Prospective, Pilot, Open-Label, Short-Term Study of Conversion to Leflunomide Reverses Chronic Renal Allograft Dysfunction

Leflunomide (LEF) is a synthetic isoxazole derivative with anti-inflammatory and antiviral properties, which has been reported to prevent acute rejection and delay progression of chronic allograft nephropathy (CAN) in animal models. We performed a pilot, crossover trial in 22 renal transplant recipients who were converted from azathioprine (AZA) or mycophenolate mofetil (MMF) to LEF in an effort to slow progression of renal dysfunction [deteriorating renal function (n = 5), cyclosporine (CyA) nephrotoxicity (n = 4) or biopsy-proven CAN (n = 13)]. Baseline maintenance immunosuppression consisted of CyA, AZA or MMF and prednisone. Six-month postconversion patient and graft survival was 100% and 91%, respectively. Mean serum creatinine 6months preconversion was 2.2 +/- 0.6mg/dL, at initiation was 3.0 +/- 1.1 mg/dL, and 6 months postconversion was 2.8 +/- 1.3 mg/dL. The rate of change in serum creatinine was 35 +/- 39%/6 months preconversion and -5 +/- 21%/6 months postconversion to LEF (p = 0.003). Two patients discontinued LEF for diarrhea and myalgia. No readmissions, increase in liver function tests, infections or acute rejection episodes occurred. Mean CyA levels did not change, 146 +/- 72 ng/ mL pre-LEF vs. 132 +/- 51 ng/mL post-LEF, p = NS. Conversion to LEF reversed progression of chronic renal allograft dysfunction with minimal toxicity.     

Interstitial expression of alpha-SMA: an early marker of chronic renal allograft dysfunction.

BACKGROUND: Renal myofibroblast infiltration has been shown to be strongly associated with renal function decline in several chronic renal diseases. The purpose of the present study was to investigate whether early detection of myofibroblast infiltration using alpha-smooth-muscle actin (alpha-SMA) expression in time-zero biopsies predicts renal allograft dysfunction. METHODS: We studied renal tissue from 38 renal transplant patients from whom biopsies had been taken after vascular anastomosis during transplantation to ascertain whether myofibroblasts infiltration predicts renal graft survival. Immunohistochemistry was performed on time-zero biopsies to determine alpha-SMA expression, and this was compared to annual glomerular filtration rate (GFR) variation and other parameters including cold ischaemic time (CIT), donor and recipient age, number of acute rejections, and delayed graft function (DGF). GFR was measured by inulin clearance during of 3 years of follow-up after the transplantation. Progressors were defined as patients with an annual GFR decline >5 ml/min/year. RESULTS: We found a significant correlation between interstitial alpha-SMA expression in time-zero biopsies and GFR evolution during the post-transplantation course (r=0.60, P<0.001). Although progressors had greater interstitial alpha-SMA expression than non progressors (7.9+/-0.7 vs 4.3+/-0.4%), they showed only a tendency towards higher glomerular alpha-SMA expression. In addition, progressors had more interstitial fibrosis in time-zero biopsies than non-progressors. There was no relationship between alpha-SMA expression and CIT, donor and recipient ages, number of acute rejections, and occurrence of DGF. CONCLUSION: This study suggests that alpha-SMA evaluation in time-zero biopsies, especially the combination of alpha-SMA expression and interstitial fibrosis, can strongly predict chronic renal allograft dysfunctions.     

