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Robust biomarkers to predict response to immune checkpoint blockade (ICB) in metastatic urothelial carcinoma (mUC) are still in demand. Recently, early C-reactive protein (CRP) kinetics and especially the novel CRP flare-response phenomenon has been associated with immunotherapy response.We conducted a multicentre observational study comprising 154 patients with mUC treated with ICB to evaluate the predictive value of a previously described on-treatment CRP kinetics: CRP flare responders (at least doubling of baseline CRP within the first month after initiation of ICB followed by a decline below baseline within three months), CRP responders (decline in baseline CRP by ≥ 30% within three months without a prior flare) and the remaining patients as CRP non-responders. CRP kinetics groups were correlated with baseline parameters, PD-L1 status, progression-free survival (PFS) and overall survival (OS).Objective response was observed in 57.1% of CRP responders, 45.8% of CRP flare responders and 17.9% of CRP non-responders (P 0.001). CRP flare response was associated with prolonged PFS and OS (P 0.001). In multivariable Cox regression analysis, CRP flare responders showed a risk reduction of ∼70% for tumour progression and death compared to CRP non-responders. Subgroup analysis of CRP flare responders revealed that patients with a long-flare response (completed flare-response kinetics ≥6 weeks on-treatment) showed even more favourable outcomes following ICB (HR = 0.18, 95%-CI: 0.07-0.48, P 0.001).CRP (flare)response robustly predicts immunotherapy response and outcomes in mUC independent of PD-L1 status. Thus, early on-treatment CRP kinetics is a promising low-cost and easy-to-implement biomarker to optimise therapy monitoring in patients with mUC treated with ICB.

Zusammenfassung Hintergrund Immun-Checkpoint-Inhibitoren (ICI) sind seit wenigen Jahren in der Uroonkologie zugelassen. Real-world-Erfahrung zu Nutzen und Risiken bei neuartigen Nebenwirkungen liegt kaum vor. Material und Methoden In einer retrospektiven Analyse wurden an zwei Krankenhäusern in Deutschland von 2016–2021 Patienten erfasst, die aufgrund eines metastasierten Nierenzell- (NCC) oder Urothelkarzinoms (UCA) eine ICI-Therapie erhielten. Es wurde das radiologische Ansprechen, das progressionsfreie Überleben (PFS) sowie Nebenwirkungen, die zu einer Therapieunterbrechung führten, erhoben. Das onkologische Ansprechen wurde den Zulassungsstudien gegenübergestellt. Ergebnisse Bei 145 Patienten (111 Männer [77 %] und 34 Frauen [23 %]) wurden 1185 ICI-Zyklen appliziert. 64 (44,1 %) Patienten mit NCC und 81 (55,9 %) Patienten mit UCA erhielten eine ICI-Therapie. Von 141 Patienten mit Verlaufsbildgebung wurde ein objektives Ansprechen bei 21,3 % (n = 13) der Patienten mit NCC und 20,0 % (n = 16) mit UCA beobachtet (mediane Ansprechdauer 14,9 (3,0–51,3) Monate). Das PFS betrug bei Patienten mit NCC im Median 5,3 Monate und mit UCA 4,8 Monate. ICI-assoziierte Nebenwirkungen mit der Notwendigkeit einer Therapieunterbrechung wurden bei 17,2 % der NCC- und 20,9 % der UCA-Patienten beobachtet. Hierbei handelte es sich am häufigsten um renale (5,5 %: Nephritis) und gastrointestinale (4,8 %: Kolitis, Diarrhö) Nebenwirkungen. 22 (15,1 %) Patienten mussten deshalb hospitalisiert werden. Schlussfolgerung Diese Real-world-Erfahrung kann die patientenzentrierte Beratung in der Therapieentscheidung unterstützen. Weitere Studien zu prognostischen Faktoren sind notwendig. Therapieunterbrechungen sind häufig und das Nebenwirkungsspektrum erfordert eine interdisziplinäre Behandlung.

