Prevalencia, valor diagnóstico y características clínicas asociadas a la presencia de niveles circulantes y depósitos renales de anticuerpos contra el receptor tipo M de la fosfolipasa A2 en nefropatía membranosa idiopática / Prevalence, diagnostic value and clinical characteristics associated with the presence of circulating levels and renal deposits of antibodies against the M-type phospholipase A2 receptor in idiopathic membranous nephropathy

El receptor tipo M de la fosfolipasa A2 (PLA2R) ha sido identificado como uno de los antígenos diana de la respuesta autoinmune en la nefropatía membranosa (NM) idiopática. La prevalencia de anticuerpos anti-PLA2R en enfermos con NM idiopática oscila en torno al 70 %, pero varía en función del área geográfica y hasta la fecha no se ha demostrado que la presencia de anti-PLA2R se asocie a un determinado perfil clínico de presentación de la enfermedad. Métodos: Se estudiaron 64 adultos con síndrome nefrótico y diagnóstico de NM confirmado por biopsia renal. Cuarenta y siete pacientes presentaban NM idiopática y 17 NM secundaria. Se determinó la presencia de anticuerpos circulantes antiPLA2R por inmunofluorescencia indirecta (IFI) y su título mediante ELISA. La presencia de depósitos renales de anticuerpos anti-PLA2R se determinó mediante técnicas de inmunohistoquímica. Se calculó la sensibilidad y especificidad de las técnicas de IFI y ELISA para la identificación de los enfermos con depósitos renales y para la identificación de los enfermos con NM idiopática. Se analizó si había diferencias en el perfil clínico de la enfermedad en el momento del diagnóstico en función de la presencia o no de anticuerpos anti-PLA2R. Resultados: No se observaron diferencias significativas en las variables clínico-demográficas entre enfermos con NM idiopática y secundaria. La prevalencia de depósitos glomerulares de anti-PLA2R por IHQ fue del 76,6 %. Las técnicas de IFI y de ELISA tuvieron una sensibilidad (94,4 % IFI y 97,2 % ELISA) y una especificidad (100 %) similar para la identificación de los enfermos con depósitos renales de anti-PLA2R. La determinación de anti-PLA2R por IFI identificó a los enfermos con NM idiopática con una sensibilidad del 72,3 % y una especificidad del 94,2 %. Un título de anticuerpos > 15 RU/ml medido por ELISA tuvo una sensibilidad del 74,45 % y una especificidad del 94,2 % para la identificación de los enfermos con NM idiopática. Los pacientes con NM idiopática y anti-PLA2R presentaron cifras de proteinuria significativamente mayores (13,25 [P25-P75: 9,05-15,87] frente a 9,43 [P25-P75: 6,30-15] g/día, p: 0,018). No se apreció correlación estadística entre el título de anticuerpos medido por ELISA con la edad, el filtrado glomerular, la albuminemia y la proteinuria en 24 horas. Conclusiones: Las técnicas empleadas para la determinación de anti-PLA2R en pacientes con NM presentan alta especificidad para el diagnóstico de formas idiopáticas de la enfermedad glomerular. La frecuencia con la que se identifican pacientes con NM y anti-PLA2R es parecida a la descrita en estudios previos. La tinción por inmunohistoquímica es el método más sensible para la detección de casos de NM asociados a presencia de anticuerpos anti-PLA2R. Las técnicas de IFI y de ELISA permiten la detección de anticuerpos circulantes anti-PLA2R en la mayor parte de los enfermos con depósitos renales, pero con muy baja frecuencia pueden dar resultados falsamente negativos. La concordancia de estas pruebas es alta. Los enfermos con NM idiopática y depósitos renales de anticuerpos anti-PLA2R tienen mayor proteinuria que los enfermos anti-PLA2R negativos, pero las diferencias tienen escasa relevancia clínica (AU)

