Supplemental material table of contents
1. Supplemental Table 1. Number of observations included in present analysis stratified by visit year, and percentageof missing values for variables among CRIC Study participants included in the current analysis
2. Supplemental Table 2. Baseline characteristics of the CRIC cohort stratified by prevalent pruritus at the baseline visit
3. Supplemental Table 3. Incidence rates of moderate-to-severe pruritus stratified by baseline characteristics amongCRIC Study participants
4. Supplemental Table 4. Multivariable associations of demographic and clinical factors, including eGFR and urineprotein, and risk of incident moderate-to-severe pruritus among 1,951 CRIC Study
participants
5. Supplemental Table 5. Multivariable associations of demographic and clinical factors, using new race- free eGFRequations, and risk of incident moderate-to-severe pruritus among 1,951 CRIC Study participants
6. Supplemental Table 6. Hazard ratios for the risk of incident pruritus associated with a 10 mL/min/1.73 m2 lowereGFR calculated for incremental durations of follow-up time
Supplemental Table 1. 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
Variable Visit Year
0 1 2 3 4 5 6 7 8 9 10 11 12 13
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 Participants included in present analysis*, N 1,951 1,713 1,448 1,253 1,092 957 867 783 695 614 525 474 333 171 Demographic factors
Age 0 -- -- -- -- -- -- -- -- -- -- -- -- --
Sex 0 -- -- -- -- -- -- -- -- -- -- -- -- --
Race/ethnicity 0 -- -- -- -- -- -- -- -- -- -- -- -- --
Kidney measures
eGFR-CRIC 0 1.1 2.0 2.1 3.8 4.9 5.8 7.8 10.1 10.4 8.0 11.6 12.6 13.5
Urine protein 0 6.7 14.1 18.3 21.0 20.7 12.6 12.3 13.1 14.0 11.1 15.2 16.5 20.5
Clinical factors
Body mass index 0 0.8 1.9 2.3 3.6 5.9 6.3 8.1 10.1 11.1 8.4 9.9 13.8 13.5
Diabetes 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Hypertension 0 0 0 0.1 0.2 0.3 0.6 0.4 0.9 1.0 0.8 1.5 1.8 0
Coronary artery disease 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
Congestive heart failure 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Lung disease 0 1.1 1.2 1.0 1.2 0.2 1.7 0.6 0.6 0.7 1.0 0.6 1.2 0.6
Active smoking 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Opioid use 0 0.9 1.5 1.1 2.3 1.5 2.6 2.8 2.6 1.8 1.5 2.0 3.5 0
Depressive symptoms 0 -- -- -- -- -- -- -- -- -- -- -- -- --
Laboratory parameters
Calcium† 1.5 1.1 2.6 2.3 3.9 4.9 5.8 7.7 10.2 10.4 8.0 11.6 12.6 13.5
Phosphate† 1.6 49.9 51.5 52.4 58.1 100 100 100 100 100 100 100 100 100
PTH† 1.9 28.1 52.5 55.9 65.5 90.0 100 100 100 100 100 100 100 100
Hemoglobin† 0.4 1.6 2.8 2.9 4.3 5.6 6.5 8.6 10.8 11.1 8.2 11.6 13.5 12.9
hs-CRP† 0.1 97.5 98.9 99.4 95.7 97.5 94.9 98.0 100 100 100 100 100 100
Serum albumin† 1.5 0.9 2.6 2.2 3.9 4.9 5.8 7.7 10.1 10.4 8.0 11.6 12.6 13.5
IL-6† 1.5 97.5 98.8 99.4 23.4 97.5 94.7 98.0 100 100 100 100 100 100
Data displayed as % missingness, unless otherwise indicated. “--” Indicates only baseline values of variable were included in our models.
*Participants were included in the present analysis if they did not report any pruritus at the baseline visit and had complete baseline data on all demographic factors, kidney measures (except for urine protein), and clinical factors listed in the table. Participants were removed from the analysis set as they developed incident pruritus or were censored
†Only baseline values of these lab parameters were included in our primary analysis. We did a sensitivity analysis using all available data for calcium, phosphate, and PTH, reported in the supplementary data.
