Background <p>Metabolic disorders are highly prevalent in patients with native and transplanted chronic kidney disease (CKD). However, little is known about the metabolic similarities and differences associated with declining kidney function between non-transplant patients and kidney transplant recipients (KTRs).</p> Methods <p>This cross-sectional study employed gas chromatography-mass spectrometry to compare serum metabolomic profiles among native CKD subgroups and KTR subgroups, aiming to identify differential metabolites associated with kidney dysfunction in both clinical settings.</p> Results <p>11 and 13 metabolites were associated with kidney dysfunction in native CKD patients and KTRs, respectively. Among these, L-tryptophan, D-lyxose, xylitol, erythritol, 3,4-dihydroxybutanoic acid and 2,4-dihydroxybutanoic acid were selected as common differential metabolites in both cohorts. Pathway analysis revealed that the pentose and glucuronate interconversions pathway was significantly affected in native CKD patients, whereas phenylalanine, tyrosine, and tryptophan biosynthesis pathway and tyrosine metabolism pathway were the most affected pathways in KTRs. Further comparisons between native CKD and KTRs who were at the same kidney dysfunction stages demonstrated that KTRs showed significantly higher levels of malic acid, but lower levels of D-allose compared to native CKD patients.</p> Conclusions <p>Our study not only identified the 6 metabolites associated with kidney function in both non-transplant patients and KTRs, but also determined 5 and 7 metabolites that were specifically associated with kidney dysfunction in native CKD patients and KTRs, respectively. These data suggest that the metabolic process may be influenced by the unique characteristics of kidney transplantation, such as allogeneic immunity and immunosuppressive drugs, in KTRs.</p>