Hraniční změny jsou častým histologickým nálezem ledvinných štěpů, jak v období brzy po transplantaci, tak v tříměsíčních protokolárních biopsiích. Přestože tento nález není považován za rejekci, jeho prognóza je nejistá a u podskupiny pacientů dochází následně ke vzniku chronické rejekce. Predikce chronické rejekce v době diagnózy hraničních změn je v současné době problematická. Cílem tohoto projektu je korelovat imunologické a molekulární markery hraničních změn s následnou tvorbou donor specifických protilátek a přítomností dalších znaků chronické T buňkami či protilátkami zprostředkované rejekce.; Borderline changes are quite common histological findings of kidney allografts, both early after transplantation and in protocol 3-months biopsies. Although this phenotype has been considered as non-rejection, its prognosis remains unclear and in a subgroup of patients subsequently develops chronic rejection. Prediction of chronic rejection after borderline changes diagnosis is currently impossible. The aim of this project is to correlate immunological and molecular markers associated with borderline changes with subsequent donor specific antibody formation and presence of other markers of chronic T cell mediated or antibody mediated chronic allograft rejection.

• MeSH
• biologické markery MeSH
• diagnostické techniky molekulární MeSH
• fenotyp MeSH
• lidé MeSH
• příjemce transplantátu MeSH
• prognóza MeSH
• rejekce štěpu diagnóza   MeSH
• rizikové faktory MeSH
• T-lymfocyty MeSH
• transplantace ledvin MeSH
• Check Tag
• lidé MeSH

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

PURPOSE: Functional electrical stimulation-assisted cycle ergometry (FESCE) enables in-bed leg exercise independently of patients' volition. We hypothesised that early use of FESCE-based progressive mobility programme improves physical function in survivors of critical care after 6 months. METHODS: We enrolled mechanically ventilated adults estimated to need >7 days of intensive care unit (ICU) stay into an assessor-blinded single centre randomised controlled trial to receive either FESCE-based protocolised or standard rehabilitation that continued up to day 28 or ICU discharge. RESULTS: We randomised in 1:1 ratio 150 patients (age 61±15 years, Acute Physiology and Chronic Health Evaluation II 21±7) at a median of 21 (IQR 19-43) hours after admission to ICU. Mean rehabilitation duration of rehabilitation delivered to intervention versus control group was 82 (IQR 66-97) versus 53 (IQR 50-57) min per treatment day, p<0.001. At 6 months 42 (56%) and 46 (61%) patients in interventional and control groups, respectively, were alive and available to follow-up (81.5% of prespecified sample size). Their Physical Component Summary of SF-36 (primary outcome) was not different at 6 months (50 (IQR 21-69) vs 49 (IQR 26-77); p=0.26). At ICU discharge, there were no differences in the ICU length of stay, functional performance, rectus femoris cross-sectional diameter or muscle power despite the daily nitrogen balance was being 0.6 (95% CI 0.2 to 1.0; p=0.004) gN/m2 less negative in the intervention group. CONCLUSION: Early delivery of FESCE-based protocolised rehabilitation to ICU patients does not improve physical functioning at 6 months in survivors. TRIAL REGISTRATION NUMBER: NCT02864745.

• MeSH
• časové faktory MeSH
• elektrická stimulace MeSH
• ergometrie metody   MeSH
• jednotky intenzivní péče * MeSH
• kritický stav rehabilitace   MeSH
• kvalita života * MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• prospektivní studie MeSH
• svalová síla fyziologie   MeSH
• svalová slabost patofyziologie   rehabilitace   MeSH
• terapie cvičením metody   MeSH
• umělé dýchání metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: Preclinical studies suggested that pharmacological inhibition of the renin-angiotensin-aldosterone system (RAAS) by ACE inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) may increase local angiotensin-converting enzyme 2 (ACE2) expression. METHODS: In this study, we evaluated the effect of ACEi or ARB treatment on expression of ACE2, ACE, and AGTR1 in 3-month protocol kidney allograft biopsies of stable patients using RT-qPCR (n = 48). Protein ACE2 expression was assessed using immunohistochemistry from paraffin sections. RESULTS: The therapy with RAAS blockers was not associated with increased ACE2, ACE, or ATGR1 expression in kidney allografts and also ACE2 protein immunohistochemistry did not reveal differences among groups. CONCLUSIONS: ACEis or ARBs in kidney transplant recipients do not affect local ACE2 expression. This observation supports long-term RAAS treatment in kidney transplant recipients, despite acute complications such as COVID-19 where ACE2 serves as the entry protein for infection.

