肾移植术后早期排斥反应的处理

目的：探讨。肾移植术后早期排斥反应(AR)的处理方法。方法：对14例。肾移植术后3周内发生AR的患者,应用甲基泼尼松龙(MP)治疗7例,改硫唑嘌呤(Aza)为霉酚酸脂(MMF?)治疗5例,抗CD3治疗6例。结果：应用MP治疗的7例中5例AR逆转,2例无效;改Aza为MMF治疗的5例3例逆转,2例无效(其中包括MP无效的2例改Aza为MMF治疗后1例逆转1例无效)。抗CD3治疗6例4例逆转,2例无效(其中MP治疗无效改Aza为MMF治疗后仍无效的1例逆转,MP治疗无效的基础免疫为CsA加MMF?加Pred的1例无效)。结论：MP可使大部分术后早期AR逆转。应用Aza的患者改用MMP后可使早期AR逆转,MP不能完全逆转的AR改用MMF后也有良好的效果。及时应用抗CD3几乎可使术后早期AR全部逆转。     

Steroid-resistant acute allograft rejection in renal transplantation

Steroid-resistant rejection after pediatric renal transplantation forms a rare but severe complication with a guarded prognosis particularly if this occurs late after transplantation. There is a paucity of data on how to manage these challenging rejection episodes, particularly in the pediatric literature. Mohan Shenoy et al. published a case series of 15 patients who were treated with anti-thymocyte globulin for steroid-resistant acute allograft rejection over a 15-year period in a single center in this issue of Pediatric Nephrology. While the results for the early rejection group were encouraging, the results in the eight patients with late rejection episodes after transplantation were unfavorable and afflicted with a high incidence of side-effects. Important diagnostic tools such as C4d staining of the renal transplant biopsy and the measurement of donor-specific antibodies were underutilized. The editorial reviews the importance of the differentiation between humoral and cellular rejection and the challenges of treating late antibody-mediated acute rejection in these patients. A multi-center approach is required to establish a registry of these events and ideally prospective randomized interventions should be designed to provide some evidence base for the management of this challenging complication after pediatric renal transplantation.     

Osteopontin expression in acute renal allograft rejection

BACKGROUND: Osteopontin (OPN) is a potent chemoattractant for mononuclear cells that is up-regulated in various inflammatory states of the kidney. The role of OPN and its expression in human renal allograft rejection are unknown. METHODS: We examined by immunohistochemistry and in situ hybridization, renal biopsies from patients with acute rejection (N= 22), protocol biopsies without rejection (N= 9), and perioperative donor biopsies (N= 35) for intrarenal expression of OPN, and its correlation with clinical, laboratory, and histopathologic parameters. In the rejection biopsies, interstitial monocyte/macrophage infiltration, tubulointerstitial cell proliferation/regeneration and apoptosis were investigated. RESULTS: In the majority of rejection biopsies, OPN expression by proximal tubular epithelium was widespread, and tended to be enhanced in the tubules surrounded by numerous inflammatory cells. Conversely, in patients that did not experience episodes of rejection and in donor biopsies, OPN expression by proximal tubules was nil or weak. OPN mRNA was colocalized with its translated protein in the renal tubular epithelium. OPN expression positively correlated with the degree of interstitial inflammation (P < 0.05), CD68+ monocyte infiltration (P < 0.01), Ki-67+ regenerating tubular and interstitial cells (P < 0.05 and P < 0.005, respectively), but not with terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL)-positive apoptotic tubular cells. CONCLUSION: These data suggest that inducible expression of OPN in the tubular epithelium may have a pathogenic role in acute renal allograft rejection by mediating interstitial monocyte infiltration and possibly tubular regeneration.     

