Introduction: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is frequently observed in maintenance hemodialysis (MHD) patients and is associated with fracture, muscle weakness, malnutrition, etc.; however, relationships of CKD-MBD markers and fatigue are not well established. Methods: This was a cross-sectional study including 244 MHD patients (89 elders) from July to September 2021 in the First Affiliated Hospital of Shandong First Medical University. CKD-MBD markers and other clinical data were collected from medical records. Fatigue in the past week was measured by Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) fatigue measure; fatigue at the end of hemodialysis was measured by numeric rating scale (NRS). Spearman correlation, linear regression, and robust linear regression were. Results: In all MHD patients, lg[25(OH)D] (nmol/L) was negatively correlated with SONG-HD score (β = −1.503, 95% CI: −2.826 to 0.18, p = 0.026) and NRS score (β = −1.532, p = 0.04) in multiple regression models adjusting for sex, age, and all CKD-MBD characters; but no correlations were found on univariate regression or in other multiple regression models. Interaction effects between age ≥65 years and lg(25[OH]D [nmol/L]) in terms of fatigue scores were significant based on multiple linear regressions (SONG-HD score β = −3.613, p for interaction = 0.006; NRS score β = −3.943, p for interaction = 0.008). Compared with non-elderly patients, elderly patients were with higher ACCI scores (7 [6, 8] vs. 4 [3, 5], p < 0.001), higher SONG-HD scores (3 [2, 6] vs. 2 [1, 3], p < 0.001), higher NRS score (4 [2, 7] vs. 3 [1, 5], p < 0.001), lower serum phosphate levels (1.65 [1.29, 2.10] vs. 1.87 [1.55, 2.26] mmol/L, p = 0.002), and lower serum iPTH levels (160.6 [90.46, 306.45] vs. 282.2 [139, 445.7] pg/mL, p < 0.001). There were no differences in serum calcium, alkaline serum, or 25(OH)D levels between the two groups. In elderly patients, lg[25(OH)D] was negatively correlated with SONG-HD score (β = −3.323, p = 0.010) and NRS score (β = −3.521, p = 0.006) on univariate linear regressions. Following adjustment for sex, age, and all CKD-MBD characters, lg[25(OH)D] was negatively correlated with SONG-HD scores (multiple linear regression β = −4.012, p = 0.004; multiple robust regression β = −4.012, p = 0.003) or NRS scores (multiple linear regression β = −4.104, p = 0.002; multiple robust regression β = −4.104, p = 0.001). There were no significant correlations between fatigue scores and other CKD-MBD markers (calcium, phosphate, lgiPTH, alkaline phosphatase) in elderly MHD patients, on either univariate linear regressions or multiple regressions. Conclusion: Serum 25(OH)D level is negatively associated with fatigue in elderly MHD patients.

Fatigue is a common and increasingly recognized symptom in maintenance hemodialysis (MHD) patients and is associated with poor quality of life, death, and hospitalization [1‒3]. Contributing factors include but are not limited to complications of end-stage renal disease (such as anemia, malnutrition, sarcopenia), treatments (such as post-dialysis fatigue, certain drugs), psychological factors (such as depression, anxiety, sleep disorders), lifestyles (such as physical activities, alcohol abuse) [1‒3]. Chronic kidney disease-mineral and bone disorder (CKD-MBD) is one of the most common and uncontrollable complications in MHD patients. Abnormal calcium (Ca) [4], phosphorus (P) [5], vitamin D [6], and/or intact parathyroid hormone (iPTH) [7] can lead to falls and fractures, muscle weakness, malnutrition, sleep disorders, and other factors associated with fatigue; however, relationships between fatigue and CKD-MBD markers were unknown; the present study explored this topic in MHD patients. The primary aim of study was to assess the relationships between fatigue and CKD-MBD markers. Considering positive associations between increased age and fatigue in individuals with CKD, hemodialysis, and peritoneal dialysis populations has been observed [8]; there are significant differences between elders and non-elders in CKD-MBD characters [9], some clinical factors associated with fatigue (such as employment status, number of comorbidities, protein energy malnutrition, and so on) [1, 8]; so, secondary aim of study was to assess the relationships between fatigue and CKD-MBD markers in elderly patients.

Study Design and Participants

This was a single-center, cross-sectional observational study. All stable adult MHD patients from July to September 2021 in the First Affiliated Hospital of Shandong First Medical University who met the criteria for inclusion and exclusion were included. This study complied with the Declaration of Helsinki and was approved by the Ethics Committees of the First Affiliated Hospital of Shandong First Medical University (IRB:YXLL-KY-2021(062)) where the study was conducted. Written informed consent was obtained from all participants of the study.

Inclusion criteria were: (1) hemodialysis for at least 3 months, (2) age ≥18 years, (3) ability to communicate normally and (4) with complete basic information and clinical data. Exclusion criteria were: (1) systemic infection, malignant tumor, trauma, surgery, or hospitalization within 3 months, (2) spKt/V <1.2 and (3) cognitive impairment or mental illness.

Demographic, Socioeconomic, and Clinical Characteristics

Characteristics were collected from medical records, including age, gender, dialysis duration, whether participating in work, payment for treatment cost, marriage status, whether living alone, whether smoking, whether drinking, BMI, primary diseases, comorbidities, vascular access for HD. Accumulated exercise hours per week was conducted by trained interviewers; hours of activities or any physical exertion (walking, running, bicycling, dancing, housework or physical labor, and so on) in 1 week was collected.

Systolic blood pressure, diastolic blood pressure, and laboratory tests were examined before the dialysis with a longer interval. Blood pressures were measured by trained nurses, repeated three times, and the average value was taken. Laboratory tests were measured using standard methods in the routine clinical laboratory. Hemoglobin was detected by flow cytometry (hematology analyzer XN-9000); serum total Ca, P, alkaline phosphatase (ALP), carbonate ion, potassium, sodium, blood urea nitrogen, creatinine (Cr), albumin (Alb), pre-albumin, low-density lipoprotein, triglyceride, cholesterol, and transferrin saturation were detected by automatic biochemical analyzer (Roche Cobas 8000). C-reactive protein, iPTH, 25-hydroxyvitamin D (25[OH]D), and serum ferritin were detected by chemiluminescent immunoassay (Roche Cobas E602). The spKt/V was tested by “Online Clearance Monitor” of Fresenius dialysis machine 4008S version V10, and the principle was based on the calculation of gradient changes in electrical conductivity during dialysis [10].

