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.

How to Estimate Kidney Growth in Patients with Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a disease characterized by a progressive kidney growth due to the development of cysts that lead to gradual destruction of the surrounding parenchyma. In the first stage, the estimated GFR will remain stable despite the reduction of the renal parenchyma because of an increase in glomerular hyperfiltration. The total kidney volume (TKV) measured with computed tomography or magnetic resonance imaging is related to the future GFR decline. Thus, TKV has become an early marker to be analyzed in all patients with ADPKD. In addition, in recent years, it has been pointed out that kidney growth rate estimated with a single TKV measurement can be a clear prognostic marker for future glomerular filtration decline. However, there is no consensus on how to measure kidney volume growth in ADPKD, so each author has used different models that, not having the same meaning, have been handled as if they produced similar values. This may lead to erroneous estimates of kidney growth rate with the consequent prognostic error. The Mayo Clinic classification is now the most widely accepted prognostic model in clinical practice to predict patients who will deteriorate faster and to decide what patients should be treated with tolvaptan. However, some aspects of this model have not been discussed in depth. Our aim in this review was to present the models that can be used to estimate kidney volume growth rate in ADPKD, to facilitate their applicability in daily clinical practice.

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)

Riñón, hipertensión y activación del complemento. En búsqueda de nuevas dianas terapéuticas / Kidney, hypertension and complement activation. In search of new therapeutic targets

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El depósito de C3 en la glomerulonefritis extracapilar de tipo IIIcondiciona un mal pronóstico / C3 deposits worsens the prognosis in type III extracapillary glomerulonephritis

Introducción: La glomerulonefritis extracapilar (GNEC) pauciinmune o de tipo III es una de las causas más comunes de glomerulonefritis rápidamente progresiva y suele estar asociada con la presencia de anticuerpos antineutrófilos citoplasmáticos (ANCA). Están reportándose evidencias sobre la importancia de la activación del complemento en la patogénesis de la GNEC. El objetivo de nuestro estudio fue evaluar el papel pronóstico del depósito de C3 en las GNEC de tipo III. Métodos: Se estudió a pacientes diagnosticados de GNEC de tipo IIIentre 1995 y 2015 (n=72). Comparamos a pacientes con tinción positiva para C3 en el estudio de inmunofluorescencia con aquellos con tinción negativa. Se analizaron variables clínicas e histológicas y se relacionaron con progresión a enfermedad renal terminal. Resultados: Se encontró tinción positiva para C3 en 22 pacientes de un total de 72 (30,5%). Basalmente los pacientes con depósitos de C3 tenían peor función renal que aquellos sin depósitos (creatinina sérica 5 vs. 3,85mg/dl; p=0,050). La supervivencia renal a los 10 años fue del 36,9% en los pacientes con tinción positiva para C3 frente al 64,4% en los pacientes con tinción negativa (p=0,005). La supervivencia a los 10 años fue peor en los pacientes con depósitos de C3 (77 vs. 49,3%). Conclusiones: Nuestro estudio revela que la presencia de depósito de C3 en la GNEC de tipo III se asocia a un peor pronóstico renal y de la supervivencia del paciente. Estos resultados son compatibles con la hipótesis de que la activación de la vía alternativa del complemento contribuye al daño renal asociado a la GNEC de tipo III (AU)

Introduction: Type III extracapillary glomerulonephritis (PEGN) is a common cause of rapidly progressive glomerulonephritis and it is usually associated with circulating anti-neutrophil cytoplasmic antibodies (ANCAs). Recent evidence points to complement activation as an important factor in the pathogenesis of PEGN. The aim of the present study was to assess the value of C3 deposits in the prognosis of PEGN. Methods: All patients diagnosed of PEGN from 1995 to 2015 (n=72) were included in this study. Progression of renal disease in patients with positive staining for C3 by immunofluorescence was compared with those with negative staining. Mean follow up was 73 months. Progression to end-stage renal disease in relation to clinical and histological variables was analyzed. Results: Positive staining for C3 was observed in 22 out of the 72 patients (30.5%). At the time of diagnosis, patients with C3 deposits had higher serum creatinine concentration than those without C3 staining (5.00 vs. 3.85mg/dl, P=0.050). Renal survival at 10 years was 36.9% in patients with positive C3 staining vs. 64.4% in patients with negative staining (P=0.005). Mortality at 10 years was higher in patients with C3 deposits than in patients without deposits (77 vs. 49.3%). Conclusions: Thus, our study shows that PEGN with deposits of C3 is associated with worse renal prognosis and greater mortality. These results would support the hypothesis that activation of the alternative pathway complement may play an important role in the generation of renal injury associated with PEGN (AU)

