Calcineurin inhibitor substitution with sirolimus vs. reduced-dose calcineurin inhibitor plus sirolimus is associated with improved renal dysfunction in heart transplant patients

Heart transplant (HTx) patients are at risk of developing renal dysfunction. Sirolimus has been used as an alternative for calcineurin inhibitors (CNI) in transplant patients with renal dysfunction. Recent data suggest that the combination of sirolimus with a CNI is associated with a deterioration of renal function in renal transplant patients. The purpose of the present study was to compare the effect on the creatinine clearance (CrCl) of heart transplant (HTx) patients with renal dysfunction (RD) on CNI-based sirolimus-free regimens of conversion to either reduced-dose CNI plus sirolimus or outright substitution of CNI with sirolimus. We retrospectively identified 29 treatment switches for 26 patients with RD defined as a decline in the CrCl > 25% post-HTx. Treatment switches were divided into two groups. Group 1 included 13 switches in 13 patients (four women, nine men, age 62 +/- 10 yr) in whom sirolimus replaced CNI. Group 2 included 16 switches in 15 patients [two women, 13 men (one man underwent two such switches), age 61 +/- 9 yr] in whom CNI dose was reduced and sirolimus was added. Two men appear in both groups. Average follow-up was 10.4 +/- 3.2 months. Overall mortality, rejection, and side-effects rates were comparable between groups. At 12-months post-switch, the mean CrCl had increased from 48 +/- 15 at time of treatment switch to 56 +/- 22 mL/min in group 1 and decreased from 53 +/- 19 to 47 +/- 17 mL/min in group 2 (p = 0.02). In conclusion, substitution of CNI with sirolimus provided improved renal recovery compared with lower-dose CNI plus sirolimus in HTx patients with renal dysfunction.     

蛋白质谱技术预测大鼠心脏移植后急性排斥反应

目的 探讨蛋白质谱技术对大鼠心脏移植后急性排斥反应的预测.方法 建立颈部异位异种大鼠心脏移植模型.(1)急性排斥A和B组,供受体不作预处理.(2)治疗A和B组,受体术前1d腹腔注射环孢素A(CsA) 20 mg/kg,术后每天10 mg/kg.A和B组分别在术后5d和7d取血液标本及移植物(供心)标本.(3)空白组,取大鼠移植前血液及心肌组织作标本.应用蛋白质谱技术对各组的血清及心肌组织蛋白质样本进行质谱测定,统计分析各组之间的差异蛋白质,并比较分析差异蛋白质的峰强度.结果 与空白组血清比较,急性排斥A组与之存在7个差异蛋白质峰,急性排斥B组与之存在11个差异蛋白质峰.急性排斥A组与治疗A组比较,有4个差异蛋白质峰,急性排斥B组与治疗B组比较,有6个差异蛋白质峰.与空白组心肌组织蛋白质比较,急性排斥A和B组与之分别存在7个和13个差异蛋白质峰.以上比较差异均有统计学意义(P＜0.01).结论 正常与急性排斥反应后不同时相点血清及心肌组织中的蛋白存在明显差异,这种差异蛋白可能与急性排斥反应相关.     

Correlation between circulating endothelial progenitor cell function and allograft rejection in heart transplant patients

Endothelial progenitor cells (EPCs) may contribute to rejection and cardiac allograft vasculopathy (CAV) by being intrinsically involved in the rejection process and causing neointimal hyperplasia. The mammalian target of rapamycin inhibitors (mTORi), sirolimus and everolimus, have been demonstrated to attenuate the progression of CAV and are cytotoxic to EPC. Thus, one mechanism by which mTORi may protect against CAV is by altering EPC function. Our study measured circulating EPC function and correlated this assessment with rejection episodes in heart transplant (HT) recipients. In addition, we examined the effect of mTORi on EPCs. Patients who received HT at our institution between 1995 and 2007 were included and stratified by International Society for Heart and Lung Transplantation (ISHLT) rejection grade. Group A (n = 13) consisted of patients with at least one moderate/severe rejection episode (grade ≥ 2). Group B (n = 28) patients had no moderate/severe episodes (grade < 2). Patients were also independently stratified based on exposure as mTORi (n = 21) vs. non mTORi (n = 20). To assess EPC functional capacity, we counted the number of colony‐forming units (CFU) of EPCs in peripheral blood samples from HT recipients. There were no significant differences in baseline characteristics between groups. The mean EPC‐CFU counts/plate for group A (rejecting) were 30 ± 6 vs.16 ± 3 for group B (nonrejecting) (P = 0.03). The EPC‐CFU counts/plate in the mTORi group (15 ± 3) were lower compared to the non mTORi (27 ± 5) group (P = 0.04). We found that EPC colony‐forming capacity was higher in HT patients who experienced moderate/severe rejection episodes. Patients on mTORi showed a reduced EPC colony count consistent with our previous findings of EPC cytotoxicity. Detection of circulating EPC function post‐transplant may reliably identify patient risk level for subsequent allograft rejection and allow for appropriate adjustments to immunosuppression. Converting to mTORi therapy may reduce EPC function and provide a novel mechanism to prevent rejection and possibly attenuate the development of CAV.     

