJ Am Soc Nephrol \u003c/em\u003e2010, \u003cstrong\u003e21\u003c/strong\u003e(11):1961-1969.\u003c/li\u003e\n\u003cli\u003eJones C, Roderick P, Harris S, Rogerson M: \u003cstrong\u003eDecline in kidney function before and after nephrology referral and the effect on survival in moderate to advanced chronic kidney disease\u003c/strong\u003e. \u003cem\u003eNephrol Dial Transplant \u003c/em\u003e2006, \u003cstrong\u003e21\u003c/strong\u003e(8):2133-2143.\u003c/li\u003e\n\u003cli\u003eLeikis MJ, McKenna MJ, Petersen AC, Kent AB, Murphy KT, Leppik JA, Gong X, McMahon LP: \u003cstrong\u003eExercise performance falls over time in patients with chronic kidney disease despite maintenance of hemoglobin concentration\u003c/strong\u003e. \u003cem\u003eClin J Am Soc Nephrol \u003c/em\u003e2006, \u003cstrong\u003e1\u003c/strong\u003e(3):488-495.\u003c/li\u003e\n\u003cli\u003eJohn SG, Sigrist MK, Taal MW, McIntyre CW: \u003cstrong\u003eNatural history of skeletal muscle mass changes in chronic kidney disease stage 4 and 5 patients: an observational study\u003c/strong\u003e. \u003cem\u003ePLoS One \u003c/em\u003e2013, \u003cstrong\u003e8\u003c/strong\u003e(5):e65372.\u003c/li\u003e\n\u003cli\u003eJohansen KL, Chertow GM, Ng AV, Mulligan K, Carey S, Schoenfeld PY, Kent-Braun JA: \u003cstrong\u003ePhysical activity levels in patients on hemodialysis and healthy sedentary controls\u003c/strong\u003e. \u003cem\u003eKidney Int \u003c/em\u003e2000, \u003cstrong\u003e57\u003c/strong\u003e(6):2564-2570.\u003c/li\u003e\n\u003cli\u003eHawkins MS, Sevick MA, Richardson CR, Fried LF, Arena VC, Kriska AM: \u003cstrong\u003eAssociation between physical activity and kidney function: National Health and Nutrition Examination Survey\u003c/strong\u003e. \u003cem\u003eMed Sci Sports Exerc \u003c/em\u003e2011, \u003cstrong\u003e43\u003c/strong\u003e(8):1457-1464.\u003c/li\u003e\n\u003cli\u003eSarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, McCullough PA, Kasiske BL, Kelepouris E, Klag MJ\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eKidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention\u003c/strong\u003e. \u003cem\u003eCirculation \u003c/em\u003e2003, \u003cstrong\u003e108\u003c/strong\u003e(17):2154-2169.\u003c/li\u003e\n\u003cli\u003eTing SM, Iqbal H, Kanji H, Hamborg T, Aldridge N, Krishnan N, Imray CH, Banerjee P, Bland R, Higgins R\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eFunctional cardiovascular reserve predicts survival pre-kidney and post-kidney transplantation\u003c/strong\u003e. \u003cem\u003eJ Am Soc Nephrol \u003c/em\u003e2014, \u003cstrong\u003e25\u003c/strong\u003e(1):187-195.\u003c/li\u003e\n\u003cli\u003eKrutzen E, Back SE, Nilsson-Ehle I, Nilsson-Ehle P: \u003cstrong\u003ePlasma clearance of a new contrast agent, iohexol: a method for the assessment of glomerular filtration rate\u003c/strong\u003e. \u003cem\u003eJ Lab Clin Med \u003c/em\u003e1984, \u003cstrong\u003e104\u003c/strong\u003e(6):955-961.\u003c/li\u003e\n\u003cli\u003eLevey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eA new equation to estimate glomerular filtration rate\u003c/strong\u003e. \u003cem\u003eAnn Intern Med \u003c/em\u003e2009, \u003cstrong\u003e150\u003c/strong\u003e(9):604-612.\u003c/li\u003e\n\u003cli\u003eWallquist C, Mansouri L, Norrback M, Hylander B, Jacobson SH, Lundahl J: \u003cstrong\u003eEarly Changes in Monocyte Adhesion Molecule Expression and Tumor Necrosis Factor-alpha Levels in Chronic Kidney Disease - A 5-Year Prospective Study\u003c/strong\u003e. \u003cem\u003eAm J Nephrol \u003c/em\u003e2016, \u003cstrong\u003e44\u003c/strong\u003e(4):268-275.\u003c/li\u003e\n\u003cli\u003eNational Kidney F: \u003cstrong\u003eK/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification\u003c/strong\u003e. \u003cem\u003eAm J Kidney Dis \u003c/em\u003e2002, \u003cstrong\u003e39\u003c/strong\u003e(2 Suppl 1):S1-266.\u003c/li\u003e\n\u003cli\u003eBorg G: \u003cstrong\u003ePerceived exertion as an indicator of somatic stress\u003c/strong\u003e. \u003cem\u003eScand J Rehabil Med \u003c/em\u003e1970, \u003cstrong\u003e2\u003c/strong\u003e(2):92-98.\u003c/li\u003e\n\u003cli\u003eLang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eRecommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology\u003c/strong\u003e. \u003cem\u003eJ Am Soc Echocardiogr \u003c/em\u003e2005, \u003cstrong\u003e18\u003c/strong\u003e(12):1440-1463.\u003c/li\u003e\n\u003cli\u003eSaltin B, Grimby G: \u003cstrong\u003ePhysiological analysis of middle-aged and old former athletes. Comparison with still active athletes of the same ages\u003c/strong\u003e. \u003cem\u003eCirculation \u003c/em\u003e1968, \u003cstrong\u003e38\u003c/strong\u003e(6):1104-1115.\u003c/li\u003e\n\u003cli\u003eFleg JL, Strait J: \u003cstrong\u003eAge-associated changes in cardiovascular structure and function: a fertile milieu for future disease\u003c/strong\u003e. \u003cem\u003eHeart Fail Rev \u003c/em\u003e2012, \u003cstrong\u003e17\u003c/strong\u003e(4-5):545-554.\u003c/li\u003e\n\u003cli\u003eCarrick-Ranson G, Hastings JL, Bhella PS, Shibata S, Fujimoto N, Palmer D, Boyd K, Levine BD: \u003cstrong\u003eThe effect of age-related differences in body size and composition on cardiovascular determinants of VO2max\u003c/strong\u003e. \u003cem\u003eJ Gerontol A Biol Sci Med Sci \u003c/em\u003e2013, \u003cstrong\u003e68\u003c/strong\u003e(5):608-616.\u003c/li\u003e\n\u003cli\u003eFleg JL, Morrell CH, Bos AG, Brant LJ, Talbot LA, Wright JG, Lakatta EG: \u003cstrong\u003eAccelerated longitudinal decline of aerobic capacity in healthy older adults\u003c/strong\u003e. \u003cem\u003eCirculation \u003c/em\u003e2005, \u003cstrong\u003e112\u003c/strong\u003e(5):674-682.\u003c/li\u003e\n\u003cli\u003eChinnappa S, White E, Lewis N, Baldo O, Tu YK, Glorieux G, Vanholder R, El Nahas M, Mooney A: \u003cstrong\u003eEarly and asymptomatic cardiac dysfunction in chronic kidney disease\u003c/strong\u003e. \u003cem\u003eNephrol Dial Transplant \u003c/em\u003e2017.