An increase in myeloid-related protein serum levels precedes acute renal allograft rejection

Upon interaction with activated endothelium, monocytes and neutrophils form complexes of myeloid-related protein 8 (MRP8) (S100A8) and MRP14 (S100A9), two members of the calcium-binding S100 family that are secreted during transendothelial migration. In a pilot study of 20 renal transplant recipients and a validation study of 36 renal transplant recipients, MRP8/14 serum levels were measured with an enzyme-linked immunosorbent assay for 28 d, associated with C-reactive protein and creatinine serum levels, and grouped according to biopsy-proven acute rejection. Serum levels of MRP8/14 but not C-reactive protein were significantly increased for several days during the first 2 wk for the acute rejection groups in both studies (P < 0.005, on day 6 after transplantation). As determined by using receiver operating characteristic curves, the optimal cutoff for 100% specificity and high sensitivity (67%) for acute rejection on day 6 after transplantation was calculated to be 4.2 microg/ml for MRP8/14 in the pilot study; this value was confirmed in the validation study. Positive MRP8/14 serum levels preceded acute rejection episodes by a median of 5 d. A 3-d course of intravenous methylprednisolone therapy reduced prerejection MRP8/14 serum levels from 5.7 microg/ml to 3.3 microg/ml (P < 0.05). All MRP8/14 serum levels were below the cutoff during urinary tract infections, delayed graft function, or cytomegalovirus infections, and these values did not differ significantly from control values. It is concluded that the MRP8/14 complex is a very early serum marker suitable for monitoring of acute rejection with high sensitivity and specificity.     

移植肾急性排斥反应的免疫表型

目的阐明移植肾急性排斥反应的发生机制。方法发生严重急性排斥反应的１６例移植肾行免疫组化染色,其中６例行免疫胶体金电镜观察。结果移植肾组织中主要免疫活性细胞为Ｔ细胞,动脉壁及肾小管细胞间的Ｔ细胞均为ＣＤ８细胞。结论移植肾急性排斥反应主要是由Ｔ淋巴细胞尤其是ＣＤ８细胞介导的一种免疫损伤。     

Plasma cell-rich acute renal allograft rejection.

BACKGROUND: Acute renal allograft rejection is usually seen within the first 3 months posttransplant, and is characterized by an intense infiltrate of T cells. Some acute rejections, however, contain many plasma cells and/or appear late posttransplant. METHODS: We have investigated 27 cases of intensely plasma cell-rich acute rejections (PCAR) from 1987 to 1997 and have compared them to 21 control cases (CAR) of typical acute rejection. Each group was divided into early (<6 months) and late (>6 months) subgroups. PCAR and CAR cases were matched for histological features of chronic allograft nephropathy. In all four groups, most cases had Banff '97 type IB and IIA acute rejection. RESULTS: A significantly greater number of PCAR cases experienced graft failure due to chronic allograft nephropathy or complications of acute rejection (P<0.05). There was no significant difference between PCAR and CAR in HLA matching, occurrence of posttransplant acute tubular necrosis, presence versus absence of previous allografts, number of previous or subsequent acute rejection episodes, Banff '97 sum scores for acute rejection, cyclosporine A or FK506 levels, or percent change from baseline creatinine at time of biopsy. Plasma cells in PCAR cases showed IgG predominance whereas those in CAR had comparable staining for IgG and IgA. Kappa and lambda light chain immunostaining of all PCAR cases revealed polyclonality. Three of 18 PCAR cases studied for the presence of Epstein-Barr virus RNA showed scattered positivity in 2-7% of lymphoid cells, although the remainder was negative. None of the PCAR cases developed post-transpland lymphoproliferative disorder. CONCLUSIONS: We conclude that PCAR can occur from 1 month to many years posttransplant, is associated with poor graft survival, and is not a manifestation of concomitant chronic allograft nephropathy or viral infection, including posttransplant lymphoproliferative disorder.     

移植肾急性排斥反应新认识

急性排斥反应是影响肾移植长期预后的重要因素。在新型免疫抑制剂应用下,急性排斥反应具有表现不典型、难治性排斥反应比例高等特点。本文从发生急性排斥反应高危因素的术前筛查与处理、急性排斥反应早期诊断方法以及对急性排斥反应的干预和免疫抑制药物合理应用、移植后感染预防等方面,综合浙江大学医学院附属第一医院肾脏病中心的临床研究结果,探讨发生急性排斥反应的高危因素、诊断和防控措施,以提高肾移植后长期存活率。     

