Impact of variability of sirolimus trough level on chronic allograft nephropathy

The efficacy of sirolimus is strictly dose-dependent; an inappropriate exposure may cause either rejection episodes or drug toxicity. The variability of sirolimus trough levels (C(0)) may also have an impact on renal allograft function. We prospectively evaluated the impact of the dose-normalized C(0) of sirolimus and the intrapatient coefficient of variation (% CV) on renal allograft function at 6 months after the administration of sirolimus to kidney transplant recipients with chronic allograft nephropathy (CAN). We enrolled 51 recipients with CAN who were treated with sirolimus. The dose-normalized C(0) of sirolimus was 3.8 +/- 1.9 ng/mL/mg. The intra- and interpatient variabilities of sirolimus C(0) were 26.1% and 51.9%, respectively. Based on receiver operating characteristic analysis, patients were divided into 2 groups: group I, sirolimus % CV <22.9% (n = 36) versus group II, sirolimus % CV >22.9% (n = 15). Patients in group II experienced significantly greater risk for progressive deterioration of allograft function (group I vs group II: 11.1% vs 73.3%; P < .05). Multiple logistic regression analysis revealed that higher baseline serum creatinine, but not age, gender, or concomitant immunosuppressants, positively correlated with the sirolimus % CV. In conclusion, both higher baseline serum creatinine and higher intraindividual variability of sirolimus C(0) impact the outcome of renal allograft function in CAN. Thus, we suggest that close monitoring of sirolimus C(0) is necessary for recipients treated with sirolimus, especially for patients with CAN.     

西罗莫司替代钙调磷酸酶抑制剂治疗肾移植后慢性移植肾肾病

目的 探讨采用西罗莫司（SRL）替换钙调磷酸酶抑制剂（CNI）治疗肾移植术后慢性移植肾肾病（CAN）的有效性和安全性。方法 在42例肾移植术后发生CAN的患者中，有32例采用以环孢素A（CsA）为主的免疫抑制方案；10例采用以他克莫司（FK506）为主的免疫抑制方案。将患者的CsA或FK506替换为SRL，停用CNI 12h后口服SRL，SRL的初始剂量为4mg，然后改为2mg／d，以后根据SRL的血药谷值浓度调整其使用剂量，使其血药谷值浓度维持在5～8μg／L。药物替换前、后霉酚酸酯和激素的用量不变。所有患者均随访1年，观察血肌酐、肌酐清除率的变化并监测血常规、血糖、血脂、肝功能等指标。结果 SRL替换CNI治疗1年后，25例患者的移植肾功能明显改善，替换治疗3～20周后移植肾功能好转；10例患者的移植肾功能维持稳定；但7例患者的肾功能继续恶化。替换治疗后，患者血肌酐从替换前的（218±14）μmol／L降为（187±11）μmol／L，肌酐清除率从替换前的（0．83±0．03）ml／s升高为（0．90±0．03）ml／s，替换前后比较，差异有统计学意义（P〈0．05）。所有患者均未发生急性排斥反应和肿瘤等不良反应。结论 SRL替换CNI治疗慢性移植肾肾病是安全有效的，该方案的副作用主要是血脂增高。     

慢性移植物肾病生物学标志物的研究进展

慢性移植物肾病(CAN)是导致晚期移植物功能丧失的主要原因,目前我们仍缺乏有效的无创方法 来对其进行早期诊断从而进行早期干预,本文就新近发现并有希望用于早期诊断的 CAN 新型标志物作一综述.     

慢性移植物肾病生物学标志物的研究进展

慢性移植物肾病(CAN)是导致晚期移植物功能丧失的主要原因,目前我们仍缺乏有效的无创方法 来对其进行早期诊断从而进行早期干预,本文就新近发现并有希望用于早期诊断的 CAN 新型标志物作一综述.     

慢性移植物肾病生物学标志物的研究进展

慢性移植物肾病(CAN)是导致晚期移植物功能丧失的主要原因,目前我们仍缺乏有效的无创方法 来对其进行早期诊断从而进行早期干预,本文就新近发现并有希望用于早期诊断的 CAN 新型标志物作一综述.     