C3 deposits worsens the prognosis in type iii extracapillary glomerulonephritis. / El depósito de C3 en la glomerulonefritis extracapilar de tipo iii condiciona un mal pronóstico.

INTRODUCTION: Type iii extracapillary glomerulonephritis (PEGN) is a common cause of rapidly progressive glomerulonephritis and it is usually associated with circulating anti-neutrophil cytoplasmic antibodies (ANCAs). Recent evidence points to complement activation as an important factor in the pathogenesis of PEGN. The aim of the present study was to assess the value of C3 deposits in the prognosis of PEGN. METHODS: All patients diagnosed of PEGN from 1995 to 2015 (n=72) were included in this study. Progression of renal disease in patients with positive staining for C3 by immunofluorescence was compared with those with negative staining. Mean follow up was 73 months. Progression to end-stage renal disease in relation to clinical and histological variables was analyzed. RESULTS: Positive staining for C3 was observed in 22 out of the 72 patients (30.5%). At the time of diagnosis, patients with C3 deposits had higher serum creatinine concentration than those without C3 staining (5.00 vs. 3.85mg/dl, P=0.050). Renal survival at 10 years was 36.9% in patients with positive C3 staining vs. 64.4% in patients with negative staining (P=0.005). Mortality at 10 years was higher in patients with C3 deposits than in patients without deposits (77 vs. 49.3%). CONCLUSIONS: Thus, our study shows that PEGN with deposits of C3 is associated with worse renal prognosis and greater mortality. These results would support the hypothesis that activation of the alternative pathway complement may play an important role in the generation of renal injury associated with PEGN.

Estudio prospectivo de las complicaciones asociadas a la biopsia percutánea en riñón nativo: experiencia en un centro / Prospective study of the complications associated with percutaneous renal biopsy of native kidneys: experience in a centre

Introducción: La biopsia renal percutánea (BRP) es una exploración invasiva fundamental para el estudio de enfermedades renales que lleva asociada una apreciable morbilidad. Estudios retrospectivos han mostrado que el 10-20 % de los casos presentan complicaciones menores y el 1,2-6,6 % complicaciones consideradas mayores. Sin embargo, este aspecto no ha sido examinado prospectivamente. Objetivo: El objetivo del estudio fue evaluar prospectivamente las complicaciones asociadas a la BRP en el riñón nativo. Métodos: Estudio prospectivo desde enero de 2009 hasta mayo de 2013 de las BRP realizadas por nefrólogos en riñón nativo bajo control ecográfico. Se analizaron variables clínicas y analíticas. Definimos complicación menor como la caída de la hemoglobina (Hb) de más de 1 g/dl y complicación mayor la necesidad de transfusión o técnica invasiva. Resultados: En este período se han realizado 241 BRP. La edad media de los pacientes fue de 49 años (± 17), la mayoría eran varones (56 %) y el 58,1 % padecían hipertensión arterial. Se realizaron dos punciones en el 51 %. Se observaron complicaciones menores en 46 pacientes (19,1 %) y mayores en 9 pacientes (3,7 %). En el análisis univariante, la Hb pre-BRP fue 10,3 g/dl (± 1,3) en aquellos que desarrollaron complicaciones mayores y 12,3 g/dl (± 2,2) en los demás (p = 0,003); en el análisis multivariante: OR 0,51, IC 95 %(0,2-0,9), p < 0,05. Conclusiones: La BRP es un procedimiento no exento de riesgos, ya que las complicaciones menores se presentaron en el 19,1 % y las mayores en el 3,7 % de los casos. La Hb pre-BRP es un factor de riesgo independiente para el desarrollo de complicaciones mayores (AU)

