C4D deposition and positive posttransplant crossmatch are not necessarily markers of antibody-mediated rejection in renal allograft recipients

The aim of the study was to search for serologic, immunopathologic, and morphologic evidence of antibody-mediated rejection (AMR) among patients with acute renal allograft dysfunction. The study included 19 patients with episodes of acute rejection (ARE) within the first year after transplantation. All patients had negative crossmatch tests before transplantation. Patients underwent biopsy for histologic and C4d examinations. All patients were monitored for donor-specific HLA alloantibodies during the first posttransplant year. Complement-dependent cytotoxic crossmatches were performed with donor lymphocytes. In eight patients, the crossmatch test results changed to positive during ARE. In all biopsies except one with cortical infarction, we observed C4d staining (group 1). The biopsies of four patients showed histologic changes of AMR, and all of their grafts were lost. In one patient, cellular and vascular rejection (Banff II) were present; in two, Banff I; and in one, borderline lesions. These results were compared with 11 patients with ARE but negative posttransplant crossmatches and negative staining for C4d (group 2). The histologic findings in the biopsies of these patients were cellular interstitial and vascular rejection (Banff I and Banff II). With no features suggestive of AMR. During the first year after transplantation, the creatinine levels of group 1 patients, were significantly higher than group 2 patients. One-year graft survival was 50% in group 1 and 91% in group 2. CONCLUSIONS: C4d and a positive posttransplant crossmatch were not associated with histologic features of AMR in half of the ARE. Nevertheless, C4d deposition and positive posttransplant crossmatches correlated with allograft injury among renal transplant patients.     

Renal allograft biopsies in the era of C4d staining: the need for change in the Banff classification system.

C4d immunostaining in the peritubular capillaries (PTC) is a marker of antibody-mediated rejection (AMR). We evaluated the histopathologic diagnoses of 388 renal transplant biopsies since the implementation of routine C4d immunostaining at our center. Of these, 155 (40%) biopsies had evidence of acute cellular rejection (ACR), out of which 119 (77%) had pure ACR, 31 (20%) had ACR with concomitant features of AMR, and five (3%) had ACR with focal C4d staining. Sixty-four (16%) biopsies exhibited features of AMR [33 (52%) pure AMR, and 31(48%) concomitant AMR and ACR]. One hundred and fifty-five (40%) biopsies had features of interstitial fibrosis and tubular atrophy (IFTA). Of these, 20 (13%) had concomitant AMR [13 (8.5%) had pure AMR and seven (4.5%) had concomitant ACR and AMR]. Creatinine at the time of biopsy was higher in patients with mixed ACR and AMR and the clinical behavior of mixed lesions is more aggressive over time. Despite having a lower serum creatinine at the time of biopsy, patients with IFTA experienced gradual decline in graft function over time. The pathologic findings in renal allograft biopsies are often mixed and mixed lesions appear to have more aggressive clinical behavior. These findings suggest the need for change in the Banff classification system to better capture the complexity of renal allograft pathologies.     

Antibody-mediated rejection of the kidney after simultaneous pancreas-kidney transplantation

The prevalence, risk factors, and outcome of antibody-mediated rejection (AMR) of the kidney after simultaneous pancreas-kidney transplantation are unknown. In 136 simultaneous pancreas-kidney recipients who were followed for an average of 3.1 yr, 21 episodes of AMR of the kidney allograft were identified. Eight episodes occurred early (相似文献   

Early Ultrastructural Changes in Renal Allografts: Correlation With Antibody‐Mediated Rejection and Transplant Glomerulopathy

Transplant glomerulopathy (TG) is associated with antibody‐mediated renal allograft rejection (AMR) and reduced graft survival. Histologically, TG is typically seen >1 year posttransplantation. However, ultrastructural changes including glomerular endothelial swelling, subendothelial widening and early glomerular basement membrane duplication are associated with development of TG but appear much earlier. We examined the specificity of these changes for AMR, and whether these are inevitably associated with development of TG. Of 98 for cause renal allograft biopsies carried out within 3 months of transplantation with available serologic data, 17 showed C4d‐positive AMR and 16 had histologic changes of AMR and donor‐specific antibodies (DSA), but no C4d. All three ultrastructural changes were seen in 11 of 17 biopsies with C4d‐positive AMR, 8 of 16 with histologic changes of AMR and DSA but no C4d, and 0 of 65 without histologic changes of AMR and/or DSA (p < 0.0001 for both of the former groups vs. the latter). Twenty patients with positive DSA (18 with histologic changes of AMR and 11 C4d‐positive) had ≥1 follow‐up biopsy; eight developed overt TG 3.5–30 months posttransplantation. Among the 18 patients with DSA and histologic changes of AMR, 11 C4d‐positive and 7 C4d‐negative, treatment for AMR after the early biopsy significantly reduced subsequent development of overt TG.     