• MeSH
• alografty účinky léků   metabolismus   MeSH
• angiotensin-konvertující enzym 2 analýza   antagonisté a inhibitory   genetika   MeSH
• antagonisté receptorů pro angiotenzin farmakologie   terapeutické užití   MeSH
• antihypertenziva farmakologie   terapeutické užití   MeSH
• COVID-19 komplikace   genetika   MeSH
• dospělí MeSH
• exprese genu účinky léků   MeSH
• ledviny účinky léků   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA analýza   genetika   MeSH
• renin-angiotensin systém účinky léků   MeSH
• senioři MeSH
• transplantace ledvin MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The tubulitis with/without interstitial inflammation not meeting criteria for T-cell-mediated rejection (minimal allograft injury) is the most frequent histological findings in early transplant biopsies. The course of transcriptional changes in sequential kidney graft biopsies has not been studied yet. Molecular phenotypes were analyzed using the Molecular Microscope® Diagnostic System (MMDx) in 46 indication biopsies (median 13 postoperative days) diagnosed as minimal allograft injury and in corresponding follow-up biopsies at 3 months. All 46 patients with minimal injury in early biopsy received steroid pulses. MMDx interpreted indication biopsies as no-rejection in 34/46 (74%), T-cell-mediated rejection (TCMR) in 4/46 (9%), antibody-mediated rejection in 6/46 (13%), and mixed rejection in 2/46 (4%) cases. Follow-up biopsies were interpreted by MMDx in 37/46 (80%) cases as no-rejection, in 4/46 (9%) as TCMR, and in 5/46 (11%) as mixed rejection. Follow-up biopsies showed a decrease in MMDx-assessed acute kidney injury (P = 0.001) and an increase of atrophy-fibrosis (P = 0.002). The most significant predictor of MMDx rejection scores in follow-up biopsies was the tubulitis classifier score in initial biopsies (AUC = 0.84, P = 0.002), confirmed in multivariate binary regression (OR = 16, P = 0.016). Molecular tubulitis score at initial biopsy has the potential to discriminate patients at risk for molecular rejection score at follow-up biopsy.

• MeSH
• alografty MeSH
• biopsie MeSH
• kohortové studie MeSH
• ledviny MeSH
• lidé MeSH
• rejekce štěpu * MeSH
• transplantace ledvin * škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The Banff 2019 kidney allograft pathology update excluded isolated tubulitis without interstitial inflammation (ISO-T) from the category of borderline (suspicious) for acute T cell-mediated rejection due to its proposed benign clinical outcome. In this study, we explored the molecular assessment of ISO-T. ISO-T or interstitial inflammation with tubulitis (I + T) was diagnosed in indication biopsies within the first 14 postoperative days. The molecular phenotype of ISO-T was compared to I + T either by using RNA sequencing (n = 16) or by Molecular Microscope Diagnostic System (MMDx, n = 51). RNA sequencing showed lower expression of genes related to interferon-y (p = 1.5 *10-16), cytokine signaling (p = 2.1 *10-20) and inflammatory response (p = 1.0*10-13) in the ISO-T group than in I + T group. Transcripts with increased expression in the I + T group overlapped significantly with previously described pathogenesis-based transcript sets associated with cytotoxic and effector T cell transcripts, and with T cell-mediated rejection (TCMR). MMDx classified 25/32 (78%) ISO-T biopsies and 12/19 (63%) I + T biopsies as no-rejection. ISO-T had significantly lower MMDx scores for interstitial inflammation (p = 0.014), tubulitis (p = 0.035) and TCMR (p = 0.016) compared to I + T. Fewer molecular signals of inflammation in isolated tubulitis suggest that this is also a benign phenotype on a molecular level.

• MeSH
• alografty metabolismus   patologie   MeSH
• biologické markery * MeSH
• biopsie MeSH
• intersticiální nefritida diagnóza   etiologie   MeSH
• lidé MeSH
• přežívání štěpu genetika   imunologie   MeSH
• rejekce štěpu etiologie   metabolismus   patologie   MeSH
• stanovení celkové genové exprese MeSH
• transkriptom MeSH
• transplantace ledvin * škodlivé účinky   MeSH
• výpočetní biologie MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Chronic kidney disease stage 5 (CKD5) dialysis patients who stay long term in uremic environment often exhibit several, poorly defined, immune impairments. In this study, we assessed peripheral virus-specific effector/memory cells and subpopulations of T, B and DC cells using ELISPOT and FACS methods in 74 low-risk kidney transplant candidates without anti-HLA antibodies, prior to transplantation in pre-emptive (never experienced dialysis) and dialysis cohorts. There was difference in circulating marginal zone B cells (MZB) (IgDhighCD27high) between dialysis patients and those receiving kidney grafts pre-emptively (P = .002). Patients treated on dialysis >12 months had also 4.2-fold greater risk of increased absolute numbers of MZB (95%CI:1.6-11.2; P = .004). There were no other differences in B-, T- and DC-cell subsets. Numbers of effector/memory T cells reactive to major opportunistic virus-specific antigens (CMV, BKV and EBV) were not affected by dialysis. Non-sensitised dialysis-treated patients displayed significantly more circulating MZB compared to those CKD5 patients that had never undergone dialysis therapy.

