Immunohistochemical evidence of activated lectin pathway in kidney allografts with peritubular capillary C4d deposition.

BACKGROUND: Complement 4d (C4d) deposition in the peritubular capillary (PTC) in the kidney allograft is a useful diagnostic marker for humoral rejection. C4d is produced not only by the classical pathway but also by the lectin pathway of the complement activation cascade. We have recently reported the in situ role of the later phase of the complement cascade in renal allografts with C4d deposition; however, the initial process prior to C4d deposition is yet to be resolved. METHODS: To clarify the early phases of the complement activation cascade, we evaluated the deposition of initial proteins of the above two pathways; IgG, IgM, mannose-binding lectin (MBL), H-ficolin, L-ficolin, MBL-associated serine protease (MASP)-1 and MASP-2 in kidney allografts with PTC C4d deposition. RESULTS: Sixty kidney allograft specimens were divided into two groups on the basis of the presence of C4d deposition in PTC. The C4d-positive group (n = 18) included nine ABO-identical and nine ABO-incompatible cases, and the C4d-negative group (n = 42) had 34 ABO-identical and eight ABO-compatible (but not identical) cases. In the C4d-positive group, 16 of 18 cases showed diffuse H-ficolin and IgM deposition in PTC. In contrast, H-ficolin and IgM were not detected in PTC in the C4d-negative group. Other initial proteins were not detected in all cases. CONCLUSIONS: Our study suggested for the first time that the lectin pathway activated by H-ficolin may be involved in C4d deposition on PTC in the kidney allograft.     

Capillary C4d deposition in kidney allografts: a specific marker of alloantibody-dependent graft injury

Capillary deposition of the complement split product C4d has been discussed as a marker for antibody-mediated kidney allograft rejection. The relationship between C4d staining and posttransplant alloantibody detection remains to be thoroughly investigated, however. In this study, C4d staining in peritubular capillaries (PTC) and the incidence of alloantibody formation, as detected with sensitive techniques, were evaluated among a cohort of transplant recipients who had undergone biopsies and had not been selected for a specific histologic diagnosis. One hundred thirteen biopsies, obtained from 58 cadaveric kidney transplant recipients, were tested. Serum samples obtained at the time of biopsy were evaluated by flow cytometric crossmatch (FCXM) testing and FlowPRA (One Lambda, Inc., Canoga Park, CA) analysis of anti-HLA panel reactivity. Most biopsies with C4d deposits in PTC (C4d(PTC)(+), n = 21 of 24) were associated with positive posttransplant FCXM results (T and/or B cell FCXM) and/or > or =5% FlowPRA (anti-HLA class I and/or II) reactivity. Approximately 50% of the C4d(PTC)(-) biopsies were observed to be associated with donor-specific alloantibodies. Accordingly, high specificity (93%) but low sensitivity (31%) were calculated for capillary C4d staining (with FCXM testing as the standard method). For clinical evaluation, three patient groups were defined, i.e., a group of recipients with positive C4d staining in at least one allograft biopsy (C4d(PTC)(+), n = 16) and two C4d(PTC)(-) groups, which were discriminated on the basis of posttransplant FCXM results as C4d(PTC)(-)/FCXM(+) (n = 22) and C4d(PTC)(-)/FCXM(-) (n = 20) groups. Univariate analyses revealed significant differences between these groups with respect to serum creatinine levels at 12 mo [median, 2.83 mg/dl (interquartile range, 1.93 to 4.2 mg/dl) versus 1.78 mg/dl (1.47 to 2.24 mg/dl) versus 1.59 mg/dl (1.2 to 1.71 mg/dl), P < 0.001]. Of the five immunologic graft losses, four occurred in the C4d(PTC)(+) group and one occurred in the C4d(PTC)(-)/FCXM(+) group. In a multivariate analysis, C4d positivity was observed to have an independent predictive value for inferior 12-mo graft function (P = 0.02), whereas the observed moderate difference between C4d(PTC)(-)/FCXM(+) and C4d(PTC)(-)/FCXM(-) recipients did not achieve significance. In conclusion, these data demonstrate that positive C4d staining, which is an independent predictor of kidney graft dysfunction, represents a reliable specific marker for antibody-dependent graft injury.     

