Background: The complement system activation and regulation have been linked to post-transplant pathologies including chronic antibody mediated rejection (cAMR) and the recurrence of IgA nephropathy (ReIgAN) but distinct mechanisms remain to be elucidated. Methods: In this retrospective single center study, the outcome of kidney transplantation was studied in 150 patients with late histological diagnosis to be either cAMR or ReIgAN, 14 stable kidney grafts at 3 months and finally 11 patients with native kidney IgAN nephropathy. To study a role of complement cascade and regulation in cAMR and ReIgAN, the RNA was extracted from available frozen kidney biopsy samples and using RT-qPCR transcripts of 11 target genes along with clinical data were determined and compared with stable grafts at 3 months protocol biopsies or IgAN native kidney nephropathy. Immunohistologically, CD46 (MCP), and C5 proteins were stained in biopsies. Results: Interestingly, there were no differences in kidney graft survival between cAMR and ReIgAN since transplantation. cAMR was associated with significantly higher intragraft transcripts of C3, CD59, and C1-INH as compared to ReIgAN (p < 0.05). When compared to normal stable grafts, cAMR grafts exhibited higher C3, CD55, CD59, CFH, CFI, and C1-INH (p < 0.01). Moreover, ReIgAN was associated with the increase of CD46, CD55, CD59 (p < 0.01), and CFI (p < 0.05) transcripts compared with native kidney IgAN. Rapid progression of cAMR (failure at 2 years after biopsy) was observed in patients with lower intrarenal CD55 expression (AUC 0.77, 78.6% sensitivity, and 72.7 specificity). There was highly significant association of several complement intrarenal transcripts and the degree of CKD regardless the diagnosis; C3, CD55, CFH, CFI, and C1-INH expressions positively correlated with eGFR (for all p < 0.001). Neither the low mRNA transcripts nor the high mRNA transcripts biopsies were associated with distinct trend in MCP or C5 proteins staining. Conclusions: The intrarenal complement system transcripts are upregulated in progressively deteriorated kidney allografts.

• MeSH
• alografty MeSH
• biopsie MeSH
• buněčná cytotoxicita závislá na protilátkách MeSH
• chronická nemoc MeSH
• dítě MeSH
• dospělí MeSH
• genetická transkripce MeSH
• IgA nefropatie diagnóza   etiologie   terapie   MeSH
• isoprotilátky imunologie   MeSH
• komplement genetika   imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• přežívání štěpu genetika   imunologie   MeSH
• recidiva MeSH
• rejekce štěpu genetika   imunologie   MeSH
• ROC křivka MeSH
• senioři MeSH
• stanovení celkové genové exprese MeSH
• transplantace ledvin škodlivé účinky   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Accommodation in ABO-incompatible (ABOi) transplantation and subclinical antibody-mediated rejection in HLA-incompatible (HLAi) transplantation share several morphological similarities. Because the clinical long-term outcomes differ, we hypothesized different molecular processes involved in ABOi transplantation and subclinical antibody-mediated rejection. METHODS: Using Illumina Human HT-12 v4 Expression BeadChips, the whole transcriptome was evaluated based on 3-month protocol C4d+ biopsies in otherwise stable ABOi and HLAi kidney grafts, as well as in C4d-negative HLA-compatible grafts exhibiting normal histological findings. Top differently regulated genes were further validated using real-time quantitative polymerase chain reaction in another patient cohort and complement regulatory proteins by immunohistochemistry. RESULTS: In the case of genes involved in immune response-related biological processes, ABOi and HLAi cohorts had similar transcriptomic profiles to C4d-negative controls. The majority of deregulated genes in the ABOi and HLAi groups consisted of metallothioneins and epithelial transporter genes. Increased expression of epithelial transporters (SLC4A1, SLC4A9, SLC17A3, SLC12A3, and SLC30A2) and class 1 metallothioneins (MT1F, MT1G, and MT1X) in HLAi transplantation was validated by real-time quantitative polymerase chain reaction. In comparison to controls, both incompatible cohorts were characterized by the upregulation of intrarenal complement regulatory genes. CD46 and CD59 transcripts were increased in the ABOi cohort, whereas CD46 solely in HLAi group, and CD59 protein expression was similar in both incompatible groups. CONCLUSIONS: Several epithelial transporters and metallothioneins discriminate subclinical antibody-mediated rejection in HLAi transplantation from accommodation in ABOi transplantation, which suggest different involved downstream mechanisms and increased risk of injury in HLAi settings. Metallothioneins with their antioxidative properties may help to attenuate the inflammation response induced by donor-specific anti-HLA antibody binding.