慢性移植物肾病生物学标志物的研究进展

慢性移植物肾病(CAN)是导致晚期移植物功能丧失的主要原因,目前我们仍缺乏有效的无创方法 来对其进行早期诊断从而进行早期干预,本文就新近发现并有希望用于早期诊断的 CAN 新型标志物作一综述.     

慢性移植物肾病生物学标志物的研究进展

慢性移植物肾病(CAN)是导致晚期移植物功能丧失的主要原因,目前我们仍缺乏有效的无创方法 来对其进行早期诊断从而进行早期干预,本文就新近发现并有希望用于早期诊断的 CAN 新型标志物作一综述.     

慢性移植物肾病生物学标志物的研究进展

慢性移植物肾病(CAN)是导致晚期移植物功能丧失的主要原因,目前我们仍缺乏有效的无创方法 来对其进行早期诊断从而进行早期干预,本文就新近发现并有希望用于早期诊断的 CAN 新型标志物作一综述.     

慢性移植物肾病生物学标志物的研究进展

慢性移植物肾病(CAN)是导致晚期移植物功能丧失的主要原因,目前我们仍缺乏有效的无创方法 来对其进行早期诊断从而进行早期干预,本文就新近发现并有希望用于早期诊断的 CAN 新型标志物作一综述.     

慢性移植物肾病生物学标志物的研究进展

慢性移植物肾病(CAN)是导致晚期移植物功能丧失的主要原因,目前我们仍缺乏有效的无创方法 来对其进行早期诊断从而进行早期干预,本文就新近发现并有希望用于早期诊断的 CAN 新型标志物作一综述.     

慢性移植物肾病生物学标志物的研究进展

慢性移植物肾病(CAN)是导致晚期移植物功能丧失的主要原因,目前我们仍缺乏有效的无创方法 来对其进行早期诊断从而进行早期干预,本文就新近发现并有希望用于早期诊断的 CAN 新型标志物作一综述.     

慢性移植物肾病生物学标志物的研究进展

慢性移植物肾病(CAN)是导致晚期移植物功能丧失的主要原因,目前我们仍缺乏有效的无创方法 来对其进行早期诊断从而进行早期干预,本文就新近发现并有希望用于早期诊断的 CAN 新型标志物作一综述.     

钙调磷酸酶抑制剂转换为西罗莫司治疗慢性移植物肾病的疗效研究

探讨钙调磷酸酶抑制剂(CNI)转换为西罗莫司治疗慢性移植物肾病(chronic allograft nephropathy,CAN)的疗效及不良反应.方法 回顾性研究对象为2005年1月至2010年12月在西安交通大学医学院第一附属医院肾移植科随访的95例肾移植后并发CAN患者,术后均接受CNI为主的免疫抑制剂方案.所有患者均签署知情同意书,符合医学伦理学规定.患者确诊CAN后将CNI转换为西罗莫司.记录西罗莫司的维持剂量及血药浓度水平,了解转换治疗后血清肌酐(Scr)的变化,根据转换前Scr水平高低分为两组,Scr≥266 μmol/L为Scr高水平组(22例),Scr<266 μmol/L为Scr低水平组(73例);比较两组转换治疗后Scr变化幅度的差异;了解转换治疗的不良反应.结果 95例患者的随访时间6~48个月,西罗莫司的维持剂量为0.5~4 mg/d(中位数为1.5 mg/d),血药浓度为1.3~12 ng/ml(中位数为5.4 ng/ml).Scr低水平组转换治疗效果明显高于Scr高水平组(P<0.05).95例患者均未发生急性排斥反应.新发或蛋白尿加重32例(34%),新发或高脂血症加重25例(26%),1例患者发生肺部感染,经对症治疗后均治愈或缓解.结论 CNI类药物转换为西罗莫司治疗CAN是安全有效的,转换前Scr水平较低者的治疗效果优于转换前Scr水平较高者,转换后的主要并发症是蛋白尿和高脂血症.     

