3.christiangraft function after reduction of calcineurin inhibitor dosage in paediatric kidney transplant patients在兒童腎移植患者中將CNI減量并保持穩(wěn)

1、Background. Chronic calcineurin inhibitor (CNI) toxicity contributes to the developmentand progresof chronic allograft nephropathy (CAN), which is still the major cause oftransplant dysfunction and graft loss. Reduction in dosage of CNI may delay the development of CAN, leading to longer graft survi

2、val.Methods. Therefore, 19 paediatric kidney transplant patients under immunosuppressive therapy with CNI (12/19 ciclosporin A, CSA, 7/19 tacrolimus, Tac), mycophenolatmofetil and some patients on steroids were included in a prospective study. Overriodof 9 months CNI dosage was stepwise reduced from

3、 CSA trough levels of 100150 ng/ml to 5070 ng/ml and Tac trough levels of 58 ng/ml to 23 ng/ml, respectively.Results. Glomerular filtration rate was stabilized in patients after CSA and Tac reduction. One borderline rejection occurred in a patient prior to reduction of Tac. In patients onAbstractSta

4、ble graft function after reductionof calcineurin inhibitor dosage inpaediatric kidney transplant patients在兒童腎移植患者中將 CNI 減量并保持穩(wěn)定的腎功能Christian Pl1 ,*,Kerstin Benz 1 ,*,Kerstin Amann 2 ,Kai-Dietrich Nsken1 ,Katalin Dittrich 1 ,Wolfgang Rascher 1 ,Katja Sauerstein 1 ,Anja Stuppy1 ,Bernd Klare 3 andJrg D

5、tsch 1+Author Affiliations1.1Klinik fr Kinder und Jugendliche, 2Pathologisches Institut, UniversittErlangen-Nrnberg and 3Kinderklinik Mnchen-Schwabing, Germany1.Correspondence and offprrequests to: Jrg Dtsch, MD, Klinik fr Kinder und Jugendliche,Friedrich-Alexander-Universitt Erlangen-Nrnberg, Losch

6、gestrasse 15, 91054 Erlangen, Germany.: HYPERLINK mailto:joerg.doetschkinder.imed.uni-erlangen.de joerg.doetschkinder.imed.uni-erlangen.deReceived November 3, 2005.Accepted April 24, 2006.Next Sectioncalcineurin inhibitor toxicityciclosporinpaediatric renal transplan iontacrolimusroduction of calcin

7、eurin inhibitors (CNI) and mycofenolat mofetil (MMF)o immunosuppressive therapy significantly improvedyear kidney graft survival and reduced the rate of acute rejections 1,2. 一年內移植腎存活率和急性排斥反應發(fā)生率因為 CNI 和 MMF 的應用被顯著提高了。In contrast, long-term graft survival did not similarly improve,sibly due to negati

8、ve long-term effects of CNI on kidney function and structure.但是長期的移植腎存活率并沒有相應幅度的提高，這可能是由于 CNI對腎臟的長期作用所致。 It is well knownt chronic use of CNI, in particular in high doses, contributes to the development and progresof chronic allograft nephropathy (CAN) 3, 眾所周知，長期大劑量地應用 CNI 會促使 CAN 的發(fā)生和發(fā)展，而 CAN 是腎功能失

9、調和移植腎喪失的主要原因。which is still the major cause of transplant dysfunction and final graft loss. CAN is clinically characterized by slowly increasing serum creatinine, progressive proteinuria and moderate hyperten4.CAN的臨床特征是緩慢上升的血肌酐、進展性的蛋白尿和中度的高血壓。 Histological changes, such as glomerulosclerosis, tubula

10、r atrophy witherstitial fibrosis and arteriosclerosis, are characteristics of CAN. CAN 的組織學病理特征是腎小球硬化、小管萎縮和動脈硬化。The pathogenesis of CAN is multifactorial, i.e. immunological and non-immunological risk factors are known. CAN 的發(fā)病機制可以分為免疫學和非免疫學。Toxicity of CNI, however, is one of the major non-immunolo

