The IMBG Test for Evaluating the Pharmacodynamic Response to Immunosuppressive Therapy in Kidney Transplant Patients: Current Evidence and Future Applications.

Immunosuppressive drugs are widely used to prevent rejection after kidney transplantation. However, the pharmacological response to a given immunosuppressant can vary markedly between individuals, with some showing poor treatment responses and/or experiencing serious side effects. There is an unmet need for diagnostic tools that allow clinicians to individually tailor immunosuppressive therapy to a patient's immunological profile. The Immunobiogram (IMBG) is a novel blood-based in vitro diagnostic test that provides a pharmacodynamic readout of the immune response of individual patients to a range of immunosuppressants commonly used in kidney transplant recipients. Here, we discuss the current approaches used to measure the pharmacodynamic responses of individual patients to specific immunosuppressive drugs in vitro, which can then be correlated with patient's clinical outcomes. We also describe the procedure of the IMBG assay, and summarize the results obtained using the IMBG in different kidney transplant populations. Finally, we outline future directions and other novel applications of the IMBG, both in kidney transplant patients and other autoimmune diseases.

The natural history of autosomal dominant polycystic kidney disease. A strategy for grouping families and mutations.

Autosomal dominant polycystic kidney disease (ADPKD) is a main cause of end-stage renal disease. Today, knowledge of its genetic basis has made it possible to develop strategies that prevent the transmission of the disease. OBJECTIVES: The objective of the study was to analyze the natural history of ADPKD in the province of Córdoba and to design a database that allows grouping families with different mutations. PATIENTS AND METHODS: All patients (n = 678) diagnosed with ADPKD followed by the Córdoba nephrology service are included. Various clinical variables (age and sex), genetic variables (mutation in PKD1, PKD2) and the need for renal replacement therapy (RRT) were retrospectively analyzed. RESULTS: The prevalence was 61 cases per 100,000 inhabitants. Median renal survival was significantly worse in PKD1 (57.5 years) than in PKD2 (70 years) (log-rank p = 0.000). We have genetically identified 43.8% of the population, detecting PKD1 mutations in 61.2% and PKD2 mutations in 37.4% of cases, respectively. The most frequent mutation, in PKD2 (c.2159del), appeared in 68 patients belonging to 10 different families. The one with the worst renal prognosis was a truncating mutation in PKD1 (c.9893 G > A). These patients required RRT at a median age of 38.7 years. CONCLUSIONS: Renal survival of ADPKD in the province of Córdoba is similar to that described in the literature. We detected PKD2 mutations in 37.4% of cases. This strategy allows us to know the genetic basis of a large proportion of our population while saving resources. This is essential to be able to offer primary prevention of ADPKD through preimplantation genetic diagnosis.

The Immunobiogram, a novel in vitro diagnostic test to measure the pharmacodynamic response to immunosuppressive therapy in kidney transplant patients.

BACKGROUND: Diagnostic tools to measure the response to individual immunosuppressive drugs for transplant patients are currently lacking. We previously developed the blood-based Immunobiogram bioassay for in-vitro characterization of the pharmacodynamic response of patients' own immune cells to a range of immunosuppressants. We used Immunobiogram to examine the association between patients' sensitivity to their prescribed immunosuppressants and clinical outcome. METHODS: We conducted an international, multicenter, observational study in a kidney transplant population undergoing maintenance immunosuppressive therapy. Patients were selected by clinical course poor [PCC] N = 53 (with renal dysfunction, and rejection signs in biopsy or/and an increase in DSA strength in last 12 months) versus good [GCC] N = 50 (with stable renal function and treatment, no rejection and no DSA titers). Immunobiogram dose-response curve parameters were compared between both subgroups in patients treated with mycophenolate, tacrolimus, corticosteroids, cyclosporine A or everolimus. Parameters for which significant inter-group differences were observed were further analyzed by univariate and subsequent multivariate logistic regression. RESULTS: Clinical outcome was associated with following parameters: area over the curve (AOC) and 25% (ID25) and 50% (ID50) inhibitory response in mycophenolate, tacrolimus, and corticosteroid-treated subgroups, respectively. These statistically significant associations persisted in mycophenolate (OR 0.003, CI95% <0.001-0.258; p = 0.01) and tacrolimus (OR < 0.0001, CI95% <0.00001-0.202; p = 0.016) subgroups after adjusting for concomitant corticosteroid treatment, and in corticosteroid subgroup after adjusting for concomitant mycophenolate or tacrolimus treatment (OR 0.003; CI95% <0.0001-0.499; p = 0.026). CONCLUSIONS: Our results highlight the potential of Immunobiogram as a tool to test the pharmacodynamic response to individual immunosuppressive drugs.

