Risk Factors and Outcomes of Acute Graft Pyelonephritis with Bacteremia Due to Multidrug-Resistant Gram-Negative Bacilli among Kidney Transplant Recipients

Acute graft pyelonephritis (AGP) is the leading cause of bloodstream infection in kidney transplant (KT) recipients. The prevalence of urinary tract infections caused by multidrug-resistant (MDR) Gram-negative bacilli is increasing. This 14-year prospective observational study sought to determine the clinical characteristics, risk factors, and outcomes of AGP with bacteremia due to MDR Gram-negative bacilli. Overall, 278 episodes of AGP with bacteremia due to MDR Gram-negative and non-MDR Gram-negative bacilli were identified and compared in 214 KT recipients; MDR Gram-negative bacilli were the cause in 28.4%. Overall 30-day mortality was low (1.1%). Risk factors independently associated with AGP due to MDR Gram-negative bacilli were male sex (OR 3.08; 95%CI 1.60-5.93), previous episode of bacteremic AGP (OR 2.11, 95%CI 1.09-4.09), prior antibiotic therapy in the preceding month (OR 2.47, 95%CI 1.33-4.57), and nosocomial acquisition (OR 2.03, 95%CI 1.14-3.62). Forty-three percent of MDR Gram-negative episodes received inappropriate empirical antibiotic therapy. The risk factors identified in this study may help physicians when selecting empirical antibiotic treatment for AGP. Previous antibiotic use was the main modifiable factor. Its presence highlights the importance of avoiding unnecessary antibiotics in order to bring down the high rates of MDR Gram-negative bacilli infections in this population

Collapsing Glomerulonephritis in a Kidney Transplant Recipient after mRNA SARS-CoV-2 Vaccination

With the vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), studies are describing cases of glomerulonephritis arising after vaccination. We present the first case of a kidney transplant patient who, after mRNA vaccination against SARS-CoV-2, developed nephrotic proteinuria and renal dysfunction, with a biopsy diagnostic of collapsing glomerulonephritis. No other triggers for this glomerulonephritis were identified. Antibodies against the spike protein were negative, but the patient developed a specific T-cell response. The close time between vaccination and the proteinuria suggests a possible determinant role of vaccination. We should be aware of nephropathies appearing after COVID-19 vaccination in kidney transplant recipients also

Donor/Recipient HLA Molecular Mismatch Scores Predict Primary Humoral and Cellular Alloimmunity in Kidney Transplantation

Donor/recipient molecular human leukocyte antigen (HLA) mismatch predicts primary B-cell alloimmune activation, yet the impact on de novo donor-specific T-cell alloimmunity (dnDST) remains undetermined. The hypothesis of our study is that donor/recipient HLA mismatches assessed at the molecular level may also influence a higher susceptibility to the development of posttransplant primary T-cell alloimmunity. In this prospective observational study, 169 consecutive kidney transplant recipients without preformed donor-specific antibodies (DSA) and with high resolution donor/recipient HLA typing were evaluated for HLA molecular mismatch scores using different informatic algorithms [amino acid mismatch, eplet MM, and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II)]. Primary donor-specific alloimmune activation over the first 2 years posttransplantation was assessed by means of both dnDSA and dnDST using single antigen bead (SAB) and IFN-γ ELISPOT assays, respectively. Also, the predominant alloantigen presenting pathway priming DST alloimmunity and the contribution of main alloreactive T-cell subsets were further characterized in vitro. Pretransplantation, 78/169 (46%) were DST+ whereas 91/169 (54%) DST-. At 2 years, 54/169 (32%) patients showed detectable DST responses: 23/54 (42%) dnDST and 31/54 (57%) persistently positive (persistDST+). 24/169 (14%) patients developed dnDSA. A strong correlation was observed between the three distinct molecular mismatch scores and they all accurately predicted dnDSA formation, in particular at the DQ locus. Likewise, HLA molecular incompatibility predicted the advent of dnDST, especially when assessed by PIRCHE-II score (OR 1.014 95% CI 1.001-1.03, p=0.04). While pretransplant DST predicted the development of posttransplant BPAR (OR 5.18, 95% CI=1.64-16.34, p=0.005) and particularly T cell mediated rejection (OR 5.33, 95% CI=1.45-19.66, p=0.012), patients developing dnDST were at significantly higher risk of subsequent dnDSA formation (HR 2.64, 95% CI=1.08-6.45, p=0.03). In vitro experiments showed that unlike preformed DST that is predominantly primed by CD8+ direct pathway T cells, posttransplant DST may also be activated by the indirect pathway of alloantigen presentation, and predominantly driven by CD4+ alloreactive T cells in an important proportion of patients. De novo donor-specific cellular alloreactivity seems to precede subsequent humoral alloimmune activation and is influenced by a poor donor/recipient HLA molecular matching

Impaired antigen-specific B-cell responses after Influenza vaccination in kidney transplant recipients receiving co-stimulation blockade with Belatacept

Emerging data suggest that costimulation blockade with belatacept effectively controls humoral alloimmune responses. However, whether this effect may be deleterious for protective anti-infectious immunity remains poorly understood. We performed a mechanistic exploratory study in 23 kidney transplant recipients receiving either the calcineurin-inhibitor tacrolimus (Tac, n=14) or belatacept (n=9) evaluating different cellular immune responses after influenza vaccination such as activated T follicular Helper (Tfh), plasmablasts and H1N1 hemagglutinin (HA)-specific memory B cells (HA(+)mBC) by flow-cytometry, and anti-influenza antibodies by hemagglutination inhibition test (HI), at baseline and days 10, 30 and 90 post-vaccination. The proportion of CD4+CD54RA-CXCR5+ Tfh was lower in belatacept than Tac patients at baseline (1.86%[1.25-3.03] vs 4.88%[2.40-8.27], p=0.01) and remained stable post-vaccination. At M3, HA(+)mBc were significantly higher in Tac-treated patients (0.56%[0.32-1.49] vs 0.27%[0.13-0.44], p=0.04) and correlated with activated Tfh numbers. When stratifying patients according to baseline HA(+)mBc frequencies, belatacept patients with low HA(+)mBC displayed significantly lower HA(+)mBc increases after vaccination than Tac patients (1.28[0.94-2.4] vs 2.54[1.73-5.70], p=0.04). Also, belatacept patients displayed significantly lower seroprotection rates against H1N1 at baseline than Tac-treated patients (44.4% vs 84.6%) as well as lower seroconversion rates at days 10, 30 and 90 after vaccination (50% vs 0%, 63.6% vs 0%, and 63.6% vs 0%, respectively). We show the efficacy of belatacept inhibiting T-dependent antigen-specific humoral immune responses, active immunization should be highly encouraged before starting belatacept therapy

Recovery of dialysis patients with COVID-19 : health outcomes 3 months after diagnosis in ERACODA

Background. Coronavirus disease 2019 (COVID-19)-related short-term mortality is high in dialysis patients, but longer-term outcomes are largely unknown. We therefore assessed patient recovery in a large cohort of dialysis patients 3 months after their COVID-19 diagnosis. Methods. We analyzed data on dialysis patients diagnosed with COVID-19 from 1 February 2020 to 31 March 2021 from the European Renal Association COVID-19 Database (ERACODA). The outcomes studied were patient survival, residence and functional and mental health status (estimated by their treating physician) 3 months after COVID-19 diagnosis. Complete follow-up data were available for 854 surviving patients. Patient characteristics associated with recovery were analyzed using logistic regression. Results. In 2449 hemodialysis patients (mean ± SD age 67.5 ± 14.4 years, 62% male), survival probabilities at 3 months after COVID-19 diagnosis were 90% for nonhospitalized patients (n = 1087), 73% for patients admitted to the hospital but not to an intensive care unit (ICU) (n = 1165) and 40% for those admitted to an ICU (n = 197). Patient survival hardly decreased between 28 days and 3 months after COVID-19 diagnosis. At 3 months, 87% functioned at their pre-existent functional and 94% at their pre-existent mental level. Only few of the surviving patients were still admitted to the hospital (0.8-6.3%) or a nursing home (∼5%). A higher age and frailty score at presentation and ICU admission were associated with worse functional outcome. Conclusions. Mortality between 28 days and 3 months after COVID-19 diagnosis was low and the majority of patients who survived COVID-19 recovered to their pre-existent functional and mental health level at 3 months after diagnosis

Clinical and immunological characterization of SARS-CoV-2 infection in Solid Organ Transplantation

[eng] INTRODUCTION: Coronavirus disease 2019 (COVID-19) became, and remains, one of the most common preventable causes of early death among solid organ transplant (SOT) patients. Exhaustive clinical and immune-biological evaluations are needed to improve our understanding of the virus-host interaction under the effects of chronic immunosuppression. More specifically, the quality, quantity and duration of infection- derived immune responses are key features that need to be thoroughly characterized to eventually guide preventive decision-making strategies in this high-risk patient population. HYPOTHESIS: The hypothesis of this thesis is that by investigating main clinical and demographic features of COVID-19 as well as by accurately assessing SARS-CoV-2- specific adaptive immunity, both during infection and convalescence in SOT patients as compared to immunocompetent (IC) patients, we would gain relevant insights on major determinants driving distinct clinical outcomes as well as on the degree of anti-viral immune protection achieved in this highly vulnerable group of patients. OBJECTIVES: -To analyze main clinical, demographic, and immunological risk factors associated with the development of adult respiratory distress syndrome (ARDS) and death in a large multicentric cohort of kidney transplant recipients hospitalized due to COVID-19 during the first wave of the pandemic. -To characterize the kinetics and magnitude of SARS-CoV-2 specific adaptive immune responses at the T-cell and serological immune compartments, among SOT patients hospitalized due to COVID-19 and compare them to those exhibited by a matched group of IC patients. - To investigate the relative persistence of peripheral adaptive immune memory specific to SARS-CoV-2 up to six months after COVID-19 by evaluating both serological and T and B-cell memory/effector immune compartments in SOT recipients, compared to a matched cohort of IC convalescents patients. - To comprehensively characterize the strength and durability of SARS-CoV-2-specific adaptive immunity across distinct clinical presentations of COVID-19, from severe to asymptomatic infections, in convalescent SOT and IC patients.[cat] INTRODUCCIÓ: La malaltia per coronavirus 2019 (COVID-19) continua representant una de les causes més freqüents de mort precoç evitable entre els individus trasplantats d'òrgan sòlid (TOS). L'estudi detallat de la seva clínica i inmunobiologia és essencial per millorar el nostre coneixement sobre la interacció virus-hoste en el context de la immunosupressió crònica. Així mateix, la caracterització detallada de la qualitat, quantitat i durada de la resposta immunològica que genera la COVID-19 és imprescindible per a la presa de decisions en quant a les mesures preventives aplicables en aquesta població a risc. HIPÒTESI: La hipòtesi d’aquesta tesi és que l'estudi de les característiques clíniques i demogràfiques de la COVID, així com l’avaluació de les respostes adaptatives SARS-CoV-2-específiques durant la infecció aguda i la convalescència dels pacients trasplantats d’òrgan sòlid en comparació a les presentades pels pacients immunocompetents, podria aportar evidència sobre els principals factors pronòstic i determinar el grau d’immunitat virus específica que assoleix aquest grup de població a risc. OBJECTIUS: - Analitzar els principals factors de risc associats al desenvolupament de la síndrome de dificultat respiratòria aguda (SDRA) i mortalitat en una cohort multicèntrica de trasplantats renals hospitalitzats per COVID-19 durant la primera onada de la pandèmia. - Determinar la cinètica i la magnitud de la resposta immunològica adaptativa a diferents compartiments, cel·lular T i serològic, front el SARS-CoV-2 en pacients TOS hospitalitzats per COVID19, tot comparant-les amb les exhibides per un grup control de pacients immunocompetents. - Investigar la persistència de la resposta adaptativa sis mesos després de la infecció mitjançant l'avaluació dels compartiments immunològics de memòria, serològic i cel·lular (T i B) dels pacients TOS, utilitzant una cohort comparativa d'individus convalescents no immunodeprimits. - Caracteritzar la magnitud i persistència de la immunitat adaptativa SARS-CoV-2 específica generada per les diferents formes clíniques de la COVID-19, des de els casos severs fins als asimptomàtics, en pacients convalescents TOS i immunocompetents.[spa] INTRODUCCIÓN: La enfermedad por coronavirus 2019 (COVID-19) sigue siendo una de las causas prevenibles de muerte temprana más comunes entre los individuos trasplantados de órgano sólido (TOS). El estudio detallado de su clínica e inmunobiología es esencial para mejorar nuestro conocimiento acerca de la interacción virus-huésped en el contexto de la inmunosupresión crónica. Así mismo, la caracterización detallada de la calidad, magnitud y duración de la respuesta inmune generada por la COVID-19 es imprescindible para la toma de decisiones en cuanto a las medidas preventivas aplicables en esta población a riesgo. HIPÓTESIS: La hipótesis de esta tesis es que el estudio de las características clínicas y demográficas de la COVID-19, así como la evaluación de las respuestas inmunológicas adaptativas SARS-CoV-2-específicas durante la infección aguda y la convalecencia de los pacientes trasplantados de órgano sólido en comparación a las presentadas por pacientes inmunocompetentes, podría generar evidencia entorno a los principales factores pronóstico y determinar el grado de inmunidad virus específica generada por este grupo de población a riesgo. OBJETIVOS: - Analizar los principales factores de riesgo asociados al desarrollo del síndrome de dificultad respiratoria aguda (SDRA) y mortalidad en una cohorte multicéntrica de trasplantados renales hospitalizados por COVID-19 durante la primera ola de la pandemia. - Determinar la cinética y la magnitud de la respuesta inmune adaptativa en distintos compartimentos, celular T y serológico, frente al SARS-CoV-2 en pacientes TOS hospitalizados por COVID-19, en comparación a las exhibidas por un grupo control de pacientes inmunocompetentes. - Investigar la persistencia de la respuesta adaptativa seis meses después de la infección mediante la evaluación de los compartimentos inmunológicos de memoria, serológico y celular (T y B) de los pacientes TOS, utilizando una cohorte comparativa de individuos convalecientes no inmunodeprimidos. - Caracterizar la magnitud y persistencia de la inmunidad adaptativa SARS-CoV-2 específica generada por las distintas formas clínicas de la COVID-19, desde los casos severos a los asintomáticos, en pacientes convalecientes TOS e inmunocompetentes