11、gical reasons for the progresof CAN. CNI 的毒性是 CAN 進展的主要非免疫學之一。CNIare known to have acute and chronic toxic effects on the kidney. CNI 對腎臟有急性毒性roductionPrevious SectionNext SectionKey wordsCSA, oneerstitial cellular rejection (BANFF IA) was noted. Reduction of CNI had no significant effects on blood

12、prere, lisus and the infection frequency.s. In paediatric kidney transplant patients, reduction of CNI down to low trough levels stabilizes renal function. However, the risk of acute rejectionsodes may be increased. Therefore, further studies based on protocol biopsies within a randomized trial are

13、warranted.Nineteen paediatric patients were includedo the prospective study. 這個前瞻性的研究納入了 19 個人。Patients characteristics are givenable 1. Immunosuppressivetherapy at the time of study enrolment consisted of CSA and MMF in 12 out of 19 patients. 其中 12 個人在納入時聯(lián)合使用 CSA 和MMF。Seven patients were treated wi

14、th MMF and tacrolimus (Tac) and three of them received an additional low dose ofprednisone.另外 7 個使用 Tac 和 MMF，其中 3 個還加用了小劑量View this table:his window。In a new windowMaterials and methods和慢性毒性。Acuy vasoconstriction of the afferent arteriole leads to reduction of renal blood flow. 急性毒性表現(xiàn)在入球小動脈的收縮和腎血流的

15、減少。Chronic effects are predominantly structural changes of the kidney, such aserstitial fibrosis and thickening as well as hyalinosis ofrarenal arteries 5.慢性毒性表現(xiàn)在腎臟的結構變化上，例如間質化、腎內的壁增厚和透明樣變。Therefore, treatment strategies aiming to reduce CNI toxicity by lowering the treatment doses androduction of d

16、rugs with different modes of action and without nephrotoxicity are of major importance. 所以，尋找沒有腎毒性的新型機制藥物和減少 CNI 劑量的治療方案尤為重要。In adults, studies wizathioprine and prednisone as additional immunosuppressive therapy to CNI reduction or withdrawal led to increased rates of acute rejections 6. 在成人的試驗中，CN

17、I 減量和的試驗導致急性排斥反應發(fā)生率的上升。A combination with othotent immunosuppressive drugch as MMF is mandatory before CNI can be在I 減量之前和其它諸如MMF的強大免疫抑制劑聯(lián)用是必須的。 As a result,roduction of MMF could reduce the rate of acute rejections after withdrawal of ciclosporin A (CSA) compared wizathioprine 7.結果發(fā)現(xiàn) MMF 的應用比硫唑嘌呤更能夠

18、減少急性排斥反應的發(fā)生率。Reduction of CSAheyear after kidney transplanion is also assoted wihigher risk of acute rejection. 一年內將 CsA 減量也和急性排斥反應發(fā)生率增高有關。Withhe last few years, several studies in adult patients demonstrated a benefit of CSA reduction or withdrawal in patients moren 1 year after transplanion, who w

19、ere additionally treated with MMF and steroids.在過去幾年中，成人試驗發(fā)現(xiàn)聯(lián)合 MMF 和皮質激素治療時，1 年后將CsA 減量或對腎功能的保存有利。It was shownt graft function even ameliorated after CSA reduction.研究顯示在 CsA 減量之后移植物功能甚至有所。 In parallel, hyperten, hyperliaemia, glucose metabolism andhyperuricaemia were improved. 相應的，高血壓、高血脂、糖代謝和高脂血癥的狀

20、況也改善了。The rate of acute rejections was not increased in recent studies 810.在近期研究中沒有發(fā)現(xiàn)急性排斥反應發(fā)生率的上升。Therefore, it was the aim of the present prospective study in paediatric recipients of kidney transplants receiving MMF to stepwise reduce CNI dosage down to relatively low trough levels in order to sta

21、bilize or even improve kidney function.所以，本試驗的目的是在聯(lián)合 MMF 治療的兒童腎移植患者中逐步降低 CNI 的劑量以期穩(wěn)定甚至提高腎功能。Previous SectionNext SectionThe median age of patients at kidney transplanion was 4.8 years (range 1.813.7 years)in CSA-treated patients and 9.3 years (range 4.113.8 years)ac-treated patients. The median dura

