Acute Renal Allograft Rejection Research Articles

Identifying 4 Novel lncRNAs as Potential Biomarkers for Acute Rejection and Graft Loss of Renal Allograft.

Acute rejection (AR) after kidney transplant is one of the major obstacles to obtain ideal graft survival. Reliable molecular biomarkers for AR and renal allograft loss are lacking. This study was performed to identify novel long noncoding RNAs (lncRNAs) for diagnosing AR and predicting the risk of graft loss. The several microarray datasets with AR and nonrejection specimens of renal allograft downloaded from Gene Expression Omnibus database were analyzed to screen differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs). Univariate and multivariate Cox regression analyses were used to identify optimal prognosis-related DElncRNAs for constructing a risk score model. 39 common DElncRNAs and 185 common DEmRNAs were identified to construct a lncRNA-mRNA regulatory relationship network. DElncRNAs were revealed to regulate immune cell activation and proliferation. Then, 4 optimal DElncRNAs, ATP1A1-AS1, CTD-3080P12.3, EMX2OS, and LINC00645, were selected from 17 prognostic DElncRNAs to establish the 4-lncRNA risk score model. In the training set, the high-risk patients were more inclined to graft loss than the low-risk patients. Time-dependent receiver operating characteristics analysis revealed the model had good sensitivity and specificity in prediction of 1-, 2-, and 3-year graft survival after biopsy (AUC = 0.891, 0.836, and 0.733, respectively). The internal testing set verified the result well. Gene set enrichment analysis which expounded NOD-like receptor, the Toll-like receptor signaling pathways, and other else playing important role in immune response was enriched by the 4 lncRNAs. Allograft-infiltrating immune cells analysis elucidated the expression of 4 lncRNAs correlated with gamma delta T cells and eosinophils, etc. Our study identified 4 novel lncRNAs as potential biomarkers for AR of renal allograft and constructed a lncRNA-based model for predicting the risk of graft loss, which would provide new insights into mechanisms of AR.

Acute Rejection of Renal Allograft Caused by Drug-Induced Acute Interstitial Nephritis

Acute Rejection of Renal Allograft Caused by Drug-Induced Acute Interstitial Nephritis

Deceased vs. living donor kidney transplantation in prediction of acute renal allograft rejection using Tc-99m DTPA renal scan

No data are available regarding different prognostic values of Tc-99m diethylenetriaminepentaacetic acid (DTPA) renal scan in kidney transplantation (KT) recipients according to two distinct donor types: deceased donor KT (DDKT) and living donor KT (LDKT). We evaluated whether the interpretation of Tc-99m DTPA renal scan should be different by the donor type in predicting acute renal allograft rejection (AR). One hundred and seven KT recipients (61 DDKT and 46 LDKT) were included in this study. Tc-99m DTPA renal scan was performed 1week after KT. AR was defined as pathological evidence of renal allograft rejection during the first 6months of KT. Clinical factors and Tc-99m DTPA renal scan findings were compared between patients with and without AR. To further analyze the effect of the donor type, they were again compared within DDKT and LDKT recipients, respectively. AR occurred in 15 patients (7 DDKT and 8 LDKT recipients). Among all patients, time to peak uptake (TTP) of the cortex (TTPCX) measured by Tc-99m DTPA renal scan was independently predictive of AR. Moreover, TTPKD (TTP of the whole transplanted kidney) and TTPCX were the only predictors of AR among DDKT recipients. The most accurate predictors were TTPCX and kidney area on renal scan for DDKT and LDKT, respectively. However, these parameters could not predict AR for the opposite donor type. AR could be effectively predicted by Tc-99m DTPA renal scan obtained at 1week post-KT. Different parameters should be applied according to the donor type in the prediction of AR.