\u003c/li\u003e\n\u003cli\u003ePagels A, Heiwe S, Hylander B: \u003cstrong\u003e[Nutritional status of pre-dialysis patients]\u003c/strong\u003e. \u003cem\u003eJ Ren Care \u003c/em\u003e2006, \u003cstrong\u003e32\u003c/strong\u003e(3):162-166.\u003c/li\u003e\n\u003cli\u003eHiraki K, Yasuda T, Hotta C, Izawa KP, Morio Y, Watanabe S, Sakurada T, Shibagaki Y, Kimura K: \u003cstrong\u003eDecreased physical function in pre-dialysis patients with chronic kidney disease\u003c/strong\u003e. \u003cem\u003eClin Exp Nephrol \u003c/em\u003e2013, \u003cstrong\u003e17\u003c/strong\u003e(2):225-231.\u003c/li\u003e\n\u003cli\u003eMcIntyre CW, Selby NM, Sigrist M, Pearce LE, Mercer TH, Naish PF: \u003cstrong\u003ePatients receiving maintenance dialysis have more severe functionally significant skeletal muscle wasting than patients with dialysis-independent chronic kidney disease\u003c/strong\u003e. \u003cem\u003eNephrol Dial Transplant \u003c/em\u003e2006, \u003cstrong\u003e21\u003c/strong\u003e(8):2210-2216.\u003c/li\u003e\n\u003cli\u003eAsp AM, Wallquist C, Rickenlund A, Hylander B, Jacobson SH, Caidahl K, Eriksson MJ: \u003cstrong\u003eCardiovascular changes in patients with mild-to-moderate chronic kidney disease compared with healthy subjects: a 5-year follow-up study\u003c/strong\u003e. \u003cem\u003eClin Physiol Funct Imaging \u003c/em\u003e2019.\u003c/li\u003e\n\u003cli\u003eTsai CW, Ting IW, Yeh HC, Kuo CC: \u003cstrong\u003eLongitudinal change in estimated GFR among CKD patients: A 10-year follow-up study of an integrated kidney disease care program in Taiwan\u003c/strong\u003e. \u003cem\u003ePLoS One \u003c/em\u003e2017, \u003cstrong\u003e12\u003c/strong\u003e(4):e0173843.\u003c/li\u003e\n\u003cli\u003eBaek SD, Baek CH, Kim JS, Kim SM, Kim JH, Kim SB: \u003cstrong\u003eDoes stage III chronic kidney disease always progress to end-stage renal disease? A ten-year follow-up study\u003c/strong\u003e. \u003cem\u003eScand J Urol Nephrol \u003c/em\u003e2012, \u003cstrong\u003e46\u003c/strong\u003e(3):232-238.\u003c/li\u003e\n\u003cli\u003eWeinstein JR, Anderson S: \u003cstrong\u003eThe aging kidney: physiological changes\u003c/strong\u003e. \u003cem\u003eAdv Chronic Kidney Dis \u003c/em\u003e2010, \u003cstrong\u003e17\u003c/strong\u003e(4):302-307.\u003c/li\u003e\n\u003cli\u003e\u0026Aring;strand P-O., Rodahl K., Dahl H. A., Str\u0026oslash;mme S. B. : \u003cstrong\u003eTextbook of Work Physiology: Physiological Bases of Exercise.\u003c/strong\u003e, 4th edn. Leeds, UK: Human Kinetics; 2003.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003ctable style=\"width: 939.15pt; margin-left: -67.35pt; border-collapse: collapse;\" width=\"1252\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 21.7pt;\"\u003e\n\u003ctd style=\"width: 814.6pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 21.7pt;\" colspan=\"10\" width=\"1086\"\u003e\n\u003cp style=\"line-height: 115%; page-break-before: always;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003eTable 2. \u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003eFunctional measurements at baseline and 5-year follow-up.\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 21.7pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 21.7pt;\"\u003e\n\u003ctd style=\"width: 814.6pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 21.7pt;\" colspan=\"10\" width=\"1086\"\u003e\n\u003cp style=\"line-height: 115%; tab-stops: 212.0pt 450.25pt;\"\u003e\u003cem\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Controls\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; CKD\u003c/span\u003e\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 21.7pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 48.65pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 48.65pt;\" width=\"146\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 48.65pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eBaseline\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e(n = 54)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 48.65pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eYear 5\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 48.65pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eP\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e-value time\u003csup\u003ea\u003c/sup\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 48.65pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eBaseline\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e(n = 52)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 48.65pt;\" width=\"104\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Year 5\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 48.65pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eP\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e-value time\u003csup\u003ea\u003c/sup\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 48.65pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eP\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e-value group\u003csup\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 48.65pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eP\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e-value group*time\u003csup\u003ec\u003c/sup\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 48.65pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eCovariates\u003csup\u003ed\u003c/sup\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 48.65pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 16.0pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003ePeak workload (W)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e237 (225\u0026ndash;249)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e233 (221\u0026ndash;245)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.3\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e195 (184\u0026ndash;207)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e190 (178\u0026ndash;202)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.2\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026lt; 0.001/\u0026lt; 0.001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.8\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eAge, sex, height\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 16.0pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003en = 40\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003en = 45\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.95pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003ePeak heart rate (bpm)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e175 (171\u0026ndash;179)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e171 (167\u0026ndash;176)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.04\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e161 (157\u0026ndash;165)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e160 (155\u0026ndash;164)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.3\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026lt; 0.001/0.001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.4\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eAge, BB medication\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.95pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003en = 40\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003en = 43\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.95pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eHR reserve (bpm)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e99 (94\u0026ndash;104)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e102 (96\u0026ndash;107)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.4\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e91 (86\u0026ndash;96)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e89 (84\u0026ndash;95)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e0.5\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.03/0.002\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.2\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eAge, BB medication\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 19.95pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 20.65pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003en = 40\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003en = 43\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 20.65pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eHandgrip strength (kg)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e44(43\u0026ndash;46)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e43 (41\u0026ndash;44)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.006\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e41 (39\u0026ndash;42)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e41 (39\u0026ndash;42)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.8\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026lt; 0.001/0.07\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.06\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eAge, sex, height \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 20.65pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003en = 40\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003en = 48\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 20.65pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eLV systolic function LVEF (%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e65 (63\u0026ndash;68)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e61 (59\u0026ndash;64)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e62 (60\u0026ndash;65)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e61 (58\u0026ndash;63)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e0.1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.06/0.7\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e*\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 20.65pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003en = 41\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003en = 45\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 20.65pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 16.0pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eLV diastolic function E/\u0026eacute;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e5.0 (4.7\u0026ndash;5.4)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e5.7 (5.3\u0026ndash;6.1)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003e\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e5.6 (5.3\u0026ndash;6.0)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e5.9 (5.6\u0026ndash;6.3)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.06\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.01/0.3\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eAge\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 16.0pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003en = 43\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003en = 46\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 16.0pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eRV systolic function TAPSE (cm)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e2.5 (2.4\u0026ndash;2.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e2.5 (2.4\u0026ndash;2.