大剂量甲氨蝶呤肾功能损伤后对其他不良反应的影响
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摘要
研究背景和目的：
HD-MTX是治疗白血病尤其是急性淋巴细胞白血病(ALL)、淋巴瘤和中枢神经系统白血病的重要手段,其不良反应的发生率和严重程度直接取决于MTX血药浓度的高低和持续时间的长短。大剂量甲氨蝶呤(HD-MTX)的主要毒副反应有骨髓抑制、皮肤粘膜反应、肝肾功能损害、口腔炎、口唇溃疡、咽喉炎、恶心、呕吐、腹痛、腹泻、消化道出血等,尤以肾功能损害较为重要。
国外有文献显示大剂量甲氨蝶呤引起肾功能的损伤的比例为2.41%,国内尚未这方面报道。因为HD-MTX所致肾功能损伤比较少见,并未引起重视,国内文献多为个案报道,一旦发生肾功能损伤其相关的不良反应是比较严重的,死亡率极高。现将本院应用甲氨蝶呤后出现肾功能损害患者的不良反应给予统计,以在实际的临床应用中可以作为参考。
材料与方法：
2001年1月至2012年12月在河南省肿瘤医院住院的急性白血病及淋巴瘤患者共540例,年龄为3-65岁,中位年龄32岁。在行HD-MTX治疗前WBC>3.0×109/L,ANC>1.5×109/L,肝、肾功能均正常,尿蛋白(-),肌酐清除率均在正常范围内。骨髓增生活跃,均处于缓解状态。MTX用量2-3g／m2,同时给予水化碱化及亚叶酸钙解救。并在应用静脉滴注MTX前,应用当天,及应用后定期采集静脉血监测血常规及肾功能,观察治疗,后体温及口腔黏膜变化,观察外周血象的变化及其他相关不良反应。将这些不良反应与肾功能之间的关系用统计学软件SPSS17.0给予分析。
结果：
1.540例患者中发生肾功能损害的共13例,肾功能损害的百分比为2.41%。
2.13例肾功能损伤的患者中出现皮肤及粘膜改变的有7例次,胸部CT明确提示肺部有炎症的9例次,带状疱疹5例次、胸腔积液4例次,心包积液3例次,尿路感染3例次,皮下出血点6例次,皮肤黏膜瘀斑3例次,G,GM.实验阳性2例次,腹泻7例次,电解质紊乱3例次,肠道感染2例次,血培养或咽式子证实阳性的有4例次。
3.13例肾功能损伤的病人中,发现肾功能损伤距化疗的平均时间为3.69天,中位时间为4天(3-4天)。肾功能损伤恢复在化疗后平均时间为14天,中位时间为17天(9-24天)。BUN范围为10.4～44.7mmol/L,血CR范围为138～390umol/L。
4.粒缺的比例为100%,中性粒细胞降低至粒缺距化疗的平均时间为9.77天,中位时间为9天(5-12天)。粒缺持续的时间平均为20天,中位时间为20天(14-29天)。肾功能损伤越严重其粒缺持续时间越长。
5.血小板低于20×109/L的比例为100%,血小板降低至20×109/L以下距化疗的平均时间为11.5天,中位时间为11天(8-23天)。血小板低于20×109/L持续时间平均为21天,中位时间为20天(8-31天)。。肾功能损伤越严重其血小板<20×109／L的持续时间越长。
6.13例患者都有输红细胞及血小板的记录。平均输血小板5.55个治疗量,平均输红细胞数量8个单位。有3例给予新鲜冰冻血浆输注。
7.发热的比例为100%,其中度热为9例,高热为4例。且发热持续的时间较长。开始发热的时间(距化疗)平均时间10.3天,中位时间11天(3-15天)。发热的持续的时间平均为18天,中位时间为16天(14-31天)。
8.口腔粘膜的糜烂的比例为100%。口腔粘膜糜烂距化疗的平均时间为9.25天,中位时间为7.5天(6-14天)。口腔粘膜糜烂持续的时间为21.5天,中位时间21.5天(13-36天)。
9.13例肾损伤的患者中其中有2例患者死亡,2例放弃治疗患者经随访证实均在出院后死于HD-MTX化疗的并发症。死亡率高达30.8%,9例患者经积极治疗后好转。其中1例死于肾衰竭,2例死于感染性休克,1例死于消化道出血。
结论：
1.大剂量甲氨蝶呤所引起的肾功能损伤基本是可逆的。
2.大剂量甲氨蝶呤所致肾功能损伤死亡主要原因是：肾功能异常使甲氨蝶呤排泄减少,甲氨蝶呤在体内蓄积,所致严重骨髓抑制,粒细胞缺乏和出血。
Background:
High-dose methotrexate(HD-MTX) is the treatment of leukemia, especially acute lymphoblastic leukemia (ALL), Also is an important means of lymphoma and CNS leukemia, The incidence of adverse reactions and severity depend on the MTX blood drug concentration and duration. High dose methotrexate (HD-MTX) of the main side effects were bone marrow suppression, skin and mucous membrane reaction, liver and kidney damage, stomatitis, oral ulcers, sore throat, nausea, vomiting, abdominal pain, diarrhea, gastrointestinal bleeding, especially in renal function damage is more important.
