重症巨细胞病毒感染和急性排斥肾移植受者T淋巴细胞亚群的动态变化

目的：探讨肾移植受者外周血Ｔ淋巴细胞亚群与发生重症巨细胞病毒（ＣＭＶ）感染和急性排斥反应（ＡＲ）之间的关系。方法：采用ＣＯＵＬＴＥＲ公司生产的鼠抗人Ｔ淋巴细胞亚群单克隆抗体ＯＫＴ系列及ＥＬＩＴＥ型流式细胞仪对２３例重症ＣＭＶ感染者、８例ＡＲ患者和２０例正常肾移植者的外周血Ｔ淋巴细胞亚群进行动态测定。结果：术后无ＡＲ者与ＡＲ者、排斥反应缓解者与未缓解者,其ＣＤ４／ＣＤ８比值变化差异有显著性意义（Ｐ〈     

Increased intracellular adenosine triphosphate level as an index to predict acute rejection in kidney transplant recipients

Background: Peripheral blood CD4 + T cell adenosine triphosphate (ATP) release has been reported to be an adjunct tool to evaluate global cellular immune response in solid-organ transplant recipients. However, the correlation between the ATP level and rejection was controversial. The aim of this prospective clinical study was to explore the association between the intracellular ATP level and the occurrence, progression, and treatment of acute rejection (AR) episodes, determine the predicting value of intracellular ATP level for AR in kidney transplant (KT) recipients. Patients and methods: In the period of October 2011 to October 2012, 140 KT recipients were recruited and followed for six months after transplantation. Patients were categorized into stable group and AR group according to their clinical course. Whole blood samples were collected pretransplantation, and at 7, 14, 21, and 28 days, and at 2, 3, 4, 5 and 6 months post-transplantation. Additional blood samples were obtained from AR patients on the day AR occurred, on the day before and 3 and 7 days after intravenous anti-rejection therapy started, and on the day when AR reversed. The intracellular ATP in CD4 + T cells was detected by ImmuKnow Immune Cell Function Assay according to the manufacturer's instruction. The absolute number of CD4 + T cells and the trough levels of tacrolimus and cyclosporine were also measured. Results: The ATP level detected on the day AR occurred (627.07 ± 149.85 ng/ml) was obviously higher than that of the stable group (320.48 ± 149.11 ng/ml, P < 0.05). ATP value decreased to 265.35 ± 84.33 ng/m at the end of anti-rejection therapy, which was obviously lower than that measured on the day before the anti-rejection therapy started (665.87 ± 162.85 ng/ml, P < 0.05). ROC analysis revealed that increased intracellular adenosine triphosphate level showed better sensitivity and specificity than those obtained using single time point detection (89.5% vs 85.0%;95.0% vs 88.9%). The best cutoff value was 172.55 ng/ml. A positive correlation between the intracellular ATP level and absolute CD4 + T cell number (r = 0.656, P < 0.001) was found in the patients with CD4 + T cell counts < 200/μl.     

移植肾急性排斥反应136例次治疗

我院自１９７８年４月至１９９３年３月，在尸体肾移植４７５例次中，发生移植肾急性排斥反应１３６例次，发生率为２８．６％。应用甲基强的松龙冲击治疗，急性排斥逆转率为７０．６％。单克隆抗体ＯＫＴ治疗逆转率为８３．９％，其中进口ＯＫＴ３逆转率达９２．３％。本文对其治疗方法作扼要讨论。     

Clinical determinants of multiple acute rejection episodes in kidney transplant recipients

BACKGROUND: Recipients with multiple (more than one) acute rejection (AR) episodes have significantly lower graft survival rates than those with no AR or only one treated episode. However, fewer than 50% of recipients treated for one AR episode will have another episode. METHODS: We studied recipients with at least one AR episode to determine whether any clinical features could identify risk factors for multiple AR. RESULTS: Between January 1, 1984, and June 30, 1997, a total of 1793 recipients underwent a kidney transplant at our institution. Of these, 354 were treated for one AR episode, 307 for more than one. By multivariate analysis, recipients at highest risk for multiple AR episodes were those with initial delayed or slow graft function (relative risk=1.5, P=0.05), those with initially severe AR (as judged by vascular involvement or steroid resistance), and those with an initial early AR episode (<6 months posttransplant). The remaining variables tested were not significant. Graft survival in recipients with more than one AR episode was significantly lower than in those with only one AR episode. Graft survival at 5 years posttransplant was 52.5% in recipients with more than one AR episode and 85.1% in recipients with one AR episode (P=0.0001). Chronic rejection as a cause of graft loss was significantly more common in recipients with more than one vs. only one AR episode (34.8% vs. 8.9%, P=0.001). CONCLUSION: Clinical features may be used to identify recipients at higher risk for multiple AR episodes. These recipients can then be targeted with more aggressive or novel immunosuppressive regimens in an attempt to reduce the likelihood of another AR episode.     