Adhesion molecule polymorphisms in acute renal allograft rejection

Acute rejection is the main cause of early renal allograft failure. Adhesion molecules provide signals for activation and recruitment of effector cells leading to graft infiltration by host T cells, which are key to allograft rejection. This study was undertaken to analyze the adhesion molecule gene polymorphisms in renal transplant recipients and to investigate their potential association with the development of acute allograft rejection. A total of 120 renal transplant recipients and 100 controls were retrospectively genotyped. Seven nucleotide polymorphisms in intracellular adhesion molecule (ICAM)-1, platelet endothelial cell adhesion molecule (PECAM)-1, L-selectin, and E-selectin were analyzed using allele-specific polymerase chain reaction (PCR)-SSP assay and PCR-restriction fragment length polymorphism (RFLP). Recipients were selected on the basis of the development of acute allograft rejection in the first 6 months after renal transplantation. Forty-one patients developed acute allograft rejection and 79 showed uneventful courses. There was no evidence for an association of any polymorphism with acute rejection. Thus, we concluded that these genes do not predispose to acute renal allograft rejection.     

Study of acute antibody-mediated rejection in renal allograft biopsies

INTRODUCTION: Acute B-cell-mediated rejection (AMR) was ill-defined until the 6(th) Banff meeting establishing the criteria. We performed a retrospective analysis of renal allograft biopsies to evaluate immune injury with reference to the Ahmedabad Tolerance Induction Protocols (ATIP). METHODS: We evaluated renal allograft biopsies belonging to 3 groups: group A patients (n = 120) underwent a modified ATIP with addition of mesenchymal stem cells, anti-B-cell antibodies, and higher target-specific irradiation; group B patients (n = 351) belong to the old ATIP; and group C (n = 142) were controls who opted out of ATIP. The majority were biopsied 2 or 3 times. Biopsies were subdivided: 相似文献   

Determinants of hypofiltration during acute renal allograft rejection

This study sought to determine the extent to which GFR is decreased during acute renal allograft rejection in human subjects and to determine the mechanism of the decrease in GFR. Eight patients with biopsy-proven acute rejection were compared with 18 recipients of optimally functioning renal allografts. GFR and renal plasma flow (RPF) were measured as the clearance of inulin and para-aminohippuric acid, respectively. Arterial BP was determined, blood was sampled, and plasma oncotic pressure (pi(A)) was measured. Glomeruli obtained by biopsy during rejection were subjected to morphometric analysis, for determination of K(f). Control morphometric values for healthy glomeruli were provided by 10 living donors from whom biopsies were obtained at the time of organ donation. The subjects in the acute rejection group exhibited a significantly reduced GFR of 17 +/- 4 ml/min per 1.73 m(2), compared with 72 +/- 4 ml/min per 1.73 m(2) for control subjects (P < 0.001). With the use of a sensitivity analysis to take into account the unknown para-aminohippuric acid extraction ratio, the RPF rate was calculated to have likely been significantly decreased, by 45 to 70%, in the acute rejection group. Neither the plasma oncotic pressure nor the mean arterial pressure differed between the two groups. Morphometric analysis revealed no difference in the single-nephron K(f) values for the acute rejection group, compared with the control group. These results indicate that acute renal allograft rejection causes a profound decrease in GFR, which is attributable to a decrease in RPF alone or in combination with a decrease in the glomerular transcapillary hydraulic pressure gradient (DeltaP).     

RS-61443 reverses acute renal allograft rejection in dogs

RS-61443 is a noncompetitive allosteric inhibitor of inosine monophosphate dehydrogenase. At blocks the proliferative response of T and B lymphocytes, prevents the generation of cytotoxic T cells, and inhibits antibody formation. This study was conducted to see whether or not RS-61443 can reverse acute renal allograft rejection in dogs. At was possible to reverse this process.     

