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Conversion of Ciclosporin a to Tacrolimus in Kidney Transplant Recipients with Chronic Allograft Nephropathy

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Conversion of Ciclosporin a to Tacrolimus in Kidney Transplant Recipients with Chronic Allograft Nephropathy Nephrol Dial Transplant (2006) 21: 3243–3251 doi:10.1093/ndt/gfl397 Advance Access publication 28 July 2006 Original Article Conversion of ciclosporin A to tacrolimus in kidney transplant recipients with chronic allograft nephropathy Sydney Chi-Wai Tang, Kwok Wah Chan, Colin Siu-On Tang, Man Fai Lam, Chung Ying Leung, Kai Chung Tse, Chun Sang Li, Yiu Wing Ho, Matthew Kwok-Lung Tong, Kar Neng Lai and Downloaded from https://academic.oup.com/ndt/article/21/11/3243/1875343 by guest on 04 October 2021 Tak Mao Chan, for the Hong Kong Nephrology Study Groupy Division of Nephrology, Department of Medicine, University of Hong Kong and Queen Mary Hospital, Hong Kong, China Abstract patient number. Further studies with a larger cohort Background. Tacrolimus and ciclosporin might have are needed for validation. different effects on intra-renal fibrosis and allograft function in chronic allograft nephropathy (CAN). It is Keywords: chronic allograft nephropathy; difficult to predict the response to calcineurin inhibitor ciclosporin A; minimization; tacrolimus conversion minimization in patients with CAN. Methods. This prospective randomized study com- pared ciclosporin A (CsA)-to-tacrolimus conversion Introduction (group A, target tacrolimus trough level 6–8 ng/ml) vs CsA minimization (group B, target CsA trough level Despite improvements in immunosuppressive 80–100 ng/ml) with regard to efficacy and safety in protocols for kidney transplantation, chronic allograft patients with CAN and deteriorating allograft func- nephropathy (CAN) remains one of the most impor- tion. The primary efficacy endpoint was improvement tant causes of graft loss in the first post-transplant in the slope of inverse serum creatinine (1/SCr) vs decade [1]. CAN is characterized clinically by progres- time plot. sive graft failure associated with variable degrees of Results. There were 34 evaluable patients (n ¼ 16 in hypertension and proteinuria, and histologically by group A; n ¼ 18 in group B), with similar baseline non-specific chronic changes in the vascular (afferent characteristics. Both groups reached target drug levels arteriosclerosis), glomerular (glomerulosclerosis) and after a 3-month run-in period. Over the ensuing tubulointerstitial (tubular atrophy and interstitial 12 months, nine (56.3%) subjects in group A and fibrosis) compartments of the kidney [2]. Five years 10 (55.6%) in group B reached the primary end point after transplantation, up to two-thirds of allografts (P ¼ 0.968). Both groups showed considerable have been shown to demonstrate features of moderate improvement in the slope of 1/SCr vs time plot. to severe CAN [3]. The aetiology of CAN is not There was no significant difference in the slope well understood, and a variety of immunological between groups before and after intervention. Graft and nonimmunological factors, including histo- survival was 87% in group A and 100% in group B incompatibility, acute rejection, preservation injury, (P ¼ 0.121). Acute rejection was encountered in two donor status, hypertension, hyperlipidaemia and the group A subjects. There was no significant change or use of calcineurin inhibitors (CNI), notably ciclosporin difference in blood glucose, lipids, and blood pressure A (CsA), have been incriminated [1]. between groups. To date, there is no specific treatment for CAN. Conclusion. Our results suggest that in patients with Emerging evidence indicates that growth factors, CAN and deteriorating allograft function, CsA-to- such as transforming growth factor-b (TGF-b), are tacrolimus conversion or CsA minimization achieved critically important in both CAN and chronic CsA comparable efficacies in retarding the decline of graft toxicity, suggesting that these two entities share function. Such contention may be biased by the low common pathophysiological pathways, and chronic CsA nephrotoxicity may contribute significantly to CAN [4–7]. Because of this, several studies have investigated the role of an alternative immunosuppres- Correspondence and offprint requests to: Prof. T. M. Chan, Department of Medicine, Queen Mary Hospital, 102 Pokfulam sive agent, such as mycophenolate mofetil (MMF), and Road, Hong Kong SAR, China. Email: [email protected] found that the introduction of MMF with reduction yPlease refer to Appendix for participants in the Study Group. or withdrawal of CsA had a favourable outcome ß The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: [email protected] 3244 S. C.