The M-type phospholipase A2 receptor (PLA2R) has been identified as one of the target antigens of the autoimmune response in idiopathic membranous nephropathy (MN). The prevalence of anti-PLA2R antibodies in patients with idiopathic MN is around 70% but this varies in accordance with geographic region, and until present, anti-PLA2R has not been shown to be associated with any particular clinical profile of the disease. Methods: We studied 64 adults with nephrotic syndrome who were diagnosed with MN, confirmed by renal biopsy. Forty-seven patients had idiopathic MN and 17 had secondary MN. We determined the presence of circulating anti-PLA2R antibodies by indirect immunofluorescence (IIF) and their titre by ELISA, and we analysed the presence of anti-PLA2R antibody renal deposits by immunohistochemical techniques. We calculated the sensitivity and specificity of the IIF and ELISA techniques for the identification of patients with renal deposits and for the identification of those with idiopathic MN and we tested whether there were differences in the clinical profile of the disease at the time of diagnosis according to the presence or absence of anti-PLA2R antibodies. Results: We did not observe significant differences in the clinical-demographic variables between patients with idiopathic and secondary MN. The prevalence of anti-PLA2R glomerular deposits by IHC was 76.6%. The IIF and ELISA techniques had a similar sensitivity (IIF 94.4% and ELISA 97.2%) and specificity (100%) for the identification of patients with anti-PLA2R renal deposits and the detection of circulating anti-PLA2R antibodies. The determination of anti-PLA2R by IIF identified patients with idiopathic MN with a sensitivity of 72.3% and a specificity of 94.2%. A titre of antibodies >15RU/ml measured by ELISA had a sensitivity of 74.45% and a specificity of 94.2% for the identification of patients with idiopathic MN. Patients with idiopathic MN and anti-PLA2R had significantly higher proteinuria figures (13.25 [P25-P75: 9.05-15.87] compared to 9.43 [P25-P75: 6.30-15] g/day, P:.018). No statistical correlation was observed between the antibody titre measured by ELISA and age, glomerular filtration rate or 24-hour proteinuria or albuminaemia. Conclusions: The techniques employed to determine anti-PLA2R in patients with MN are highly specific for the diagnosis of idiopathic forms of the glomerular disease. The frequency with which patients with MN and anti-PLA2R were identified is similar to that reported in previous studies. Staining by immunohistochemistry is the most sensitive method for detecting cases of MN associated with the presence of anti-PLA2R antibodies. The IIF and ELISA techniques allow circulating anti-PLA2R antibodies to be detected in most patients with renal deposits, but they may very infrequently have false negative results. The concordance of these tests is high. Patients with idiopathic MN and anti-PLA2R antibody renal deposits have higher proteinuria than patients that are anti-PLA2R negative, but the differences have little clinical importance (AU)

Prevalence, diagnostic value and clinical characteristics associated with the presence of circulating levels and renal deposits of antibodies against the M-type phospholipase A2 receptor in idiopathic membranous nephropathy.

UNLABELLED: The M-type phospholipase A2 receptor (PLA2R) has been identified as one of the target antigens of the autoimmune response in idiopathic membranous nephropathy (MN). The prevalence of anti-PLA2R antibodies in patients with idiopathic MN is around 70% but this varies in accordance with geographic region, and until present, anti-PLA2R has not been shown to be associated with any particular clinical profile of the disease. METHODS: We studied 64 adults with nephrotic syndrome who were diagnosed with MN, confirmed by renal biopsy. Forty-seven patients had idiopathic MN and 17 had secondary MN. We determined the presence of circulating anti-PLA2R antibodies by indirect immunofluorescence (IIF) and their titre by ELISA, and we analysed the presence of anti-PLA2R antibody renal deposits by immunohistochemical techniques. We calculated the sensitivity and specificity of the IIF and ELISA techniques for the identification of patients with renal deposits and for the identification of those with idiopathic MN and we tested whether there were differences in the clinical profile of the disease at the time of diagnosis according to the presence or absence of anti-PLA2R antibodies. RESULTS: We did not observe significant differences in the clinical-demographic variables between patients with idiopathic and secondary MN. The prevalence of anti-PLA2R glomerular deposits by IHC was 76.6%. The IIF and ELISA techniques had a similar sensitivity (IIF 94.4% and ELISA 97.2%) and specificity (100%) for the identification of patients with anti-PLA2R renal deposits and the detection of circulating anti-PLA2R antibodies. The determination of anti-PLA2R by IIF identified patients with idiopathic MN with a sensitivity of 72.3% and a specificity of 94.2%. A titre of antibodies >15RU/ml measured by ELISA had a sensitivity of 74.45% and a specificity of 94.2% for the identification of patients with idiopathic MN. Patients with idiopathic MN and anti-PLA2R had significantly higher proteinuria figures (13.25 [P25-P75: 9.05-15.87] compared to 9.43 [P25-P75: 6.30-15] g/day, P:.018). No statistical correlation was observed between the antibody titre measured by ELISA and age, glomerular filtration rate or 24-hour proteinuria or albuminaemia. CONCLUSIONS: The techniques employed to determine anti-PLA2R in patients with MN are highly specific for the diagnosis of idiopathic forms of the glomerular disease. The frequency with which patients with MN and anti-PLA2R were identified is similar to that reported in previous studies. Staining by immunohistochemistry is the most sensitive method for detecting cases of MN associated with the presence of anti-PLA2R antibodies. The IIF and ELISA techniques allow circulating anti-PLA2R antibodies to be detected in most patients with renal deposits, but they may very infrequently have false negative results. The concordance of these tests is high. Patients with idiopathic MN and anti-PLA2R antibody renal deposits have higher proteinuria than patients that are anti-PLA2R negative, but the differences have little clinical importance.

