Supplemental Material
Table of Contents
1. Item S1. Supplementary methods on covariate and data collection in CRIC
2. Supplemental Table S1: Additional metrics of model fit and model characteristics from multivariable adjusted linear mixed-effects models of eGFR on uremic symptom severity
3. Supplemental Table S2: Number of observations included in present analysis stratified by visit year and percentage of missing values for variables among CRIC Study participants included in the current analysis
4. Supplemental Table S3: Percentage of patients reporting marked symptom worsening or improvement over follow-up for 3,297 CRIC Study participants using 0.3*SD to define marked symptom change
5. Supplemental Table S4: Comparison of effect estimate for the association between eGFR and anorexia severity score using different eGFR estimating equations in multivariable adjusted linear mixed-effects models
6. Supplemental Table S5: Predicted change in anorexia symptom severity score associated with a 5 mL/min/1.73 m2 decrease in eGFR using different eGFR estimating equations
7. Supplemental Table S6: Predicted change in uremic symptom severity score associated with a 5 mL/min/1.73 m2 decrease in eGFR, with depressive symptoms modeled as a time-updated covariate using last observation carried forward to account for missing values
8. Supplemental Table S7: Additional clinical and laboratory characteristics of CRIC Study participants included in the current study, classified by baseline CKD stage
9. Supplemental Table S8: Baseline characteristics of CRIC Study participants, stratified by inclusion or exclusion in the current study
10. Supplemental Table S9: Spearman correlation between individual symptom scores at baseline in 3,685 CRIC Study participants
11. Supplemental Table S10: Spearman correlation between mean annual rates of change in symptom
12. Supplemental Table S11: Uremic symptom severity of CRIC Study participants, stratified by enrollment G-stage of 4 or 5, versus progression to G-stage 4 or 5 during follow-up
13. Supplemental Table S12: Population average annual change in symptom score and percentage of patients reporting marked symptom worsening or improvement over follow-up for 3,685 CRIC Study participants, stratified by symptom severity at the baseline assessment
14. Supplemental Table S13: Number of uremic symptoms significantly worsening, improving, or remaining stable for each CRIC Study participant
15. Supplemental Table S14: Predicted change in uremic symptom severity score associated with a 5 mL/min/1.73 m2 decrease in eGFR calculated from multivariable models including laboratory parameters
16. Supplemental Table S15: Comparison of effect estimate for the association between eGFR and uremic symptom severity score between multivariable adjusted linear mixed-effects models and joint models
17. Supplemental Table S16: Final multivariable-adjusted models of symptom severity among CRIC Study participants using automated algorithm for covariate selection
Item S1: Supplementary methods on covariate and data collection in CRIC
Socioeconomic characteristics (e.g., age, sex, race/ethnicity, employment, etc.) were self-reported at the initial study visit. Body mass index (BMI; weight [kg] divided by height [m2]) and systolic and diastolic blood pressure were measured by trained study personnel at annual visits. Comorbid medical conditions (e.g., cardiovascular disease, cancer, etc.) and health-related behaviors (e.g., smoking and alcohol use) were self- reported at the initial study visit and updated annually. Development of dialysis-dependent CKD and
cardiovascular events were ascertained through biannual contact via participant self-report and supplemented by information from the US Renal Data System and review of hospital records, respectively. Current
medications were recorded at annual study visits by review of participant medication bottles or updated medication lists. Hemoglobin, serum albumin and bicarbonate levels were measured at annual visits.
Parathyroid hormone was measured on the entire cohort at the baseline visit only. Depressive symptoms were assessed using the Beck’s Depression Inventory (BDI), with a score >14 was used to define presence of depressive symptoms.14 Cognitive function was evaluated with the Mini-Mental State Exam (MMSE) and a score ≥ 1 standard deviation below the cohort mean considered significant cognitive impairment. Weekly vigorous activity was considered completion of any activity with metabolic equivalent of task (MET) score ≥6 as reported on the Typical Week Physical Activity Survey. Depressive symptoms, cognitive impairment, and physical activity were assessed at the baseline visit and intermittently thereafter.