22、tion betn transplanion and study enrolment was 2.8 years (range1.37.5 years) in CSA-treated patients and 5.0 years (range 2.311.0 years)ac-treatedpatients. Inclucriteria were as follows: Boys and girls who were youngern 18years were eligible for the study if they (i) had received a cadaveric or livi

23、ng kidneytransplant (1st or 2nd kidney transplanion), (ii) had undergone transplanion 12months previously, (iii) had been rejection-free foreast 6 months and (iv) had receivedCSA or Tac foreast 6 months and MMF foreast 3 months (MMF trough level1.54 ng/ml). Exclucriteria were: (i) glomerular filtrat

24、ion rate (GFR)40 ml/min/1.73 m2, (ii) moren two rejectionsodes withhe last 12 months, (iii)any steroid-resistant rejectionsodehe past medical history, (iv) relapse of theunderlying disease, (v) infection with CMV or EBVt required treatment withhe last3 months and (vi) pregnancy or lacion 哺乳.Initial

25、immunosuppresafter transplanion was azathioprine, CSA and prednisone infive patients and MMF, CSA and prednisone in 14 patients. Initial prednisone treatmentwas performed according to standard regimen and was continued foreast one yearafter transplanion. One patient additionally received antithymocy

26、te globulinimmediay after transplanion, one patient, daclizumab and another took partheplacebo-controlled basiliximab study for children of the Arbeitsgemeinschaft Pdiatrische Nephrologie (APN). Seven of 19 patients were switched from CSA to Tac for thefollowing reasons: development of CAN (four pat

27、ients), acute rejectionsodes (twopatients) andeA-induced ponitist improved after switch to Tac (onepatient).前面講的是納入時服藥的情況，這里講剛移植完的服藥情況：14 個用 MMF,CSA and prednisone，5 個用 azathioprine, CSA and prednisone。起始足量，維持 1 年以上。有 1 個額外用了 antithymocyte globulin，Before study enrolment, renal biopsy was performedh

28、ree of 12 patients under CSA,all of whom had histological signs of chronic CNI toxicity. 在納入之前就有 3 個服用CSA 的做了腎活檢，結果都有慢性 CNI 腎病的組織學改變。In patients receivingTac, renal biopsy was performed in all seven patients, five of whom had histological signsof chronic CNI toxicity. 另外有 7 個服用 Tac 的也做了腎活檢，其中 5 個有慢性

29、CNI 腎病的組織學改變。After study enrolment, dosage of CNI was stepwise reducedoverriod of 9 months to trough levels of CSA of 5070 ng/ml and Tac of 23 ng/ml(details of reduction procedure are shown in Figure 1). 他們納入研究之后 CSA 和 Tac的劑量都逐漸降低了。At the following time pos, regular study visits were performed:the b

30、eginning of the study as well as 3, 6, 9, 12, 15 and 18 months after start of reduction of CNI. 納入之后 0、3、6、9、12、15、18 月隨訪 The following parameters were determined: serum creatinine, sodium, potassium, phosphate, magnesium, cholesterol,high-density lipoprotein cholesterol and triglycerides.收集以下信息肌酐、N

31、a、K、P、Mg、膽固醇、HDL-c、TG 還有 CSA, Tac and MMF 的藥物濃度。In addition, troughTable 1.Characteristics of the study population are shown, including 12 patients treated with CSA and seven patients with Taclevels of CSA, Tac and MMF were determined. Before reduction of CSA and after the reduction period, CSA leve

32、ls 2 h after administration of CSA (C2) were determined.View larger ver:his pageIn a new windowDownload asSlideFig. 1.Schematic study design with different time pos, separated in a retrospective and a prospective part. The retrospective part begins 12 months before study enrolment. At study enrolmen

33、t CSA or Tac reduction was started andCSA or Tac trough levels were shownhe design. The different time pos were 3, 6, 9, 12 and 18 months after study enrolment.Moreover, the following patient data were recorded on a regular basis: height, weight, blood prere, CSA dosage, MMF dosage, number and dosag

34、e of antihypertensive drugs as well as number and nature of adverse events due to the medication (i.e. infectious adverse events or adverse events due to administered drugs). The patients 24 h bloodprere was kept below the 50th percentile according to Soergel et al. 11. At all time pos GFR was calcu