Background: Percutaneous renal biopsy (PRB) is a key invasive technique in the study of kidney disease and it is associated with considerable morbidity. Retrospective studies have shown minor complications in 10%-20% and major complications in 1.2%-6.6% of cases. However, this aspect has not been studied prospectively. Objective: The aim of our study was to prospectively assess complications related to PRB in the native kidney. Methods: From January 2009 to May 2013, we prospectively analysed PRB performed by nephrologists in native kidneys under ultrasound guidance. We analysed clinical and laboratory variables. We defined minor complications as the decrease in haemoglobin (Hb) of more than 1g/dL and major complications as the need for a transfusion or invasive technique. Results: 241 PRB were performed over this period. The mean patient age was 49 years (±17), the majority (56%) were male and 58.1% had high blood pressure. In 51% of cases, we carried out 2 punctures. There were minor complications in 46 patients (19.1%) and major complications in 9 patients (3.7%). In the univariate analysis, pre-PRB Hb was 10.3g/dL (±1.3) in patients with major complications and 12.3g/dL (±2.2) in the remaining patients (p=.003); in the multivariate analysis: OR 0.51, 95% CI (0.2-0.9),p<.05. Conclusions: PRB is a procedure that is not without risk, since minor complications occurred in 19.1% and major complications in 3.7% of cases. Pre-PRB Hb is an independent risk factor for the development of major complications (AU)

Prospective study of the complications associated with percutaneous renal biopsy of native kidneys: experience in a centre.

BACKGROUND: Percutaneous renal biopsy (PRB) is a key invasive technique in the study of kidney disease and it is associated with considerable morbidity. Retrospective studies have shown minor complications in 10%-20% and major complications in 1.2%-6.6% of cases. However, this aspect has not been studied prospectively. OBJECTIVE: The aim of our study was to prospectively assess complications related to PRB in the native kidney. METHODS: From January 2009 to May 2013, we prospectively analysed PRB performed by nephrologists in native kidneys under ultrasound guidance. We analysed clinical and laboratory variables. We defined minor complications as the decrease in haemoglobin (Hb) of more than 1g/dL and major complications as the need for a transfusion or invasive technique. RESULTS: 241 PRB were performed over this period. The mean patient age was 49 years (±17), the majority (56%) were male and 58.1% had high blood pressure. In 51% of cases, we carried out 2 punctures. There were minor complications in 46 patients (19.1%) and major complications in 9 patients (3.7%). In the univariate analysis, pre-PRB Hb was 10.3g/dL (±1.3) in patients with major complications and 12.3g/dL (±2.2) in the remaining patients (p=.003); in the multivariate analysis: OR 0.51, 95% CI (0.2-0.9), p<.05. CONCLUSIONS: PRB is a procedure that is not without risk, since minor complications occurred in 19.1% and major complications in 3.7% of cases. Pre-PRB Hb is an independent risk factor for the development of major complications.

C4d como herramienta diagnóstica en la nefropatía membranosa / C4d as a diagnostic tool in membranous nephropathy