Covariates for which data was collected at annual visits were included as time-varying covariates in our models. This includes BMI, systolic and diastolic blood pressure, urine protein-creatinine ratio, comorbid medical conditions, health-related behaviors, medications (both total number and use of specific medications), serum albumin, hemoglobin, and bicarbonate. For these variables, participants with missing values at baseline were excluded from analyses, and missing values at visits after the baseline assessment were imputed by carrying forward the prior, non-missing value. Baseline values for all socioeconomic factors were included as fixed covariates in models. For depressive symptoms and cognitive impairment, the mean BDI and MMSE scores were calculated for each participant, respectively, and used to classify depressive symptoms and cognitive impairment as described above. The prior value for weekly vigorous activity was carried forward to impute missing values. Because parathyroid hormone was measured on the entire cohort at only the baseline
Table S1. Additional metrics of model fit and model characteristics from multivariable adjusted linear mixed-effects models of eGFR on uremic symptom severity
Model metric Fatigue Anorexia Pruritus Nausea Paresthesia Pain
KDQOL symptom
domain
R2 60% 54% 53% 50% 62% 64% 68%
Random intercepts, SD (SE)* 6.8 (0.3) 4.1 (0.2) 6.4 (0.1) 4.1 (0.2) 6.5 (0.3) 6.4 (0.3) 4.1 (0.1) Random slopes, SD (SE)† 1.5 (0.1) 1.2 (0.04) 1.5 (0.1) 1.1 (0.04) 1.7 (0.1) 1.6 (0.1) 0.9 (0.02) Displaying the standard deviation (SD) and standard error (SE) for the random intercepts and random slopes of multivariable adjusted linear mixed-effects models. This method models uremic symptom score over time for the population (fixed effect) and for each participant (random effects). The distribution of random intercepts represents the participant-level deviation from the population mean symptom score at baseline. The distribution of random slopes represents the participant-level deviation from the population- averaged slope of symptom score over time. Models adjusted for time, clinical site, age, sex, race, ethnicity, employment, education, marital status, BMI, proteinuria, coronary artery disease, diabetes, hypertension, congestive heart failure, peripheral vascular disease, history of malignancy, cerebrovascular disease, depressive symptoms, and smoking.
Table S2. Number of observations included in present analysis stratified by visit year and percentage of missing values for variables among CRIC Study participants included in the current analysis
Visit Year
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
CRIC participants completing visit, N 3,939 3,520 3,271 3,077 2,870 2,710 2,555 2,424 2,252 2,074 1,841 1,660 1,206 671 147 Complete eGFR and KDQOL symptoms, N 3,882 3,363 2,978 2,710 2,384 2,170 1,652 1,746 1,500 1,303 1,061 934 667 344 101 Observations included in current analysis,* N 3,685 3,158 2,789 2,536 2,228 2,022 1,822 1,628 1,402 1,223 986 876 621 318 98
Variable
Age† 0 -- -- -- -- -- -- -- -- -- -- -- -- -- --
Sex† 0 -- -- -- -- -- -- -- -- -- -- -- -- -- --
Socioeconomic factors
Race/ethnicity† 0 -- -- -- -- -- -- -- -- -- -- -- -- -- --
Employment† 0.2 -- -- -- -- -- -- -- -- -- -- -- -- -- --
Educational attainment† 0.03 -- -- -- -- -- -- -- -- -- -- -- -- -- --
Annual income† 0 -- -- -- -- -- -- -- -- -- -- -- -- -- --
Marital status† 0 -- -- -- -- -- -- -- -- -- -- -- -- -- --
Clinical parameters
BMI category 0.3 0.1 1.0 1.1 0.9 1.8 1.3 1.2 1.4 1.5 1.0 1.4 1.7 1.2 2.0
Systolic blood pressure 0.03 0.4 0.4 0.2 0.6 0.5 0.7 0.7 0.9 0.7 1.0 0.9 1.1 0.6 3.0
Diastolic blood pressure 0.03 0.5 0.4 0.4 0.9 0.5 0.7 0.8 0.9 0.7 1.1 0.9 1.1 0.6 3.0
Urine protein-to-creatinine ratio 4.1 7.5 13.6 16.9 18.5 18.2 7.9 6.5 5.8 5.6 5.0 8.1 6.7 11.8 11.0 Clinical characteristics
Coronary artery disease 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Diabetes 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Hypertension 0 0.1 0.03 0.04 0.04 0 0.1 0 0.1 0 0 0.1 0 0 0
Congestive heart failure 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Peripheral vascular disease 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Cerebrovascular disease 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Malignancy within past 5 years 0 0.03 0 0.04 0.04 0.1 0.2 0.1 0.1 0.2 0.2 0 0 0 0
Depressive symptoms†† 1.1 -- 1.1 -- 2.7 -- 10.8 -- -- -- -- -- -- -- --
Cognitive impairment†† 0.6 -- 1.5 -- 3.5 -- 10.0 -- 11.6 -- 4.3 3.4 3.3 7.9 7.0
Active smoking 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Weekly alcohol use 0 0.03 0.03 0.07 0.1 0.1 0.2 0.1 0.1 0.2 0.2 0 0 0 0
Weekly vigorous activity†† 0.2 -- 0.4 -- 3.5 -- 11.0 -- 9.3 -- 2.5 1.5 1.5 2.1 3.0
Medications
Total number of medications 1.4 1.2 1.5 1.4 1.5 1.2 0.9 1.3 1.2 1.2 0.8 0.8 0.8 0.3 1.0
Beta blockers 0.7 0.4 0.7 0.6 0.8 0.6 0.3 0.6 0.5 0.6 0.2 0.3 0.5 0.0 1.0
NSAIDs 0.7 0.4 0.7 0.6 0.8 0.6 0.3 0.6 0.5 0.6 0.2 0.3 0.5 0.0 1.0
Opioids 1.4 1.2 1.5 1.4 1.5 1.2 0.9 1.3 1.2 1.2 0.8 0.9 0.8 0.3 1.0
Gabapentin 1.4 1.2 1.5 1.4 1.5 1.2 0.9 1.3 1.2 1.2 0.8 0.9 0.8 0.3 1.0
Antidepressants 0.7 0.4 0.7 0.6 0.8 0.6 0.3 0.6 0.5 0.6 0.2 0.3 0.5 0.0 1.0
Anxiolytics 0.7 0.4 0.7 0.6 0.8 0.6 0.3 0.6 0.5 0.6 0.2 0.3 0.5 0.0 1.0
Laboratory parameters
Hemoglobin 0.5 1.1 1.4 0.9 1.0 0.7 0.8 0.9 1.2 0.7 0.4 0.7 0.9 0.3 1.0
PTH§ 2.0 -- -- -- -- -- -- -- -- -- -- -- -- -- --
Albumin 1.5 0.1 0.7 0.04 0.2 0.1 0 0 0 0 0 0 0 0 0
Bicarb 0.8 0.1 0.03 0.04 0 0 0 0 0 0 0 0 0 0 0
Data displayed as % missingness, unless otherwise indicated. For the baseline visit (Visit Year = 0), the denominator used to calculate the percent missingness is 3,882. For all other visit years, the denominator used is the value in the row “complete eGFR and KDQOL symptoms”. “--” Indicates variable was not assessed at visit per CRIC Study protocol. The most common reason for CRIC Study participants to have missing eGFR values is progression to dialysis-dependent CKD.
