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Blockade of C5a signalling by NOX-D21 moderates altered lipid metabolism in diabetes and improved tubulointerstitial fibrosis by reduction of lipid accumulation and TGF-β-driven fibrosis in diabetic kidney.

Imbalance of Wnt/β-catenin signaling in renal cells is associated with renal dysfunction, yet the precise mechanism is poorly understood. Previously we observed activated Wnt/β-catenin signaling in renal tubules during proteinuric nephropathy with an unknown net effect. Therefore, to identify the definitive role of tubular Wnt/β-catenin, we generated a novel transgenic "Tubcat" mouse conditionally expressing stabilized β-catenin specifically in renal tubules following tamoxifen administration. Four weeks after tamoxifen injection, uninephrectomized Tubcat mice displayed proteinuria and elevated blood urea nitrogen levels compared to non-transgenic mice, implying a detrimental effect of the activated signaling. This was associated with infiltration of the tubulointerstitium predominantly by M1 macrophages and overexpression of the inflammatory chemocytokines CCL-2 and RANTES. Induction of overload proteinuria by intraperitoneal injection of low-endotoxin bovine serum albumin following uninephrectomy for four weeks aggravated proteinuria and increased blood urea nitrogen levels to a significantly greater extent in Tubcat mice. Renal dysfunction correlated with the degree of M1 macrophage infiltration in the tubulointerstitium and renal cortical up-regulation of CCL-2, IL-17A, IL-1β, CXCL1, and ICAM-1. There was overexpression of cortical TLR-4 and NLRP-3 in Tubcat mice, independent of bovine serum albumin injection. Finally, there was no fibrosis, activation of epithelial-mesenchymal transition or non-canonical Wnt pathways observed in the kidneys of Tubcat mice. Thus, conditional activation of renal tubular Wnt/β-catenin signaling in a novel transgenic mouse model demonstrates that this pathway enhances intrarenal inflammation via the TLR-4/NLRP-3 inflammasome axis in overload proteinuria.

<b><i>Introduction:</i></b> Renal involvement in COVID-19 is less well characterized in settings with vigilant public health surveillance, including mass screening and early hospitalization. We assessed kidney complications among COVID-19 patients in Hong Kong, including the association with risk factors, length of hospitalization, critical presentation, and mortality. <b><i>Methods:</i></b> Linked electronic records of all patients with confirmed COVID-19 from 5 major designated hospitals were extracted. Duplicated records due to interhospital transferal were removed. Primary outcome was the incidence of in-hospital acute kidney injury (AKI). Secondary outcomes were AKI-associated mortality, incident renal replacement therapy (RRT), intensive care admission, prolonged hospitalization and disease course (defined as &#x3e;90th percentile of hospitalization duration [35 days] and duration from symptom onset to discharge [43 days], respectively), and change of estimated glomerular filtration rate (GFR). Patients were further stratified into being symptomatic or asymptomatic. <b><i>Results:</i></b> Patients were characterized by young age (median: 38.4, IQR: 28.4–55.8 years) and short time (median: 5, IQR: 2–9 days) from symptom onset to admission. Among the 591 patients, 22 (3.72%) developed AKI and 4 (0.68%) required RRT. The median time from symptom onset to in-hospital AKI was 15 days. AKI increased the odds of prolonged hospitalization and disease course by 2.0- and 3.5-folds, respectively. Estimated GFR 24 weeks post-discharge reduced by 7.51 and 1.06 mL/min/1.73 m² versus baseline (upon admission) in the AKI and non-AKI groups, respectively. The incidence of AKI was comparable between asymptomatic (4.8%, <i>n</i> = 3/62) and symptomatic (3.7%, <i>n</i> = 19/519) patients. <b><i>Conclusion:</i></b> The overall rate of AKI among COVID-19 patients in Hong Kong is low, which could be attributable to a vigilant screening program and early hospitalization. Among patients who developed in-hospital AKI, the duration of hospitalization is prolonged and kidney function impairment can persist for up to 6 months post-discharge. Mass surveillance for COVID-19 is warranted in identifying asymptomatic subjects for earlier AKI management.