Clinicopathological relevance of granular C4d deposition in peritubular capillaries of kidney allografts

While linear C4d staining in peritubular capillaries (PTC) is established as a marker of antibody‐mediated rejection, the significance of a distinct granular C4d deposition pattern has not yet been clarified. In this study, 329 renal allograft recipients who underwent indication biopsies were analysed for immunohistochemical C4d staining characteristics. Fifty‐six (17%) recipients showed granular C4d in PTC, without any relationship to conventional risk factors and morphological features of rejection. We found a strong association with long‐term overall graft survival (7‐year survival: 41% vs. 66% in granular C4d‐negative subjects, P = 0.001), which was mainly driven by a greater risk of mortality [hazard ratio: 3.12 (95% confidence interval: 1.23–7.94); P = 0.02]. Granular C4d was associated with delayed graft function [39% vs. 22% (C4d‐negative subjects), P = 0.007], higher 1‐year serum creatinine [median 2.1 (interquartile range: 1.7–2.6) mg/dl vs. 1.6 (1.3–2.0) mg/dl, P = 0.001] and a trend towards worse death‐censored graft survival (P = 0.07). In support of a role of capillary immune complex formation, granular C4d was associated with electron‐dense deposits in PTC basement membranes, which were occasionally accompanied by focally distributed capillary IgG deposits. In conclusion, our study suggests clinical relevance of detecting capillary granular C4d deposition. Our results point to a pathogenetic role of alloimmune‐independent immune complex deposition.     

C4d deposition in allografts: current concepts and interpretation

Alloantibody responses are not prevented by the latest immunosuppressive regimens and contribute to increased early and late renal allograft graft loss. Numerous papers have set forth the clinical, pathological, and immunopathological features of acute humoral rejection, in particular the strong correlation between the presence of C4d deposition and circulating antidonor HLA class I and class II antibodies. Humoral rejection also occurs in a chronic setting, associated with chronic allograft glomerulopathy and arteriopathy. C4d deposition can also be found in stable grafts without concurrent graft pathology, a finding that may indicate accommodation. The central diagnostic criterion for humoral rejection is the demonstration of C4d in peritubular capillaries. The criteria for humoral rejection are not as widely accepted for other organs, such as the heart, lung, and pancreas, although humoral rejection, including C4d deposition, has been described. This review focuses on the practical aspects of this test, particularly as applied routinely in renal allografts since 1998 in our laboratory.     

移植肾组织中补体C4d沉积在CAN的诊断和治疗中的临床意义

目的 探讨移植肾组织中补体C4d沉积在慢性移植肾肾病(CAN)的诊断和治疗中的临床意义.方法 将2000年1月至2008年8月间诊断为CAN,且已行移植肾活检,并能收集到活检后2年以上随访资料者纳入研究.符合标准者共有86例,其中男性53例,女性33例,移植时年龄18～65岁.应用免疫组织化学染色方法检测移植肾组织活检标本C4d的表达.所有患者在行移植肾穿刺诊断为CAN后均给予了常规治疗.结果 86例患者中,C4d沉积阳性者(C4d阳性组)39例,C4d沉积阴性者(C4d阴性组)47例,两组患者在性别、年龄、供肾来源、多次移植、移植时群体反应性抗体水平等各指标的比较,差异均无统计学意义(P＞0.05).活检2年后,C4d阳性组和阴性组患者的SCr水平分别为(551.5±140.4)和(443.0±133.1)μmol/L,两组比较,差异有统计学意义(P＜0.05);并且C4d阳性组患者移植肾功能丧失率(23.1%,10/39)也显著高于C4d阴性组(8.5%,4/47),两组比较,差异有统计学意义(P＜0.05).CAN治疗前,C4d阳性组发生高血压和高血脂者多于阴性组(P＜0.05);常规治疗后,剔除移植肾功能丧失者,两组间发生高血压、高血脂、高血糖和高血尿酸者差异无统计学意义(P＞0.05).结论 C4d阳性的CAN患者提示有慢性体液排斥反应的参与,临床常规治疗预后较差,若针对体液免疫反应进行干预,能够改善移植肾长期存活.     