*This row indicates the number of participants with complete information on eGFR, KDQOL symptom data, and covariates
†Variable only assessed at baseline visit.
††Per CRIC Study protocol, these variables were not assessed at every CRIC Study visit. In the current analysis, the mean value across available assessments for each participant is used as a fixed variable.
§Missingness >20% after Baseline visit. In the current analysis, the baseline value for PTH was used as a fixed variable.
Abbreviations: KDQOL, Kidney Disease Quality of Life instrument; BMI, body mass index; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; NSAID, non-steroidal anti-inflammatory drug; PTH, parathyroid hormone
Table S3. Percentage of patients reporting marked symptom worsening or improvement over follow-up for 3,297 CRIC Study participants using 0.3*SD to define marked
symptom change
Symptom % Worsening,
≥ +5 points/year % Stable % Improved,
≥ -5 points/year
Fatigue 9% 85% 6%
Anorexia 8% 87% 4%
Pruritus 7% 83% 10%
Nausea 8% 86% 6%
Paresthesia 7% 86% 7%
Pain 7% 85% 8%
KDQOL, symptoms domain† 8% 86% 6%
To estimate the uremic symptom trajectory for each participant, individual slopes were calculated using linear regression of symptom severity score on time. An absolute mean change in the symptom score of (0.3 * the standard deviation for each symptom score) points per year or greater was considered a significant worsening or improvement in the symptom severity score.
Table S4. Comparison of effect estimate for the association between eGFR and anorexia severity score using different eGFR estimating equations in multivariable adjusted linear mixed-effects models
eGFR CKD-EPI (n=3,685)
eGFR CKD-EPI Cystatin C
(n=3,685) eGFR ! coefficient (-0.28, -0.17) -0.22 -0.18
(-0.14, -0.23) eGFR2 ! coefficient (0.001, 0.003) 0.002 0.001
(0.001, 0.002)
*Multivariable adjusted for time, clinical site, age, sex, race, ethnicity, employment, education, marital status, BMI, proteinuria, coronary artery disease, diabetes, hypertension, congestive heart failure, peripheral vascular disease, history of malignancy, cerebrovascular disease, depressive symptoms, and smoking.
Table S5. Predicted change in anorexia symptom severity score associated with a 5 mL/min/1.73 m2 decrease in eGFR using different eGFR estimating equations
Baseline eGFR, mL/min/1.73 m2
Predicted change in anorexia severity score (0-100 scale)*
eGFR CKD-EPI eGFR CKD-EPI Cystatin C
20 0.79
(0.60, 0.99)
0.70 (0.54, 0.85)
30 0.60
(0.45, 0.74)
0.57 (0.45, 0.70)
40 0.41
(0.31, 0.51)
0.44 (0.35, 0.54)
50 0.22
(0.13, 0.31)
0.32 (0.25, 0.39)
60 0.03
(-0.08, 0.14) 0.19
(0.13, 0.25)
70 -0.16
(-0.31, -0.01)
0.07 (0.0, 0.13) Values reported as mean (95% CI). Predicted symptom severity scores for different values of eGFR were calculated following use of multivariable adjusted linear mixed- effects models with random intercepts and random slopes. Mean values for all covariates were used. Bold font indicates statistically significant results (p<0.05).
*0 denotes symptom not present; 100 denotes extreme symptom severity. A positive value indicates worsening symptom severity; a negative value indicates improving symptom severity.
