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.

Valor diagnóstico de los niveles séricos del receptor soluble de la uroquinasa en adultos con síndrome nefrótico idiopático / Diagnostic value of soluble urokinase-type plasminogen activator receptor serum levels in adults with idiopathic nephrotic syndrome

Introducción: Estudios recientes sugieren que los niveles del receptor soluble de la uroquinasa (suPAR) podrían ser útiles para diferenciar la glomeruloesclerosis focal y segmentaria (GFS) idiopática de otras glomerulopatías causantes de síndrome nefrótico, pero estos datos no han sido confirmados en estudios independientes. El objetivo de nuestro estudio es analizar si los niveles circulantes de suPAR son útiles para identificar la enfermedad renal primaria en enfermos afectos de síndrome nefrótico secundario a GFS, enfermedad por cambios mínimos o nefropatía membranosa (NM) idiopática. Métodos: Se realizaron mediciones de niveles de suPAR circulante en el momento del diagnóstico en 60 pacientes con síndrome nefrótico secundario a GFS, enfermedad por cambios mínimos (ECM) y NM. Se analizaron las correlaciones entre niveles de suPAR y variables demográficas, clínicas y bioquímicas. La sensibilidad y la especificidad de suPAR para diferenciar a los enfermos con GFS se analizaron mediante curvas ROC. Resultados: Tras ajustar por edad y función renal, los niveles de suPAR fueron significativamente más elevados en enfermos con GFS que en ECM (p < 0,001), pero no hubo diferencias entre GFS y NM (p = 0,12). Un valor de suPAR ≥ 3452 pg/ml tuvo una sensibilidad del 73,7 % y una especificidad del 72,5 %, con un área bajo la curva (ABC) de 0,782 ± 0,124, p = 0,001, para identificar a los enfermos con GFS. Tras excluir a los enfermos con NM, un valor ≥ 3531 pg/ml tuvo una especificidad del 99,93 % para diferenciar entre ECM y GFS. Conclusiones: Los valores de suPAR por sí solos no diferencian entre los tres tipos de glomerulopatía. Sin embargo, tras excluir el diagnóstico de NM, un nivel de suPAR > 3531 pg/ml podría tener una elevada especificidad (pero baja sensibilidad) para el diagnóstico de GFS

Introduction: Recent studies suggest that soluble urokinase-type plasminogen activator receptor (suPAR) levels could be useful for distinguishing idiopathic focal segmental glomerulosclerosis (FSGS) from other glomerulopathies that cause nephrotic syndrome, but these data have not been confirmed in independent studies. The objective of our study is to analyse whether circulating levels of suPAR are useful for identifying primary kidney disease in patients with nephrotic syndrome secondary to FSGS, minimal change disease or idiopathic membranous nephropathy (MN). Methods: We measured circulating suPAR at diagnosis in 60 patients with nephrotic syndrome secondary to FSGS, minimal change disease (MCD) and membranous nephropathy (MN). The correlations between suPAR levels and demographic, clinical and biochemical variables were analysed. The sensitivity and specificity of suPAR in distinguishing FSGS patients were analysed by ROC curves. Results: After adjusting for age and renal function, suPAR levels were significantly higher in patients with FSGS than in those with MCD (p<.001), but there were no differences between FSGS and MN (P=.12). A suPAR value ≥3452pg/ml had a sensitivity of 73.7% and a specificity of 72.5%, with an area under the curve (AUC) of 0.782±0.124, p=.001, for identifying patients with FSGS. After excluding patients with MN, a value ≥3531pg/ml had a specificity of 99.93% for distinguishing between MCD and FSGS. Conclusions: suPAR values alone do not distinguish between the three types of glomerulopathy. Nevertheless, after excluding the diagnosis of MN, a suPAR level >3531pg/ml could have a high specificity (but a low sensitivity) in the diagnosis of FSGS

Valor de los niveles séricos del receptor soluble de la uroquinasa en el diagnóstico diferencial entre glomeruloesclerosis focal y segmentaria idiopática y secundaria / Value of soluble urokinase receptor serum levels in the differential diagnosis between idiopathic and secondary focal segmental glomerulosclerosis