Foreign literature shows high dose methotrexate induced renal damage ratio of2.41%, the domestic has not been reported. Because HD-MTX renal function damage induced by relatively rare, did not pay attention, the domestic literature mostly case reports, once the incidence of renal adverse effects related to the injury is more serious, the mortality rate is very high. Now the application of methotrexate after adverse reactions in patients with kidney impairment to statistics, to the clinical application in practice can be used as reference.
Materials and methods:
Between January2001and December2012in Henan Cancer hospital, a total of 540patients with acute leukemia and lymphoma, aged3～65years, with a median age of32years. HD-MTX before treatment the WBC>3.0×109/L, the ANC>1.5x109/L, liver and renal function were normal, urine protein (-), creatinine clearance rate were within the normal range. Bone marrow hyperplasia, were in remission. The amount of MTX was2-3g/m2, while giving the hydration and alkalization and calcium folinate rescue. And in the application of intravenous infusion of MTX, application on the same day, and after application regularly collected venous blood monitoring blood routine and renal function were observed after treatment, changes in body temperature and oral mucosa, changes were observed in the peripheral blood and other related adverse reaction. The relationship between these adverse reaction and renal function given by statistical analysis software SPSS17.0.
Results:
1The incidence of renal damage in540patients, a total of13cases, the percentage of renal damage is2.41%.
213patients with renal injury appeared in the change of skin and mucous membrane in7cases, chest CT clear tips of lung inflammation in9cases,5cases of herpes zoster,4cases of pleural effusion, pericardial effusion in3cases, urinary tract infection in3cases, subcutaneous bleeding in6cases, skin mucosai ecchymosis in3cases, G, GM. test positive in2cases,7cases of diarrhea, electrolyte disorder in3cases, intestinal infection in2cases, blood culture or pharyngeal expression confirmed positive in4cases.
313cases of renal injury patients, found that the average time of renal damage from chemotherapy was3.69days, the median time of4days (3～4days). Injury of renal function recovery after chemotherapy in the average time was14days, the median time of17days (9-24days). The BUN range is10.4～44.7mmol/L, CR ranges from138to390umol/L.
4Agranulocytosis ratio is100%, the average time to agranulocytosis neutropenia from chemotherapy was9.77days, the median time of9days (5～12days). Agranulocytosis lasted for an average of20days, the median time of20days (14～29days). Renal damage more serious and the longer the duration of the agranulocytosis
5The proportion of Platelets less than20x109/L is100%, the decrease of platelet to average distance of time chemotherapy for20x109/L for11.5days, the median time of11days (8～23days). Platelet lower than20×109/L lasted for an average of21days, the median time of20days (8-31days). The duration of renal injury more longer of serious platelet<20×109/L.
613patients have lost red blood cell and platelet record. Mean platelet transfusion5.55treatment, the average number of red blood cell transfusion of8units. There are3cases with infusion of fresh frozen plasma.
7Heating ratio is100%, the degree of heat in9cases, fever in4cases. And the fever continued for a long time. Start heating time (from chemotherapy) in an average of10.3days, the median time of11days (3～15days). The fever lasted for an average of18days, the median time of16days (14～31days).
8Oral mucosal erosion ratio of100%. The average time of oral mucosal erosion from chemotherapy was9.25days, the median time of7.5days (6～14days). Oral mucosal erosion duration was21.5days, the median time of21.5days (13～36days).Among the patients with renal injury
913cases,2patients died,2patients gave up treatment of complications in patients with follow-up confirmed after discharge and died of HD-MTX chemother apy. Mortality rate as high as30.8%, improved after treatment in9patients. Of which1cases died of renal failure,2cases died of septic shock,1cases died of hemorrhage of digestive tract.
