Development and validation of a prognostic nomogram for the renal relapse of lupus nephritis / Desarrollo y validación de un nomograma pronóstico para la recaída renal de la nefritis lúpica

Objectives This study aims to assess the risk of relapse after complete remission (CR) and partial remission (PR), and to develop a prognostic nomogram predicting the probability in lupus nephritis (LN) patients. Methods Data from patients with LN who had been in remission were collected as a training cohort. The prognostic factors were analyzed using the univariable and multivariable Cox model for the training group. A nomogram was then developed using significant predictors in multivariable analysis. Both discrimination and calibration were assessed by bootstrapping with 100 resamples. Results A total of 247 participants were enrolled, including 108 in the relapse group and 139 in the no relapse group. In multivariate Cox analysis, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), erythrocyte sedimentation rate (ESR), complement 1q (C1q), and antiphospholipid (aPL), anti-Sm antibody were found to be significant for predicting relapse rates. The prognostic nomogram including the aforementioned factors effectively predicted 1- and 3-year probability of flare-free. Moreover, a favorable consistency between the predicted and actual survival probabilities was demonstrated using calibration curves. Conclusions High SLEDAI, ESR, and positive aPL, anti-Sm antibody are potential risk factors for LN flare, while high C1q can reduce its recurrence. The visualized model we established can help predict the relapse risk of LN and aid clinical decision-making for individual patients (AU)

Objetivos Este estudio pretende evaluar el riesgo de recaída tras la remisión completa y la remisión parcial, y desarrollar un nomograma pronóstico que prediga la probabilidad en pacientes con nefritis lúpica (NL). Métodos Se recogieron datos de pacientes con NL que habían estado en remisión como cohorte de entrenamiento. Se analizaron los factores pronósticos utilizando el modelo COX univariable y multivariable para el grupo de entrenamiento. A continuación se desarrolló un nomograma utilizando los predictores significativos en el análisis multivariable. Tanto la discriminación como la calibración se evaluaron mediante bootstrapping con 100 remuestreos. Resultados Se inscribió a un total de 247 participantes, incluidos 108 en el grupo de recaída y 139 en el grupo sin recaída. En el análisis multivariante de Cox, el índice de actividad de la enfermedad lúpica eritematosa sistémica (SLEDAI), la velocidad de sedimentación globular (VSG), el complemento 1q (C1q) y los anticuerpos antifosfolípidos (aPL) y anti-Sm resultaron significativos para predecir las tasas de recaída. El nomograma pronóstico que incluía los factores mencionados predijo eficazmente la probabilidad a 1 y a 3 años de estar libre de reagudizaciones. Además, se demostró una coherencia favorable entre las probabilidades de supervivencia previstas y las reales mediante curvas de calibración. Conclusiones SLEDAI alto, VSG y aPL positivo, anticuerpos anti-Sm son factores de riesgo potenciales de reagudización de la NL, mientras que C1q alto puede reducir su recurrencia. El modelo visualizado que establecimos puede ayudar a predecir el riesgo de recidiva de la NL y ayudar a la toma de decisiones clínicas para pacientes individuales (AU)

Development and validation of a prognostic nomogram for the renal relapse of lupus nephritis.

OBJECTIVES: This study aims to assess the risk of relapse after complete remission (CR) and partial remission (PR), and to develop a prognostic nomogram predicting the probability in lupus nephritis (LN) patients. METHODS: Data from patients with LN who had been in remission were collected as a training cohort. The prognostic factors were analyzed using the univariable and multivariable Cox model for the training group. A nomogram was then developed using significant predictors in multivariable analysis. Both discrimination and calibration were assessed by bootstrapping with 100 resamples. RESULTS: A total of 247 participants were enrolled, including 108 in the relapse group and 139 in the no relapse group. In multivariate Cox analysis, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), erythrocyte sedimentation rate (ESR), complement 1q (C1q), and antiphospholipid (aPL), anti-Sm antibody were found to be significant for predicting relapse rates. The prognostic nomogram including the aforementioned factors effectively predicted 1- and 3-year probability of flare-free. Moreover, a favorable consistency between the predicted and actual survival probabilities was demonstrated using calibration curves. CONCLUSIONS: High SLEDAI, ESR, and positive aPL, anti-Sm antibody are potential risk factors for LN flare, while high C1q can reduce its recurrence. The visualized model we established can help predict the relapse risk of LN and aid clinical decision-making for individual patients.

Loss of Sirt1 promotes exosome secretion from podocytes by inhibiting lysosomal acidification in diabetic nephropathy.

Podocyte injury is a characteristic feature of diabetic nephropathy (DN). The secretion of exosomes in podocytes increases significantly in DN; however, the precise mechanisms remain poorly understood. Here, we demonstrated that Sirtuin1 (Sirt1) was significantly downregulated in podocytes in DN, which correlated negatively with increased exosome secretion. Similar results were observed in vitro. We found that lysosomal acidification in podocytes following high glucose administration was markedly inhibited, resulting in the decreased lysosomal degradation of multivesicular bodies. Mechanistically, we indicated that loss of Sirt1 contributed to the inhibited lysosomal acidification by decreasing the expression of the A subunit of the lysosomal vacuolar-type H+ ATPase proton pump (ATP6V1A) in podocytes. Overexpression of Sirt1 significantly improved lysosomal acidification with increased expression of ATP6V1A and inhibited exosome secretion. These findings suggest that dysfunctional Sirt1-mediated lysosomal acidification is the exact mechanism of increased secretion of exosomes in podocytes in DN, providing insights into potential therapeutic strategies for preventing DN progression.

Long noncoding RNA SNHG5 promotes podocyte injury via the microRNA-26a-5p/TRPC6 pathway in diabetic nephropathy.

Podocyte injury is a characteristic pathological hallmark of diabetic nephropathy (DN). However, the exact mechanism of podocyte injury in DN is incompletely understood. This study was conducted using db/db mice and immortalized mouse podocytes. High-throughput sequencing was used to identify the differentially expressed long noncoding RNAs in kidney of db/db mice. The lentiviral shRNA directed against long noncoding RNA small nucleolar RNA host gene 5 (SNHG5) or microRNA-26a-5p (miR-26a-5p) agomir was used to treat db/db mice to regulate the SNHG5/miR-26a-5p pathway. Here, we found that the expression of transient receptor potential canonical type 6 (TRPC6) was significantly increased in injured podocytes under the condition of DN, which was associated with markedly decreased miR-26a-5p. We determined that miR-26a-5p overexpression ameliorated podocyte injury in DN via binding to 3'-UTR of Trpc6, as evidenced by the markedly reduced activity of luciferase reporters by miR-26a-5p mimic. Then, the upregulated SNHG5 in podocytes and kidney in DN was identified, and it was proved to sponge to miR-26a-5p directly using luciferase activity, RNA immunoprecipitation, and RNA pull-down assay. Knockdown of SNHG5 attenuated podocyte injury in vitro, accompanied by an increased expression of miR-26a-5p and decreased expression of TRPC6, demonstrating that SNHG5 promoted podocyte injury by controlling the miR-26a-5p/TRPC6 pathway. Moreover, knockdown of SNHG5 protects against podocyte injury and progression of DN in vivo. In conclusion, SNHG5 promotes podocyte injury via the miR-26a-5p/TRPC6 pathway in DN. Our findings provide novel insights into the pathophysiology of podocyte injury and a potential new therapeutic strategy for DN.