Tratamiento de la glomeruloesclerosis focal y segmentaria idiopática: opciones en caso de resistencia a corticosteroides y anticalcineurínicos / Treatment of idiopathic focal segmental glomerulosclerosis: options in the event of resistance to corticosteroids and calcineurin inhibitors

La mitad de los enfermos con síndrome nefrótico causado por glomeruloesclerosis focal y segmentaria (GFS) primaria presentan resistencia al tratamiento con esteroides. En caso de corticorresistencia, la mejor opción basada en la evidencia ha sido clásicamente el tratamiento con inhibidores de calcineurina, aunque estudios recientes indican que micofenolato podría tener una eficacia similar. En los enfermos con resistencia a anticalcineurínicos, no existe ninguna opción capaz de modificar el curso clínico de la enfermedad, avalada por ensayos clínicos de diseño apropiado, aunque en estudios observacionales se ha sugerido la posible utilidad de micofenolato, sirolimus, rituximab, aféresis o altas dosis de galactosa como opciones terapéuticas. En las GFS de origen idiopático, resistentes a esteroides y anticalcineurínicos, antes de tomar la decisión de ensayar o no otros fármacos inmunosupresores, podría ser apropiado realizar un análisis sistemático que contemplara: 1) considerar si la dosis y el tiempo de tratamiento con esteroides y anticalcineurínicos fueron adecuados; 2) analizar el nivel de expresión de la glicoproteína P en los linfocitos; 3) considerar realizar una nueva biopsia renal en caso de que en la primera no se disponga de estudio de microscopía electrónica; 4) en enfermos jóvenes, considerar un estudio genético para descartar la presencia de la variante p.R229Q de la podocina en combinación con mutaciones heterozigotas en NPHS2, y 4) considerar la gravedad y dificultad de manejo del síndrome nefrótico y la probabilidad de pérdida progresiva de la función renal. En la actualidad, hay múltiples vías de estudio para intentar identificar los mecanismos patogénicos causantes de la lesión podocitaria y hay también en curso varios estudios para analizar la eficacia de fármacos como adalimumab, fresolimumab, rosiglitazona, ACTH (corticotropina) o galactosa a altas dosis, cuyos resultados preliminares han generado expectativas que requieren ser confirmadas en estudios clínicos a mayor escala. En un futuro, es posible que el mejor conocimiento de la vía o vías patogénicas causantes de GFS permita diferenciar entre las formas inmunomodulables y las que no lo son, pero, hoy por hoy, este desafío continúa plenamente vigente

Half of patients with nephrotic syndrome caused by primary focal segmental glomerulosclerosis (FSGS) have resistance to treatment with steroids. In the case of corticosteroid resistance, the best evidence-based option has classically been treatment with calcineurin inhibitors, although recent studies indicate that mycophenolate may have similar efficacy. In patients with resistance to calcineurin inhibitors, there is no option that allows the clinical course of the disease to be modified, and this is supported by appropriately designed clinical trials, although observational studies have suggested the potential usefulness of mycophenolate, sirolimus, rituximab, apheresis or high galactose doses as treatment options. In FSGS of idiopathic origin, resistant to steroids and calcineurin inhibitors, before taking the decision whether or not to test other immunosuppressive drugs, it might be appropriate to conduct a systematic analysis that considers: 1) evaluating whether the dose and duration of treatment with steroids and calcineurin inhibitors were suitable, 2) analysing the level of P-glycoprotein expression in lymphocytes, 3) performing a new renal biopsy if there is no electron microscopic study available for the first, 4) in young patients, considering a genetic study to rule out the presence of the podocin variant pR229Q in combination with heterozygous mutations in NPHS2, and 5) evaluating the seriousness and difficulty of managing the nephrotic syndrome and the likelihood of progressive loss of renal function. Currently, there are multiple study avenues that attempt to identify the pathogenic mechanisms that cause podocyte injury and there are also several studies underway to analyse the efficacy of drugs such as adalimumab, fresolimumab, rosiglitazone, ACTH (corticotropin) or galactose at high doses, whose preliminary results have generated expectations that require confirmation in larger-scale clinical studies. In the future, it is possible that a better understanding of the pathogenic pathway or pathways that cause FSGS may allow differentiation between immunomodulable and non-immunomodulable forms, however, this continues to be a challenge for today

Treatment of idiopathic focal segmental glomerulosclerosis: options in the event of resistance to corticosteroids and calcineurin inhibitors.