Gene Expression of Toll-Like Receptors 2 and 4 in Renal Transplant Rejection

Toll-like receptors are a crucial part of the innate immune system and have a pivotal role in the acquired immunity system. Studies have shown that Toll-like receptors 2 and 4 are important during the transplant process. Therefore, we analyzed the gene expression of Toll-like receptors 2 and 4 in cases of renal transplant rejection. We measured the messenger RNA expression levels of Toll-like receptors 2 and 4 in renal transplant rejection recipients compared with nonrejection recipients. We enrolled 151 deceased-donor kidney transplant recipients, whom we divided into 2 groups: 101 nonrejection recipients and 50 recipients with acute allograft rejection. We collected 3 mL of blood (treated with ethylenediaminetetraacetic acid) from each patient. Ribonucleic acid extraction and complementary DNA synthesis were conducted for all samples, and the constructed complementary DNAs were used for real-time polymerase chain reaction analysis. We measured gene expression levels of Toll-like receptors 2 and 4 in renal transplant recipients with acute allograft rejection and in recipients who did not experience acute renal allograft rejection, and the results showed that messenger RNA expression levels for both Toll-like receptors 2 and 4 were significantly increased in the acute rejection group compared with the nonrejection group. Toll-like receptors 4 and 2 could increase the risk of acute rejection after renal transplant and could be defined as a risk factor for rejection. Further studies are recommended.

Clinical and Analytical Validation of a Novel Urine-Based Test for the Detection of Allograft Rejection in Renal Transplant Patients.

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 receiver–operator characteristic curve area under the curve of 99.8% and an accuracy of 98.2%. Q-Scores < 32 indicated the absence of active rejection and Q-Scores ≥ 32 indicated an increased risk of active rejection. At the Q-Score cutoff of 32, the overall sensitivity was 95.8% and specificity was 99.3%. At a prevalence of 25%, positive and negative predictive values for active rejection were 98.0% and 98.6%, respectively. The Q-Score also detected subclinical rejection in patients without an elevated serum creatinine level but identified by a protocol biopsy. This study confirms that QSant is an accurate and quantitative measurement suitable for routine monitoring of renal allograft status.

Proteomic analysis of differentially expressed proteins in the serum of patients with acute renal allograft rejection using iTRAQ labelling technology.

Transplantation is currently the best treatment for patients with end-stage renal disease. However, acute rejection (AR) is the major source of failure in renal transplantation. The current best practice for the diagnosis of AR involves renal biopsy, but it is invasive, time-consuming, costly and inconvenient. Sensitive and less invasive detection of AR episodes in renal transplant patients is essential to preserve allograft function. The present study applied isobaric tags for relative and absolute quantitation (iTRAQ) mass spectrometry to analyze serum protein expression in patients with AR and healthy controls. Overall, 1,399 proteins were identified. Using a cut-off of Q<0.05 and a fold change of >1.2 for the variation in expression, 109 proteins were identified to be differentially expressed between the AR and control groups, 72 of which were upregulated and 37 were downregulated. Several proteins, including properdin, keratin 1, lipoprotein(a) and vitamin D-binding protein, may have roles in the pathogenesis of AR. The present study focused on iTRAQ-based proteomic profiling of serum samples in AR. Insight from the present study may help advance the understanding of the molecular mechanisms of AR and identify potential novel biomarkers of AR for further characterization.