Supplemental Table 2. Baseline characteristics of the CRIC cohort stratified by prevalent pruritus at the baseline visit
Characteristics Pruritus at baseline visit
Yes No P
N (%) 1,783 (46) 2,131 (54)*
Demographic factors
Mean age (SD), yr 58 (±11) 57 (±11) 0.05
Female, N (%) 842 (47) 924 (43) 0.02
Race/ethnicity, N (%) 0.33
NH-White 732 (41) 901 (42)
NH-Black 738 (41) 897 (42)
Hispanic 244 (14) 250 (12)
Other 69 (4) 83 (4)
Kidney measures
Mean eGFR (SD), mL/min/1.73 m2 43 (±17) 47 (±17) <0.001 Median urine protein (IQR), mg/gCr 187 (62-977) 132 (54-626) <0.001 Clinical factors
Mean body mass index (SD), kg/m2 32 (±8) 33 (±9) <0.001
Diabetes, N (%) 931 (52) 967 (45) <0.001
Hypertension, N (%) 1,547 (87) 1,823 (86) 0.27
Coronary artery disease, N (%) 447 (25) 411 (19) <0.001 Peripheral vascular disease, N (%) 154 (9) 108 (5) <0.001 Congestive heart failure, N (%) 229 (13) 150 (7) <0.001
Lung disease, N (%) 315 (18) 261 (12) <0.001
Current smoking, N (%) 239 (13) 271 (13) 0.52
Opioid use, N (%) 215 (12) 195 (9) 0.003
Depressive symptoms, N (%) <0.001
None (BDI 0-10) 1,112 (63) 1,697 (81)
Moderate (BDI 11-13) 206 (12) 151 (7)
Severe (BDI ≥14) 445 (25) 259 (12)
Mineral metabolism markers
Mean serum calcium (SD), mg/dL 9.2 (±0.5) 9.2 (±0.5) 0.71 Mean serum phosphate (SD), mg/dL 3.8 (±0.7) 3.7 (±0.7) <0.001 Median intact PTH (IQR), pg/mL 57 (36-96) 51 (33-83) <0.001 Hemoglobin
Male: Mean hemoglobin (SD), g/dL 13.0 (±1.8) 13.2 (±1.8) 0.01 Female: Mean hemoglobin (SD), g/dL 11.9 (±1.5) 12.1 (±1.5) 0.01 Inflammatory markers
Median hsCRP (IQR), mg/L 3.0 (1.2-7.5) 2.2 (1.0-5.6) <0.001 Mean serum albumin (SD), g/dL 3.9 (±0.5) 3.9 (±0.5) 0.04 Median IL-6 (IQR), pg/mL 2.1 (1.3-3.6) 1.7 (1.1-2.8) <0.001 Out of 3,939 total CRIC participants, 25 CRIC participants were missing KDQOL data on pruritus at the baseline visit. Groups compared using t-tests, Pearson’s Chi-squared, or Wilcoxon rank- sum tests as appropriate.
*The number of CRIC participants reporting no pruritus at the baseline visit is 2,131. Because we used a complete case analysis for the present study, we excluded 180 of these participants due to missing data on key covariates (clinical factors included in our main model).
Abbreviations: SD, standard deviation; NH, non-Hispanic; IQR, interquartile range; BDI, Beck’s Depression Inventory; PTH, parathyroid hormone; hsCRP, high-sensitivity C-reactive protein; IL- 6, interleukin-6
Supplemental Table 3. Incidence rates of moderate-to-severe pruritus stratified by baseline characteristics among CRIC Study participants
Incident pruritus per 100 person-years (95% CI)
P Demographic factors
Age 0.10
≤44 y 4.2 (3.4 - 5.3)
45-64 y 4.8 (4.4 - 5.4)
≥65 y 5.6 (4.9 - 6.5)
Sex 0.01
Male 4.5 (4.1 – 5.0)
Female 5.6 (5.0 - 6.2)
Race/ethnicity 0.002
NH-White 4.2 (3.7 - 4.7)
NH-Black 5.8 (5.1 - 6.5)
Hispanic 6.2 (4.9 - 7.8)
Other 4.9 (3.3 - 7.2)
Kidney measures
CKD stage <0.001
G4&5 7.4 (6.0 – 9.0)
G3b 6.3 (5.6 - 7.2)
G3a 4.6 (4.0 - 5.3)
G1&2 3.2 (2.6 - 3.8)
Urine protein-to-creatinine ratio <0.001
<200 mg/gCr 4.3 (3.9 - 4.8) 200-1,000 mg/gCr 5.6 (4.8 - 6.6)
>1,000 mg/gCr 7.5 (6.2 – 9.0) Clinical factors
Body Mass Index <0.001
<25 kg/m2 4.1 (3.4 - 5.1) 25 to <30 kg/m2 4.1 (3.5 - 4.8)
≥30 kg/m2 5.8 (5.2 - 6.4)
Diabetes <0.001
No 4.1 (3.7 - 4.6)