Table S6. Predicted change in uremic symptom severity score associated with a 5 mL/min/1.73 m2 decrease in eGFR, with depressive symptoms modeled as a time-updated, categorical covariate using last observation carried forward to account for missing values
Baseline eGFR, mL/min/1.73 m2
Predicted change in symptom score (0-100 scale)*
Fatigue Anorexia Pruritus Nausea Paresthesia Pain
KDQOL symptom
domain
20 1.26
(1.01, 1.52) 0.77
(0.57, 0.96) 0.76
(0.50, 1.02) 0.71
(0.50, 0.92) 0.34
(0.09, 0.60) 0.54
(0.26, 0.82) 0.66 (0.53, 0.78)
30 0.99
(0.80, 1.18)
0.58 (0.44, 0.73)
0.60 (0.41, 0.79)
0.53 (0.37, 0.68)
0.29 (0.10, 0.47)
0.42 (0.21, 0.62)
0.53 (0.44, 0.62)
40 0.72
(0.59, 0.85)
0.40 (0.29, 0.50)
0.44 (0.30, 0.58)
0.34 (0.23, 0.45)
0.23 (0.10, 0.36)
0.29 (0.15, 0.44)
0.40 (0.33, 0.47)
50 0.45
(0.33, 0.56)
0.21 (0.12, 0.30)
0.28 (0.16, 0.39)
0.15 (0.06, 0.25)
0.17 (0.05, 0.28)
0.17 (0.04, 0.29)
0.27 (0.21, 0.33)
60 0.18
(0.03, 0.32)
0.03 (-0.08, 0.14)
0.12 (-0.03, 0.26)
-0.03 (-0.15, 0.08)
0.11 (-0.03, 0.25)
0.04 (-0.11, 0.20)
0.14 (0.07, 0.21)
70 -0.09
(-0.30, 0.11) -0.16
(-0.31, -0.00) 0.05
(-0.25, 0.16) -0.22
(-0.38, -0.05) 0.05
(-0.15, 0.25) -0.08
(-0.30, 0.14) 0.01 (-0.09, 0.11) Values reported as mean (95% CI). Predicted symptom severity scores for different values of eGFR were calculated following use of multivariable adjusted linear mixed-effects models with random intercepts and random slopes. Models adjusted for time, clinical site, age, sex, race, ethnicity, employment, education, marital status, BMI, proteinuria, coronary artery disease, diabetes, hypertension, congestive heart failure, peripheral vascular disease, history of malignancy, cerebrovascular disease, depressive symptoms, and smoking. Mean values for all covariates were used. Bold font indicates statistically significant results (p<0.05).
*0 denotes symptom not present; 100 denotes extreme symptom severity. A positive value indicates worsening symptom severity; a negative value indicates improving symptom severity.
Table S7. Additional clinical and laboratory characteristics of CRIC Study participants included in the current study, classified by baseline CKD stage.
Characteristics Stage of CKD
Overall G1 & 2 G3a G3b G4 & 5
N (%) 3,685 545 (15) 1,117 (30) 1,338 (36) 685 (19) Socioeconomic factors
Annual income, N (%)
<$20,000 1,147 (31) 98 (18) 276 (25) 486 (36) 287 (42)
$20-50,000 903 (25) 126 (23) 286 (26) 321 (24) 170 (25)
$50-100,000 693 (19) 150 (28) 230 (21) 213 (16) 100 (15)
>$100,000 371 (10) 83 (15) 148 (13) 105 (8) 35 (5)
Wish not to answer 571 (15) 88 (16) 177 (16) 213 (16) 93 (14) Clinical parameters
Mean systolic BP (SD), mmHg 128 (±22) 122 (±20) 127 (±21) 130 (±23) 132 (±24) Mean diastolic BP (SD), mmHg 71 (±13) 74 (±13) 72 (±12) 71 (±13) 70 (±13) Clinical characteristics, N (%)
Cognitive impairment 494 (13) 26 (5) 106 (9) 214 (16) 148 (22)
Weekly alcohol use 745 (20) 155 (28) 262 (23) 228 (17) 100 (15)
Weekly vigorous activity 869 (24) 191 (35) 311 (28) 260 (19) 107 (16) Hospitalized for cardiovascular event 1,389 (38) 120 (22) 381 (34) 551 (41) 337 (49) Medications
Median medication number (IQR) 8 (6-11) 7 (5-10) 8 (5-11) 9 (6-12) 9 (6-12)
ACEi/ARB, N (%) 2,512 (69) 285 (53) 786 (71) 975 (73) 466 (68)
Alpha blockers, N (%) 531 (15) 43 (8) 153 (14) 208 (16) 127 (19)
Beta blockers, N (%) 1,814 (50) 173 (32) 517 (47) 728 (55) 396 (58)
NSAIDs, N (%) 1,894 (52) 262 (48) 606 (55) 701 (53) 325 (48)
Opioids, N (%) 381 (10) 53 (10) 127 (12) 136 (10) 65 (10)
Gabapentin, N (%) 181 (5) 22 (4) 51 (5) 73 (5) 35 (5)
Antidepressants, N (%) 665 (18) 122 (23) 208 (19) 232 (17) 103 (15)
Anxiolytics, N (%) 142 (4) 25 (5) 49 (4) 48 (4) 20 (3)
Abbreviations: SD, standard deviation; IQR, interquartile range; BP, blood pressure; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; NSAID, non-steroidal anti-inflammatory drugs; PTH, parathyroid hormone.