Assessments of Fatigue

Two methods were used to assess fatigue in MHD patients. Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) Fatigue measure was performed before the dialysis with a longer interval, and numeric rating scale (NRS) was conducted at the end of the same hemodialysis session. “SONG-HD Fatigue measure consists of three items that assess (1) the effect of fatigue on life participation, (2) tiredness, and (3) level of energy. These dimensions are assessed on a four-point Likert scale indicating increasing severity, ranging from zero (not at all) to three (severely). Patients respond on the basis of their experience of fatigue in the past week. An overall score for fatigue is obtained by summing the responses across the three questions, resulting in a scale ranging from zero (no fatigue) to nine (maximum fatigue) [11].” NRS [12] was used to assess patients’ fatigue at the end of hemodialysis. “The fatigue NRS is a patient-administered, single-item, 11-point horizontal scale anchored at zero and 10, with zero representing ‘no fatigue’ and 10 representing ‘as bad as you can imagine’.” Patients are asked to do the following: “please rate your fatigue (tiredness, weakness, exhaustion, or lack of energy) by selecting the number that describes your worst level of fatigue at the end of hemodialysis.”

Statistical Analysis

All data were entered by two researchers. Descriptive statistics are expressed as frequencies (percentages) for categorical variables, mean ± standard deviation for normally distributed continuous variables, and median (interquartile range) for variables with skewed distribution. Patients were subsequently divided into 2 groups according to age ≥65 years or not. Differences between elderly and non-elderly MHD patients were assessed using the t test, Mann-Whitney U test, or χ2 analysis, as appropriate. Correlation analyses were performed in the total MHD patients and elderly subgroup. Linear regression and Spearman correlation were used to analyze relationships between fatigue scores and CKD-MBD markers. Univariate linear regression was performed to identify potential contributing factors for fatigue; candidate variables with a p value <0.2 on univariate analysis, age, sex, and all CKD-MBD markers (Ca, P, iPTH, ALP, 25[OH]D) were included in multiple linear regressions and robust multiple linear regressions. Both iPTH and 25(OH)D are hormones, they were skewness distribution, and the differences between values were exponential, so we took l g value for these two variables. All statistical tests were two-sided, and a p value of less than 0.05 was considered as statistically significant. All statistical analyses were performed using SPSS (version 18.0, SPSS Inc., Chicago, USA) and STATA (version 16.0, Stata Corporation LLC, College Station, USA).

Demographic, Clinical Characteristics, and Fatigue Measurement of Total MHD Patients

In total, 244 MHD patients were included in this study; online supplementary Figure 1 (for all online suppl. material, see www.karger.com/doi/10.1159/000529514) shows the flowchart for patient selection, and Table 1 shows their characteristics. The median age was 59 (47, 69) years old, and median dialysis duration was 43 (22, 82) months, with a male-to-female ratio of 2.2:1. Primary diseases were diabetic nephropathy 36.5%, chronic glomerulonephritis 20.9%, hypertensive nephropathy 26.6%, polycystic kidney 3.3%, others 5.3%, and unknown 7.4%. Age-adjusted Charlson comorbidity index score was 5 (4, 7). Median SONG-HD fatigue score was 3 (1, 4) and 83.6% patients with SONG-HD fatigue score ≥1; median NRS fatigue score was 3 (1, 5) and 86.1% patients with NRS score ≥1. Results of CKD-MBD markers were Ca 2.26 (2.15, 2.37) mmol/L, P 1.80 (1.46, 2.21) mmol/L, iPTH238.50 (119.08, 363.75) pg/mL, ALP 79.5 (63, 103.75) U/L, 25(OH) D 55.9 (41.03, 78.73) nmol/L.

Table 1.

Demographic, socioeconomic, clinical characteristics, and fatigue of maintenance hemodialysis patients

