Does Theophylline Prevent Vancomycin-Induced Nephrotoxicity in Children? A Two-Group, Single-Blind Clinical Trial

Background: Vancomycin-induced nephrotoxicity is a well-documented adverse effect, occurring in 5 - 25% of patients, primarily due to the production of free radicals and reactive oxygen species. Objectives: This study aimed to evaluate the potential protective effect of theophylline against vancomycin-induced nephropathy. Methods: A two-group, single-blind randomized clinical trial was conducted at Heshmatieh Subspecialty Hospital in Sabzevar, Iran. Sixty-eight children were randomly assigned to either an intervention group (n = 34) or a control group (n = 34) using permuted block randomization. The primary analysis followed the intention-to-treat (ITT) principle using the last observation carried forward (LOCF) method; a per-protocol (PP) analysis was also conducted for sensitivity. Participants were divided into two groups: The intervention group received theophylline alongside vancomycin, while the control group received vancomycin alone. Serum and urine samples were collected at baseline and on the 3rd, 10th, and 30th days of treatment. Measurements included serum levels of blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), and urinary microalbumin. Data were analyzed using the independent t-test, Mann-Whitney U test, and chi-square test. A repeated-measures ANOVA was conducted to assess changes over time, with Greenhouse-Geisser correction applied where sphericity was violated. Results: The mean urinary microalbumin levels on the 3rd, 10th, and 30th days post-treatment in the intervention group showed a notable decrease compared to the control group. The differences were statistically significant on the 10th and 30th days (P = 0.023 and P = 0.048, respectively). Additionally, the mean BUN levels decreased, and the eGFR increased in the intervention group compared to the control group over the same time points. The changes in BUN were significant on the 10th and 30th days (P = 0.031 and P = 0.045, respectively), while the changes in eGFR were significant on the 10th and 30th days (P = 0.016 and P = 0.039, respectively). No significant differences were observed on the 3rd day for BUN (P = 0.683) or eGFR (P = 0.282). It is important to note that urinary microalbumin values remained within the normal range (< 30 mg/g creatinine) in both groups throughout the study, suggesting these changes may reflect subclinical rather than clinically overt kidney injury. Conclusions: The results showed that theophylline may attenuate vancomycin-induced nephrotoxicity, as reflected by improvements in renal biomarkers. However, the clinical relevance of these biomarker changes requires further validation through trials using standardized clinical endpoints such as KDIGO-defined acute kidney injury (AKI).