Half of patients with nephrotic syndrome caused by primary focal segmental glomerulosclerosis (FSGS) have resistance to treatment with steroids. In the case of corticosteroid resistance,  the best evidence-based option has classically been treatment with calcineurin inhibitors,  although recent studies indicate that mycophenolate may have similar efficacy. In patients with resistance to calcineurin inhibitors,  there is no option that allows the clinical course of the disease to be modified, and this is supported by appropriately designed clinical trials, although observational studies have suggested the potential usefulness of mycophenolate, sirolimus, rituximab, apheresis or high galactose doses as treatment options. In FSGS of idiopathic origin, resistant to steroids and calcineurin inhibitors, before taking the decision whether or not to test other immunosuppressive drugs, it might be appropriate to conduct a systematic analysis that considers: 1) evaluating whether the dose and duration of treatment with steroids and calcineurin inhibitors were suitable, 2) analysing the level of P-glycoprotein expression in lymphocytes, 3) performing a new renal biopsy if there is no electron microscopic study available for the first, 4) in young patients,  considering a genetic study to rule out the presence of the podocin variant pR229Q in combination with heterozygous mutations in NPHS2,  and 5) evaluating the seriousness and difficulty of managing the nephrotic syndrome and the likelihood of progressive loss of renal function. Currently, there are multiple study avenues that attempt to identify the pathogenic mechanisms that cause podocyte injury and there are also several studies underway to analyse the efficacy of drugs such as adalimumab, fresolimumab, rosiglitazone, ACTH (corticotropin) or galactose at high doses, whose preliminary results have generated expectations that require confirmation in larger-scale clinical studies.  In the future, it is possible that a better understanding of the pathogenic pathway or pathways that cause FSGS may allow differentiation between immunomodulable and non-immunomodulable forms,  however, this continues to be a challenge currently.

Biomarcadores en el síndrome nefrótico: algunos pasos más en el largo camino / Biological markers of nephrotic syndrome: a few steps forward in the long way

Uno de los retos a los que debe enfrentarse la nefrología moderna es el de identificar biomarcadores que se asocien a patrones anatomopatológicos o a mecanismos patogénicos definidos y permitan el diagnóstico no invasivo de la causa del síndrome nefrótico o establecer subgrupos pronósticos en cada tipo de enfermedad, prediciendo la respuesta al tratamiento y/o la aparición de recidivas. Los avances en el conocimiento de la patogenia de las distintas enfermedades causantes de síndrome nefrótico, sumados al progresivo desarrollo y estandarización de las técnicas de proteómica plasmática y urinaria, han permitido ir identificando un número creciente de moléculas que podrían ser útiles para los fines anteriormente mencionados. En el momento actual, los datos de muchos de los candidatos identificados, sobre todo mediante técnicas de proteómica, son todavía muy preliminares. En la presente revisión, se resume la evidencia disponible sobre las moléculas que en la actualidad cuentan con mayor evaluación en estudios clínicos (AU)

One of the major challenges modern nephrology should face is the identification of biomarkers that are associated with histopathological patterns or defined pathogenic mechanisms that might aid in the non-invasive diagnosis of the causes of nephrotic syndrome, or in establishing prognosis sub-groups based on each type of disease, thus predicting response to treatment and/or recurrence. Advancements in the understanding of the pathogenesis of the different diseases that cause nephrotic syndrome, along with the progressive development and standardisation of plasma and urine proteomics techniques, have facilitated the identification of a growing number of molecules that might be useful for these objectives. Currently, the available information for many of the possible candidates identified to date, above all those discovered using proteomics, are still very preliminary. In this review, we summarise the available evidence for the different molecules that have been best assessed using clinical studies (AU)

Biological markers of nephrotic syndrome: a few steps forward in the long way.

One of the major challenges modern nephrology should face is the identification of biomarkers that are associated with histopathological patterns or defined pathogenic mechanisms that might aid in the non-invasive diagnosis of the causes of nephrotic syndrome, or in establishing prognosis sub-groups based on each type of disease, thus predicting response to treatment and/or recurrence. Advancements in the understanding of the pathogenesis of the different diseases that cause nephrotic syndrome, along with the progressive development and standardisation of plasma and urine proteomics techniques, have facilitated the identification of a growing number of molecules that might be useful for these objectives. Currently, the available information for many of the possible candidates identified to date, above all those discovered using proteomics, are still very preliminary. In this review, we summarise the available evidence for the different molecules that have been best assessed using clinical studies.