In atherosclerotic lesions, macrophages are exposed to CSFs and various microenvironmental cues, which ultimately drive their polarization state. We studied the expression of different CSFs in artery specimen and cultured vascular cells and assessed whether concurrent stimulation (CS) of monocytes with CSF1 and polarizing cytokines generated macrophages (CSM1 and CSM2) that were phenotypically and functionally different from classically polarized M1 and M2 macrophages. We also assessed the influence of acetylsalicylic acid (ASA) on the capacity of polarized macrophages to stimulate T-cell proliferation. CSF1 was the most prominent CSF expressed in arteries and cultured vascular cells. M1 and CSM1 macrophages differed in CD86 and CD14 expression, which was up-regulated respectively down-regulated by LPS. M2 and CSM2 macrophages were phenotypically similar. Cyclooxygenase expression was different in CSM1 (COX-1− and COX-2+ after LPS stimulation) and CSM2 (COX-1+ and COX-2−) macrophages. TNFα production was more pronounced in CSM1 macrophages, whereas IL-10 was produced at higher levels by CSM2 macrophages. Proliferation of allogeneic T cells was strongly supported by CSM2, but not by CSM1 polarized macrophages. Although ASA did not affect anti-CD3/CD28-mediated proliferation, it significantly reduced CSM2 and CSM1-mediated T-cell proliferation. Supernatants of LPS-stimulated CSM2 but not of CSM1 macrophages could overcome the inhibition by ASA. Hence, we demonstrate that CSM1 and CSM2 macrophages are phenotypically and to some extent functionally distinct from classically polarized M1 and M2 macrophages. CSM2 macrophages produce a COX-1-dependent soluble factor that supports T-cell proliferation, the identity hereof is still elusive and warrants further studies.

Purpose Advances in therapy of metastatic castration-refractory prostate cancer (mCRPC) resulted in more therapeutic options and led to a higher need of predictive/prognostic biomarkers. Systemic inflammatory biomarkers could provide the basis for personalized treatment selection. This study aimed to assess the modified Glasgow Prognostic Score (mGPS), the neutrophile-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR) and the systemic immune-inflammation index (SII) in men with mCRPC under docetaxel. Methods Patients with mCRPC and taxane chemotherapy at a tertiary care centre between 2010 and 2019 were screened retrospectively. The biomarkers mGPS, NLR, PLR and SII were assessed and analyzed for biochemical/radiologic response and survival. Results We included 118 patients. Of these, 73 (61.9%) had received docetaxel as first-line, 31 (26.2%) as second-line and 14 (11.9%) as third-line treatment. For biochemical response, mGPS (odds ratio (OR) 0.54, p = 0.04) and PLR (OR 0.63, p = 0.04) were independent predictors in multivariable analysis. SII was significant in first-line cohort only (OR 0.29, p = 0.02). No inflammatory marker was predictive for radiologic response. In multivariable analysis, mGPS and NLR (hazard ratio (HR) 1.71 and 1.12, both p p Conclusions Pre-treatment mGPS seems a promising prognostic biomarker. A combination of mGPS, NLR and further routine markers (e.g., Hb and AP) could yield optimized stratification for treatment selection. Further prospective and multicentric assessment is needed.

To assess the baseline inflammatory markers modified Glasgow Prognostic Score (mGPS), systemic immune-inflammation index (SII), and neutrophile-to-lymphocyte ratio (NLR) as pragmatic tools for predicting response to chemohormonal therapy (docetaxel plus ADT) and prognosis in men with metastatic hormone-sensitive prostate cancer (mHSPC).Male patients who received docetaxel at a tertiary university care center between 2014 and 2019 were screened for completion of 6 cycles. NLR, SII, mGPS, overall survival (OS), three-year survival, and radiologic response were assessed. Complete response (CR), partial response (PR), and stable disease (SD) were analyzed alone and in combination.Thirty-six mHSPC-patients were included. In thirty patients, baseline mGPS was assessed and was either 0 (n=22) or 2 (n=8). In Cochran-Armitage Trend Test, mGPS showed significant association with the combined radiologic endpoint of "CR, PR, or SD" (p=0.01), three-year survival (p=0.02), and OS (p0.01). Next to prostate-specific antigen (PSA) (HR per 100 units 1.16, 95%CI=1.04-1.30, p0.01), NLR (HR=1.31, 95%CI=1.03-1.66, p=0.03), and mGPS (2 vs. 0, HR=6.53, 95%CI=1.6-27.0, p0.01) at baseline showed significant association with OS in univariable cox regression. However, mGPS remained the only independent predictor for OS in multivariable cox regression (p0.01) and for the combined radiologic endpoint of "CR, PR or SD" (p=0.01) in multivariable logistic regression. SII showed no statistical relevance.Baseline mGPS seems to be a pragmatic tool for clinical decision-making in patients with mHSPC in daily routine.

