Subclinical Acute Rejection Research Articles

Kidney allograft subclinical rejection modulates systemic inflammation measured by C-reactive protein at 1year after transplantation.

Kidney allograft inflammation is associated with proinflammatory modifications of peripheral blood mononuclear cells, suggesting that renal inflammation contributes to systemic inflammation. Thus, the aim of this study was to evaluate the relationship between subclinical inflammation in surveillance biopsies performed at 1year and systemic inflammation assessed by C-reactive protein (CRP) levels at the time of biopsy. We analyzed 544 surveillance biopsies performed at 1year that were classified as normal (n=368), borderline (n=148), or subclinical rejection (SCR) (n=28). CRP levels were divided into quartiles. Patients in 1st, 2nd, and 3rd quartile were classified as low CRP (n=408) and patients in the 4th quartile as high CRP (n=136). Univariate analysis showed that the proportion of patients with SCR was higher in the high CRP group (10.3% vs 3.4%, P=0.0067). Multivariate analysis showed that independent predictors of high CRP were body mass index (odds ratio [OR] 1.072 and 95% confidence interval [CI] 1.027-1.119), a positive urine culture at the day of the biopsy (OR 2.760 and 95% CI 1.205-6.323), and the presence of SCR at 1-year surveillance biopsy (OR 7.260 and 95% CI 3.530-14.935). In summary, we describe that subclinical acute rejection constitutes an independent predictor of systemic inflammation as measured by CRP.

The utility of surveillance biopsies in pediatric kidney transplantation.

Surveillance biopsies (SBs) are performed in some pediatric kidney transplant programs, based on data obtained in earlier immunosuppressive eras that the treatment of subclinical acute rejection results in better graft survival. The benefit of SBs for patients on modern immunosuppression regimens is unclear. We have therefore evaluated the clinical utility of SBs in a population of children receiving a kidney transplant. We have performed SBs at 3, 6 and 12months post-transplantation as standard of care at our institution since 2013 in patients on a regimen of rabbit anti-thymocyte globulin, tacrolimus, mycophenolate and rapid steroid taper (RST; steroids maintained in some exceptions). We reviewed pathology reports of 82 SBs from 34 transplants in 34 children for all abnormal findings and adequacy of specimens. Clinical records were reviewed for changes in management resulting from SB findings and for significant procedure complications. Of the 82 biopsies, 41 (50%) had abnormal findings separate from fibrosis, including five Banff Grade I rejections, ten borderline rejections, six calcineurin-inhibitor nephrotoxicity, four BK-virus nephropathy, five recurrent disease and three acute pyelonephritis. Moderate or more fibrosis was present in nine of the 82 (11%) biopsies. Management changes due to SB findings occurred in nine cases (11.0%). The proportion of abnormal findings or management changes did not differ between the RST or steroid-based groups. Patients performing clean intermittent catheterization showed inflammatory changes often read as rejection, but were managed differently. Three biopsies were deemed inadequate. No significant complications occurred. A high percentage of the SBs performed under modern immunosuppression showed abnormal findings even when fibrosis was excluded. However, management changes due to the SB findings were less frequent, although they occurred in a clinically meaningful percentage of cases. Complications or inadequate specimens were rare.

Utility of Serial Protocol Biopsies Performed After 1 Year in Predicting Long-Term Kidney Allograft Function According to Histologic Phenotype.

Prognostic implications of early protocol biopsies have been studied; however, the value of late protocol biopsy in predicting graft outcome has not been well defined. Here, we compared the effects of early and late protocol biopsy histologic findings in stable kidney allografts and aimed to understand the significance of "borderline" rejection on allograft function. We studied 261 biopsies from 159 renal transplant recipients who were on a steroid-free, calcineurin inhibitor and mycophenolate mofetil regimen and who received transplants between 2004 and 2012 with mean follow-up of 5 years. Early (between 3 and 9 mo) and subsequent late (between 12 and 24 mo) protocol biopsies were performed. Biopsies were classified as normal, interstitial fibrosis and/or tubular atrophy, subclinical acute rejection with interstitial fibrosis and/or tubular atrophy, and borderline rejection with interstitial fibrosis and/or tubular atrophy. A linear mixed-effects model was used to determine the effects of early and late protocol biopsies on estimated glomerular filtration rate changes, with baseline time for estimated glomerular filtration rate fixed at 12 months. The adjusted model showed that estimated glomerular filtration rate at 3 months, donor age, delayed graft function, and early protocol biopsies were associated with baseline estimated glomerular filtration rate at 12 months. Estimated glomerular filtration rate changes over time were associated with findings of interstitial fibrosis and/or tubular atrophy at early biopsy and subclinical acute rejection and borderline rejection at late biopsy. At last follow-up, final estimated glomerular filtration rate was significantly associated with interstitial fibrosis and/or tubular atrophy at early biopsy and with subclinical acute rejection at late biopsy. Although early protocol biopsy predicted baseline estimated glomerular filtration rate, late biopsy was important for predicting changes in function over time. In addition, a diagnosis of "borderline" rejection on protocol biopsies predicted long-term graft function.

