Impact of renal and hepatic function on dihydropyrimidine dehydrogenase phenotype assessed by enzyme activity in peripheral blood mononuclear cells and uracilemia
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Sara Contu
Abstract
Objectives
To investigate the relationship between uracilemia (U) and dihydropyrimidine dehydrogenase (DPD) activity in peripheral blood mononuclear cells (PBMC) and whether they are influenced by renal or hepatic impairment.
Methods
This retrospective study included 176 cancer patients with pre-treatment U (UPLC-MSMS assay) and PBMC-DPD (radioenzymatic assay) analyzed the same day (routine phenotyping). Blood renal (creatinine, BUN) and hepatic (ALT, AST, GGT, ALP, albumin, bilirubin) work-up was performed within 15 days before or up to 4 days after DPD phenotyping. Biochemical markers were categorized according to CTCAEv5.0 grade (G). Glomerular filtration rate (eGFR) was estimated (CKD-EPI and EKFC). Non-parametric statistical tests were used.
Results
Prevalence of partial deficiency was 3.4 % based on PBMC-DPD (i.e. ≤100 pmol/min/mg) and 6.3 % based on U (i.e. ≥16 μg/L). No complete deficiency was observed. Fifteen patients out of 176 (8.5 %) exhibited discordant DPD status between PBMC activity and U. The correlation between PBMC-DPD and U was significant but weak (r= −0.309, p<0.001). PBMC-DPD (mean 246, median 235, range 62–926 pmol/min/mg prot) was not influenced by renal or hepatic impairment. U (mean 9.6, median 8.5, range 1.7–57.8 μg/L) was significantly higher in patients with elevated BUN (normal vs. >1-UNL, p=0.009), GGT (G0 vs. G1 vs. G2 vs. G3, p<0.001), AST (G0 vs. G≥1, p=0.015), or with hypoalbuminemia (G0 vs. G ≥ 1, p=0.045). Categorized creatinine or eGFR did not influence U.
Conclusions
It remains unclear whether renal and/or hepatic impairment acts as a confounding factor affecting the accuracy of uracilemia testing, or whether truly impacts DPD activity, suggesting caution in U interpretation.
Acknowledgments
The authors would like to thank the oncologists who clinically manage the patients included in the present study, namely Eric François, Caroline Bailleux, Jean-Marc Ferrero, Agnes Ducoulombier, Delphine Borchiellini, Thibault Le bourgeois, Nina Pujol, Gérard Cavaglione, Marc Pujalte and Claire Jaraudias.
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Research ethics: According to French regulations, the study was registered under the MR-004 methodology in the Health Data Hub registry, N° 19352093, and approval from the Institutional Review Board was not required.
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Informed consent: Following French regulations for MR-004 studies, patients were informed of the use of their data for this study, they had the possibility to oppose, and none of them objected to the use of their data.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: The authors state no conflict of interest.
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Research funding: None declared.
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Data availability: GDPR and French regulations prohibit open data sharing. According to these regulations, we are required to inform patients each time their data is shared and specify the recipient. If the data were made freely available, it would be impossible to identify all parties accessing the data and therefore technically unfeasible to notify patients of each instance of data sharing.
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