The role of C4d immunostaining in the evaluation of the causes of renal allograft dysfunction.

BACKGROUND: Renal biopsy is the gold standard for diagnosis of acute rejection in renal transplant recipients. The Banff (1997) classification was revised in 2003 incorporating morphological criteria and C4d immunostaining for the diagnosis of acute antibody-mediated rejection. AIMS: The aim of this study was to evaluate the role of histomorphology and C4d immunostaining in indicated renal allograft biopsies with a clinical follow-up for a minimum duration of 1 year. MATERIAL AND METHODS: Histological analysis and C4d immunostaining were performed on 132 needle core biopsies and 2 nephrectomy specimens from 107 patients from July 2004 to June 2005. RESULTS: Histological analysis revealed 59 cases of acute rejection, 10 biopsies of acute tubular necrosis, 41 cases of chronic allograft nephropathy (CAN), either alone or in combination with other diseases, and 18 biopsies of normal morphology. There were four cases of BK nephropathy (BK N) and eight cases had miscellaneous diagnoses. C4d immunostaining was performed on 126 biopsies. Overall, the prevalence of C4d positivity was 45% (57 of 126). Fifty-five percent (28 of 51) of the cases of acute rejection showed C4d positivity including 81% of presumptive antibody-mediated rejection (P-AbAR), 20% acute cellular rejection and 58% acute cellular rejection + P-AbAR. Overall C4d positivity was 37% in chronic allograft nephropathy. Acute tubular necrosis and borderline rejection showed 25 and 50% C4d positivity, respectively. Amongst various histological features, capillary margination of polymorphs and dilatation of peritubular capillaries (PTC-D) showed significant association with C4d positivity (P < 0.005). In cases of CAN, transplant glomerulopathy had significant association with C4d positivity. C4d-positive cases had a higher mean value of serum creatinine at the time of biopsies. CONCLUSION: It is concluded that C4d staining is a useful adjunct marker of the humoral limb of rejection, both in early and late post-transplant periods.     

C4d-negative antibody-mediated rejection in renal allografts: evidence for its existence and effect on graft survival

The use of C4d staining as a tissue marker for humoral immunity has served an important role in allowing pathologists to more accurately diagnose acute antibody-mediated rejection (AMR) in renal and other allograft biopsies, and also to recognize the contribution of humoral immunity to lesions of chronic renal allograft rejection, including transplant glomerulopathy. However, while C4d remains a specific marker of a humoral response, recent evidence indicates that a considerable fraction of renal allograft biopsies showing antibody-mediated injury are C4d-negative, even by immunofluorescence. This review summarizes the current evidence supporting the existence of C4d-negative AMR, as well as evidence that this entity may, if untreated, lead to the development of scarring within the graft, transplant glomerulopathy and even graft loss.     

Analysis of Different Staining Techniques for C4d Detection in Renal Allograft Biopsies

