Molecular Diagnosis of Antibody-Mediated Rejection in Human Kidney Transplants.

• Sellarés J, Reeve J, Loupy A, et al. 
• Molecular Diagnosis of Antibody-Mediated Rejection in Human Kidney Transplants. [JOURNAL ARTICLE]
• Am J Transplant 2013 Feb 15.
• AbstractPublisher Full Text

Antibody-mediated rejection is the major cause of kidney transplant failure, but the histology-based diagnostic system misses most cases due to its requirement for C4d positivity. We hypothesized that gene expression data could be used to test biopsies for the presence of antibody-mediated rejection. To develop a molecular test, we prospectively assigned diagnoses, including C4d-negative antibody-mediated rejection, to 403 indication biopsies from 315 patients, based on histology (microcirculation lesions) and donor-specific HLA antibody. We then used microarray data to develop classifiers that assigned antibody-mediated rejection scores to each biopsy. The transcripts distinguishing antibody-mediated rejection from other conditions were mostly expressed in endothelial cells or NK cells, or were IFNG-inducible. The scores correlated with the presence of microcirculation lesions and donor-specific antibody. Of 45 biopsies with scores >0.5, 39 had been diagnosed as antibody-mediated rejection on the basis of histology and donor-specific antibody. High scores were also associated with unanimity among pathologists that antibody-mediated rejection was present. The molecular score also strongly predicted future graft loss in Cox regression analysis. We conclude that microarray assessment of gene expression can assign a probability of ABMR to transplant biopsies without knowledge of HLA antibody status, histology, or C4d staining, and predicts future failure.

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Página original: http://www.unboundmedicine.com/medline/citation/23414212/Molecular_Diagnosis_of_Antibody_Mediated_Rejection_in_Human_Kidney_Transplants_

Effects of ureteral stents on risk of bacteriuria in renal allograft recipients

Abstract

Background

Placement of ureteral stents at the time of renal transplantation is thought to decrease the incidence of postoperative complications, such as anastomotic leakage and stenosis. However, stents may also predispose to post-transplantation urinary tract infection, which can lead to increased risks of graft dysfunction, sepsis, and death. The aim of this study was to analyze the risk of post-transplantation bacteriuria with ureteral stent placement in renal allograft recipients.

Methods

A retrospective single-center analysis was conducted to investigate the incidence of bacteriuria in all renal allograft recipients transplanted between January 2007 and March 2009. Recipients were categorized as in the nonstent group (NSTG) or the stent group (STG). Stent removal was performed per protocol at 6 weeks, and all patients were followed for at least 1 year post transplantation. In the NSTG, the incidence of bacteriuria was assessed at 0–6, 6–12, and 12 weeks to 1 year post transplantation. In the STG, bacteriuria was assessed prior to stent removal, 6 weeks after stent removal, and thereafter until 1 year post transplantation.

Results

A total of 395 renal allograft recipients, 183 in the NSTG and 212 in the STG groups, were studied. The overall incidence of bacteriuria within 1 year post transplantation was similar between NSTG and STG (28.0 vs. 24.0%, P = 0.38). No difference was found in the incidence of bacteriuria when NSTG and STG were compared at 0–6 weeks or prior to stent removal (9.7% vs. 9.1%, P = 0.81), at 6–12 weeks, or 6 weeks after stent removal (6.7% vs. 5.8%, P = 0.75), and thereafter for 1 year post transplantation (13.3% vs. 10.8%, P = 0.46). The incidence of graft failure at 1 year was similar in NSTG and STG (6.2% vs. 4.9%, P = 0.6). Urinary anastomotic leakage occurred in none of the NSTG and 2 of the STG recipients. On multivariate analysis, risk factors for bacteriuria were female recipient gender (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.5–4.3, P = 0.001), delayed graft function (DGF) (OR 2.1, 95% CI 1.2–3.8, P = 0.01), and postoperative Foley catheterization for >5 days (OR 4.7, 95% CI 1.3–17.6, P = 0.02).

Conclusion

Independent risk factors for bacteriuria following kidney transplantation include DGF, prolonged postoperative Foley catheterization, and recipient female gender, but not placement of ureteral stents.

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Página original: http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1111%2Ftid.12062

The Clinical and Molecular Significance of C4d Staining Patterns in Renal Allografts

Background: We investigated the clinical and molecular significance of minimal peritubular capillary (PTC) and isolated glomerular C4d+ staining using microarrays. Methods: Two hundred fifty-five clinically indicated transplant biopsies were included in the analyses. C4d staining was performed on paraffin sections using a polyclonal rabbit anti-C4d antibody. Gene expression profiles in a subset of patients were studied using Affymetrix HuGene 1.0ST arrays. Results: Immunohistochemistry for C4d of 255 biopsies showed 51% C4d negative, 4% minimal PTC C4d+, 15% focal or diffuse PTC C4d+, and 31% isolated glomerular C4d+ biopsies. Patients with minimal and focal/diffuse PTC C4d+ staining had higher frequency of donor-specific anti-HLA antibodies (DSA) (67% and 82%) and antibody mediated rejection (AMR) (66% and 89%) when compared with C4d-negative biopsies (25% and 19%, respectively) (P<0.001). The glomerulitis, interstitial inflammation, and peritubular capillaritis scores were also significantly higher in minimal (0.88, 1.25, and 1.5) and focal/diffuse PTC C4d+ biopsies (0.65, 1.41, and 1.5), compared with C4d-negative biopsies (0.25, 079, and 0.34), respectively. There were no differences in the DSA frequency, AMR rate, or Banff scores between isolated glomerular C4d+ and C4d-negative patients. Although both minimal and focal/diffuse C4d+ biopsies showed increased expression of genes related to the immune response, interferon-gamma and rejection-induced, cytotoxic T cell and constitutive macrophage-associated pathogenesis-based transcripts, there was no activation of immune-response–related genes in isolated glomerular C4d+ biopsies. Conclusion: Minimal PTC C4d+ staining but not isolated glomerular C4d+ staining is associated with AMR, circulating DSAs and immune-response–related gene activation.

