Infection-associated cellular activation accelerates chronic renal allograft rejection in rats

The etiology of chronic rejection is unknown, although acute rejection, viral infection, and initial graft ischemia have been implicated. To test the effects of infections on the process of chronic rejection, we simulated bacterial infection by the administration of the endotoxin lipopolysaccharide (LPS), a potent activator of various cell types in an established rat model of chronic rejection. Lewis recipients of Fisher 344 kidneys were treated with a single dose of LPS or vehicle 8 weeks following transplantation and grafts were examined at various time points. In the chronically rejecting controls leukocytic infiltration and the expression of cytokines peaked at 16 weeks. In LPS-treated hosts, leukocyte infiltration and cytokine expression peaked at 12 weeks. By 16 weeks, glomeruli in LPS-treated recipients had become far more sclerotic than those in controls, mimicking the changes observed in controls at 24 weeks. We conclude that infections may play an important role in the development of chronic rejection.     

The influence of primary non-function on the accuracy of ultrasound measurements in the diagnosis of renal allograft rejection

Daily ultrasonographic measurements of transplant cross-sectional area were used to quantify allograft swelling as a diagnostic test for acute rejection in a series of 120 renal transplants. Initial graft function (IF) occurred in 86 patients (72%) and primary non-function (PNF) occurred in the remaining 34 (28%). An increase in allograft cross-sectional area greater than or equal to 10% was defined as a positive ultrasound scan suggesting an acute rejection episode and was investigated by needle core biopsy. During periods of PNF, allografts with consistently negative ultrasound scans were submitted to needle core biopsy on a weekly basis. The diagnosis of rejection was based exclusively on the histological findings. In the IF group, agreement between ultrasound and histological diagnosis was good (k=0.63, sensitivity 81%, specificity 83%, positive predictive value 76%, negative predictive value 86% and overall accuracy 82%). In the PNF group, agreement between ultrasound and histology was only fair (k=0.46, sensitivity 77%, specificity 70%, positive predictive value 69%, negative predictive value 78% and overall accuracy 73%). It it concluded that a degree of allograft swelling is sometimes associated with acute tubular necrosis, and this makes ultrasound measurements of transplant size a less useful technique of monitoring kidneys with PNF.     

Serum HGF levels in acute renal rejection after living related renal transplantation

Hepatocyte growth factor (HGF), a long sought-after hepatotrophic factor, has recently been shown to act as a renotrophic factor in regeneration of the kidney. We investigated serum HGF levels in 16 renal transplant patients. In patients with acute rejection, the serum HGF level was markedly increased (over 1 ng/ml), and its elevation was accompanied by an increase in serum creatinine and blood urea nitrogen (BUN). In contrast, serum HGF levels were continuously low in patients without rejection. We conclude that serum HGF may become a clinically useful marker for the assessment of acute renal rejection.     

移植肾排异反应中肾小管上皮细胞的表型转化

目的 观察人移植肾肾穿刺标本不同排异反应病变中肾小管上皮细胞表型转化状态,探讨排异反应与肾小管上皮细胞表型转化的相关性。 方法 免疫组织化学SP法检测55例移植肾穿刺不同病变组中肾小管上皮细胞α平滑肌肌动蛋白（α-SMA）的表达。 结果 各组萎缩病变的肾小管上皮细胞均有α-SMA阳性表达,表现为近基底膜处胞质阳性染色,提示出现了表型转化。在无萎缩病变的肾小管中,仍有部分肾小管细胞呈α-SMA阳性染色。7例基本正常病例组均无肾小管上皮细胞的表型转化。28例急性T细胞介导排异 IA级病例组中,1例肾小管上皮细胞α-SMA阳性表达率为25%~50%,3例为10%~25%。14例排异反应IB 级中,1例α-SMA阳性表达率达50%以上,2例25%~50%,2例10%~25%。 结论 随着急性T细胞介导性排异反应加重,肾小管上皮细胞发生表型转化的现象明显增强。     

Magnetic resonance imaging for the evaluation of rejection of a kindney allograft in the rat