Immune checkpoint inhibitors (ICI) have been approved in uro-oncology for a few years. Real-world experience regarding benefits and risks with novel side effects are rare.In a retrospective analysis, all patients who received ICI therapy due to metastatic renal cell carcinoma (NCC) or urothelial carcinoma (UCA) were enrolled at two maximum care hospitals in Germany between July 2016 and May 2021. Radiologic response, progression-free survival (PFS), and adverse events leading to treatment interruption were collected. Oncologic response was compared to randomized controlled trials.In all, 1185 ICI cycles were administered to 145 patients (111 men [77%] and 34 women [23%]): 64 (44.1 %) patients with NCC and 81 (55.9%) patients with UCA received ICI therapy. Of 141 patients with radiological follow-up, an objective response was observed in 21.3% (n = 13) of patients with NCC and 20.0% (n = 16) with UCA (median duration of response 14.9 months [3.0-51.3]). Median PFS was 5.3 months in patients with NCC and 4.8 months with UCA. ICI-associated adverse events requiring treatment interruption were observed in 17.2% patients with NCC and 20.9% with UCA. These were most commonly renal (5.5%: nephritis) and gastrointestinal (4.8%: colitis, diarrhea) adverse events. Hospitalization was required for 22 (15.1%) patients.This real-world experience may support patient-centered consultation in treatment decision-making. Further studies on prognostic factors are needed. Therapy interruptions are frequent and the spectrum of side effects requires interdisciplinary treatment.HINTERGRUND: Immun-Checkpoint-Inhibitoren (ICI) sind seit wenigen Jahren in der Uroonkologie zugelassen. Real-world-Erfahrung zu Nutzen und Risiken bei neuartigen Nebenwirkungen liegt kaum vor.In einer retrospektiven Analyse wurden an zwei Krankenhäusern in Deutschland von 2016–2021 Patienten erfasst, die aufgrund eines metastasierten Nierenzell- (NCC) oder Urothelkarzinoms (UCA) eine ICI-Therapie erhielten. Es wurde das radiologische Ansprechen, das progressionsfreie Überleben (PFS) sowie Nebenwirkungen, die zu einer Therapieunterbrechung führten, erhoben. Das onkologische Ansprechen wurde den Zulassungsstudien gegenübergestellt.Bei 145 Patienten (111 Männer [77 %] und 34 Frauen [23 %]) wurden 1185 ICI-Zyklen appliziert. 64 (44,1 %) Patienten mit NCC und 81 (55,9 %) Patienten mit UCA erhielten eine ICI-Therapie. Von 141 Patienten mit Verlaufsbildgebung wurde ein objektives Ansprechen bei 21,3 % (n = 13) der Patienten mit NCC und 20,0 % (n = 16) mit UCA beobachtet (mediane Ansprechdauer 14,9 (3,0–51,3) Monate). Das PFS betrug bei Patienten mit NCC im Median 5,3 Monate und mit UCA 4,8 Monate. ICI-assoziierte Nebenwirkungen mit der Notwendigkeit einer Therapieunterbrechung wurden bei 17,2 % der NCC- und 20,9 % der UCA-Patienten beobachtet. Hierbei handelte es sich am häufigsten um renale (5,5 %: Nephritis) und gastrointestinale (4,8 %: Kolitis, Diarrhö) Nebenwirkungen. 22 (15,1 %) Patienten mussten deshalb hospitalisiert werden.Diese Real-world-Erfahrung kann die patientenzentrierte Beratung in der Therapieentscheidung unterstützen. Weitere Studien zu prognostischen Faktoren sind notwendig. Therapieunterbrechungen sind häufig und das Nebenwirkungsspektrum erfordert eine interdisziplinäre Behandlung.