P1703RESULTS OF RENAL TRANSPLANTATION IN PATIENTS WITH RHEUMATIC DISEASES

Abstract Background and Aims Rheumatic diseases often involve the kidneys and it might lead to chronic kidney disease (CKD). In its final stage it must be treated with renal replacement methods such as dialysis (hemodialysis or peritoneal dialysis) or renal transplantation. Kidney transplantation is the preferred and most cost-effective treatment for the end-stage renal disease, it offers a better quality of life than dialysis. The most common types of renal pathology in rheumatic diseases include glomerular (systemic lupus erythematosus), vascular (ANCA-associated vasculitides) and tubulointerstitial (goat) diseases. According to a research conducted in 2010 at the Minsk Rheumatological Department, 25% of patients had clinical or laboratory features of CKD. The aims were to reveal the most frequent rheumatic diseases affecting the kidneys and evaluate the post-transplant period in these patients. Method 94 medical case were studied retrospectively. All these patients had the end-stage renal disease with GFR of &amp;lt;15 ml/min/1.73m2 and underwent renal transplantation between January 2011 and September 2019. Results A retrospective study of 94 kidney transplant patients was conducted on renal transplantation centers in Belarus. Among the patients that underwent renal transplantation from January 2011 till September 2019, the percentage of recipients with rheumatic diseases was 3.64%. The majority of the recipients (52 %) were females. The mean age was 44.36 years (range, 16-78 years). Of the sample, 90% of kidney allografts were received from brain-dead donors, whereas only 10% of recipients got a new kidney from living-donors. Systemic lupus erythematosus was the most common causative disease in patients with rheumatic diseases (31 cases, 33%) followed by goat (28 cases, 30%) and secondary amyloidosis (17 cases, 18%) that complicated the course of rheumatoid arthritis and seronegative spondylarthritis. The remaining part of patients suffered from ANCA-associated vasculitides (10 cases, 10.6%), anti-glomerular basement membrane disease (6 cases, 6.4%), and single cases were represented by progressive systemic sclerosis and antiphospholipid syndrome (2%). In the post-transplant period, the most common complications were arterial hypertension (38%), anemia (20%), infectious diseases (27%), among them the most frequent were urinary tract infection (20%) and cytomegalovirus infection (7%). The 1-year allograft survival rate was 86%, the 5-year rate was about 82%. The main reasons for failed outcomes were acute renal allograft rejection, postoperative complications and infection. The patient survival rate after 1 and 5 years after transplantation was 93% and 86%, respectively. Infectious diseases (44%) such as nosocomial pneumonia, sepsis and cardiovascular disease (33%) are still the two most important reasons of death. Conclusion 1. The most common rheumatic diseases causing the end-stage renal disease are systemic lupus erythematosus (33%), goat (30%), rheumatoid arthritis, and seronegative spondylarthritis that lead to secondary amyloidosis (18%). 2. The 1-year allograft survival rate was 86%, the 5-year rate was about 82%, the patient survival rate after 1 and 5 years after transplantation was 93% and 86%, respectively. 3. The survival of patients with rheumatic diseases who underwent renal transplantation is comparable to patient survival after transplantation with another kidney pathology. 4. The main causes of death following renal transplantation are infectious and cardiovascular complications. Acute renal allograft rejection, postoperative complications, and infection are the main reasons of allograft failure.

P1678ASSOCIATION OF EPIDERMAL GROWTH FACTOR(EGF) AND EGF RECEPTOR POLYMORPHISMS WITH END STAGE RENAL DISEASE AND ACUTE RENAL ALLOGRAFT REJECTION IN KOREAN POPULATION

Abstract Background and Aims Epidermal growth factor (EGF) has been found to be associated with development and repair mechanisms of several renal diseases. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) of the EGF or its receptor genes might have association with end stage renal disease (ESRD) or acute renal allograft rejection (AR) in Korean patients. Method 347 recipients of the first renal transplants for ESRD including 63 AR patients among them and 289 healthy adults were included in the study. Five EGF gene SNPs (rs11568835, rs11568943, rs2237051, rs11569017, rs3756261) and four EGFR gene SNPs (rs1140475, rs2293347, rs1050171, rs6965469) were analyzed. The genotypes of these SNPs were analyzed using AxiomTM genome-wide human assay. For statistical analysis we used SNPStats and Haploview version 4.2. Multiple logistic regression models (codominant, dominant, recessive and Log-additive) were produced to obtain odds ratio (OR), 95% confidence interval (CI), and p value. Results One SNP (rs11569017) in EGF gene showed significant association with ESRD but not with AR. Another SNP (rs11568835) in EGF gene showed significant association with susceptibility to AR but not with ESRD. One SNP (rs1050171) in EGFR gene showed significant association with susceptibility to AR but not with ESRD. Conclusion We suggest that genetic polymorphisms of EGF and EGFR gene may be associated with the risk of development of ESRD and AR in the Korean population.

Signaling through tumor necrosis receptor 2 induces stem cell marker in CD133+ regenerating tubular epithelial cells in acute cell-mediated rejection of human renal allografts.

