大剂量甲氨蝶呤治疗急性淋巴细胞白血病患儿对肝肾功能影响的临床研究

Clinical studies of effects of high-dose methotrexate on liver and renal function in children with acute lymphoblastic leukemia

目的:研究大剂量甲氨蝶呤治疗急性淋巴细胞白血病患儿对肝肾功能的影响。方法:2004年3月至2008年5月期间165例急性白血病住院患儿纳入研究,并分为2个组:3g/m2剂量组(119例)和5g/m2剂量组(46例)。3g/m2剂量组中男64例,女55例,平均年龄(104.88±21.40)月。5g/m2剂量组中男37例,女9例,平均年龄(101.57±20.43)月。给药方法:甲氨蝶呤先按3g/m2或5g/m2总剂量的1/6作为突击量于30min内静脉滴注,其余5/6剂量于23.5h内滴注完毕,同时给予5%碳酸氢钠注射液3～5ml/kg静脉滴注至甲氨蝶呤血浓度<0.1μmol/L和尿液pH值6～8时停用。每天给予2～3L/m2液体水化。给予甲氨蝶呤36h后静脉注射亚叶酸钙解救,其总量为甲氨蝶呤的3%～5%,分6～8次给予,每6h1次,首次剂量加倍;给予还原型谷胱甘肽0.6～1.2g/d,多烯磷脂酰胆碱232.5～465mg/d,均静脉滴注,连续给药10～14d。甲氨蝶呤给药后于24、36、48、72和96h测定其血浓度,记录甲氨蝶呤使用前和使用后2～7d及化疗结束后的肝肾功能,记录化疗开始后24h尿量和pH值。结果:5g/m2剂量组和3g/m2剂量组给药24、36、48h后甲氨蝶呤的血浓度分别为(130.99±67.23)μmol/L、(1.95±0.98)μmol/L、(2.13±3.03)μmol/L与(55.02±29.46)μmol/L、(1.22±0.75)μmol/L、(1.28±2.75)μmol/L,差异有统计学意义(P<0.01,P<0.05,P<0.05)。化疗过程中5g/m2剂量组与3g/m2剂量组的γ-GT、TBil、DBil值分别为(63.94±76.41)U/L、(24.87±42.91)μmol/L、(12.19±29.92)μmol/L与(40.72±35.34)U/L、(13.01±6.26)μmol/L、(4.39±2.59)μmol/L,差异均有统计学意义(均P<0.01);5g/m2与3g/m2剂量组的ALT、AST和ALP值分别为(187.29±171.18)U/L、(85.47±111.59)U/L、(141.71±69.24)U/L与(165.93±178.84)U/L、(73.45±82.42)U/L、(138.60±59.92)U/L,差异有统计学意义(均P<0.05)。2组的肾功能,治疗中与治疗前比较,以及治疗中2组间比较,差异均无统计学意义(P>0.05)。保肝治疗后,5g/m2与3g/m2剂量组的ALT、AST及ALP明显下降,分别为(47.86±37.84)U/L、(24.00±10.78)U/L、(115.40±34.43)U/L与(75.16±68.52)U/L、(32.78±27.65)U/L、(151.27±60.18)U/L,差异有统计学意义(均P<0.05)。5g/m2剂量组与3g/m2剂量组首日与次日液体排出量分别为(3673±974)ml、(4216±1189)ml与(3236±1039)ml、(3832±1134)ml,5g/m2剂量组的液体排出量高于3g/m2剂量组,差异有统计学意义(P<0.05)。尿pH值无明显改变。结论:大剂量甲氨蝶呤能致急性淋巴细胞白血病患儿肝损害,损害程度与剂量相关。应用还原型谷胱甘肽和多烯磷酯酰胆碱对肝脏有保护作用。