C4d deposition in peritubular capillary and alloantibody in the allografted kidney suffering severe acute rejection

Abstract:  Background: Alloantibodies and C4d deposition in peritubular capillaries (PTCs) are thought to be related to antibody-mediated acute rejection. The purpose of this study was to evaluate the relationship between C4d deposition in PTCs and alloantibodies at various days after allograft dysfunction due to severe acute rejection. Method: There were 620 renal transplantations (Tx) performed. Forty patients diagnosed with acute humoral and/or vascular rejection showed graft dysfunction with anuria or dysuria. The patients were divided into four groups by ABO compatibility and clinical course after graft dysfunction: compatible recipients with graft loss (c-GL ; n  = 6); compatible recipients with recovery from graft dysfunction (c-RE; n  = 10); incompatible recipients with graft loss (i-GL; n  = 9); and incompatible recipients with recovery from graft dysfunction (i-RE; n  = 15). Results: C4d depositions in 4/6 c-GL recipients increased, and those in 8/10 c-RE recipients decreased after graft dysfunction. These changes in C4d deposition between the c-GL and the c-RE groups were significantly different ( P  < 0.01). These titres of anti-A/B IgG antibody in 7/9 i-GL recipients increased and those in 8/15 i-RE recipients decreased after graft dysfunction. These changes in titre between the i-GL and the i-RE groups were significantly different ( P  < 0.01). All c-GL recipients and 4/10 c-RE recipients had anti-HLA antibody at the last biopsy. There was a significant difference in the number of recipients who had anti-HLA antibody between the c-GL and the c-RE groups ( P  < 0.05). Conclusions: These results indicate that changes in C4d deposition in PTCs in the c-ABO group and titre of anti-A/B IgG antibody in the ABO-incompatible groups exert a strong impact on graft survival after dysfunction in the early period after Tx.     

Focal peritubular capillary C4d deposition in acute rejection.

BACKGROUND: Diffuse peritubular capillary (PTC) C4d deposition has been shown to be associated with relatively poor graft outcome. The significance of focal PTC C4d staining in the early post-transplant period is uncertain. METHODS: Sixty-five biopsies from 53 patients with acute rejection were graded (Banff '97 criteria), stained for C4d, monocytes and T cells, and divided into three groups according to PTC C4d: (i) focal C4d (F) (14 biopsies, 14 patients), (ii) diffuse C4d (D) (23 biopsies, 15 patients) and (iii) no C4d (N) (28 biopsies, 24 patients). The three groups were compared with respect to a variety of biopsy and clinical parameters including outcome. RESULTS: The incidence of transplant glomerulitis and glomerular monocyte infiltration were significantly greater in F (64% and 2.0+/-2.0) and D (57% and 3.4+/-2.0) than in N (11% and 0.2+/-0.2). A significantly higher proportion of F (93%) demonstrated acute cellular rejection (Banff '97 grade > or = 1A) than did D (35%). The F and D groups included significantly more females (50 and 67%, respectively) than did N (21%). The percentage of patients with a second or third transplant was higher in F (29%) and D (40%) than in N (8%) (P = 0.0589). The proportion of patients with glomerular filtration rate < 30 ml/min at 12, 24 and 48 months was higher in the D and F groups than in the N, and there was a statistically significant increasing trend in odds of this outcome occurring at 48 months across the three groups (D > F > N group) (P = 0.0416). CONCLUSION: The results suggest that the biopsy findings and clinical course in patients with focal PTC C4d staining are similar to those associated with diffuse C4d.     

C4d deposition in lung allografts is associated with circulating anti-HLA alloantibody

The complement activation demonstrated by vascular C4d deposition is used to diagnose antibody-mediated rejection (AMR) in renal allografts, but remains controversial in lung transplantation (LTX). METHODS: C4d deposition was assessed by immunohistochemistry in 192 lung transplant biopsies from 32 patients. ELISA analysis was performed on 415 serum samples in those 32 temporally and rejection-grade matched LTX patients; 16 patients developed HLA-Ab, while the other 16 patients remained negative. The specificity of C4d staining was further compared in 18 additional LTX patients without HLA-Ab or acute cellular rejection (ACR), but in the presence of CMV-pneumonitis or reperfusion injury. RESULTS: Specific subendothelial C4d deposition was seen in 5 of 16 (31%) patients with HLA-Ab and was absent in 16 patients without HLA-Ab (p<0.05). All patients with specific C4d deposition exhibited donor-specific HLA-Ab. There were 13 patients with bronchiolitis obliterans syndrome in the group of 16 HLA-Ab positive patients, versus 2/16 in ELISA-negative patients (p<0.005). One of 7 patients with CMV pneumonitis and 2 of 11 patients with reperfusion injury also showed C4d positivity (not statistically significant). CONCLUSIONS: In this study, specific subendothelial C4d deposition was a marker for the involvement of HLA-Ab in lung allograft rejection. The patchy nature, low sensitivity, and specificity of C4d staining might limit clinical use in protocol biopsies. However, in patients with decreasing pulmonary function, refractory ACR and/or HLA-Ab, specific C4d deposition may serve as a marker of coexistent AMR.     

