High‐dose methotrexate‐induced nephrotoxicity in patients with osteosarcoma

Abstract

BACKGROUNDHigh‐dose methotrexate (HDMTX)‐induced renal dysfunction can be life threatening, because it delays methotrexate (MTX) excretion, thereby exacerbating the other toxicities of MTX. HDMTX‐induced nephrotoxicity has been managed with high‐dose leucovorin, dialysis‐based methods of MTX removal, thymidine, and with the recombinant enzyme, carboxypeptidase‐G2 (CPDG2), which cleaves MTX to inactive metabolites. The objectives of the current study were to estimate the current incidence of HDMTX‐induced renal dysfunction in patients with osteosarcoma and to compare the efficacy and recovery of renal function for dialysis‐based methods of MTX removal with treatment using CPDG2.METHODSThe literature was reviewed for osteosarcoma trials, use of dialysis‐based methods for MTX removal, and reports of MTX‐induced nephrotoxicity, including information regarding recovery of renal function. Clinical trial databases of select osteosarcoma studies were reviewed. The efficacy of CPDG2 and renal recovery after CPDG2 rescue was obtained from the database of a compassionate‐release trial.RESULTSApproximately 1.8% of patients with osteosarcoma (68 of 3887 patients) who received HDMTX developed nephrotoxicity Grade ≥ 2. The mortality rate among those patients was 4.4% (3 of 68 patients). Dialysis‐based methods of MTX removal were used frequently but had limited effectiveness in removing MTX compared with the rapid reductions > 98% in plasma MTX concentrations achieved with CPDG2. CPDG2 did not appear to increase the time to recovery of renal function compared with supportive treatment that included dialysis‐based methods.CONCLUSIONSHDMTX‐induced renal dysfunction continues to occur in approximately 1.8% of patients with osteosarcoma who are treated on clinical protocols with optimal supportive care. For patients with delayed MTX excretion and high plasma MTX concentrations, CPDG2 should be considered over hemodialysis to lower plasma MTX concentrations rapidly and efficiently. Cancer 2004. © 2004 American Cancer Society.

Glucarpidase (Carboxypeptidase G2) Intervention in Adult and Elderly Cancer Patients with Renal Dysfunction and Delayed Methotrexate Elimination After High-Dose Methotrexate Therapy

“…According to a previously used definition of renal recovery (sCrea Ͻ1.5ϫ baseline), 16 patients recovered within a median of 19 days, and 19 patients still had a sCrea above this threshold within a median observation period of 12 days [6]. This suggests that the renal recovery in this study was somewhat slower than in patients treated with supportive care measures, including extracorporeal removal of MTX but not glucarpidase, whose reported median time to renal recovery was 16 days [6].…”

“…This suggests that the renal recovery in this study was somewhat slower than in patients treated with supportive care measures, including extracorporeal removal of MTX but not glucarpidase, whose reported median time to renal recovery was 16 days [6]. The severity of renal damage in this study, as indicated by the median peak creatinine level, was, however, higher (232 mol/l ϭ 3 mg/ dl) than that of previously evaluated patients treated with supportive care not including glucarpidase or dialysisbased interventions (2.1 mg/dl), but was less than in patients who received extracorporeal removal of MTX (3.9 mg/dl) [6]. Remarkably, some patients in this study received nephrotoxic agents in addition to HD-MTX, which may have contributed in part to delays in renal recovery.…”

“…HD-MTX-induced renal failure with persistence of toxic blood MTX levels is a rare but life-threatening complication that occurs more frequently in adults, particularly those with advanced age and CNS lymphoma [5][6][7]. Hemodialysis, hemoperfusion, or a combination of the two in this condition have been repeatedly investigated, but these invasive procedures require prolonged application, might add treatment-related morbidity, and result in a limited decline in blood MTX levels with frequent rebound increases [8].…”

“…However, around 2%-10% of patients experience grade Ն2 HD-MTX-related nephrotoxicity, which could result in delayed further treatment or may occasionally be life threatening. Frequencies of grade 3 or 4 HD-MTX-related nephrotoxicity vary from only 0.6% in osteosarcoma patients to 4%-5% in mostly elderly patients with primary CNS lymphoma [5][6][7]. Precipitation of methotrexate (MTX) in renal tubules is thought to be the main mechanism causing HD-MTX-induced renal failure, and consequently, prolonged exposure to toxic blood MTX concentrations.…”

Blood purification therapies in methotrexate-induced acute kidney injury: four case reports

“…Reduction rate is calculated by dividing the difference of MTX blood concentration before and after blood purification by MTX blood concentration before blood purification. HD + HP therapy #1-#3 was done in case 3; HD + HP therapy #4 was done in case 4 [25]. MTX elimination was low after peritoneal dialysis and plasma exchange, and the highest reduction rate (78%) was found after HP + HD treatment.…”