The Immunobiogram, a Novel In Vitro Assay to Evaluate Treatment Resistance in Patients Receiving Immunosuppressive Therapy.

Immunosuppressive drugs are widely used to treat several autoimmune disorders and prevent rejection after organ transplantation. However, intra-individual variations in the pharmacological response to immunosuppressive therapy critically influence its efficacy, often resulting in poor treatment responses and serious side effects. Effective diagnostic tools that help clinicians to tailor immunosuppressive therapy to the needs and immunological profile of the individual patient thus constitute a major unmet clinical need. In vitro assays that measure immune cell responses to immunosuppressive drugs constitute a promising approach to individualized immunosuppressive therapy. Here, we present the Immunobiogram, a functional pharmacodynamic immune cell-based assay for simultaneous quantitative measurement of a patient's immune response to a battery of immunosuppressive drugs. Peripheral blood mononuclear cells collected from patients are immunologically stimulated to induce activation and proliferation and embedded in a hydrogel mixture in which they are exposed to a concentration gradient of the immunosuppressants of interest. Analysis of samples from kidney transplant patients using this procedure revealed an association between the sensitivity of individual patients to the immunosuppressive regimen and their immunological risk of transplant rejection. Incorporation of the Immunobiogram assay into clinical settings could greatly facilitate personalized optimization and monitoring of immunosuppressive therapy, and study of the mechanisms underlying resistance to immunosuppressants.

Historia natural de la poliquistosis renal autosómica dominante en Córdoba: utilidad de una base de datos para agrupar familias y mutaciones / The natural history of autosomal dominant polycystic kidney disease. A strategy for grouping families and mutations

La poliquistosis renal autosómica dominante (PQRAD) es una de las principales causas de insuficiencia renal terminal. Hoy día el conocimiento de sus bases genéticas está permitiendo desarrollar estrategias que eviten la transmisión de la enfermedad. Objetivos: El objetivo del estudio fue analizar la historia natural de la PQRAD en la provincia de Córdoba y diseñar una base de datos que permita agrupar a las familias y a las diferentes mutaciones. Pacientes y métodos: Se incluyen todos los pacientes (n=678) diagnosticados de PQRAD seguidos en el servicio de Nefrología de Córdoba. Se analizaron de manera retrospectiva diversas variables clínicas (edad y sexo), necesidad de terapia renal sustitutiva (TRS) y genéticas. Resultados: La prevalencia fue de 61 casos por 100.000 habitantes. La mediana de supervivencia renal fue significativamente peor en PKD1 (57,5 años) que en PKD2 (70 años) (Log-rank p=0,000). Tenemos identificada genéticamente al 43,8% de la población, detectando mutaciones en PKD1 en el 61,2% y en PKD2 en el 37,4% de los casos. La mutación más frecuente fue detectada en PKD2 (c.2159del) en 68 pacientes pertenecientes a 10 familias diferentes. La de peor pronóstico renal fue una mutación truncante detectada en PKD1 (c.9893G>A). Conclusiones: La supervivencia renal de la PQRAD en la provincia de Córdoba es similar a la descrita en la literatura. Con nuestra metodología y estudiando genéticamente al 43,8% de la población, detectamos mutaciones en PKD2 en una mayor proporción de pacientes, en el 37,4% de los casos. Esta estrategia permite conocer las bases genéticas de gran parte de nuestra población con ahorro de recursos. Esto es fundamental para poder ofrecer prevención primaria de la PQRAD mediante diagnóstico genético preimplantacional. (AU)