Conclusions:
1Renal function caused by high-dose methotrexate damage is reversible.
2The death of renal function injury caused by high-dose methotrexate is the main reason:abnormal renal function decreased excretion to methotrexate, MTX accumulation in the body, caused by severe bone marrow suppression, agranulocytosis and bleeding, and bleeding.
HD-MTX是治疗白血病尤其是急性淋巴细胞白血病(ALL)、淋巴瘤和中枢神经系统白血病的重要手段,其不良反应的发生率和严重程度直接取决于MTX血药浓度的高低和持续时间的长短。大剂量甲氨蝶呤(HD-MTX)的主要毒副反应有骨髓抑制、皮肤粘膜反应、肝肾功能损害、口腔炎、口唇溃疡、咽喉炎、恶心、呕吐、腹痛、腹泻、消化道出血等,尤以肾功能损害较为重要。
国外有文献显示大剂量甲氨蝶呤引起肾功能的损伤的比例为2.41%,国内尚未这方面报道。因为HD-MTX所致肾功能损伤比较少见,并未引起重视,国内文献多为个案报道,一旦发生肾功能损伤其相关的不良反应是比较严重的,死亡率极高。现将本院应用甲氨蝶呤后出现肾功能损害患者的不良反应给予统计,以在实际的临床应用中可以作为参考。
材料与方法：
2001年1月至2012年12月在河南省肿瘤医院住院的急性白血病及淋巴瘤患者共540例,年龄为3-65岁,中位年龄32岁。在行HD-MTX治疗前WBC>3.0×109/L,ANC>1.5×109/L,肝、肾功能均正常,尿蛋白(-),肌酐清除率均在正常范围内。骨髓增生活跃,均处于缓解状态。MTX用量2-3g／m2,同时给予水化碱化及亚叶酸钙解救。并在应用静脉滴注MTX前,应用当天,及应用后定期采集静脉血监测血常规及肾功能,观察治疗,后体温及口腔黏膜变化,观察外周血象的变化及其他相关不良反应。将这些不良反应与肾功能之间的关系用统计学软件SPSS17.0给予分析。
结果：
1.540例患者中发生肾功能损害的共13例,肾功能损害的百分比为2.41%。
2.13例肾功能损伤的患者中出现皮肤及粘膜改变的有7例次,胸部CT明确提示肺部有炎症的9例次,带状疱疹5例次、胸腔积液4例次,心包积液3例次,尿路感染3例次,皮下出血点6例次,皮肤黏膜瘀斑3例次,G,GM.实验阳性2例次,腹泻7例次,电解质紊乱3例次,肠道感染2例次,血培养或咽式子证实阳性的有4例次。
3.13例肾功能损伤的病人中,发现肾功能损伤距化疗的平均时间为3.69天,中位时间为4天(3-4天)。肾功能损伤恢复在化疗后平均时间为14天,中位时间为17天(9-24天)。BUN范围为10.4～44.7mmol/L,血CR范围为138～390umol/L。
4.粒缺的比例为100%,中性粒细胞降低至粒缺距化疗的平均时间为9.77天,中位时间为9天(5-12天)。粒缺持续的时间平均为20天,中位时间为20天(14-29天)。肾功能损伤越严重其粒缺持续时间越长。
5.血小板低于20×109/L的比例为100%,血小板降低至20×109/L以下距化疗的平均时间为11.5天,中位时间为11天(8-23天)。血小板低于20×109/L持续时间平均为21天,中位时间为20天(8-31天)。。肾功能损伤越严重其血小板<20×109／L的持续时间越长。
6.13例患者都有输红细胞及血小板的记录。平均输血小板5.55个治疗量,平均输红细胞数量8个单位。有3例给予新鲜冰冻血浆输注。
7.发热的比例为100%,其中度热为9例,高热为4例。且发热持续的时间较长。开始发热的时间(距化疗)平均时间10.3天,中位时间11天(3-15天)。发热的持续的时间平均为18天,中位时间为16天(14-31天)。
8.口腔粘膜的糜烂的比例为100%。口腔粘膜糜烂距化疗的平均时间为9.25天,中位时间为7.5天(6-14天)。口腔粘膜糜烂持续的时间为21.5天,中位时间21.5天(13-36天)。
9.13例肾损伤的患者中其中有2例患者死亡,2例放弃治疗患者经随访证实均在出院后死于HD-MTX化疗的并发症。死亡率高达30.8%,9例患者经积极治疗后好转。其中1例死于肾衰竭,2例死于感染性休克,1例死于消化道出血。
结论：
1.大剂量甲氨蝶呤所引起的肾功能损伤基本是可逆的。
2.大剂量甲氨蝶呤所致肾功能损伤死亡主要原因是：肾功能异常使甲氨蝶呤排泄减少,甲氨蝶呤在体内蓄积,所致严重骨髓抑制,粒细胞缺乏和出血。
Background:
High-dose methotrexate(HD-MTX) is the treatment of leukemia, especially acute lymphoblastic leukemia (ALL), Also is an important means of lymphoma and CNS leukemia, The incidence of adverse reactions and severity depend on the MTX blood drug concentration and duration. High dose methotrexate (HD-MTX) of the main side effects were bone marrow suppression, skin and mucous membrane reaction, liver and kidney damage, stomatitis, oral ulcers, sore throat, nausea, vomiting, abdominal pain, diarrhea, gastrointestinal bleeding, especially in renal function damage is more important.