Antecedentes: Se ha descrito que el nivel circulante del receptor soluble de la uroquinasa (suPAR) podría ser útil para diferenciar la glomeruloesclerosis focal y segmentaria idiopática de las formas secundarias, pero los resultados publicados son discordantes. En el presente estudio, se analiza la variabilidad intraindividual, las variables clínicas y anatomopatológicas asociadas con los niveles de suPAR y si los niveles circulantes de suPAR permiten diferenciar las formas de glomeruloesclerosis focal y segmentaria (GFS) idiopáticas de las GFS secundarias, independientemente de la presencia de síndrome nefrótico y de la fase de actividad. Métodos: Se estudiaron 35 pacientes afectos de GFS idiopática y 48 con GFS secundaria (83 en total). Se realizaron mediciones de suPAR circulante en el momento del diagnóstico y/o tras la remisión y se analizaron las correlaciones entre niveles de suPAR y variables demográficas, clínicas y bioquímicas. La capacidad de suPAR para diferenciar entre ambas formas de GFS se analizó mediante curvas ROC y análisis de regresión logística. Resultados: En ambas formas de GFS, los niveles de suPAR fueron independientes de la proteinuria y del subtipo histopatológico de GFS y se asociaron significativamente a la edad y a la función renal. Tras ajustar por ambas variables, los niveles de suPAR fueron significativamente superiores en los enfermos con GFS idiopática, tanto en fase de síndrome nefrótico como en situación de remisión parcial o total. El nivel de suPAR con mayor sensibilidad (80 %) y mayor especificidad (73 %) para discriminar entre formas idiopáticas y secundarias fue de 3443,6 pg/ml (área bajo la curva [ABC] 0,78 ± 0,083, p < 0,001). En el análisis de regresión logística, tras ajustar por edad, función renal y presencia de síndrome nefrótico, los niveles de suPAR se asociaron de forma independiente con el diagnóstico de GFS idiopática, pero el modelo tuvo un mal ajuste para categorías de riesgo bajas, en las que tendió a clasificar las formas primarias como secundarias (χ 2 = 11,2 p = 0,027). Conclusiones: Los niveles de suPAR carecen de sensibilidad para diferenciar entre GFS idiopática y secundaria. Sin embargo, valores de suPAR superiores a 4000 ng/ml son altamente específicos de GFS primaria, por lo que, ante un patrón morfológico de GFS asociado a proteinuria no nefrótica, indicarían una baja probabilidad de GFS secundaria (AU)

Background: It has been reported that the circulating level of the soluble urokinase receptor (suPAR) could be useful for distinguishing idiopathic from secondary focal segmental glomerulosclerosis, but the results published are conflicting. In this study, we analyse the intraindividual variability and clinical and anatomopathological variables associated with the suPAR levels and if circulating suPAR levels allow the different forms of focal segmental glomerulosclerosis (FSGS) to be distinguished, i.e., idiopathic forms from secondary FSGS, regardless of the presence of nephrotic syndrome and the activity phase. Method: We studied 35 patients affected by idiopathic FSGS and 48 with secondary FSGS (83 in total). We carried out measurements of circulating suPAR at the time of diagnosis and/or after remission and we analysed correlations between suPAR levels and demographic, clinical and biochemical variables. The ability of suPAR to distinguish between both forms of FSGS was analysed by ROC curves and logistic regression analysis. Results: In both forms of FSGS, suPAR levels were independent of proteinuria and the histopathological subtype of FSGS and they were significantly associated with age and renal function. After adjusting for both variables, suPAR levels were significantly higher in patients with idiopathic FSGS, both in the nephrotic syndrome phase and in partial or complete remission. The most sensitive suPAR level (80%) and the most specific (73%) for discriminating between idiopathic and secondary forms was 3443.6pg/ml (area below curve [ABC] 0.78±0.083, P<.001). In the logistic regression analysis, after adjusting for age, renal function and presence of nephrotic syndrome, suPAR levels were independently associated with the diagnosis of idiopathic FSGS, but the model was poorly adjusted for low risk categories in which it tended to classify primary forms as secondary forms (χ 2 = 11.2 p=.027). Conclusions: SuPAR levels lack sensitivity for differentiating between idiopathic and secondary FSGS. However, suPAR values greater than 4000ng/ml are highly specific to primary FSGS, and as such, with a morphological FSGS pattern associated with non-nephrotic proteinuria, they would indicate a low probability of secondary FSGS (AU)

[Diagnostic value of soluble urokinase-type plasminogen activator receptor serum levels in adults with idiopathic nephrotic syndrome]. / Valor diagnóstico de los niveles séricos del receptor soluble de la uroquinasa en adultos con síndrome nefrótico idiopático.