NFAT-regulated cytokine gene expression during tacrolimus therapy early after renal transplantation.

Despite pharmacokinetic monitoring of calcineurin inhibitors, the long-term outcome after transplantation (Tx) is still hampered by the side effects of these drugs. The aim of the present study was to characterize nuclear factor of activated T cells (NFAT)-regulated gene expression as a potential pharmacodynamic biomarker for further individualization of tacrolimus (Tac) therapy. In 29 renal allograft recipients, samples were drawn once pre-Tx, and before and 1.5h after Tac dosing at approximately 1week, 6weeks and 1year post-Tx. Tac concentrations were measured by immunoassay, while the expression of genes encoding NFAT-regulated cytokines [interleukin 2 (IL2), interferon gamma (IFNG), colony stimulating factor 2 (CSF2)] and cytochrome P450 3A5 (CYP3A5) genotyping were determined by real-time polymerase chain reaction. The cytokine response after Tac dosing varied up to 46-fold between patients and changed significantly with time post-engraftment. Tac concentrations 1.5h postdose (C1.5 ) >15μg l-1 were associated with strong cytokine inhibition and residual gene expression (RGE) ≤10%, while lower Tac C1.5 resulted in more variable responses (RGE 2.5-68.7%). Patients with ongoing subclinical acute rejection (n = 5) demonstrated limited cytokine inhibition (RGE 39.7-72.6%), while patients with polyoma virus viraemia (n = 3) had relatively strong inhibition of cytokines (RGE 2.5-32.5%). By contrast, there was no association between Tac exposure and rejection or viraemia. The findings of our study support the potential of NFAT-regulated gene expression measurements as a pharmacodynamic tool for additional monitoring of Tac therapy, especially in the context of overimmunosuppression and viraemia.

Molecular and Functional Noninvasive Immune Monitoring in the ESCAPE Study for Prediction of Subclinical Renal Allograft Rejection.

Subclinical acute rejection (sc-AR) is a main cause for functional decline and kidney graft loss and may only be assessed through surveillance biopsies. The predictive capacity of 2 novel noninvasive blood biomarkers, the transcriptional kidney Solid Organ Response Test (kSORT), and the IFN-γ enzyme-linked immunosorbent spot assay (ELISPOT) assay were assessed in the Evaluation of Sub-Clinical Acute rejection PrEdiction (ESCAPE) Study in 75 consecutive kidney transplants who received 6-month protocol biopsies. Both assays were run individually and in combination to optimize the use of these techniques to predict sc-AR risk. Subclinical acute rejection was observed in 22 (29.3%) patients (17 T cell-mediated subclinical rejection [sc-TCMR], 5 antibody-mediated subclinical rejection [sc-ABMR]), whereas 53 (70.7%) showed a noninjured, preserved (stable [STA]) parenchyma. High-risk (HR), low-risk, and indeterminate-risk kSORT scores were observed in 15 (20%), 50 (66.7%), and 10 (13.3%) patients, respectively. The ELISPOT assay was positive in 31 (41%) and negative in 44 (58.7%) patients. The kSORT assay showed high accuracy predicting sc-AR (specificity, 98%; positive predictive value 93%) (all sc-ABMR and 58% sc-TCMR showed HR-kSORT), whereas the ELISPOT showed high precision ruling out sc-TCMR (specificity = 70%, negative predictive value = 92.5%), but could not predict sc-ABMR, unlike kSORT. The predictive probabilities for sc-AR, sc-TCMR, and sc-ABMR were significantly higher when combining both biomarkers (area under the curve > 0.85, P < 0.001) and independently predicted the risk of 6-month sc-AR in a multivariate regression analysis. Combining a molecular and immune cell functional assay may help to identify HR patients for sc-AR, distinguishing between different driving alloimmune effector mechanisms.