Acute antibody-mediated rejection in kidney transplant recipients

Antibody-mediated rejection has now been recognized as one of the most important causes of graft loss. Transplantation across HLA barriers and nonadherence can result in acute antibody-mediated rejection, which is associated with particularly worse graft outcomes. New technologies, including genomic studies and assays to detect and define donor-specific antibodies, have provided important insights into the pathophysiology and diagnosis of acute antibody-mediated rejection but have engendered many questions about the clinical application of these tests in the prognosis and prevention of this protean disease process. In this article, we review the pathophysiology of acute antibody-mediated rejection, the evolving diagnostic criteria, and specific challenges related to its prognosis, treatment, and prevention.     

Basiliximab and mycophenolate mofetil in combination with low-dose cyclosporine and methylprednisolone effectively prevent acute rejection in kidney transplant recipients

The aim of the study was to analyze whether immunosuppressive treatment with basiliximab and mycophenolate mofetil (MMF), allowed a reduction in methylprednisolone and cyclosporine dosages without increasing the incidence of acute rejection episodes, reducing 1-year graft and patient survivals, or increasing the rates of infections and malignancy in the first year. The two groups were group A (n = 72), treated with methylprednisolone and cyclosporine and in the first 2 weeks with azathioprine; group B (n = 72), treated with basiliximab, MMF, and low-dose cyclosporine and methylprednisolone. The patients were followed for 1 year. The incidence of acute rejection episodes in the first year was significantly lower in group B (2.8%) than group A (12.5%; P < .05). The cumulative methylprednisolone dose, the daily dose, and the average cyclosporine trough blood level were significantly lower in group B (P < .001). One-year serum creatinine was significantly lower in group B (112 +/- 45 micromol/L) than group A (138 +/- 51 micromol/L; P < .01). One-year graft survival was 91.7% in group A and 98.6% in group B. One-year patient survival was 98.6% in group A and 100% in group B. The groups did not differ significantly in the incidence of bacterial, viral, or fungal infections. Immunosuppression with basiliximab and MMF allowed a reduction in cyclosporine and methylprednisolone dosages and was associated with significantly lower incidences of acute rejections episodes with better graft function in the first year as opposed to immunosuppression with higher doses of cyclosporine and methylprednisolone alone. Both immunosuppressive regimens showed the same infection rates and did not differ significantly in the occurrence of malignant diseases within the first year.     

The relationship between cyclosporine pharmacokinetic parameters and subsequent acute rejection in renal transplant recipients

The best approach to determining the optimal dose of cyclosporine in renal transplant recipients is unclear. In this prospective investigation, CsA pharmacokinetic studies were performed in 45 patients 1, 4, and 12 weeks after the initiation of CsA. Data from 104 studies were then combined to analyze the relationship between CsA kinetic parameters and posttransplant clinical events. Random trough levels, used in the day-to-day adjustment of CsA dose, were examined separately in 19 of the 45 study patients. All CsA levels were measured with high-performance liquid chromatography. Results showed: (1) trough CsA levels, obtained by random sampling, or from the kinetic studies, correlated poorly with dose; however, there was a good correlation between CsA dose and maximum concentration (Cmax, r = .39, P less than .001), area under the concentration-time curve (AUC, r = .45, P less than .001), and terminal elimination half-life (r = .43, P less than .001); (2) several pharmacokinetic parameters correlated with subsequent rejection episodes; patients with acute rejection within 2 or 4 weeks after study had 15-31% lower Cmax (P less than .05) and 13-19% lower AUC (P less than .05) compared to those who were rejection-free; and (3) levels of blood constituents known to bind CsA also correlated with rejection, and this correlation was independent of the impact of kinetic parameters on rejection. Altogether, these results suggested that a limited number of CsA pharmacokinetic studies may be more useful than multiple, random trough levels in monitoring CsA therapy.     