CharacteristicTotal (N = 244)Elderly (≥65 years) (N = 89)Non-elderly (<65 years) (N = 155)p value
Male/female 167/77 54/35 113/42 0.048 
Age, years 59 (47, 69) 71 (68, 77) 52 (42, 59) <0.001 
Dialysis duration, months 43 (22, 82) 43 (23.5, 83) 42 (22, 81) 0.707 
Participate in work, % 32.0 11.2 43.9 <0.001 
Payment for treatment cost, % 
 Medical insurance for urban employees 62.3 62.9 61.9 0.878 
 Medical insurance for urban residents 23.4 15.7 27.7 0.033 
 Free medical insurance 11.1 19.1 6.1 0.002 
 Others 3.3 2.2 3.9 0.493 
Marriage status, % 
 Married 83.6 82.0 84.5 0.613 
 Unmarried 7.0 11.0 <0.001 
 Divorced or widowed 9.4 18.0 4.5 0.001 
Live alone, % 5.3 7.9 3.9 0.181 
Accumulated exercise hours per week 8.0 (3.6, 15) 6.0 (2.75, 14.0) 12 (7, 20) <0.001 
Smoking (never/quit/always), % 85.3/9.0/5.7 97.8/1.1/1.1 78.1/13.5/8.4 <0.001 
Drinking (never/quit/always), % 84.9/14.3/0.8 91.1/7.8/1.1 81.3/18.1/0.6 0.087 
SBP, mm Hg 152.3±21.2 152.18±21.21 152.41±21.3 0.936 
DBP, mm Hg 76.0±14.3 67.75±12.26 80.72±13.29 <0.001 
BMI, kg/m2 22.8 (20.5, 25.0) 22.84 (20.17, 24.09) 22.75 (20.59, 25.65) 0.173 
Primary diseases, % 
 DN 36.5 50.6 28.4 <0.001 
 CGN 20.9 16.9 23.2 0.239 
 HTN 26.6 20.2 30.3 0.086 
 Polycystic kidney 3.3 1.1 4.5 0.152 
 Others 5.3 6.7 4.5 0.456 
 Unknown 7.4 4.5 9.0 0.192 
ACCI score 5 (4, 7) 7 (6, 8) 4 (3, 5) <0.001 
SONG-HD fatigue score 3 (1, 4) 3 (2, 6) 2 (1, 3) <0.001 
SONG-HD fatigue score ≥1, % 83.6 89.9 80.0 0.045 
NRS fatigue score 3 (1, 5) 4 (2, 7) 3 (1, 5) <0.001 
NRS fatigue score ≥1, % 86.1 92.1 82.6 0.038 
Ca, mmol/L 2.26 (2.15, 2.37) 2.26 (2.18, 2.37) 2.26 (2.14, 2.37) 0.712 
P, mmol/L 1.80 (1.46, 2.21) 1.65 (1.29, 2.10) 1.87 (1.55, 2.26) 0.002 
iPTH, pg/mL 238.50 (119.08, 363.75) 160.6 (90.46, 306.45) 282.2 (139.0, 445.7) <0.001 
ALP, U/L 79.5 (63, 103.75) 80.5 (63, 103) 78 (63, 105) 0.764 
25(OH)D, nmol/L 55.9 (41.03, 78.73) 56.8 (41.70, 77.15) 55.1 (40.5, 79.3) 0.600 
HCO3, mmol/L 22.90 (20.42, 25.08) 22.80 (20.55, 24.90) 23.10 (20.10, 25.40) 0.842 
K, mmol/L 5.03 (4.54, 5.53) 4.82 (4.29, 5.34) 5.17 (4.64, 5.60) 0.002 
Na, mmol/L 139.4 (138.0, 141.3) 139 (137.90, 141.95) 139.8 (138.0, 141.2) 0.358 
BUN, mmol/L 23.07±6.96 22.22±6.18 23.56±7.34 0.148 
Cr, μmol/L 857.89±246.95 741.64±209.00 924.6±242.8 <0.001 
Alb, g/L 41.50±3.76 40.02±3.80 42.35±3.47 <0.001 
Pre-albumin, mg/L 315.90 (256.30, 360.70) 262.20 (234.85, 329.05) 331.9 (287.0, 371.4) <0.001 
CRP, mg/L 0 (0, 5.95) (n = 229) 0 (0, 9.18) (n = 80) 0 (0, 4.66) (n = 149) 0.013 
LDL, mmol/L 1.94 (1.46, 2.39) (n = 242) 2.02 (1.42, 2.51) (n = 80) 1.90 (1.48, 2.32) (n = 154) 0.291 
TG, mmol/L 1.22 (0.87, 1.75) (n = 241) 1.16 (0.75, 1.47) (n = 87) 1.27 (0.98, 1.90) (n = 154) 0.006 
CH, mmol/L 3.76 (3.16, 4.45) 3.77 (3.14, 4.47) 3.76 (3.17, 4.42) 0.810 
Hb, g/L 116 (108, 125.75) 118 (109.50, 127) 116 (107, 124) 0.411 
SF, μg/L 156.17 (74.05, 272.44) 147.54 (78.97, 282.87) 160.10 (73.95, 272.64) 0.441 
TSAT, % 26.41 (19.65, 35.50) (n = 237) 25.96 (19.82, 32.19) (n = 86) 26.59 (19.59, 37.70) (n = 152) 0.069 
Dialyzer membrane, % 
 CTA 13.5 22.5 8.4 0.002 
 PS 76.2 65.2 82.6 0.002 
 PMMA 10.2 12.4 9.0 0.409 
Dialyzer effective surface, m2 1.5 (1.5, 1.6) 1.5 (1.5, 1.5) 1.5 (1.4,1.6) 0.703 
High-efficiency HD, %/high-flux HD, % 26.6/73.4 37.1/62.9 20.6/79.4 0.005 
Duration of dialysis session, h 4 (4, 4) 4 (4, 4) 4 (4, 4) 0.691 
Dialysis frequency (sessions per week) 3 (3, 3) 3 (3, 3) 3 (3, 3) 0.836 
Vascular access for HD (fistula, %/catheter, %) 88.5/11.5 79.8/20.2 93.5/6.5 0.001 
SpKt/V 1.2 (1.2, 1.2) 1.2 (1.2, 1.2) 1.2 (1.2, 1.2) 0.750 
Ca, % 34.8 29.2 38.1 0.162 
Ca-free phosphorus binders, % 30.7 28.1 32.3 0.497 
Calcitriol, % 9.4 9.0 9.7 0.859 
Paricalcitol, % 14.8 11.2 16.8 0.240 
Calcimimetics, % 28.3 21.3 32.3 0.069 
CharacteristicTotal (N = 244)Elderly (≥65 years) (N = 89)Non-elderly (<65 years) (N = 155)p value
Male/female 167/77 54/35 113/42 0.048 
Age, years 59 (47, 69) 71 (68, 77) 52 (42, 59) <0.001 
Dialysis duration, months 43 (22, 82) 43 (23.5, 83) 42 (22, 81) 0.707 
Participate in work, % 32.0 11.2 43.9 <0.001 
Payment for treatment cost, % 
 Medical insurance for urban employees 62.3 62.9 61.9 0.878 
 Medical insurance for urban residents 23.4 15.7 27.7 0.033 
 Free medical insurance 11.1 19.1 6.1 0.002 
 Others 3.3 2.2 3.9 0.493 
Marriage status, % 
 Married 83.6 82.0 84.5 0.613 
 Unmarried 7.0 11.0 <0.001 
 Divorced or widowed 9.4 18.0 4.5 0.001 
Live alone, % 5.3 7.9 3.9 0.181 
Accumulated exercise hours per week 8.0 (3.6, 15) 6.0 (2.75, 14.0) 12 (7, 20) <0.001 
Smoking (never/quit/always), % 85.3/9.0/5.7 97.8/1.1/1.1 78.1/13.5/8.4 <0.001 
Drinking (never/quit/always), % 84.9/14.3/0.8 91.1/7.8/1.1 81.3/18.1/0.6 0.087 
SBP, mm Hg 152.3±21.2 152.18±21.21 152.41±21.3 0.936 
DBP, mm Hg 76.0±14.3 67.75±12.26 80.72±13.29 <0.001 
BMI, kg/m2 22.8 (20.5, 25.0) 22.84 (20.17, 24.09) 22.75 (20.59, 25.65) 0.173 
Primary diseases, % 
 DN 36.5 50.6 28.4 <0.001 
 CGN 20.9 16.9 23.2 0.239 
 HTN 26.6 20.2 30.3 0.086 
 Polycystic kidney 3.3 1.1 4.5 0.152 
 Others 5.3 6.7 4.5 0.456 
 Unknown 7.4 4.5 9.0 0.192 
ACCI score 5 (4, 7) 7 (6, 8) 4 (3, 5) <0.001 
SONG-HD fatigue score 3 (1, 4) 3 (2, 6) 2 (1, 3) <0.001 
SONG-HD fatigue score ≥1, % 83.6 89.9 80.0 0.045 
NRS fatigue score 3 (1, 5) 4 (2, 7) 3 (1, 5) <0.001 
NRS fatigue score ≥1, % 86.1 92.1 82.6 0.038 
Ca, mmol/L 2.26 (2.15, 2.37) 2.26 (2.18, 2.37) 2.26 (2.14, 2.37) 0.712 
P, mmol/L 1.80 (1.46, 2.21) 1.65 (1.29, 2.10) 1.87 (1.55, 2.26) 0.002 
iPTH, pg/mL 238.50 (119.08, 363.75) 160.6 (90.46, 306.45) 282.2 (139.0, 445.7) <0.001 
ALP, U/L 79.5 (63, 103.75) 80.5 (63, 103) 78 (63, 105) 0.764 
25(OH)D, nmol/L 55.9 (41.03, 78.73) 56.8 (41.70, 77.15) 55.1 (40.5, 79.3) 0.600 
HCO3, mmol/L 22.90 (20.42, 25.08) 22.80 (20.55, 24.90) 23.10 (20.10, 25.40) 0.842 
K, mmol/L 5.03 (4.54, 5.53) 4.82 (4.29, 5.34) 5.17 (4.64, 5.60) 0.002 
Na, mmol/L 139.4 (138.0, 141.3) 139 (137.90, 141.95) 139.8 (138.0, 141.2) 0.358 
BUN, mmol/L 23.07±6.96 22.22±6.18 23.56±7.34 0.148 
Cr, μmol/L 857.89±246.95 741.64±209.00 924.6±242.8 <0.001 
Alb, g/L 41.50±3.76 40.02±3.80 42.35±3.47 <0.001 
Pre-albumin, mg/L 315.90 (256.30, 360.70) 262.20 (234.85, 329.05) 331.9 (287.0, 371.4) <0.001 
CRP, mg/L 0 (0, 5.95) (n = 229) 0 (0, 9.18) (n = 80) 0 (0, 4.66) (n = 149) 0.013 
LDL, mmol/L 1.94 (1.46, 2.39) (n = 242) 2.02 (1.42, 2.51) (n = 80) 1.90 (1.48, 2.32) (n = 154) 0.291 
TG, mmol/L 1.22 (0.87, 1.75) (n = 241) 1.16 (0.75, 1.47) (n = 87) 1.27 (0.98, 1.90) (n = 154) 0.006 
CH, mmol/L 3.76 (3.16, 4.45) 3.77 (3.14, 4.47) 3.76 (3.17, 4.42) 0.810 
Hb, g/L 116 (108, 125.75) 118 (109.50, 127) 116 (107, 124) 0.411 
SF, μg/L 156.17 (74.05, 272.44) 147.54 (78.97, 282.87) 160.10 (73.95, 272.64) 0.441 
TSAT, % 26.41 (19.65, 35.50) (n = 237) 25.96 (19.82, 32.19) (n = 86) 26.59 (19.59, 37.70) (n = 152) 0.069 
Dialyzer membrane, % 
 CTA 13.5 22.5 8.4 0.002 
 PS 76.2 65.2 82.6 0.002 
 PMMA 10.2 12.4 9.0 0.409 
Dialyzer effective surface, m2 1.5 (1.5, 1.6) 1.5 (1.5, 1.5) 1.5 (1.4,1.6) 0.703 
High-efficiency HD, %/high-flux HD, % 26.6/73.4 37.1/62.9 20.6/79.4 0.005 
Duration of dialysis session, h 4 (4, 4) 4 (4, 4) 4 (4, 4) 0.691 
Dialysis frequency (sessions per week) 3 (3, 3) 3 (3, 3) 3 (3, 3) 0.836 
Vascular access for HD (fistula, %/catheter, %) 88.5/11.5 79.8/20.2 93.5/6.5 0.001 
SpKt/V 1.2 (1.2, 1.2) 1.2 (1.2, 1.2) 1.2 (1.2, 1.2) 0.750 
Ca, % 34.8 29.2 38.1 0.162 
Ca-free phosphorus binders, % 30.7 28.1 32.3 0.497 
Calcitriol, % 9.4 9.0 9.7 0.859 
Paricalcitol, % 14.8 11.2 16.8 0.240 
Calcimimetics, % 28.3 21.3 32.3 0.069 

Descriptive statistics are expressed as frequencies (percentages) for categorical variables, mean ± standard deviation for normally distributed continuous variables, and median (interquartile range) for variables with skewed distribution.

SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; DN, diabetic nephropathy; CGN, chronic glomerulonephritis; HTN, hypertensive nephropathy; ACCI, age-adjusted Charlson comorbidity index; HD, hemodialysis; SONG-HD, Standardized Outcomes in Nephrology-Hemodialysis; NRS, numeric rating scale; Ca, serum total calcium; P, phosphate; iPTH, intact parathyroid hormone; ALP, alkaline phosphatase; HCO3-, carbonate ion; K, potassium; Na, sodium; BUN, blood urea nitrogen; Cr, creatinine; Alb, albumin; CRP, c-reactive protein; LDL, low-density lipoprotein; TG, triglyceride; CH, cholesterol; Hb, hemoglobin; SF, serum ferritin; TSAT, transferrin saturation; CTA, cellulose triacetate; PS, polysulfone; PMMA, polymethylmethacrylate.

Correlation Studies of Fatigue and CKD-MBD Markers in Total MHD Patients

There were no correlations between fatigue in the past week (SONG-HD score) and serum CKD-MBD markers (Ca, P, iPTH, ALP, or 25[OH]D), in univariate linear regressions (online suppl. Table 1). SONG-HD score was negatively correlated with lg(25[OH]D) in a multiple linear regression model adjusting for sex, age, and all CKD-MBD characters (Ca, P, iPTH, ALP, 25[OH]D) (β = −1.503, 95% CI: −2.826 to 0.18, p = 0.026); no other correlations were found between SONG-HD scores and CKD-MBD markers in multiple regression models (online suppl. Table 2) or multiple robust regression models (online suppl. Table 3).

Based on univariate linear regressions (online suppl. Table 4), lg(iPTH) was negatively correlated with fatigue at the end of hemodialysis (NRS score) (β = −0.836, 95% CI: −1.613 to 0.058, p = 0.035), but the correlation disappeared after multifactor adjusting (online suppl. Tables 5, 6). Lg(25[OH]D) was negatively correlated with NRS score in a multiple regression model which adjusted for sex, age, and all CKD-MBD markers (Ca, P, iPTH, ALP, 25(OH)D) (β = −1.532, 95% CI: −3.022–0.041, p = 0.04); no other correlations were found between SONG-HD scores and CKD-MBD markers in multiple regression models (online suppl. Table 5) or multiple robust regression models (online suppl. Table 6). Table 2 shows interaction effects between age ≥65 years, and lg(25[OH]D (nmol/L)) in terms of fatigue scores was significant based on multiple linear regressions (SONG-HD score β = −3.613, p for interaction = 0.006; NRS score β = −3.943, p for interaction = 0.008).

Table 2.

The interaction effects between age ≥65 years and lg(25(OH)D [nmol/L]) in terms of fatigue scores based on multiple linear regressions in maintenance hemodialysis patients (N = 244)

Fatigue in the past week (SONG-HD score)Fatigue at the end of hemodialysis (NRS score)
CharacteristicΒ95% CIp valueΒ95% CIp value
Lg(25[OH]D [nmol/L]) 0.289 −1.335 to 1.913 0.726 0.422 −1.428 to 2.271 0.654 
Age ≥65 years 7.880 3.371–12.390 <0.001 8.243 3.106–13.380 0.002 
Lg(25[OH]D [nmol/L])* (age ≥65 years) −3.613 −6.178 to –1.047 0.006a −3.943 −6.865 to −1.021 0.008a 
Fatigue in the past week (SONG-HD score)Fatigue at the end of hemodialysis (NRS score)
CharacteristicΒ95% CIp valueΒ95% CIp value
Lg(25[OH]D [nmol/L]) 0.289 −1.335 to 1.913 0.726 0.422 −1.428 to 2.271 0.654 
Age ≥65 years 7.880 3.371–12.390 <0.001 8.243 3.106–13.380 0.002 
Lg(25[OH]D [nmol/L])* (age ≥65 years) −3.613 −6.178 to –1.047 0.006a −3.943 −6.865 to −1.021 0.008a 

ap for interaction.