Herramientas para un ajuste de dosis de tacrolimus más personalizado en el seguimiento de los pacientes con transplante renal. Fenotipo metabolizador según polimorfismos genéticos del CYP3A vs. el cociente concentración-dosis

Resumen: Antecedentes y justificación: La estrategia de la aproximación concentración-dosis (C/D) y los distintos perfiles del tacrolimus (Tac), según los polimorfismos del citocromo P450 (CYPs) se centran en el metabolismo de Tac y se plantean como herramientas para el seguimiento de los pacientes trasplantados. El objetivo de este estudio es comparar la exposición al Tac analizado según ambas estrategias. Materiales y métodos: Se han incluido 425 pacientes trasplantados renales. El cálculo del cociente concentración Tac/dosis (C/D) permitió dividir la población en terciles y clasificar los pacientes según su tasa de metabolismo del Tac en tres grupos (rápida, intermedia y lenta). Con base en los polimorfismos del CYP3A4 y A5, los pacientes se agruparon en metabolizadores rápidos (portadores del CYP3A5*1 y CYP34A *1/*1), intermedios (CYP3A5*3/3 y CYP3A4*1/*1) y lentos (CYP3A5 *3/*3 y portadores del CYP3A4*22). Resultados: Al comparar los pacientes de cada grupo metabolizador según los dos criterios, coincidieron 47% (65/139) de los metabolizadores rápidos, 85% (125/146) de los intermedios y solo 12% (17/140) de los lentos. Se observaron concentraciones de Tac estadísticamente menores en los metabolizadores rápidos y concentraciones mayores en los lentos, comparándolos con el grupo intermedio según el cociente C/D o según polimorfismos. Los metabolizadores rápidos requirieron alrededor de 60% más de dosis de Tac que los intermedios a lo largo del seguimiento, mientras que los lentos aproximadamente 20% menos de dosis que los intermedios. Los metabolizadores rápidos clasificados por ambos criterios presentan un porcentaje mayor de veces con valores de concentración de Tac en sangre infraterapéuticos. Conclusión: La determinación del fenotipo metabolizador según los polimorfismos del CYP o bien cociente C/D permite distinguir los pacientes según su exposición al Tac. Probablemente la combinación de ambos criterios de clasificación sería una buena herramienta en el manejo de la dosificación de Tac para los pacientes trasplantados. Abstract: Background and justification: The strategy of the concentration–dose (C/D) approach and the different profiles of tacrolimus (Tac) according to the cytochrome P450 polymorphisms (CYPs) focus on the metabolism of Tac and are proposed as tools for the follow-up of transplant patients. The objective of this study is to analyse both strategies to confirm whether the stratification of patients according to the pharmacokinetic behaviour of C/D corresponds to the classification according to their CYP3A4/5 cluster metabolizer profile. Materials and methods: Four hundred and twenty-five kidney transplant patients who received Tac as immunosuppressive treatment have been included. The concentration/dose ratio (C/D) was used to divided patients in terciles and classify them according to their Tac metabolism rate (fast, intermediate, and slow). Based on CYP3A4 and A5 polymorphisms, patients were classified into three metabolizer groups: fast (CYP3A5*1 and CYP34A*1/*1 carriers), intermediate (CYP3A5*3/3 and CYP3A4*1/*1) and slow (CYP3A5*3/*3 and CYP3A4*22 carriers). Results: When comparing patients included in each metabolizer group according to C/D ratio, 47% (65/139) of the fast metabolizers, 85% (125/146) of the intermediate and only 12% (17/140) of the slow also fitted in the homonym genotype group. Statistically lower Tac concentrations were observed in the fast metabolizers group and higher Tac concentrations in the slow metabolizers when compared with the intermediate group both in C/D ratio and polymorphisms criteria. High metabolizers required approximately 60% more Tac doses than intermediates throughout follow-up, while poor metabolizers required approximately 20% fewer doses than intermediates. Fast metabolizers classified by both criteria presented a higher percentage of times with sub-therapeutic blood Tac concentration values. Conclusion: Determination of the metabolizer phenotype according to CYP polymorphisms or the C/D ratio allows patients to be distinguished according to their exposure to Tac. Probably the combination of both classification criteria would be a good tool for managing Tac dosage for transplant patients

