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Enhancement of methotrexate nephrotoxicity after cisplatin therapy
Insights
Methotrexate chemotherapy can cause kidney damage in children with osteosarcoma. Monitoring specific urinary markers can detect early signs of methotrexate-induced nephrotoxicity, especially when combined with cisplatin.
Area of Science:
- Oncology
- Nephrology
- Pharmacology
Background:
- Osteosarcoma treatment often involves combination chemotherapy.
- Methotrexate is a common chemotherapeutic agent with potential nephrotoxic side effects.
- Early detection of kidney damage is crucial for managing treatment toxicity.
Purpose of the Study:
- To assess subclinical methotrexate-induced nephrotoxicity in children with osteosarcoma.
- To identify urinary markers indicative of renal tubular damage during chemotherapy.
- To investigate the impact of cisplatin on methotrexate-induced nephrotoxicity.
Main Methods:
- Urinary levels of total protein, N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase, and adenosine deaminase-binding protein were measured.
- Ten children with osteosarcoma receiving combination chemotherapy including methotrexate were studied.
- Changes in urinary markers were analyzed in relation to methotrexate dosage and cisplatin co-administration.
Main Results:
- Methotrexate monotherapy caused transient increases in all four urinary markers.
- Concurrent or sequential cisplatin administration with methotrexate led to persistent elevations in NAG and alanine aminopeptidase, indicating irreversible nephrotoxicity.
- A biphasic pattern of total protein and NAG excretion suggested multiple mechanisms of methotrexate-induced kidney damage.
Conclusions:
- Urinary markers can detect subclinical methotrexate-induced nephrotoxicity.
- Cisplatin potentiates methotrexate-induced nephrotoxicity, leading to irreversible kidney damage.
- Monitoring renal tubular function is essential for optimizing chemotherapy regimens and preventing severe nephrotoxicity.
Abstract:
We measured urinary levels of total protein, N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase, and adenosine deaminase-binding protein in ten children with osteogenic sarcoma who were receiving combination chemotherapy that included 12 doses of methotrexate (12 g/m2). Analysis of the changes in these sensitive markers of renal tubular damage permitted detection of subclinical methotrexate-induced nephrotoxicity. In the absence of cisplatin, methotrexate therapy was associated with significant but transient increases in each of the four markers. Irreversible nephrotoxicity, indicated by persistent rises in NAG and alanine aminopeptidase as well as increased serum creatinine levels, was associated with doses of methotrexate that followed the administration of cisplatin (400 mg/m2). The biphasic pattern of total protein and NAG excretion observed in all patients suggests more than one mechanism of methotrexate-induced nephrotoxicity. Monitoring renal tubular damage in patients who are receiving methotrexate in combined-drug regimens would provide useful information for scheduling nephrotoxic drugs in clinical trials.