-W. Tang et al. on post-transplantation graft function and survival dysfunction (de novo or recurrent disease, obstruction or [8,9]. However, such strategy, although safe in most transplant renal artery stenosis detected by Doppler ultra- instances, may be offset by the potentially increased sonography during the preceding 12 months), biopsy proven risk of acute rejection and graft loss [10,11], and it may acute rejection of Banff 97 grades I, II or III within 3 months not be entirely desirable to withdraw CNI altogether. prior to study entry, and patients who were receiving Tacrolimus is a newer CNI that is more potent tacrolimus or rapamycin before recruitment were excluded. than CsA in rejection prophylaxis [12], and has been Additional exclusion criteria were systemic infection, intro- associated with reduced intrarenal expression of duction of angiotensin converting enzyme inhibitor or TGF-b [13,14] and other profibrotic genes [15], and receptor blocker within 3 months before recruitment, receipt less allograft fibrosis [16] compared with patients of other solid organ transplant, concurrent participation treated with CsA. These observations suggest that in other investigational immunosuppressive protocol, and women lactating, pregnant or of childbearing potential not tacrolimus substitution for CsA may be beneficial for using, or who were unwilling to use a reliable contraceptive patients with documented CAN without compromising method during and for 6 weeks following the study. immunosuppressive efficacy. Downloaded from https://academic.oup.com/ndt/article/21/11/3243/1875343 by guest on 04 October 2021 In this study, we prospectively compared CsA-to- tacrolimus conversion with CsA minimization, with regard to renal function preservation in patients with Randomization and intervention protocol CAN and progressive loss of graft function. Eligible and consenting subjects were assigned by simple randomization using a computer-generated sequence into either the tacrolimus conversion (group A) or the CsA Methods minimization (group B) arm (Figure 1). Patients randomized to group A underwent a clean conversion to tacrolimus at a dose of 0.16 mg/kg/day in two divided doses 12 h after Study design and patients the last dose of CsA. The dose of tacrolimus was then This was a randomized, controlled, open-label, prospective titrated during a 3-month run-in phase to attain a 12-h study conducted in five major renal transplant centres in trough whole blood level of 6–8 ng/ml using a microparticle Hong Kong between July 2001 and June 2004. The study enzyme immunoassay on a Viva analyser (Dade Behring, protocol was approved by the Institutional Review Board UK). Other concomitant medications remained unchanged and Research Ethics Committee of the Hong Kong Hospital according to individual centre protocol. Patients randomized Authority, and all participating subjects gave written, to group B continued to receive CsA with dosages adjusted informed consent before study entry. Cadaveric or living- to maintain a 12-h trough blood level of 80–100 ng/ml related renal transplant recipients of either gender between using the Dade–Behring Emit Enzyme Immunoassay, and age 18 and 65, at least 12 months post-transplant and other medications according to centre protocol. All patients maintained on a CsA-based immunosuppressive regimen were followed-up every 2 weeks for the first month, then at with steady-state whole blood trough levels not exceeding 4-weekly intervals till 6 months, and then at 2-monthly 150 ng/ml and serum creatinine (SCr) between 100 and intervals till the study end. The total follow-up duration for 400 mmol/l, histologically proven CAN within the preceding both groups was 15 months. Pertinent clinical data including 12 months, and deteriorating graft renal function as body weight, blood pressure, urine dipstick test, complete evidenced by a negative slope of 1/SCr plotted against blood count, liver and renal function panels, blood glucose time, were eligible. A regression line plotted with at least six and 12-h trough blood levels of tacrolimus (for group A) or SCr values over the preceding 12 months had to demonstrate CsA (for group B), were recorded on each visit. Fasting a negative slope that had a significant P-value <0.05 and an blood glucose, haemoglobin A1C level, full lipid profile, adjusted R2 > 0.35. All biopsies were independently reviewed and 24-h urine for protein and creatinine were assayed and scored by a single pathologist in accordance with the every 2 months. All adverse events and medication log were Banff 97 criteria [2]. Patients with alternative causes of graft carefully documented throughout the study. Group A: clean conversion to tacrolimus (n=16) Eligible subjects at least 12 months post-transplant Group B: CsA-minimizing protocol (n=18) −12 or more 0 3 15 Month Screening for CAN and Run-in deteriorating graft function Phase Randomization Attained Study target drug end level Fig. 1. Study design. CsA-to-tacrolimus
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