Qidong Ren

Purpose: To evaluate significant risk variables for sepsis incidence and develop a predictive model for rapid screening and diagnosis of sepsis in patients from the emergency department (ED). Methods: Sepsis-related risk variables were screened based on the PIRO (Predisposition, Insult, Response, Organ dysfunction) system. Training (n = 1,272) and external validation (n = 568) datasets were collected from Peking Union Medical College Hospital (PUMCH) and Beijing Tsinghua Changgung Hospital (BTCH), respectively. Variables were collected at the time of admission. Sepsis incidences were determined within 72 h after ED admissions. A predictive model, Early Assessment of Sepsis Engagement (EASE), was developed, and an EASE-based nomogram was generated for clinical applications. The predictive ability of EASE was evaluated and compared with the National Early Warning Score (NEWS) scoring system. In addition, internal and external validations were performed. Results: A total of 48 characteristics were identified. The EASE model, which consists of alcohol consumption, lung infection, temperature, respiration rate, heart rate, serum urea nitrogen, and white blood cell count, had an excellent predictive performance. The EASE-based nomogram showed a significantly higher area under curve (AUC) value of 86.5% (95% CI, 84.2%–88.8%) compared with the AUC value of 78.2% for the NEWS scoring system. The AUC of EASE in the external validation dataset was 72.2% (95% CI, 66.6%–77.7%). Both calibration curves of EASE in training and external validation datasets were close to the ideal model and were well-calibrated. Conclusions: The EASE model can predict and screen ED-admitted patients with sepsis. It demonstrated superior diagnostic performance and clinical application promise by external validation and in-parallel comparison with the NEWS scoring system.

Dear Editor,The efficacy of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) in correcting renal anemia, including in special populations, has been demonstrated in several randomiz...

Renal involvement has been implicated in coronavirus disease 2019 (COVID-19), but the related prevalence and prognosis were largely unknown. In this meta-analysis, we searched the literature from PubMed, Embase, through bioRxiv, and medRxiv until April 26, 2020. Studies reporting chronic kidney diseases (CKDs) and/or acute kidney injury (AKI) were included. Demographics, relevant data of disease severity, and patient's prognosis were extracted and aggregated. Twenty-one thousand one hundred sixty-four patients from 52 peer-reviewed studies were included. Thirty-seven studies (n = 16,922) reported CKD in COVID-19 patients at diagnosis, and the pooled prevalence was 3.52% (95% CI, 1.98–5.48%; I² = 93%). Subgroup analysis showed that CKD prevalence was higher in severe cases [odds ratio (OR), 3.42; 95% CI 2.05–5.61; I² = 0%] compared to those with non-severe disease and deceased cases (6.46, 3.40–12.29; I² = 1%) compared with survivors. Pooled prevalence of CKD was lower in Chinese patients (2.56%; 95% CI, 1.79–3.47%; I² = 80%) compared to those outside of China (6.32%; 95% CI, 0.9–16.12%; I² = 93%) (p = 0.08). The summary estimates for AKI prevalence was 11.46% (95% CI, 6.93–16.94%). Patients with AKI had a higher prevalence of developing into severe cases (OR, 6.97; 95% CI, 3.53–13.75; I² = 0%) and mortality risk (45.79, 36.88–56.85; I² = 17%). The prevalence estimates of CKD or AKI were not significantly different from preprint publications (p > 0.05). Our study indicates that renal condition, either in CKD or AKI, is associated with COVID-19 prognosis, and taking care of such patients needs further awareness and investigations.

Cultured cell models are an essential complement to dissecting kidney proximal tubule (PT) function in health and disease but do not fully recapitulate key features of this nephron segment. We recently determined that culture of opossum kidney (OK) cells under continuous orbital shear stress (OSS) significantly augments their morphological and functional resemblance to PTs in vivo. Here we used RNASeq to identify temporal transcriptional changes upon cell culture under static or shear stress conditions. Comparison of gene expression in cells cultured under static or OSS conditions with a database of rat nephron segment gene expression confirms that OK cells cultured under OSS are more similar to the PT in vivo compared with cells maintained under static conditions. Both improved oxygenation and mechanosensitive stimuli contribute to the enhanced differentiation in these cells, and we identified temporal changes in gene expression of known mechanosensitive targets. We observed changes in mRNA and protein levels of membrane trafficking components that may contribute to the enhanced endocytic capacity of cells cultured under OSS. Our data reveal pathways that may be critical for PT differentiation in vivo and validate the utility of this improved cell culture model as a tool to study PT function.

