2,4-Diamino-N10-methylpteroic acid (DAMPA) crystalluria in a patient with osteosarcoma treated with carboxypeptidase-G2 rescue after high-dose methotrexate-induced nephrotoxicity

Berga, Francisco; Luna, Pablo; Martorell, C. Nicolau; Rey, Juan; Gomila, Isabel; Giménez, Sandra; Costa-Bauzà, Antònia; Elorza, Miguel Ángel; Sanchez, I M; Gráses, F.; Barceló, Bernardino

doi:10.1016/j.cca.2018.09.006

Cited by 5 publications

(4 citation statements)

References 24 publications

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“…To our knowledge, in Spain the incidence and clinical management of delayed MTX elimination due to HDMTX-induced AKI remain unexplored. Only few case studies have been reported to this respect, but no works have been published regarding the incidence, the management and the outcomes in the context of MTX toxicity in Spain [23][24][25] The present study aims to determine the epidemiology, clinical and therapeutic management of patients receiving HDMTX as part of their chemotherapy treatment developing MTX toxicity due to delayed MTX elimination in Spain through experts' consensus Delphi methodology.…”

Section: Introductionmentioning

confidence: 99%

Incidence and management of patients with methotrexate delayed elimination in the clinical practice: A Delphi study

Gros

Pérez

Cabero-Martínez

et al. 2022

J Oncol Pharm Pract

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Introduction High-dose methotrexate (HDMTX) is administered for the treatment of some cancers. HDMTX is usually safe but may crystallize in renal tubules causing acute kidney injury (AKI). Consequently, MTX elimination is delayed, resulting in a severe and life-threatening condition. No studies have been published about the impact of MTX toxicity in Spain. This study aims to estimate the incidence and management of MTX delayed elimination and toxicity. Methods A two-round Delphi study was performed to reach consensus between 10 medical experts on haemato-oncology and paediatric oncology with experience in the management of HDMTX treated patients from leading Spanish hospitals. An online questionnaire was developed based on national and international guidelines and previous evidence regarding HDMTX-related toxicity. Consensus was established at 80% agreement. Median and interquartile ranges were calculated, and incidence data were extrapolated to the Spanish general population. Results Out of 1.475 patients estimated to receive HDMTX treatment annually in Spain, 27.5% present MTX delayed elimination and 11.6% develop HDMTX-induced AKI (35.4% with severe systemic toxicities (>grade 3) and 18.8% develop chronic renal disease). Mortality is estimated in 4.2%. Immuno-enzymatic assay is used in most of the hospitals (90%) for MTX serum level monitoring. All experts use increased supportive care and high leucovorin as first-line treatment. Available treatments in experts’ hospitals in case toxicity persists are haemodialysis (90% of hospitals), glucarpidase (60%) and hemofiltration (50%). Most prevalent non-renal systemic toxicities are haematologic and mucositis (21–40% of patients). Patients with HDMTX-induced AKI require from intensive care (5% of patients), more than 3 sessions and 4 days of dialysis, and about 8.5 days of hospitalization (non-ICU patients) and 12 days in case of patients requiring ICU. Conclusions These results are the first evidence regarding HDMTX-induced AKI in Spain. Incidence and mortality results are in line with previous studies. Clinical management is based on preventive measures and the treatment depend on the availability in the hospital. The need for effective, safe and rapid treatment for the reduction of MTX toxic levels and the improvement of monitoring methods were noted by experts as urgent needs. Further observational studies to validate these results would be needed.

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Section: Introductionmentioning

confidence: 99%

Incidence and management of patients with methotrexate delayed elimination in the clinical practice: A Delphi study

Gros

Pérez

Cabero-Martínez

et al. 2022

J Oncol Pharm Pract

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“…1 The major problem for high-dose MTX therapy is life-threatening toxicities especially nephrotoxicity, 1 which is partly caused by the formation of crystal deposits in the kidney due to poor water solubility of MTX and its metabolites 7-hydroxy methotrexate (7-OH MTX), deoxyaminopteroic acid (DAMPA) and 7-hydroxy deoxyaminopteroic acid (7-OH DAMPA) in acid conditions. [1][2][3][4][5][6] In alkaline conditions, water solubility of MTX and its metabolites dramatically increases because their carboxylic acid groups transformed into carboxylate ions. Therefore urine alkalinization, in combination with MTX monitoring guided glucarpidase detoxification and leucovorin rescue are routine strategies to overcome MTX induced toxicities.…”