INTRODUCTION: Recent studies suggest that soluble urokinase-type plasminogen activator receptor (suPAR) levels could be useful for distinguishing idiopathic focal segmental glomerulosclerosis (FSGS) from other glomerulopathies that cause nephrotic syndrome, but these data have not been confirmed in independent studies. The objective of our study is to analyse whether circulating levels of suPAR are useful for identifying primary kidney disease in patients with nephrotic syndrome secondary to FSGS, minimal change disease or idiopathic membranous nephropathy (MN). METHODS: We measured circulating suPAR at diagnosis in 60 patients with nephrotic syndrome secondary to FSGS, minimal change disease (MCD) and membranous nephropathy (MN). The correlations between suPAR levels and demographic, clinical and biochemical variables were analysed. The sensitivity and specificity of suPAR in distinguishing FSGS patients were analysed by ROC curves. RESULTS: After adjusting for age and renal function, suPAR levels were significantly higher in patients with FSGS than in those with MCD (p<.001), but there were no differences between FSGS and MN (P=.12). A suPAR value ≥3452 pg/ml had a sensitivity of 73.7% and a specificity of 72.5%, with an area under the curve (AUC) of 0.782 ± 0.124, p=.001, for identifying patients with FSGS. After excluding patients with MN, a value ≥3531 pg/ml had a specificity of 99.93% for distinguishing between MCD and FSGS. CONCLUSIONS: suPAR values alone do not distinguish between the three types of glomerulopathy. Nevertheless, after excluding the diagnosis of MN, a suPAR level >3531 pg/ml could have a high specificity (but a low sensitivity) in the diagnosis of FSGS.

[Value of soluble urokinase receptor serum levels in the differential diagnosis between idiopathic and secondary focal segmental glomerulosclerosis]. / Valor de los niveles séricos del receptor soluble de la uroquinasa en el diagnóstico diferencial entre glomeruloesclerosis focal y segmentaria idiopática y secundaria.

BACKGROUND: It has been reported that the circulating level of the soluble urokinase receptor (suPAR) could be useful for distinguishing idiopathic from secondary focal segmental glomerulosclerosis, but the results published are conflicting. In this study, we analyse the intraindividual variability and clinical and anatomopathological variables associated with the suPAR levels and if circulating suPAR levels allow the different forms of focal segmental glomerulosclerosis (FSGS) to be distinguished, i.e., idiopathic forms from secondary FSGS, regardless of the presence of nephrotic syndrome and the activity phase. METHOD: We studied 35 patients affected by idiopathic FSGS and 48 with secondary FSGS (83 in total). We carried out measurements of circulating suPAR at the time of diagnosis and/or after remission and we analysed correlations between suPAR levels and demographic, clinical and biochemical variables. The ability of suPAR to distinguish between both forms of FSGS was analysed by ROC curves and logistic regression analysis. RESULTS: In both forms of FSGS, suPAR levels were independent of proteinuria and the histopathological subtype of FSGS and they were significantly associated with age and renal function. After adjusting for both variables, suPAR levels were significantly higher in patients with idiopathic FSGS, both in the nephrotic syndrome phase and in partial or complete remission. The most sensitive suPAR level (80%) and the most specific (73%) for discriminating between idiopathic and secondary forms was 3443.6 pg/ml (area below curve [ABC] 0.78 ± 0.083, P<.001). In the logistic regression analysis, after adjusting for age, renal function and presence of nephrotic syndrome, suPAR levels were independently associated with the diagnosis of idiopathic FSGS, but the model was poorly adjusted for low risk categories in which it tended to classify primary forms as secondary forms (χ(2) = 11.2 p=.027). CONCLUSIONS: SuPAR levels lack sensitivity for differentiating between idiopathic and secondary FSGS. However, suPAR values greater than 4000 ng/ml are highly specific to primary FSGS, and as such, with a morphological FSGS pattern associated with non-nephrotic proteinuria, they would indicate a low probability of secondary FSGS.