Missings (N): 10 cognitive impairment, 4 weekly activity, 48 total medications, 24 ACEi/ARB, alpha blockers, beta blockers, NSAIDs, and anxiolytics, 49 opioids and gabapentin
Table S8. Baseline characteristics of CRIC Study participants, stratified by inclusion or exclusion in the current study. Participants were excluded if they were missing KDQOL symptom response, eGFR, or covariate data at the baseline visit.
Characteristics Excluded Included
N 254 3,685
Mean age (SD), yr 57 (±11) 58 (±11)
Female, N (%) 125 (49) 1,653 (45)
Socioeconomic factors, N (%)
Black race 146 (57) 1,504 (41)
Hispanic ethnicity 19 (7) 478 (13)
Employed 84 (34) 1,457 (40)
Completed high school or above 186 (74) 2,924 (79)
Currently married 125 (49) 2,033 (55)
Clinical factors
Mean eGFR (SD), mL/min/1.73 m2 46 (±16) 44 (±15) Body mass index, N (%)
≤25 kg/m2 47 (19) 581 (16)
25-30 kg/m2 69 (28) 1,055 (29)
>30 kg/m2 127 (52) 2,049 (56)
Urine protein-creatinine ratio, N (%)
<200 mg/gCr 146 (57) 1,913 (52)
200-1,000 mg/gCr 45 (18) 844 (23)
≥1,000 mg/gCr 44 (17) 780 (21)
Missing 19 (7) 148 (4)
Clinical characteristics, N (%)
Coronary artery disease 51 (20) 811 (22)
Diabetes 120 (47) 1,788 (49)
Hypertension 219 (86) 3,172 (86)
Congestive heart failure 26 (10) 356 (10)
Peripheral vascular disease 15 (6) 247 (7)
Cerebrovascular disease 29 (11) 363 (10)
Malignancy within past 5 years 15 (6) 181 (5)
Depressive symptoms 37 (15) 620 (17)
Active smoking 54 (21) 463 (13)
Laboratory values, N (%) Serum albumin
≥3.4 g/dL 176 (92) 3,308 (90)
<3.4 g/dL 16 (8) 377 (10)
Hemoglobin
M: <12 g/dL, F: <11 g/dL 53 (23) 950 (26) M: 12-13.9 g/dL, F: 11-12.9 g/dL 110 (47) 1,640 (45) M: ≥14 g/dL, F: ≥13 g/dL 71 (30) 1,095 (30) Serum bicarbonate
≥22 mmol/L 189 (85) 3,043 (83)
<22 mmol/L 34 (15) 642 (17)
Baseline PTH
0-65 pg/mL 106 (61) 2,219 (60)
>65 pg/mL 68 (39) 1,466 (40)
Symptoms
Median score [IQR], 0-100 scale*
KDQOL, symptom domain 13 [5, 27] 14 [5, 25]
Fatigue 25 [0, 50] 25 [0, 25]
Anorexia 0 [ 0, 0] 0 [0, 0]
Pruritus 0 [0, 25] 0 [0, 25]
Nausea 0 [0, 25] 0 [0, 25]
Paresthesia 0 [0, 50] 0 [0, 25]
Pain 25 [0, 50] 25 [0, 50]
Median number of symptoms [IQR] † 2 [1, 4] 2 [1, 4]
Abbreviations: SD, standard deviation; eGFR, estimated glomerular filtration rate.
*0 denotes absence of symptom; 100 denotes extreme symptom severity
†Out of 6 possible uremic symptoms
Table S9. Spearman correlation between individual symptom scores at baseline in 3,685 CRIC Study participants
Symptoms Fatigue Anorexia Pruritus Nausea Paresthesia Pain
Fatigue 1
Anorexia 0.36 1
Pruritus 0.27 0.21 1
Nausea 0.37 0.34 0.23 1
Paresthesia 0.36 0.22 0.27 0.25 1
Pain 0.42 0.27 0.23 0.28 0.35 1
Values are Spearman correlation coefficients
Table S10. Spearman correlation between mean annual rates of change in symptom scores in 3,685 CRIC Study participants
Annual rate of change in symptom score
Symptoms Fatigue Anorexia Pruritus Nausea Paresthesia Pain
Fatigue 1
Anorexia 0.25 1
Pruritus 0.16 0.13 1
Nausea 0.19 0.20 0.14 1
Paresthesia 0.23 0.12 0.15 0.14 1
Pain 0.23 0.10 0.11 0.11 0.13 1
Values are Spearman correlation coefficients.
Mean annual rate of change in symptom score calculated from individual linear regression models of symptom score on time.
