Evaluation of hepatocyte growth factor as a sensitive marker for early detection of acute renal allograft rejection

BACKGROUND: It has been shown that hepatocyte growth factor (HGF), besides its well-established hepatotrophic effect in liver regeneration, is involved in the regeneration of the kidney after injury. In the present study we investigated whether HGF can serve as a marker for detection of acute rejection in the early posttransplantation period. METHODS: HGF levels were determined in pre- and posttransplant sera (up to day 21) of 26 recipients with biopsy-proven acute rejection, 30 recipients with acute tubular necrosis (ATN), and 32 recipients without posttransplant complications. RESULTS: Although no association was found between pretransplant HGF and death-censored functional graft survival, receiver operating characteristic (ROC) curves demonstrated that HGF measured during the entire posttransplant study period, and especially on days 3 to 5, was a good marker for differentiating recipients who subsequently developed acute rejection from recipients with an uncomplicated course (P<0.0001, specificity 87%, sensitivity 84%). HGF measured from day 3 until day 21 posttransplantation, and especially on days 7 to 9, was also a sensitive marker for differentiating recipients with ATN from recipients with an uncomplicated course (P<0.0001). If considered in combination with sCD30, the diagnostic value of HGF was further improved. While 73% of samples from patients with impending rejection were positive for both HGF and sCD30, 94% of samples from nonrejecting patients were double-negative and none of the samples from this group fell into the double-positive category (P<0.0001). CONCLUSIONS: Our data suggest that HGF measured during the early posttransplant period might be a useful parameter for early detection of acute renal allograft rejection.     

Prediction of acute renal allograft rejection in early post-transplantation period by soluble CD30

To evaluate the feasibility of serum sCD30 for prediction of acute graft rejection, we analyzed clinical data of 231 patients, whose serum levels of sCD30 were detected by ELISA before and after transplantation. They were divided into three groups: acute rejection group (AR, n = 49), uncomplicated course group (UC, n = 171) and delayed graft function group (DGF, n = 11). Preoperative sCD30 levels of three groups were 183 +/- 74, 177 +/- 82 and 168 +/- 53 U/ml, respectively (P = 0.82). Significant decrease of sCD30 was detected in three groups on day 5 and 10 post-transplantation respectively (52 +/- 30 and 9 +/- 5 U/ml respectively, P < 0.001). Compared with Group UC and DGF, patients of Group AR had higher sCD30 values on day 5 post-transplantation (92 +/- 27 U/ml vs. 41 +/- 20 U/ml and 48 +/- 18 U/ml, P < 0.001). However, sCD30 levels on day 10 post-transplantation were virtually similar in patients of three groups (P = 0.43). Receiver operating characteristic (ROC) curve demonstrated that sCD30 level on day 5 post-transplantation could differentiate patients who subsequently suffered acute allograft rejection from others (area under ROC curve 0.95). According to ROC curve, 65 U/ml may be the optimal operational cut-off level to predict impending graft rejection (specificity 91.8%, sensitivity 87.1%). Measurement of soluble CD30 on day 5 post-transplantation might offer a noninvasive means to recognize patients at risk of impending acute graft rejection during early post-transplantation period.     

Serial Soluble CD30 Measurements as a Predictor of Kidney Graft Outcome

Background

High levels of soluble CD30 (sCD30), a marker for T-helper 2-type cytokine-producing T cells, pre or post-renal transplantation serves as a useful predictor of acute rejection episodes. Over the course of 1-year, we evaluated the accuracy of serial sCD30 tests to predict acute rejection episodes versus other pathologies that affect graft outcomes.

Patients and methods

Fifty renal transplant recipients were randomly selected to examine sCD30 on days 0, 3, 5, 7, 14, and 21 followed by 1, 3, 6, and 12 months. The results were analyzed for development of an acute rejection episode, acute tubular necrosis (ATN), or other pathology as well as the graft outcome at 1 year.