Yes 6.3 (5.7 - 7.1)
Hypertension 0.04
No 4.0 (3.3 - 4.9)
Yes 5.2 (4.8 - 5.6)
Coronary artery disease 0.06
No 4.8 (4.4 - 5.2)
Yes 5.9 (5.0 – 7.0)
Peripheral vascular disease 0.001
No 4.8 (4.5 - 5.2)
Yes 8.5 (6.2 - 11.7)
Congestive heart failure 0.01
No 4.8 (4.5 - 5.2)
Yes 7.7 (5.7 - 10.3)
Lung disease 0.15
No 4.9 (4.5 - 5.3)
Yes 5.7 (4.7 – 7.0)
Current smoker <0.001
No 4.7 (4.3 - 5.1)
Yes 7.9 (6.5 - 9.6)
Opioids <0.001
No 4.7 (4.3 - 5.1)
Yes 8.0 (6.5 - 9.9)
Depressive symptoms <0.001
None (BDI 0-10) 4.4 (4.0 - 4.8) Moderate (BDI 11-13) 6.9 (5.2 - 9.1) Severe (BDI ≥14) 9.6 (8.0 - 11.6) Mineral metabolism markers
Serum calcium 0.02
<9 mg/dL 4.1 (3.5 - 4.8)
9 – 9.4 mg/dL 5.3 (4.8 – 6.0)
≥9.5 mg/dL 5.4 (4.6 - 6.3)
Serum phosphate 0.01
<3 mg/dL 3.9 (3.1 – 5.0)
3-3.9 mg/dL 4.8 (4.3 - 5.3)
≥4.0 mg/dL 6.0 (5.2 - 6.9)
Intact PTH <0.001
0-64 pg/mL 4.4 (4.0 - 4.8)
≥65 pg/mL 6.2 (5.5 - 7.1)
Markers of anemia and inflammation
Hemoglobin <0.001
M: <12 g/dL; F: <11 g/dL 6.9 (5.9 - 8.1) M: ≥12 g/dL; F: ≥11 g/dL 4.6 (4.2 – 5.0)
hsCRP 0.002
0-3.0 mg/L 4.5 (4.0 - 4.9)
>3 mg/L 5.7 (5.1 - 6.4)
Serum albumin <0.001
<3.5 g/dL 7.3 (5.8 - 9.2) 3.5-3.9 g/dL 5.8 (5.1 - 6.5)
≥4.0 g/dL 4.3 (3.8 - 4.8)
IL-6 <0.001
0-3.0 pg/mL 4.5 (4.1 - 4.9)
>3 pg/mL 7.2 (6.2 - 8.5)
P-values from log-rank tests for equality of survivor functions
Abbreviations: NH, non-Hispanic; BDI, Beck’s Depression Inventory; PTH, parathyroid hormone; hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin-6
Supplemental Table 4. Multivariable associations of demographic and clinical factors, including eGFR and urine protein, and risk of incident moderate-to-severe pruritus among 1,951 CRIC Study participants
Risk Factors
Model 2
Without proteinuria Model 2 With proteinuria
HR 95% CI HR 95% CI
eGFR, per 10 mL/min/1.73 m2 decrease 1.16 1.10-1.23 1.14 1.07 - 1.22 Log-proteinuria, per 1 g/24h increase -- -- 1.03 0.96 - 1.09 Demographic factors
Age
≤44 y 0.95 0.74 - 1.22 0.93 0.73 - 1.20
45-64 y 1.0 Ref 1.0 Ref
≥65 y 1.28 1.06 - 1.53 1.31 1.09 - 1.57
Sex
Male 1.0 Ref 1.0 Ref
Female 1.15 0.97 - 1.36 1.16 0.98 - 1.37
Race/ethnicity
NH-White 1.0 Ref 1.0 Ref
NH-Black 1.10 0.92 - 1.32 1.12 0.93 - 1.34
Hispanic 0.92 0.66 - 1.28 0.91 0.65 - 1.27
Other 1.09 0.71 - 1.67 1.10 0.72 - 1.69
Clinical factors
BMI, per kg/m2 increase 1.02 1.01 - 1.03 1.02 1.01 - 1.03
Diabetes (vs none) 1.24 1.05 - 1.46 1.22 1.03 - 1.45
Hypertension (vs none) 0.94 1.06 - 0.83 0.89 0.66 - 1.20 Coronary artery disease (vs none) 1.04 0.97 - 1.11 1.03 0.85 - 1.25 Peripheral vascular disease (vs none) 1.18 0.87 - 1.61 1.20 0.88 - 1.64 Congestive heart failure (vs none) 1.10 0.82 - 1.48 1.12 0.84 - 1.50 Lung disease (vs none) 1.14 0.93 - 1.39 1.100 0.90 - 1.35
Opioid use (vs none) 1.28 1.02 - 1.61 1.28 1.02 - 1.60
Current smoking (vs none) 1.56 1.25 - 1.96 1.59 1.26 - 1.99 Depressive symptoms
None (BDI 0-10) 1.0 Ref 1.0 Ref
Moderate (BDI 11-13) 1.40 1.03 - 1.9 1.40 1.03 - 1.91
Severe (BDI ≥14) 1.95 1.56 - 2.43 1.99 1.59 - 2.49
Bold font denotes a p value <0.05. Results shown above are from joint modeling of linear mixed effects models and proportional hazards survival models. Missing values for proteinuria were filled in with last value carried forward. Models were also adjusted for clinical center site.