Loss of peritubular capillaries in the development of chronic allograft nephropathy

BACKGROUND: Chronic allograft nephropathy (CAN) remains the most important cause of late renal graft loss. In this study, we examined the role of peritubular capillary (PTC) injury in the development of CAN. METHODS: We studied renal biopsies (n = 79) obtained from grafts with CAN. PTC injury was examined morphologically by immunohistochemistry for CD34. These findings were correlated with interstitial fibrosis and graft dysfunction. Humoral immunity involved in CAN was studied by C4d staining. RESULTS: The CAN cases in the present study included chronic rejection (CR) (n = 14, 17.8%) and C4d-positive chronic humoral rejection (CHR; n = 6, 42.9% in CR cases). Irrespective of CR, CHR, or other CAN, the development of CAN was characterized by injury to and loss of identifiable PTCs, accompanied with the development of interstitial fibrosis. In CR and CHR cases, the loss of PTCs was prominent and seemed to progress within a relatively short period after transplantation. A decrease in the number of PTCs significantly correlated with the development of interstitial fibrosis (r = -0.75, P < .001) and impairment of graft function (r = -0.69, P < .001). CONCLUSIONS: Irrespective of whether CR, CHR, or other factors contribute to CAN, the processes involved in its development appear similar and are characterized by progressive injury and loss of PTCs, with the development of renal scarring. Immunohistochemistry for CD34 in human renal biopsies is a useful method for the detection of microvascular injury.     

Protective effects of sirolimus by attenuating connective tissue growth factor expression in human chronic allograft nephropathy

BACKGROUND: Chronic allograft nephropathy (CAN) remains a great challenge for the transplant clinician. The introduction of sirolimus (RAPA) with cyclosporine (CsA) reduction maybe shed new light to improve graft survival. The aim of this study was to investigate the overall effects of sirolimus conversion on biopsy-proven CAN. METHODS: One hundred and ten renal transplant recipients with biopsy-proven CAN were randomized into two groups: 54 for CsA reduction and 56 for sirolimus conversion treatment. After 24-month follow-up, the outcome variables included graft function and survival as well as CAN Banff grading and intrarenal expression of connective tissue growth factor (CTGF) via repeated biopsy. RESULTS: Graft function and survival rate were significantly better in the RAPA group. CAN grading worsened in the CsA group, whereas they were stable in the RAPA group. There was weak expression in the RAPA group but significant, increased expression of CTGF in glomeruli and interstitial area in the CSA group (P < .01) both by immunohistochemical staining or real-time polymerase chain reaction detection. CONCLUSION: Sirolimus conversion provided a beneficial strategy to improve long-term graft survival in CAN. Attenuation of renal CTGF expression may be one of its antifibrotic and antiproliferation effects.     

Peritubular capillaritis in early renal allograft is associated with the development of chronic rejection and chronic allograft nephropathy

Abstract:  Peritubular capillaritis (PTCitis) has been recognized as one form of acute/active allograft rejection, and its relation to humoral immunity has been suggested. However, its mechanisms remain to be fully clarified, and there are no criteria for evaluating the extent of PTCitis in a biopsied allograft. In this study, we first evaluated the extent of PTCitis in early allografts in patients presenting with acute cellular rejection (ACR) and antibody-mediated rejection (AbAR). We also included patients who showed no evidence of ACR and/or AbAR. Next, we investigated whether or not PTCitis persisted and if peritubular capillary basement membrane (PTCBM) thickening was present in their follow-up biopsy specimens. We adopted the scoring system of PTCitis, which was presented at the Seventh Banff Conference on Allograft Pathology in 2003. In total, 53 patients were included in this study. At first biopsy, 17 showed ACR, eight showed AbAR, 16 showed mild PTCitis only, and 14 were without significant pathologic changes. The PTC score was the highest in the AbAR group, and in some patients the score gradually increased during the follow-up period. Similar changes were also observed in the group with mild PTCitis only. In late allografts, half of the patients with AbAR developed chronic rejection (CR), and the PTCBM score was the highest in that group. Surprisingly, CR was present in more than 30% of patients without ACR and/or AbAR but mild PTCitis only. In the control group, only a few showed CR and/or chronic allograft nephropathy (CAN). In conclusion, it became clear that we should carefully monitor for mild PTCitis in early allografts. In addition, our data also proved the usefulness of the PTC score and PTCBM score.     