35、lated using the Schwartz formula (height/creatinine ratio) 12. As an index of change in GFR over time, i.e. delta-GFR per month (inml/min/1.73 m2/month) was estimated. The area under the time concentration curve (AUC) of CSA was estimated according to the formula of David-Neto et al. 13: AUC04 = 462

36、 + (2.75 C2).還有一些規(guī)律的信息：身高體重、血壓、藥物劑量、藥物不良反應。所有的觀察時間點都計算了 GFR。During the 2-year recruitment period (January 2002January 2004) a total of 40 patients were seen in our paediatric nephrology unit after kidney transplanion. Nineteen patients were includedo the present study. Twenty patients could not be i

37、ncluded for different reasons: In seven patients, kidney transplanion was 1 yearast recruitment timepoin January 2004. Six patients were 18 years old in 2002 orhe beginning of 2003. Two patients had recurrent pyelonephritis due to urological malformation, one patiend the 3rd kidney transplanion, one

38、 patient was not included because of steroid-resistant acute rejection in past medical history, one patient with ongoing underlying disease (cystinosis) and one patient treated without MMF because of MMF-induced severe diarrhoea. Two patients rejected study enrolment.period CNI 的劑量、濃度和 C2 水平After th

39、ereduction of dosage at study enrolment, dosage of CSA or Tac was reduced every 3 months sot the trough levels were withherange at about 9 monthsKidney functionKidney function was determined as GFR according to the Schwartz formula. In patientstreated with CSA, GFR was stable over the total 9 month

40、reduction period and the following 9 month observation period. There was no significant difference betn GFR 12 months before the start of the study, study enrolment and 18 months after study enrolment (Figure 2A). 研究開始前的 12 個月、開始時、開始后 18 個月的 GFR 在 CSA 組沒有顯著差異。We also calculated a delta-GFR per month

41、 計算這個東西的目的何在？: in CSA patients before CNI reduction a mean loss of GFR of 7.32 26.3 ml/min/1.73 m2/year was found. During the 18 months of follow-up the mean overalldelta GFR was 0.48 4.56 ml/min/1.73 m2/year. The differenin delta-GFR comparinghis windowIn a new windowTable 2.CSA and Tac dosagesilli

42、grer square metre body surface arer day were demonstrated at the different time pos of the study, shown as mean SDMean concentration 2 h after CSA dose (C2) was 642 ng/ml before reduction of CSA and 486 ng/ml after reduction of CSA. The estimated area under the curve (AUC) was2227 ng/ml/h before red

43、uction of CSA and 1799 ng/ml/h after reduction of CSA.after study enrolment. 每 3 個月減一次 CNI 的劑量，用 9 個月的時間減到目標濃度。目標濃度是服藥 2h 后 486ng/ml。CSA dosage was reduced during the reduction periodby 32% (0 vs 9 months) and Tac dosage was reduced by 42% (0 vs 9 months) (Table 2).View this table:CSA and Tac dosage

44、, trough levels and C2 levels during the CNI reductionResultsSisticalysis這一段里面涉及的概念希望弄懂Data are presented as mean SD for parametrical data and as median (range) fornon-parametrical data.The delta-GFR per month before and after study enrolment was compared wipaired two-tailed t-test. The GFR of the d

45、ifferent time pos andervals as well as electrolytes and liprofile were compared by ANOVA andt hoc t-test.Previous SectionNext SectionInformed consent was obtained from all patients and their parents, respectively. The study protocol was approved by the local ethics committee of the University ofErla

46、ngen-Nrnberg.CSA patient groupElectrolytes (mean SD)the period of 12 months before study enrolment and the 18 months after study enrolmentwere not significant (P = 0.56, paired t-test two-tailed). Overall, eight of 11 CSA patientshad a stable or improved renal function during the follow-up period of

47、 18 months. Three of 11 patients had a decrease of GFR of moren 10% in 18 months.View larger ver:his pageIn a new windowDownload asSlideFig. 2.(A) In patients treated with CSA, GFR was stable over the 12 months before study enrolment and the 18 months of follow-up after start of CSA reduction.he red

48、uction period, CSA was reduced stepwise and after 9 months trough levels of CSA were stable. CSA trough levels are shown with dotted line, GFRs are shown with continuous line. Data are given as mean SD. (B) In patients treated with Tac, GFR was stable over the 12 months before study enrolment and th