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.4\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e2.3 (2.2\u0026ndash;2.4)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e2.4 (2.3\u0026ndash;2.5)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.09\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.06/0.2\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.6\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e*\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 16.0pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003en = 43\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003en = 45\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 16.0pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eVascular function\u0026nbsp;\u0026nbsp;\u0026nbsp; Ep ((N/m\u003csup\u003e2\u003c/sup\u003e) \u003c/span\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: Symbol; color: black;\"\u003e\u0026acute;\u003c/span\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e 10\u003csup\u003e4\u003c/sup\u003e)\u003csup\u003ee\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e5.8 (5.4\u0026ndash;6.3)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e6.0 (5.5\u0026ndash;6.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.5\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e6.5 (5.8\u0026ndash;7.1)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e6.8 (6.2\u0026ndash;7.4)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e0.4\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.06/0.08\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eAge\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 16.0pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black; background: yellow;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003en = 43\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003en = 47\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 17.95pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 17.95pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eeGFR (mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 17.95pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e96 (92\u0026ndash;100)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 17.95pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e92 (87\u0026ndash;96)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 17.95pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.03\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 17.95pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e59 (55\u0026ndash;62)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 17.95pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e50 (46\u0026ndash;54)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 17.95pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 17.95pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026lt; 0.001/\u0026lt; 0.001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 17.95pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 17.95pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 17.95pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 16.0pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black; background: yellow;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003en = 43\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003en = 47\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 16.0pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eHaemoglobin (g/dL)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e14.2 (13.8\u0026ndash;14.5)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e14.7 (14.3\u0026ndash;15.0)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.002\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e13.6 (13.3\u0026ndash;13.9)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e13.9 (13.6\u0026ndash;14.2)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.04\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.01/0.001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eSex\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 16.0pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black; background: yellow;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003en = 40\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003en = 49\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 16.0pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003eHs-CRP (mg/L)\u003csup\u003ee\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e1.0 (0.7\u0026ndash;1.3)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e1.0 (0.8\u0026ndash;1.3)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.9\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e1.9 (1.4\u0026ndash;2.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e1.8 (1.4\u0026ndash;2.4)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e0.8\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.002/0.006\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e0.8\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 16.0pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003en = 43\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003en = 49\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 16.0pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 15.85pt;\"\u003e\n\u003ctd style=\"width: 109.75pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 15.85pt;\" width=\"146\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.9pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 15.85pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 3.5pt 0in 3.5pt; height: 15.85pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 15.85pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.05pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 15.85pt;\" width=\"113\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 3.5pt 0in 3.5pt; height: 15.85pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-right: solid windowtext 1.0pt; padding: 0in 3.5pt 0in 3.5pt; height: 15.85pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: #010204;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; padding: 0in 3.5pt 0in 3.5pt; height: 15.85pt;\" width=\"95\"\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.6pt; padding: 0in 3.5pt 0in 3.5pt; height: 15.85pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 102.3pt; padding: 0in 3.5pt 0in 3.5pt; height: 15.85pt;\" width=\"136\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 