Renal and Urinary Levels of Endothelial Protein C Receptor Correlate with Acute Renal Allograft Rejection (original) (raw)
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Clinical Chemistry and Laboratory Medicine, 2009
Background: Endothelial cell antigens are important targets in acute rejection (AR). Our goal was to measure the serum concentrations of pre-transplant antiendothelial cell antibody (AECA) in panel reactive antibody (PRA) negative recipients and its impact on AR within 6 months following renal transplantation. Methods: We retrospectively examined pre-transplant sera from 392 patients using cellular enzyme linked immunosorbent assay (ELISA) with substrate from a permanent endothelial cell line EAhy926. Equal volumes of serum from 40 healthy volunteers were mixed and used as the negative control. Results: The positive rate of AECA was 15.8%. There were no significant differences with respect to age, gender, original disease, dialysis history, immune suppressive regimen, cytomegalovirus (CMV) antigen positive rate, complement dependent cytotoxicity (CDC) level and soluble CD30 (sCD30) levels between the AECA positive group and AECA negative group. AR rate in the AECA positive group was higher than that in the AECA negative group (35.5% vs. 22.4%, ps0.023). The AECA positive patients had significantly higher rates of acute grade II T-cell mediated rejection (TMR) and acute antibody mediated rejection (AMR) compared with AECA negative patients. The concentrations of sCD30, and AECA were independent risk factors for AR within 6 months; the odds ratios were 7.005 and 2.469, respectively. Conclusions: Positive AECA was an independent risk factor for AR and appeared to correlate with relatively severe rejection subtypes.
A urinary Common Rejection Module (uCRM) score for non-invasive kidney transplant monitoring
PLOS ONE
A Common Rejection Module (CRM) consisting of 11 genes expressed in allograft biopsies was previously reported to serve as a biomarker for acute rejection (AR), correlate with the extent of graft injury, and predict future allograft damage. We investigated the use of this gene panel on the urine cell pellet of kidney transplant patients. Urinary cell sediments collected from patients with biopsy-confirmed acute rejection, borderline AR (bAR), BK virus nephropathy (BKVN), and stable kidney grafts with normal protocol biopsies (STA) were analyzed for expression of these 11 genes using quantitative polymerase chain reaction (qPCR). We assessed these 11 CRM genes for their abundance, autocorrelation, and individual expression levels. Expression of 10/11 genes were elevated in AR when compared to STA. Psmb9 and Cxcl10could classify AR versus STA as accurately as the 11-gene model (sensitivity = 93.6%, specificity = 97.6%). A uCRM score, based on the geometric mean of the expression levels, could distinguish AR from STA with high accuracy (AUC = 0.9886) and correlated specifically with histologic measures of tubulitis and interstitial inflammation rather than tubular atrophy, glomerulosclerosis, intimal proliferation, tubular vacuolization or acute glomerulitis. This urine gene expression-based score may enable the non-invasive and quantitative monitoring of AR.
Immunological Monitoring and Early Prediction of Rejection in Renal Allograft Recipients
International Archives of Allergy and Immunology, 1987
Graft rejection remains the major problem complicating renal allograft transplantation. A reliable posttransplant predictor of impending rejection will be valuable to help maintain better graft function. We monitored 47 patients with end-stage renal disease treated by renal allograft starting 1 day pretransplantation and continuing for up to 90 days postgrafting. Peripheral blood mononuclear cells (PBMC) from both patients and 71 healthy subjects were compared for: (1) DNA synthesis in T and B lymphocytes in response to mito gens; (2) interleukin-2 (IL-2) production; (3) natural killer (NK) and antibody-dependent cell-mediated cytoxic (ADCC) activities; (4) induced augmentation of NK and ADCC activities by the biological response modifiers (BRM), lymphoblastoid interferon, recombinant alpha-2-interferon, gamma-interferon and recombinant IL-2. During the 2 weeks preceding rejection we found lower than normal levels of IL-2 production (p <0.0005) and DNA synthesis (p <0.01) in concanavalin A-stimulated PBMC. IL-2 yield reached its lowest level on the day of rejection and increased sharply the following week after antirejection therapy was started. Mitogen-stimulated DNA synthesis rose in parallel with increasing levels of IL-2 production. Both NK and ADCC activities increased during rejection (p < 0.05). The ADCC response to BRM activation measured dur ing the first 2 weeks postgrafting was found to correlate with the stability of the graft. Recipients whose graft function remained stable had a minimal ADCC response to BRM. In contrast, recipients experiencing early la tent rejection, i.e. prior to any clinical or biochemical sign of rejection, had a sustained and significant increase in ADCC response to BRM (p <0.01). We concluded that the ADCC response to BRM may be used in the postgrafting period for the early immunological prediction of impending renal allograft rejection.