Autosomal dominant polycystic kidney disease (ADPKD) is one of the main causes of end-stage renal disease. Today, the knowledge of its genetic base has made it possible to develop strategies that prevent the transmission of the disease. Objectives: The objective of the study was to analyze the natural history of ADPKD in the Province of Córdoba and to design a database that allows families and different mutations to be grouped. Patients and methods: All patients (n=678) diagnosed with ADPKD followed up in the Cordoba nephrology service are included. Various clinical variables (age and sex), genetic variables (mutation in PKD1, PKD2) and the need for renal replacement therapy (RRT) were retrospectively analyzed. Results: The prevalence was 61 cases per 100,000 inhabitants. Median renal survival was significantly worse in PKD1 (57.5 years) than in PKD2 (70 years) (Log-rank p=0.000). We have genetically identified 43.8% of the population, detecting mutations in PKD1 in 61.2% and in PKD2 in 37.4% of cases. The most frequent mutation was detected in PKD2 (c.2159del) in 68 patients belonging to 10 different families. The one with the worst renal prognosis was detected in PKD1 (c.9893G>A). These patients required RRT at a median age of 38.7 years. Conclusions: The renal survival of ADPKD in the Province of Córdoba is similar to that described in the literature. Mutations in PKD2 were detected in 37.4%. Our strategy allows us to know the genetic bases of our population with a great saving of resources. This is essential to be able to offer primary prevention of ADPKD through preimplantation genetic diagnosis. (AU)

Narrowing the Genetic Causes of Language Dysfunction in the 1q21.1 Microduplication Syndrome.

The chromosome 1q21.1 duplication syndrome (OMIM# 612475) is characterized by head anomalies, mild facial dysmorphisms, and cognitive problems, including autistic features, mental retardation, developmental delay, and learning disabilities. Speech and language development are sometimes impaired, but no detailed characterization of language problems in this condition has been provided to date. We report in detail on the cognitive and language phenotype of a child who presents with a duplication in 1q21.1 (arr[hg19] 1q21.1q21.2(145,764,455-147,824,207) × 3), and who exhibits cognitive delay and behavioral disturbances. Language is significantly perturbed, being the expressive domain the most impaired area (with significant dysphemic features in absence of pure motor speech deficits), although language comprehension and use (pragmatics) are also affected. Among the genes found duplicated in the child, CDH1L is upregulated in the blood of the proband. ROBO1, a candidate for dyslexia, is also highly upregulated, whereas, TLE3, a target of FOXP2, is significantly downregulated. These changes might explain language, and particularly speech dysfunction in the proband.

Variable Penetrance of the 15q11.2 BP1-BP2 Microduplication in a Family with Cognitive and Language Impairment.

The 15q11.2 BP1-BP2 region is found duplicated or deleted in people with cognitive, language, and behavioral impairment. We report on a family (a father and 3 male twin siblings) that presents with a duplication of the 15q11.2 BP1-BP2 region and a variable phenotype: the father and the fraternal twin are normal carriers, whereas the monozygotic twins exhibit severe language and cognitive delay as well as behavioral disturbances. The genes located within the duplicated region are involved in brain development and function, and some of them are related to language processing. The probands' phenotype may result from changes in the expression level of some of these genes important for cognitive development.

Language Impairment Resulting from a de novo Deletion of 7q32.1q33.

We report on a girl who presents with hearing loss, behavioral disturbances (according to the Inventory for Client and Agency Planning) as well as motor and cognitive delay (according to Battelle Developmental Inventories) which have a significant impact on her speech and language abilities [according to the Peabody Picture Vocabulary Test (ed 3), and the Prueba de Lenguaje Oral de Navarra-Revisada (Navarra Oral Language Test, Revised)]. Five copy number variations (CNVs) were identified in the child: arr[hg18] 7q32.1q33(127109685-132492196)×1, 8p23.1(7156900-7359099) ×1, 15q13.1(26215673-26884937)×1, Xp22.33(17245- 102434)×3, and Xp22.33(964441-965024)×3. The pathogenicity of similar CNVs is mostly reported as unknown. The largest deletion is found in a hot spot for cognitive disease and language impairment and contains several genes involved in brain development and function, many of which have been related to developmental disorders encompassing language deficits (dyslexia, speech-sound disorder, and autism). Some of these genes interact with FOXP2. The proband's phenotype may result from a reduced expression of some of these genes.

[Effectiveness of inhaled corticosteroids in chronic obstructive lung disease: systematic review]. / Utilidad de los glucocorticoides inhalados en la enfermedad pulmonar obstructiva crónica: revisión sistemática.