124.55pt; padding: 0in 3.5pt 0in 3.5pt; height: 15.85pt;\" width=\"166\"\u003e\n\u003cp style=\"text-align: center; line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cem\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003eBB\u003c/span\u003e\u003c/em\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003e beta-blocker; \u003cem\u003ebpm\u003c/em\u003e beats per minute; \u003cem\u003eCKD\u003c/em\u003e chronic kidney disease; \u003cem\u003eE/\u0026eacute;\u003c/em\u003e left-ventricular early filling velocity/early diastolic myocardial velocity (a variable of left-ventricular diastolic function); \u003cem\u003eeGFR\u003c/em\u003e glomerular filtration rate estimated by CKD\u0026ndash;EPI; \u003cem\u003eEp\u003c/em\u003e pressure strain elastic modulus in the carotid artery; \u003cem\u003eHR\u003c/em\u003e heart rate; \u003cem\u003ehs-CRP\u003c/em\u003e high-sensitivity C-reactive protein; \u003cem\u003eLV\u003c/em\u003e left ventricular; \u003cem\u003eLVEF\u003c/em\u003e left-ventricular ejection fraction; \u003cem\u003en\u003c/em\u003e number; \u003cem\u003eRV\u003c/em\u003e right ventricular; \u003cem\u003eTAPSE\u003c/em\u003e tricuspid annular plane systolic excursion (a variable of right-ventricular systolic function).\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003eValues reported as mean (95% confidence interval). \u003cem\u003eP\u003c/em\u003e-value: linear mixed models. Mean values are adjusted for covariates.\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003csup\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003ea\u003c/span\u003e\u003c/sup\u003e \u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003eSignificance of the change over time in the control group and the CKD group, respectively.\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003csup\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003eb\u003c/span\u003e\u003c/sup\u003e \u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003eSignificance of the difference between the control group and the CKD group at baseline/year 5.\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003csup\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003ec\u003c/span\u003e\u003c/sup\u003e \u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003eSignificance of the difference in change over time between the CKD group and the control group.\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003csup\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003ed\u003c/span\u003e\u003c/sup\u003e \u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003eBaseline values are used as fixed covariates.\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003csup\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003ee\u003c/span\u003e\u003c/sup\u003e \u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003eValues presented in the table are the calculated anti-logs of the log-scale estimates that were used in linear mixed models analyses.\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 115%;\"\u003e\u003cspan style=\"font-size: 10.5pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003e* Age was tested as a covariate but was not significant.\u003c/span\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Exercise capacity, Non-dialysis chronic kidney disease, Grip strength, Peak heart rate","lastPublishedDoi":"10.21203/rs.2.18456/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.18456/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Aerobic exercise capacity is reduced in non-dialysis chronic kidney disease (CKD), but little is known about the magnitude of changes in exercise capacity over time. Our main hypothesis was that aerobic ExCap would decline over 5 years in individuals with mild-to-moderate CKD along with a decline in renal function. A secondary hypothesis was that such a decline in ExCap would be associated with a decline in muscle strength, cardiovascular function and physical activity. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We\u0026nbsp;performed a 5-year-prospective study on individuals with mild-to-moderate CKD, who were closely monitored at a nephrology clinic. Fiftytwo\u0026nbsp;individuals with CKD stage 2–3 and 54 age- and sex-matched healthy controls\u0026nbsp;were included. Peak workload was assessed through a maximal cycle exercise test. Muscle strength and lean body mass, cardiac function, vascular stiffness, self-reported physical activity level, renal function and haemoglobin level were evaluated. Tests were repeated after 5 years. Statistical analysis of longitudinal data was performed using linear mixed models.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Exercise capacity did not change significantly over time in either the CKD group or controls, although the absolute workloads were significantly lower in the CKD group. Only in a CKD subgroup reporting low physical activity at baseline, exercise capacity declined. Renal function decreased in both groups, with a faster decline in CKD (\u003cem\u003ep\u003c/em\u003e = 0.05 between groups). Peak heart rate, haemoglobin level, handgrip strength, lean body mass and cardiovascular function did not decrease significantly over time in CKD individuals. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e On a group level, aerobic exercise capacity and peak heart rate were maintained over 5 years in patients with well-controlled mild-to-moderate CKD, despite a slight reduction in glomerular filtration rate, mirroring the lack of progression of cardiovascular and muscular dysfunction in this group. In patients with mild-to-moderate CKD, physical activity level at baseline seems to have a predictive value for exercise capacity at follow-up.