Hyperlipidemia in pediatric kidney transplant recipients treated with cyclosporine

Hyperlipidemia is a risk factor for cardiovascular disease in adult kidney transplant (Tx) recipients. We sought to determine the prevalence of, and the risk factors associated with, hyperlipidemia in pediatric kidney Tx recipients on cyclosporine (CsA). We identified 59 patients (mean age 8.2+/-5.7 years) transplanted between 1 January 1991 and 31 December 1993. Pre Tx, 34% had elevated total cholesterol [TC >200 mg/dl (5.17 mmol/l)]; 54% had elevated triglycerides [TG >200 mg/dl (2.26 mmol/L)]. Mean TG was higher pre Tx in dialysis (versus nondialysis) patients: 306 mg/dl (3.46 mmol/l) versus 228 mg/dl (2.58 mmol/l) ( P=0.04). Mean TC was higher in peritoneal dialysis than hemodialysis patients: 222 mg/dl (5.74 mmol/l) versus 169 mg/dl (4.37 mmol/l) ( P=0.03). Pre Tx and 3-year values correlated (TC, r=0.49, P=0.0008; TG, r=0.41, P=0.001); 3- and 5-year TC values correlated ( r=0.57, P=0.003). At 5 years post Tx, 41% of the recipients had elevated TC; 14% had elevated TG. Recipients with elevated TC had higher mean CsA concentrations at 1 year post Tx ( P=0.03). Recipients with elevated TG tended to receive more prednisone ( P=0.06). At 5 years post Tx, recipients had a high prevalence of hyperlipidemia. The identification and treatment of hyperlipidemia should be included in pediatric kidney Tx protocols.     

Conversion from cyclosporine to tacrolimus in pediatric kidney transplant recipients

In pediatric kidney transplant recipients, tacrolimus has been proposed either for primary immunosuppression or as a rescue agent for refractory acute rejection, chronic rejection, and cyclosporine toxicity. This paper describes our experience with tacrolimus conversion from cyclosporine-based therapy in six selected cases: four due to refractory acute rejections unresponsive to conventional therapy, one to chronic graft rejection, and one to cyclosporine-related hypertrichosis. A "simple-switch" conversion was used without any overlap, starting with a dose of 0.2 mg/kg per day. The time to conversion varied from 10 to 730 days after the transplant. In the patients with acute rejection, the median time to reversal after tacrolimus conversion was 12 days. The symptoms of the patient with cyclosporine toxicity completely resolved without any loss of allograft function. The patient with chronic rejection maintained stable renal function for more than 1 year after conversion. A new onset of post-transplant diabetes mellitus and dose-related nephrotoxicity were recorded as adverse events. In conclusion, our experience suggests that tacrolimus can play an important role in the salvage treatment of pediatric kidney transplantations with deteriorating graft function due to acute rejection refractory to standard therapy. Tacrolimus conversion also provides excellent results in the presence of cyclosporine toxicity.     

国产AHTG在治疗肾移植术后排斥反应中的应用

从１９９４年５月－１９９６年２月间应用猪抗人胸腺淋巴细胞球蛋白治疗肾移植术后排斥反应１９例。结果１７例完全逆转，血脂酐降至１５０μｍｏｌ／Ｌ以下；１例无效；另１例并发巨细胞病毒肺炎死亡。指出在肾移植术后发生排斥反应的早期应用ＡＨＴＧ疗效最为满意。     

大黄制剂对肾移植受者环孢素血药浓度的影响分析

目的研究肾移植受者服用大黄制剂对环孢素血药浓度的影响。方法 2008年1月至2012年12月,湖州市第一人民医院10例肾移植受者术后采用环孢素＋吗替麦考酚酯/硫唑嘌呤＋泼尼松三联免疫抑制方案,环孢素用量为5~7 mg·kg-1·d-1,受者术后2~5年因便秘同时服用大黄苏打片（每片含大黄0.15 g,碳酸氢钠0.15 g）,3片/次,3次/d。服用当天及15 d监测受者环孢素血药浓度谷值（C0）、2h后血药浓度峰值（C2）以及肝肾功能,停药15d复查环孢素C0和C2。结果服用大黄苏打片15 d受者环孢素C0、C2均高于服用当天检测值,差异均有统计学意义（t=11.754和12.822,P均〈0.05）。停用大黄苏打片15 d复查环孢素C0、C2均低于服用15 d时检测值,差异均有统计学意义（t=10.020和13.596,P均〈0.05）;与服用当天检测值比较,差异均无统计学差异（t=1.375和0.251,P均〉0.05）。服用大黄苏打片15 d,受者肝肾功能指标与服用当天比较差异均无统计学差异（P均〉0.05）。结论肾移植术后服用环孢素的受者在长期使用含有大黄制剂的药物时,应注意监测环孢素血药浓度,必要时适当调整环孢素用量。     