Table S11. Uremic symptom severity of CRIC Study participants, stratified by enrollment G-stage of 4 or 5, versus progression to G-stage 4 or 5 during follow-up Characteristics
Start at G4 & 5 Progress to G4 & 5
N (%) 685 1,151
Symptoms
Mean score (SD), 0-100 scale†
KDQOL, symptom domain 18 (±14) 20 (±16)
Fatigue 24 (±28) 25 (±29)
Anorexia 10 (±21) 11 (±21)
Pruritus 19 (±25) 23 (±28)
Nausea 11 (±21) 12 (±21)
Paresthesia 22 (±29) 25 (±30)
Pain 30 (±31) 30 (±32)
Mean number of symptoms (SD)‡ 2.7 (±1.7) 2.8 (±1.8)
†0 denotes absence of symptom; 100 denotes extreme symptom severity
‡Out of 6 possible uremic symptoms
Table S12. Population average annual change in symptom score and percentage of patients reporting marked symptom worsening or improvement over follow-up for 3,685 CRIC Study participants, stratified by symptom severity at the baseline assessment*
Symptom,
Baseline severity (N)
Mean annual change in symptom score (95% CI),
(0-100 scale)
% Worsening,
≥ +5 points/year % Stable % Improved,
≥ -5 points/year Fatigue
None (1,775) 1.0 (0.9, 1.1) 15% 85% 0%
Mild (1,016) 0.4 (0.2, 0.6) 14% 75% 11%
Mod-severe (894) -1.4 (-1.6, -1.1) 9% 62% 29%
Anorexia
None (2,929) 0.6 (0.5, 0.7) 10% 90% 0%
Mild (449) 0.2 (-0.2, 0.5) 12% 76% 12%
Mod-severe (307) -2.5 (-3.0, -2.0) 7% 51% 42%
Pruritus
None (2,146) 1.3 (1.2, 1.4) 17% 83% 0%
Mild (873) 0.4 (0.2, 0.6) 13% 73% 14%
Mod-severe (666) -1.2 (-1.5, -0.9) 7% 63% 30%
Nausea
None (2,677) 0.5 (0.4, 0.5) 10% 90% 0%
Mild (642) -0.4 (-0.6, -0.2) 8% 76% 16%
Mod-severe (366) -2.6 (-3.0, -2.2) 6% 55% 39%
Paresthesia
None (2,030) 0.8 (0.7, 0.9) 11% 89% 0%
Mild (857) 0.2 (0.0, 0.5) 14% 74% 12%
Mod-severe (798) -1.8 (-2.1, -1.5) 8% 59% 33%
Pain
None (1,587) 1.3 (1.2, 1.5) 18% 81% 1%
Mild (816) 0.8 (0.6, 1.0) 18% 70% 12%
Mod-severe (1,282) -0.8 (-1.0, -0.7) 8% 68% 24%
KDQOL, symptoms domain†
Low (1,271) 0.5 (0.5, 0.6) 7% 93% 0%
Medium (1,167) 0.6 (0.5, 0.7) 9% 89% 2%
High (564) 0.2 (0.1, 0.4) 9% 84% 7%
Very high (683) -0.6 (-0.7, -0.4) 7% 77% 17%
Mean annual change in symptom score for the population was determined by linear mixed-effects model of symptom score on time with random intercept and random slope. A positive value indicates worsening symptom severity; a negative value indicates improving symptom severity.
To estimate the uremic symptom trajectory for each participant, individual slopes were calculated using linear
regression of symptom severity score on time. An absolute mean change in the symptom slope of 5 points per year or greater was considered a significant worsening or improvement in the symptom severity score.18 Because a minimum of 2 observations of symptom score were necessary to calculate the slope using linear regression, the number of participants included in this analysis is N=3,297.
†Symptom severity at baseline categorized as low [score 0-8.9], medium [9.0-18.9], high [19.0-28.9], and very high [29.0-100], based on quartiles of scores in US dialysis-dependent CKD patients.36
Table S13. Number of uremic symptoms significantly worsening, improving, or remaining stable for each CRIC Study participant
Number of worsening symptoms
Total
0 1 2 3 4 5 6
Number of improving symptoms
0 1,994 355 166 95 58 25 13 2,706
1 230 143 86 52 19 8 -- 538
2 104 77 48 18 6 -- -- 253
3 71 42 18 2 -- -- -- 133
4 23 14 2 -- -- -- -- 39
5 11 1 -- -- -- -- -- 12
6 4 -- -- -- -- -- -- 4
Total 2,437 632 320 167 83 33 13 3,685
To estimate the uremic symptom trajectory for each participant, individual slopes were calculated using linear regression of symptom severity score on time. An absolute mean change of 5 points per year or greater was considered a significant worsening or improvement in the symptom severity score (similar to Table 2). For each participant, the mean annual rates of change of the six uremic symptoms were individually classified as either improving, worsening, or stable. For example, 143 participants reported a significant improvement in 1 uremic symptom, a significant worsening of a different uremic symptom, and stability of the remaining 4 uremic symptoms.
1,994 participants reported stability of all six uremic symptoms over the duration of follow-up.
