Kidney360最新文献

Background: Chronic kidney disease (CKD) is a common complication after acute kidney injury (AKI). We aimed to evaluate whether RRT initiation strategy had an effect on CKD progression. Secondarily, we aimed to identify factors that influenced the development or progression of CKD following severe AKI.

Methods: This secondary analysis of the STARRT-AKI trial included participants with outpatient serum creatinine values available in the year prior to hospitalization and who were alive at 90 days following randomization. Our main analysis focused on patients who had definitive assessment of kidney function at 90 days following randomization. Predictor markers included patient demographics, co-morbidities, markers of acute illness, laboratory values, receipt of renal replacement therapy (RRT), and RRT treatment strategy (accelerated versus standard). The primary outcome was CKD progression, a composite of de novo CKD, defined as new eGFR < 60 ml/min/1.73 m2 if baseline eGFR was ≥ 60 ml/min; a decline in eGFR ≥ 25% if baseline eGFR was < 60 ml/min, or RRT dependence at day 90. The association of RRT treatment strategy with CKD progression was assessed in an unadjusted mixed-effect logistic regression model.

Results: Of the 401 surviving patients with a baseline serum creatinine, 39% experienced CKD progression. RRT initiation strategy had no effect on CKD progression (accelerated arm (41%), vs. the standard arm (38%), Odds ratio 1.13, (95% confidence interval 0.75 to 1.72)). Receipt of RRT and aortic surgery were the most potent risks of CKD progression.

Conclusion: These findings suggest that CKD progression is common after severe AKI. Risk factors for CKD progression included receipt of RRT and aortic surgery, suggested that these individuals should be prioritized for dedicated kidney follow up after hospital discharge.

Background: The p.Arg218Gln (R218Q) mutation in the inverted formin 2 (INF2) gene causes podocytopathy prone to focal segmental glomerulosclerosis (FSGS). This mutation disrupts the ability of INF2 to sequester DYNLL1, thus promoting dynein-mediated mistrafficking of the slit diaphragm protein, nephrin, to proteolytic pathways. Bortezomib, a proteasome inhibitor (PI), stabilizes nephrin in R218Q knockin (KI) podocytes, suggesting a role for the ubiquitin proteasome system (UPS) in dynein-driven pathogenesis. However, the link between dynein and the UPS is unknown. This study tested the hypothesis that INF2 R218Q promotes proteasome-mediated degradation of nephrin via an increased interaction between Dynll1 and Proteasomal Inhibitor of 31kD (PI31), a Dynll1 adaptor that potentially couples the UPS with dynein cargoes.

Methods: The essential role of PI31 in UPS-mediated degradation of nephrin, a known dynein cargo, was studied in cultured R218Q KI mouse podocytes by applying genetic or chemical interventions to inhibit the activity of PI31 or of the proteasome. The protective effect of bortezomib in dynein-driven podocytopathy and FSGS was tested in R218Q KI mice challenged with puromycin aminonucleoside (PA), a murine model of FSGS.

Results: The R218Q mutation in Inf2 disrupted sequestration of Dynll1 by Inf2, allowing Dynll1 to be captured by PI31 and promoting dynein-mediated transport of nephrin to the proteasome. Each of the following manipulations was sufficient to restore nephrin proteostasis in R218Q KI podocytes: knocking down Dynll1 or PI31, inactivating dynein, or inhibiting the activity of the proteasome. In R218Q KI mice challenged with PA, dynein-mediated mistrafficking and depletion of nephrin were correlated with increased Dynll1-PI31 interaction; the resulting podocytopathy and FSGS were ameliorated by bortezomib.

Conclusions: The Dynll1-PI31 interaction facilitates dynein-driven trafficking of nephrin to the proteasome and proteasome-mediated degradation of nephrin in INF2-R218Q-mediated podocytopathy. This mechanism offers new therapeutic strategies for INF2-related FSGS by using pharmacologically available proteasome inhibitors.

Systemic amyloidoses are a group of disorders that can be hereditary or acquired and have various renal manifestations and outcomes. Light chain amyloid has been considered the most common renal amyloid and, thus, has been the focus of substantial research and therapeutic interest but with improvement in diagnostic techniques. However, there has been growing interest in rarer forms of renal amyloid, including amyloid serum A protein, leukocyte chemotactic factor 2 amyloid, and transthyretin amyloid. In this review, we provide an update on diagnostics, renal outcomes, and therapeutic landscape in these specific types of amyloid.