Capillary C4d deposition has been recognized as a marker of antibody-mediated rejection (AMR). Although the detection of capillary C4d by means of immunofluorescence (IF) in cryostat sections is well established, frozen tissue is not always available, thus limiting the diagnosis of AMR. The aim of the present study was to analyze different techniques for C4d staining and the prevalence of C4d in renal allograft biopsies. Detection of C4d was carried out using IF or immunohistochemistry (IHC) on frozen and paraffin sections of renal allograft biopsies available from the same patients. Biopsies obtained from 20 patients were classified into 3 groups: no rejection, acute rejection, and chronic allograft nephropathy (CAN). The capillary C4d deposition prevalence in frozen-IF, considered the gold standard technique for C4d detection, was 45% (9/20 cases). Compared with frozen-IF, the frozen-IHC technique presented an 85% concordance rate (17/20 cases; r = .70; P < .001; sensitivity = 77.8%; specificity = 90.9%). The paraffin-IF technique showed similar results, with an 80% concordance rate (16/20 cases; r = .64; P < .005; sensitivity = 55.6%; specificity = 100%), whereas C4d detection occurred in only 65% of paraffin-IHC cases (13/20; r = .30; not significant; sensitivity = 66.7%; specificity = 63.6%). No capillary C4d deposition was detected in cases without evidence of rejection. However, 4/7 cases (57%) of acute rejection were C4d positive. In the CAN group, 5/11 cases (45%) were C4d positive. In conclusion, these results demonstrated that frozen-IHC and paraffin-IF can be considered alternative techniques to frozen-IF for C4d detection. The paraffin-IHC technique displayed the lowest concordance rate for C4d detection.     

Peritubular capillary C4d deposition and renal outcome in post-transplant IgA nephropathy

BACKGROUNDS: Immunological staining of the transplanted kidney for C4d in peritubular capillaries (C4d(PTC)) has emerged as a useful method to detect antibody-mediated rejection in situ. In this retrospective study, we evaluated the prevalence of C4d(PTC) deposition in allograft renal biopsies diagnosed of IgA nephropathy (IgAN) and analysed its clinical significance. METHOD: Sixty-six biopsy specimens of post-transplant IgAN, which were obtained to evaluate azotemia and/or heavy proteinuria, were examined by immunohistochemical staining of the paraffin sections with polyclonal antibody for C4d. RESULTS: C4d was stained positively in peritubular capillaries in 16 (24%) of the 66 cases. The C4d(PTC)-negative (n=50) and C4d(PTC)-positive groups (n=16) were not different in recipient gender, age, donor age, type of donor (living vs. cadaveric), interval from transplantation to graft biopsy (41.6+/- 21.8 vs. 48.3+/-26.1 months) and post-biopsy follow-up period (60.3+/-23.3 vs. 56.9+/-25.4 months). During the follow-up period, 12 of 50 (24%) although the incidence of graft failure was not different by the C4d deposition in peritubular capillaries, intervals from renal biopsy to graft failure tended to be shorter in C4d(PTC)-positive cases than C4d(PTC)-negative cases. In Kaplan-Meier analysis, the renal allograft function of the C4d(PTC)-positive group deteriorated more rapidly than that of the C4d(PTC)-negative group (p<0.05). Histologically, the C4d(PTC)-positive group had findings suggestive of acute cellular rejection more commonly than the C4d(PTC)-negative group (p<0.01). CONCLUSIONS: Evidence of humoral rejection, as demonstrated by C4d(PTC) deposition, was concurrently present in significant portions of post-transplant IgAN biopsy specimens and was associated with more rapid deterioration of renal function. These results suggest that C4d(PTC) positivity needs to be determined at the time of biopsy even in cases of post-transplant glomerulonephritis and immunosuppression may need to be modified accordingly.     

Re‐examination of the Lymphocytotoxic Crossmatch in Liver Transplantation: Can C4d Stains Help in Monitoring?

C4d-assisted recognition of antibody-mediated rejection (AMR) in formalin-fixed paraffin-embedded tissues (FFPE) from donor-specific antibody-positive (DSA+) renal allograft recipients prompted study of DSA+ liver allograft recipients as measured by lymphocytotoxic crossmatch (XM) and/or Luminex. XM results did not influence patient or allograft survival, or cellular rejection rates, but XM+ recipients received significantly more prophylactic steroids. Endothelial C4d staining strongly correlates with XM+ (<3 weeks posttransplantation) and DSA+ status and cellular rejection, but not with worse Banff grading or treatment response. Diffuse C4d staining, XM+, DSA+ and ABO- incompatibility status, histopathology and clinical-serologic profile helped establish an isolated AMR diagnosis in 5 of 100 (5%) XM+ and one ABO-incompatible, recipients. C4d staining later after transplantation was associated with rejection and nonrejection-related causes of allograft dysfunction in DSA- and DSA+ recipients, some of whom had good outcomes without additional therapy. Liver allograft FFPE C4d staining: (a) can help classify liver allograft dysfunction; (b) substantiates antibody contribution to rejection; (c) probably represents nonalloantibody insults and/or complete absorption in DSA- recipients and (d) alone, is an imperfect AMR marker needing correlation with routine histopathology, clinical and serologic profiles. Further study in late biopsies and other tissue markers of liver AMR with simultaneous DSA measurements are needed.     