• MeSH
• antigeny CD27 metabolismus   MeSH
• B-lymfocyty imunologie   MeSH
• chronická renální insuficience imunologie   terapie   MeSH
• dendritické buňky imunologie   MeSH
• dialýza MeSH
• dospělí MeSH
• ELISPOT MeSH
• imunologická paměť MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• senioři MeSH
• slezina patologie   MeSH
• T-lymfocyty imunologie   MeSH
• Check Tag
• 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

The fate of transplanted kidneys is substantially influenced by graft quality, with transplantation of kidneys from elderly and expanded criteria donors (ECDs) associated with higher occurrence of delayed graft function, rejection, and inferior long-term outcomes. However, little is known about early molecular fingerprints of these events in different donor categories. Borderline changes represent the most frequent histological finding early after kidney transplantation. Therefore, we examined outcomes and transcriptomic profiles of early-case biopsies diagnosed as borderline changes in different donor categories. In this single-center, retrospective, observational study, we compared midterm outcomes of kidney transplant recipients with early borderline changes as a first pathology between ECD (n = 109), standard criteria donor (SCDs, n = 109), and living donor (LD, n = 51) cohorts. Intragraft gene expression profiling by microarray was performed in part of these ECD, SCD, and LD cohorts. Although 5 year graft survival in patients with borderline changes in early-case biopsies was not influenced by donor category (log-rank P = 0.293), impaired kidney graft function (estimated glomerular filtration rate by Chronic Kidney Disease Epidemiology Collaboration equation) at M3, 1, 2, and 3 years was observed in the ECD cohort (P < 0.001). Graft biopsies from ECD donors had higher vascular intimal fibrosis and arteriolar hyalinosis compared to SCD and LD (P < 0.001), suggesting chronic vascular changes. Increased transcripts typical for ECD, as compared to both LD and SCD, showed enrichment of the inflammatory, defense, and wounding responses and the ECM-receptor interaction pathway. Additionally, increased transcripts in ECD vs. LD showed activation of complement and coagulation and cytokine-cytokine receptor pathways along with platelet activation and cell cycle regulation. Comparative gene expression overlaps of ECD, SCD, and LD using Venn diagrams found 64 up- and 16 down-regulated genes in ECD compared to both LD and SCD. Shared increased transcripts in ECD vs. both SCD and LD included thrombospondin-2 (THBS2), angiopoietin-like 4 (ANGPTL4), collagens (COL6A3, COL1A1), chemokine CCL13, and interleukin IL11, and most significantly, down-regulated transcripts included proline-rich 35 (PRR35) and fibroblast growth factor 9. Early borderline changes in ECD kidney transplantation are characterized by increased regulation of inflammation, extracellular matrix remodeling, and acute kidney injury transcripts in comparison with both LD and SCD grafts.

• MeSH
• alografty * patologie   patofyziologie   MeSH
• dárci tkání * MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• opožděný nástup funkce štěpu genetika   MeSH
• retrospektivní studie MeSH
• transkriptom * MeSH
• transplantace ledvin metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH

PURPOSE OF REVIEW: This review summarises recent developments in monitoring and immunosuppressive management in kidney transplantation. RECENT FINDINGS: Long-term kidney allograft outcomes have not changed substantially mainly as a result of acute and chronic antibody-mediated rejection. Several groups have recently attempted to determine peripheral molecular fingerprints of ongoing rejection. But while this research is promising, it is not generalised for further spreading among different cohorts. Measurements of donor-derived cell-free DNA levels in recent studies have revealed better predictive values for antibody-mediated rejection. The Molecular Microscope Diagnostic System for assessing kidney graft biopsies has been gradually introduced within clinical practice, especially in complicated cases aimed at improving histological diagnostics. Molecular studies on accommodation in ABO-incompatible transplantation have shown increased complement regulation and lower expression of epithelial transporters and class 1 metallothioneins. Additionally, in clinical studies of sensitised patients, imlifidase has been shown to enable transplantation across significant immunological barriers, while the co-stimulation blockade has been tested to prevent donor specific antibodies development. In low-risk patients, everolimus/tacrolimus-based regimens have also proven their antiviral effects in large clinical trials. SUMMARY: Recent developments in non-invasive monitoring have paved the way for the introduction of future larger clinical trials with multiple patient cohorts.

• MeSH
• imunosupresivní léčba metody   MeSH
• lidé MeSH
• transplantace ledvin metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH