内皮素在移植肾急性或慢性排斥反应中的变化

目的：探讨内皮素—1(ET—1)在移植肾急性或慢性排斥反应(简称急排或慢排)中的变化。方法：对43例肾移植术1年后患者(对照组18例，急排组9例，慢排组16例)行血液、尿液ET—1、肌酐、β2—M排泄量等测定，对部分急排和慢排移植肾行ET—1及A受体免疫组织化学染色。结果：急排组血、尿ET—1高于对照组(P＜0．01)；急排组尿ET—1明显高于慢排组(P＜0．01)，两组间血ET—1的差异无明显意义(P＞0．05)；急排和慢排时血ET—1均与血肌酐呈正相关(P＜0.01)，尿ET—1均与尿β2—M排泄量呈正相关(P＜0．01)；免疫组织化学染色显示ET—1与ETA受体在移植肾内的分布较一致，与相应病理类型大致吻合，急排和慢排检测时，其染色强度明显高于正常肾脏。结论：检测尿ET—1排泄量可鉴别急排和慢排，术后监测尿ET—1较监测血ET—1更有意义；在急排和慢排中ET系统可能担当重要角色。     

Aggressive treatment of the first acute rejection episode using first-line anti-lymphocytic preparation reduces further acute rejection episodes after human kidney transplantation

Abstract The detrimental effect of acute rejection episodes on long-term outcome of renal allografts in cyclosporin-treated patients is well established, although has not been seen by all investigators. To analyse the possibility that aggressive treatment of the first episode may ameliorate this detrimental effect, we performed an open label, randomised prospective trial in cyclosporin-based, immunosuppressed recipients of postmortem renal allografts in order to compare two different treatment protocols during primary acute rejection episodes: (1) group 1 of 25 patients received 3 × 250 mg methylprednisolone (MP) i.v.; (2) group 2 of 25 patients received 7 × anti-thymocyte globulin (ATG)-Fresenius i.v. (4 mg/kg body weight). During a period of 4 years, the following clinical observations were made: (1) The incidence of an acute re-rejection episode was significantly reduced in the ATG-treated study group (16%) compared to the MP-treated study group (72 %); (2) The severity of the first acute rejection episode (intensity of renal dysfunction measured in terms of 10-day creatinine area under curve) showed no significant difference between the groups (37 mg × 10-d/dl to 58 mg × 10-d/dl); and (3) The half-lives of allografts in both groups have not shown any significant differences so far. In conclusion, aggressive treatment of the first rejection episode of renal allografts with the use of ATG reduced the incidence of re-rejection episodes which, however, are not reflected so far by improvement of the 4-year survival rate of these allografts. Since it could be observed that re-rejection is an even worse predictor for chronic transplant failure, a better long-term outcome of renal allografts in ATG-treated patients may be expected during a longer observation period. The incidence of a third episode was also reduced in the ATG-treated group (0 %) compared to the MP-treated group (12%).     

肾移植后急性排斥反应发生相关术前因素分析

目的探讨影响肾移植术后发生急性排斥反应的相关术前因素,为预防移植肾急性排斥反应的发生提供临床依据。方法回顾性分析2002年1月～2008年12月在浙江大学医学院附属第一医院肾脏病中心首次接受同种异体尸体肾移植受者1316例资料,记录基线资料及术后急性排斥反应发生情况;按群体反应性抗体(PRA)水平10%和≥10%将受者分为PRA阴性组和致敏组;以2005年10月1日为界分为回顾性HLA配型组和前瞻性HLA配型组。统计分析各基线资料对术后急性排斥反应发生的影响以及不同组间急性排斥反应发生率的差异。结果手术时受者年龄、术前PRA水平、热缺血时间、HLA错配数对术后急性排斥反应的发生有显著影响。致敏组术后6个月内急性排斥反应发生率(58.8%比17.9%,P0.001)以及6个月内组织病理学检查证实急性排斥反应发生率(29.4%比11.9%,P=0.028)均显著高于PRA阴性组。采用前瞻性HLA配型后受者HLA错配数减少,且术后6个月内急性排斥反应发生率也降低(20.9%比15.5%,P=0.012)。结论术前检测受者的PRA水平从而准确评估其致敏状态,尽可能选择良好的HLA配型谱可减少移植肾术后急性排斥反应的发生。     

Circumocular exanthema associated with chronic rejection after kidney transplantation

A 43-year-old man had severe circumocular exanthema associated with chronic rejection 10 years after receiving a kidney transplant to treat end-stage renal failure. After the renal allograft was extracted, the exanthema diminished rapidly without any treatment. Donor-reactive immune cells seem to have cross-reacted with unknown pathogens on the skin and contributed to inflammation.     