Subclinical Antibody-Mediated Rejection

Subclinical Antibody-Mediated Rejection

Orthogonal Comparison of Molecular Signatures of Kidney Transplants With Subclinical and Clinical Acute Rejection: Equivalent Performance Is Agnostic to Both Technology and Platform.

We performed orthogonal technology comparisons of concurrent peripheral blood and biopsy tissue samples from 69 kidney transplant recipients who underwent comprehensive algorithm-driven clinical phenotyping. The sample cohort included patients with normal protocol biopsies and stable transplant (sTx) function (n=25), subclinical acute rejection (subAR, n=23), and clinical acute rejection (cAR, n=21). Comparisons between microarray and RNA sequencing (RNA-seq) signatures were performed and demonstrated a strong correlation between the blood and tissue compartments for both technology platforms. A number of shared differentially expressed genes and pathways between subAR and cAR in both platforms strongly suggest that these two clinical phenotypes form a continuum of alloimmune activation. SubAR is associated with fewer or less expressed genes than cAR in blood, whereas in biopsy tissues, this clinical phenotype demonstrates a more robust molecular signature for both platforms. The discovery work done in this study confirms a clear ability to detect gene expression profiles for sTx, subAR, and cAR in both blood and biopsy tissue, yielding equivalent predictive performance that is agnostic to both technology and platform. Our data also provide strong biological insights into the molecular mechanisms underlying these signatures, underscoring their logistical potential as molecular diagnostics to improve clinical outcomes following kidney transplantation.

Single center experience of subclinical rejections and BK nephropathies by kidney allografts’ surveillance biopsies

PurposeAcute rejection of the kidney allograft remains the most important factor affecting the long-term graft outcome and is a major predictor of development of chronic damage and graft loss. Several studies have shown that early detection and treatment of subclinical rejection episodes may be beneficial for the graft outcome. The role of protocol (surveillance) biopsies and the value of donor specific antibodies (DSA) monitoring are still debatable. MethodsThis is a prospective observational study involving seventeen kidney recipients transplanted in north-eastern part of Poland who underwent “zero”, 3-month and 12-month allograft biopsies as well as DSA assessment. ResultsHistologic analysis of the biopsies showed subclinical acute cellular rejection in 17.6% of patients (two tubulointerstitial, one vascular) at 3-months post transplantation, and additional case of borderline rejection at the 12-month point. Moreover, two cases (11.8%) of polyomavirus BK nephropathy were diagnosed (one at 3 and one at 12 month point). None of the patients developed de novo DSA. ConclusionsOur protocol biopsies allowed us to detect significant proportion of patients with subclinical, but histologically relevant acute cellular rejection and BK nephropathy. Early therapeutic intervention had beneficial effects in a 4-year follow up.

Looking for the needle in the kidney transplantation haystack.

The diagnosis of acute rejection still relies on renal allograft biopsy. In fact, histological features including C4d staining can be useful to differentiate cellular and antibody-mediated acute rejection. However, the pathogenic mechanism to define the type of rejection is usually assessed by anti-HLA donor specific antibodies (DSA) monitoring. Suspicion of acute rejection is usually based on renal function deterioration. This method has low sensitivity. Moreover, creatinine increase follows graft injury and therefore the diagnosis is performed when there is an ongoing acute rejection. One strategy to overcome the limitation of serum creatinine as predictor of acute rejection is to perform surveillance protocol biopsies. However, the low incidence of subclinical acute rejection among patients treated with tacrolimus-based immunosuppression makes this procedure questionable in terms of cost-effectiveness. In this scenario new biomarkers predicting acute rejection are urgently needed. Ideally, such biomarkers should anticipate acute rejection, thus allowing preventive actions such as maintenance immunosupression intensification and/or modification. Alternatively, these new biomarkers should at least improve the predictive value of serum creatinine monitoring. Although many of the new biomarkers are promising, none have been translated to the clinic to date because of a lack of validation studies and the existence of major methodological concerns.

Biomarkers in renal transplantation: An updated review.