Demographic, Clinical Characteristics and Fatigue Measurement of Elderly MHD Patients

There were 89 elderly MHD patients (Table 1): 54 were male and 35 were female. The median age was 71 (68, 77) years old, and median dialysis duration was 43 (23.5, 83) months. In elderly MHD patients, diabetic nephropathy accounted for 50.6% of primary diseases, which was significantly higher than in non-elderly patients (28.4%, p < 0.001). Compared with non-elderly patients, elderly patients were with higher age-adjusted Charlson comorbidity index score (7 [6, 8] vs. 4 [3, 5], p < 0.001), higher fatigue scores (SONG-HD: 3 [2, 6] vs. 2 [1, 3], p < 0.001; NRS: 4 [2, 7] vs. 3 [1, 5], p < 0.001), lower serum p levels (1.65 [1.29, 2.10] vs. 1.87 [1.55, 2.26] mmol/L, p = 0.002), and lower serum iPTH levels (160.6 [90.46, 306.45] vs. 282.2 [139, 445.7] pg/mL, p < 0.001). There were no differences in serum Ca, ALP, or 25(OH)D levels between the two groups.

Correlation Studies of Fatigue and CKD-MBD Markers in Elderly MHD Patients

In elderly MHD patients, both SONG-HD score (β = −3.323, 95% CI: −5.825 to 0.822, p = 0.010; online suppl. Table 7) and NRS score (β = −3.521, 95% CI: −5.984 to 1.058, p = 0.006; online suppl. Table 8) were negatively correlated with lg(25[OH]D), on univariate linear regressions. Following adjustment for sex, age, and all CKD-MBD markers (Ca, P, iPTH, ALP, 25[OH]D), only lg(25[OH]D) was negatively correlated with SONG-HD scores (multiple linear regression β = −4.012, 95% CI: −6.668 to 1.356, p = 0.004; multiple robust regression β = −4.012, 95% CI: −6.396 to 1.444, p = 0.003) or NRS scores (multiple linear regression β = −4.104, 95% CI: −6.701 to 1.506, p = 0.002; multiple robust regression β = −4.104, 95% CI: −6.421 to 1.786, p = 0.001). There were no significant correlations between fatigue scores and other CKD-MBD markers (Ca, P, ALP, or lgiPTH) in elderly MHD patients, either on univariate linear regressions (online suppl. Tables 7, 8) or multiple regressions (Table 3).

Table 3.

The associations of CKD-MBD markers with fatigue in the past week (SONG-HD score) and fatigue at the end of hemodialysis (NRS score) of elderly (age ≥65 years) maintenance hemodialysis patients, generalized multiple regression models (N = 89)

SONG-HD scoreNRS score
multiple linear regressionsmultiple robust regressionmultiple linear regressionsmultiple robust regression
β95% CIp valueΒ95% CIp valueβ95% CIpvalueβ95% CIp value
Ca (mmol/L) 2.274 −1.631 to 6.18 0.250 2.274 −1.743–6.292 0.263 2.875 −0.944–6.695 0.138 2.875 −0.973–6.723 0.141 
P (mmol/L) 0.177 −0.928 to 1.282 0.751 0.177 −0.904–1.258 0.746 0.303 −0.778–1.384 0.579 0.303 −0.857–1.463 0.605 
Lg(iPTH [pg/mL]) 0.262 −1.39 to 1.914 0.753 0.262 −1.392–1.917 0.753 0.094 −1.522–1.709 0.908 0.094 −1.608–1.796 0.913 
ALP (U/L) −0.012 −0.034 to 0.01 0.265 −0.012 −0.029–0.005 0.152 −0.011 −0.033–0.01 0.290 −0.011 −0.029–0.005 0.191 
Lg(25[OH]D [nmol/L]) −4.012 −6.668 to 1.356 0.004 −4.012 −6.396–1.444 0.003 −4.104 −6.701–1.506 0.002 −4.104 −6.421–1.786 0.001 
SONG-HD scoreNRS score
multiple linear regressionsmultiple robust regressionmultiple linear regressionsmultiple robust regression
β95% CIp valueΒ95% CIp valueβ95% CIpvalueβ95% CIp value
Ca (mmol/L) 2.274 −1.631 to 6.18 0.250 2.274 −1.743–6.292 0.263 2.875 −0.944–6.695 0.138 2.875 −0.973–6.723 0.141 
P (mmol/L) 0.177 −0.928 to 1.282 0.751 0.177 −0.904–1.258 0.746 0.303 −0.778–1.384 0.579 0.303 −0.857–1.463 0.605 
Lg(iPTH [pg/mL]) 0.262 −1.39 to 1.914 0.753 0.262 −1.392–1.917 0.753 0.094 −1.522–1.709 0.908 0.094 −1.608–1.796 0.913 
ALP (U/L) −0.012 −0.034 to 0.01 0.265 −0.012 −0.029–0.005 0.152 −0.011 −0.033–0.01 0.290 −0.011 −0.029–0.005 0.191 
Lg(25[OH]D [nmol/L]) −4.012 −6.668 to 1.356 0.004 −4.012 −6.396–1.444 0.003 −4.104 −6.701–1.506 0.002 −4.104 −6.421–1.786 0.001 

Adjusted for sex, age, and all CKD-MBD characters (Ca, P, iPTH, ALP, 25[OH]D).

CKD-MBD, chronic kidney disease-mineral and bone disorder; SONG-HD, Standardized Outcomes in Nephrology-Hemodialysis; HD, hemodialysis; NRS, numeric rating scale; Ca, serum total calcium; P, phosphate; iPTH, intact parathyroid hormone; ALP, alkaline phosphatase.

Additional models were performed to verify the correlations between lg(25[OH]D) and fatigue scores on multiple linear regressions or robust regressions: model 2: adjusted for sex, age, candidate demographics variables, and HD-related variables with a p value <0.2 on univariate analysis; model 3: adjusted for sex, age, candidate test results with a p value <0.2 on univariate analysis; model 4: adjusted for sex, age, and all CKD-MBD-related medicines (Ca, Ca-free P binders, calcitriol, paricalcitol, calcimimetics); statistical analysis results showed similar negative correlations (Table 4). Scatter diagrams and Spearman coefficient (Fig. 1) also showed similar results between fatigue scores and lg(25[OH]D) (SONG-HD score r = −0.243, p = 0.022; NRS score: r = −0.274, p = 0.009).

Table 4.