Results

Compared with pretransplantation sCD30, there was a significant reduction in the average sCD30 immediately posttransplantation from day 3 onward (P < .0001). Patients were divided into four groups: (1) uncomplicated courses (56%); (2) acute rejection episodes (18%); (3) ATN (16%); and (4) other diagnoses (10%). There was a significant reduction in sCD30 immediately posttransplantation for groups 1, 2, and 3 (P < .0001, .004, and .002 respectively) unlike group 4 (P = .387). Patients who developed an acute rejection episode after 1 month showed higher pretransplantation sCD30 values than these who displayed rejection before 1 month (P = .019). All groups experienced significant improvement in graft function over 1-year follow-up without any significant differences.

Conclusion

Though a significant drop of sCD30 posttransplantation was recorded, serial measurements of sCD30 did not show a difference among subjects who displayed acute rejection episodes, ATN, or other diagnoses.     

Immunological monitoring after organ transplantation: potential role of soluble CD30 blood level measurement

Analysing the relevance of soluble CD30 (sCD30) in the bloodstream before and after transplantation may be important for the monitoring of transplant recipients. In this study, 27 patients (15 pediatric liver and 12 adult kidney graft recipients) were investigated. In the liver graft group, the patients who developed acute rejection during the first month (n=9) had a slightly higher sCD30 value on pre-transplantation baseline (day 0) and post-transplantation day 7, when compared to patients with normal graft function (n=6) (day 0: 102(1.6) U/ml versus 118(1.5) U/ml, p=0.52) and (day 7: 69(1.5) U/ml versus 83(1.6) U/ml, p=0.47). Increased serum sCD30 was shown to correlate with increased interleukin-10 circulating levels between day 0 and day 7 (r=0.53; p=0.04), whereas, no correlation could be evidenced between interferon-gamma (IFN-gamma) and sCD30 (r=0.02; p=0.47). Similarly, in the kidney transplantation group, no significant difference was found in sCD30 levels at day 0 in both groups with graft rejection or normal graft function (n=6) (85(1.3) U/ml versus 77(1.6) U/ml, p=0.66), but sCD30 decreased significantly at day 7 post-transplantation from baseline value in the rejection group (n=6) (77(1.6) versus 35(1.4); p=0.02). We conclude that increased serum sCD30 was correlated with increased IL-10 (interleukin-10) circulating levels, but not with IFN-gamma levels in the post-transplantation period. Neither pre-transplantation sCD30 nor sCD30 at day 7 post-transplantation could be correlated with acute rejection in liver graft recipient. The monitoring of sCD30 might constitute a tool to assess the risk of acute rejection in renal transplant but did not appear as a valuable mean for early immunological monitoring in the small group of liver allograft recipients patients analysed in this study.     

肾移植患者急性排斥反应与sCD30的相关性

目的 研究检测肾移植患者手术前后血清溶解性CD30（sCD30）水平的临床意义。方法 采用酶联免疫吸附剂测定法（ELISA）检测69例肾移植患者术前及术后sCD30的水平，并分析sCD30与肾移植受者术后急性排斥发生的关系。结果 术前sCD30阳性患者11例，其中有6例发生急性排斥，sCD30阴性患者58例，发生急性排斥5例。两组相比排斥反应发生率差异有统计学意义（P〈0．01）。术后5dsCD30在发生排斥患者组中的水平与对照组间差异有统计学意义（P〈0．05），而术后1、3d水平两组间差异无统计学意义（P〉0．05）。结论 肾移植手术前后监测sCD30水平，特别是术前及术后第5天左右时的检测水平，对于评估和预测急性排斥反应发生的可能性，具有重要的参考价值。     

Evaluation of Serum sCD30 in Renal Transplantation Patients With and Without Acute Rejection

Despite new immunosuppressive approaches, acute rejection episodes (ARE) are still a major cause of early kidney dysfunction with a negative impact on long-term allograft survival. Noninvasive markers able to identify renal ARE earlier than creatinine measurement include sCD30. We sought to establish whether circulating levels of sCD30 in pretransplantation and posttransplantation periods were of clinical relevance to avoid graft damage. Quantitative detection of serum sCD30 was performed using an enzyme-linked immunosorbent assay. Our results demonstrated that the mean concentrations of sCD30 were significantly higher in the sera of renal transplant recipients with ARE (30.04 U/mL) and in uremic patients on the waiting list (37.7 U/mL) compared with healthy controls (HC; 9.44 U/mL), but not nonrejecting patients (12.01 U/mL). Statistical analysis revealed a strong association between high sCD30 levels in posttransplantation sera and ARE risk. This study suggested that sCD30 levels were a reliable predictor of ARE among deceased-donor kidney recipients.     

High pretransplantation soluble CD30 levels: impact in renal transplantation

In a retrospective study, the impact of the level of pretransplantation soluble CD30 molecule (sCD30) was evaluated on 3 year transplant survival, as well as the number and grade of acute rejection episodes among kidney recipients engrafted between 2000 and 2002. One hundred and ninety sera of 190 patients sampled on the cross-match day were tested for sCD30 concentrations using an enzyme-linked immunosorbent assay (ELISA) kit (Biotest). For the analysis, a sCD30 cutoff level of 100 U/mL was chosen: 87 (46%) recipients had a level >100, and 103 (54%) <100. All cases (5) of immunological graft loss showed a high sCD30 level. The rate of biopsy-proven acute rejection was 26% in the sCD30 >100 group versus 22% in the sCD30 <100 groups. Among the first graft population (n = 157), the rate was 27% for sCD30 >100 versus 20% for the lower level. The difference was more important for grade II acute rejection (Banff criteria): 6/87 (7%) showed high sCD30 versus 2/103 (2%) with sCD30 <100. This analysis became significant for anti-HLA immunization: 11 (13%) recipients developed anti-HLA class II antibodies in the first group (sCD30 >100) versus 1 (1%) in the second group (sCD30 <100; P < .01). A high pretransplantation sCD30 was not a significant risk factor for an acute rejection episode, but it seemed to be more predictive for antibody-mediated acute rejection and immunological graft loss. However, many recipients showed an increased pretransplantation concentration without any rejection episode or graft loss. Consequently, sCD30 pregraft measurements cannot be used as a predictor for acute kidney rejection among our transplant center, nor as an aid to adapt the immunosuppressive regimen.     

Identification of patients at risk of acute rejection by pretransplantation and posttransplantation monitoring of soluble CD30 levels in kidney transplantation

In this study, we investigated the impact of pre- and posttransplantation sCD30 monitoring on early (<6 months) acute rejection (AR) risk and analyzed the effect of different immunosuppressive regimens on posttransplantation sCD30 levels in kidney recipients. Fifty patients receiving kidney allograft and 10 healthy donors were included in this retrospective cohort study. Eight patients developed biopsy-proven AR (19%). In pretransplantation samples, patients showed a significantly higher sCD30 than healthy controls. The pretransplantation and posttransplantation (day-15) sCD30 levels were significantly elevated in rejecting patients compared to non-rejecting patients. No significant differences among immunosuppressive regimens were found in posttransplantation sCD30 levels. High pretransplantation and posttransplantation (day 15) sCD30 levels are associated with increased risk of early AR, and sCD30 can be another tool to evaluate immunological risk prior to kidney transplantation. There was no difference in immunosuppressive regimens used in this study on posttransplantation sCD30 levels at the first month.     

Plasma levels of soluble CD30 in kidney graft recipients as predictors of acute allograft rejection