体液性排斥反应患者移植物组织C4d沉积和浆细胞聚集性浸润初探

目的检测移植肝及肾组织中浆细胞的浸润和补体C4裂解产物C4d的沉积情况,分析浆细胞浸润、C4d沉积与体液性排斥反应的相关性。方法25例肝移植术后出现不同程度肝脏损害的患者的34次经皮肝脏穿刺活体组织病理检查标本与43例因排斥反应而丧失功能的移植肾组织,进行HE染色和免疫组织化学染色,对排斥反应进行病理分型,检测移植物组织中C4d和CD138的表达,分析二者之间的相关性。同时以10例非排斥反应导致移植肾功能丧失者和供肝术前标本作为对照。结果34个移植肝组织标本病理检查诊断为急性排斥反应16个,慢性排斥反应9个,非排斥反应9个。移植前供肝病理标本中均未见C4d沉积,急性排斥反应和慢性排斥反应标本中分别有9／16（56．3％）和5／9（55．6％）见到C4d沉积现象,非排斥反应标本只有1例非吻合口胆管狭窄患者C4d染色也呈阳性（11．1％）。移植肝排斥反应标本中11／25（44．0％）CD138阳性,8／25（32．0％）标本C4d和CD138均阳性。C4d的沉积与CD138的表达存在相关性（r=0．346,P〈0．05）。43例移植肾排斥反应中,超急性排斥反应5例,急性排斥反应9例,慢性排斥反应29例;43例中,C4d阳性19例（44．2％）,CD138阳性24例（55．8％）;有10例（23．3％）C4d和CD138均阳性,C4d的沉积与CD138的表达亦存在相关性（r=0．5051,P〈0．01）。10个对照标本中,C4d阳性1个,无CD138阳性标本。结论CD138与C4d的沉积存在相关性,提示移植肝和肾组织中聚集性浸润的浆细胞可能通过局部分泌抗体的方式参与体液性排斥反应。     

Peritubular capillary C4d staining in late acute renal allograft rejection – is it relevant?

Abstract: Background: In the early post-transplant period, renal allograft rejection with diffuse peritubular capillary (PTC) C4d deposition predicts poor graft survival. In the late post-transplant setting, that is, one or more yr after transplantation, the implication of diffuse PTC C4d deposition is still a topic of debate. The purpose of our study was to see if diffuse PTC C4d deposition, in late acute rejection (LAR), occurring more than one yr post-transplant, has any impact on graft survival and function. Methods: We selected cases, both cadaveric as well as living donor renal transplant recipients, in whom acute rejection with PTC C4d deposition was first detected after the first year post-transplant. Recipients with multiple acute rejection episodes during the first year post-transplant were excluded from the study. The first biopsy diagnosed with LAR was considered the index biopsy (n = 40). We formed two groups: group 1, C4d-positive LAR (n = 20), and group 2, C4d-negative LAR (n = 20). Groups were matched for maintenance and post-rejection immunosuppressive therapy, baseline serum creatinine levels before the time of the index biopsy, time from transplant to index biopsy, as well as chronic allograft damage index (CADI) score in the index biopsies. We compared the rate of graft loss, and the graft function of the surviving grafts at the end of the study period, as well as histologic parameters in the index biopsy specimens between the two groups. The mean follow-up period was 20 months. Results: No significant differences in the rate of graft loss or graft function were found between groups 1 and 2 at the end of the follow-up period. Histologically, PTC margination and transplant glomerulopathy were more common in the C4d-positive group, and this difference was statistically significant. There was no statistically significant difference in the degree of plasma cell infiltrates. Conclusions: Unlike in the acute setting, the presence or absence of PTC C4d staining in renal allografts with LAR may not have a predictive value regarding graft outcome.     

