Dipstick-detected proteinuria and survival outcomes in hepatocellular carcinoma treated with lenvatinib with or without immune checkpoint inhibitors: a retrospective cohort study

To assess whether adding immune checkpoint inhibitors (ICIs) to lenvatinib was associated with new-onset dipstick-detected proteinuria and whether treatment-emergent dipstick-detected proteinuria was associated with survival in hepatocellular carcinoma (HCC). This single-center retrospective cohort study included patients with HCC who received lenvatinib monotherapy (LEN) or lenvatinib plus ICIs (LEN+ICIs) as initial systemic therapy between October 2018 and October 2024. New-onset dipstick-detected proteinuria was defined as two consecutive on-treatment urine dipstick results of 1+ to 4+. The association between treatment strategy and new-onset dipstick-detected proteinuria was evaluated using inverse probability of treatment weighting and a Fine–Gray competing-risk model, with permanent lenvatinib discontinuation before the qualifying proteinuria event treated as a competing event. Treatment-emergent dipstick-detected proteinuria was modelled as a time-varying exposure, and its associations with overall survival (OS) and progression-free survival (PFS) were evaluated using Cox models. A prespecified 6-month landmark analysis was performed as a sensitivity analysis. A total of 90 patients were included, with 44 receiving LEN and 46 receiving LEN+ICIs. During follow-up, 38 patients developed new-onset dipstick-detected proteinuria. In the primary weighted Fine–Gray analysis, treatment strategy was not statistically significantly associated with new-onset dipstick-detected proteinuria, and the estimate was imprecise (LEN+ICIs vs. LEN: subdistribution hazard ratio [sHR] = 1.42; 95% confidence interval [CI]: 0.72–2.79; P = 0.312). In covariate-adjusted time-varying analyses, treatment-emergent dipstick-detected proteinuria was not statistically significantly associated with OS (hazard ratio [HR] = 0.93; 95% CI: 0.52–1.68; P = 0.819) or PFS (HR = 1.15; 95% CI: 0.72–1.83; P = 0.555). The 6-month landmark analyses showed a similar overall pattern, with HRs of 1.08 for OS (95% CI: 0.58–2.01; P = 0.812) and 1.26 for PFS (95% CI: 0.73–2.16; P = 0.402). Adding immune checkpoint inhibitors to lenvatinib was not statistically significantly associated with new-onset dipstick-detected proteinuria, although the estimate was imprecise and did not exclude an association in either direction. Treatment-emergent dipstick-detected proteinuria showed no consistent prognostic pattern for overall or progression-free survival. Dipstick-detected proteinuria should be interpreted in the context of treatment course and monitoring intensity rather than as an isolated prognostic marker.