Orthotopic DA (RT1^a) into Lewis (RT1¹) rat kidney allografts and control Lewis-into-Lewis grafts were assessed by magnetic resonance imaging (MRI) and perfusion measurement after intravenous injection of a superparamagnetic contrast agent. MRI anatomical scores (range 1–6) and perfusion rates were compared with graft histology (rank of rejection score 1–6). Not only acute rejection, but also chronic events were monitored after acute rejection was prevented by daily cyclosporine (Sandimmune) treatment during the first 2 weeks after transplantation. In acute allograft rejection (n=11), MRI scores reached the maximum value of 6 and perfusion rates were severely reduced within 5 days after transplantation; histology showed severe acute rejection (histologic score 5–6). In the chronic phase (100–130 days after transplantation), allografts (n=5) manifested rejection (in histology cellular rejection and vessel changes), accompanied by MRI scores of around 2–3 and reduced perfusion rates. Both in the acute and chronic phases, the MRI anatomical score correlated significantly with the histological score (Spearman rank correlation coefficient r _s 0.89, n=30, P<0.01), and perfusion rates correlated significantly with the MRI score or histological score (r _s values between-0.60 and -0.87, n=23, P<0.01). It is concluded that MRI represents an interesting tool for assessing the anatomical and hemodynamical status of a kidney allograft in the acute and chronic phases after transplantation.     

T-cell receptors and ICAM-1 expression in renal allografts during rejection

Sixty-two biopsies taken from 38 kidney grafts were studied for 15 histological and 10 immunohistological parameters. The biopsies were divided into three groups, according to the clinical diagnosis at the time they were performed: group 1, rejection (n=43); group 2, other causes of dysfunction (n=10); and group 3, stable function (n=9). Histological signs of acute rejection included diffuse interstitial infiltrate, tubular basement membrane damage, mononuclear leukocyte infiltration, and congestion of the peritubular capillaries. Immunoperoxidase staining with monoclonal antibodies to ten markers showed a statistically significant association between detection of T-cell receptor subunits alpha-beta (TcR2) and gamma-delta (TcR1) on infiltrating lymphocytes and of intercellular adhesion molecule-1 (ICAM-1) in tubular cells and acute rejection. These results suggest that T-cell receptors and ICAM-1 may be useful markers to differentiate acute rejection from renal graft dysfunctions due to other abnormalities.     

Late ureteral obstruction after kidney transplantation

Today, the incidence of urological complications following renal transplantation is 2%–10%. Most of these complications occur within the 1st year and affect the distal ureter. We report on two patients who developed very late ureteral obstruction, 14 and 18 years after transplantation. Both patients had rejection episodes 1 and 10 months prior to the ureteral stenosis. Histological examination of one resected ureter revealed findings strongly suggestive of a rejection process. Open surgery with antirefluxive reimplantation into the bladder was successful in both patients, with a postoperative observation time of 20 and 8 months, respectively. We conclude that a percutaneous nephrostomy may be required in patients with rising creatinine and incipient hydronephrosis even long after transplantation has been performed.     