Presentation and Outcomes of C4d‐Negative Antibody‐Mediated Rejection After Kidney Transplantation

The updated Banff classification allows for the diagnosis of antibody‐mediated rejection (AMR) in the absence of peritubular capillary C4d staining. Our objective was to quantify allograft loss risk in patients with consistently C4d‐negative AMR (n = 51) compared with C4d‐positive AMR patients (n = 156) and matched control subjects without AMR. All first‐year posttransplant biopsy results from January 2004 through June 2014 were reviewed and correlated with the presence of donor‐specific antibody (DSA). C4d‐negative AMR patients were not different from C4d‐positive AMR patients on any baseline characteristics, including immunologic risk factors (panel reactive antibody, prior transplant, HLA mismatch, donor type, DSA class, and anti‐HLA/ABO‐incompatibility). C4d‐positive AMR patients were significantly more likely to have a clinical presentation (85.3% vs. 54.9%, p < 0.001), and those patients presented substantially earlier posttransplantation (median 14 [interquartile range 8–32] days vs. 46 [interquartile range 20–191], p < 0.001) and were three times more common (7.8% vs 2.5%). One‐ and 2‐year post–AMR‐defining biopsy graft survival in C4d‐negative AMR patients was 93.4% and 90.2% versus 86.8% and 82.6% in C4d‐positive AMR patients, respectively (p = 0.4). C4d‐negative AMR was associated with a 2.56‐fold (95% confidence interval, 1.08–6.05, p = 0.033) increased risk of graft loss compared with AMR‐free matched controls. No clinical characteristics were identified that reliably distinguished C4d‐negative from C4d‐positive AMR. However, both phenotypes are associated with increased graft loss and thus warrant consideration for intervention.     

C4d immunostaining is an independent predictor of cardiac allograft vasculopathy and death in heart transplant recipients

Antibody‐mediated rejection (AMR) occurs in 10–20% of patients after heart transplantation. C4d immunostaining is one parameter used in its diagnosis. This study aimed to determine whether C4d staining has prognostic significance for mortality, coronary allograft vasculopathy (CAV), cell‐mediated rejection (CMR), and graft dysfunction in patients post‐transplantation. Consecutive patients receiving an endomyocardial biopsy between 2007 and 2008 were selected. Left ventricular function, angiography, episodes of AMR/CMR, and death were noted. C4d was graded from 0 to 3 (immunostaining). Cox proportional models (recurrent events analysis) were used to evaluate C4d staining with mortality, graft dysfunction, CAV (≥grade 2), and episodes of ≥2R‐CMR. We analyzed 2525 biopsy specimens (n = 217). During a follow‐up of 4.5 ± 2 years, 35 died, 49 had graft dysfunction, seven had ≥grade 2 CAV, and 95 episodes of CMR occurred. A one‐grade increase in C4d staining was associated with an increase in mortality (HR 1.57; 95% CI 1.0–2.5), a higher risk of CAV (HR 2.4, 95% CI 1.04–5.4), and a trend toward graft dysfunction (HR 1.42; 95% CI 1.0–2.09). C4d was not associated with CMR. C4d immunostaining was a significant predictor of CAV and death but not subsequent episodes of CMR. There was also a trend toward increased graft failure.     

Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and pathologic classification