BackgroundSystematic data on the efficacy and safety of COVID-19 vaccine in patients on renal replacement therapy (RRT) remains limited. We conducted a meta-analysis on the efficacy and safety of COVID-19 vaccine in patients on RRT.MethodsEligible studies were identified by systematic literature search in four electronic databases. Twenty-seven studies (4,264 patients) were included for meta-analysis. 99% patients received mRNA vaccine.ResultsPatients on RRT showed inferior seropositivity after two-dosed COVID-19 vaccine, 44% lower than the general population. Kidney transplant recipients (KTRs) had significantly lower seropositivity than patients on haemodialysis (HD) or peritoneal dialysis (PD) (26.1 vs. 84.3% and 92.4% respectively, p &lt; 0.001 for both). Compared with healthy controls, KTRs, HD and PD patients were 80% (95% CI: 62–99%), 18% (95% CI: 9–27%) and 11% (95% CI: 1–21%) less likely to develop antibodies after vaccination (p &lt; 0.001, &lt;0.001 and 0.39 respectively). In KTRs, every 1% increase in using mycophenolate was associated with 0.92% reduction in seropositivity (95% CI: −1.68, −0.17, p = 0.021) at population level. The overall adverse event rate attributed to vaccination was 2.1%. Most events were mild.ConclusionPatients on RRT, particularly KTRs, had significantly reduced antibody response after two-dosed COVID-19 vaccination. Vaccination is generally well tolerated.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42021261879.

Recent advances in the understanding of lipid metabolism suggest a critical role of endoplasmic reticulum (ER) stress in obesity‐induced kidney injury. Hepatocyte growth factor (HGF) is a pleiotropic cytokine frequently featured in stem cell therapy with distinct renotropic benefits. This study aims to define the potential link between human induced pluripotent stem cell‐derived mesenchymal stem cells (iPS‐MSCs)/bone marrow‐derived MSCs (BM‐MSCs) and ER stress in lipotoxic kidney injury induced by palmitic acid (PA) in renal tubular cells and by high‐fat diet (HFD) in mice. iPS‐MSCs or BM‐MSCs alleviated ER stress (by preventing induction of Bip , chop , and unfolded protein response), inflammation ( Il6 , Cxcl1 , and Cxcl2 ), and apoptosis ( Bax/Bcl2 and terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end labeling‐positive cells) in renal cortex of animals exposed to HFD thus mitigating histologic damage and albuminuria, via activating HGF/c‐Met paracrine signaling that resulted in enhanced HGF secretion in the glomerular compartment and c‐Met expression in the tubules. Coculture experiments identified glomerular endothelial cells (GECs) to be the exclusive source of glomerular HGF when incubated with either iPS‐MSCs or BM‐MSCs in the presence of PA. Furthermore, both GEC‐derived HGF and exogenous recombinant HGF attenuated PA‐induced ER stress in cultured tubular cells, and this effect was abrogated by a neutralizing anti‐HGF antibody. Taken together, this study is the first to demonstrate that MSCs ameliorate lipotoxic kidney injury via a novel microenvironment‐dependent paracrine HGF/c‐Met signaling mechanism to suppress ER stress and its downstream pro‐inflammatory and pro‐apoptotic consequences. stem cells translational medicine 2019;8:898&910

The presence of three root canals in the mandibular premolar may sometimes be recognized when there is persistent postoperative discomfort following root canal therapy. This paper presents two cases of root canal treatment of mandibular premolars with three root canals including one mandibular first premolar and one mandibular second premolar. The possibility that there is more than one root canal in lower premolar teeth must be considered in the radiographic and clinical examination during root canal treatment.

Background: Difference of perspective between patients and physicians over integrative medicine (IM) research and service provision remains unclear despite significant use worldwide. We observed an exceptionally low utilisation of IM and potential underreporting in diabetes. We aimed to explore the barriers and recommendations regarding service delivery and research of IM service among diabetes patients and physicians. Methods: A 10-group, 50-participant semi-structured focus group interview series was conducted. Twenty-one patients with diverse severity of disease, comorbidities and education levels; and 29 physicians (14 conventional medicine (ConM) and 15 Chinese medicine (CM)) with diverse clinical experience, academic background and affiliation were purposively sampled from private and public clinics. Their perspectives were qualitatively analysed by constant comparative method. Results: Seven subthemes regarding barriers towards IM service were identified including finance, service access, advice from medical professionals, uncertainty of service quality, uncertainty of CM effect, difficulty in understanding CM epistemology and access to medical records. Patients underreported the use of CM due to the concern over neutrality of medical advice among physicians. Inconvenience of service access, frequent follow-up, use of decoction and long-term financial burden were identified as key obstacles among patients. Regarding research design, ConM physicians emphasised standardisation and reproducibility while CM physicians emphasised personalisation. Some CM-related outcome measurements were suggested as non-communicable. Both physicians acknowledged the discordance in epistemology should be addressed by pragmatic approach. Conclusion: Key obstacles of CAM clinical utilisation are different between patients. Further assessment on IM should be pragmatic to balance between standardisation, reproducibility and real-world practice. Evidence-based IM programs and research should merge with existing infrastructure.