Objective To examine the disease-specific survival(DSS) after checkpoint inhibitor(CPI) therapy based on FGFR alterations and FGFR mRNA expression levels in patients with metastatic urothelial cancer(mUCa) within a multi-center cohort. Methods Within a cohort of 72 patients with mUCa from five academic centers in Germany FGFR alterations, as well as FGFR1-4 mRNA expression levels in tumor samples from the primary tumor or metastatic sites. Spearman rank correlations, logistic regression, as well as Kaplan-Meier survival analyses and univariate Cox proportional hazards regression models were employed to examine the impact of different FGFR patterns on the DSS after CPI treatment. Results FGFR3 mutations or gene fusions (gene alterations) were detected in 16.9% of all samples. Patients with or without FGFR3 gene alterations did not show different oncological outcomes undergoing CPI treatment. Low expression of FGFR2 mRNA alone, as well as the combination of either low FGFR2mRNA expression and FGFR3 gene alteration or high FGFR3mRNA expression (P = 0.027), identified a subgroup of patients with unfavorable outcomes, comprising 40% of the total cohort. This trend was also observed in univariate Cox proportional hazards regression analysis(FGFR3 gene alteration: Hazard ratio(HR) 5.33, 95%Confidence interval(CI)1.76-15.0, P = 0.004; FGFR3mRNA expression:HR 3.04, 95%CI 1.40-7.13, P = 0.005). Conclusion Assessment of FGFR mRNA expression identified a high-risk subgroup of patients with mUCa. These patients showing overexpression of FGFR3 mRNA were found to have unfavorable DSS after CPI treatment. Using this approach may be suitable for identifying a patient population with poor response to CPI treatment, which may benefit from early FGFR inhibition.

Muscle-invasive bladder cancer (MIBC) is characterized by high recurrence and rapid progression. Progression is linked to changes in glycan structures and altered levels of glycosyltransferases. The relationship of mRNA expression by glycosyltransferase genes B4GALT1, EXT1, MGAT5B, and POFUT1 to the probability of surviving MIBC after radical cystectomy has not yet been investigated. mRNA expression was analyzed using qRT-PCR in formalin-fixed and paraffin-embedded tumor samples (n = 105; 74% male patients and 26% female patients; median age = 72 years), correlated with histopathological variables, and evaluated by means of multivariable Cox regression analysis regarding to overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). Multivariable Cox regression analysis identified POFUT1 mRNA expression as superior prognostic marker, compared with currently used histological tumor stage methods, for CSS by MIBC patients following radical cystectomy. Thus, the patients with low POFUT1 mRNA were at a 4.9-fold greater risk for cancer-specific death according to the multivariable analysis (p = 0.0001). Low mRNA levels predicted poor survival according to the Kaplan-Meier analysis ((POFUT1:OS p = 0.0014; CSS p = 0.0007; DFS p = 0.0088); (EXT1:OS p = 0.0150; CSS p = 0.0130; DFS p = 0.0286); (B4GALT1:CSS p = 0.0134; DFS p = 0.0493)). A subgroup analysis of patients without lymph node metastasis (pN−; n = 73) indicated that low expression of POFUT1 predicted reduced OS (p = 0.0073), CSS (p = 0.0058,) and DSS (p = 0.0079). Low levels of POFUT1 mRNA are an independent prognostic indicator for OS and CSS in MIBC patients following radical cystectomy. This finding demonstrates the importance of altered glycosylation for the progress of MIBC., Highlights • Low POFUT1 mRNA expression is associated with a higher risk for overall and cancer-specific death in MIBC treated with RC. • MIBC patients with pN0 histology and, decreased POFUT1 mRNA levels showed poor outcome for OS, CSS and, DFS. • POFUT1 mRNA is an independent prognostic indicator for OS and CSS in multivariable analysis of MIBC patients following RC.