Tumor necrosis factor receptor 2 (TNFR2) is strongly upregulated on renal tubular epithelial cells by acute cell-mediated rejection (ACR. In human kidney organ culture, TNFR2 signaling both upregulates TNFR2 expression and promotes cell cycle entry of tubular epithelial cells. We find significantly more cells express CD133 mRNA and protein, a putative stem cell marker, in allograft biopsy samples with ACR compared to acute tubular injury without rejection or pretransplant "normal kidney" biopsy samples. Of CD133+ cells, ~85% are within injured tubules and ~15% are interstitial. Both populations express stem cell marker TRA-1-60 and TNFR2, but only tubular CD133+ cells express proximal tubular markers megalin and aquaporin-1. TNFR2+ CD133+ cells in tubules express proliferation marker phospho-histone H3S10 (pH3S10 ). Tubular epithelial cells in normal kidney organ cultures respond to TNFR2 signaling by expressing CD133 mRNA and protein, stem cell marker TRA-1-60, and pH3S10 within 3hours of treatment. This rapid response time suggests that CD133+ cells in regenerating tubules of kidneys undergoing ACR represent proliferating tubular epithelial cells with TNFR2-induced stem cell markers rather than expansion of resident stem cells. Infiltrating host mononuclear cells are a likely source of TNF as these changes are absent in acute tubular injury .

418 Acute Rejection of Renal Allograft Caused by Drug-Induced Acute Interstitial Nephritis

418 Acute Rejection of Renal Allograft Caused by Drug-Induced Acute Interstitial Nephritis

Association between epidermal growth factor (EGF) and EGF receptor gene polymorphisms and end-stage renal disease and acute renal allograft rejection in a Korean population

Purpose Epidermal growth factor (EGF) has been found to be associated with the development and repair mechanisms of several renal diseases. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) in EGF or its receptor genes might have an association with end-stage renal disease (ESRD) or acute renal allograft rejection (AR) in a Korean population. Methods Three-hundred and forty seven recipients of the first renal transplants for ESRD, including 63 AR patients along with 289 healthy adults were included in the study. Five EGF gene SNPs (rs11568835, rs11568943, rs2237051, rs11569017, and rs3756261) and four EGFR gene SNPs (rs1140475, rs2293347, rs1050171, and rs6965469) were analyzed. The genotypes of these SNPs were analyzed using the AxiomTM genome-wide human assay. Statistical analysis was performed using SNPStats and Haploview version 4.2 software. Multiple logistic regression models (codominant, dominant, recessive, and Log-additive) were used to estimate the odds ratio (OR), 95% confidence interval (CI), and P value. Results One SNP (rs11569017) in the EGF gene showed significant association with ESRD but not with AR. Another SNP (rs11568835) in the EGF gene showed significant association with susceptibility to AR but not with ESRD. One SNP (rs1050171) in the EGFR gene showed significant association with susceptibility to AR but not with ESRD. Conclusion Our findings suggest that SNPs in the EGF and EGFR gene may be associated with the risk of ESRD and AR development in the Korean population.