Urinary secretory immunoglobulin A in acute renal allograft rejection

Periodical determinations of the urinary secretory immunoglobulin A (S-IgA) excretion rate were performed in 12 cadaveric graft recipients. In five patients with primary functioning grafts the S-IgA excretion on the first postoperative day was 4.2 +/- 2.6 mg/g creatinine, decreasing to 1.8 +/- 1.2 mg/g creatinine (P less than 0.05) at the day of discharge. Acute tubular necrosis developed in the seven remaining patients. In this group the initial S-IgA excretion was 12.6 +/- 7.5 mg/g creatinine (P less than 0.05 compared to the former group), decreasing to 2.0 +/- 0.9 mg/g creatinine (P less than 0.05) at discharge. An acute rejection episode was observed in six patients. The S-IgA excretion increased from 3.0 +/- 1.5 mg/g creatinine 3-4 days before rejection to 6.4 +/- 3.1 mg/g creatinine (P less than 0.05) 1-2 days before rejection, and peaked at 14.0 +/- 8.6 mg/g creatinine (P less than 0.05) when the diagnosis of rejection was established and anti-rejection treatment was started. In three patients the initial steroid pulse therapy was not successful and S-IgA excretion further increased to 29.0 +/- 15.6 mg/g creatinine. After successful anti-rejection treatment, using steroids and OKT3, the S-IgA excretion decreased to 3.4 +/- 2.6 mg/g creatinine. In acute graft rejection, the elevated globulin synthesis by infiltrating plasma cells. In the early phase of rejection, dimeric IgA is the only immunoglobulin able to penetrate into the urine by transepithelial transport after binding to secretory component expressed on tubular epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

肾移植急性排斥反应中肾小管上皮细胞凋亡的观察

目的 探讨肾移植急性排斥小以细胞凋亡与移植排斥的关系。方法 选用近交系ＤＡ大鼠,ＬＥＷ大鼠进行原位左肾移植。实验组：异基因移植组（ＤＡ－ＬＥＷ）,对照组;基因移植组（ＬＥＷ→ＬＥＷ）。于手术后第２、４、６天分别取移植肾进行病理学检查及电镜扫描,采用ＴｄＴ介导的脱氧核苷酸原位末端标记法（ＴＵＮＥＬ）检测移植肾脏中的凋主血清肌酐水平。结果 病理学检查结果显示实验组大鼠在术后第２、４、６天分别发生轻、中     

The renal medulla in acute renal allograft rejection: comparison with renal cortex

A retrospective cohort study was undertaken to evaluate thediagnostic value of the renal medulla in acute renal allograftrejection (ARAR). One hundred and ninety-five biopsies from98 patients were randomly selected out of 565 transplant biopsies.Biopsies were graded blindly from Grade 0 (no rejection) toGrade 3 (severe rejection) using standard criteria; ARAR wasconfirmed by a fall in all cases of mean serum creatinine concentrationfrom 0.331 ± 0.182 to 0.184 ± 0.079 mmol/l, withanti-rejection therapy. In the 43 biopsies which contained bothcortex and medulla, the ARAR grades and the intensities of mononuclearcell, plasma cell, polymorphonuclear cell and eosinophil infiltrates,and of interstitial oedema and haemorrhage, were similar incortex and medulla (Spearman's Rank Correlation r=0.55–0.81,P < 0.001 ). The sensitivity, specificity and overall accuracyof medullary changes in predicting ARAR changes in the cortexwere 77%, 100% and 38%, respectively. Acute vascular rejectionchanges could not be compared between renal cortex and renalmedulla because of the anatomical differences between cortexand medulla. Further evaluation of ARAR in the all 195 biopsies,of which 188 had cortical tissue and 50 had medullary tissue,showed no significant differences in histological features (P> 0.05), except for more cortical biopsies with plasma cells(29%) than medullary biopsies with plasma cells (10%; P <0.02). It is concluded that: (1) ARAR histological changes aresimilar in cortex and medulla; (2) the predictive value of ARARmedullary changes for cortical rejection changes has low sensitivity(77%) and high specificity (100%). It is suggested that a predominantlynormal medullary renal biopsy in suspected rejection shouldbe repeated to obtain cortical tissue.     

