Effective clearance of methotrexate using high-flux hemodialysis membranes

Wall, Susan M.; Johansen, Mary; Molony, Donald A.; DuBose, Thomas D.; Jaffe, Norman; Madden, Timothy

doi:10.1016/s0272-6386(96)90384-4

Cited by 100 publications

(65 citation statements)

References 13 publications

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“…As described by Wall et al (42), high-dose therapy with Mtx results in plasma concentrations of 1,700 M 1 h pi, followed by a rapid decrease that can be accelerated by dialysis or diuretics. After 5 to 6 days, concentrations of less than 0.3 M were measured after hemodialysis.…”

Section: Discussionmentioning

confidence: 90%

Sodium-dependent methotrexate carrier-1 is expressed in rat kidney: cloning and functional characterization

Kneuer

Honscha

2004

American Journal of Physiology-Renal Physiology

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Previous Northern blot studies suggested strong expression of a homolog to the sodium-dependent hepatocellular methotrexate transporter in the kidneys. Here, we report on the cloning of the cDNA for the renal methotrexate carrier isoform-1 (RK-MTX-1) and its functional characterization. Sequencing revealed 97% homology to the rat liver methotrexate carrier with an identical open reading frame. Differences were located in the 5Ј-untranslated region and resulted in the absence of putative regulatory elements (Barbie box, Ah/ARNT receptor) identified in the cDNA for the hepatocellular carrier. For functional characterization, MTX-1 cDNA was stably expressed in Madin-Darby canine kidney (MDCK) cells. A sodium-dependent transport of methotrexate with a Km of 41 M and a V max of 337 pmol⅐mg protein Ϫ1 ⅐min Ϫ1 was observed. This uptake was blocked by the reduced folates dihydro-and tetrahydrofolate as well as by methotrexate itself. Folate was inhibiting only weakly, whereas 5-methyltetrahydrofolate was a strong inhibitor. Further inhibitors of the methotrexate transport included the bile acids cholate and taurocholate and xenobiotics like bumetanide and BSP. PAH, ouabain, bumetanide, cholate, taurocholate, and acetyl salicylic acid were tested as potential substrates. However, none of these substances was transported by MTX-1. Furthermore, expression of RK-MTX-1 in MDCK cells enhanced methotrexate toxicity in these cells fivefold. Analysis of a fusion protein of RK-MTX-1 and the influenza virus hemagglutinin epitope by immunoblotting revealed a major band at 72 kDa within the cell membrane but not in the soluble fraction of transfected MDCK. Indirect immunofluorescence staining revealed an exclusive localization of the carrier in the plasma membrane, and by confocal laser-scanning microscopy we were able to demonstrate that the protein is expressed in the serosal region of MDCK tubules grown in a morphogenic collagen gel model.

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Section: Discussionmentioning

confidence: 90%

Sodium-dependent methotrexate carrier-1 is expressed in rat kidney: cloning and functional characterization

Kneuer

Honscha

2004

American Journal of Physiology-Renal Physiology

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“…Rebound increases in MTX concentrations to levels approaching those that existed prior to institution of the dialysis-based method have been reported. The most effec- 24,25,28,70 Such methods of mechanical MTX removal, however, may not be available readily outside of major medical centers and include the risks associated with the insertion of vascular-access devices, the transfusion of blood products, electrolyte imbalances, and the risk of bleeding secondary to heparinization, thrombocytopenia, and anemia. 24,25,70,74 Compared with dialysis-based methods, the use of CPDG 2 is tolerated well and results in a more profound, rapid, and consistent decrease in plasma MTX concentrations, and rebounds Ͻ 10% in plasma MTX concentrations were observed in only 60% of patients who were treated with CPDG 2 .…”

Section: Discussionmentioning

confidence: 99%

“…Only 3 patients had a decrease Ͼ 90% in MTX concentrations with the use of a single method in 1 dialysis session. 28,69,70 Increases in MTX plasma concentrations after the completion of dialysis-based methods were reported and quantified in seven reports. Rebound increases in postdialysis plasma MTX concentrations by 10 -221% of the postprocedure MTX levels 21,71,72 and to 90 -100% of the preprocedure MTX levels were reported.…”

Section: Use Of Dialysis-based Methods To Remove Mtxmentioning

confidence: 99%

“…A rebound increase in plasma MTX concentrations was observed in 60% of patients who were treated with CPDG 2 , which reached 2.8%, 8.8%, and 2.5% of the MTX concentration prior to administration of CPDG 2 for patients with osteosarcoma (n ϭ 7 patients), NHL or ALL (n ϭ 5 patients), and gastric carcinoma (n ϭ 1 patient), respectively. For 17 patients with complete data regarding renal recovery, serum creatinine levels peaked at a median of 3.4 mg/dL (range, from 0.8 mg/dL in an infant age 3 months to 12.5 mg/dL) and returned to values within 24 and Kawabata et al 26 h See Wall et al 28 normal limits (median, 1.1 mg/dL; range, 0.3-1.3 mg/ dL), corresponding to a median of 1.4 times the baseline creatinine level at a median of 22 days (range, 5-40 days) after the initiation of the MTX infusion. Additional MTX infusions were administered to 5 patients after recovery of renal function (full dose, n ϭ 1 patient; 20 -75% of the protocol-prescribed dose, n ϭ 4 patients) without recurrence of nephrotoxicity.…”

Section: Mtx Pharmacokinetics and Recovery Of Renal Function After Cpmentioning

confidence: 99%

“…Hemodialysis-based methods of MTX removal have been described for over 20 years. [21][22][23][24][25][26][27][28][29] More recently, carboxypeptidase-G 2 (CPDG 2 ), a recombinant bacterial enzyme 30,31 that hydrolyzes MTX to the inactive metabolite 2,4-diamino-N 10 -methylpteroic acid (DAMPA), 32,33 has become available as an investigational new drug for the treatment of HDMTX-induced renal dysfunction. When administered to patients with MTX-induced renal dysfunction, CPDG 2 lowers plasma MTX concentrations within 15 minutes of administration by a median of 98.7% (range, 95.6 -99.6%).…”

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confidence: 99%

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High‐dose methotrexate‐induced nephrotoxicity in patients with osteosarcoma

Widemann

Balis

Kempf-Bielack

et al. 2004

Cancer

262

224

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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.

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