Chronic rejection of rat renal allograft

Chronic allograft rejection is both a clinical and a histopathological diagnosis. Until recently, the histological definition of chronic renal allograft rejection was based on clinical diagnostic biopsies, where the evidence was partially obscured by recurrence of the original renal disease, and/or by administration of immunosuppressive drugs. In this communication, we present an experimental rat model for chronic renal allograft rejection, devoid of recurrence of the original disease. By comparing allografts to similarly immunosuppressed syngeneic transplants, we define which histological features should be attributed to chronic rejection and which to cyclosporin nephrotoxicity. Rat renal transplants were performed from DA (Ag-B4, RT1^av1) to WF strain (Ag-B2, RT1^u) or, for control, to DA strain, and immunosuppressed for 2 or 3 weeks with cyclosporin using a variety of different dosages. The animals were monitored weekly for serum creatinine levels and for blood cyclosporin concentrations, and core needle biopsies were performed on the grafts at regular intervals. At 3 months post-transplantation the animals were sacrificed and a complete histopathological evaluation was performed. Thirty-one histological variables were scored blindly by two investigators and separately for the graft interstitium, glomeruli, tubuli, and the graft vasculature. The following histological alterations were significantly more prominent in allografts than in similarly immunosuppressed syngeneic transplants: the intensity of interstitial inflammation, particularly the degree of pyroninophilia within the inflammatory cell population; the extent of glomerular mesangial matrix increase, basement membrane thickening, and glomerular sclerosis; the increase in the vascular intimal thickness affecting in particular the first and second order branches of the renal artery; and the obliteration of the graft vasculature. These alterations were considered as being primarily due to chronic rejection. In contrast, the extent of interstitial fibrosis and the extent of tubular changes, including tubular epithelial vacuolation, epithelial atrophy, and tubular basement membrane changes, were not significantly different in the allografts as compared to the syngeneic controls. These alterations were attributed primarily to cyclosporin nephrotoxicity. Serial monitoring of the grafts by needle biopsies clarified the sequence of events in the development of the chronic alterations in the transplant. The first event, as expected, was tubulointerstitial pyroninophilic inflammation, resembling that of acute episodes of rejection. This was significantly stronger and appeared earlier in allografts immunosuppressed for 2 rather than for 3 weeks. Vascular alterations developed next. The last to develop were the glomerular lesions.     

Renal allograft rejection: the temporal relationship and predictive value of plasma TNF (alpha and beta), IFN-gamma and soluble ICAM-1

Recently, close interactions have been described between the tumour necrosis factors alpha and beta (TNF-alpha and beta), interferon-gamma (INF-gamma) and intercellular adhesion molecule-1 (ICAM-1) in T-cell mediated immune activation. During the process of renal graft rejection, the properties of these cytokines to act as powerful stimulators of macrophages, to upregulate class II MHC expression and to stabilise cell-to-cell binding make them of great potential interest. The aim of the present study was to determine the plasma levels of each cytokine and soluble ICAM-1 in 16 renal allograft recipients. We examined plasmas of patients for the first 2 weeks after transplantation and correlated results with the clinical pattern of rejection. Our data suggest an immunopathologic involvement of TNF-alpha, TNF-beta and slCAM-1 in renal allograft rejection and showed that there was a significant elevation in plasma concentrations of these parameters 2 or 3 days prior to the diagnosis of clinical rejection. Rises in INF-gamma did not appear to be significant with regard to rejection as very high levels were found in patients showing no evidence of clinical rejection.     

Acute rejection in kidney grafts with delayed onset of graft function

Forty-five kidney transplant recipients with delayed onset of diuresis due to acute tubular necrosis (ATN) were examined with duplex ultrasonography (DU). Resistive index (RI) was measured on the 4th post-transplant day. Eleven grafts (24%) developed acute rejection. Mean RI prior to rejection of the 4th postoperative day in these grafts was 0.97 and in the 34 grafts which did not develop rejection mean RI was 0.82. There were 2/26 rejections (8%) in the group of grafts with an initial RI below 0.9 and 9/19 rejections (47%) in the group of grafts with RI of 0.9 or above on the 4th post-transplant day. Six months postoperatively there were 2/26 nonfunctioning grafts in the group with lower initial RI values (<0.9) and 6/19 nonfunctioning grafts in the group with higher indices (0.9). In nonfunctioning grafts a high initial RI (0.9) indicates that these grafts will be prone to developing actute rejection.     