3084 A Case of CMV Colitis: Both a Cause and Consequence of Acute Renal Allograft Rejection

INTRODUCTION: Cytomegalovirus is an extremely common pathogen that usually causes a mild, self-limiting disease in the immunocompetent host. The risk of active CMV disease increases in states of immunosuppression (AIDS, transplant recipients, cancer, IBD, use of immunosuppressive agents). CMV infection in transplant recipients has a predilection for the gastrointestinal tract. CASE DESCRIPTION/METHODS: A 46 yo African American male with history renal transplant in 2002 presented to the hospital for worsening creatinine. He was previously doing well on immunosuppression with sirolimus, cyclosporine, and prednisone. His baseline creatinine was 2.2-2.6 mg/dL. On admission his Cr was 5.8. He underwent a renal biopsy that was suspicious for antibody-mediated rejection. He received high dose IV steroids, plasmapheresis, and IVIG. His Cr improved to 4 and he was discharged on tacrolimus, mycophenolate, and a tapering prednisone dose. He returned to the hospital 3 weeks later with dyspnea and peripheral edema. He also had 2 episodes of hematochezia the day prior. His Cr increased to 7.2 and his hemoglobin dropped from 8.9 g/dL to 6.9. He was started on dialysis. His hemoglobin initially improved with a transfusion but 3 days later dropped to 6.9. GI was consulted. Colonoscopy revealed a 7 × 7 mm ulcer at the ileocecal valve. Biopsies confirmed CMV colitis. He was evaluated by infectious disease for treatment. DISCUSSION: CMV infection of the GI tract is relatively common in organ transplant recipients and can involve the upper or lower GI tract. It can result in mucosal injury, ulcerations, hemorrhage, GI dysmotility, or perforations. CMV colitis can present with fever, abdominal pain, diarrhea, hematochezia, toxic megacolon, or perforation. Lower GI bleeding is the most common initial presentation. Endoscopic findings of CMV colitis are categorized into 3 groups: well-demarcated ulcers, diffuse infiltrative ulcers, and pseudomembranous patterns. Sometimes hemorrhagic colitis is seen with multiple punctuate lesions. CMV reactivation can be elicited by high intensity immunosuppression and disease can lead to allograft dysfunction and rejection. Patients at risk for CMV infection should be started on antiviral prophylaxis. With symptoms of disease, a prompt diagnosis is necessary in order to start antiviral therapy with IV ganciclovir or oral valganciclovir. A delay in treatment can result in high morbidity and mortality and therefore clinicians need to have a high index of suspicion.

P171 Donor specific antibody in simultaneous liver-kidney transplantation: preformed class II HLA antibodies and acute renal and hepatic allograft rejection

P171 Donor specific antibody in simultaneous liver-kidney transplantation: preformed class II HLA antibodies and acute renal and hepatic allograft rejection

P213 The association between mononuclear inflammatory cells infiltration and histopathologic changes of acute renal allograft rejection; a local experience and review of literatures

P213 The association between mononuclear inflammatory cells infiltration and histopathologic changes of acute renal allograft rejection; a local experience and review of literatures

Using functional magnetic resonance imaging to evaluate an acute allograft rejection model in rats

PurposeTo assess the longitudinal changes of allograft pathophysiology by intravoxel incoherent motion (IVIM) and blood oxygen level-dependent (BOLD) MRI in a rat model of acute renal allograft rejection. Materials and methodsAcute rejection (AR) was induced by transplantation of Dark Agouti donor kidneys into Lewis recipients (n = 18). A Lewis-Lewis rat syngeneically transplanted (sTX) model served as the control (n = 6). Acute tubular necrosis (n = 6) and acute calcineurin inhibitor toxicity (n = 6) groups were established using Lewis rats. MRI was performed on postoperative day (POD) 1, 4 and 7 in the allogeneically transplanted (aTX) group and on POD4 in the other groups. Histological evaluation and PCR were performed. ResultsAfter the allogenic transplantation, all MRI parameters of allograft further decreased until POD7, and the D and ADC values in the cortex were significantly lower than that in the sTX group (1.03 ± 0.09 vs 1.52 ± 0.09 × 10−3 mm2/s, Padj < 0.05; 1.21 ± 0.03 vs 1.78 ± 0.07 × 10−3 mm2/s, Padj < 0.05). The D*, f and R2* values of the aTX group in the cortex and medulla were significantly lower than those in the sTX group on POD7 (cortex, D*: 25.60 ± 4.78 vs 69.32 ± 9.79 × 10−3 mm2/s, Padj < 0.05; f: 7.84 ± 1.83 vs 20.34 ± 3.08%, Padj < 0.05; R2*: 16.61 ± 4.18 vs 31.48 ± 6.43 1/s, Padj < 0.05; medulla, D*: 13.59 ± 6.08 vs 62.75 ± 9.20 × 10−3 mm2/s, Padj < 0.05; f: 7.46 ± 1.62 vs 14.68 ± 2.05%, Padj < 0.05; R2*: 21.59 ± 3.45 vs 39.53 ± 4.34 1/s, Padj < 0.05). AR grafts presented serve interstitial inflammation, tubulitis and infiltration of T-lymphocytes and macrophages. The MRI parameters, including D, ADC, D*, f and R2*, were significantly correlated with the histological changes, cell infiltration and inflammatory cytokine mRNA levels. ConclusionsIVIM coupled with BOLD MRI allows longitudinal assessment of allograft diffusion, perfusion and oxygen consumption impairment caused by acute renal allograft rejection in rat model.