Putative antibody-mediated rejection with C4d deposition in HLA-identical, ABO-compatible renal allografts

We sought evidence for non-MHC antibody-mediated rejection in renal allografts by a systematic study of rejected HLA-identical sibling renal allografts. Among 162 recipients of HLA-identical, ABO-compatible sibling donor kidneys transplanted at the Massachusetts General Hospital from 1964 to 2005, we identified 15 grafts that were lost from rejection and two additional grafts with reversible acute rejection, which provided 30 samples for study. All samples were stained for C4d by immunofluorescence in frozen tissue (n = 7) or by immunohistochemistry in paraffin embedded tissues (n = 10). We found that two of 17 grafts had positive C4d staining of peritubular capillaries. Histology revealed acute antibody-mediated rejection in one and acute cellular rejection type 1 in the other. Both grafts were matched at HLA-A, B, and C loci and had a nonreactive mixed lymphocyte response. Genotyping and serological analysis were not available. Compared with a published series, C4d+ irreversible rejection was more common in HLA nonidentical than HLA-identical grafts (75% vs 6.7%, respectively, P < .002). We conclude that antibody-mediated rejection, presumably due to non-MHC antigens other than ABO-blood groups does occur, but infrequently. This may account for some of the HLA antibody negative cases that develop antibody-mediated rejection.     

移植肾切除标本中C4d表达分析

目的 检测C4d在难治性排斥反应移植肾组织中的表达情况,分析体液免疫参与难治性排斥反应与移植肾长期存活的相关性.方法 以40例难治性排斥反应致移植肾切除患者为研究组(A组),20例移植术后因移植肾功能一过性异常行穿刺活检患者作为对照组(B组);应用C4d多克隆抗体对移植肾组织的石蜡切片行免疫组织化学染色,检测C4d在切除移植肾中的表达情况,分析2组标本中C4d的表达差异.结果 A组中检测到C4d阳性17例(42.5%),17例C4d阳性患者中存活时间＜5年的移植肾12例(70.6%),明显多于存活时间＞5年者的阳性数(5例,29.4%);B组中C4d阳性2例(10.0%),2组比较P=0.024.A组中受者男28例,女12例;年龄27～67岁,平均(39±10)岁;冷缺血时间6～12 min,热缺血时间170～720 min;免疫抑制方案为吗替麦考酚酯加环孢素加糖皮质激素19例、吗替麦考酚酯加他克莫司加糖皮质激素7例、硫唑嘌呤加环孢素加糖皮质激素14例;二次移植4例;31例术后仍有高血压.经t检验与X2检验,以上各因素与移植.肾C4d的阳性沉积无明显相关(P＞0.05).结论 体液免疫参与的难治性排斥反应是影响移植物长期存活的危险因素.     

Detection of humoral rejection in human cardiac allografts by assessing the capillary deposition of complement fragment C4d in endomyocardial biopsies.

BACKGROUND: There are no well-established diagnostic criteria to detect humoral rejection in organ transplantation. The value of commonly used markers in immunohistochemistry, such as C1q, C3c, IgG, IgM and fibrinogen, is questioned by some groups. Complement fragment C4d is a more stable marker of complement activation as it is covalently bound to graft capillaries. C4d has been shown to identify clinically relevant, but otherwise undetectable humoral anti-graft reactions in human kidney transplants. METHODS: Immunohistochemical techniques were used to evaluate 155 endomyocardial biopsies from 56 heart transplant recipients less than 3 months post transplantation for the presence of capillary C4d staining. In a subset of patients, C4d staining was compared with C1q, C3c, IgM and fibrin staining and was correlated with clinical outcome. RESULTS: Within 3 months 9 of 56 patients died. Five of these nonsurvivors had prominent C4d staining (p < .05), whereas C1q, C3c and IgM showed no correlation with clinical outcome. Presence of fibrin correlated with clinical outcome and C4d staining (p < .05). CONCLUSIONS: The capillary deposition of complement split product C4d in human endomyocardial biopsies was significantly associated with graft loss. Determination of fibrin deposition may yield additional information to establish a diagnosis of humoral rejection. The immunohistochemical assessment of capillary deposition of C4d and fibrin appears to be an appropriate tool for the identification of patients, who may require additional or alternative immunosuppressive therapy targeted against the humoral immune system.     