Long-term outcome of the use of OKT3 to treat steroid-resistant acute renal allograft rejection

OKT3 was used to treat steroid-resistant acute renal allograft refection in 30 of 496 adult patients transplanted over a 6-year period. Rejection was reversed (defined as a fall in serum creatinine by 50% or more within 30 days of treatment with OKT3) in 40% of cases. Successful reversal was significantly more likely when rejection occurred shortly after transplantation (t ratio-2.53; P=0.019). The long-term outcome was disappointing; the actuarial graft survival at 1 year from the start of treatment with OKT3 was 42%, and no grafts have thus far survived longer than 3 years. Graft survival was horter in older patients (coefficient/standard error 2.226; P<0.05), and no other predictor of long-term outcome was identified. Patient survival at 3 years was 88%. Serious infection occurred in 33% of patients, with two deaths. Our experience suggests that treatment with OKT3 is unlikely to reverse acute renal allograft rejection in more than half of patients where rejection is resistant to steroids. Although long-term graft survival occurred in a few cases, the overall long-term outcome was disappointing, particularly in older patients. Finally, our analysis indicates the difficulty of predicting which patients will derive long-term benefit when OKT3 is used to treat steroidresistant rejection.     

Urinary tubular biomarkers as potential early predictors of renal allograft rejection

Confirmation of kidney transplant rejection still requires a histological diagnosis on renal allograft biopsy. Research continues for new non-invasive means for early diagnosis and treatment of kidney allograft rejection. Examination of the urine in renal transplant recipients provides a logical and readily accessible non-invasive window on allograft function, reflecting the function of the kidney in its transplanted environment. Renal tubular epithelial cells (TEC) respond dynamically to the surrounding microenvironment and play an important role in allograft survival. Proteins released from TEC into the urine potentially serve as biomarkers for the early diagnosis of graft dysfunction and rejection. Activated proximal TEC express human leucocyte antigens and co-stimulatory molecules, transiently transforming into non-professional antigen-presenting cells that augment renal allograft rejection. Chemokines and chemoattractants expressed on proximal tubules may also facilitate the migration of alloreactive lymphocytes to local site of injury and stimulate cytokine release from infiltrating lymphocytes. Proximal TEC are also potential targets for circulating alloreactive antibodies and complement leading to cell damage. Changes in cell state during development, regeneration or immune response require a rapid modulation of both surface protein expression and secretion, altering the repertoire of proteins secreted or expressed at the TEC plasma membrane. Due to the proximity of TEC to the tubular lumen, these proteins are passed into the urine. In this regard, TEC possess a unique anatomic location within the transplanted organ and are therefore ideal indicators of graft function. Hence, measurement of the changes of TEC-derived molecules in the urine, in response to different challenges or modification, may predict graft outcome.     

肾移植排斥反应时血浆骨桥蛋白水平的变化及意义

目的 探讨肾移植排斥反应时血浆骨桥蛋白( OPN)水平的变化及意义.方法 对46例肾移植受者的临床资料及生物样本进行回顾性分析.根据移植肾组织学检查结果,46例受者被分为3组:移植肾功能稳定,且移植肾组织学检查未显示有排斥反应证据者16例,为非排斥组;移植肾组织学检查证实有急性细胞性排斥反应者22例,为急排组;移植肾组织学检查证实为慢性移植肾肾病(CAN)者8例,为慢排组.另以6名亲属活体供者作为对照组.于移植肾组织样本采集前抽取外周血,用人OPN酶联免疫吸附试验检测试剂盒测定血浆OPN水平,参照Banff 03标准对排斥反应进行分级.结果 对照组血浆OPN水平为(12.23±5.95)μg/L,非排斥组稍高,为(19.38±8.23)μg/L,两组间的差异无统计学意义( P＞0.05);慢排组血浆OPN水平为(27.77±12.27)μg/L,与非排斥组比较,差异无统计学意义(P＞0.05);急排组血浆OPN水平为(41.84±18.51)μg/L,与非排斥组比较,差异有统计学意义(P＜0.05),与慢排组比较,差异也有统计学意义(P＜0.05).急排组血浆OPN水平与排斥反应的级别具有正相关性(r=0.87,P＜0.05),发生Ⅰa级排斥反应和Ⅱb级排斥反应者间血浆OPN水平的差异有统计学意义(P＜0.05).结论 血浆OPN水平变化与急性排斥反应关系密切,其水平高低与排斥反应的级别呈正相关,可以作为诊断移植肾急性细胞性排斥反应、评估其严重程度的一个辅助指标.     