Table S14. Predicted change in uremic symptom severity score associated with a 5 mL/min/1.73 m2 decrease in eGFR calculated from multivariable models including laboratory parameters
Baseline eGFR, mL/min/1.73 m2
Predicted change in symptom score (0-100 scale)
Fatigue Anorexia Pruritus Nausea Paresthesia Pain KDQOL
symptom domain
20 1.15
(0.88, 1.41) 0.65
(0.45, 0.86) 0.76
(0.48, 1.03) 0.69
(0.47, 0.91) 0.34
(0.08, 0.61) 0.40
(0.10, 0.69) 0.63 (0.50, 0.77)
30 0.90
(0.69, 1.09) 0.49
(0.33, 0.64) 0.60
(0.39, 0.80) 0.51
(0.34, 0.67) 0.29
(0.09, 0.49) 0.30
(0.07, 0.52) 0.51 (0.41, 0.61)
40 0.65
(0.50, 0.79)
0.32 (0.21, 0.43)
0.44 (0.29, 0.59)
0.33 (0.21, 0.45)
0.23 (0.09, 0.38)
0.20 (0.04, 0.36)
0.39 (0.31, 0.46)
50 0.40
(0.27, 0.51) 0.16
(0.06, 0.25) 0.28
(0.15, 0.41) 0.15
(0.05, 0.25) 0.18
(0.05, 0.30) 0.10
(-0.04, 0.23) 0.26 (0.21, 0.32)
60 0.15
(-0.01, 0.29) 0.01
(-0.12, 0.1) 0.12
(-0.03, 0.27) -0.03
(-0.15, 0.09) 0.12
(-0.03, 0.26) -0.01
(-0.17, 0.15) 0.14 (0.07, 0.21)
70 -0.11
(-0.31, 0.10) -0.17
(-0.33, -0.02) -0.04
(-0.25, 0.17) -0.21
(-0.38, -0.05) 0.06
(-0.14, 0.26) -0.10
(-0.33, 0.12) 0.01 (-0.08, 0.11) Values reported as mean (95% CI). Predicted symptom severity scores for different values of eGFR were calculated following use of multivariable adjusted linear mixed-effects models with random intercepts and random slopes. Models adjusted for covariates included in primary analysis, with the addition of hemoglobin, serum albumin, bicarbonate, and baseline parathyroid hormone level. Mean values for all covariates were used. Bold font indicates statistically significant results (p<0.05).
*0 denotes symptom not present; 100 denotes extreme symptom severity. A positive value indicates worsening symptom severity; a negative value indicates improving symptom severity.
Table S15. Comparison of effect estimate for the association between eGFR and uremic symptom severity score between multivariable adjusted* linear mixed-effects models and joint models
Fatigue Anorexia Pruritus Nausea Paresthesia Pain
Linear mixed-effects model
eGFR ! coefficient (-0.43, -0.28) -0.35 -0.22
(-0.28, -0.17) -0.22
(-0.30, -0.15) -0.21
(-0.27, -0.14) -0.11
(-0.18, -0.03) -0.17 (-0.25, -0.09) eGFR2 ! coefficient (0.002, 0.004) 0.003
0.002 (0.001, 0.003)
0.002 (0.001, 0.002)
0.002 (0.001, 0.002)
0.001 (0.000, 0.002)
0.001 (0.001, 0.002) Joint model†
eGFR ! coefficient (-0.43, -0.28) -0.36
-0.23 (-0.29, -0.17)
-0.23 (-0.31, -0.16)
-0.22 (-0.28, -0.16)
-0.11 (-0.19, -0.04)
-0.18 (-0.26, -0.09) eGFR2 ! coefficient (0.002, 0.004) 0.003
0.002 (0.001, 0.003)
0.002 (0.001, 0.003)
0.002 (0.001, 0.003)
0.001 (0.000, 0.002)
0.001 (0.001, 0.002) For this analysis, n=3,685.
*Multivariable adjusted for time, clinical site, age, sex, race, ethnicity, employment, education, marital status, BMI, proteinuria, coronary artery disease, diabetes, hypertension, congestive heart failure, peripheral vascular disease, history of malignancy, cerebrovascular disease, depressive symptoms, and smoking.