ABSTRACT Objective： To study the effects of high-dose methotrexate on liver and renal function in children with acute lymphoblastic leukemia. Methods：From March 2004 to May 2008, 165 hospitalized children with acute lymphoblastic leukemia were enrolled in the study and divided into two groups： the 3 g/m： dose group （119 cases） and the 5 g/m2 dose group （46 cases）. The 3 g/m2 dose group comprised 64 men and 55 women with average age of（104.88 ±21,40）months. The 5 g/m2 dose group comprised 37 men and 9 women with average age of（ 101.57 ±0 20.43 ） months. The drug administration was as follows ： A bolus dose of one-sixth of a total dose of methotrexate 3 g/m2 or 5 g/m2 was infused intravenously and was completed within 30 minutes, then the rest fivesixths dose was infused intravenously and was completed within 23.5 hours, while an IV infusion of 5% sodium bicarbonate 3-5 ml/kg was given until the blood methotrexate concentration was 〈 0.1 μmol./L and urinary pH was 6-8. An IV fluid hydration 2-3 L/m2 daily was given. An IV calcium foliate was given 36 hours after methotrexate administration for rescue. A total calcium foliate dose was 3% - 5% of methotrexate dose, and the total dose was divided into 6-8 doses, one dose every 6 hours was given, and the initial dose was double. An Ⅳ infusion of reduced glutathione 0. 6-1.2 g/d and an Ⅳ infusion of polygene phosphateidylcholine 232.5- 465 mg/d were given for 10-1d days, respectively. Blood methotrexate concentration was measured 24, 36, 48, 72, and 96 hours after administration. Liver and renal function was recorded before and 2-7 days after methotrexate administration, as well as after chemotherapy completion. The urinary volume and pH were recorded 24 hours after chemotherapy initiation. Results ： Blood methotrexate concentrations 24, 36, and 48 hours after administration in the 5 g/m2 dose and the 3 g/m2 dose groups were （ 130.99 ± 67.23 ） μmol/L, （ 1.95 ± 0.98 ）μmol/L, （ 2.13 ± 3.03 ） μmol/L, and（55.02 ± 29.46 ）μmol/L, （ 1.22 ± 0.75 ）μmol/L, （ 1.28 ± 2.75 ） μmol/L, respectively. The differences were statistically significant（ P 〈 0.01, P 〈 0.05, P 〈 0.05 ）. During chemotherapy, γ-GT, TBill, and DBill levels in the 5 g/m2 dose and the 3 g/m2 dose groups were respectively （ 63.94± 76.41 ） U/L, （ 24.87 ± 42.91 ）μmol/L, （ 12.19 ± 29.92 ） μmol/L, and （40.72 ± 35.34） U/L, （ 13.01 ± 6.26 ） μmol/L, （4.39 ± 2.59 ） μmol/L, the differences were statistically significant （ all P 〈 0.01 ）. The ALT, AST and ALP levels in the 5 g/m2 dose and 3 g/m2 dose groups were respectively （ 187.29 ±171.18） U/L, （85.47 ± 11 1. 59 ） U/L, （ 141.71 ± 69.24 ） U/L, and （ 165.93 ± 178.84 ） U/L, （73.45 ± 82.42 ） U/L, （ 138.60±59.92 ） U/L, the differences were statistically significant （ all P 〈 0.05 ）. There were no statistical differences between during treatment and before treatment in both groups, as well as between both groups during treatment （ all P 〉 0.05 ）. After liver-protective treatment, the ALT, AST and ALP levels decreased markedly, and the ALT, AST and ALP levels in the 5 g/m2 dose and 3 g,/m2 dose groups were respectively（47.86± 37.84） U/L, （ 24.00 ± 10.78 ） U/L, （ 115.40 ± 34.43 ） U/L and （ 75.16 ± 68.52 ） U/L, （ 32.78 ± 27.65 ） U/L, （ 151.27 ± 60. 18 ） U/L, and the differences were statistically Significant （ all P 〈 0.05 ）. In the first and second days, the fluid output in the 5 g/m2 dose and 3 g/m2 dose groups were respectively （3 673 ±974） ml, （4 216 ± 1 189）ml and（3 236 ± 1 039）ml, （3 832 ± 1 134）ml, the fluid output was higher in the 5 g/m2 dose group than in the 3 g,/m2 dose group, and the differences were statistically significant （P 〈 0. 05）. No marked changes in urinary pH were found. Conclusion： High-dose methotrexate can cause liver damage in children with acute lymphoblastic leukemia, and the intensity of damage is dose-related. Reduced glutethine plus polygene phosphateidylcholine has protective effects to liver.