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[2]	王晓勃, 王长安, 韩健乐, 杨青彦, 杨帅平, 杨俊伟. 环孢素转换为他克莫司对稳定期肾移植受者糖代谢和心血管风险的影响[J]. 中国组织工程研究, 2021, 25(14): 2236-2240.
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Despite the enormous advancement of immunosuppressive therapy and a significant improvement in short-term graft survival rate after renal allografting, CAN is the leading cause of late renal allograft loss and a headache problem to clinicians[1-4].
Recent studies have suggested that conversion to tacrolimus reduces cyclosporine (CsA) toxicity and immunosupression can improve allograft function, but the clinical efficacy and safety are discrepant[5-6]. For this reason, such an intervention has been considered to produce different outcomes in different pathological types of CAN. The present study performed CsA conversion to FK506 in different pathological types of CAM.

CAN has become a major cause of renal dysfunction and renal allograft loss after transplantation. Both FK506 and CsA belong to calcineurin inhibitors (CNI). But CsA has a series of side effects such as nephrotoxicity, hypertension, metabolic disturbances of blood lipids, etc, which are primary causes of CAN in the triple immunosuppressive regimen[7-8]. FK506 had been proved more effective than CsA for CAN. Scientists further researched FK506 and concluded that FK506 can suppress the progression of CAN. The potential mechanisms include: ① The immunosuppressive efficacy of FK506 is 50–100 times than that of CsA, it can not only be used as basal immunosuppressants to prevent rejection but also be effective to steroid-resistant and intractable rejection. Thus the administration of FK506 will play an important part in preventing CAN[9].② The nephrotoxicity of CNI is a very important factor in the progression of CAN. As the dosage of FK506 clinically prescribed is much lower than that of CsA, it will notably lessen the nephrotoxicity of CNI and slow the progression of CAN[10]. ③ Hypertension and hyperlipidemia are important risk factors in the occurrence and progression of CAN. CsA can activate rennin-angiotensin system and influence the constriction/dilation function of renal vessels to cause hypertension, It can also cause a high level of LDL and enhance the side effects of steroids to cause hypertension. On the contrary, FK506 would not bring these side effects. So after conversion, hypertension and hyperlipidemia will be more efficiently controlled and the renal allograft function will be improved[11]. In the present study, at 12 months after conversion, the level of Scr, TC, TG and LDL in both groups was lower and GFR was higher than prior to conversion. Comparisons between pre- and post conversion in both groups reveal significant statistical difference. In the CR group, the level of Scr, TC, TG and LDL was (236.6±75.6) μmol/L, (5.2±0.7), (1.9±0.8), and (2.5±0.8) mmol/L respectively, and they were all at a significantly lower level than the non-CR group. The mean GFR was significantly higher in the CR group than in the non-CR group (P < 0.05, Table 1). ④CsA can injure P-glycoprotein and make it accumulated in the cells. The accumulation will injure proximal tubule and finally cause tubular interstitial fibrosis[12]. In vivo and in vitro experiments reveal that CsA stimulate the expression of tumor growth factor beta 1, which will cause fibrosis and stimulate the expression of platelet derived growth factor and finally cause smooth muscle cell hyperplasia. This plays an important role in the progression of graft arteriosclerosis. Different from CsA, FK506 has the same binding site with tumor growth factor beta receptor (TGF-β), which is called FKBP-12. It will interfere the expression of TGF-β by competitive combination, and may ameliorate graft fibrosis and finally slow the progression of CAN[13]. Proteinuria is one of the important characteristics in the progression of CAN. Meantime, protein in the urine will subside in the basement membrane and protein cast will block the tubule, which will accelerate the progression of CAN[14].
In the present study, at 12 months after conversion, proteinuria in the both groups was significantly lower than prior to conversion, the level of 24-hour proteinuria in the CR group was decreased from (3.7±0.8) g to (2.0±0.3) g, which was significantly lower compared with the non-CR group (P < 0.05, Table 3). This indicates that FK506 could efficiently improve proteinuria in CAN patients, in particular CR patients, and delay the progression of renal dysfunction. The present results suggest that conversion from CsA to FK506 markedly improve the allograft function and slow the progression of renal failure. The side effects and toxicity of FK506 have positive correlation with its dosage. The 5–10 ng/mL target FK506 is considered to be safe at 6 months after renal allografting[15].
In the present study, there was no significant statistical difference in the incidence of side effects and toxicity between the CR and non-CR groups. Compared with a prospective, randomized, multicenter, clinical trail[16] , we found low dosage of FK506 and well controlled blood concentration would not increase the allografting risk.
There are several limitations in the present study, and protocol biopsies are not a part of the routine practice in our center. Without histological information, subclinical rejection and CNI toxicity cannot be diagnosed early or accurately. This may influence our observation results. Based on early diagnosis and recognition of these disorders, proper FK506 adjustment in our immunosuppressive regimen may improve the worse outcomes. The mechanisms as to why FK506 produces different efficacies in treatment of different pathological types of CAN need to be further investigated.

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