急性体液性排斥反应对移植肾预后的影响

Objective To explore the effect of acute humoral rejection on kidney graft survival.Methods 1098 patients received cadaveric renal transplant from January 2002 to December 2008 in our center. All patients were given triple immunosuppressants including tacrolimus or cyclosporine.According to patients who experienced biopsy-proved humoral rejection and cellular rejection within one year post-transplant, there were 53 cases in humoral rejection group, 109 in cellular rejection group (including 63 patients with borderline change), and 936 in normal group. Patients who experienced acute rejection received mythyl-prednisolone pulse, or received anti-CD3 antibody/plasma exchange/globulin. Clinical characteristics before operation including sex, age, HLA mismatch, panel reactive antibody, cold/warm ischemic time, graft loss rate and graft survival were compared among three groups. The effect of completely reversed cellular rejection and humoral rejection on graft survival was analyzed. Results There was no significant difference in sex, age and cold ischemic time among three groups, but there was significant difference in warm ischemic time, level of PRA and HLA mismatch between cellular rejection group or humor rejection group and normal group (P＜0. 05). During a follow-up period, the incidence of graft loss in humoral rejection group was 27.4 %, significantly higher than 7.3 % in cellular rejection group and 2.2 % in normal group, P＜0. 001. Kaplan-Meier analysis revealed the survival rate of grafts in humoral rejection group was significantly lower than in cellular rejection group and normal group (P＜0.001 ). After patients with irreversible rejection were excluded,there was no significant difference in the survival rate of grafts among the three groups.Conclusion Patients with acute humoral rejection survived with inferior graft outcome,but completely reversible rejection showed no effect on the graft survival.     

In vivo prostanoid formation during acute renal allograft rejection

Vasoconstriction during acute renal allograft rejection maybe regulated by increased formation of vasoactive prostanoids.To address this hypothesis we investigated the biosynthesisof thromboxane (Tx)A₂, a potent vasoconstrictor and plateletagonist, of prosta-cyclin (PGI₂), a vasodilator and plateletantagonist, and of prostaglandin (PG)E₂, a mediator of saltand water excretion, in nine children with 12 acute rejectionepisodes, prospectively during the first 7 weeks after renaltransplantation. We used physicochemical analysis of stableurinary prostanoid index metabolites. Rejection crises wereassociated with an increase in TxB₂ excretion from baselinemedian 9.2 (range 1.9–18.6) ng/h/1.73m² to 21.2 (range10.0–133.0) ng/h/1.73m² (P<0.005) during acute rejectionepisodes. Methylprednisolone pulse therapy resulted in a partialreduction, but not normalization of TxB₂ excretion. Urinary2,3-dinor-TxB₂ was slightly stimulated during allograft rejection,urinary 1 l-dehydro-TxB₂ did not change significantly. RenalPGI₂ and PGE₂ biosynthesis remained essentially unchanged. Incontrast to acute graft rejection, patients with chronic graftrejection and those with stable graft function on differentimmunosuppressive regimens with or without cyclosporin A didnot present stimulated renal TxA₂ formation. Increased renalTxA₂ formation in acute renal allograft rejection is likelyto mediate vasoconstriction and potentiate the loss of renalblood flow and glomerular filtration rate, in the absence ofan adequate response of the renoprotective prostanoids PGI₂and PGE₂.     

Refractory acute renal allograft rejection successfully treated with photopheresis

INTRODUCTION: Acute rejection episodes still occur in spite of modern immunosuppressive protocols. We present seven patients with biopsy-proven acute rejections after kidney transplantation refractory to repeated pulses of high-dose steroids and antithymocyte globulin (ATG) or OKT-3, but responsive to photopheresis therapy. METHODS: Photopheresis is a nontoxic immunomodulatory, apheresis-based treatment with no general immunosuppressive action. Rather, it suppresses specific pathogenic T-cell clones. During photopheresis mononuclear leukocytes are collected from the patient using centrifugation technique, treated with a photosensitizing agent, irradiated, and subsequently retransfused. RESULTS: All patients tolerated the treatment well, with no notable side effects. At the 12-month follow-up the median creatinine had decreased to 161 mumol/L compared to 282 mumol/L at the start of photopheresis and at the last follow-up 12 to 43 months after transplantation all patients still had functioning grafts. In five of the seven cases there had been a significant improvement in renal function, whereas in two of the patients the renal function remained stable but without a decrease in creatinine. CONCLUSIONS: It is our experience that the prognosis for renal allografts with acute rejection unresponsive to conventional antirejection treatment (ie, repeated pulses of methylprednisolone and ATG or OKT-3) is very poor. Therefore, we conclude that the photopheresis treatment contributed to the favorable outcome in this small group of patients. We are presently designing a prospective randomized study to further evaluate the effect of photopheresis after renal transplantation.