BACKGROUND: Inhaled corticosteroids are increasingly being used in patients with chronic obstructive lung disease (COPD), but their effectiveness is disputed. The aim of this study was to define the clinical effectiveness of inhaled corticosteroids in non-asthmatic COPD by a systematic review of the literature. MATERIAL AND METHOD: Literature searches were conducted in Medline, the Cochrane library and the Spanish Medical Index. Only placebo-controlled trials were included. All trials were reviewed by two authors and data were extracted in a pre-defined manner. Meta-analytic techniques were used to estimate global effects when data were comparable. RESULTS: No clinical trials on the role of inhaled corticosteroids during COPD exacerbations were found. Twelve studies on patients under a stable condition were identified and included in the review. Short-term studies showed that inhaled corticosteroids induced a small increase in FEV1 (average: 96 ml after 1-6 months). Longer term studies indicated that after 1-3 years of continued therapy, FEV1 was higher in treated than in control patients, but the difference was small (51 ml, CI 3-98). There were no consistent effects on symptom scores or the frequency of exacerbations. CONCLUSION: The results of this review do not support the systematic use of inhaled corticosteroids in patients with non-asthmatic COPD.

Diagnóstico de aneuplodias en células en interfase de líquido amniótico mediante hibridación in situ fluorescente. Concordancia con el cariotipo / Diagnosis of aneuploidy in interphase cells of amniotic fluid by fluorescence in situ hybridization. Concordance with the karyotype

Introducción. En los últimos años la aplicación de la hibridación in situ fluorescente (FISH) permite el diagnóstico precoz de aneuploidias. El objetivo de este estudio es el análisis descriptivo mediante FISH de los líquidos amnióticos procesados en el laboratorio y la concordancia con el cariotipo. Material y métodos. Análisis de 821 muestras de líquidos amnióticos (enero 2009 a diciembre 2010) remitidas por Medicina Fetal desde la semana 13 a 36 de gestación para estudio prenatal de aneuploidias, (kit Aneuvysion) con sondas centroméricas para los cromosomas X, Y y 18, y locus específicas para los cromosomas 13 y 21. El estudio se completa con el cariotipo mediante método de bandeo G. Resultados. De las 821 muestras, 776 (94,52%) fueron normales y 45 (5,48%) presentaron aneuploidias: en 22 casos (48,88%) el sexo cromosómico del feto fue masculino, en las 23 restantes (51,12%) femenino. La cromosopatía más frecuente fue la trisomía 21 (19 casos en fetos masculinos y 11 femeninos), la de menor presentación fue la trisomía 13 (2 casos) que representa el 0,24% del total de los líquidos amnióticos procesados. En todos los casos, la concordancia con el cariotipo fue del 100%. Conclusiones. El estudio de aneuploidias mediante FISH en núcleos en interfase en líquido amniótico permite un diagnóstico prenatal rápido de las principales cromosomopatías, siendo la trisomía 21 la más frecuentemente detectada. Los resultados del FISH coincidieron en el 100% con el cariotipo, gold estándar en el diagnóstico prenatal de cromosomopatías (AU)

Background. The application of fluorescence in situ hybridization (FISH) techniques in the last few years has led to the prenatal diagnosis of aneuploidies. The objective of this investigation was a descriptive analysis of amniotic fluids processed in the laboratory using FISH and the agreement with the karyotype. Material and methods. A total of 821 amniotic fluid samples (January 2009 to December 2010) at gestational ages 13 to 36 weeks, from Fetal Medicine Unit for prenatal testing for aneuploidies (Aneuvysion kit) with centromeric probes for chromosomes X,Y and 18, and locus specific for chromosomes 13 and 21. The study was complemented by the karyotype by G-banding method. Results. Of the 821 samples, 776 (94.52%) were normal and 45 (5.48%) had aneuploidy: in 22 cases (48.88%) the chromosomal sex of the foetus was male, in the remaining 23 (51.12%) female. The most common chromosomal abnormality detected was trisomy 21 (19 cases in males and 11 cases in female foetuses), the lowest performance was the trisomy 13 (2 cases) representing 0.24% of total processed amniotic fluids. In all cases, the concordance with the karyotype was 100%. Conclusions. The study of aneuploidy by FISH of interphase nuclei present in the amniotic fluid enables rapid prenatal diagnosis of major chromosomal abnormalities, trisomy 21 was more frequently detected. FISH results in 100% agreed with the karyotype, the gold standard in prenatal diagnosis of chromosomal abnormalities (AU)