49、e 18 months of follow-up after start of Tac reduction.he reduction period Tac was reduced stepwise and after 9 months trough levels of Tac were stable. Tac trough levels are shown with dotted line, GFRs are shown with continuous line. Data are given as mean SD.In patients treated with Tac, GFR was s

50、table over the total period of reduction and the following observation time. Comparing the GFR 12 months before and 18 months after study enrolment, there was no significant difference (Figure 2B). We also calculated a delta-GFR per month for the differentervals: during the 12 months before study en

51、rolment, the mean loss of GFR was 0.24 5.76 ml/min/1.73 m2/year. During the 18 months of follow-up, the mean overall delta-GFR was 1.56 3.72 ml/min/1.73 m2/year. The differenin delta-GFR betn the period of 12 months before study enrolment and the 18 months after study enrolment were not significant

52、(P = 0.99, pairedtwo-tailed t-test). Overall five of six Tac patients had a stable or improved renal function during the follow-up period of 18 months, and only one of six patients had a decrease in GFR of more n 10% in 18 months. Blood prere (blood prere SDS according to de Man et al. 14)Systolic a

53、nd diastolic blood prere determined by correlation to standard SDS was notsignificantly different, and the number of antihypertensive drugs was equal in both CSA- and Tac-treated patients (data not shown)., in patients treated with CSA, a slightCSA patient groupThere were no significant differenfor

54、cholesterol (i.e. at study enrolment 168 42.4 mg/dl vs 164 23.9 mg/dl 18 months after enrolment; ANOVA, P = 0.71),high-density lipoprotein cholesterol (i.e. at study enrolment 42.5 8.2 mg/dl vs 45.5 9.9 mg/dl 18 months after enrolment; ANOVA, P = 0.48) and triglycerides (i.e. at study enrolment 141

55、65.0 mg/dl vs 124 76.1 mg/dl 18 months after enrolment;ANOVA, P = 0.89) betn study enrolment and the subsequent measurements after CSA reduction.Tac patient groupThere were no significant differenfor cholesterol (i.e. at study enrolment 144 37.5 mg/dl vs 145 39.7 mg/dl 18 months after enrolment; ANO

56、VA, P = 0.998),high-density lipoprotein cholesterol (i.e. at study enrolment 44.7 18.1 mg/dl vs 37.7 18.4 mg/dl 18 months after enrolment; ANOVA, P = 0.95) and triglycerides (i.e. at study enrolment 118 35.4 mg/dl vs 127 42.3 mg/dl 18 months after enrolment;ANOVA, P = 0.64) betn study enrolment and

57、the subsequent measurements after Tac reduction.Liprofile (mean SD)There were no significant differenbetn study enrolment and the subsequent measurements after CSA reductionagnesium (i.e. at study enrolment 0.76 0.06 mmol/l vs 0.78 0.20 mmol/l 18 months after enrolment; ANOVA, P = 0.97), phosphate (

58、i.e. at study enrolment 1.43 0.19 mmol/l vs 1.32 0.23 mmol/l 18 months after enrolment; ANOVA, P = 0.91) and potassium (i.e. at study enrolment 4.71 0.45 mmol/l vs 4.65 0.54 mmol/l 18 months after enrolment; ANOVA, P = 0.67).Tac patient groupThere were no significant differenbetn study enrolment and

59、 the subsequent measurements after Tac reductionagnesium (i.e. at study enrolment 0.70 0.08 mmol/l vs 0.73 0.09 mmol/l 18 months after enrolment; ANOVA, P = 0.20), phosphate (i.e. at study enrolment 1.46 0.24 mmol/l vs 1.21 0.25 mmol/l 18 months after enrolment; ANOVA, P= 0.54) and potassium (i.e. a

60、t study enrolment 4.69 0.65 mmol/l vs 4.77 0.61 mmol/l 18 months after enrolment; ANOVA, P = 0.33).結果：1.GFR；2.電解質decrease in systolic blood prere was seen after CSA reduction. The difference,however, was not significant systolic blood prere at study enrolment median was0.24 (range 2.42 to +0.56) and