• MeSH
• ABO systém krevních skupin imunologie   MeSH
• alografty imunologie   metabolismus   patologie   MeSH
• biologické markery metabolismus   MeSH
• biopsie MeSH
• dospělí MeSH
• HLA antigeny imunologie   MeSH
• isoprotilátky imunologie   MeSH
• ledviny imunologie   metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové transportní proteiny metabolismus   MeSH
• metalothionein metabolismus   MeSH
• mladý dospělý MeSH
• následné studie MeSH
• nekompatibilita krevních skupin diagnóza   imunologie   patologie   MeSH
• přežívání štěpu imunologie   MeSH
• rejekce štěpu diagnóza   imunologie   patologie   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• stanovení celkové genové exprese MeSH
• transplantace ledvin škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH

Acute renal rejection is a major risk factor for chronic allograft dysfunction and long-term graft loss. We performed a genome-wide association study to detect loci associated with biopsy-proven acute T cell-mediated rejection occurring in the first year after renal transplantation. In a discovery cohort of 4127 European renal allograft recipients transplanted in eight European centers, we used a DNA pooling approach to compare 275 cases and 503 controls. In an independent replication cohort of 2765 patients transplanted in two European countries, we identified 313 cases and 531 controls, in whom we genotyped individually the most significant single nucleotide polymorphisms (SNPs) from the discovery cohort. In the discovery cohort, we found five candidate loci tagged by a number of contiguous SNPs (more than five) that was never reached in iterative in silico permutations of our experimental data. In the replication cohort, two loci remained significantly associated with acute rejection in both univariate and multivariate analysis. One locus encompasses PTPRO, coding for a receptor-type tyrosine kinase essential for B cell receptor signaling. The other locus involves ciliary gene CCDC67, in line with the emerging concept of a shared building design between the immune synapse and the primary cilium.

• MeSH
• akutní nemoc MeSH
• celogenomová asociační studie MeSH
• chronické selhání ledvin chirurgie   MeSH
• dospělí MeSH
• genetické markery MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové supresorové proteiny genetika   MeSH
• prognóza MeSH
• proteiny asociované s mikrotubuly genetika   MeSH
• rejekce štěpu diagnóza   etiologie   genetika   MeSH
• studie případů a kontrol MeSH
• transplantace ledvin škodlivé účinky   MeSH
• tyrosinfosfatasy receptorového typu, třída 3 genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cytomegalovirus (CMV) infection influences both short and long term outcomes in immunosuppressed organ transplant recipients. The aim of this study was to evaluate the effect of different induction immunosuppression regimens on CMV specific T cell response in patients with already established CMV immunity. In 24 seropositive living donor kidney recipients, the frequency of CMV specific T cells was determined by ELISPOT (Enzyme-Linked ImmunoSpot) assay prior and 6 months after transplantation. Recipients' peripheral blood mononuclear cells were stimulated with immediate-early (IE1) and phosphoprotein 65 (pp65) CMV-derived peptide pools and the number of cells producing interferon gamma (IFN-gamma) was assessed. Patients received quadruple immunosuppression based either on depletive rabbit antithymocyte globulin (rATG) or non-depletive basiliximab induction and tacrolimus/mycophenolate mofetil/steroids. Patients with rATG induction received valgancyclovir prophylaxis. No effects of different induction agents on CMV specific T cell immunity were found at sixth month after kidney transplantation. There were no associations among dialysis vintage, pretransplant CMV specific T cell immunity, and later CMV DNAemia. Similarly, no effect of CMV prophylaxis on CMV specific T cell immunity was revealed. This study shows no effect of posttransplant immunosuppression on CMV specific T cell immunity in living donor kidney transplant recipients with CMV immunity already established, regardless of lymphocyte depletion and CMV prophylaxis.

• MeSH
• buněčná imunita MeSH
• cytomegalovirové infekce prevence a kontrola   MeSH
• Cytomegalovirus imunologie   MeSH
• dospělí MeSH
• fosfoproteiny imunologie   MeSH
• imunosupresiva terapeutické užití   MeSH
• imunosupresivní léčba metody   MeSH
• indukční chemoterapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• monitorování imunologické MeSH
• proteiny virové matrix imunologie   MeSH
• T-lymfocyty imunologie   MeSH
• thymocyty imunologie   MeSH
• transplantace ledvin metody   MeSH
• žijící dárci * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The increased demand for kidney transplantation and organ shortage resulted in the increased use of kidneys from suboptimal donors. Therefore, identification of kidneys that can be accepted without significantly compromising the outcome of allograft or recipient has become critical. A robust assessment of organ quality is of particular importance especially in kidneys from elderly donors in whom morphological and functional changes associated with aging and diseases are obvious. A number of predictive tools have been developed to help with evaluating the suitability of a deceased-donor kidney for transplantation. Among those, Kidney Donor Profile Index and zero hour graft biopsy in elderly donors have been already implemented in several transplant programs. This review captures the recent literature on this subject and discusses approaches for evaluating the quality of kidney grafts from elderly donors.