Rituximab therapy for acute humoral rejection after kidney transplantation

A pilot study was performed on eight consecutive renal-transplant (RT) patients presenting with acute humoral rejection (AHR) to assess the efficacy of monoclonal anti-B cell antibodies, such as rituximab (375 mg/m weekly) for 3 to 5 consecutive weeks, in addition to plasma exchange (PE), steroids, mycophenolate mofetil, and tacrolimus. AHR was associated with increased serum creatinine, the appearance of donor-specific alloantibodies (DSA), and the presence of C4d in a transplant biopsy. After a follow-up of 10 months (range 7-23), patient and graft survivals were 100% and 75%, respectively. Renal function improved in six cases in which serum creatinine decreased from 297+/-140 to 156+/-53 micromol/L (P=0.015); graft loss occurred in two cases; and four patients had infectious complications. At last follow-up, DSA had disappeared or decreased in four cases. Rituximab therapy, in addition to PE, might be of benefit for RT patients presenting with AHR.     

超声造影技术在肾移植术后急性排斥反应中的应用进展

急性排斥反应的早期诊断对于移植肾功能保护具有重要意义。病理穿刺活组织检查是诊断移植肾急性排斥反应的金标准,但随之可能出现的出血、感染、肾实质损伤等并发症限制了其应用。近年来,超声造影技术诊断急性排斥反应的灵敏度不断提升,其中靶向超声微泡技术更是进一步提升了超声造影技术诊断的特异度,使其替代病理穿刺活组织检查成为可能。此外,在急性排斥反应治疗领域,空化的超声微泡可以通过诱发声孔效应,促进免疫抑制药局部传递而发挥其抗排斥反应作用。本文对超声造影技术在肾移植术后急性排斥反应的诊断及治疗中的应用进行总结,为超声造影技术在肾移植中进一步应用提供参考。     

The impact of late acute rejection after cadaveric kidney transplantation

BACKGROUND: Acute graft rejection (AR) following renal transplantation results in reduced graft survival. However, there is uncertainty regarding the definition, aetiology and long-term graft and patient outcome of AR occurring late in the post-transplant period. AIM: To determine if rejection episodes can be classified by time from transplantation by their impact on graft survival into early acute rejection (EAR) and late acute rejection (LAR). MATERIALS AND METHODS: 687 consecutive adult renal transplant recipients who received their first cadaveric renal transplant at a single centre. All received cyclosporine (CyA)-based immunosuppression, from 1984 to 1996, with a median follow-up of 6.9 yr. Details were abstracted from clinical records, with emphasis on age, sex, co-morbid conditions, HLA matching, rejection episodes, patient and graft survival. ANALYSIS: Patients were classified by the presence and time to AR from the date of transplantation. Using those patients who had no AR (NAR) as a baseline, we determined the relative risk of graft failure by time to rejection. The characteristics of patients who had no rejection, EAR and LAR were compared. RESULTS: Compared with NAR, the risk of graft failure was higher for those patients who suffered a rejection episode. A much higher risk of graft failure was seen when the first rejection episode occurred after 90 d. Thus, a period of 90 d was taken to separate EAR and LAR (relative risk of 3.06 and 5.27 compared with NAR as baseline, p<0.001). Seventy-eight patients (11.4%) had LAR, 271 (39.4%) had EAR and 338 (49.2%) had NAR. The mean age for each of these groups differed (LAR 39.6 yr, EAR 40.8 yr compared with NAR 44 yr, p<0.003). The 5-yr graft survival for those who had LAR was 45% and 10-yr survival was 28%. HLA mismatches were more frequent in those with EAR vs. NAR (zero mismatches in HLA-A: 36 vs. 24%, HLA-B: 35 vs. 23% and HLA-DR: 63 vs. 41%, p<0.003). There was no difference in mismatching frequency between NAR and LAR. CONCLUSIONS: AR had a deleterious impact on graft survival, particularly if occurring after 90 d. AR episodes should therefore be divided into early and late phases. In view of the very poor graft survival associated with LAR, it is important to gain further insight into the main aetiological factors. Those such as suboptimal CyA blood levels and non-compliance with medication should be further investigated with the aim of developing more effective immunosuppressive regimens in order to reduce the incidence of LAR.     