The associations of lg(25[OH]D [nmol/L]) with fatigue in the past week (SONG-HD score) and fatigue at the end of hemodialysis (NRS score) of elderly (age ≥65 years) maintenance hemodialysis patients, multiple regression models (N = 89)

SONG-HD scoreNRS score
multiple linear regressionsmultiple robust regressionmultiple linear regressionsmultiple robust regression
modelsβ95% CIp valueβ95% CIp valuemodelsβ95% CIp valueβ95% CIp value
SONG-HD model 1 −4.012 −6.668 to 1.356 0.004 −4.012 −6.396–1.444 0.003 NRS Model 1 −4.104 −6.701–1.506 0.002 −4.104 −6.421–1.786 0.001 
SONG-HD model 2 −3.335 −5.748 to −0.922 0.007 −3.335 −5.892–−0.779 0.011 NRS Model 2 −3.433 −5.898–−0.968 0.007 −3.433 −5.714–−1.152 0.004 
SONG-HD model 3 −2.795 −5.525 to −0.066 0.045 −2.795 −5.739–−0.149 0.063 NRS Model 3 −3.514 −6.114–−0.915 0.009 −3.514 −5.897–−1.131 0.004 
SONG-HD model 4 −3.682 −6.236 to 1.128 0.005 −3.682 −6.188–1.175 0.005 NRS Model 4 −3.953 −6.502–−1.404 0.003 −3.953 −6.221–−1.685 0.001 
SONG-HD scoreNRS score
multiple linear regressionsmultiple robust regressionmultiple linear regressionsmultiple robust regression
modelsβ95% CIp valueβ95% CIp valuemodelsβ95% CIp valueβ95% CIp value
SONG-HD model 1 −4.012 −6.668 to 1.356 0.004 −4.012 −6.396–1.444 0.003 NRS Model 1 −4.104 −6.701–1.506 0.002 −4.104 −6.421–1.786 0.001 
SONG-HD model 2 −3.335 −5.748 to −0.922 0.007 −3.335 −5.892–−0.779 0.011 NRS Model 2 −3.433 −5.898–−0.968 0.007 −3.433 −5.714–−1.152 0.004 
SONG-HD model 3 −2.795 −5.525 to −0.066 0.045 −2.795 −5.739–−0.149 0.063 NRS Model 3 −3.514 −6.114–−0.915 0.009 −3.514 −5.897–−1.131 0.004 
SONG-HD model 4 −3.682 −6.236 to 1.128 0.005 −3.682 −6.188–1.175 0.005 NRS Model 4 −3.953 −6.502–−1.404 0.003 −3.953 −6.221–−1.685 0.001 

SONG-HD model 1: adjusted for sex, age, and all CKD-MBD characters (Ca, P, iPTH, ALP, 25[OH]D).

SONG-HD model 2: adjusted for sex, age, candidate demographics variables, and HD-related variables with a p value <0.2 on univariate analysis (participate in work, payment for treatment cost, marriage status, accumulated exercise hours per week, dialysis frequency).

SONG-HD model 3: adjusted for sex, age, candidate test results with a p value <0.2 on univariate analysis (carbonate ion, sodium, blood urea nitrogen, creatinine).

SONG-HD model 4: adjusted for sex, age, and all CKD-MBD-related medicines (calcium, calcium-free phosphorus binders, calcitriol, paricalcitol, calcimimetics).

NRS model 1: adjusted for sex, age, and all CKD-MBD characters (Ca, P, iPTH, ALP, 25(OH)D).

NRS model 2: adjusted for sex, age, candidate demographics variable, and HD-related variables with a p value <0.2 on univariate analysis (participate in work, payment for treatment cost, smoking, dialysis frequency).

NRS model 3: adjusted for sex, age, candidate test results with a p value <0.2 on univariate analysis (carbonate ion, sodium, cholesterol).

NRS model 4: adjusted for sex, age, and all CKD-MBD-related medicines (calcium, calcium-free phosphorus binders, calcitriol, paricalcitol, calcimimetics).

CKD-MBD, chronic kidney disease-mineral and bone disorder; SONG-HD, Standardized Outcomes in Nephrology-Hemodialysis; HD, hemodialysis; NRS, numeric rating scale; Ca, serum total calcium; P, phosphate; iPTH, intact parathyroid hormone; ALP, alkaline phosphatase.

Fig. 1.

Scatter diagrams and Spearman coefficient between lg(25(OH)D [nmol/L]) and fatigue scores in elderly (age ≥65 years) maintenance hemodialysis patients (n = 89).

Fig. 1.

Scatter diagrams and Spearman coefficient between lg(25(OH)D [nmol/L]) and fatigue scores in elderly (age ≥65 years) maintenance hemodialysis patients (n = 89).

Close modal

Fatigue is a common symptom of patients with chronic kidney disease. This study on stable MHD patients showed that the rate of fatigue in the past week (SONG-HD score) was 83.6%, and rate of fatigue at the end of hemodialysis (NRS score) was 86.1%, which were generally consistent with previous reports [1‒3]. Fatigue is associated with mortality, hospitalization, and other adverse outcomes in patients with chronic kidney disease and other chronic somatic diseases. Numerous risk factors fatigue in MHD patients have been identified, including anemia [3], metabolic acidosis [13], malnutrition, protein energy wasting [14, 15], and so on.

CKD-MBD which refers to CKD leading to a series of mineral and bone metabolism abnormalities is one of the most common complications in MHD patients [16]. CKD-MBD includes abnormalities of Ca, P, PTH, and/or vitamin D; abnormalities in bone turnover, mineralization, volume, linear growth or strength; and/or vascular or other soft tissue calcification. In this study, serum CKD-MBD markers and potential factors that may affect fatigue were collected as completely as possible for multifactor adjusting; negative correlations between fatigue scores and serum 25(OH)D were found in elderly MHD patients. This is a novel discovery; although there is no direct pathophysiological or clinical evidence about the effect of 25[OH]D on fatigue in MHD patients reported, some evidences indirectly suggest the potential mechanisms of their interaction. 25[OH]D deficiency can cause abnormal muscle mass and strength [17], which will contribute to fatigue; on the other hand, hypoactivity caused by fatigue can lead to the decline of 25(OH)D level [18].

It is known that dietary intake and skin synthesis of vitamin D are catalyzed to 25(OH)D by 25-hydroxylase in the liver and then catalyzed to 1,25(OH)2D by 1α-hydroxylase in the kidney; 1,25(OH)2D is the main active form which regulates bone and mineral metabolism through vitamin D receptors (VDRs). Although the activation ability of 25(OH)D is only 1% of that of 1,25(OH)2D, serum 25(OH)D is a reliable indicator for the determination of vitamin D because of its higher blood concentration, longer half-life, and greater stability. Vitamin D status is associated not only with fractures and osteoporosis, but also with extra-skeletal health problems such as myasthenia and sarcopenia, cachexia, tumors, metabolic abnormalities, cardiovascular diseases, immune abnormalities, and cognitive decline [19]. A number of clinical observational studies have confirmed the correlations between 25(OH)D and muscle mass and muscle strength in patients with CKD: 25[OH]D level was correlated with proximal muscle strength of lower limbs in elderly patients with CKD before dialysis [20], 25[OH]D was positively correlated with grip strength of MHD patients [21], and 25(OH)D deficiency in peritoneal dialysis patients (<20 ng/mL) was associated with sarcopenia and decreased grip strength [22]. Studies in vivo have further verified the conclusions of clinical observational studies: both VDR gene knockout mice and mice with vitamin D deficiency caused by restricted diet showed decreased muscle mass and muscle strength [23]. Another study showed that mRNA and VDR expressions appear in larger numbers in satellite cells than in mature muscle fibers, suggesting a more prominent role in muscle progenitors [24]. When VDR is inhibited by anti-VDR, it is possible to inhibit 1,25(OH)D-dependent mechanisms by which the rapid intracellular entry of Ca can be downregulated, implying a direct nongenomic role for VDR in manipulating Ca in muscle tissue [25].