493 Background: The tumor microenvironment in UC harboring FGFR gene alterations is characterized by decreased T-cell infiltration and low immune marker expression, potentially implicating suboptimal response to immune checkpoint inhibitors. The association between FGFR gene mutations/fusions and anti-PD-(L)1 treatment outcomes in advanced UC was assessed using real-world pt data. Methods: A pooled dataset of matched clinical and genomic data for advanced UC pts treated with anti-PD-(L)1 in any line from the Bladder Cancer Research Initiative for Drug Targets in Germany (BRIDGE) Consortium and UNC-CH was assessed. FGFR status was defined by a prespecified panel of FGFR2/3 mutations and fusions. Overall survival (OS) was analyzed using Kaplan-Meier estimates and Cox proportional hazards models. Multivariate analyses were performed using potential prognostic covariates (sex, age, baseline tumor stage, urothelial histology, smoking history, primary tumor location, and ECOG) in a Cox regression model for OS to assess their impact on the effect of FGFR alterations. Results: Median OS for FGFR+ pts (n=28) who received any line of anti-PD-(L)1 therapy was 9.5 mo vs 7.5 mo for FGFR− pts (n=139) (HR: 1.03, 95% CI: 0.60-1.76, p=0.93). Median OS for pts treated with first-line anti-PD-(L)1 was 5.42 mo in FGFR+ pts (n=10) and was not reached for FGFR− pts (n=31) (HR: 2.06, 95% CI: 0.68-6.24, p=0.19); median OS in second-line anti-PD-(L)1 was 6.5 mo (FGFR+; n=14) vs 5.7 mo (FGFR−; n=86) (HR: 0.89, 95% CI: 0.44-1.81, p=0.74). The multivariate analyses showed a significant trend of poorer OS in FGFR+ pts with first-line anti-PD-(L)1 (HR: 10.42, 95% CI: 1.45-74.97, p=0.02); wide CI may be attributed to small sample size for some categories in several covariates. Conclusions: Treatment with first-line anti-PD-(L)1 in FGFR+ pts may be associated with poorer OS outcomes in FGFR+ pts; however, this trend was not observed in FGFR+ pts treated with any line and second-line anti-PD-(L)1. Investigation of the predictive value of FGFR alterations to immunotherapy outcomes in larger real-world pt datasets is warranted.

Background In the era of individualized oncological therapy in bladder cancer, FGFR3 mutations, FGFR2/FGFR3 gene fusions and FGFR mRNA expression as potential oncological targets and their association to anti-PD-1/anti-PD-L1 (IO) treatment outcomes in patients with advanced urothelial cancer of the bladder (UCB) were studied in a German patient cohort. Methods Within a cohort of 72 patients with metastatic UCB from 5 academic centers in Germany (collected between 2016 and 2018) FGFR3 mutations, FGFR2 and FGFR3 gene fusions as well as FGFR expression in formalin-fixed, paraffin embedded (FFPE) tumour samples and their association to survival were examined using SNaPshot PCR, RT-qPCR as well as Next Generation Sequencing. Statistical analyses comprised Kaplan-Meier survival analyses, Spearman rank correlations, non-parametric testing. Results In 17% of all patients FGFR3 mutations or gene fusions could be detected. Patients with FGFR3 alterations did not have better outcome after immunoncology (IO) treatment, but rather tended to have inferior disease specific survival. All alterations of FGFR3 resulted in overexpression of FGFR3 mRNA. Combination of FGFR mutation analysis and FGFR mRNA assessment improved IO outcome prediction. Overexpression of FGFR3 mRNA was negatively associated with PDL1 expression (mRNA and protein level). High FGFR2 mRNA expression in primary tumors predicted better disease specific survival of UCB patients receiving IO therapy, whereas high FGFR3 mRNA expression was associated with tumor specific death in patients exhibiting of low FGFR2 mRNA expressions (p Conclusions The assessment of FGFR mRNA by standardized RT-qPCR identified a high risk UCB patient cohort, which does have inferior disease specific survival despite IO treatment and does overexpress FGFR3 mRNA. The assessment of FGFR mRNA levels by using this standardized, locally applicable FGFR test system could identify an FGFR inhibitor target population with poor response to IO treatment which is twice the size as currently detected by FGFR genomic alterations alone. Legal entity responsible for the study BRIDGE Consortium e.V. Funding Janssen. Disclosure F. Roghmann: Advisory / Consultancy: Janssen; Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Ipsen. All other authors have declared no conflicts of interest.

