Renal ontogeny of ifosfamide nephrotoxicity
Bibliographic record
Abstract
Ifosfamide (IF) -induced nephrotoxicity adversely affects the health and well-being of children with cancer. We have recently shown age-dependent nephrotoxicity of IF, with younger children (less than 3 years of age) substantially more vulnerable. The mechanisms leading to this age-related IF-induced renal damage have not been identified. The hypothesis underlying this work was that there is renal ontogeny in the expression and activity of cytochrome P450 (CYP) enzymes responsible for IF metabolism to the nephrotoxic chloroacetaldehyde. The presence of renal CYP3A and 2B22 activity was evaluated in pigs between 1 day of age to adulthood, as was the metabolism of IF by renal microsomes to 2- and 3-dechloroethylifosfamide (2-DCEIF and 3-DCEIF). Kidney CYP3A mRNA expression peaked at 15 to 60 days (0.7–76±0.19 CYP3A/actin ratio) (P<0.001). Subsequently, this level decreased to adult values (0.54±0.03 CYP3A/actin ratio) (P=0.04). In a similar manner, there was an increase in IF metabolic rate between young (18±2 pM/mg protein/min) vs adults (12.2±0.17 pM/mg protein/min) (P=0.002). This is the first documentation of ontogeny of renal CYP3A and of renal IF metabolism. These data suggest that age-dependent IF nephrotoxicity is, at least in part, due to ontogeny in the production chloroacetaldehyde. Clinical Pharmacology & Therapeutics (2005) 77, P80–P80; doi: 10.1016/j.clpt.2004.12.198
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".