Genomics, proteomics and molecular biology lead to tremendous advances in all fields of medical sciences. Among these the finding of biomarkers as non invasive indicators of biologic processes represents a useful tool in the field of transplantation. In addition to define the principal characteristics of the biomarkers, this review will examine the biomarker usefulness in the different clinical phases following renal transplantation. Biomarkers of ischemia-reperfusion injury and of delayed graft function are extremely important for an early diagnosis of these complications and for optimizing the treatment. Biomarkers predicting or diagnosing acute rejection either cell-mediated or antibody-mediated allow a risk stratification of the recipient, a prompt diagnosis in an early phase when the histology is still unremarkable. The kidney solid organ response test detects renal transplant recipients at high risk for acute rejection with a very high sensitivity and is also able to make diagnosis of subclinical acute rejection. Other biomarkers are able to detect chronic allograft dysfunction in an early phase and to differentiate the true chronic rejection from other forms of chronic allograft nephropathies no immune related. Finally biomarkers recently discovered identify patients tolerant or almost tolerant. This fact allows to safely reduce or withdrawn the immunosuppressive therapy.

Post-transplant surveillance for acute rejection and allograft vasculopathy by echocardiography: Usefulness of myocardial velocity and deformation imaging

Diagnosing and monitoring acute rejection (AR) and cardiac allograft vasculopathy (CAV) is essential for graft and transplant patient survival and, consequently, a major objective for heart transplant patient surveillance. Because functionally relevant CAV can arise and progress without clinical symptoms and sub-clinical ARs can facilitate the development of CAV, standard surveillance of AR and CAV includes routine endomyocardial biopsy (EMB) and coronary angiography (CA) screenings at pre-defined time intervals. However, these invasive screenings (distressing and risky for the patients) cannot solely diagnose all sub-clinical AR episodes and also not always detect coronary stenoses before a clinical event. Additional close-meshed, non-invasive AR and CAV surveillance strategies are therefore mandatory. After the introduction of tissue Doppler imaging (TDI) and strain imaging for myocardial wall motion and deformation analysis, echocardiography became particularly promising for that purpose. Allowing quantification of minor myocardial dysfunction not detectable by standard echocardiography, TDI and strain imaging can reveal sub-clinical AR. Thus, these approaches can be a valuable supplement to EMB, enabling more efficient AR monitoring with fewer EMBs (only diagnostic EMBs) instead of unnecessary and distressing routine EMB screenings. Their use can also improve therapeutic decisions and monitoring of myocardial function during anti-rejection therapy. Myocardial velocity and deformation imaging is also suited to early detection of myocardial dysfunction induced by CAV and may be useful for prognostic evaluation and timing of CAs, with an aim of reducing the number of routine CA screenings. However, further studies are necessary before specific recommendations for the use of TDI and strain imaging for CAV surveillance become possible.

Decreased Kidney Graft Survival in Low Immunological Risk Patients Showing Inflammation in Normal Protocol Biopsies.

IntroductionThe pros and cons for implementing protocol biopsies (PB) after kidney transplantation are still a matter of debate. We aimed to address the frequency of pathological findings in PB, to analyze their impact on long-term graft survival (GS) and to analyze the risk factors predicting an abnormal histology.MethodsWe analyzed 946 kidney PB obtained at a median time of 6.5 (±2.9) months after transplantation. Statistics included comparison between groups, Kaplan-Meier and multinomial logistic regression analysis.Results and DiscussionPB diagnosis were: 53.4% normal; 46% IFTA; 12.3% borderline and 4.9% had subclinical acute rejection (SCAR). Inflammation had the strongest negative impact on GS. Therefore we split the cases into: “normal without inflammation”, “normal with inflammation”, “IFTA without inflammation”, “IFTA with inflammation” and “rejection” (including SCAR and borderline). 15-year GS in PB diagnosed normal with inflammation was significantly decreased in a similar fashion as in rejection cases. Among normal biopsies, inflammation increased significantly the risk of 15-y graft loss (P = 0.01). Variables that predicted an abnormal biopsy were proteinuria, previous AR and DR-mismatch.ConclusionWe conclude that inflammation in normal PB is associated with a significantly lower 15-y GS, comparable to rejection or IFTA with inflammation.

Failure of Calcineurin Inhibitor (Tacrolimus) Weaning Randomized Trial in Long-Term Stable Kidney Transplant Recipients.