The significance of a single episode of minimal acute rejection after lung transplantation

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) remains the leading obstacle to better long-term outcomes after lung transplantation. Acute rejection has been identified as the primary risk factor for BOS, but the impact of minimal acute rejection, especially a solitary episode, has usually been discounted as clinically insignificant. METHODS: We performed a retrospective cohort study of 259 adult lung transplant recipients to determine the risk of BOS associated with a single episode of A1 rejection, without recurrence or subsequent progression to a higher grade. The cohort was divided into 3 groups based on the severity of acute rejection (none, single episode of A1, and single episode of A2). We determined the risks of BOS stages 1, 2, 3, and death for each group using univariate and multivariate Cox regression analyses. RESULTS: A solitary episode of A1 rejection was a significant risk factor for BOS stages 1 and 2, but not stage 3 or death, in the univariate analysis. Multivariate Cox regression models confirmed that the risk of BOS attributable to a single episode of A1 rejection was independent of other potential risk factors, such as community acquired respiratory viral infections, number of HLA mismatches, and cytomegalovirus pneumonitis. Likewise, univariate and multivariate analyses demonstrated that a single episode of A2 rejection was a significant risk factor for all stages of BOS but not death. CONCLUSIONS: A single episode of minimal acute rejection without recurrence or subsequent progression to a higher grade is a significant predictor of BOS independent of other risk factors.     

Histopathological diagnosis of acute and chronic rejection in pediatric kidney transplantation

ABO-compatible as well as ABO-incompatible kidney transplantation are well established in the pediatric population. There are particularities in the histopathological evaluation of pediatric kidney transplant biopsies as for example the recurrence of certain diseases different from the adult population. Furthermore, the challenging transition of pediatric renal transplant recipients to adulthood is associated with an increased rate of non-adherence triggered rejection episodes. With modern immunosuppressive drugs, T-cell-mediated rejection of renal allografts is well controlled. In contrast, antibody-mediated rejection (AMR) is increasingly recognized as one of the major reasons for allograft loss. However, the 2001 diagnostic Banff criteria for antibody-mediated rejection require further refinement, as the morphological spectrum of AMR expands while effective therapeutic strategies are lacking. For example, endarteritis, which traditionally has been attributed to T-cell-mediated rejection, has recently been shown to be part of the AMR spectrum in some cases. Many findings in transplant renal biopsies are not specific for a certain disease but need consideration of differential diagnoses. To use the term “chronic allograft nephropathy” as a diagnostic entity is no longer appropriate. Therefore, the precise identification of specific diseases is paramount in the assessment of transplant renal biopsies in order to enable tailored therapeutic management.     

Association of four DNA polymorphisms with acute rejection after kidney transplantation

Renal transplant outcomes exhibit large inter-individual variability, possibly on account of genetic variation in immune-response mediators and genes influencing the pharmacodynamics/pharmacokinetics of immunosuppressants. We examined 21 polymorphisms from 10 genes in 237 de novo renal transplant recipients participating in an open-label, multicenter study [Cyclosporine Avoidance Eliminates Serious Adverse Renal-toxicity (CAESAR)] investigating renal function and biopsy-proven acute rejection (BPAR) with different cyclosporine A regimens and mycophenolate mofetil. Genes were selected for their immune response and pharmacodynamic/pharmacokinetic relevance and were tested for association with BPAR. Four polymorphisms were significantly associated with BPAR. The ABCB1 2677T allele tripled the odds of developing BPAR (OR: 3.16, 95% CI [1.50–6.67]; P  =   0.003), as did the presence of at least one IMPDH2 3757C allele (OR: 3.39, 95% CI [1.42–8.09]; P  =   0.006). BPAR was almost fivefold more likely in patients homozygous for IL-10 -592A (OR: 4.71, 95% CI [1.52–14.55]; P  =   0.007) and twice as likely in patients with at least one A allele of TNF-α G-308A (OR: 2.18, 95% CI [1.08–4.41]; P  =   0.029). There were no statistically significant interactions between polymorphisms, or the different treatment regimens. Variation in genes of immune response and pharmacodynamic/pharmacokinetic relevance may be important in understanding acute rejection after renal transplant.     

A case of acute vascular rejection after overseas deceased kidney transplantation

Abstract:  A 54-yr-old Japanese male received overseas deceased kidney transplantation in January 2006. His allograft functioned immediately and he received immunosuppression with cyclosporine A (CyA), mycophenolate mofetil (MMF), and prednisone (PR). On day 24 after transplantation, he came back to Japan. His serum creatinine level (s-Cr) was 1.39 mg/dL at two months after transplantation when he was admitted into Toda Central General Hospital on March 2006, for follow-up his renal allograft. He had taken only two immunosuppressive drugs, MMF and PR, and had not taken CyA at that time. His serum creatinine gradually rose after hospitalization. Allograft biopsy performed on April 6, 2006, showed acute vascular rejection (Banff 97 acute/active cellular rejection Grade III), together with suspicious for acute humoral rejection (Banff 97 antibody-mediated rejection Grade II). After treatment of two courses of steroid pulses and five d of gusperimus, acute vascular rejection and acute humoral rejection were relieved, which had been proven by the third allograft biopsy. In conclusion, this was a case of acute vascular rejection after overseas deceased kidney transplantation, resulted from non-compliance with immunosuppressive therapy.     

