Title: Association Between Proteinuria Changes and Colorectal Cancer Incidence: Evidence
from a Nationwide Cohort Study
Version: 1 Date: 15 Feb 2025
Reviewer's report:
The authors examined the association of changes in proteinuria status between two consecutive
health screenings with the risk of CRC incidence during a 10-year follow-up based on data
from South Korea. They found that persistent proteinuria is associated with highest risk of CRC.
Newly developed and recovered proteinuria may also be associated with an elevated risk of CRC.
1. Abstract – The authors may provide hazard ratios to quantify the findings in the results.
2. General – Despite the emphasis on the dynamic nature of PU changes over time, only a single
change between two consecutive screenings was captured.
3. Previous epidemiological studies on the associations of proteinuria or its related markers with
CRC were not discussed in detail.
4. Methods –  Behavioral factors including smoking, alcohol use, and physical activity were
assessed during the health screenings. Are the baseline variables measured in this study based
on the second screening? How about if some individuals had changed their behavioral status
between two screenings?
5. Diabetes, hypertension, dyslipidemia, chronic kidney disease, SBP, DBP, fasting glucose, and
lipids were assessed in this study and reported in Table 1. However, these variables were not
controlled in the models reported in Table 2.
6. Proteinuria status may also change during the 10-year follow-up. Since individuals underwent
health screenings biennially, how about the subsequent changes in proteinuria status during
follow-up?
7. “…participants diagnosed with CRC in the first year immediately following the initial
screening (n = 9,955) were excluded from the cohort…” Does this initial screening assessment
refer to the second screening in Figure 2?
8. Results – “A total of 3,043,148 participants were included in the analysis after excluding
individuals with missing data and incomplete follow-up information (Figure 1).” What does this
incomplete follow-up information specifically refer to?
9. “Compared with the PU-free group, the PU-persistent group had the highest risk of CRC
(adjusted HR (aHR): 1.32; 95% CI, 1.19-1.49), followed by the PU-developed group (aHR:
1.10; 95% CI, 1.03-1.19), and the PU-recovered group (aHR: 1.08; 95% CI, 1.01-1.16) (p for
trend < 0.001) (Model 4 of Table 2)”. The numbers reported in the main text are not consistent
with those reported in Table 2.
10. In Table 1, units of measurement were not clearly specified.
11. “In addition, PU is often associated with metabolic syndrome, diabetes, and CKD, all of
which are recognized risk factors for malignancies, including CRC (27-30)” However, diabetes
and CKD reported in Table 1 were not adjusted in the models.
12. Lack of information on dietary exposure may also be another limitation.
13. Changes in PU status with CRC risk within the general population has been previously
shown.
Title: Association Between Proteinuria Changes and Colorectal Cancer Incidence: Evidence
from a Nationwide Cohort Study
Version: 1 Date: 15 Feb 2025
Reviewer's report:
The authors examined the association of changes in proteinuria status between two consecutive
health screenings with the risk of CRC incidence during a 10-year follow-up based on data
from South Korea. They found that persistent proteinuria is associated with highest risk of CRC.
Newly developed and recovered proteinuria may also be associated with an elevated risk of CRC.
1. Abstract – The authors may provide hazard ratios to quantify the findings in the results.
2. General – Despite the emphasis on the dynamic nature of PU changes over time, only a single
change between two consecutive screenings was captured.
3. Previous epidemiological studies on the associations of proteinuria or its related markers with
CRC were not discussed in detail.
4. Methods –  Behavioral factors including smoking, alcohol use, and physical activity were
assessed during the health screenings. Are the baseline variables measured in this study based
on the second screening? How about if some individuals had changed their behavioral status
between two screenings?
5. Diabetes, hypertension, dyslipidemia, chronic kidney disease, SBP, DBP, fasting glucose, and
lipids were assessed in this study and reported in Table 1. However, these variables were not
controlled in the models reported in Table 2.
6. Proteinuria status may also change during the 10-year follow-up. Since individuals underwent
health screenings biennially, how about the subsequent changes in proteinuria status during
follow-up?
7. “…participants diagnosed with CRC in the first year immediately following the initial
screening (n = 9,955) were excluded from the cohort…” Does this initial screening assessment
refer to the second screening in Figure 2?
8. Results – “A total of 3,043,148 participants were included in the analysis after excluding
individuals with missing data and incomplete follow-up information (Figure 1).” What does this
incomplete follow-up information specifically refer to?
9. “Compared with the PU-free group, the PU-persistent group had the highest risk of CRC
(adjusted HR (aHR): 1.32; 95% CI, 1.19-1.49), followed by the PU-developed group (aHR:
1.10; 95% CI, 1.03-1.19), and the PU-recovered group (aHR: 1.08; 95% CI, 1.01-1.16) (p for
trend < 0.001) (Model 4 of Table 2)”. The numbers reported in the main text are not consistent
with those reported in Table 2.
10. In Table 1, units of measurement were not clearly specified.
11. “In addition, PU is often associated with metabolic syndrome, diabetes, and CKD, all of
which are recognized risk factors for malignancies, including CRC (27-30)” However, diabetes
and CKD reported in Table 1 were not adjusted in the models.
12. Lack of information on dietary exposure may also be another limitation.
13. Changes in PU status with CRC risk within the general population has been previously
shown.
Please review this paper.
user
Title: Association Between Proteinuria Changes and Colorectal Cancer Incidence: Evidence
from a Nationwide Cohort Study
Version: 1 Date: 15 Feb 2025
Reviewer's report:
The authors examined the association of changes in proteinuria status between two consecutive
health screenings with the risk of CRC incidence during a 10-year follow-up based on data
from South Korea. They found that persistent proteinuria is associated with highest risk of CRC.
Newly developed and recovered proteinuria may also be associated with an elevated risk of CRC.
1. Abstract – The authors may provide hazard ratios to quantify the findings in the results.
2. General – Despite the emphasis on the dynamic nature of PU changes over time, only a single
change between two consecutive screenings was captured.
3. Previous epidemiological studies on the associations of proteinuria or its related markers with
CRC were not discussed in detail.
4. Methods –  Behavioral factors including smoking, alcohol use, and physical activity were
assessed during the health screenings. Are the baseline variables measured in this study based
on the second screening? How about if some individuals had changed their behavioral status
between two screenings?
5. Diabetes, hypertension, dyslipidemia, chronic kidney disease, SBP, DBP, fasting glucose, and
lipids were assessed in this study and reported in Table 1. However, these variables were not
controlled in the models reported in Table 2.
6. Proteinuria status may also change during the 10-year follow-up. Since individuals underwent
health screenings biennially, how about the subsequent changes in proteinuria status during
follow-up?
7. “…participants diagnosed with CRC in the first year immediately following the initial
screening (n = 9,955) were excluded from the cohort…” Does this initial screening assessment
refer to the second screening in Figure 2?
8. Results – “A total of 3,043,148 participants were included in the analysis after excluding
individuals with missing data and incomplete follow-up information (Figure 1).” What does this
incomplete follow-up information specifically refer to?
9. “Compared with the PU-free group, the PU-persistent group had the highest risk of CRC
(adjusted HR (aHR): 1.32; 95% CI, 1.19-1.49), followed by the PU-developed group (aHR:
1.10; 95% CI, 1.03-1.19), and the PU-recovered group (aHR: 1.08; 95% CI, 1.01-1.16) (p for
trend < 0.001) (Model 4 of Table 2)”. The numbers reported in the main text are not consistent
with those reported in Table 2.
10. In Table 1, units of measurement were not clearly specified.
11. “In addition, PU is often associated with metabolic syndrome, diabetes, and CKD, all of
which are recognized risk factors for malignancies, including CRC (27-30)” However, diabetes
and CKD reported in Table 1 were not adjusted in the models.
12. Lack of information on dietary exposure may also be another limitation.
13. Changes in PU status with CRC risk within the general population has been previously
shown.
assistant