Eficacia de los glucocorticoides en las reagudizaciones de la enfermedad pulmonar obstructiva crónica: metaanálisis de los estudios publicados / The efficacy of corticosteroids in exacerbations of chronic obstructive pulmonary disease: meta-analysis of published studies

Fundamento: Los glucocorticoides se emplean frecuentemente en los pacientes con reagudizaciones de la enfermedad pulmonar obstructiva crónica (EPOC), pero su utilidad es controvertida. Para intentar aclarar esta cuestión hemos efectuado una revisión sistemática de los estudios publicados. Métodos: Revisión sistemática de los trabajos publicados (MEDLINE, Cochrane Library, Índice Médico Español) hasta agosto de 1999. Extracción de la información y valoración de la calidad de los estudios por dos investigadores independientes. Se seleccionaron los estudios controlados con placebo que analizaban la utilidad de la administración de una o más dosis de glucocorticoides por vía tópica o sistémica en pacientes con reagudizaciones de EPOC no asmática. Cuando fue posible se calcularon los estimadores globales de efecto. Resultados: No se encontró ningún estudio que analizara la utilidad de los glucocorticoides inhalados. El uso de glucocorticoides por vía sistémica se asoció a diferencias significativas en el FEV1, tanto a los 3 días (89 ml; intervalo de confianza del 95 por ciento: 25-153; 4 estudios) como a los 7-14 días (200 ml; intervalo de confianza del 95 por ciento: 7-393; 3 estudios). La duración de la estancia hospitalaria fue también menor en los tratados (p = 0,03). A medio plazo desaparecían las diferencias entre ambos grupos. Hubo también una tendencia, no estadísticamente significativa, a menor tasa de fracasos en los tratados con glucocorticoides, pero sin hallar diferencias en la mortalidad. Conclusión: La utilización de glucocorticoides por vía sistémica se asocia a una más rápida mejoría de los parámetros espirométricos, de amplitud relevante desde el punto de vista clínico. Aunque no se encuentran cambios definitivos en las variables pronósticas, los resultados parecen justificar su administración durante períodos breves, no superiores a dos semanas. (AU)

Utilidad de los glucocorticoides inhalados en la enfermedad pulmonar obstructiva crónica: revisión sistemática / Effectiveness of inhaled corticosteroids in chronic obstructive lung disease: systematic review

FUNDAMENTO: El objetivo del estudio fue analizar la eficacia de los glucocorticoides inhalados en la enfermedad pulmonar obstructiva crónica (EPOC), ya que, a pesar de prescribirse con frecuencia, su utilidad es controvertida. MATERIAL Y MÉTODO: Revisión sistemática de la bibliografía (Medline, bases Cochrane e Índice Médico Español) y análisis de los ensayos clínicos publicados que incluyeran un grupo control sin tratamiento activo. Evaluación de la calidad de los estudios y extracción de los datos independientemente por dos investigadores. Cálculo de estimadores globales de efecto mediante procedimientos metaanalíticos cuando los datos eran comparables. RESULTADOS: No se encontró ningún estudio acerca de la eficacia de los glucocorticoides inhalados en las fases de reagudización de la EPOC. Se identificaron 12 trabajos que incluyeron a pacientes en situación estable. Los ensayos a corto plazo (1-6 meses) demostraron un ligero aumento del volumen espirado en el primer segundo (FEV1) en el grupo tratado (96 ml). En los estudios a más largo plazo (1-3 años) el FEV1 era también ligeramente superior en el grupo tratado (51 ml; intervalo de confianza [IC] del 95 por ciento, 3-98). Aunque algunos ensayos encontraron ligeros beneficios, no se hallaron efectos consistentes sobre los síntomas o la frecuencia de reagudizaciones. CONCLUSIONES: Los resultados de esta revisión no demuestran que los glucocorticoides inhalados produzcan efectos clínicamente relevantes. Por tanto, no apoyan la utilización sistemática de estos fármacos en los pacientes con EPOC sin hiperreactividad bronquial (AU)

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