Long-term renal transplant outcome is limited by side effects of immunosuppressive drugs, particularly calcineurin inhibitor (CNI). We assumed that some patients selected for a "low immunological risk of rejection" could be eligible and benefit from a CNI weaning strategy. We designed a prospective, randomized, multicenter, double-blind placebo-controlled clinical study (Eudract: 2010-019574-33) to analyze the benefit-risk ratio of tacrolimus weaning on highly selected patients (≥4 years of transplantation, normal histology, stable graft function, no anti-HLA immunization). The primary endpoint was improvement of renal function. Fifty-two patients were scheduled in each treatment arm, placebo compared to the CNI maintenance arm. Only 10 patients were eligible and randomized. Five patients were assigned to the placebo arm and five were assigned to the tacrolimus maintenance arm. In the tacrolimus maintenance arm, all patients maintained stable graft function and no immunological events occurred. Contrastingly, in the placebo arm, all five patients had to reintroduce a full dose of tacrolimus since three of them presented an acute rejection episode (one humoral, one mixed, and one borderline) and two displayed anti-HLA antibodies without histological lesion (one donor-specific antibodies [DSA] and one non-DSA). Clearly, tacrolimus withdrawal must be avoided even in long-term highly selective stable kidney recipients.

Usefulness of High-Sensitivity Troponin I for the Monitoring of Subclinical Acute Cellular Rejection After Cardiac Transplantation

BackgroundThere are conflicting data about the role of cardiac troponin I (cTnI) as determined by means of conventional methods for the prediction of acute rejection after heart transplantation (HT). The purpose of this study was to evaluate whether cTnI as measured by means of the early prototype high-sensitivity assay (hs-cTnI) can predict acute rejection episode after HT compared with grade of rejection in endomyocardial biopsy (EMB). MethodsThis was a single-center cross-sectional study evaluating cTnI levels with the use of both hs-cTnI and current less sensitive conventional cTnI (conv-cTnI) assays measured at the time of EMB after HT. We calculated an index ratio of observed cTnI to expected mean cTnI for each individual patient defined as the mean cTnI measurements at EMB 60 days after HT. ResultsA total of 252 biopsies from 47 patients were included in this study. In the multivariable mixed model analysis in relation to the presence of acute rejection 60 days after HT, hs-cTnI level was significantly related to the presence of rejection (P = .010). The hs-cTnI ratio index was significantly higher at the time of rejection (median, 1.37; interquartile range [IQR], 1.23–2.88) compared with those without rejection (median, 0.90; IQR, 0.51–1.16; P < .001). In receiver operating characteristic curve analysis, an hs-cTnI ratio index of ≥1.17 could predict the acute rejection with a sensitivity of 82.4% and a specificity of 77.1%. ConclusionsAn increased hs-cTnI ratio index was significantly related to rejection episodes. Serial monitoring of hs-cTnI and comparing it with the values without rejection might be useful for the detection of acute rejection after HT.

Immuno-histological assessment of sub-clinical acute and borderline rejection in renal allograft recipients: Data from a transplant center in India.

This single-center study was carried out on living related and unrelated renal transplant recipients (RTRs) to evaluate the usefulness of surveillance biopsies in monitoring stable renal allografts using immuno-histological markers for immune-activation. This is a prospective, longitudinal study. Protocol biopsies of 60 RTRs with stable graft function were evaluated at three, six and 12 months post-transplant. Immuno-histological evaluation was carried out using immune-activation markers (perforins, granzyme and interleukin-2R), phenotypic markers (CD-3 and CD-20), viral markers and C4d. The demographic and clinical profile was recorded for each patient. All cases of acute sub-clinical rejection (SCR) were treated and borderline SCR cases were followed-up without treatment. SCR at three and six months post-transplant was evident in 16.7% and 3.7% of RTRs, respectively. Positive statistical association of SCR was seen with HLA-DR mismatches, whereas patients receiving induction therapy and tacrolimus-based immunosuppression exhibited a lower incidence of SCR. T cell phenotype with persistent expression of immune-activation markers exhibited positive statistical association with interstitial fibrosis and tubular atrophy at 12-month follow-up biopsy. The mean creatinine levels were significantly lower in the protocol biopsy group than the non-protocol biopsy group. No significant difference was found between the mean creatinine levels of the SCR group after treatment and the non-SCR cases within the protocol biopsy group. Early treatment of sub-clinical acute rejection leads to better functional outcomes. However, persistent immune-activation is associated with chronicity and may have implications on long-term graft survival.