Background Immunotherapy (IO) with antibodies against PD1 or PD-L1 has been approved for 1st and 2nd line treatment of metastasized urothelial bladder cancer (mUC). Here we evaluated efficacy in a retrospective Real-World-Phase IV trial based on molecular subtypes and PD-L1 status. Methods Cancer specific survival from start of IO treatment to death was retrospectively analyzed in a multicenter cohort of 65 patients having received palliative immune checkpoint inhibition for mUC in 1st and 2nd line setting. Intrinsic molecular subtypes were assessed by CK5, CK20, GATA3, FOXA1 and CD44 immunohistochemistry and RT-qPCR of KRT5 and KRT20. PD-L1 status was determined using the 28-8 Dako-assay. Stromal tumor infiltrating lymphocytes were assessed on HE slides (Salgado et al, 2015). Survival analyses were performed by applying clinically relevant cut-offs and using Kaplan-Meier analysis and logistic regression for cancer specific survival (CSS). Results Altogether, 43% of tumors presented with basal differentiation, 57% were luminal. As expected, basal tumors exhibited significantly higher levels of PD-1 and PD-L1 gene expression, higher amounts of sTILs and PD-L1+ immune and tumor cells. Hierarchical clustering of all immunological biomarkers revealed three cluster: “Inflamed high” (n = 13, 20%), “Inflamed low” (n = 22, 33.8%), and “Uninflamed” (n = 30, 46.2%). There were no significant survival differences for any of these groups (CSS). However, patients with good performance status (ECOG 0) and low PD-L1 expression showed significantly better CSS compared to those with ECOG0 / PD-L1 high and ECOG1 or ECOG2, respectively (30.3 months vs. 16.33, 12.07 and 15.13 months; p = 0.0047). Conclusions Immunological determinants of mUC show comparable distributions and correlations with subtypes of localized curatively treated MIBC patients. Interestingly, data indicate improved CSS after PD-1/PD-L1 treatment in patients with good performance and low PD-L1 expression, which warrants validation in larger cohorts. Clinical trial identification DRKS00016925. Legal entity responsible for the study STRATIFYER Molecular Pathology GmbH. Funding Janssen-Cilag GmbH. Disclosure R. Wirtz: Leadership role: CEO & CSO, STRATIFYER Molecular Pathology GmbH. All other authors have declared no conflicts of interest.

Background This study investigated the potential use of N-octanoyl dopamine (NOD) in donor management to ameliorate the damage caused by brain death and ischemia-reperfusion injury in a rat model of kidney and heart transplantation. Methods Brain-dead Fisher rats were treated for 6 hours with either saline or saline plus NOD. Orthotopic kidney and heterotopic heart transplantation were performed in different Lewis recipient rats. The right donor kidneys were stored for biochemical analysis. Blood samples were taken from the donor and on several days after transplantation from the recipient. All grafts were harvested after 7 days. Results There was no effect on donor heart rate and blood pressure under NOD treatment. The release of lactate dehydrogenase (LDH) during brain death was reduced in the NOD group. The right kidneys from NOD-preconditioned animals revealed diminished expression of the proinflammatory cell adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). Nevertheless, there was no difference in renal infiltration with ED1 (CD68) or major histocompatibility complex (MHC) class II-positive cells. Recipients receiving a renal allograft from NOD-treated donors had a significantly better renal function at day 1 after transplantation. Banff-grading after 7 days showed significantly reduced scores for tubulitis and vasculitis in the grafts of these recipients. In the heart allograft recipients, lower plasma LDH levels were observed. Conclusions Donor preconditioning with NOD leads to better graft function and reduced acute rejection in untreated renal allograft recipients without displaying adverse effects on heart allografts.

Background. Although it has been shown that a vagus nerve stimulation of brain dead (BD) donors leads to an improvement of renal function in recipients in an acute allograft rejection model, its influence on chronic allograft nephropathy is still unknown. In the present study, we assessed the influence of donor vagus nerve stimulation on survival, renal function and histology in a chronic allograft model. Methods. Brain death was induced in Fisher rats, and electrostimulation of the vagus nerve was applied in one group (BD + vagus) during the whole course of BD (6 h). Unstimulated BD Fisher donor rats served as controls. Allogeneic Lewis rats were used as recipients and no immunosuppressive medication was administered. Blood and urine samples were collected every second week. Banff classification was assessed from harvested allografts. Results. Vagal stimulation of BD donors resulted in an improved survival of recipients. Long-term renal function was significantly better in these recipients as refl ected by improved creatinine clearance. Banff classification revealed significantly reduced vasculopathy and less tubulopathy in the BD + vagus group. Conclusions. In conclusion, our data demonstrate a longlasting beneficial effect of vagus nerve stimulation in BD donors on the renal transplantation outcome. Hence, activation of the cholinergic anti-inflammatory pathway in BD donors may represent a novel therapeutic modality to reduce chronic allograft nephropathy without any side effects for the recipient.