新生小鼠睾丸组织和作为异种移植物的人类胎儿睾丸组织在免疫缺陷小鼠中的发育情况(英文)

目的:采用同种和异种睾丸组织移植的方法,研究新生小鼠睾丸组织及人类未成熟睾丸组织异种移植物在免疫缺陷小鼠体内发育不同时期生精细胞的组成和基因表达情况中生精细胞的发育情况。方法:以免疫缺陷小鼠为受体,新生小鼠睾丸组织和人类未成熟睾丸组织为供体,分别进行同种和异种移植。通过对移植物的组织形态学观察和分子生物学检测,对各个时期同种移植物中的生精细胞组成及其特异性基因的表达情况进行评估并与末受损小鼠的情况相比较;对人睾丸组织异种移植物的存活及其生精细胞在异体异位的发育情况进行探讨。结果:新生小鼠睾丸组织在成年雄性去势免疫缺陷小鼠体内的发育状况在移植开始的一个阶段与在体睾丸组织的发育情况基本相同,各级生精细胞的出现及其基因表达均与在体睾丸组织中相类似,而移植7-8星期后生精小管发生退化现象。人未成熟睾丸组织在受体中存活并且进一步生长;组织学观察还发现,生精细胞的发育速度与在体相比具有加速的倾向。结论:新生小鼠睾丸组织同种移植物的发育与在体情况基本相同,而人类未成熟睾丸组织异种移植物的发育与正常生理状态相比较呈现出加速的倾向。     

Reconstruction of Disrupted Extensor Mechanism After Total Knee Arthroplasty

Background

Disruption of the extensor mechanism after total knee arthroplasty (TKA) is a debilitating complication that results in extension lag, limited range of motion, difficulty in walking, frequent falls, and chronic pain. This study presents the clinical and radiographic results of reconstruction after extensor mechanism disruption in TKA patients.

Workshop on Late Renal Allograft Dysfunction

Despite continued improvement in incidence of acute immune injury and short-term graft survival, late allograft dysfunction remains a significant problem in the renal transplant population. Recent reports suggest that rates of renal function decline are quite varied in the overall recipient population, and that individual rates for many recipients may not change substantially over time. Moreover, analyses also reveal distinct predictive factors for both early and late functional decline. Long-term outcome studies for renal transplantation, however, might be significantly limited by incomplete data sets for assessing clinical endpoints. In view of the heterogeneous factors that may cause progressive allograft injury, more routine biopsy sampling would allow a more complete characterization of induced injuries. Elucidating mechanisms of renal fibrosis in response to injury, in experimental systems and humans, is also an important goal in better understanding chronic allograft damage. Regulation of cell senescence genes and epithelial to mesenchymal transition, studied in other models of renal fibrosis, are likely relevant to studies of renal allograft dysfunction. Recent technical advances in analyzing biological samples may play a pivotal role in identifying and validating surrogate markers of allograft function for future interventional trials in transplantation.     

Ultrastructural analysis of the Fisher to Lewis rat model of chronic allograft nephropathy

Chronic allograft nephropathy (CAN) is the leading cause of graft loss following kidney transplantation. One factor contributing to CAN is chronic alloimmune injury. However, the involvement of alloantigen-dependent and -independent factors in CAN is unclear. The pathomechanism of CAN has been extensively studied by utilizing the Fischer-to-Lewis (F344-to-LEW) rat model. Transplant capillaropathy (circumferential multiplication of the peritubular capillary basement membrane) and transplant glomerulopathy (reduplication of the glomerular basement membrane) have recently been validated clinicopathologically as ultrastructural indicators of chronic alloimmune injury. To investigate the presence of these markers, F344-to-LEW kidneys were examined by electron and light microscopy 32, 40 and 52 weeks after implantation. F344 rats with or without 30-min ischemia of the left kidney following right nephrectomy served as controls. All transplanted rats displayed marked proteinuria. On electron microscopy, transplant capillaropathy, transplant glomerulopathy, and T-cell cytotoxicity (indicator of ongoing cellular rejection) were absent. On light microscopy, the arteries were devoid of intimal fibrosis. Focal-segmental glomerulopathy resembling hyperfiltration injury was encountered, with mild interstitial infiltration, fibrosis, and tubular atrophy. The proteinuria and kidney pathology were more severe in transplanted than in ischemic or uninephrectomized rats. Because chronic-active rejection could not be detected between weeks 32 and 52, we propose that the alloantigen-dependent initial graft injury subsides, but induces the late events: glomerular hyperfiltration, proteinuria, and glomerulosclerosis. Accordingly, the model - in the late phase - is suitable to investigate alloantigen-independent factors of CAN and lacks markers of alloantigen-dependent processes.     