Lymphocyte depletion and risk of acute rejection in renal transplant recipients at increased risk for delayed graft function.

Delayed graft function (DGF) is a risk factor for acute rejection (AR) in renal transplant recipients, and KDIGO guidelines suggest use of lymphocyte-depletion induction when DGF is anticipated. We analyzed the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) database to assess the impact of induction immunosuppression on the risk of AR in deceased kidney recipients based on pretransplant risk of DGF using a validated model. Recipients were categorized into 4 groups based upon the induction immunosuppression: (1) Rabbit anti-thymocyte globulin (rATG); (2) Alemtuzumab (C1H); (3) IL2-receptor antagonists (IL2-RA; basiliximab or daclizumab), and (4) No antibody induction. The primary endpoint for analysis was a composite endpoint of treated AR or graft failure by 1-year posttransplantation. Compared to no antibody induction, rATG and C1H had consistently lower adjusted odds of the composite endpoint across all risk strata for DGF risk, whereas IL2-Ra was associated with increased adjusted odds of the composite endpoint with increasing DGF risk. When the induction agents were compared, rATG and C1H were associated with decreasing adjusted odds for the composite endpoint with increasing risk of DGF, especially at the higher risk spectrum of DGF. Consideration must be given to use of lymphocyte-depletion induction when the anticipated risk of DGF is increased.

Efficacy and Safety of a Tofacitinib-based Immunosuppressive Regimen After Kidney Transplantation: Results From a Long-term Extension Trial.

BackgroundTofacitinib is an oral Janus kinase inhibitor. This open-label, long-term extension (LTE) study (NCT00658359) evaluated long-term tofacitinib treatment in stable kidney transplant recipients (n = 178) posttransplant.MethodsPatients who completed 12 months of cyclosporine (CsA) or tofacitinib treatment in the phase IIb parent study (NCT00483756) were enrolled into this LTE study, evaluating long-term tofacitinib treatment over months 12 to 72 posttransplant. Patients were analyzed by tofacitinib less-intensive (LI) or more-intensive (MI) regimens received in the parent study. For both groups, tofacitinib dose was reduced from 10 to 5 mg twice daily by 6 months into the LTE. Patients were followed up through month 72 posttransplant, with a focus on month 36 results.ResultsTofacitinib demonstrated similar 36-month patient and graft survival rates to CsA. Biopsy-proven acute rejection rates at month 36 were 11.2% for CsA, versus 10.0% and 7.4% (both P > 0.05) for tofacitinib LI and MI, respectively. Least squares mean estimated glomerular filtration rates were 9 to 15 mL/min per 1.73 m2 higher for tofacitinib versus CsA at month 36. The proportions of patients with grade 2/3 interstitial fibrosis and tubular atrophy in month 36 protocol biopsies were 20.0% for LI and 18.2% for MI (both P > 0.05) versus 33.3% for CsA. Kaplan-Meier cumulative serious infection rates at month 36 were numerically higher for tofacitinib LI (43.9%; P = 0.45) and significantly higher for MI (55.9%; P < 0.05) versus CsA (37.1%).ConclusionsLong-term tofacitinib continued to be effective in preventing renal allograft acute rejection and preserving renal function. However, long-term tofacitinib and mycophenolic acid product combination was associated with persistent serious infection risk.

Multiple-biomarkers provide powerful prediction of early acute renal allograft rejection by combination of serum fractalkine, IFN-γ and IP-10