Histological features of acute pancreatic allograft rejection after pancreaticoduodenal transplantation in the rat

For characterization of histopathological changes during pancreas graft rejection, pancreaticoduodenal transplants were performed in three groups: (1) Brown Norway into diabetic Lewis rats without immunosuppression, (2) Brown Norway into diabetic Lewis rats with cyclosporin A, and (3) Lewis into Lewis rats. Diffuse inflammatory infiltration of the acini by mononuclear cells indicated the onset of rejection (stage I). Shortly after acinar infiltration, damage to small and large interlobular excretion ducts occurred. This took the form of florid circumferential inflammation and vacuolar degeneration of epithelium similar to the bile duct damage seen in primary biliary cirrhosis, graft-versus-host disease, and liver allograft rejection (stage II). Thereafter, endothelialitis and destruction of islets were evident, consistent with a more advanced and irreversible stage of rejection (stage III). Acinar inflammation and moderate duct lesions were not prevented by immunosuppression but were delayed. Nonetheless, severe vascular changes and loss of islets were avoided. We conclude that duct lesions are a reliable criterion for pancreas allograft rejection. They are more sensitive than vascular changes and more specific than cellular infiltration of acinar tissue, which may also occur in infection.     

The increasing importance of chronic rejection as a cause of renal allograft failure

A consequence of reducing early graft failure due to acute rejection has been that more patients are at risk of chronic rejection, something which has become an increasingly important cause of graft loss. We examine the graft survival rates and reasons for failure in our unit from 1981 to 1986. Patients were divided into two series according to treatment of acute rejection episodes. From 1983 onwards, by treating acute vascular (poor prognosis) episodes with antilymphocyte globulin (ALG), we have significantly improved the 6-month actuarial graft survival rate. However, the percentage of total graft failure due to chronic rejection in this second series has significantly increased. The need for greater understanding of the aetiology of chronic rejection, together with its present unsatisfactory treatment, is discussed.     

急性体液性排斥反应对移植肾预后的影响

目的 探讨急性体液性排斥反应对移植肾预后的影响.方法 共有1098例接受首次尸体肾移植的受者纳入研究.所有受者术后均采用以他克莫司或环孢素A为基础的三联免疫抑制方案,当发生排斥反应时,采用甲泼尼龙冲击治疗,疗效较差者则联合应用莫罗单抗-CD3或丙种球蛋白或行血浆置换进行治疗.术后1年内经病理检查证实,有53例受者发生急性体液性排斥反应(急性体液性排斥反应组),109例发生急性细胞性排斥反应(急性细胞性排斥反应组),其余936例受者术后1年内肾功能稳定(对照组).分析和比较3组受者性别、年龄、术前淋巴毒、HLA抗原错配数、群体反应性抗体(PRA)水平及供肾冷/热缺血时间等冈素间的差异,比较3组受者术后移植肾功能丧失情况及移植肾存活率,分析完全逆转的急性体液性排斥反应与细胞性排斥反应对移植肾预后的影响.结果 3组受者在性别、年龄、术前淋巴细胞毒性试验、供肾冷缺血时间及术后随访时间等方面比较,差异均无统计学意义(P＜0.05).急性体液性排斥反应组和急性细胞性排斥反应组受者在术前HLA抗原错配数、PRA水平及供肾热缺血时间等方面均明显高于对照组,与对照组比较,差异均有统计学意义(P＜0.05).随访期间,急性体液性排斥反应组受者移植肾功能丧失的发生率为27.4%(14/53),明显高于急性细胞性排斥反应组的7.3%(8/109)和对照组的2.2%(21/936),3组间差异均有统计学意义(P＜0.01).通过kaplan-meier生存分析发现,急性体液性排斥反应组受者的移植肾存活率明显低于急性细胞性排斥反应组和对照组(P＜0.01).剔除发生排斥反应后未逆转者,3组间移植肾存活率的比较,差异均无统计学意义(P＞0.05).结论 急性体液性排斥反应明显影响移植肾存活,但完全逆转的急性体液排斥反应并不影响移植肾的预后.     