Early Immunological Prediction of Renal Allograft Rejection
International Archives of Allergy and Immunology, 1987
Reliable predictors of impending renal allograft rejection would be valuable for better patient management. To date, no available test has been shown to be consistently predictive and results have often been conflicting. We evaluated an effector of cell-mediated immunity, antibody-dependent cell-mediated cyto toxicity (ADCC) as well as the response of these cells to different biological response modifiers (BRM) in pa tients following renal allograft transplantation. The in vitro test used assayed monocytes as ADCC effector cells against antibody-sensitized chicken red blood cells. The effects of BRM were studied by preincubating the monocytes with lymphoblastoid IFN, recombinant c^-interferon or y-interferon. A follow-up study was per formed on 47 patients with end-stage renal disease treated with renal allograft transplantation. ADCC activity and its response to BRM were assayed prior to transplantation, 2, 4, and 9 weeks post transplantation. In the case of rejection, ADCC was then studied prior to initiation of antirejection therapy and for 2 months follow ing treatment of rejection episode. We noted that in patients with stable grafts, the ADCC activity as well as its response to BRM declined gradually during the first 2 weeks post grafting and remained decreased up to 3 months after transplantation. In contrast, in recipients who experienced rejection episodes there was a sus tained and significant increase in ADCC response to BRM during the first 3 weeks post grafting. By the time the diagnosis of rejection had been established the baseline ADCC activity had also increased. Following treat ment and stabilization of the graft, ADCC activity and its response to BRM was decreased, similar to that in patients with stable grafts. Thus, by monitoring ADCC and the effect of different BRM on this activity we could predict rejection episodes in renal allograft recipients as early as 15 days in advance of any clinical or bi ochemical sign of rejection.
Developing renal allograft surveillance strategies – urinary biomarkers of cellular rejection
Canadian Journal of Kidney Health and Disease, 2015
Purpose of review: Developing tailored immunosuppression regimens requires sensitive, non-invasive tools for serial post-transplant surveillance as the current clinical standards with serum creatinine and proteinuria are ineffective at detecting subclinical rejection. The purpose of this review is: (i) to illustrate the rationale for allograft immune monitoring, (ii) to discuss key steps to bring a biomarker from bench-to-bedside, and (iii) to present an overview of promising biomarkers for cellular rejection. Sources of information: PubMed. Findings: Recent multicentre prospective observational cohort studies have significantly advanced biomarker development by allowing for the adequately powered evaluation of multiple biomarkers capable of detecting allograft rejection. These studies demonstrate that urinary CXCR3 chemokines (i.e. CXCL9 and CXCL10) are amongst the most promising for detecting subclinical inflammation; increasing up to 30 days prior to biopsy-proven acute rejection...
Journal of the American Society of Nephrology : JASN, 2015
Urinary levels of C-X-C motif chemokine 9 (CXCL9) and CXCL10 can noninvasively diagnose T cell-mediated rejection (TCMR) of renal allografts. However, performance of these molecules as diagnostic/prognostic markers of antibody-mediated rejection (ABMR) is unknown. We investigated urinary CXCL9 and CXCL10 levels in a highly sensitized cohort of 244 renal allograft recipients (67 with preformed donor-specific antibodies [DSAs]) with 281 indication biopsy samples. We assessed the benefit of adding these biomarkers to conventional models for diagnosing/prognosing ABMR. Urinary CXCL9 and CXCL10 levels, normalized to urine creatinine (Cr) levels (CXCL9:Cr and CXCL10:Cr) or not, correlated with the extent of tubulointerstitial (i+t score; all P<0.001) and microvascular (g+ptc score; all P<0.001) inflammation. CXCL10:Cr diagnosed TCMR (area under the curve [AUC]=0.80; 95% confidence interval [95% CI], 0.68 to 0.92; P<0.001) and ABMR (AUC=0.76; 95% CI, 0.69 to 0.82; P<0.001) with...
PROTEOMICS - Clinical Applications, 2011
Purpose: Noninvasive diagnosis of acute renal allograft rejection may be advantageous compared with the allograft biopsy. Experimental design: In this study, a multi-marker classification model for rejection was defined on a training set of 39 allograft patients by statistical comparison of capillary electrophoresis mass spectrometry (CE-MS) peptide spectra in urine samples from 16 cases with subclinical acute T-cell-mediated tubulointerstitial rejection and 23 nonrejection controls. Results: Application of the rejection model to a blinded validation set (n 5 64) resulted in an AUC value of 0.91 (95% CI: 0.82-0.97, p 5 0.0001). In total, 16 out of 18 subclinical and 10 out of 10 clinical rejections (BANFF grades Ia/Ib), and 28 out of 36 controls without rejection were correctly classified. Acute tubular injury in the biopsies or concomitant urinary tract infection did not interfere with CE-MS-based diagnosis. Sequence information of identified altered collagen a(I) and a (III) chain fragments in rejection samples suggested an involvement of matrix metalloproteinase-8 (MMP-8). Biopsy stainings revealed matrix metalloproteinase-8 exclusively in neutrophils located within peritubular capillaries and sparsely, in the tubulointerstitium during rejection. Conclusions and clinical relevance: The established marker set contains peptides related to tubulointerstitial infiltration seen in acute rejection. The set of urinary peptide markers will be used for early diagnosis of acute kidney allograft rejection marker in a multicenter phase III prospective study.
Journal of Clinical Medicine
In this clinical validation study, we developed and validated a urinary Q-Score generated from the quantitative test QSant, formerly known as QiSant, for the detection of biopsy-confirmed acute rejection in kidney transplants. Using a cohort of 223 distinct urine samples collected from three independent sites and from both adult and pediatric renal transplant patients, we examined the diagnostic utility of the urinary Q-Score for detection of acute rejection in renal allografts. Statistical models based upon the measurements of the six QSant biomarkers (cell-free DNA, methylated-cell-free DNA, clusterin, CXCL10, creatinine, and total protein) generated a renal transplant Q-Score that reliably differentiated stable allografts from acute rejections in both adult and pediatric renal transplant patients. The composite Q-Score was able to detect both T cell-mediated rejection and antibody-mediated rejection patients and differentiate them from stable non-rejecting patients with a receive...