DNA fragmentation in acute and chronic rejection after renal transplantation

Acute and chronic rejections are important denominators for the long-term function of renal grafts. One important indicator of cell damage is enzymatic DNA fragmentation. To investigate possible mechanisms, the rate of DNA fragmentation (TUNEL staining), the expression of tissue transglutaminase II (a marker of advanced DNA damage), and 8-hydroxy-2'-deoxyguanosine (8-OhdG), an indicator of oxidative injury of nucleic acids, were studied by immunohistochemistry. Semithin sections of renal biopsies revealed 23 patients to show acute interstitial rejections (Banff 97 IA, IB); eight patients, acute vascular rejection (Banff 97 IIA, IIB); and 20 patients, chronic allograft nephropathy (Banff 97 I to III). Correlations were calculated between apoptotic cells and serum creatinine at the time of biopsy and after 6 months. In acute rejection, the proximal tubular cells were apoptotic, particularly in regions with mononuclear infiltrates. In consecutive sections, these apoptotic tubular cells also showed damage by reactive oxygen species (positive 8-OhdG staining). Patients with acute interstitial rejection revealed the highest number of tubular DNA fragmentation (14.9 +/- 10.3) versus chronic allograft nephropathy (9.2 +/- 5.6) as TUNEL-positive cells per 80,000 micro m(2) (P < .05). Patients with acute vascular rejection showed a low degree of tubular apoptosis (6.8 +/- 5.1). There was no significant difference in glomerular DNA fragmentation between acute interstitial and chronic rejections: acute interstitial rejection = 7.1 +/- 5.9 versus chronic allograft nephropathy=6.1 +/- 3.9 TUNEL-positive cells per 80,000 micro m(2). There was a significant negative correlation between the degree of tubular (P < .01) and glomerular (P < .05) apoptosis and the serum creatinine at the time of biopsy as well as after 6 months in all patients irrespective of the Banff class. However, there was heterogeneity in the correlation between renal function and the degree of apoptosis in the glomerular and tubular compartments in the various Banff classes. A positive correlation (P < .01) was observed between the degree of tubular apoptosis and serum creatinine at 6 months after biopsy among patients with acute vascular rejection (Banff 97 IIA, IIB). The present data revealed a high degree of tubular DNA fragmentation associated with oxidative stress in acute interstitial rejection. Nevertheless, apoptosis did not generally negatively influence future renal function and may be important to clear proliferating cells. Apoptosis may also play a different pathophysiological role depending on the type of rejection.     

肾移植术后中远期急性排斥反应临床研究

目的探讨肾移植术后中远期移植肾急性排斥反应(AR)发生影响因素及移植肾生存情况。 方法回顾性分析浙江大学医学院附属第一医院肾脏病中心2018年1月至2019年12月因血清肌酐水平升高而接受移植肾病理活检并确诊移植肾AR受者临床资料,共纳入43例受者,其中急性抗体排斥反应组17例,急性T细胞排斥反应组26例;同时纳入同期(2周内)肾移植且移植肾功能正常的39例受者为对照组。正态分布计量资料比较采用配对t检验或单因素方差分析。计数资料比较采用χ²检验或Fisher确切概率法。采用Kaplan-Meier进行生存分析,并采用log-rank进行比较。P<0.05为差异有统计学意义。 结果急性抗体排斥反应组HLA-A错配2个比例(4/17)高于对照组(1/39),差异有统计学意义(P＝0.026)。急性抗体排斥反应组和急性T细胞排斥反应组AR发生时和末次血清肌酐和估算肾小球滤过率(eGFR)均高于AR发生前(P均<0.05);急性抗体排斥反应组和急性T细胞排斥反应组AR发生时和末次血清肌酐和eGFR均高于对照组(P均<0.05);急性抗体排斥反应组进入慢性肾脏病(CKD)-4期受者比例低于急性T细胞排斥反应组(χ²＝5.73,P<0.05);急性T细胞排斥反应组进入CKD-4期受者比例以及急性抗体排斥反应组移植肾失功比例均高于对照组(χ²＝17.727和9.882,P均<0.05)。AR发生时急性抗体排斥反应组和急性T细胞排斥反应组受者均接受PRA检测,前者PRA-Ⅰ和PRA-Ⅱ阳性比例分别为41.2%(7/17)和88.2%(15/17),均高于后者[11.5%(3/26)和26.9%(7/26)],差异均有统计学意义(P＝0.042,P<0.001)。急性抗体排斥反应组、急性T细胞排斥反应组及对照组术后分别有13、24和38例受者应用他克莫司。发生AR时,急性抗体排斥反应组他克莫司血药浓度[(3.72±0.76)ng/mL]与急性T细胞排斥反应组[(3.37±0.86)ng/mL]均低于对照组[(5.73±1.25)ng/mL],差异均有统计学意义(P均<0.05);急性抗体排斥反应组与急性T细胞排斥反应组他克莫司血药浓度均低于发生AR前[(6.27±1.18)和(6.33±1.63)ng/mL],差异均有统计学意义(t＝7.120和6.216,P均<0.05)。急性抗体排斥反应组4例受者应用以环孢素为基础的免疫抑制方案,其中3例术后33、36和55个月环孢素血浓度分别为112.4、138.3和7.0 ng/mL,均低于要求血药浓度。急性T细胞排斥反应组2例应用环孢素受者术后16和177个月环孢素血药浓度分别为43.2和24.6 ng/mL,均低于要求血药浓度。随访至2021年6月30日,急性抗体排斥反应组移植肾生存率低于对照组(χ²＝8.738,P<0.05)。 结论HLA-A位点错配及他克莫司低血药浓度是肾移植术后中远期诱发AR的重要原因。急性抗体介导排斥反应是移植肾生存重要影响因素。     