Conversion to sirolimus with calcineurin inhibitor elimination vs. dose minimization and renal outcome in heart and lung transplant recipients

Abstract:  Sirolimus (SRL) has been used as an alternative immunosuppressant strategy to allow either dose minimization or complete withdrawal of calcineurin inhibitors (CNI) therapy to improve renal outcome. One hundred thirty-one heart and 55 lung transplant patients were converted from a CNI to SRL based immunosuppression, with CNI elimination in 25 patients, and dose reduction in 161 patients. Fifty-six (28%) patients died and 65 (33%) patients had a 25% or more decline in estimated glomerular filtration rate (eGFR) during a median follow-up of 18 months. The three groups (SRL only group n = 25; SRL + tacrolimus n = 94; SRL + cyclosporine n = 67) had an initial improvement in estimated glomerular filtration rate (p = 0.05), with subsequent similar slow decline in mean eGFR (repeated measures ANOVA, p = 0.96). After controlling for important potential confounding variables, the three groups had similar renal outcome (p = 0.40) and overall survival (p = 0.45). In conclusion, the benefits of CNI withdrawal vs. minimization as part of SRL-based regimens are similar with regard to renal outcomes and patient survival.     

Serum and urinary biomarkers in acute kidney transplant rejection

Background

Acute rejection (AR) is a common medical problem among kidney transplant recipients, which may cause a significant impact on patients’ and allografts’ survival. Kidney allograft biopsy remains the “gold standard” for assessing the cause of kidney transplant dysfunction. However, there are limitations for the allograft biopsy; these include the risk of bleeding, injury to the adjacent organs, and the possibility of sampling error leading to misdiagnosis.

Methods

We conducted a comprehensive review of the literature and main published data that discussed the most relevant serum and urine biomarkers in acute allograft dysfunction, along with their clinical significance.

Results

There have been significant discoveries of several important biomarkers that correlated with biopsy findings, clinical outcomes and possibly graft survival. Proteomic and genomic have been utilized in this area with some success, along with a growing discoveries of cytokines surrogate makers.

Summary

The discovery of surrogate biomarkers in kidney transplantation is an evolving field of crucial importance that may change the way we practice transplant nephrology in the future.     

原位心脏移植术后急性排斥反应的监测

为了探讨心脏移植术后急性排斥反应的监测指标，我们对３例原位心脏移植患者在发生急性中、重度排斥反应时出现的各种临床征象进行了分析，结果发现，心电图、超声心动图、单光子计算机体层扫描、外周血Ｔ淋巴细胞计数、Ｘ线影象等检查枯早期诊断急性排斥反应时产不是敏感指标，认为心的膜心甩活 诊断急性排斥反应的可靠指标     

Clinical response and temporal patterns of acute cellular rejection: relationship to chronic transplant nephropathy

Abstract The association between acute cellular rejection (ACR) and the development of chronic rejection has been the subject of much debate. Studies have suggested that the two phenomena may be linked, or, conversely that there may be no association at all. In order to clarify this relationship the outcome of 284 renal allografts were examined. The transplants were all performed at a single institution between April 1989 and December 1991, allowing a minimum follow up of 5 years. ACR was classified into three clinical response groups: (1) fully responsive to therapy (type 1 ACR), (2) partially responsive (type 2) and (3) ACR requiring treatment with ATG or OKT3 (type 3). Acute and chronic rejection were determined by histological (Banff) criteria. Chronic transplant nephropathy (CTN) occurred significantly more frequently in those with late ACR after day 60 than in those who had early rejection (53.5% versus 17.3%, respectively, P < 0.00001). Acute rejection that was fully responsive to therapy (type 1) had no association with CTN, but partially responsive rejection and rejection requiring seconD-line treatment were both significantly associated with CTN ( P < 0.0001 and P < 0.001, respectively). This study suggests that it is the clinical behaviour and response to treatment of ACR that is paramount in determining the onset of chronic rejection, and not the mere presence or absence of the clinical phenomenon.     