In renal transplant recipients elevated soluble serum CD30 levels are associated with increased rejection and graft loss. We sought to determine the sCD30 plasma levels before and after kidney transplantation and to assess whether sCD30 was a predictive factor of immunological risk. sCD30 plasma levels were determined by an enzyme-linked immunosorbent assay assay in 52 kidney graft recipients before as well as 7, 15, and 21 days after transplantation. Eighteen patients developed acute allograft rejection (group I) and 34 patients showed uneventful courses (group II). Before transplantation sCD30 plasma levels were elevated in both groups (mean: 162.6 +/- 89.5 U/mL). After transplantation, group I recipients with acute rejection showed higher relative levels of plasma sCD30 on days 7 and 15 (120.8 +/- 74.6 U/mL and 210.6 +/- 108.7 U/mL respectively) compared with group II patients without rejection (95 +/- 45 U/mL and 59.4 +/- 31.6 U/mL), a difference that was significant for group I (P = .0003) and not significant for group II (P = .09). On day 21, sCD30 decreased in the two groups but remained higher among group I patients (120.6 +/- 92.7 U/mL). HLA antibodies were positive in 18 patients (34.6%) with 9 (50%) experiencing at last one episode of acute rejection. Among 34 patients negative for anti-HLA antibodies, nine displayed acute rejection only (26.4%), a difference that was not significant (P > .05). If we consider 100 U/mL as the minimum predictive level for allograft rejection, our results suggested that levels of sCD30 should be taken into consideration with the presence of HLA-antibodies detectable before and after transplantation, especially in patients with more than three HLA mismatches [RR = 3.20 (0.94 < RR < 10.91)]. These data suggested that measurement of plasma sCD30 is a useful procedure for the recognition of rejection in its earliest stages.     

Effect of panel-reactive antibody positivity on graft rejection before or after kidney transplantation

INTRODUCTION: Because it is well known that kidney transplant recipients with preformed lymphocytotoxic antibodies against HLA antigens have increased graft rejection rates, a serological crossmatch is routinely performed before kidney transplantation. But, the presence of these antibodies is not routinely monitored after transplantation. We investigated the panel-reactive antibody (PRA) response to know whether variations before or after kidney transplantation were associated with graft rejection. METHODS: We prospectively analyzed sera from 350 renal allograft recipients from September 1998 to March 2003. Pretransplantation and posttransplantation sera at 3 or 5 weeks postoperatively were tested in PRA. Recipients were stratified into 3 groups according to their PRA levels group I, PRA = 0; group II, PRA = less than 50%, and group III, PRA = more than 50%. RESULTS: The total graft rejection rate among 350 recipients was 9.4% (n = 33). Twenty-four pretransplantation PRA-positive recipients had a graft rejection rate of 20.8% (n = 5), compared with an 8.6% (n = 28) rate among 326 pretransplantation PRA-negative recipients. Six of 24 posttransplantation PRA-positive recipients (25%) experienced a graft rejection versus 27 (8.3%) of 326 posttransplantation PRA-negative subjects. Among the pretransplantation PRA stratae, the rejection rate in group III was 25% (1 of 4) versus 20% (4 of 20) in group II and 8.6% (28 of 326) in group I (P < .05). According to the postransplantation PRA level, 37.5% (3 of 8) in group III versus 18.8% (3 of 16) in group II and 8.3% (27 of 326) in group I (P < .05) had a graft rejection. CONCLUSION: Our study suggests that the PRA response pretransplantation and in the early posttransplantation period correlates with the kidney allograft rejection rate.     

Activated Effector and Memory T Cells Contribute to Circulating sCD30: Potential Marker for Islet Allograft Rejection

T-cell activation up-regulates CD30 resulting in an increase in serum soluble CD30 (sCD30). CD4+ T cells, a major source for sCD30, play a significant role in the pathogenesis of rejection. In this study, sCD30 was measured pre- and posttransplant in mouse islet allograft models and human islet allograft recipients. sCD30 was measured by ELISA in diabetic C57BL/6, CD4Knockout (KO) and CD8KO islet allograft recipients. sCD30 increased significantly prior to rejection (1.8 ± 1 days) in 80% of allograft recipients. Sensitization with donor splenocytes, or a second graft, further increased sCD30 (282.5 ± 53.5 for the rejecting first graft vs. 374.6 ± 129 for the rejecting second graft) prior to rejection suggesting memory CD4+ T cells contribute to sCD30. CD4KO failed to reject islet allograft and did not demonstrate sCD30 increase. CD8KO showed elevated (227 ± 107) sCD30 (1 day) prior to rejection. High pretransplant sCD30 (>20 U/ml) correlated with poor outcome in human islet allograft recipients. Further, increase in sCD30 posttransplant preceded (3–4 months) loss of islet function. We conclude that sCD30 is released from activated CD4 T cells prior to islet allograft rejection and monitoring sCD30 can be a valuable adjunct in the follow-up of islet transplant recipients.     