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.     

Vascular Endothelial Growth Factor Expression and Cyclosporine Toxicity in Renal Allograft Rejection

The aim of this study was to evaluate the influence of vascular endothelial growth factor (VEGF) on renal function and on development of interstitial fibrosis (IF) in renal allografts. Tubular and interstitial expressions of VEGF and TNF-α, and density of macrophages in the interstitium were examined in 92 patients with nonrejected kidneys, acute rejection (AR), chronic allograft nephropathy (CAN), borderline changes (BC) and acute cyclosporin A (CsA) toxicity. Follow-up biopsy specimens from patients with AR and BC were evaluated for development of IF. A significant difference in tubular and interstitial VEGF expressions was found between patients with AR, BC, CAN and CsA toxicity (p < 0.001). Macrophage infiltration was positively correlated with VEGF and TNF-α expressions (p < 0.001). VEGF expression increased with increasing expression of TNF-α (p < 0.001). Renal function in first 6 months after initial biopsy was better in patients with marked tubular VEGF expression (p < 0.01); however, in follow-up, development of IF and graft loss was found earlier in these patients (p < 0.01 and p < 0.05, respectively). Increased renal VEGF expression has protective properties immediately following renal allograft but allows for increased risk of early IF, and therefore poor graft outcome in the long term.     

综合骨库在现代矫形外科中的作用

[目的]介绍并分享综合骨库建立20年来的成功经验;探讨骨库在现代矫形外科中的地位和作用.[方法]提供并总结分析综合骨库自1988～2007年间有关同种异体骨,系列异种骨生产、使用的数据.[结果]同种骨:得到死亡供体69具,存活供体88例;收获半关节540件,骨板237件,松质骨粒2 632份;以上同种骨共使用于1 390例病人;系列异种骨:重组合异种骨2 495份,抗感染重组合异种骨208份,注射型BMP 542份,系列异种骨共使用于2 771例病人;20年来,共培训骨库技术人员18名,培养博士48名,硕士36名.[结论]临床植骨材料需求量大,在细胞型组织工程尚无满意的产品问世前,综合骨库所提供的异种骨和同种骨根据不同的植骨需要,取长补短,相互补充,使之成为最理想的选择.综合骨库这种集加工生产,科研开发及教学培训于一体的运行模式必将在中国的组织库事业中发挥愈加重要的作用.     

Outcome of Subclinical Antibody-Mediated Rejection in Kidney Transplant Recipients with Preformed Donor-Specific Antibodies

This study describes clinical relevance of subclinical antibody-mediated rejection (SAMR) in a cohort of 54 DSA-positive kidney transplant recipients receiving a deceased donor. In 3 months screening biopsies, 31.1% of patients met the criteria of SAMR. A total of 48.9% had an incomplete form of SAMR (g+/ptc+/C4d-negative) whereas 20% had no humoral lesions. Patients with SAMR at 3 months had at 1 year: a higher C4d score, ptc score, and arteriosclerosis score, higher rate of IFTA (100% vs. 33.3%, p < 0.01) and a higher rate of transplant glomerulopathy (43% vs. 0%, p = 0.02) compared to patients without 3-month SAMR. Patients with SAMR at 3 months exhibited at 1 year a higher class II MFImax-DSA and a lower mGFR compared to patients without SAMR (39.2 ± 13.9 vs. 61.9 ± 19.2 mL/min/1.73 m² respectively, p < 0.01). The group of patients with C4d-negative SAMR at 3 months developed more ptc and IFTA lesions, and lower GFR at 1 year in comparison to biopsies without humoral lesions. SAMR is a frequent entity in KTR with preexisting DSAs and promotes subsequent GFR impairment and development of chronic AMR. C4d-negative SAMR patients displayed an intermediate course between the no-SAMR group and the C4d+ SAMR group. Screening biopsies may be useful to recognize patients more likely to develop SAMR.