Response to the Letter to the Editor Entitled “The Weight of Disease, the Loss Within: Rethinking Frailty Assessment in ADPKD”

We thank Paolisi et al. 1 for their thoughtful comments on our study examining frailty among patients with autosomal dominant polycystic kidney disease (ADPKD). 2 We appreciate their recognition of our methodological approach and their emphasis on potential disease-specific heterogeneity.We have the following responses to their insightful comments.First, we fully agree that ADPKD is genetically heterogeneous, with PKD1 truncating variants associated with more severe phenotypes than PKD2 pathogenic variants.Because genotypic data were unavailable in our database, as already acknowledged in the limitation section of our article, 2 we primarily addressed ADPKD as encountered in routine clinical practice, during which genetic information is often unclear because of various reasons.Our findings therefore reflect population-level risk within a realworld cohort carefully matched for age, kidney function, comorbidities, medications, and baseline frailty status.Although it is plausible that high-risk genotypic subgroups may carry differential vulnerability, our results indicate that ADPKD was not independently associated with incident or worsening frailty during 4.8 years of follow-up, for those of middle age and with predominantly early-stage CKD (1 and 2).We agree that future genetically stratified studies would provide in-depth data for addressing this issue.We also acknowledge the potential influence of organomegaly and volumetric burden on our results.Gastrointestinal compression and nutritional compromise represent biologically plausible pathways to sarcopenia development in kidney patients.3 However, in our matched cohort, baseline body mass index, laboratory indices, and FRAIL scores were comparable between groups.Importantly, worsening frailty was defined by longitudinal change across multiple FRAIL domains, not weight loss alone.Even if organ mass confounded the weight component, divergence in fatigue, resistance, ambulation, or illness burden would