†Joint model consists of linear mixed-effects model with random intercept and random slopes and Weibull proportional hazards model with participants censored for death, progression to dialysis-dependent CKD, receipt of kidney transplant, or loss to follow-up
Table S16. Final multivariable-adjusted models of symptom severity among CRIC Study participants using automated algorithm for covariate selection
Covariates
Fatigue score b (SE)
Anorexia score b
(SE)
Pruritus score b (SE)
Nausea score b (SE)
Paresthesia score b
(SE)
Pain score b (SE)
KDQOL symptom
domain score b (SE)
eGFR, mL/min/1.73 m2 -0.3 (0.0) -0.2 (0.0) -0.2 (0.0) -0.2 (0.0) -0.1 (0.0) -0.1 (0.0) -0.2 (0.0)
eGFR2 0.002 (0.000) 0.002 (0.000) 0.002 (0.000) 0.002 (0.000) 0.001 (0.000) 0.001 (0.000) 0.001 (0.000)
Baseline symptom score, per 10-point increase 6.2 (0.0) 5.7 (0.0) 6.3 (0.0) 5.3 (0.0) 6.7 (0.0) 6.1 (0.0) 7.5 (0.0)
Age, per 10-year increase -1.2 (0.2) -- -- -1.0 (0.2) -- -- --
Female (vs Male) 1.3 (0.4) -- -- 1.3 (0.3) -1.1 (0.4) 1.2 (0.5) --
Race/Ethnicity (vs NH White)
NH Black -- 2.0 (0.4) -- -- 1.7 (0.5) -- 1.2 (0.3)
Hispanic -- 0.1 (0.6) -- -- 0.7 (0.8) -- 0.2 (0.4)
Employed -1.8 (0.5) -0.7 (0.4) -1.5 (0.4) -1.5 (0.4) -- -1.6 (0.5) -0.7 (0.2)
Income category (vs <$20,000)
$20-50,000 -- -0.7 (0.4) -- -- -1.0 (0.6) -1.5 (0.6) --
$50-100,000 -- -1.1 (0.5) -- -- -1.0 (0.7) -2.5 (0.7) --
>$100,000 -- -1.5 (0.6) -- -- -2.2 (0.8) -3.6 (0.9) --
Prefer to not answer -- -0.5 (0.5) -- -- -0.6 (0.7) -1.2 (0.7) --
BMI (vs BMI≤25)
Overweight -- -2.3 (0.4) -- -0.2 (0.4) -- 0.5 (0.5) --
Obese -- -3.5 (0.4) -- -0.8 (0.4) -- 2.1 (0.5) --
Urine protein-creatinine ratio (vs ≤200mg/gCr)
200-1,000 mg/gCr -- -- 0.5 (0.4) -- -- -- --
≥1,000 mg/gCr -- -- 1.2 (0.5) -- -- -- --
Missing -- -- 0.5 (0.4) -- -- -- --
Diabetes -- -- 0.9 (0.4) 0.9 (0.3) 2.3 (0.4) -0.9 (0.4) --
Cardiovascular disease -- 0.9 (0.3) -- -- 0.9 (0.4) -- 0.6 (0.2)
Congestive heart failure 2.1 (0.6) -- -- -- -- 1.4 (0.7) --
Peripheral vascular disease -- -- -- -- -- 2.1 (0.8) --
History of malignancy 1.9 (0.6) -- -- -- -- -- 0.8 (0.3)
Depressive symptoms 8.9 (0.6) 5.0 (0.5) 5.2 (0.6) 5.4 (0.5) 5.7 (0.6) 6.4 (0.6) 3.9 (0.3)
Cognitive impairment -1.6 (0.7) -- -- -- -- -- --
Current smoking -- 1.8 (0.4) -- -- -- -- --
Any vigorous exercise -1.5 (0.3) -- -- -- -0.8 (0.3) -1.4 (0.4) -0.6 (0.2)
Hospitalization for cardiovascular event -- -- -- -- -- 1.2 (0.5) --
Number of medications (vs ≤ 5)
6-10 0.5 (0.4) 0.8 (0.3) 1.1 (0.4) 0.6 (0.3) 0.8 (0.4) 0.5 (0.4) 0.4 (0.2)
11-15 1.0 (0.5) 0.5 (0.4) 1.8 (0.5) 0.9 (0.4) 1.3 (0.5) 1.4 (0.5) 0.5 (0.2)
>15 2.1 (0.6) 1.5 (0.5) 3.2 (0.6) 2.1 (0.5) 1.2 (0.6) 2.6 (0.7) 1.3 (0.3)
ACEi/ARB -- -- -0.7 (0.3) -- -- -- --
Beta blockers -- -- -- -- -1.2 (0.3) -- --
NSAIDs -- -0.7 (0.2) -1.0 (0.3) -- -- -- --
Gabapentin -- 0.9 (0.5) -- -- 5.0 (0.6) 3.4 (0.7) --
Opioids 1.8 (0.4) 1.8 (0.3) -- 2.1 (0.4) 1.8 (0.4) 7.6 (0.5) 1.2 (0.2)
Antidepressants 2.1 (0.4) 1.4 (0.4) 1.9 (0.4) -- -- 1.0 (0.5) 0.8 (0.2)
Anxiolytics -- -- -- -- -- 1.8 (0.8) --
Serum albumin (vs ≥3.4)
<3.4 -- 1.9 (0.4) 1.5 (0.6) 1.8 (0.5) -- 1.4 (0.6) 1.0 (0.3)
Hemoglobin (vs ref range*)
M: <12 g/dL, F: <11 g/dL 1.9 (0.4) 1.4 (0.3) -- 0.6 (0.3) -- 0.9 (0.4) 0.7 (0.2)
M: ≥14 g/dL, F: ≥13 g/dL -0.3 (0.3) -0.5 (0.3) -- 0.1 (0.3) -- -1.0 (0.4) -0.3 (0.2)
Baseline PTH (vs 0-65 pg/mL)
>65 pg/mL -- -- -- -- -- -- -0.7 (0.2)
Regression coefficients (SE) from linear mixed-effects models using backward selection algorithm (p-value<0.05) for covariate selection are shown. For each symptom, only those covariates that were selected in the final multivariable model are shown. Covariates with “--” indicate that variable was not included in final model for that uremic symptom. Covariates not selected into any model included education, marital status, systolic and diastolic blood pressure, hypertension, cerebrovascular disease, weekly alcohol use, use of alpha blockers, and serum bicarbonate.
*Reference range for hemoglobin: M: 12-13.9 g/dL, F: 11-12.9 g/dL