The incidence of acute humoral rejection (AHR) in renal allograft biopsies has been difficult to determine because widely accepted diagnostic criteria have not been established. C4d deposition in peritubular capillaries (PTC) of renal allografts has been proposed as a useful marker for AHR. This study was designed to test the relative value of C4d staining, histology, and serology in the diagnosis of AHR. Of 232 consecutive kidney transplants performed at a single institution from July 1995 to July 1999, all patients (n = 67) who developed acute rejection within the first 3 mo and had a renal biopsy with available frozen tissue at acute rejection onset, as well as posttransplant sera within 30 d of the biopsy, were included in this study. Hematoxylin and eosin and periodic acid-Schiff stained sections were scored for glomerular, vascular, and tubulointerstitial pathology. C4d staining of cryostat sections was done by a sensitive three-layer immunofluorescence method. Donor-specific antibodies (DSA) were detected in posttransplant recipient sera using antihuman-globulin-enhanced T cell and B cell cytotoxicity assays and/or flow cytometry. Widespread C4d staining in PTC was present in 30% (20 of 67) of all acute rejection biopsies. The initial histologic diagnoses of the C4d(+) acute rejection cases were as follows: AHR only, 30%; acute cellular rejection (ACR) and AHR, 45%; ACR (CCTT types 1 or 2) alone, 15%; and acute tubular injury (ATI), 10%. The distinguishing morphologic features in C4d(+) versus C4d(-) acute rejection cases included the following: neutrophils in PTC, 65% versus 9%; neutrophilic glomerulitis, 55% versus 4%; neutrophilic tubulitis, 55% versus 9%; severe ATI, 75% versus 9%; and fibrinoid necrosis in glomeruli, 20% versus 0%, or arteries, 25% versus 0%; all P < 0.01. Mononuclear cell tubulitis was more common in the C4d(-) group (70% versus 100%; P < 0.01). No significant difference between C4d(+) and C4d(-) acute rejection was noted for endarteritis, 25% versus 32%; interstitial inflammation (mean % cortex), 27.2 +/- 27% versus 38 +/- 21%; interstitial hemorrhage, 25% versus 15%; or infarcts, 5% versus 2%. DSA were present in 90% (18 of 20) of the C4d(+) cases compared with 2% (1 of 47) in the C4d(-) acute rejection cases (P < 0.001). The pathology of the C4d(+) but DSA(-) cases was not distinguishable from the C4d(+), DSA(+) cases. The C4d(+) DSA(-) cases may be due to non-HLA antibodies or subthreshold levels of DSA. The sensitivity of C4d staining is 95% in the diagnosis of AHR compared with the donor-specific antibody test (90%). Overall, eight grafts were lost to acute rejection in the first year, of which 75% (6 of 8) had AHR. The 1-yr graft failure rate was 27% (4 of 15) for those AHR cases with only capillary neutrophils versus 40% (2 of 5) for those who also had fibrinoid necrosis of arteries. In comparison, the 1-yr graft failure rates were 3% and 7%, respectively, in ACR 1 (Banff/CCTT type 1) and ACR 2 (Banff/CCTT type 2) C4d(-) groups. A substantial fraction (30%) of biopsy-confirmed acute rejection episodes have a component of AHR as judged by C4d staining; most (90%), but not all, have detectable DSA. AHR may be overlooked in the presence of ACR or ATI by histology or negative serology, arguing for routine C4d staining of renal allograft biopsies. Because AHR has a distinct therapy and prognosis, we propose that it should be classified separately from ACR, with further sub-classification into AHR 1 (neutrophilic capillary involvement) and AHR 2 (arterial fibrinoid necrosis).     

C1q binding is not an independent risk factor for kidney allograft loss after an acute antibody‐mediated rejection episode: a retrospective cohort study

After kidney transplantation, C4d is an incomplete marker of acute antibody‐mediated rejection (AMR) and C1q‐binding donor‐specific antibodies (DSA) have been associated with allograft survival. However, the impact on allograft survival of C1q+ DSA after clinical AMR has not been studied yet. We analysed retrospectively in clinical AMR C4d staining and C1q‐binding impact on allograft survival. We compared clinical, histological and serological features of C4d− and C4d+ AMR, C1q+ and C1q− DSA AMR and analysed C4d and C1q‐binding impact on allograft survival. Among 500 for‐cause kidney allograft biopsies, 48 fulfilled AMR criteria. C4d+ AMR [N = 18 (37.5%)] have significantly higher number class I DSA (P = 0.02), higher microvascular score (P = 0.02) and more transplant glomerulopathy (P = 0.04). C1q+ AMR [N = 20 (44%)] presented with significantly more class I and class II DSA (P = 0.005 and 0.04) and C4d+ staining (P = 0.01). Graft losses were significantly higher in the C4d+ group (P = 0.04) but similar in C1q groups. C4d+ but not C1q+ binding was an independent risk factor for graft loss [HR = 2.65; (1.11–6.34); P = 0.028]. In our cohort of clinical AMR, C4d+ staining but not C1q+ binding is an independent risk factor for graft loss. Allograft loss and patient survival were similar in C1q+ and C1q− AMR.     