Hepatitis E virus infection and rejection in kidney transplant recipients

BackgroundHepatitis E virus (HEV) infection has been associated with immune-mediated kidney diseases in developing countries. However, its relationship with kidney transplant outcomes has never been studied. We investigated the association between HEV infection and kidney graft rejection among kidney transplant recipients (KTRs).MethodsWe conducted a matched cohort and longitudinal study utilizing banked sera following kidney transplantation during 1988–2012. Studies with evidence of post-transplantation HEV infection were identified by positive ELISA tests (anti-HEV IgM or anti-HEV IgG seroconversion) or positive HEV PCR and matched to KTR controls with negative HEV ELISA and PCR tests in a 1:5 ratio by age, sex, crossmatch status, immunosuppression era, and time of HEV testing. Outcome data collected included time to first kidney graft rejection, transaminases, and glomerular filtration rates. Log-ranked test was used to analyze survival.ResultsOf 271 KTRs, 9 (3%) had evidence of post-transplantation HEV infection and were compared to 45 negative, matched controls. Median age at transplantation was 46 years. Kidney graft rejection was reported in 8 (89%) of cases and 21 (47%) of controls. Median time to first episode of kidney graft rejection was 17.4 months in cases and 30.8 months in controls (p = 0.029), with a higher hazard of developing kidney graft rejection in cases (HR = 3.23, 95% CI: 1.19–8.79). Lower mean glomerular filtration rates over time were observed in cases (35 mL/min/1.73m²) versus controls (42.4 mL/min/1.73m²) but did not reach significance (p = 0.24).ConclusionSubjects with evidence of post-transplantation HEV infection demonstrated earlier kidney graft rejection compared to controls.     

Fluvastin therapy affects TAFI concentration in kidney transplant recipients

Thrombin activatable fibrinolysis inhibitor (TAFI) is a glycoprotein, linking coagulation and fibrinolysis. Recently, attention has been drawn to the beneficial effects of statins on haemostasis in kidney patients prone to dyslipidaemia and with a high risk of cardiovascular death. The purpose of this study was to assess whether fluvastatin affects TAFI concentration in renal transplant recipients. We evaluated thrombin-antithrombin (TAT) complexes, prothrombin fragments 1+2, thrombomodulin, plasmin-antiplasmin (PAP) complexes, TAFI, P-selectin, and lipoprotein (a), 1, 2, and 3 months before and after fluvastatin treatment and in normolipaemic kidney transplant recipients and healthy volunteers. Cholesterol and LDL fell significantly as soon as 1 month after treatment had begun and remained lowered during the therapy. TAFI and prothrombin fragments 1+2 decreased significantly after 3 months of fluvastatin administration, whereas P-selectin decreased significantly after 2 months and remained significantly lower after 3 months of this therapy. We can conclude that fluvastatin is an effective hypolipaemic agent that favourably affects haemostasis.     

A truncated-dose regimen of daclizumab for prevention of acute rejection in kidney transplant recipients: a single-center experience

Daclizumab can decrease the incidence of acute rejection (AR) in renal transplant (RTx) recipients. In this prospective study, 52 RTx patients were divided into two groups according to the dose of daclizumab: 1 mg/kg on day 0 and every 14 days for five doses (group 1, n = 30) or a truncated regimen of 2 mg/kg on day 0 and on the day of discharge (group 2, n = 22). The following variables were recorded: demographics; delayed graft function; AR at 3, 6, and 12 months; time to AR; chronic allograft nephropathy (CAN); and serum creatinine. The overall incidences of AR were 23% and 27% (P = 0.76) in groups 1 and 2, respectively, whereas at 6 months they were 21% and 18% (P = 1.0). Median time to AR was 10 days in group 1 and 94 days in group 2 (P = 0.09). The incidence of CAN was 6.6% in group 1 and 13% in group 2 (P = 0.63). These data suggest that the truncated dose of daclizumab is as effective as the standard regimen for AR prophylaxis.     

Validation of single nucleotide polymorphisms associated with acute rejection in kidney transplant recipients using a large multi-center cohort

There have been numerous reports proposing a statistically significant association between a genetic variant, usually in the form of a single nucleotide polymorphism (SNP), and acute rejection (AR). Unfortunately, there are additional publications reporting a lack of association with AR when a different cohort of recipients was analyzed for the same SNP. The objective of this report was to attempt replication of these published finding in our own kidney allograft recipient cohort. We analyzed 23 genetic variants, previously reported to have a significant association with AR, using a cohort of 969 clinically well-defined kidney transplant recipients. Only one SNP, rs6025 (Leiden mutation), within the coagulation factor V gene, showed a significant association with a P-value of 0.011 in a race-adjusted analysis and a P-value of 0.0003 in multiple variable analysis. An additional SNP, rs11706052 in IMPDH2, gave a modest P-value of 0.044 using multiple variable analysis, which is not significant when multiple testing is taken into consideration. Our results suggest that careful validation of previously reported associations with AR is necessary, and different strategies other than candidate gene studies can help to identify causative genetic variants associated with AR.