Sirolimus in chronic allograft nephropathy

Chronic allograft nephropathy (CAN) is the most common cause of late renal transplant loss. Calcineurin inhibitor (CNI) nephrotoxicity is known to contribute to CAN. A sirolimus-based regimen way allow for early CNI reduction or elimination. The aim of the present study was to determine the efficacy and safety of a sirolimus-based regimen for CAN. From December 2001 to August 2003, kidney transplant (KTx) recipients with CAN were enrolled for treatment with sirolimus. Among 32 studied patients, 24 (75%) underwent graft biopsy before the initiation of sirolimus. Baseline maintenance immunosuppression consisted of cyclosporine/tacrolimus and prednisone with or without mycophenolate mofetil. The follow-up duration on sirolimus therapy was 8.5 +/- 5.9 months (range: 1 to 22 months). The average dosage of sirolimus was 1.8 +/- 0.5 mg/d at the end of follow-up. The mean trough level of sirolimus was 5.1 +/- 2.1 ng/mL. Sirolimus was effective in 16 (50%) patients while 3 (9.4%) patients improved (serum creatinine [Cr] decrease > 10%) and 13 (40.6%) maintained stable (change of serum Cr within 10%). Sirolimus was effective in 5 (35.7%) patients whose serum Cr was over 3.0 mg/dL but failed to rescue all four patients whose serum Cr was over 4.0 mg/dL. Eleven (68.8%) of 16 responders showed a reduction (29.8% +/- 13.8%) in CNI dosage. The most common adverse events were hyperlipidemia (37.5%), anemia (25%), and diarrhea (21.8%). Twelve patients discontinued sirolimus due to graft failure (4), severe infection (3), stroke related mortality (1), anemia (2), diarrhea (1), and edema (1). In conclusion, sirolimus is effective in 50% of KTx recipients with CAN, especially when the serum Cr is less than 3.0 mg/dL. However, the increased incidence of infection, diarrhea, and hyperlipidemia are of major concern.     

Hepatocyte growth factor prevents the development of chronic allograft nephropathy in rats

Long-term renal isografts in humans and laboratory animals exhibit features similar to those of chronic allograft nephropathy (CAN), indicating that antigen-independent factors, such as acute renal ischemia, are likely to be involved in the development of CAN. Hepatocyte growth factor (HGF) has been demonstrated to play a renotropic role in renal regeneration and protection from acute ischemic injury. This study was thus conducted to investigate the effect of HGF on the development of CAN, using an established rat model. HGF was administered daily (100 microg/d, intravenously) for 4 wk after engraftment. Control animals received saline solution. Allografts from control animals exhibited early evidence of severe structural collapse and necrotic cell death in the proximal tubules and outer medulla, with mononuclear cell infiltration, within 1 wk after engraftment. This was followed by sequential upregulation of adhesion molecules and cytokines, accompanied by dense macrophage infiltration. Fibrogenic events, as indicated by marked increases in transforming growth factor-beta1 expression and the accumulation of smooth muscle alpha-actin, occurred during the same period. Control animals ultimately developed features typical of CAN, with functional deterioration and severe histologic changes; a survival rate of 50.6% by 32 wk was observed. In contrast, remarkably little early injury and no late fibrogenic events were observed for the HGF-treated group. All treated animals survived, with well preserved graft function, during the 32-wk follow-up period. These results indicate that renal protection and recovery from early allograft injury with HGF treatment greatly contribute to a reduction of susceptibility to the subsequent development of CAN in a rat model. The potential application of HGF in the prevention of CAN warrants further attention.