Some intervention researches have explored impacts of vitamin D supplementation on muscle mass and function in specific populations. In elderly mobility-limited vitamin D-insufficient women, 4-month vitamin D supplementation increased muscle fiber size by 10% and increased intramyonuclear VDR concentration by 30% [26]. Seasonal vitamin D supplementation could enhance some aspects of strength/power in college swimmers [27]. Meta-analysis showed that calcifediol has a positive effect on muscle strength parameters [28], and daily vitamin D dose of 800 to 1,000 IU was the most probable way to reduce fall risk [29]. However, a RCT study that enrolled dialysis patients with 25(OH)D concentration <50 nmol/L showed that high-dose cholecalciferol “had no effect on muscle strength or symptoms but appears safe” [30].

For patients with CKD, especially end-stage renal disease, the action of 1α-hydroxylase declines, vitamin D function is impaired. Considering that at least 10 kinds of extra-renal tissue cells (gastrointestinal tract, skin, blood vessels, mammary epithelial cells, osteoblasts and osteoclasts, etc.) express 1α-hydroxylase [19], activated 1,25(OH)2D can be generated and produces physiological effects through autocrine or paracrine pathways. Therefore, vitamin D3 can be used as a general nutritional supplement for patients with CKD and vitamin D deficiency. This study showed a negative correlation between blood 25(OH)D and fatigue in elderly MHD patients, suggesting that MHD elders may benefit more from vitamin D supplementation and further follow-up and intervention studies are worth expecting.

In our study, negative correlations between fatigue scores and 25(OH)D levels were observed in elderly patients but not in non-elderly (young and middle aged) patients. One explanation for this finding is that elderly patients were with higher ratio of fatigue and higher fatigue score levels, and they were more susceptible to related factors. Furthermore, interactions were found between age ≥65 years and 25(OH)D in terms of fatigue scores, which suggests that certain aging factors may mediate interaction between vitamin D and fatigue, and Klotho may be a potential candidate. Klotho is an increasingly recognized anti-aging hormone that also affects vitamin D metabolism [31]. “Klotho-deficient mice exhibit complex aging-like phenotypes including hypogonadism, arteriosclerosis (vascular calcification), cardiac hypertrophy, osteopenia, sarcopenia, frailty, and premature death” [32].

There were several limitations in the present study. First, our study was a single-center study with a limited sample size which might affect the representativeness of MHD patients. Second, there are more than ten fatigue scales used in studies of patients with CKD [1], and our study used SONG-HD fatigue measure to access experience of fatigue in the past week and NRS to assess the level of fatigue at the end of hemodialysis; however, duration and frequency of post-dialysis fatigue were not assessed. NRS is a simple and practical clinical tool to assess patients’ fatigue level [11], but there were no studies to validate it in dialysis patients. Third, depression, anxiety, and sleep scales were absent from our study, which might contribute to residual confounding. In conclusion, we reported that serum 25(OH)D level is negatively associated with fatigue in elderly MHD patients, which suggest novel pathophysiology and treatment for fatigue in MHD patients.

We would like to thank the staff at the Center for Big Data Research in Health and Medicine, the First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, for their valuable contribution.

This study complied with the Declaration of Helsinki and was approved by the First Affiliated Hospital of Shandong First Medical University, where the study was conducted, approval number YXLL-KY-2021 (062). Written informed consent for each participant was obtained.

The authors have no conflicts of interest to declare.

Nephropathy Medical Development Research Project of China Primary Health Care Foundation (SO.20220217SD to Xiaoyan Jia) was responsible for analysis of data and manuscript writing; Medical and Health Science and Technology Development Plan of Shandong Province (202014011363 to Lili Wang) was responsible for the collection, management, and interpretation of data.

M.P collected, analyzed, and interpreted data, and drafted the manuscript. L.C. and N.J. collected, analyzed, and interpreted data. M.J. and B.W. collected and interpreted the data. L.W. and X.J. conceived and designed the study, helped draft the manuscript, had full access to all the study data, and take responsibility for the integrity of the data and the accuracy of the analysis. All authors provided critical feedback and approved the final manuscript.

Additional Information

Clinical Trial Registration: This study has been registered (ChiCTR2100045493) 2021/04/03.

All data generated or analyzed during this study are included in this article and its online supplementary materials. Further inquiries can be directed to the corresponding author.