Section: Introductionmentioning

confidence: 99%

“…Glucarpidase, an efficient drug for MTX detoxification, can rapidly and completely transform MTX into its inactive form DAMPA, which can form crystal deposits in the urine due to its poor water solubility. 4,7 Therefore urine DAMPA level is recommended to monitor in patients receiving glucarpidase therapy. 4 Prediction of MTX induced toxicities is a challenge for clinicians due to huge intra-and inter-individual variances of MTX pharmacokinetics and pharmacodynamics.…”

Section: Introductionmentioning

confidence: 99%

“…4,7 Therefore urine DAMPA level is recommended to monitor in patients receiving glucarpidase therapy. 4 Prediction of MTX induced toxicities is a challenge for clinicians due to huge intra-and inter-individual variances of MTX pharmacokinetics and pharmacodynamics. 1,2,5,11 Therefore MTX plasma level is routinely monitored in clinical practice for leucovorin dose adjustment especially in patients receiving high dose MTX therapy.…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous Determination of Urine Methotrexate, 7-Hydroxy Methotrexate, Deoxyaminopteroic Acid, and 7-Hydroxy Deoxyaminopteroic Acid by UHPLC-MS/MS in Patients Receiving High-dose Methotrexate Therapy

et al. 2020

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Nephrotoxicity, the most important toxicity in high dose methotrexate (MTX) therapy, is partly caused by the formation of crystal deposits in the kidney due to poor water solubility of MTX and its metabolites 7-hydroxy methotrexate (7-OH MTX), deoxyaminopteroic acid (DAMPA) and 7-hydroxy deoxyaminopteroic acid (7-OH DAMPA). Plasma MTX level guided urine alkalinization, leucovorin rescue and glucarpidase detoxification are common strategies to overcome MTX related nephrotoxicity. However, overestimation is a problem for MTX analysis by immunoassays due to cross-reactivity of MTX metabolites (7-OH MTX and DAMPA). An UHPLC-MS/MS method for simultaneous determination of MTX, 7-OH MTX, DAMPA and 7-OH DAMPA in human urine was developed, validated and applied in clinical practice.Samples were treated by one-step protein precipitation and analyzed within 3 min. The calibration range was 0.02 to 4 µmol/L for MTX and DAMPA, and 0.1 to 20 µmol/L for 7-OH MTX and 7-OH DAMPA. For all analytes, the intra-day and inter-day bias and imprecision were -8.0% to 7.6% and < 9.0%, the internal standard normalized recovery and matrix factor were 92.34% to 109.49% and < 20.68%. Plasma MTX and 7-OH MTX levels increased with urine drug levels, age, serum creatinine and alanine transaminase, but urine could not replace blood for MTX monitoring due to their poor correlation (R 2 , 0.16 to 0.51). Dose normalized urine and plasma MTX and 7-OH MTX levels were similar between different patient groups (urine pH < 7 or ≥ 7). Due to the large inter-individual variance of the analytes levels in both plasma and urine, these findings should be treated with caution.

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2,4-Diamino-N10-methylpteroic acid (DAMPA) crystalluria in a patient with osteosarcoma treated with carboxypeptidase-G2 rescue after high-dose methotrexate-induced nephrotoxicity

Cited by 5 publications

References 24 publications

Incidence and management of patients with methotrexate delayed elimination in the clinical practice: A Delphi study

Incidence and management of patients with methotrexate delayed elimination in the clinical practice: A Delphi study

Simultaneous Determination of Urine Methotrexate, 7-Hydroxy Methotrexate, Deoxyaminopteroic Acid, and 7-Hydroxy Deoxyaminopteroic Acid by UHPLC-MS/MS in Patients Receiving High-dose Methotrexate Therapy

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