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.

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)

COVID-19 in Patients with Glomerular Disease: Follow-Up Results from the IRoc-GN International Registry.

Background: The acute and long-term effects of severe acute respiratory syndrome coronavirus 2 infection in individuals with GN are still unclear. To address this relevant issue, we created the International Registry of COVID-19 infection in GN. Methods: We collected serial information on kidney-related and -unrelated outcomes from 125 GN patients (63 hospitalized and 62 outpatients) and 83 non-GN hospitalized patients with coronavirus disease 2019 (COVID-19) and a median follow-up period of 6.4 (interquartile range 2.3-9.6) months after diagnosis. We used logistic regression for the analyses of clinical outcomes and linear mixed models for the longitudinal analyses of eGFR. All multiple regression models were adjusted for age, sex, ethnicity, and renin-angiotensin-aldosterone system inhibitor use. Results: After adjustment for pre-COVID-19 eGFR and other confounders, mortality and AKI did not differ between GN patients and controls (adjusted odds ratio for AKI=1.28; 95% confidence interval [CI], 0.46 to 3.60; P=0.64). The main predictor of AKI was pre-COVID-19 eGFR (adjusted odds ratio per 1 SD unit decrease in eGFR=3.04; 95% CI, 1.76 to 5.28; P<0.001). GN patients developing AKI were less likely to recover pre-COVID-19 eGFR compared with controls (adjusted 6-month post-COVID-19 eGFR=0.41; 95% CI, 0.25 to 0.56; times pre-COVID-19 eGFR). Shorter duration of GN diagnosis, higher pre-COVID-19 proteinuria, and diagnosis of focal segmental glomerulosclerosis or minimal change disease were associated with a lower post-COVID-19 eGFR. Conclusions: Pre-COVID-19 eGFR is the main risk factor for AKI regardless of GN diagnosis. However, GN patients are at higher risk of impaired eGFR recovery after COVID-19-associated AKI. These patients (especially those with high baseline proteinuria or a diagnosis of focal segmental glomerulosclerosis or minimal change disease) should be closely monitored not only during the acute phases of COVID-19 but also after its resolution.

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.

Glomerulopatías C3. Una nueva perspectiva en enfermedades glomerulares / C3 Glomerulopathies. A new perspective on glomerular diseases

El término glomerulonefritis membranoproliferativa denota un patrón general de daño glomerular fácilmente reconocido por microscopía óptica. Con estudios adiciones de microscopía electrónica e inmunofluorescencia, la clasificación en subgrupos es posible. El estudio por microscopía electrónica resuelve las diferencias según la localización de los depósitos electrodensos, mientras que la inmunofluorescencia detecta la composición de los depósitos electrodensos. La glomerulopatía C3 es una entidad descrita de forma reciente, una glomerulonefritis proliferativa (normalmente, pero no siempre), con un patrón de glomerulonefritis membranoproliferativa en la microscopía óptica y con depósitos de C3 aislados en el estudio de inmunofluorescencia, implicando una hiperactividad de la vía alternativa del complemento. La evaluación de un paciente con glomerulopatía C3 debe centrarse en la cascada del complemento, en la desregulación de la vía alternativa del complemento y en la cascada terminal del complemento. Aunque no hay actualmente tratamientos específicos para las glomerulopatías C3, una mejor comprensión de la patogénesis sentaría las bases para el posible uso de drogas anticomplemento como terapia de elección, como el eculizumab. En la presente revisión, se resume la patogenia de las glomerulopatías C3, centrándonos en el papel del complemento, las series de casos recientemente publicados y las opciones terapéuticas hasta el momento actual (AU)

Membranoproliferative glomerulonephritis (MPGN) denotes a general pattern of glomerular injury that is easily recognized by light microscopy. With additional studies, MPGN subgrouping is possible. For example, electron microscopy resolves differences in electron-dense deposition location, while immunofluorescence typically detects the composition of electron-dense deposits. A C3 glomerulopathy (C3G) is a recently described entity, a proliferative glomerulonephritis (usually but not always), with a MPGN pattern on light microscopy, with C3 staining alone on inmunoflouresencie, implicating hyperactivity of the alternative complement pathway. The evaluation of C3G should focus on the complement cascade, as dysregulation of the alternative pathway and terminal complement cascade underlies pathogenesis. Although there are no specific treatments currently available for C3G, a better understanding of their pathogenesis would set the stage for the possible use of anti-complement drugs, as eculizumab. In this review, we summarise the pathogenesis of the C3 glomerulopathies, focusing on the role of complement, the patient cohorts recently reported and options of treatment up to the current moment (AU)

C3 glomerulopathies. A new perspective on glomerular diseases.

Membranoproliferative glomerulonephritis denotes a general pattern of glomerular injury that is easily recognised by light microscopy. With additional studies, MPGN subgrouping is possible. For example, electron microscopy resolves differences in electron-dense deposition location, while immunofluorescence typically detects the composition of electron-dense deposits. A C3 glomerulopathy (C3G) is a recently described entity, a proliferative glomerulonephritis (usually but not always), with a MPGN pattern on light microscopy, with C3 staining alone on immunofluorescence, implicating hyperactivity of the alternative complement pathway. The evaluation of C3G in a patient should focus on the complement cascade, as deregulation of the alternative pathway and terminal complement cascade underlies pathogenesis. Although there are no specific treatments currently available for C3G, a better understanding of their pathogenesis would set the stage for the possible use of anti-complement drugs, as eculizumab. In this review, we summarise the pathogenesis of the C3 glomerulopathies, focusing on the role of complement, the patient cohorts recently reported and options of treatment up to the current moment.