Foreign literature shows high dose methotrexate induced renal damage ratio of2.41%, the domestic has not been reported. Because HD-MTX renal function damage induced by relatively rare, did not pay attention, the domestic literature mostly case reports, once the incidence of renal adverse effects related to the injury is more serious, the mortality rate is very high. Now the application of methotrexate after adverse reactions in patients with kidney impairment to statistics, to the clinical application in practice can be used as reference.
Materials and methods:
Between January2001and December2012in Henan Cancer hospital, a total of 540patients with acute leukemia and lymphoma, aged3～65years, with a median age of32years. HD-MTX before treatment the WBC>3.0×109/L, the ANC>1.5x109/L, liver and renal function were normal, urine protein (-), creatinine clearance rate were within the normal range. Bone marrow hyperplasia, were in remission. The amount of MTX was2-3g/m2, while giving the hydration and alkalization and calcium folinate rescue. And in the application of intravenous infusion of MTX, application on the same day, and after application regularly collected venous blood monitoring blood routine and renal function were observed after treatment, changes in body temperature and oral mucosa, changes were observed in the peripheral blood and other related adverse reaction. The relationship between these adverse reaction and renal function given by statistical analysis software SPSS17.0.
Results:
1The incidence of renal damage in540patients, a total of13cases, the percentage of renal damage is2.41%.
213patients with renal injury appeared in the change of skin and mucous membrane in7cases, chest CT clear tips of lung inflammation in9cases,5cases of herpes zoster,4cases of pleural effusion, pericardial effusion in3cases, urinary tract infection in3cases, subcutaneous bleeding in6cases, skin mucosai ecchymosis in3cases, G, GM. test positive in2cases,7cases of diarrhea, electrolyte disorder in3cases, intestinal infection in2cases, blood culture or pharyngeal expression confirmed positive in4cases.
313cases of renal injury patients, found that the average time of renal damage from chemotherapy was3.69days, the median time of4days (3～4days). Injury of renal function recovery after chemotherapy in the average time was14days, the median time of17days (9-24days). The BUN range is10.4～44.7mmol/L, CR ranges from138to390umol/L.
4Agranulocytosis ratio is100%, the average time to agranulocytosis neutropenia from chemotherapy was9.77days, the median time of9days (5～12days). Agranulocytosis lasted for an average of20days, the median time of20days (14～29days). Renal damage more serious and the longer the duration of the agranulocytosis
5The proportion of Platelets less than20x109/L is100%, the decrease of platelet to average distance of time chemotherapy for20x109/L for11.5days, the median time of11days (8～23days). Platelet lower than20×109/L lasted for an average of21days, the median time of20days (8-31days). The duration of renal injury more longer of serious platelet<20×109/L.
613patients have lost red blood cell and platelet record. Mean platelet transfusion5.55treatment, the average number of red blood cell transfusion of8units. There are3cases with infusion of fresh frozen plasma.
7Heating ratio is100%, the degree of heat in9cases, fever in4cases. And the fever continued for a long time. Start heating time (from chemotherapy) in an average of10.3days, the median time of11days (3～15days). The fever lasted for an average of18days, the median time of16days (14～31days).