Soluble tumor necrosis factor-receptors are not a useful marker of acute allograft rejection: a study in patients with renal or cardiac allografts

In this study, we investigated soluble tumor necrosis factor receptor (sTNF-R) levels in plasma of patients with either a kidney or cardiac allograft when clinical suspicion of acute rejection was raised. In plasma of patients with acute renal graft rejection, the sTNF-R levels were strongly enhanced (20–150 ng/ml) as compared to plasma of patients with stable renal function. Following successful treatment of the rejection, a gradual decline in sTNF-R levels occurred with improving renal function, and an inverse correlation between creatinine clearance and sTNF-R was found. To determine whether the increase was caused by an accumulation of constitutively released sTNF-R and lack of clearance by the kidney, or whether the immunological process of the rejection caused the enhancement, we measured sTNF-R in patients suffering from acute cardiac graft rejection but with predominantly stable kidney function. Rejection of a cardiac graft did not lead to a significant enhancement of sTNF-R levels. However, treatment with ATG or OKT3 did cause enhanced sTNF-R levels, followed by a decline that reached starting values after 7 days. These results provide evidence that the immune reaction that occurs during rejection of a graft does not per se induce discernible changes in sTNF-R levels, whereas that induced by ATG or OKT3 does. Thus, sTNF-R levels are not a reliable marker in transplant recipient monitoring.     

移植肾输尿管全长坏死的诊断与治疗

目的　提高对肾移植术后移植肾输尿管全长坏死的认识 ,以期及早诊断和有效治疗。方法　对 1991年 1月～ 2 0 0 1年 4月收治的 5例移植肾输尿管全长坏死患者的诊断和治疗情况进行回顾性总结。 5例患者首发症状皆为漏尿 ,B超和核磁共振 (MRI)水成像是重要的辅助诊断方法。 1例患者 1次手术探查行移植肾肾盂自体输尿管吻合术 ;4例患者第 2次探查手术行移植肾肾盂与自体输尿管或肾盂吻合术。　结果　 5例患者末次手术后尿量为 15 0 0～ 30 0 0ml/d ,2周内血清肌酐 <15 0 μmol/L ,尿素氮 <8 5mmol/L。随访 6～ 12个月 ,全部患者皆无肾积水。　 结论　肾移植术后因漏尿行手术探查 ,发现末端输尿管坏死时 ,应该考虑到可能有输尿管全长坏死。自体输尿管或肾盂重建尿路是有效的治疗方法     

Reversal of acute glomerular renal allograft rejection: a possible effect of OKT3

A major cause of renal allograft loss is glomerulovascular rejection. This case report is about an episode of histologically proven acute glomerular rejection that was successfully reversed. Monoclonal antibody OKT3 may have been the effective agent.     

IL-2R 在急性细胞性排异反应的同种异体尸体移植肾组织中的检测及意义

为探讨白介素－２受体（ＩＬ－２Ｒ，即ＣＤ２５）在同种异体肾移植急性细胞性排异（ＡＣＲ）临床诊断的作用，着重观察移植肾发生（ＡＣＲ）和无ＡＣＲ时，其间质浸润细胞中ＩＬ－２Ｒ阳性细胞数的变化，及其与间质浸润的淋巴细胞的关系。作者选择同期行异体肾移植，且无并发症患者１７例，采用ＰＡＰ四层免疫酶标法，检测移植肾组织中间质浸润细胞中ＩＬ－２Ｒ阳性细胞数的变化。结果显示：无ＡＣＲ的肾组织中，ＩＬ－２Ｒ阳性细胞仅轻度增加，当移植肾出现ＡＣＲ时，ＩＬ－２Ｒ阳性细胞数的增加十分显著，并与间质浸润的ＣＤ８密切相关。作者认为ＩＬ－２Ｒ对于ＡＣＲ的诊断及鉴别诊断具有一定的临床应用价值。