A prospective controlled, randomized clinical trial of kidney transplant recipients developed personalized tacrolimus dosing using model-based Bayesian Prediction

For three decades, tacrolimus (Tac) dose adjustment in clinical practice has been calculated empirically according to the manufacturer’s labeling based on a patient’s body weight. Here, we developed and validated a Population pharmacokinetic (PPK) model including pharmacogenetics (cluster CYP3A4/CYP3A5), age, and hematocrit. Our study aimed to assess the clinical applicability of this PPK model in the achievement of Tac Co (therapeutic trough Tac concentration) compared to the manufacturer’s labelling dosage. A prospective two-arm, randomized, clinical trial was conducted to determine Tac starting and subsequent dose adjustments in 90 kidney transplant recipients. Patients were randomized to a control group with Tac adjustment according to the manufacturer’s labeling or the PPK group adjusted to reach target Co (6-10 ng/ml) after the first steady state (primary endpoint) using a Bayesian prediction model (NONMEM). A significantly higher percentage of patients from the PPK group (54.8%) compared with the control group (20.8%) achieved the therapeutic target fulfilling 30% of the established superiority margin defined. Patients receiving PPK showed significantly less intra-patient variability compared to the control group, reached the Tac Co target sooner (5 days vs 10 days), and required significantly fewer Tac dose modifications compared to the control group within 90 days following kidney transplant. No statistically significant differences occurred in clinical outcomes. Thus, PPK-based Tac dosing offers significant superiority for starting Tac prescription over classical labeling-based dosing according to the body weight, which may optimize Tac-based therapy in the first days following transplantation

SARS‐CoV‐2‐specific serological and functional T cell immune responses during acute and early COVID‐19 convalescence in solid organ transplant patients

International audienceThe description of protective humoral and T cell immune responses specific against SARS-CoV-2 has been reported among immunocompetent (IC) individuals developing COVID-19 infection. However, its characterization and determinants of poorer outcomes among the at-risk solid organ transplant (SOT) patient population have not been thoroughly investigated. Cytokine-producing T cell responses, such as IFN-γ, IL-2, IFN-γ/IL-2, IL-6, IL-21, and IL-5, against main immunogenic SARS-CoV-2 antigens and IgM/IgG serological immunity were tracked in SOT (n = 28) during acute infection and at two consecutive time points over the following 40 days of convalescence and were compared to matched IC (n = 16) patients admitted with similar moderate/severe COVID-19. We describe the development of a robust serological and functional T cell immune responses against SARS-CoV-2 among SOT patients, similar to IC patients during early convalescence. However, at the infection onset, SOT displayed lower IgG seroconversion rates (77% vs. 100%; p = .044), despite no differences on IgG titers, and a trend toward decreased SARS-CoV-2-reactive T cell frequencies, especially against the membrane protein (7 [0-34] vs. 113 [15-245], p = .011, 2 [0-9] vs. 45 [5-74], p = .009, and 0 [0-2] vs. 13 [1-24], p = .020, IFN-γ, IL-2, and IFN-γ/IL-2 spots, respectively). In summary, our data suggest that despite a certain initial delay, SOT population achieve comparable functional immune responses than the general population after moderate/severe COVID-19