Biomarkers are urgently required for predicting rejection so that anti-rejection treatment can be taken early to protect the allograft from irreversible damage. We hypothesized that the combination of circulating fractalkine, IFN-γ and IP-10 might serve as effective biomarkers for predicting early acute renal allograft rejection. We conducted a retrospective study of 87 subjects, who were classified into acute rejection group (ARG; n = 38) and non-rejection group (NRG; n = 49). Serum fractalkine, IFN-γ and IP-10 levels were measured by Luminex. The levels of fractalkine on day 0 and 7th day, IP-10 on 4th and 7th day, and IFN-γ on 7th day in ARG was significantly higher than that in NRG. Kaplan–Meier survival analysis highlighted the higher-levels groups of fractalkine on day 0, 4th and 7th day, IFN-γ on day 0, 1st, 4th, and 7th day and IP-10 on the 4th and 7th day in rejection-free survival probability were significantly lower than low-levels groups. ROC analyses highlight the superiority of fractalkine on day 0, IP-10 on day 0, 4th and 7th day, and IFN-γ on day 0, 1st and 7th day in prediction of acute rejection. We found the combination of fractalkine on day 0, IP-10 on 7th day and IFN-γ on 7th day had the highest AUC (0.866) for predicting rejection with a sensitivity of 86.8% and a specificity of 89.8%. Our findings demonstrated a more powerful prediction of early acute renal allograft rejection during the first month after transplantation by combination of multiple-biomarkers of fractalkine, IFN-γ and IP-10, and the results might help stratify the immunologic risk of acute allograft rejection in recipients.

GC/MS-based urine metabolomics analysis of renal allograft recipients with acute rejection

BackgroundAcute renal allograft rejection is a common complication after renal transplantation that often leads to chronic rejection and ultimate graft loss. While renal allograft biopsy remains the gold standard for diagnosis of acute rejection, the possibility of biopsy-associated complications cannot be overlooked. The development of noninvasive methods for accurate detection of acute renal allograft rejection is thus of significant clinical importance.MethodsGas chromatography–mass spectrometry (GC/MS) was employed for analysis of urine metabolites in 15 renal allograft recipients with acute rejection and 15 stable renal transplant recipients. Partial least squares (PLS) regression and leave-one-out analyses were performed to ascertain whether the metabolites identified could be exploited to distinguish acute rejection from stable groups as well as their sensitivity and specificity.ResultsOverall, 14 metabolites were significantly altered in the acute rejection group (11 and 3 metabolites displayed higher and lower levels, respectively) relative to the stable transplant group. Data from PLS and leave-one-out analyses revealed that the differential metabolites identified not only distinguished acute rejection from stable transplant recipients but also showed high sensitivity and specificity for diagnosis of renal allograft recipients with acute rejection.ConclusionUrine metabolites identified with GC/MS can effectively distinguish acute rejection from stable transplant recipients, supporting the potential utility of metabolome analysis in non-invasive diagnosis of acute rejection.

The role of IL-23/IL-17 axis in human kidney allograft rejection.

Th17 cell subset has been implicated in autoimmune diseases, tumor immunity and, transplant rejection. In order to investigate the role of IL-17/IL-23 pathway in allograft outcome, intragraft expression of IL-17mRNA and single nucleotide polymorphisms (SNPs) of IL-17A, IL-17F, IL-17RC, and IL23R genes were evaluated with a quantification of IL-17A, IL-17F, and IL-23 plasma levels. This study revealed that recipients with acute rejection (AR) had a significant increase in IL-17AmRNA expression levels after transplantation compared to controls (P=0.037). Moreover, IL-17A plasma levels were significantly higher in AR group; pretransplantation (Day-1 [D-1]): P=0.00022 and posttransplantation (Day 7 [D7]): P<10-14 . IL-17F and IL-23 plasma levels were significantly higher in AR at D7 only (47.86vs. 22.99pg/ml; and 33.82vs. 18.811pg/ml; P=0.015 and P<10-17 , respectively). Using receiver-operating characteristic curves, D7 IL-17A and IL-23 plasma levels exhibited excellent sensitivities and specificities for predicting AR. Genetic study revealed no association between IL-17A, IL-17F, IL-17RC, and IL23R studied SNPs and AR. Nevertheless, a significant improvement of graft survival was found in kidney transplant recipients carrying IL-17F-rs763780*A/A, IL-17RC*G/G, and *G/A genotypes. Besides, IL-17AmRNA levels were significantly higher in patients carrying the IL-23R*G/G genotype comparatively to those with *G/A genotype. Based on these findings, significant increase of IL-17A mRNA and protein levels in AR recipients that are genetically controlled highlights the role of this cytokine that can be a useful clinical biomarker to predict early acute renal allograft rejection.