血浆置换治疗肾移植术后抗体介导的急性排斥反应的疗效观察

目的 探讨血浆置换治疗肾移植术后抗体介导的急性排斥反应的效果. 方法 2011年1月至2013年9月行同种异体肾移植术后发生抗体介导的急性排斥反应患者5例,男2例,女3例.年龄41252岁,平均46岁.术前诊断均为慢性肾功能不全尿毒症期,行规律血液透析.术后采用环孢素[5 mg/(kg·d)]或他克莫司[0.1 mg/(kg·d)],以及吗替麦考酚酯(1.5 g/d)和糖皮质激素行免疫抑制治疗.术后2周内均经移植肾穿刺病理检查及血清供者特异性抗体测定诊断为抗体介导的急性排斥反应.予甲泼尼龙(1 000 mg/d)和抗淋巴细胞球蛋白(250 mg/d)治疗无效,在环孢素[5 mg/(kg·d)]或他克莫司[0.1 mg/(kg·d)],以及吗替麦考酚酯(1.5 g/d)和糖皮质激素免疫抑制治疗的基础上,5例患者均分别行血浆置换7次.4例原发病为慢性肾小球肾炎,术前血清肌酐为(784±154) μmol/L,术后2周内开始进行血浆置换;1例原发病为抗肾小球基底膜肾病,术前血清肌酐水平为935 μmol/L,术后35 d开始进行血浆置换. 结果 4例原发病为慢性肾小球肾炎患者分别经7次血浆置换治疗后排斥反应得到逆转,肾功能恢复良好,随访3个月时血清肌酐水平为(113±12) μmol/L.原发病为抗肾小球基底膜肾病患者,血浆置换后排斥反应未得到纠正,移植肾功能未恢复,随访3个月时血清肌酐水平524 μmol/L,继续血液透析治疗,随访12个月时血清肌酐水平758 μmol/L,超声检查示移植肾萎缩,予口服他克莫司0.5mg/d治疗. 结论 2周内应用血浆置换能有效地逆转肾移植术后患者抗体介导的急性排斥反应.     

A case of acute rejection with adenovirus infection after ABO-incompatible kidney transplantation

Abstract:  We report clinical and histopathologic findings of a case of acute rejection with adenovirus infection after kidney transplantation. A 63-yr-old woman with end-stage renal disease caused by lupus nephritis received an ABO-incompatible living kidney transplantation from her husband. On the 7th post-operative day (POD), she had fever, hematuria, and bladder irritation. Although she was treated with an antibiotic, the symptoms were not improved. We diagnosed adenovirus infection as positive with the urine shell vial method and blood PCR analysis. Cyclophosphamide was interrupted and immunoglobulin therapy was performed. However, urine output decreased and serum creatinine levels increased. An episode biopsy was performed on POD 20. We diagnosed acute antibody-mediated rejection. She was treated with plasma exchange for acute rejection and antiviral drug (rivabirin) for active adenovirus infection. However, the renal graft dysfunction was deemed irreversible and the renal graft was removed on POD 34. The graftectomy specimen showed acute rejection and acute tubular necrosis with adenovirus infection.