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Aerobic exercise capacity is maintained over a 5-year period in mild-to-moderate chronic kidney disease: A longitudinal study","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2020-08-22 00:45:06","doi":"10.21203/rs.2.18456/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2020-09-16T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-09-15T12:00:00+00:00","index":3,"fulltext":"Recommendation: Accept without revision\nForm responses:\n---\n\nComments to Author:\n---\nThe authors do an excellent job.\nThe author's response to the reviewer's comments was satisfactory.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Please confirm that you have included your review in the ‘Comments to Author’ box?: **\nYes**\n* Should the manuscript be highlighted for promotional activity?: **No**\n* Declaration of competing interests: **I declare that I have no competing interests.**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please publish my name with my report.**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"editorInvitedReview","content":"","date":"2020-09-11T12:00:00+00:00","index":2,"fulltext":"Recommendation: Accept without revision\nForm responses:\n---\n\nComments to Author:\n---\nAll my concerns were addressed, and the paper has sufficient basis to grant publication.\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Please confirm that you have included your review in the ‘Comments to Author’ box?: **\nYes**\n* Should the manuscript be highlighted for promotional activity?: **No**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please publish my name with my report.**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewerAgreed","content":"","date":"2020-08-28T12:00:00+00:00","index":3,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-08-25T12:00:00+00:00","index":1,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nPEER REVIEWER ASSESSMENTS:\n\nOBJECTIVE - Full research articles: is there a clear objective that addresses one or several testable research questions? (Brief or other article types: is there a clear objective?)\nYes - there is a clear objective\n\nDESIGN - Is the current approach (including controls and analysis protocols) appropriate for the objective?\nYes - the approach is appropriate\n\nEXECUTION - Are the experiments and analyses performed with sufficient technical rigor to allow confidence in the results?\nYes - experiments and analyses were performed appropriately\n\nSTATISTICS - Is the use of statistics in the manuscript appropriate?\nYes - appropriate statistical analyses have been used in the study\n\nINTERPRETATION - Is the current interpretation/discussion of the results reasonable and not overstated?\nYes - the author's interpretation is reasonable\n\nOVERALL MANUSCRIPT POTENTIAL - Has the author addressed your concerns sufficiently for you to now recommend the work as a technically sound contribution? If not, can further revisions be made to make the work technically sound?\nMaybe - with major revisions\n\nPEER REVIEWER COMMENTS:\n\nGENERAL COMMENTS: Reviewer 3\nAerobic exercise capacity is maintained over a 5-year period in mild-to-moderate chronic kidney disease: A longitudinal study\n\n\n\nREQUESTED REVISIONS:\nComment 1: Addressed.\nComment 2: Addressed.\nComment 3: Addressed, but you could add that 'It is one of the validated formulas for ….' And then explain why you have chosen this particular formula over the so many available ones.\nComment 4: Addressed, but I cannot see the response in the paper.\nComment 5: Addressed\nComment 6: Addressed\nComment 7: Addressed in response to reviewer, but articulate this in the paper as well.\nComment 8: Addressed\nComment 9: Addressed.\nComment 10. Addressed. However, I cannot see where this addition is in the manuscript.\nADDITIONAL REQUESTS/SUGGESTIONS:\nNo further comments* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Please confirm that you have included your review in the ‘Comments to Author’ box?: **\nYes**\n* Should the manuscript be highlighted for promotional activity?: **No**\n* Declaration of competing interests: **This reviewer has been recruited by a partner organization, Research Square. Reviewers with declared or apparent competing interests are not utilized for these reviews. This reviewer has agreed to publication of their comments online under a Creative Commons Attribution License attributed to Research Square and was paid a small honorarium for completing the review within a specified timeframe. Honoraria for reviews such as this are paid regardless of the reviewer recommendation.**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please publish my name with my report.**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewersInvited","content":"","date":"2020-08-21T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-08-21T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-08-21T12:00:00+00:00","index":2,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-08-20T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-08-19T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-08-19T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2019-12-10 21:09:03","doi":"10.21203/rs.2.18456/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2020-06-10T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-06-01T12:00:00+00:00","index":3,"fulltext":"Recommendation: Accept after minor essential revisions\nForm responses:\n---\n\nComments to Author:\n---\nThe authors present a clinical study of follow-up of non-dialysis CKD patients. A control group with \"healthy\" individuals was matched for patients' age and sex. The patients were followed for 5 years. clinical, laboratory and exercise capacity data were collected at the beginning and end of the follow-up. Linear mixed model and generalizedestimate equation were used in the study statistics.\n\n1) In table 2, the author showed the covariables used in the model, but in table 1 these variables were not significantly different. In addition, the groups were matched by some covariates. so it was not clear why the use of these covariables. Has the use of covariates had a major change in results?