8Oral mucosal erosion ratio of100%. The average time of oral mucosal erosion from chemotherapy was9.25days, the median time of7.5days (6～14days). Oral mucosal erosion duration was21.5days, the median time of21.5days (13～36days).Among the patients with renal injury
913cases,2patients died,2patients gave up treatment of complications in patients with follow-up confirmed after discharge and died of HD-MTX chemother apy. Mortality rate as high as30.8%, improved after treatment in9patients. Of which1cases died of renal failure,2cases died of septic shock,1cases died of hemorrhage of digestive tract.
Conclusions:
1Renal function caused by high-dose methotrexate damage is reversible.
2The death of renal function injury caused by high-dose methotrexate is the main reason:abnormal renal function decreased excretion to methotrexate, MTX accumulation in the body, caused by severe bone marrow suppression, agranulocytosis and bleeding, and bleeding.
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[1]王忠,林雪峰.大剂量甲氨蝶呤治疗小儿急性淋巴细胞白血病不同静浦方祛不良反应比较[J].现代中西医杂志,2004,13(22)：2970-2971
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[11]韩峰,张嵘,施蓓,等.大剂量甲氨蝶呤致急性肾功能不全2例[J].中国医院药学杂志,2009,29(02)：175
[12]Brigitte C, Peter C, et al. Understanding and Managing Methotrexate Nephrotoxicity[J]. The Oncologist,2006,11:694-703
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[15]Jeffrey M, Patrick J, Robert O, et al. Effective removal of methotrexate by high-flux hemodialysis[J]. Pediatr Nephrol,2002,17:825-829
[16]Susan M. Wall, Mary d. Johansen, Donald A. Molony, et al. Effective Clearance of Methotrexate Using High-Flux Hemodialysis Membranes[J]. American Journal of Kid ney Diseases,1996,28(6):846-854
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[31]张迎春.原发性肾小球疾病患者尿中NAG活性测定的临床意义[J].中国实用内科杂志,1996,16(12)：737-738
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[1]王忠,林雪峰.大剂量甲氨蝶呤治疗小儿急性淋巴细胞白血病不同静浦方祛不良反应比较[J].现代中西医杂志,2004,13(22)：2970-2971
[2]中群.大剂量MTX治疗急性淋巴细胞白血病的研究进展[J].中华血液学杂志,1999.20(2)：10-11
[3]杨藻宸主编药理学和药物治疗学,北京：人民卫生出版社.
[4]叶辉,顾龙君.大剂量甲氨喋呤治疗急性淋巴细胞白血病的研究进展[J].中华血液学杂志,1999,2：92-93
[5]詹其林,丁美琪,潘民等.大剂量甲氨喋呤治疗急性淋巴细胞白血病和淋巴瘤副作用观察[J].内科急危重症杂志,2008.14(4)：207-209
[6]陈光道,谢瑞祥,杨瑜,等.血药浓度检测下含大剂量甲氨喋呤的联合方案治疗非霍奇金淋巴瘤的临床观察.临床肿瘤学杂志,2008,13(10)：930-931
[7]杜小红,裴仁治,马俊霞,等.大剂量甲氨喋呤联合化疗治疗难治或复发非霍奇金淋巴瘤[J].现代实用医学,2006,18(3)：166-168
[8]张红,赵新玲,等.大剂量甲氨喋呤化疗后血药浓度对口腔溃疡的影响与分析[J],中国实用医学,2011,17(7),50-53
[9]中华医学会儿科学分会血液学组,中华儿科杂志编辑委员会小儿急性淋巴细胞白血病诊疗建议[J]中华儿科杂志,1999,37(5)：305
[10]徐婷,等.急性淋巴细胞白血病患儿大剂量甲氨喋呤化疗后不良反应观察及其防治[J].浙江医学,2002,24(12),742-744
[11]韩峰,张嵘,施蓓,等.大剂量甲氨蝶呤致急性肾功能不全2例[J].中国医院药学杂志,2009,29(02)：175
[12]Brigitte C, Peter C, et al. Understanding and Managing Methotrexate Nephrotoxicity[J]. The Oncologist,2006,11:694-703
[13]Brigitte C, Frank M, Beate K, et al. High -Dose Methotrexate- Induced Nephrotoxicity in Patients with Osteosarcoma[J]. cancer,2004,100 (10):2222-2232
[14]Mary V, Relling,F, Bruder Stapleton, Judith Ochs, et al. Methotrexate, Leucovorin, and Their Metabolites by Combined Hernodialysis and Hemoperfusion[J]. Cancer,1988,62 (5):884-88
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