Monocytes and peritubular capillary C4d deposition in acute renal allograft rejection

BACKGROUND: Peritubular capillary (PTC) deposition of complement split factor C4d in renal allografts has been shown to be closely associated with circulating antidonor antibodies and a marker for relatively poor graft survival. Monocyte/macrophage (MO) infiltration of renal allografts has been shown to adversely affect graft survival. The purpose of this study was to assess whether the two phenomena are related. METHODS: Twenty-three biopsies (from 15 patients) demonstrated diffuse strong staining of PTC for C4d (C4d+ group) and acute tubular injury with or without significant cellular rejection, while 28 biopsies (with acute rejection) but negative for PTC C4d served as controls (C4d- group). RESULTS: The C4d+ group demonstrated significantly greater glomerular and interstitial MO infiltration than did the C4d- group [3.4 +/- 2.0 vs. 0.2 +/- 0.3 MO/glomerulus, P < 0.0001; 12.9 +/- 9.2 vs. 6.5 +/- 5.0 MO/high power field (hpf), P = 0.0030]. Neutrophilic (PMN) infiltration of glomeruli and PTC was also significantly greater in the C4d+ group than in the C4d- one (0.8 +/- 0.6 vs. 0.3 +/- 0.3 PMN/glomerulus, P = 0.0003; 0.9 +/- 0.8 vs. 0.4 +/- 0.3 PTC PMN/hpf, P = 0.0035). CONCLUSION: The results indicate a close association between PTC C4d deposition and MO infiltration, particularly glomerular, and confirm previous observations regarding the correlation of PTC C4d staining and PMN infiltration.     

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.     

C4d deposition without rejection correlates with reduced early scarring in ABO-incompatible renal allografts

C4d deposition in peritubular capillaries is a specific marker for the presence of antidonor antibodies in renal transplant recipients and is usually associated with antibody-mediated rejection (AMR) in conventional allografts. In ABO-incompatible grafts, however, peritubular capillary C4d is often present on protocol biopsies lacking histologic features of AMR; the significance of C4d in this setting remains unclear. For addressing this, data from 33 patients who received ABO-incompatible renal allografts (after desensitization) were retrospectively reviewed. Protocol biopsies were performed at 1 and/or 3 and 6 mo after transplantation in each recipient and at 12 mo in 28 recipients. Twenty-one patients (group A) had strong, diffuse peritubular capillary C4d staining without histologic evidence of AMR or cellular rejection on their initial protocol biopsies. The remaining 12 patients (group B) had negative or weak, focal peritubular capillary C4d staining. Three grafts (two in group B) were lost but not as a result of AMR. Excluding these three patients, serum creatinine levels were similar in the two groups at 6 and 12 mo after transplantation and at last follow-up; however, recipients in group A developed significantly fewer overall chronic changes, as scored by the sum of Banff chronic indices, than group B during the first year after transplantation. These results suggest that diffuse peritubular capillary C4d deposition without rejection is associated with a lower risk for scarring in ABO-incompatible renal allografts; the generalizability of these results to conventional allografts remains unknown.     

Risk factors for development of decreased kidney function in a southeast Asian population: a 12-year cohort study

End-stage kidney disease has become an increasing burden in all regions of the world. However, limited epidemiologic data on chronic kidney disease in Southeast Asian populations are available. Therefore, a cohort study over a period of 12 yr (1985 to 1997) in 3499 employees of the Electric Generation Authority of Thailand, aged 35 to 55 yr, was conducted to determine the prevalence of decreased kidney function and risk factors associated with future development of decreased kidney function. The prevalence of decreased kidney function (GFR <60 ml/min) increased from 1.7% (95% confidence interval [CI], 1.3 to 2.1) in 1985 to 6.8% (95% CI, 5.7 to 7.9) in 1997, and the prevalence of elevated serum creatinine was 6.1% (95% CI, 5.3 to 6.9) and 16.9% (95% CI, 15.3 to 18.5) in 1985 and 1997 surveys, respectively. The adjusted odds ratio for future development of decreased kidney function was 2.57 (1.0 to 6.81) for systolic hypertension (>159 mmHg), 1.82 (1.12 to 2.98) for hyperuricemia (>6.29 mg/dl), 1.68 (1.02 to 2.77) for elevated body mass index (>24.9 kg/m(2)) compared with subjects with systolic BP <140 mmHg, serum uric acid <4.5 mg/dl, and body mass index 20.8 to 22.8 kg/m(2). The rising prevalence of decreased kidney function in this population resulted mainly from the increasing prevalence of the risk factors in the population. Screening to detect decreased kidney function and early intervention to modify the associated risk factors should be considered in otherwise healthy individuals. Future studies are also necessary to determine whether implementation of these measures results in a reduction of ESRD incidence in the population.     

Occupational risk factors for kidney cancer: a cohort study in Sweden

Although many studies have examined the associations between occupational exposures and kidney cancer, the evidence is not consistent. To examine the risk of occupational exposures on kidney cancer, we carried out a follow-up study on the economically active Swedish population, based on the latest update of the Swedish Family-Cancer Database. We calculated standardized incidence ratios (SIR) and 95% confidence intervals (CIs) for different occupational groups, adjusted for age, period, and socioeconomic status. The reference group was all the economically active population. An increased risk of renal parenchymal cancer was observed for miners and quarry workers, drivers, sales agents, transport workers, and public safety and protection workers among men, and launderers and dry cleaners among women. Significantly increased SIRs of renal pelvical cancer were also observed for the food manufacture workers among men, and journalists and shoe and leather industry workers among women. Male forestry workers, smelters, and metal foundry workers had increased risk for unspecified kidney cancer. Although smoking may explain some of these results, exposure to gasoline, diesel, their exposure products, some metal and chemicals in shoe and leather works, and dry-cleaning products may be associated with kidney cancer.     

移植肾抗体介导排异中C4d的病理机制及临床意义

移植肾排斥反应中的抗体介导机制已得到了明确分类,而C4d在肾小管周毛细血管(PIC)中的沉积是其特征性表现,与肾功能及移植肾预后亦有紧密联系.本文对C4d在移植肾抗体介导排斥反应中的病理作用及指导治疗的意义进行综述.     

Sinusoidal C4d deposits in liver allografts indicate an antibody-mediated response: diagnostic considerations in the evaluation of liver allografts

There is a paucity of data concerning the correlation of complement component 4d (C4d) staining in liver allografts and antibody-mediated rejection. Data about the location and character of C4d deposits in native and allograft liver tissues are inconsistent. We performed C4d immunofluorescence (IF) on 141 fresh-frozen liver allograft biopsy samples and native livers, documented the pattern of C4d IF staining, and correlated the findings with the presence of donor-specific alloantibodies (DSAs). A linear/granular sinusoidal pattern of C4d IF was noted in 18 of 28 biopsy samples obtained after transplantation from patients with positive crossmatch and detectable donor-specific alloantibody (pos-XM/DSA) findings. None of the 59 tested biopsy samples from patients with negative crossmatch and detectable donor-specific alloantibody (neg-XM/DSA) findings were C4d-positive (P < 0.001). No significant association was found between pos-XM/DSA and C4d IF staining in other nonsinusoidal liver compartments. To compare the results of sinusoidal C4d staining with IF and 2 immunohistochemistry (IHC) techniques, C4d IHC was performed on 19 liver allograft biopsy samples in which a sinusoidal pattern of C4d IF had been noted. Sinusoidal C4d IHC findings were negative for 17 of the 19 biopsy samples; 2 showed weak and focal staining, and both patients had pos-XM/DSA findings. Portal vein endothelium staining was present in only 1 IF-stained biopsy sample (pos-XM/DSA) but in 11 IHC-stained biopsy samples (2 of the 11 samples had neg-XM/DSA findings). We conclude that sinusoidal C4d deposits detected by IF in frozen tissue samples from liver allograft recipients correlate with the presence of DSAs and an antibody-mediated alloresponse. These observations are similar to findings reported for other solid organ transplants and can provide relevant information for patient management. Further validation of IHC techniques for C4d detection in liver allograft tissue is required.