移植肾急性排斥反应的无创性监测与诊断

随着移植免疫研究的深入和新型免疫抑制剂不断问世，肾移植术后急性排斥反应的发生率明显下降，移植物的存活，特别是短期存活已有明显提高，但急性排斥反应仍然是影响移植肾长期存活的主要因素之一。其中发生难治性排斥反应的比例逐渐升高，其较高的移植肾失功率越来越受到关注。而与30年前相比，我们对于急性排斥反应、难治性排斥反应诊断与监测的策略一直没有很大的发展。     

Long-term follow-up of pediatric transplant recipients: mycophenolic acid trough levels are not a good indicator for long-term graft function

Abstract: Background: Mycophenolate mofetil (MMF) has the potential of decreasing acute rejection episodes early following renal transplantation. Pharmocokinetic monitoring of mycophenolic acid (MPA) trough levels is performed by many centers. MMF has also proved successful in improving long‐term graft function in patients with chronic allograft nephropathy (CAN). However, no data for long‐term monitoring of MPA in children have yet been published. Methods: MMF therapy with a dose of 600 mg/m² twice daily was initiated in 42 children (median age 9.4 yr, range 1.4–15.1) after a median period of 3.8 yr (range 1.0–10.6) post‐transplantation – according to significant increases in serum creatinine. CAN was diagnosed by renal biopsy and the amount of fibrosis was quantified with PicroSiriusRed staining. MMF therapy was combined with ciclosporin A and prednisolone. MPA‐C0‐levels, measured by high‐pressure liquid chromatography, were tested every 3 months. In 12 children a full MPA area under the curve concentration (AUC) was measured. The glomerular filtration rate (GFR) was calculated at the start of MMF therapy and 2 yr later. Results: After initiation of MMF, the calculated GFR did not decrease further in 22 children and mean GFR remained stable for 2 yr in the whole study group. There was a significant correlation between MPA levels 75 min after administration and the full AUC (r = 0.94, p < 0.001) but no correlation between trough levels and AUC (r = ?0.07, p > 0.05). The mean MPA trough level was 2.8 ± 1.3 ng/mL. The intra‐individual coefficient of variation was 2.6 ± 1.4. There was no correlation between mean MPA trough levels and GFR development after 2 yr (r = 0.03, p > 0.05). In children with an MPA level below 1.2 mg/L (n = 5), the mean GFR decline was no different to those with a higher level (p > 0.05). Conclusions: Drug monitoring of MPA trough levels had no impact on long‐term graft function in kidney recipients. MPA levels taken 75 min after administration showed a high correlation with MPA‐AUC whereas C0‐levels did not correlate. The value of C75 drug measurements for monitoring renal allograft survival will have to be judged in future studies.     

A case of Mycobacterium chelonae mediastinitis and acute humoral rejection after heart transplantation

Mediastinitis is one of the life‐threating complications that can occur after cardiac surgery. However, to the best of our knowledge, there has been no report of mediastinitis caused by Mycobacterium chelonae, which is one of the rapidly growing nontuberculous mycobacteria species. As far as we know, our case is the first case describing the curative management for mediastinitis caused by M. chelonae after heart transplantation.     

Association between vitamin D receptor genetic polymorphisms and acute cellular rejection in liver-transplanted patients

Vitamin D receptor (VDR) polymorphisms may confer susceptibility to immunologically mediated liver diseases. We aimed to verify whether recipient VDR polymorphisms might affect the incidence of acute cellular rejection (ACR) of the graft after liver transplantation (LT). Two hundred and fifty-one liver-transplanted patients surviving at least 1month were studied. ACR in the first post-LT year was graded according to the Banff score. Recipients genotyping for VDR polymorphic sites (FokI C>T, BsmI G>A, ApaI T>G, TaqI T>C) was performed. A significant difference was found between patients with and without ACR episodes in allele frequencies of BsmI (G: 0.660 vs. 0.545, P=0.017) and TaqI (T: 0.667 vs. 0.543, P=0.010). Patients carrying the G-*-T/G-*-T diplotypes of the BsmI G>A, ApaI T>G and TaqI T>C experienced more frequently ACR: 33/79 Vs 42/172, P=0.005. Carriage of G-*-T/G-*-T diplotypes was an independent predictor of ACR (OR 2.41, P=0.006), with CMV reactivation (OR 2.34, P=0.033) and HCV aetiology (OR 1.86, P=0.036). In conclusion, recipient VDR polymorphic loci are strongly associated with ACR occurrence during the first year after LT. The knowledge of VDR genetic polymorphisms may be helpful in identifying recipients at higher risk of ACR and in selecting them for a more aggressive immunosuppressive therapy.     

