Operational tolerance (OT) has been observed in patients who stopped their immunosuppression for more than a year and no destructive alloimmune response was noticed. B cell-related immunophenotypic and transcriptomic signatures were identified so far among OT kidney transplant recipients. The aim of this project is to evaluate peripheral blood transcriptomic profile using RNA-sequencing in newly identified european cohort of OT patients and compared it with well-defined controls. Moreover, we plan to validate protective role of several transcripts associated with OT in a large patient population. Next, we plan to evaluate B cell immunophenotypes in patients with long-term graft function and with chronic rejection. The identification and validation of biomarkers of operational tolerance / immune quiescence may thus allow construct bedside clinical tests enable to guide immunosuppression.

Operační tolerance (OT) byla pozorována u nemocných, kteří přestali užívat imunosupresi po více jak 1 rok a nebyla u nich zaznamenána žádná destruktivní imunitní odpověď. Imunofenotypy B lymfocytů a transcripty spojené s B lymfocyty byly identifikovány mezi nemocnými s OT. Cílem projektu je vyšetřit transkriptomický profil periferní krve nově identifikovaných evropských pacientů s OT ve srovnání s dobře definovanými kontrolními skupinami. Dále plánujeme validovat prognostickou roli několika periferních transkriptů spojených s OT na velké kohortě nemocných po transplantaci ledviny léčených imunosupresí. Dále zamýšlíme ověřit protektivní roli fenotypů B lymfocytů u nemocných s dlouhodobě stabilní funkcí štěpu ve srovnání s nemocnými s biopticky potvrzenou chronickou rejekcí. Identifikace a validace biomarkerů OT / imunitní neodpovídavosti může umožnit konstrukci jednoduchých klinických testů k řízení imunosupresivní terapie.

• Klíčová slova
• imunosuprese, B lymfocyty, immunosuppression, kidney transplantation, transplantace ledvin, operační tolerance, operational tolerance, B-cells,

• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

PURPOSE: Advanced age is associated with an impaired humoral immune response to SARS-CoV-2 mRNA vaccination in kidney transplant recipients (KTR). The mechanisms are, however, poorly understood. Frailty syndrome assessment may determine the most vulnerable population. METHODS: This study is a secondary analysis of a prospective study (NCT04832841) regarding seroconversion after BNT162b2 vaccination, including 101 SARS-CoV-2 naïve KTR 70 years and older. The Fried frailty components were evaluated, and antibodies against S1 and S2 subunits of SARS-CoV-2 were examined > 14 days after the second dose of BNT162b2 vaccine. RESULTS: Seroconversion was observed in 33 KTR. Male gender, eGFR, MMF-free immunosuppression, and a lower frailty score were associated with higher seroconversion rates in univariable regression. Concerning frailty components, physical inactivity had the most negative effect on seroconversion (OR = 0.36, 95% CI 0.14-0.95, p = 0.039). In a multivariable regression adjusted for eGFR, MMF-free immunosuppression, time from transplant and gender, pre-frail (OR = 0.27, 95% CI 0.07-1.00, p = 0.050), and frail status (OR = 0.14, 95% CI 0.03-0.73, p = 0.019) were associated with an increased risk of unresponsiveness to SARS-CoV-2 vaccines. CONCLUSION: Frailty was associated with an impaired humoral response to SARS-CoV-2 mRNA vaccination in older SARS-CoV-2 naïve KTR. TRAIL REGISTRATION: This study is registered under the identifier NCT04832841 on ClinicalTrials.gov.

• MeSH
• COVID-19 * prevence a kontrola   MeSH
• křehkost * MeSH
• křehký senior MeSH
• lidé MeSH
• messenger RNA MeSH
• příjemce transplantátu MeSH
• prospektivní studie MeSH
• protilátky virové MeSH
• SARS-CoV-2 MeSH
• senioři MeSH
• transplantace ledvin * MeSH
• vakcína BNT162 MeSH
• vakcíny proti COVID-19 MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Recurrence of immunoglobulin A nephropathy (IgAN) limits graft survival in kidney transplantation. However, predictors of a worse outcome are poorly understood. METHODS: Among 442 kidney transplant recipients (KTRs) with IgAN, 83 (18.8%) KTRs exhibited biopsy-proven IgAN recurrence between 1994 and 2020 and were enrolled in the derivation cohort. A multivariable Cox model predicting allograft loss based on clinical data at the biopsy and a web-based nomogram were developed. The nomogram was externally validated using an independent cohort (n = 67). RESULTS: Patient age <43 years {hazard ratio [HR] 2.20 [95% confidence interval (CI) 1.41-3.43], P < .001}, female gender [HR 1.72 (95% CI 1.07-2.76), P = .026] and retransplantation status [HR 1.98 (95% CI 1.13-3.36), P = .016] were identified as independent risk factors for IgAN recurrence. Patient age <43 years [HR 2.77 (95% CI 1.17-6.56), P = .02], proteinuria >1 g/24 hours [HR 3.12 (95% CI 1.40-6.91), P = .005] and C4d positivity [HR 2.93 (95% CI 1.26-6.83), P = .013] were found to be associated with graft loss in patients with IgAN recurrence. A nomogram predicting graft loss was constructed based on clinical and histological variables, with a C statistic of 0.736 for the derivation cohort and 0.807 for the external validation cohort. CONCLUSIONS: The established nomogram identified patients with recurrent IgAN at risk for premature graft loss with good predictive performance.