Soluble CD30 correlates with clinical but not subclinical renal allograft rejection

Soluble CD30 (sCD30) has been proposed as a promising noninvasive biomarker for clinical renal allograft rejection, but its diagnostic characteristics regarding detection of subclinical rejection have not been assessed. We investigated sCD30 in 146 consecutive kidney allograft recipients under tacrolimus–mycophenolate‐based immunosuppression having 250 surveillance biopsies at 3 and 6 months as well as 52 indication biopsies within the first year post‐transplant. Allograft histology results were classified as (i) acute Banff score zero or interstitial infiltrates only, (ii) tubulitis t1, (iii) tubulitis t2‐3 and (iv) isolated vascular compartment inflammation. sCD30 correlated well with the extent of clinical (P < 0.0001), but not subclinical tubulointerstitial rejection (P = 0.06). To determine diagnostic characteristics of sCD30, histological groups were assigned to two categories: no relevant inflammation (i.e. acute Banff score zero and interstitial infiltrates only) versus all other pathologies (tubulitis t1‐3 and isolated vascular compartment inflammation). For clinical allograft inflammation, AUC was 0.87 (sensitivity 89%, specificity 79%; P = 0.0006); however, for subclinical inflammation, AUC was only 0.59 (sensitivity 50%, specificity 69%; P = 0.47). In conclusion, sCD30 correlated with clinical, but not subclinical renal allograft rejection limiting its clinical utility as a noninvasive rejection screening biomarker in patients with stable allograft function receiving tacrolimus–mycophenolate‐based immunosuppression.     

C3D deposition in peritubular capillaries indicates a variant of acute renal allograft rejection characterized by a worse clinical outcome

BACKGROUND: C4d deposition in peritubular capillaries (PTCs) is a sign of humoral renal allograft rejection and an independent predictor of graft survival. Few investigators have focused on the meaning of capillary C3 deposition in rejecting grafts. Because C3 production can result from both classic and alternative pathway activation of the complement cascade, it is not clear whether C3 deposition indicates a distinct entity of acute rejection (AR) or merely represents a separate form of C4d-positive AR. METHODS: We examined the deposition of C3d in the PTCs of recipients with AR in the first year posttransplantation (n=30). Clinical outcome variables and histology were compared with C3d-negative control patients (n=82). RESULTS: C3d-positive patients demonstrated more frequent preexisting T-cell antibodies (57%) and more re-transplants (37%), and they received more blood transfusions (mean 10.3 units). C3d-positive patients experienced more frequent multiple AR episodes (57%) and delayed graft function (36.7%). All nine C3d-positive recipients screened for posttransplantation donor-specific human leukocyte antigen antibodies demonstrated positive results. Graft failure occurred in 23% of C3d-positive recipients (7.3% in the control group) (P=0.03). C3d-positive biopsies showed significantly less tubulitis (P=0.03), whereas congestive PTCs with intraluminal accumulation of polymorphonuclear leukocytes were conspicuous. Thrombi, fibrinoid necrosis, and acute tubular necrosis were not more pronounced. In 19% of rejection biopsies, C3d deposition in PTCs was present without C4d deposition. In the remaining biopsies, C3d and C4d deposition was found simultaneously. CONCLUSIONS: The deposition of complement factor C3d in PTCs indicates a variant type of AR characterized by a worse clinical outcome.     

sCD30 and neopterin as risk factors of chronic renal transplant rejection: impact of cyclosporine A, tacrolimus, and mycophenolate mofetil

High pretransplantation sCD30 levels have been shown to be associated with lower 5-year kidney graft survival in mainly Cyclosporine A (CsA)-treated recipients (Collaborative Transplant Study database). To analyze the effect of different immunosupressive regimens (CsA/Azathioprine [Aza], CsA/Mycophenolate Mofetil [MMF], Tacrolimus [Tacr]/Aza) on sCD30, we assessed serum sCD30 and neopterin together with in vitro cytokine responses in a prospective randomized study of 84 renal transplant recipients before, 4 months, and 1 year after transplantation. Panel-reactive antibody (PRA) formation, HLA matching, ATG induction therapy, and acute rejections had no impact on sCD30 levels, whereas cytomegalovirus (CMV) infections induced an up-regulation of sCD30 4 months posttransplantation (P = .003). Whereas MMF showed no effect on sCD30 compared with Aza therapy, we found a significant impact of Tacr versus CsA treatment (1-year sCD30 ≥60 U/mL: 14/42 (33%), CsA; 1/38 (3%), Tacr; P < .0005). Chronic rejection 2 years posttransplantation was associated with elevated 1-year sCD30 (P = .001) and neopterin levels (P = .006). Our data indicate that the Th2 activation marker sCD30 provides a risk factor for chronic rejection independent of classical immunological risk factors and may be down-regulated using Tacr treatment.     

肾移植受者术前血清可溶性CD30水平对急性排斥的影响

目的 研究术前血清可溶性CD30(sCD30)水平对肾移植受者术后6个月内急性排斥及排斥类型的预测作用。方法 共纳入自1998年12月至2003年8月在本中心行同种异体肾移植手术且存有术前血标本的707例受者。 回顾性总结该组受者术后6个月内急性排斥的发生情况及其它临床资料,同时选取健康对照40例。用sCD30 ELISA 试剂盒复孔检测肾移植受者术前和健康对照血清sCD30水平。根据术前sCD30水平将肾移植受者分为低sCD30组、中间sCD30组和高sCD30组。结果 肾移植组术前sCD30水平明显高于健康对照。血管性、细胞性排斥及临界改变的发生率随着sCD30水平的升高而升高(P均 < 0.05),但低、中、高sCD30 3组急性排斥逆转率却分别为100%、90.6%和78.6%,低sCD30组、中间sCD30组与高sCD30组比较差异均有统计学意义(P均 < 0.05)。血管性排斥、细胞性排斥、临界改变和临床排斥的sCD30水平[(198.95±76.09)、(165.89±44.56)、(172.94±74.22)和(161.23±64.87) U/ml]和未排斥组[(133.76±61.95) U/ml]比较,差异均有统计学意义(P均 < 0.01)。多因素logistic回归分析显示,高sCD30、群体反应性抗体(PRA)阳性和巨细胞病毒(CMV)抗原阳性均为急性排斥的危险因素,优势比分别为2.683、2.384和2.065。结论 术前高sCD30水平预示术后急性排斥发生率的增高。     

Urinary fractalkine is a marker of acute rejection

Chemokines and their receptors play an important role in the development of allograft rejection through directing mononuclear cell invasion of the graft. To study whether chemokine assays in the urine could prove to be predictive of acute rejection, we measured the urinary excretion of several chemokines, including fractalkine, chemokine monokine induced by interferon-gamma, interferon-gamma-inducible protein 10, macrophage inflammatory protein-3 alpha, granzyme B, and perforin in 215 allograft recipients and in 80 healthy control subjects. The 67 patients with acute rejection had significantly higher levels of all urinary chemokines compared to the healthy controls or patients having chronic allograft nephropathy but with stable renal function. Only changes in urinary fractalkine differentiated patients with acute rejection from those with acute tubular necrosis. The 7 patients who lost their grafts had greater urinary fractalkine, interferon-gamma, and macrophage inflammatory protein-3 alpha concentrations than those patients with reversible acute rejection. The area under the receiver operating characteristic curve for fractalkine was the best indicator among all of the markers differentiating 39 patients diagnosed with steroid-resistant from the 28 patients with steroid-sensitive acute rejection and in predicting graft loss. Our study shows that measuring urinary fractalkine levels is a noninvasive approach for detecting acute rejection where high levels were associated with steroid-resistance and poor outcome.     