Molecular Signature in the Peripheral Blood for Sub-Clinical Acute Kidney Rejection.

Background: Sub-clinical acute rejection (SCAR) is defined as histologic rejection with normal serum creatinine and is associated with worse long term graft survival. Protocol kidney biopsies (bx) are done at some centers to detect SCAR. Methods: We identified 23 whole blood samples from recipients with SCAR and profiled these using Affymetrix HG-U133 Peg microarrays. We compared these to 21 pts with clinical acute rejection (AR), and 25 with normal bx and a normal serum creatinine (TX). SCAR bx included 16 “Borderline” and 7 Banff 1A (Banff 07). 3-way ANOVA analysis was performed between Groups 1-3. Results: The arrays yielded over 6,000 differentially expressed probesets at p<0.001. Even setting a False Discovery Rate (FDR) cut-off of <10% gave us over 2,500 significantly differentially expressed probesets. For the diagnostic signature, we used only the top 200 differentially expressed probesets as ranked by p values. These 200 top probesets have FDR values of <0.05%. We used 3 different predictive algorithms: Nearest Centroid (NC), Support Vector Machines (SVM) and Diagonal Linear Discriminant Analysis (DLDA) to build predictive models. NC, SVM and DLDA picked classifier sets of 188, 192 and 200 probesets as the best classifiers, respectively. Table 1 shows the performance of the 3-way NC classifier using both one-level cross validation as well as Optimism Corrected Bootstrapping (1000 data sets) as described by Harrell. We also tested a 2-way prediction of SCAR vs. TX to further validate that a phenotype as potentially subtle clinically as SCAR can be truly distinguished from TX. At a p-value <0.001, there were 33 probesets whose expression signals highly differentiated SCAR and TX. When these 33 probesets were used in NC to predict SCAR and TX creating a 2-way classifier, the predictive accuracies with a one-level cross-validation was 96% and with the Harrell 1000 test optimism correction it was 94%. Table 1 shows NC algorithm values.Table: No Caption available.Conclusion: Peripheral blood gene expression profiling can distinguish SCAR, TX and AR and promises a minimally invasive method for monitoring KTx recipients. This signature is now being further validated. DISCLOSURE:Friedewald, J.: Grant/Research Support, Pfizer, Stockholder, TGI. Kurian, S.: Stockholder, TGI. Levitsky, J.: Stockholder, TGI. Abecassis, M.: Stockholder, TGI. Salomon, D.: Stockholder, TGI.

A Peripheral Blood Gene Expression Signature for Subclinical Acute Rejection and Associated Long-Term Graft Injury.

Currently, the diagnosis of acute rejection requires renal allograft biopsy triggered by an elevation of creatinine. Data on the impact of subclinical rejection and borderline changes on graft outcomes are conflicting, and diagnosis is impacted by subjective reporting. In our prospective genomics of chronic allograft rejection (GoCAR) cohort, we examined the impact of these diagnoses on 3-mth protocol biopsy on outcomes in 199 patients on whom concurrent peripheral blood transcriptome analysis was also performed. Twenty-eight of 199 patients had subclinical acute or borderline rejection (SCR) diagnosed by the central histology core which was blinded to clinical data. Allografts with SCR had greater renal function decline by delta eGFR-creatinine [p<0.05], and sustained significantly higher risks of subsequent acute rejection [OR - 3.4; CI - 1.25 to 9.14 & OR=7.8; CI - 1.47 to 40.89 at 1- and 2-years]. In 36-mths of follow-up, allografts with acute rejection or with borderline changes alone had significantly reduced death-censored, graft survival (Log-rank p = 0.01). Notably, 60% of borderline rejections were not diagnosed on locally reported pathology and were untreated. Transcriptome analysis was performed on 3-mths blood for the 199 recipients (RNAseq and microarray). Using RNAseq data of 66 patients with 3-mth renal biopsies as training set, we identified a 9-gene signature that accurately diagnosed SCR (AUC =0.96) with 80% cross-validation accuracy from 100 iterations. The geneset was technically confirmed using an independent cohort of GOCAR patients by microarray (n=39; AUC=0.835) and a publicly available dataset GSE 14346 ( n=75; AUC=0.865). At 1- and 2-years, allografts identified by this signature had a persistent inflammatory phenotype [i-scores - 0.9±1.0 vs 0.4±0.7 & 1.0±1.1 vs 0.3±0.7; p <0.01] with greater histological damage than allografts without this signature [CADI-scores - 3.46±2.78 vs 1.81± 2.19 & 3.80±1.62 vs 1.53±2.31; p <0.001]. In conclusion, we have identified a 9-gene peripheral blood signature that accurately diagnoses SCR and identifies allografts at risk for subsequent histological, functional decline and graft loss.

Outcomes of Liver Transplantation, Partial Hepatectomy, and Transcatheter Arterial Embolization for Massive Polycystic Liver in Autosomal Dominant Polycystic Kidney Disease Patients.

Background: Polycystic liver disease(PLD) is the most common extra-renal manifestation in autosomal dominant polycystic kidney disease(ADPKD). Patients with PLD suffer from hepatomegaly leading to pain, dyspnea and caval obstruction. Interventions for symptomatic PLD include transcatheter arterial embolization(TAE), partial hepatic resection and liver transplantation(LT). We compared outcomes of each treatment modality. Methods: We retrospectively analyzed 29 patients who had undergone TAE, partial hepatectomy, or LT in ADPKD patients in a single center. Results: Six and seven patients underwent LT and partial hepatectomy, respectively, while sixteen patients underwent TAE. Living donor LT was performed for intractable hepatomegaly-related symptoms despite TAE in 2 patients, and for uncontrolled ascites in a patient. Deceased donor(DD) LT was performed in 2 patients for hepatic failure or uncontrolled ascites after TAE. Another patient underwent DDLT for hepatic failure after partial hepatectomy. The most common complications were ascites and pleural effusion. Two patients were under hemodialysis at LT, and acute kidney injury resulted in kidney failure in 1 DDLT patient. All patients had maintained good liver function at a median follow-up of 15.5 months, although subclinical acute cellular rejection was found in 2 patients. Causes of partial hepatectomy were recurrent cyst infection and hepatomegaly-related symptoms. One patient underwent partial hepatectomy, because multiple TAE had failed to control symptoms. Preoperative CTP score was lower in the partial hepatectomy group than in the LT group. A few serious infectious complications occurred, and antibiotic treatment cured them without mortality. Eleven patients received single TAE, and five patients underwent TAE twice. Two patients died of obstructive jaundice and cyst infection. Five patients (31.3%) in the TAE group needed LT or partial hepatectomy to relieve symptoms or rescue hepatic failure. Conclusion: LT is more effective and tolerable treatment option for symptomatic PLD in ADPKD patients compared to partial hepatectomy and TAE.

Assessment of sub-clinical acute cellular rejection after heart transplantation: Comparison of cardiac magnetic resonance imaging and endomyocardial biopsy

Objective Comparing the diagnostic value of multi-sequential cardiac magnetic resonance imaging (CMR) with endomyocardial biopsy (EMB) for sub-clinical cardiac allograft rejection.

Early protocol biopsies in pediatric renal transplantation: Interest for the adaptation of immunosuppression

GPB are often performed in PRT to detect subclinical acute rejection or IF/TA. Reducing immunosuppression side effects without increasing rejection is a major concern in PRT. We report the results of GPB in children transplanted with a steroid-sparing protocol adapted to immunological risk. Children under 18 yr who received a renal transplantation between April 1, 2009 and May 31, 2012 were included. Immunosuppression consisted of an antibody induction therapy, tacrolimus, and MMF for all recipients. CSs were administered to children under five yr old, or receiving a second allograft. Twenty-eight children were included, 50% were CSs free. GPB were performed between three and six months. IF/TA was documented in seven biopsies; four of these seven children were CS free. One child, with CSs, presented a borderline rejection, and another child, steroid free, with significant inflammatory interstitial infiltrate, considered as a subclinical rejection, was treated with CSs pulses. The median eGFR was stable (74, 67.5, and 82 mL/min/1.73 m² at, respectively, seven days, three months, and one yr). Patient and graft survival were 100%. These results have to be confirmed in a larger cohort, with long-term follow-up.