\n2) Do not comment on the sample size calculation comment; if not done, I suggest presenting a statistical analysis of the power of your main result. This is enrich your informations, mainly due to the small sample size.\n3) Although the change in the level of physical activity did not correlate with the change in exercise capacity, the author cites only the data from the CKD group, hiding the data from the control group. but it shows that the CKD group increased its level of physical activity while the control group decreased. It would be interesting to make a correlation or better still a linear model with both groups together, in order to assess the effect of the level of physical activity because according to the literature, the level of physical activity could be an important factor in the variation of the capacity of exercise. This could be better addressed in the discussion section.\n4) The author compares the maximum exercise capacity with peak VO2, but it is forgotten that the determination of a valid ergospirometry test considers ergospirometric information to validate a test as maximum. which is not possible with the same reliability in a simple stress test. I understand the care and references used in the tests they performed, but I believe that the explanation on this subject was very superficial.* Please confirm that you have included your review in the ‘Comments to Author’ box?: **\nYes**\n* Are the methods appropriate and well described to allow independent reproduction of experiments?: **Yes**\n* Does the work include the necessary controls?: **Yes**\n* Are you able to assess the statistics?: **\nI have been able to assess all of the statistics in this manuscript (please refer to checklist above)**\n* Are the conclusions drawn adequately supported by the data shown?: **Yes**\n* Quality of written English: **Acceptable**\n* Should the manuscript be highlighted for promotional activity?: **No**\n* Declaration of competing interests: **I declare that I have no competing interest's below.**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please publish my name with my report.**\n"},{"type":"editorInvitedReview","content":"","date":"2020-06-01T12:00:00+00:00","index":4,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nPEER REVIEWER ASSESSMENTS:\n\nOBJECTIVE - Full research articles: is there a clear objective that addresses a testable research question(s) (brief or other article types: is there a clear objective)?\nYes - there is a clear objective\n\nDESIGN - Is the current approach (including controls and analysis protocols) appropriate for the objective?\nYes - the approach is appropriate\n\nEXECUTION - Are the experiments and analyses performed with technical rigor to allow confidence in the results?\nYes - experiments and analyses were performed appropriately\n\nSTATISTICS - Is the use of statistics in the manuscript appropriate?\nYes - appropriate statistical analyses have been used in the study\n\nINTERPRETATION - Is the current interpretation/discussion of the results reasonable and not overstated?\nYes - the author's interpretation is reasonable\n\nOVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically sound? If not, can revisions be made to make the work technically sound?\nMaybe - with major revisions\n\nPEER REVIEWER COMMENTS:\n\nGENERAL COMMENTS:\nThis is well-written manuscript stemming from a well-designed study. Below are some comments that may enhance the manuscript.\n\n1. There is need of a clear hypothesis.\n\n2. Noted that healthy controls were excluded if they had several chronic conditions as listed in the paper. How was this controlled for in the CKD group since most patients with CKD have several comorbidities? This may have introduced 'selection bias'.\n\n3. Please provide a rationale for calculation of predicted pick heart rate (220 minus age). Is this a validated method?\n\n4. How was the sample size determined?\n\n5. There is repetition in the results section regarding calculation of eGFR using the CKD-EPI formula. This should be left in the methods section only.\n\n6. \"Cardiac function and vascular stiffness showed no significant change over time in the CKD group, while the controls significantly decreased their cardiac diastolic and systolic function and their peak HR.\" Could this solely be attributed to aggressive management of the CKD or there are other factors?\n\n7. What was the rationale for measurements at only 2 time points?\n\n8. Did the authors consider recruiting participants along the entire CKD spectrum? What was the reason for focusing on stages 1 and 2 only?\n\n9. What were the strengths of this study?\n\n10 Are there any clinical and research implications from this study?* Please confirm that you have included your review in the ‘Comments to Author’ box?: **\nYes**\n* Are the methods appropriate and well described to allow independent reproduction of experiments?: **Yes**\n* Does the work include the necessary controls?: **Yes**\n* Are you able to assess the statistics?: **\nI have been able to assess all of the statistics in this manuscript (please refer to checklist above)**\n* Are the conclusions drawn adequately supported by the data shown?: **Yes**\n* Quality of written English: **Acceptable**\n* Should the manuscript be highlighted for promotional activity?: **No**\n* Declaration of competing interests: **This reviewer has been recruited by a partner organization, Research Square. Reviewers with declared or apparent competing interests are not utilized for these reviews. This reviewer has agreed to publication of their comments online under a Creative Commons Attribution License attributed to Research Square and was paid a small honorarium for completing the review within a specified timeframe. Honoraria for reviews such as this are paid regardless of the reviewer recommendation.