移植肾活组织检查191例的病理学研究

目的：研究供肾可能携带的病变及移植肾在术后出现合并症时间相应的病理组织学变化。方法对191例移植肾进行了活组织检查（以下简称“活检”,其中术中活检52例,术后活检139例,并进行病理学诊断与分类。结果（1）52例术中活检,40例（76．92％）正常,余12例（23．07％）供肾携带病变,其中细小动脉硬化3例（5．77％）、间质炎症4例（7．69％）、局部肾小管轻度萎缩3例（5．77％）、肾小管上皮细胞变性2例（3．84％）。（2）139例术后活检中明确诊断的134例（96．40％）,其中正常19例（13．66％）,超急性排斥反应（SAR）1例（0．71％）疑为急性排斥反应／临界性变化（S／B）15例（10．795）,急性排斥反应（AR）23例（16．54％、慢性移植肾肾病（CNA）37例（26．61％）、环孢素肾毒性损伤（CsA-NT)29例（20．80％）、急性肾小管坏死（ATN）8例（5．75％）、复发性肾炎（RN）2例（1．43％）、难以明确诊断的5例（3．59％）。（3）免疫细胞化学色显示AR时,侵入肾小管上皮内的Leu-7阳性细胞数增加,间质内CD68阳性细胞数明显增加。结论活检是诊断术后多种合并症的有效手段;CAN可在术后3个月发生;侵入肾小管上皮的Leu－7阳性细胞是协助诊断AR的有效指标。     

Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients

Sensitized renal transplant recipients with high levels of donor-specific alloantibody (DSA) commonly develop antibody-mediated rejection (AMR), which may cause acute graft loss or shorten allograft survival. We examined the efficacy of terminal complement inhibition with the humanized anti-C5 antibody, eculizumab, in the prevention AMR in renal transplant recipients with a positive crossmatch against their living donor. The incidence of biopsy-proven AMR in the first 3 months posttransplant in 26 highly sensitized recipients of living donor renal transplants who received eculizumab posttransplant was compared to a historical control group of 51 sensitized patients treated with a similar plasma exchange (PE)-based protocol without eculizumab. The incidence of AMR was 7.7% (2/26) in the eculizumab group compared to 41.2% (21/51) in the control group (p = 0.0031). Eculizumab also decreased AMR in patients who developed high levels of DSA early after transplantation that caused proximal complement activation. With eculizumab, AMR episodes were easily treated with PE reducing the need for splenectomy. On 1-year protocol biopsy, transplant glomerulopathy was found to be present in 6.7% (1/15) eculizumab-treated recipients and in 35.7% (15/42) of control patients (p = 0.044). Inhibition of terminal complement activation with eculizumab decreases the incidence of early AMR in sensitized renal transplant recipients (ClincalTrials.gov number NCT006707).     

C4d analysis in endomyocardial biopsies of heart transplant patients: is there a correlation with hemodynamic data?

Background

Endomyocardial biopsy (EMB) is the gold standard for immunologic follow-up to detect acute cellular rejection after cardiac transplantation. Conversely, protocols for the diagnosis and treatment of antibody-mediated rejection (AMR) are not well defined. Histologically, AMR is diagnosed by the presence of capillary damage associated with complement activation. The aim of this study was to correlate C4d expression of activated complement in EMB with hemodynamic compromise upon right heart catheterization.

Methods

Heart transplant patients underwent hemodynamic and histologic follow-up with EMB and right heart catheterization between January 2008 and December 2009 for a total of 491 procedures. The cardiac biopsy was evaluated for acute cellular and AMR by means of the presence of the C4d complement fraction. The histologic results were compared with hemodynamic data registered during right heart catheterization.

Results

Comparison of the hemodynamic data of subjects with versus without C4d positivity showed no significant difference. Furthermore, there was no significant difference comparing patients with versus without C4d positivity in the absence of significant acute cellular rejection episodes. (C4d−/ACR− vs C4d+/ACR−). The variation of each single hemodynamic parameter from its basal value (defined as the mean value in case of C4d−/ACR−) seemed to not be influenced by the presence of C4d+.

Conclusions

In our experience, C4d has been routinely evaluated in the majority of EMBs. We could not demonstrate a significant correlation of C4d positivity with hemodynamic compromise. These findings suggest that significant allograft dysfunction is not related to C4d positivity. Therefore, the diagnosis of AMR is difficult to establish, because allograft dysfunction is 1 of the 3 fundamental criteria.     

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.