Introducción: La nefropatía membranosa (NM) es la causa más frecuente de síndrome nefrótico en adultos. El diagnóstico se basa en los hallazgos típicos observados con el microscopio electrónico (ME) y el estudio de inmunofluorescencia (IF). En algunas ocasiones, sólo se dispone de tejido para estudio de microscopio óptico (MO); en estos casos puede ser complicado diferenciar entre una NM y una enfermedad por cambios mínimos (ECM). Recientemente se está extendiendo el estudio con C4d por inmunohistoquímica. Existe muy poca información sobre el depósito de C4d en la NM. Nuestro estudio consistió en analizar si el depósito de C4d realizado en la muestra en parafina podría ser útil en el diagnóstico de NM. Material y métodos: Estudio retrospectivo que incluyó a todos los pacientes diagnosticados de NM mediante biopsia renal en nuestra unidad entre enero de 2001 y octubre de 2008. Se incluyeron sólo adultos con un diagnóstico certero de NM y ECM idiopática que dispusieran de estudios con MO, IF y ME. En octubre de 2008, secciones de 3 µm de tejido renal fijado en formaldehído fueron deparafinadas y rehidratadas. Después se tiñeron mediante inmunohistoquímica con C4d usando un anticuerpo policlonal antihumano obtenido de conejo. Resultados: Se incluyeron finalmente 19 pacientes con ECM y 21 con NM. Ningún depósito de C4d fue observado en ninguno de los glomérulos de los pacientes con ECM y el 100% de estos pacientes fueron clasificados como negativos. Sin embargo, el depósito de C4d se detectó en el 100% de los pacientes con NM y en todos los glomérulos con una distribución uniforme y granular dibujando todas las asas capilares. Conclusiones: El depósito de C4d mediante inmunohistoquímica es una herramienta muy útil en el diagnóstico de NM (AU)

Introduction: membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. The diagnosis is based on typical findings observed using electron microscope (EM) and immunofluorescence (IF) studies. On some occasions, tissues are only available for analysis using an optical microscope (OM); in these cases, it can be difficult to differentiate between MN and minimal change disease (MCD). Recently, the use of C4d immunohistochemical staining has spread. Very little information is available regarding C4d deposits in MN. Our study consisted of analysing whether C4d staining of samples embedded in paraffin could be useful for diagnosing MN. Material and Method: Ours was a retrospective study including all patients diagnosed with MN by renal biopsy in our unit between January 2001 and October 2008. We only included adult patients with a definitive diagnosis of MN or idiopathic MCD by OM, IF, and ME studies. In October 2008, 3µm sections of renal tissue fixed in formaldehyde were removed from paraffin and rehydrated. The samples were then stained for C4d immunohistochemical analysis using anti-human polyclonal antibodies obtained from rabbits. Results: Our study included a final sample of 19 patients with MCD and 21 with MN. No C4d deposits were observed in any of the glomeruli in patients with MCD, and 100% of these patients were classified as negative. However, C4d deposits were detected in 100% of patients with MN, and were observable in all glomeruli with a uniform granular distribution, demarcating all capillary loops. Conclusions: C4d immunohistochemical staining is a very useful tool for diagnosing MN (AU)

C4d as a diagnostic tool in membranous nephropathy.

INTRODUCTION: membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. The diagnosis is based on typical findings observed using electron microscope (EM) and immunofluorescence (IF) studies. On some occasions, tissues are only available for analysis using an optical microscope (OM); in these cases, it can be difficult to differentiate between MN and minimal change disease (MCD). Recently, the use of C4d immunohistochemical staining has spread. Very little information is available regarding C4d deposits in MN. Our study consisted of analysing whether C4d staining of samples embedded in paraffin could be useful for diagnosing MN. MATERIAL AND METHOD: Ours was a retrospective study including all patients diagnosed with MN by renal biopsy in our unit between January 2001 and October 2008. We only included adult patients with a definitive diagnosis of MN or idiopathic MCD by OM, IF, and ME studies. In October 2008, 3µm sections of renal tissue fixed in formaldehyde were removed from paraffin and rehydrated. The samples were then stained for C4d immunohistochemical analysis using anti-human polyclonal antibodies obtained from rabbits. RESULTS: Our study included a final sample of 19 patients with MCD and 21 with MN. No C4d deposits were observed in any of the glomeruli in patients with MCD, and 100% of these patients were classified as negative. However, C4d deposits were detected in 100% of patients with MN, and were observable in all glomeruli with a uniform granular distribution, demarcating all capillary loops. CONCLUSIONS: C4d immunohistochemical staining is a very useful tool for diagnosing MN.