1.
Gregg
LP
,
Bossola
M
,
Ostrosky-Frid
M
,
Hedayati
SS
.
Fatigue in CKD: epidemiology, pathophysiology, and treatment
.
Clin J Am Soc Nephrol
.
2021
;
16
(
9
):
1445
55
.
2.
Tian
C
,
Zhang
B
,
Liang
W
,
Yang
Q
,
Xiong
Q
,
Jin
Q
.
Fatigue in peritoneal dialysis patients and an exploration of contributing factors: a cross-sectional study
.
J Pain Symptom Manage
.
2020
;
59
(
5
):
1074
81.e2
.
3.
Ju
A
,
Unruh
ML
,
Davison
SN
,
Dapueto
J
,
Dew
MA
,
Fluck
R
.
Patient-reported outcome measures for fatigue in patients on hemodialysis: a systematic review
.
Am J Kidney Dis
.
2018
;
71
(
3
):
327
43
.
4.
Tonon
CR
,
Silva
TAAL
,
Pereira
FWL
,
Queiroz
DAR
,
Junior
ELF
,
Martins
D
.
A review of current clinical concepts in the pathophysiology, etiology, diagnosis, and management of hypercalcemia
.
Med Sci Monit
.
2022
;
28
(
28
):
e935821
.
5.
Håglin
L
.
Using phosphate supplementation to reverse hypophosphatemia and phosphate depletion in neurological disease and disturbance
.
Nutr Neurosci
.
2016
;
19
(
5
):
213
23
.
6.
Ryan
JW
,
Anderson
PH
,
Morris
HA
.
Pleiotropic activities of vitamin D receptors: adequate activation for multiple health outcomes
.
Clin Biochem Rev
.
2015
;
36
(
2
):
53
61
.
7.
Romagnoli
C
,
Brandi
ML
.
Muscle physiopathology in parathyroid hormone disorders
.
Front Med
.
2021
;
8
(
8
):
764346
.
8.
Joshwa
B
,
Campbell
ML
.
Fatigue in patients with chronic kidney disease: evidence and measures
.
Nephrol Nurs J
.
2017
;
44
(
4
):
337
43
.
9.
Lertdumrongluk
P
,
Lau
WL
,
Park
J
,
Rhee
CM
,
Kovesdy
CP
,
Kalantar-Zadeh
K
.
Impact of age on survival predictability of bone turnover markers in hemodialysis patients
.
Nephrol Dial Transpl
.
2013
;
28
(
10
):
2535
45
.
10.
Aslam
S
,
Saggi
SJ
,
Salifu
M
,
Kossmann
RJ
.
Online measurement of hemodialysis adequacy using effective ionic dialysance of sodium: a review of its principles, applications, benefits, and risks
.
Hemodial Int
.
2018
;
22
(
4
):
425
34
.
11.
Ju
A
,
Teixeira-Pinto
A
,
Tong
A
,
Smith
AC
,
Unruh
M
,
Davison
SN
.
Validation of a core patient-reported outcome measure for fatigue in patients receiving hemodialysis: the SONG-HD fatigue instrument
.
Clin J Am Soc Nephrol
.
2020
;
15
(
11
):
1614
21
.
12.
Gladman
D
,
Nash
P
,
Goto
H
,
Birt
JA
,
Lin
CY
,
Orbai
AM
.
Fatigue numeric rating scale validity, discrimination and responder definition in patients with psoriatic arthritis
.
RMD Open
.
2020
;
6
(
1
):
e000928
.
13.
Raphael
KL
.
Metabolic acidosis in CKD: core curriculum 2019
.
Am J Kidney Dis
.
2019
;
74
(
2
):
263
75
.
14.
Macdonald
JH
,
Fearn
L
,
Jibani
M
,
Marcora
SM
.
Exertional fatigue in patients with CKD
.
Am J Kidney Dis
.
2012
;
60
(
6
):
930
9
.
15.
Wilkinson
TJ
,
Gould
DW
,
Nixon
DGD
,
Watson
EL
,
Smith
AC
.
Quality over quantity? Association of skeletal muscle myosteatosis and myofibrosis on physical function in chronic kidney disease
.
Nephrol Dial Transpl
.
2019
;
34
(
8
):
1344
53
.
16.
Ketteler
M
,
Block
GA
,
Evenepoel
P
,
Fukagawa
M
,
Herzog
CA
,
McCann
L
.
Executive summary of the 2017 KDIGO chronic kidney disease-mineral and bone disorder (CKD-MBD) guideline update: what’s changed and why it matters
.
Kidney Int
.
2017
;
92
(
1
):
26
36
.
17.
Hruska
KA
,
Sugatani
T
,
Agapova
O
,
Fang
Y
.
The chronic kidney disease: mineral bone disorder (CKD-MBD) – advances in pathophysiology
.
Bone
.
2017
;
100
:
80
6
.
18.
Avin
KG
,
Allen
MR
,
Chen
NX
,
Srinivasan
S
,
O’Neill
KD
,
Troutman
AD
.
Voluntary wheel running has beneficial effects in a rat model of CKD-mineral bone disorder (CKD-MBD)
.
J Am Soc Nephrol
.
2019
;
30
(
10
):
1898
909
.
19.
Hewison
M
,
Burke
F
,
Evans
KN
,
Lammas
DA
,
Sansom
DM
,
Liu
P
.
Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease
.
J Steroid Biochem Mol Biol
.
2007
103
3–5
316
21
.
20.
Saito
A
,
Hiraki
K
,
Otobe
Y
,
Izawa
KP
,
Sakurada
T
,
Shibagaki
Y
.
Relationship between serum vitamin D and leg strength in older adults with pre-dialysis chronic kidney disease: a preliminary study
.
Int J Environ Res Public Health
.
2020
;
17
(
4
):
1433
.
21.
Kang
SH
,
Do
JY
,
Cho
JH
,
Jeong
HY
,
Yang
DH
,
Kim
JC
.
Association between vitamin D level and muscle strength in patients undergoing hemodialysis
.
Kidney Blood Press Res
.
2020
;
45
(
3
):
419
30
.
22.
Wang
L
,
Luo
Q
,
Zhu
B
,
Zhou
F
.
Relation of serum 25-hydroxyvitamin D status with skeletal muscle mass and grip strength in patients on peritoneal dialysis
.
J Nutr Sci Vitaminol
.
2019
;
65
(
6
):
477
82
.
23.
Girgis
CM
,
Cha
KM
,
Houweling
PJ
,
Rao
R
,
Mokbel
N
,
Lin
M
.
Vitamin D receptor ablation and vitamin D deficiency result in reduced grip strength, altered muscle fibers, and increased myostatin in mice
.
Calcif Tissue Int
.
2015
;
97
(
6
):
602
10
.
24.
Olsson
K
,
Saini
A
,
Stromberg
A
,
Alam
S
,
Lilja
M
,
Rullman
E
.
Evidence for vitamin D receptor expression and direct effects of 1α,25(OH)2D3 in human skeletal muscle precursor cells
.
Endocrinology
.
2016
;
157
(
1
):
98
111
.
25.
Santill an
G
,
Katz
S
,
Vazquez
G
,
Boland
RL
.
TRPC3-like protein and vitamin D receptor mediate 1alpha,25(OH)2D3-induced SOC influx in muscle cells
.
Int J Biochem Cell Biol
.
2004
;
36
(
10
):
1910
8
.
26.
Ceglia
L
,
Niramitmahapanya
S
,
da Silva Morais
M
,
Rivas
DA
,
Harris
SS
,
Bischoff-Ferrari
H
.
A randomized study on the effect of vitamin D supplementation on skeletal muscle morphology and vitamin D receptor concentration in older women
.
J Clin Endocrinol Metab
.
2013
98
12
E1927
35
.
27.
Rockwell
MS
,
Frisard
MI
,
Rankin
JW
,
Zabinsky
JS
,
Mcmillan
RP
,
You
W
.
Effects of seasonal vitamin D3 supplementation on strength, power, and body composition in college swimmers
.
Int J Sport Nutr Exerc Metab
.
2020
;
30
(
2
):
165
73
.
28.
Barbagallo
M
,
Veronese
N
,
Di Prazza
A
,
Pollicino
F
,
Carruba
L
,
La Carrubba
A
.
Effect of calcifediol on physical performance and muscle strength parameters: a systematic review and meta-analysis
.
Nutrients
.
2022
;
14
(
9
):
1860
.
29.
Kong
SH
,
Jang
HN
,
Kim
JH
,
Kim
SW
,
Shin
CS
.
Effect of vitamin D supplementation on risk of fractures and falls according to dosage and interval: a meta-analysis
.
Endocrinol Metab
.
2022
;
37
(
2
):
344
58
.
30.
Singer
R
,
Chacko
B
,
Talaulikar
G
,
Karpe
K
,
Walters
G
.
Placebo-controlled, randomized clinical trial of high-dose cholecalciferol in renal dialysis patients: effect on muscle strength and quality of life
.
Clin Kidney J
.
2019
;
12
(
2
):
281
7
.
31.
Clemens
Z
,
Sivakumar
S
,
Pius
A
,
Sahu
A
,
Shinde
S
,
Mamiya
H
.
The biphasic and age-dependent impact of klotho on hallmarks of aging and skeletal muscle function
.
Elife
.
2021
;
10
:
e61138
.
32.
Kuro-O
M
.
Klotho and calciprotein particles as therapeutic targets against accelerated ageing
.
Clin Sci
.
2021
;
135
(
15
):
1915
27
.