Tacrolimus rescue therapy for children with acute renal transplant rejection

Seventeen children with renal transplants (11 living-related, age 2–18 years) were converted from cyclosporine to tacrolimus because of acute rejection that failed to respond to high-dose corticosteroids. Resistance to corticosteroids was confirmed by renal biopsy in 14 patients, and assumed in 3 patients because of failure of serum creatinine to improve to baseline values. Four patients were also treated with OKT3, and 15 children had been receiving mycophenolate maintenance therapy prior to conversion to tacrolimus. Rejection occurred at 2–174 weeks post transplant (mean 52 weeks). Actuarial 1- and 2-year graft survival was 87% and 78%. Three children progressed to end-stage renal disease after 4, 12, and 13 months of tacrolimus. The remaining 14 children have functioning allografts after 20–168 weeks of treatment (mean 80 weeks). All 14 children exhibit stable or improved renal function: serum creatinine 1.1±0.7 mg/dl versus 2.0±0.9 mg/dl prior to tacrolimus. In conclusion, tacrolimus was effective therapy for both early and late acute rejection in children who failed to respond to high-dose corticosteroids. No significant short-term adverse effects were encountered. Received: 29 August 2000 / Revised: 31 July 2001 / Accepted: 31 July 2001     

C-reactive protein in the monitoring of acute rejection after heart transplantation

Histological examination of endomyocardial biopsy (EMB) is the main technique for rejection surveillance after heart transplantation. This technique is elaborate, inconvenient for the patient, and not without complications. We prospectively analyzed whether the measurement of C-reactive protein (CRP), an acute phase protein that quickly rises when there is inflammation, can serve as a marker for immunological quiescence and as an indicator for withholding EMB. During a 6-month period, CRP was measured in all patients referred for EMB as part of the routine follow-up after heart transplantation. Acute rejection in patients with a follow-up of more than 1 year was rare (1/76). In the majority of cases, EMB was taken within the 1-year post-transplantation (170/246 = 69 %). In 71/170 biopsies (42 %), CRP was ≤ 1; in the other 99/170 (58 %), CRP was ≥ 2. When CRP was ≤ 1, acute rejection was diagnosed in 12/70 cases (17 %). In contrast, acute rejection was found in 28/99 cases (28 %) with CRP ≥ 2 (P = 0.1). Although CRP is elevated more often in the presence of acute rejection, its sensitivity does not allow CRP to replace the routine performance of EMB for monitoring rejection after heart transplantation. We did, however, find a prognostic significance with regard to the effect of rejection treatment: in all acute rejections with a CRP ≤ 3 (n = 11), steroids were effective. Received: 6 January 1998 Received after revision: 7 April 1998 Accepted: 20 April 1998     

移植心脏电生理改变与移植物排斥反应关系的研究

目的　探讨非创伤性监测及诊断心脏移植后急性移植物排斥反应(GR)方法。方法通过大鼠颈部心脏移植模型观察急性GR过程中移植心脏电生理改变,即房室传导有效不应期(ERP-AVCS)改变与移植心脏形态学改变的关系。结果　同系移植及异系移植免疫抑制剂投用组ERP-AVCS无延长;异系移植组移植后第3天,其ERP-AVCS出现明显延长［(96.88±6.77)ms,P＜0.05］,第5天为(114.62±7.46)ms(P＜0.01),第7天为(121.67±9.73)ms(P＜0.01)。同系移植及异系移植＋免疫抑制剂投用组形态学结构未见异常;异系移植组在移植后第3天开始出现急性GR,如心肌纤维间质明显增宽、排列紊乱,血管旁及间质内出现单核细胞等且第5天及第7天急性GR渐加重。异系移植心脏ERP-AVC与排斥反应形态学改变呈明显正相关(P＜0.01)。结论　检测移植心脏ERP-AVC是简便、可靠、低费用、非创伤性诊断移植心脏急性排斥反应手段。     

Acute rejection after paediatric heart transplantation: far less common and less severe

Despite improved immunosuppression, rejection accounts for significant morbidity and mortality in children after heart transplantation. We report the incidence and outcome of rejection of 105 children (male = 50; mean age of 8.3 ± 5.8 years) following heart transplantation between January 2002 and August 2007. A multi-variant model was constructed for risk factors associated with significant rejection. In 271.9 patient-years of follow-up, there were 23 episodes of significant rejection (≥3A) in 21 patients (20%). Five presented in haemodynamic collapse requiring extracorporeal membrane oxygenation support 1.6–35.9 months after transplantation; four of five survived the rejection episode. Overall rejection episodes were more common in older children, boys and those treated with sirolimus. Whereas the risk for rejection in patients on an immunosuppression regime containing tacrolimus was significantly lower. The latter finding persisted on multivariate analysis ( P  < 0.002). Interestingly, none of the patients who presented with haemodynamic collapse was on mycophenolate mofetil. While our experience is of a far lower incidence of rejection than registry data, rejection remains a serious problem after paediatric heart transplantation. Sirolimus without a calcineurin inhibitor was associated with more rejection episodes, whereas tacrolimus and mycophenolate appeared to provide the best protective profile.