• MeSH
• biologické markery analýza   MeSH
• biopsie MeSH
• dárci tkání * MeSH
• hodnocení rizik * MeSH
• lidé středního věku MeSH
• lidé MeSH
• přežívání štěpu MeSH
• rejekce štěpu MeSH
• senioři MeSH
• seznamy čekatelů MeSH
• transplantace ledvin * MeSH
• výběr dárců * MeSH
• výběr pacientů MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Transplantace ledviny od žijících dárců představují nejlepší metodu léčby nezvratného selhání ledvin. Výskyt akutních rejekcí je v tomto programu nyní vyšší než u kadaverosních transplantací, především v důsledku rozšíření geneticky nepříbuzných transplantací. Riziko vzniku rejekce se pomocí běžně používaných metod (stanovení panel reaktivních protilátek a crossmatch) dá odhadnout jen velmi těžko. Cílem této studie je posoudit aloreaktivitu příjemce pomocí panelu laboratorních testů a odhadnout riziko vzniku T buňkami a protilátkami zprostředkované rejekce. Předmětem výzkumu je detekce předtransplantačních a potransplantačních anti HLA protilátek spolu s určením dárcovsky specifické T a B lymfocytární aloreaktivity (ELISPOT), vyšetření periferních populací T a B lymfocytů a jejich specifických periferních transkriptů. Získaná data budou analyzována ve vztahu k potransplantačnímu průběhu a fenotypu rejekce.; Living donor kidney transplantation represents the best therapy of end stage renal disease. Recently, the acute rejection incidence has been observed to be higher than in deceased donor transplantation, mainly because of increasing number of genetically unrelated procedures. Prediction of acute rejection with recently available techniques often fails. The aim of this project is to analyze recipient alloreactivty using multilevel laboratory platforms to better predict risks of acute rejection, both T cell- and antibody mediated. In this project pre and posttransplant analyzes will be performed to detect anti HLA antibodies, T and B cell donor specific alloreactivity, specific populations of T and B cells along with their peripheral transcripts. Data will be analyzed in relation to postransplant outcome and distinct rejection phenotype.

• MeSH
• B-lymfocyty MeSH
• ELISPOT MeSH
• monitorování imunologické MeSH
• protilátky škodlivé účinky   MeSH
• rejekce štěpu diagnóza   MeSH
• T-lymfocyty MeSH
• transplantace ledvin škodlivé účinky   MeSH
• žijící dárci MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• transplantologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

ABO-incompatible (ABOi) kidney transplantation represents a viable tool to increase the donor pool for kidney transplantation, however, increased alloimmune response has been debated. The early outcomes of 25 low-risk ABOi kidney transplant recipients were compared with thoroughly matched 50 ABO-compatible (ABOc) ones. The matching process was based on gender and age of recipients and immunologic parameters, such as panel reactive antibodies, number of human leukocyte antigen mismatches, and transplantation era. Three-month protocol kidney graft biopsy Banff scores and 1-year clinical outcomes were compared. Apart from C4d positivity, no statistically significant differences were found regarding the Banff scores between the two groups. Similarly, microvascular inflammation and tubulointerstitial injury revealed no differences either. The eGFR at 3 months and 1 year was similar in both groups. In conclusion, blood group incompatibility yields no additional microvascular and tubulointerstitial graft injury if desensitization protocol was applied to low-risk kidney transplant recipients.

• MeSH
• ABO systém krevních skupin imunologie   MeSH
• alografty imunologie   zásobování a distribuce   MeSH
• biopsie MeSH
• desenzibilizace imunologická MeSH
• dospělí MeSH
• histokompatibilita imunologie   MeSH
• hodnoty glomerulární filtrace MeSH
• ledviny krevní zásobení   imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikrocévy MeSH
• nekompatibilita krevních skupin komplikace   imunologie   MeSH
• rejekce štěpu imunologie   MeSH
• transplantace ledvin metody   MeSH
• vaskulitida imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

The complement system is considered to be an important part of innate immune system with a significant role in inflammation processes. The activation can occur through classical, alternative, or lectin pathway, resulting in the creation of anaphylatoxins C3a and C5a, possessing a vast spectrum of immune functions, and the assembly of terminal complement cascade, capable of direct cell lysis. The activation processes are tightly regulated; inappropriate activation of the complement cascade plays a significant role in many renal diseases including organ transplantation. Moreover, complement cascade is activated during ischemia/reperfusion injury processes and influences delayed graft function of kidney allografts. Interestingly, complement system has been found to play a role in both acute cellular and antibody-mediated rejections and thrombotic microangiopathy. Therefore, complement system may represent an interesting therapeutical target in kidney transplant pathologies.