Pretransplant soluble CD30 level has limited effect on acute rejection, but affects graft function in living donor kidney transplantation

BACKGROUND: Serum soluble CD30 (sCD30) levels might be a useful marker of immunologic status in pre transplant (Tx) recipients. We retrospectively correlated preTx sCD30 levels (high versus low) on postTx graft survival, incidence of acute rejection, and graft function using stored preTx serum. METHODS: Of 254 recipients who underwent kidney Tx, 120 recipients were enrolled under the uniform criteria (living donor, age >25 years, viral hepatitis free, diabetes free). RESULTS: The preTx sCD30 was not significantly associated with differences in graft survival rate during 47.5+/-11.4 months of follow-up (P = 0.5901). High sCD30 (> or =115 U/ml) was associated with a higher incidence of clinically or pathologically defined acute rejection than low sCD30, but the difference was not statistically significant (33.9% vs. 22.4%, P = 0.164). The response rate to antirejection therapy in patients with high sCD30 was inferior to those with low sCD30, but also was not statistically significant (33.3% vs. 7.7%, P = 0.087). However, mean serum creatinine levels in high sCD30 patients at one month, one year, and three years postTx were significantly different from those with low sCD30 (P < 0.05). In multiple regression analysis, acute rejection episodes, donor age, kidney weight/recipient body weight ratio, and preTx sCD30 levels were independent variables affecting the serum creatinine level three years postTx. CONCLUSION: PreTx sCD30 level has a limited effect on the incidence of acute rejection and response to antirejection treatment, but inversely and independently affects serum creatinine level after living donor kidney transplantation.     

Soluble CD30 and ELISA‐detected human leukocyte antigen antibodies for the prediction of acute rejection in pediatric renal transplant recipients

Biomarker‐based post‐transplant immune monitoring for the prediction of impending graft rejection requires validation in specific patient populations. Serum of 28 pediatric renal transplant recipients within the framework of a well‐controlled prospective randomized trial was analyzed pre‐ and post‐transplant for soluble CD30 (sCD30), a biomarker reflecting mainly T‐cell reactivity, and anti‐human leukocyte antigen (anti‐HLA) antibody reactivity, a biomarker for B‐cell activation. A sCD30 concentration ≥40.3 U/ml on day 14 was able to discriminate between patients with or without biopsy‐proven acute rejection (BPAR) with a sensitivity of 100% and a specificity of 76%. Six of seven patients (86%) with BPAR showed a sCD30 above this cut‐off, whereas only 3/21 patients (14%) without BPAR had a sCD30 above this cut‐off (P = 0.004). For pre‐ and post‐transplant anti‐HLA class II reactivities by enzyme‐linked immunosorbent assay, a cut‐off value of 140 optical density was able to discriminate rejecters from nonrejecters with a sensitivity of 86% or 71% and a specificity of 81% or 90%, respectively. Withdrawal of steroids was associated with a approximately twofold higher serum sCD30 compared to controls, but did not affect anti‐HLA reactivities. An increased post‐transplant sCD30 serum concentration and positive pre‐ and post‐transplant anti‐HLA class II reactivities are informative biomarkers for impending BPAR in pediatric renal transplant recipients. (TWIST, Clinical Trial No: FG‐506‐02‐43)     

Association of elevated pretransplant sCD30 levels with graft loss in 206 patients treated with modern immunosuppressive therapies after renal transplantation

BACKGROUND: Recent reports suggest that high pretransplant serum levels of soluble CD30 (sCD30) are a risk factor for rejections after kidney transplantation. The aim of our study was to elucidate the predictive value of pretransplant sCD30 levels for kidney transplantation outcome in a single-center patient cohort that has been treated with modern immunosuppressive therapies after transplantation. METHODS: We retrospectively analyzed sCD30 in multiple pretransplant sera from 206 patients, of whom 174 were transplanted with a cadaveric kidney and 32 patients received an allograft from a living donor. Renal function after transplantation was estimated by measuring serum creatinine and by rejection diagnosis. RESULTS: We could demonstrate a statistically significant association between increased pretransplant sCD30 values and graft failures (P=0.005). Receiver operating curve analysis revealed a cutoff value of 124 U/mL pretransplant sCD30. A multivariate analysis confirmed pretransplant sCD30 values >124 U/mL (P=0.011) and rejection episodes (P<0.0001) as independent risk factors for graft loss. CONCLUSION: Our study revealed a strong correlation between pretransplant sCD30 levels and the incidence of graft failure, but we could not confirm that the development of rejection episodes is correlated with pretransplant sCD30 values.