Proximal tubule (PT) cells express a single saturable albumin-binding site whose affinity matches the estimated tubular concentration of albumin; however, albumin uptake capacity is greatly increased under nephrotic conditions. Deciphering the individual contributions of megalin and cubilin to the uptake of normal and nephrotic levels of albumin is impossible in vivo, as knockout of megalin in mice globally disrupts PT endocytic uptake. We quantified concentration-dependent albumin uptake in an optimized opossum kidney cell culture model and fit the kinetic profiles to identify albumin-binding affinities and uptake capacities. Mathematical deconvolution fit best to a three-component model that included saturable high- and low-affinity uptake sites for albumin and underlying nonsaturable uptake consistent with passive uptake of albumin in the fluid phase. Knockdown of cubilin or its chaperone amnionless selectively reduced the binding capacity of the high-affinity site, whereas knockdown of megalin impacted the low-affinity site. Knockdown of disabled-2 decreased the capacities of both binding sites. Additionally, knockdown of megalin or disabled-2 profoundly inhibited the uptake of a fluid phase marker, with cubilin knockdown having a more modest effect. We propose a novel model for albumin retrieval along the PT in which cubilin and megalin receptors have different functions in recovering filtered albumin in proximal tubule cells. Cubilin binding to albumin is tuned to capture normally filtered levels of the protein. In contrast, megalin binding to albumin is of lower affinity, and its expression is also essential for enabling the recovery of high concentrations of albumin in the fluid phase.

Albuminuria is frequently associated with proximal tubule (PT) cytotoxicity that can feed back to cause glomerular damage and exacerbate kidney disease. PT cells express megalin and cubilin receptors that bind to and internalize albumin over a broad concentration range. How the exposure to high concentrations of albumin leads to PT cytotoxicity remains unclear. Fatty acids and other ligands bound to albumin are known to trigger production of reactive oxygen species (ROS) that impair PT function. Alternatively or in addition, uptake of high concentrations of albumin may overload the endocytic pathway and elicit downstream responses. Here, we used a well-differentiated PT cell culture model with high endocytic capacity to dissect the effects of albumin versus its ligands on endocytic uptake and degradation of albumin, production of ROS, and cell viability. Cellular responses differed dramatically, depending on the preparation of albumin tested. Knockdown of megalin or cubilin failed to prevent ROS production mediated by albumin ligands, suggesting that receptor-mediated internalization of albumin was not necessary to trigger cellular responses to albumin ligands. Moreover, albumin induced cytotoxic responses when added to the basolateral surface of PT cells. Whereas overnight incubation with high concentrations of fatty acid-free albumin had no overt effects on cell function or viability, lysosomal degradation kinetics were slowed upon longer exposure, consistent with overload of the PT endocytic/degradative pathway. Together, the results of our study demonstrate that the PT responds independently to albumin and to its ligands and suggest that the consequences of albumin overload in vivo may be dependent on metabolic state.

Kidney proximal tubule (PT) cells have high‐metabolic demands to drive the extraordinary ion and solute transport, water reabsorption, and endocytic uptake that occur in this nephron segment. Increases in renal blood flow alter glomerular filtration rate and lead to rapid mechanosensitive adaptations in PT transport, impacting metabolic demand. Although the PT reabsorbs essentially all of the filtered glucose, PT cells rely primarily on oxidative metabolism rather than glycolysis to meet their energy demands. We lack an understanding of how PT functions are impacted by changes in O₂ availability via cortical capillaries and mechanosensitive signaling in response to alterations in luminal flow. Previously, we found that opossum kidney (OK) cells recapitulate key features of PT cells in vivo, including enhanced endocytic uptake and ion transport, when exposed to mechanical stimulation by culture on an orbital shaker. We hypothesized that increased oxygenation resulting from orbital shaking also contributes to this more physiologic phenotype. RNA seq of OK cells maintained under static conditions or exposed to orbital shaking for up to 96 hours showed significant time‐ and culture‐dependent changes in gene expression. Transcriptional and metabolomics data were consistent with a decrease in glycolytic flux and with an increased utilization of aerobic metabolic pathways in cells exposed to orbital shaking. Moreover, we found spatial differences in the pattern of mitogenesis vs development of ion transport and endocytic capacities in our culture system that highlight the complexity of O₂‐dependent and mechanosensitive crosstalk to regulate PT cell function.