Abbreviations: NH, non-Hispanic; BMI, body mass index; BDI, Beck’s Depression Inventory
Supplemental Table 5. Multivariable associations of demographic and clinical factors, using new race-free eGFR equations, and risk of incident moderate-to-severe pruritus among 1,951 CRIC Study participants
Risk Factors Model 1 Model 2
HR 95% CI HR 95% CI
eGFR, per 10 mL/min/1.73 m2 decrease 1.17 1.11 - 1.24 1.15 1.08 - 1.22 Demographic factors
Age
≤44 y 0.86 0.67 - 1.10 0.95 0.74 - 1.21
45-64 y 1.0 Ref 1.0 Ref
≥65 y 1.19 1.00 - 1.42 1.30 1.09 - 1.56
Sex
Male 1.0 Ref 1.0 Ref
Female 1.25 1.06 - 1.46 1.15 0.98 - 1.36
Race/ethnicity
NH-White 1.0 Ref 1.0 Ref
NH-Black 1.31 1.11 - 1.56 1.12 0.93 - 1.34
Hispanic 1.12 0.81 - 1.55 0.92 0.66 - 1.28
Other 1.09 0.71 - 1.66 1.11 0.72 - 1.69
Clinical factors
BMI, per kg/m2 increase -- -- 1.02 1.01 - 1.03
Diabetes (vs none) -- -- 1.25 1.05 - 1.47
Hypertension (vs none) -- -- 0.91 0.67 - 1.23
Coronary artery disease (vs none) -- -- 1.03 0.85 - 1.25 Peripheral vascular disease (vs none) -- -- 1.22 0.90 - 1.66 Congestive heart failure (vs none) -- -- 1.15 0.85 - 1.54
Lung disease (vs none) -- -- 1.09 0.90 - 1.34
Opioid use (vs none) -- -- 1.30 1.03 - 1.62
Current smoking (vs none) -- -- 1.62 1.29 - 2.03
Depressive symptoms
None (BDI 0-10) -- -- 1.0 Ref
Moderate (BDI 11-13) -- -- 1.40 1.03 - 1.90
Severe (BDI ≥14) -- -- 1.97 1.58 - 2.46
Bold font denotes a p value <0.05. Results shown above are from joint modeling of linear mixed effects models and proportional hazards survival models. All clinical factors were included as time- updated variables in survival models, with the exception of depressive symptoms, for which only the baseline values were included. Model 1 includes eGFR, age, sex, race/ethnicity, and clinical site.
Model 2 includes covariates in Model 1, plus BMI and all clinical factors.
Abbreviations: NH, non-Hispanic; BMI, body mass index; BDI, Beck’s Depression Inventory
Supplemental Table 6. Hazard ratios for the risk of incident pruritus
associated with a 10 mL/min/1.73 m2 lower eGFR calculated for incremental durations of follow-up time
Years of follow-up Average HR for moderate-to-severe pruritus (95% CI) associated with 10 mL/min/1.73 m2 lower eGFR
2 1.16 (1.04 - 1.30)
4 1.12 (1.04 - 1.20)
6 1.13 (1.06 - 1.21)
8 1.12 (1.05 - 1.18)
≥10 1.14 (1.08 - 1.20)
The similarity of these HRs suggests that the hazard remains relatively stable over the duration of follow-up