**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n"},{"type":"reviewerAgreed","content":"","date":"2020-05-22T12:00:00+00:00","index":4,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-01-31T12:00:00+00:00","index":3,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2019-12-26T12:00:00+00:00","index":2,"fulltext":"Recommendation: Accept after minor essential revisions\nForm responses:\n---\n\nComments to Author:\n---\nThe study aimed to evaluate the exercise capacity after five year of the first evaluation in CKD and Health patients. Some questions raised my concern:\n\n- Saltin-Grimby Physical Activity Level Scale? Why not the IPAQ? is way more used and more understood.\n- A very important statistical measure that is always left out is the effect size. It would be extremely important the presence of the ES so we could understand the real impact of the 5-year period. ES for repeated measures of course (refer to this website https://www.psychometrica.de/effect_size.html)\n-Well, changes in aerobic capacity in individual not doing Hemodialysis (HD) is very good, however HD is a very deteriorative process and tends to highly increase the risk for cardiovascular diseases, and accelerate muscle loss. None of your patients moved to later stages of CKD, and then to HD?\n-Why not stratify the table 2 in subgroups according to the Saltin-Grimby Physical Activity Level Scale? It would tell if the subjects who declared higher levels of PA have lower ExCap loss than those who reported lower levels. I know th sample is quite small, but it would be of great use.\n\nThe study is ver well conducted and has important findings. I undertand the problems with sample size, seen that is a very fragile group of patients.* Please confirm that you have included your review in the ‘Comments to Author’ box?: **\nYes**\n* Are the methods appropriate and well described to allow independent reproduction of experiments?: **Yes**\n* Does the work include the necessary controls?: **Yes**\n* Are you able to assess the statistics?: **\nI have been able to assess all of the statistics in this manuscript (please refer to checklist above)**\n* Are the conclusions drawn adequately supported by the data shown?: **Yes**\n* Quality of written English: **Acceptable**\n* Should the manuscript be highlighted for promotional activity?: **No**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: **\nI agree to the open peer review policy of the journal**\n"},{"type":"editorInvitedReview","content":"","date":"2019-12-26T12:00:00+00:00","index":1,"fulltext":"Recommendation: Accept without revision\nForm responses:\n---\n\nComments to Author:\n---\nThe authors do an excellent job highlighting a key and often understated aspect of mortality in CKD patients: physical activity. It is not stressed for CKD patients as for other chronic diseases in the population. I have the following comments on this study on CKD patients' exercise capacity:\n\n1. While the authors list the sample size as a limitation, this is in keeping with similar studies of aerobic exercise in CKD patients over the years. It would be insightful however to include any sample size calculations that were made.\n2. Attrition remains high in this study, which the authors acknowledge as a weakness of the study.\n3. For the subjects that were included in the 5-yr followup, were there any attempts made to study if they kept up with their physical exercise, either by way of surveys or questionnaires or monitoring of physical activity in the interim. Were any of the exercise sessions in the intervening 5 years monitored by fitness apps or monitoring devices?\n4. It is interesting that the hs-CRP did not change over time in the CKD group, in contrast to other published studies. This could be a function of relatively preserved GFR than in other studies.\n* Please confirm that you have included your review in the ‘Comments to Author’ box?: **\nYes**\n* Are the methods appropriate and well described to allow independent reproduction of experiments?: **Yes**\n* Does the work include the necessary controls?: **Yes**\n* Are you able to assess the statistics?: **\nThere are statistical tests that I am unable to assess and recommend seeking additional advice (please specify which tests these are in the ‘Comments to Editor’ box)**\n* Are the conclusions drawn adequately supported by the data shown?: **Yes**\n* Quality of written English: **Acceptable**\n* Should the manuscript be highlighted for promotional activity?: **No**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: **\nI agree to the open peer review policy of the journal**\n"},{"type":"reviewerAgreed","content":"","date":"2019-12-17T12:00:00+00:00","index":2,"fulltext":""},{"type":"editorAssigned","content":"","date":"2019-12-04T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2019-12-04T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2019-12-04T12:00:00+00:00","index":1,"fulltext":""},{"type":"checksComplete","content":"","date":"2019-12-03T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2019-12-03T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2019-11-29T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c1041177-94bf-4c94-91f8-113a7b122463","owner":[],"postedDate":"August 22nd, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":41204,"name":"Urology \u0026 Nephrology"}],"tags":[],"updatedAt":"2020-11-15T15:03:33+00:00","versionOfRecord":{"articleIdentity":"rs-9076","link":"https://doi.org/10.1186/s12882-020-02110-2","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2020-11-11 15:02:02","publishedOnDateReadable":"November 11th, 2020"},"versionCreatedAt":"2020-08-22 00:45:06","video":"","vorDoi":"10.1186/s12882-020-02110-2","vorDoiUrl":"https://doi.org/10.1186/s12882-020-02110-2","workflowStages":[]},"version":"v2","identity":"rs-9076","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-9076","version":["v2"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}