• MeSH
• alografty patologie   MeSH
• dospělí MeSH
• IgA nefropatie * komplikace   chirurgie   MeSH
• ledviny patologie   MeSH
• lidé MeSH
• nomogramy MeSH
• přežívání štěpu MeSH
• prognóza MeSH
• recidiva MeSH
• retrospektivní studie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Data on the immune response to SARS-CoV-2 in kidney transplant recipients are scarce. Thus, we conducted a single-center observational study to assess the anti-SARS-CoV-2 IgG seroprevalence in outpatient kidney transplant recipients (KTR; n = 1037) and healthcare workers (HCW; n = 512) during the second wave of the COVID-19 pandemic in fall 2020 and evaluated the clinical variables affecting antibody levels. Antibodies against S1 and S2 subunit of SARS-CoV-2 were evaluated using immunochemiluminescent assay (cut off 9.5 AU/ml, sensitivity of 91.2% and specificity of 90.2%). Anti-SARS-CoV-2 IgG seroprevalence was lower in KTR than in HCW (7% vs. 11.9%, p = .001). Kidney transplant recipients with SARS-CoV-2 infection were younger (p = .001) and received CNI-based immunosuppression more frequently (p = .029) than seronegative KTR. Anti-SARS-CoV-2 IgG positive symptomatic KTR had a higher BMI (p = .04) than asymptomatic KTR. Interestingly, anti-SARS-CoV-2 IgG levels were higher in KTR than in HCW (median 31 AU/ml, IQR 17-84 vs. median 15 AU/ml, IQR 11-39, p < .001). The presence of moderate to severe symptoms in KTR was found to be the only independent factor affecting IgG levels (Beta coefficient = 41.99, 95% CI 9.92-74.06, p = .011) in the multivariable model. In conclusion, KTR exhibit a well-preserved symptom-dependent humoral response to SARS-CoV-2 infection.

• MeSH
• COVID-19 * MeSH
• lidé MeSH
• pandemie MeSH
• příjemce transplantátu MeSH
• protilátky virové MeSH
• SARS-CoV-2 MeSH
• séroepidemiologické studie MeSH
• transplantace ledvin * škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem 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

BACKGROUND: Kidney transplant recipients (KTRs) with "operational tolerance" (OT) maintain a functioning graft without immunosuppressive (IS) drugs, thus avoiding treatment complications. Nevertheless, IS drugs can influence gene-expression signatures aiming to identify OT among treated KTRs. METHODS: We compared five published signatures of OT in peripheral blood samples from 18 tolerant, 183 stable, and 34 chronic rejector KTRs, using gene-expression levels with and without adjustment for IS drugs and regularised logistic regression. FINDINGS: IS drugs explained up to 50% of the variability in gene-expression and 20-30% of the variability in the probability of OT predicted by signatures without drug adjustment. We present a parsimonious consensus gene-set to identify OT, derived from joint analysis of IS-drug-adjusted expression of five published signature gene-sets. This signature, including CD40, CTLA4, HSD11B1, IGKV4-1, MZB1, NR3C2, and RAB40C genes, showed an area under the curve 0⋅92 (95% confidence interval 0⋅88-0⋅94) in cross-validation and 0⋅97 (0⋅93-1⋅00) in six months follow-up samples. INTERPRETATION: We advocate including adjustment for IS drug therapy in the development stage of gene-expression signatures of OT to reduce the risk of capturing features of treatment, which could be lost following IS drug minimisation or withdrawal. Our signature, however, would require further validation in an independent dataset and a biomarker-led trial. FUNDING: FP7-HEALTH-2012-INNOVATION-1 [305147:BIO-DrIM] (SC,IR-M,PM,DSt); MRC [G0801537/ID:88245] (MPH-F); MRC [MR/J006742/1] (IR-M); Guy's&StThomas' Charity [R080530]&[R090782]; CONICYT-Bicentennial-Becas-Chile (EN-L); EU:FP7/2007-2013 [HEALTH-F5-2010-260687: The ONE Study] (MPH-F); Czech Ministry of Health [NV19-06-00031] (OV); NIHR-BRC Guy's&StThomas' NHS Foundation Trust and KCL (SC); UK Clinical Research Networks [portfolio:7521].

• MeSH
• dospělí MeSH
• genové regulační sítě * účinky léků   MeSH
• imunosupresiva farmakologie   terapeutické užití   MeSH
• konsensus MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• logistické modely MeSH
• rejekce štěpu genetika   prevence a kontrola   MeSH
• senioři MeSH
• stanovení celkové genové exprese metody   MeSH
• studie případů a kontrol MeSH
• transplantace ledvin škodlivé účinky   MeSH
• transplantační tolerance * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH