Review for 10.1186/s12876-025-03935-7 (2025)

Title: Association Between Proteinuria Changes and Colorectal Cancer Incidence: Evidence
from a Nationwide Cohort Study
Version: 1 Date: 20 Feb 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-While the study adjusts for many potential confounders (e.g., smoking, BMI, alcohol
consumption), there may still be unmeasured or residual confounding factors that influence both
proteinuria and colorectal cancer risk. For instance, a family history of colorectal cancer, dietary
factors, or genetic predispositions may contribute to both conditions but were not included in
the analysis. These factors could influence the results and introduce bias.
-The study excluded participants diagnosed with CRC in the first year following screening to
minimize reverse causality, but this remains a potential concern. The presence of proteinuria may
be an early manifestation of an undiagnosed cancer, and the timing of the onset of proteinuria in
CRC development is not fully addressed. Further analysis of the temporal relationship between
PU onset and CRC development could clarify this issue.
-The use of dipstick urinalysis for measuring proteinuria is practical but has limitations in
accuracy compared to more quantitative tests such as 24-hour urine collection or protein-
to-creatinine ratio. The semi-quantitative nature of dipstick testing (e.g., trace, 1+, 2+, etc.)
can introduce measurement error, and it is unclear how variations in proteinuria severity
were accounted for in the analysis. While the study includes severity levels, a more detailed
explanation of how these levels relate to actual protein content could improve the transparency
of the findings.
-While the paper suggests that proteinuria may reflect systemic inflammation and microvascular
damage, it does not delve deeply into potential biological mechanisms linking proteinuria
to colorectal cancer. Understanding the underlying mechanisms could strengthen the paper’s
contribution to the literature by providing insights into how PU might serve as a modifiable risk
factor for CRC. Including a brief discussion of these mechanisms would enhance the depth of
the study.
-While the authors mention several key confounding factors (e.g., family history of CRC,
inflammatory bowel disease), these are not discussed in much detail. The discussion could
benefit from a more in-depth analysis of why these factors were not included and how they
might impact the results if they had been incorporated. A more thorough examination of other
unmeasured confounders could provide readers with a clearer picture of the study's limitations.
-The authors acknowledge the limitations of an observational study in establishing causality but
do not provide sufficient detail on how future studies could better establish a causal relationship.
Including more specific suggestions on the types of studies (e.g., randomized controlled trials,
Mendelian randomization) that could help establish causality would enhance the discussion and
provide clearer directions for future research.
-The authors note that the association between PU and right-sided colon cancer was weaker than
for other parts of the colon, but this observation is not fully explored. Given that right- and left-
sided colon cancers differ in clinical presentation, molecular characteristics, and risk factors,
a more detailed analysis of this discrepancy would be helpful. Further discussion on why PU
might have a differential effect on CRC in different parts of the colon would add depth to the
findings and help explain this variation.
-While the authors acknowledge that the study is based on an ethnic Korean population, the
generalizability of the findings to other ethnic groups could be better discussed. The authors
could expand on potential differences in genetic predispositions, healthcare access, and lifestyle
factors across populations and how these may influence the relevance of the findings in other
settings. Additionally, the use of only a South Korean cohort could be viewed as a limitation
for broader applicability, and it would be valuable to explore how PU might interact with ethnic
and geographic variations.