• MeSH
• aktivace komplementu imunologie   MeSH
• komplement * imunologie   škodlivé účinky   MeSH
• lidé MeSH
• pooperační komplikace MeSH
• protilátky imunologie   škodlivé účinky   MeSH
• rejekce štěpu imunologie   MeSH
• reperfuzní poškození imunologie   MeSH
• T-lymfocyty imunologie   MeSH
• transplantace ledvin * škodlivé účinky   MeSH
• transplantáty imunologie   MeSH
• trombotické mikroangiopatie imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

BACKGROUND: Steroid avoidance in immunosuppression in kidney transplantation offers several metabolic advantages, however it is associated with higher early acute rejection rate. Cellular and molecular mechanisms of this phenomenon remain poorly understood. METHODS: In this single center observational study, low-risk kidney transplant recipients randomized into large multicenter prospective ADVANCE trial with steroid avoidance/early withdrawal and center standard of care treated patients were monitored for 12months. The expressions of 28 transcripts, associated with alloimmune response and operational tolerance, were evaluated in the peripheral blood using RT-qPCR at 0, 7, 14, 90 and 365 postoperative days (POD) and in the protocol graft biopsy at 3months while lymphocyte subpopulations were analyzed by flow-cytometry within the follow-up. RESULTS: Both steroid avoidance and withdrawal regimens were associated with significantly higher granzyme B (GZMB) transcript at POD 14 and perforin 1 (PRF1) transcript at POD 7. The higher interleukin 2 (IL-2) expression at POD 7 was detected only in the steroid avoidance group. Initial steroids decreased the expression SH2D1B transcript at POD14 and there were no further differences in other operational tolerance transcripts among groups. The statistically significant decrease in absolute numbers of peripheral NK cells in the first 14days was observed in the standard of care group only. There were no differences in analyzed intrarenal transcripts in 3-month biopsies among groups. CONCLUSIONS: The enhanced expression of some of Th1 associated transcripts and limited effects on NK cells of steroid avoidance immunosuppression suggest higher susceptibility for early acute rejection.

• MeSH
• buňky NK imunologie   metabolismus   MeSH
• dospělí MeSH
• imunosupresivní léčba metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• prospektivní studie MeSH
• regulace genové exprese * MeSH
• senioři MeSH
• Th1 buňky imunologie   metabolismus   MeSH
• transplantace ledvin * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: There is high medical need for safe long-term immunosuppression monotherapy in kidney transplantation. Selective targeting of post-transplant alloantigen-(re)activated effector-T cells by anti-TNF antibodies after global T cell depletion may allow safe drug minimization, however, it is unsolved what might be the best maintenance monotherapy. METHODS: In this open, prospective observational single-centre trial, 20 primary deceased donor kidney transplant recipients received 2x20 mg Alemtuzumab (d0/d1) followed by 5 mg/kg Infliximab (d2). For 14 days all patients received only tacrolimus, then they were allocated to either receive tacrolimus (TAC, n = 13) or sirolimus (SIR, n = 7) monotherapy, respectively. Protocol biopsies and extensive immune monitoring were performed and patients were followed-up for 60 months. RESULTS: TAC-monotherapy resulted in excellent graft survival (5yr 92%, 95%CI: 56.6-98.9) and function, normal histology, and no proteinuria. Immune monitoring revealed low intragraft inflammation (urinary IP-10) and hints for the development of operational tolerance signature in the TAC- but not SIR-group. Remarkably, the TAC-monotherapy was successful in all five presensitized (ELISPOT+) patients. However, recruitment into SIR-arm was stopped (after n = 7) because of high incidence of proteinuria and acute/chronic rejection in biopsies. No opportunistic infections occurred during follow-up. CONCLUSIONS: In conclusion, our novel fast-track TAC-monotherapy protocol is likely to be safe and preliminary results indicated an excellent 5-year outcome, however, a full-scale study will be needed to confirm our findings. TRIAL REGISTRATION: EudraCT Number: 2006-003110-18.

• MeSH
• antigeny nádorové MeSH
• biologické markery metabolismus   MeSH
• CD antigeny MeSH
• dospělí MeSH
• glykoproteiny antagonisté a inhibitory   MeSH
• imunosupresiva terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• monitorování imunologické MeSH
• prospektivní studie MeSH
• rejekce štěpu farmakoterapie   etiologie   MeSH
• sirolimus terapeutické užití   MeSH
• stanovení celkové genové exprese MeSH
• takrolimus terapeutické užití   MeSH
• TNF-alfa antagonisté a inhibitory   MeSH
• transplantace ledvin škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• pozorovací studie MeSH