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Página original: http://journals.lww.com/transplantjournal/Fulltext/2013/02270/The_Clinical_and_Molecular_Significance_of_C4d.8.aspx

Rate of Renal Graft Function Decline After 1 Year Is a Strong Predictor of All-Cause Mortality.

Rate of Renal Graft Function Decline After 1 Year Is a Strong Predictor of All-Cause Mortality.

The slope of GFR associates with an increased risk for death in patients with native CKD but whether a similar association exists in kidney transplantation is not known. We studied an inception cohort of 488 kidney transplant recipients (mean follow-up of 12 ± 4 years) for whom GFR was longitudinally measured by inulin clearance (mGFR) at 1 year and then every 5 years. Association of mGFR at 1 year posttransplant and GFR slope after the first year with all-cause mortality was studied with a Cox regression model and a Fine and Gray competing risk model. While in Crude analysis, the mGFR value at 1 year posttransplant and the rate of mGFR decline were both associated with a higher risk of all-cause mortality, only the slope of mGFR remained a significant and strong predictor of death in multivariate analysis. Factors independently associated with a more rapid mGFR decline were feminine gender, higher HLA mismatch, retransplantation, longer duration of transplantation, CMV infection during the first year and higher rate of proteinuria. Our data suggest that the rate of renal graft function decline after 1 year is a strong predictor of all-cause mortality in kidney transplantation.

Incidence and Impact of De Novo Donor-Specific Alloantibody in Primary Renal Allografts

Background: To date, limited information is available describing the incidence and impact of de novo donor-specific anti–human leukocyte antigen (HLA) antibodies (dnDSA) in the primary renal transplant patient. This report details the dnDSA incidence and actual 3-year post-dnDSA graft outcomes. Methods: The study includes 189 consecutive nonsensitized, non-HLA-identical patients who received a primary kidney transplant between March 1999 and March 2006. Protocol testing for DSA via LABScreen single antigen beads (One Lambda) was done before transplantation and at 1, 3, 6, 9, and 12 months after transplantation then annually and when clinically indicated. Results: Of 189 patients, 47 (25%) developed dnDSA within 10 years. The 5-year posttransplantation cumulative incidence was 20%, with the largest proportion of patients developing dnDSA in the first posttransplantation year (11%). Young patients (18–35 years old at transplantation), deceased-donor transplant recipients, pretransplantation HLA (non-DSA)–positive patients, and patients with a DQ mismatch were the most likely to develop dnDSA. From DSA appearance, 9% of patients lost their graft at 1 year. Actual 3-year death-censored post-dnDSA graft loss was 24%. Conclusion: We conclude that 11% of the patients without detectable DSA at transplantation will have detectable DSA at 1 year, and over the next 4 years, the incidence of dnDSA will increase to 20%. After dnDSA development, 24% of the patients will fail within 3 years. Given these findings, future trials are warranted to determine if treatment of dnDSA-positive patients can prevent allograft failure.

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Página original: http://journals.lww.com/transplantjournal/Fulltext/2013/02150/Incidence_and_Impact_of_De_Novo_Donor_Specific.2.aspx

Effects of ACE Inhibitors on Long-term Outcome of Renal Transplant Recipients: A Randomized Controlled Trial

Background: Available data on the role of renin-angiotensin system blockade in renal transplantation are inconclusive. Herein, we report the long-term results of a randomized controlled trial planned to evaluate the impact of angiotensin-converting enzyme inhibitors (ACE-i) on the cardiovascular outcome of renal transplant recipients (RTRs) receiving calcineurin inhibitors, steroids, and mycophenolate mofetil. Methods: Thirty-six RTRs were allocated to receive ACE-i and 34 served as controls. Survival free of a composite endpoint consisting of death, major cardiovascular events, renal graft loss or creatinine doubling, and survival free of each single endpoint were analyzed in both groups according to a modified intention-to-treat analysis. Results: During a 10-year follow-up, three patients died (one in the ACE-i group and two controls) and three lost their graft (two receiving ACE-i and one control). Three major cardiovascular events were observed in the ACE-i group and 12 among controls (P=0.008). At the end of observation, a significant increase in urinary protein excretion rate was only observed in controls (P=0.017). Compared with controls, RTRs administered ACE-i had significantly better survival free of the combined endpoint (P=0.0102, log-rank test) and free of major cardiovascular events (P=0.0027) without significant differences in renal outcome. By Cox regression analysis, ACE-i therapy resulted in the most powerful predictor of survival free of composite endpoint (hazard ratio, 0.165; 95% confidence interval, 0.053-0.512; P=0.0018) and survival free of major cardiovascular events (hazard ratio, 0.209; 95% confidence interval, 0.068-0.636; P=0.0059). Conclusions: Prolonged therapy with ACE-i was associated with better general and cardiovascular outcome of RTRs without detrimental effects on renal graft function. (C) 2013 Lippincott Williams & Wilkins, Inc.

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Página original: http://pdfs.journals.lww.com/transplantjournal/9000/00000/Effects_of_ACE_Inhibitors_on_Long_term_Outcome_of.98691.pdf