Vidhun Jayakumar R, Sarwal Minnie M
Department of Pediatrics, Stanford University, Palo Alto, California 94305, USA.
Paediatr Drugs. 2004;6(5):273-87. doi: 10.2165/00148581-200406050-00002.
Corticosteroids have been a cornerstone therapy in renal transplantation, which is the treatment modality of choice for adult and pediatric end-stage renal disease. Their use is associated with significant morbidity, notably cardiovascular, endocrine, and bone complications, body disfiguration, and almost universal growth retardation in children. While newer immunosuppressants have reduced the incidence of these adverse effects, they continue to pose significant post-transplant challenges. There are various strategies that can be used to avoid these adverse effects including the use of an alternative corticosteroid such as deflazacort, minimization of corticosteroid dosage, corticosteroid withdrawal after a period of early use, and more recently complete corticosteroid avoidance. Recent randomized studies have demonstrated significant improvement in growth parameters, lipid profile, and in the amount of bone loss in patients treated with deflazacort, an oxazoline analog of prednisone, compared with methylprednisone.Corticosteroid minimization has been associated with an increased rate of acute rejection. While augmentation with newer immunosuppressants has helped reduce the incidence of acute rejection, significant improvements in growth have not been demonstrated. Alternate-day corticosteroid therapy has been shown to have a beneficial effect on growth but regimen compliance has limited its widespread applicability. Studies of corticosteroid withdrawal have met with varied success. Early corticosteroid withdrawal has been associated with rejection rates ranging from 10% to 81% and late corticosteroid withdrawal, from 13% to 68.8%, with acute rejection episodes occurring as late as 4 years after corticosteroid withdrawal. The rates of clinical acute rejection have been unacceptably high, and corticosteroid withdrawal is thus used very sparingly in adults and even less so in children. Complete corticosteroid avoidance as reported by an initial study has been associated with a 23% incidence of acute rejection and 'catch-up' growth post-transplantation in 14 pediatric recipients, as measured by the change in height standard deviation scores post-transplantation. A second renal transplant study, in adults, demonstrated similar rejection rates of 25% with improvement in post-transplant hypertension and lipid profiles. A more recent pediatric study using a novel extended daclizumab induction protocol demonstrated an 8% incidence of clinical acute rejection with significant improvements in graft function, hypertension, and growth, without an increased incidence of infectious complications. Renal transplantation with a corticosteroid-free protocol may offer significant advantages in the incidence of acute rejection, graft function, growth, blood pressure, lipidemia, and body appearance and appears to be well tolerated when used with a variety of current induction protocols to replace early corticosteroid use. This protocol may also be applicable to other areas of solid organ transplantation in all age groups.
皮质类固醇一直是肾移植的基础治疗药物,肾移植是成人和儿童终末期肾病的首选治疗方式。其使用与显著的发病率相关,尤其是心血管、内分泌和骨骼并发症、身体变形,以及儿童几乎普遍存在的生长发育迟缓。虽然新型免疫抑制剂降低了这些不良反应的发生率,但它们在移植后仍带来重大挑战。有多种策略可用于避免这些不良反应,包括使用替代皮质类固醇如地夫可特、尽量减少皮质类固醇剂量、在早期使用一段时间后停用皮质类固醇,以及最近的完全避免使用皮质类固醇。最近的随机研究表明,与甲基泼尼松相比,接受地夫可特(泼尼松的恶唑啉类似物)治疗的患者在生长参数、血脂水平和骨质流失量方面有显著改善。
尽量减少皮质类固醇的使用与急性排斥反应发生率增加有关。虽然使用新型免疫抑制剂加强治疗有助于降低急性排斥反应的发生率,但尚未证明对生长有显著改善。隔日皮质类固醇疗法已被证明对生长有有益影响,但治疗方案的依从性限制了其广泛应用。关于停用皮质类固醇的研究取得了不同程度的成功。早期停用皮质类固醇与10%至81%的排斥反应率相关,晚期停用皮质类固醇与13%至68.8%的排斥反应率相关,急性排斥反应发作甚至发生在停用皮质类固醇后4年。临床急性排斥反应的发生率一直高得令人无法接受,因此在成人中很少使用停用皮质类固醇的方法,在儿童中使用更少。一项初步研究报告称,完全避免使用皮质类固醇与23%的急性排斥反应发生率以及14名儿科受者移植后的“追赶性”生长相关,这通过移植后身高标准差得分的变化来衡量。另一项针对成人的肾移植研究表明,急性排斥反应率相似,为25%,移植后高血压和血脂状况有所改善。最近一项针对儿科的研究使用了一种新型的延长达利珠单抗诱导方案,结果显示临床急性排斥反应发生率为8%,移植肾功能、高血压和生长情况有显著改善,且感染并发症的发生率没有增加。采用无皮质类固醇方案进行肾移植在急性排斥反应发生率、移植肾功能、生长、血压、血脂以及身体外观方面可能具有显著优势,并且与各种当前的诱导方案一起使用以替代早期皮质类固醇使用时,似乎耐受性良好。该方案也可能适用于所有年龄组的实体器官移植的其他领域。