Cardiovascular, Kidney Failure, and All-Cause Mortality Events in Patients with Focal Segmental Glomerulosclerosis in a U.S. Real-World Database.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) leads to proteinuria and progressive decline in glomerular filtration rate which correlates with kidney failure and increased cardiovascular risk. The purpose of this study was to estimate the effects of proteinuria on kidney failure status/all-cause mortality and cardiovascular disease events/all-cause mortality, as well as the relationship between progression to kidney failure and occurrence of cardiovascular disease/mortality events among adult patients (≥18 years old) with FSGS. METHODS: This was an observational, retrospective cohort study utilizing Optum® de-identified Market Clarity Data and proprietary Natural Language Processing (NLP) data. The study period was from January 1, 2007 through March 31, 2021, with patients in the overall cohort being identified from July 1, 2007 through March 31, 2021. The index date was the first FSGS ICD-10 diagnosis code or FSGS-related NLP term within the identification period. RESULTS: Elevated proteinuria >1.5 g/g and ≥3.5 g/g increased risk for kidney failure/all-cause mortality (adjusted hazard ratio [95% CI]: 2.34 [1.99-2.74] and 2.44 [2.09-2.84], respectively) and cardiovascular disease/all-cause mortality (adjusted hazard ratio [95% CI]: 2.11 [1.38-3.22] and 2.27 [1.44-3.58], respectively). Progression to kidney failure was also associated with a higher risk of cardiovascular disease/all-cause mortality (adjusted hazard ratio [95% CI]: 3.04 [2.66-3.48]. CONCLUSIONS: A significant proportion of FSGS patients experience kidney failure and cardiovascular disease events. Elevated proteinuria and progression to kidney failure were associated with a higher risk of cardiovascular disease/all-cause mortality events, and, elevated pre-kidney failure proteinuria was associated with progression to kidney failure/all-cause mortality events. Treatments that meaningfully reduce proteinuria and slow the decline in glomerular filtration rate have the potential to reduce the risk of cardiovascular disease, kidney failure and early mortality in patients with FSGS.

NADPH and NAC synergistically inhibits chronic ocular hypertension-induced neurodegeneration and neuroinflammation through regulating p38/MAPK pathway and peroxidation.

Glaucoma, the leading cause of irreversible blindness worldwide, is characterized by neurodegeneration and neuroinflammation with retinal NAD/NADP and GSH decline. Nicotinamide adenine dinucleotide (NAD)/NAD phosphate (NADP) and glutathione (GSH) are two redox reducers in neuronal and glial metabolism. However, therapeutic strategies targeting NAD/NADP or GSH do not exert ideal effects, and the underlying mechanisms are still poorly understood. We assessed morphological changes in retinal ganglion cells (RGCs), the affected neurons in glaucoma, and Müller cells, the major glial cells in the retina, as well as the levels of phosphorylated p38 (p-p38) and Caspase-3 in glaucoma patients. We constructed a modified chronic ocular hypertensive rat model and an oxygen-glucose deprivation (OGD) cell model. After applying NADPH and N-acetylcysteine (NAC), a precursor to cysteine, the rate-limiting substrate in GSH biosynthesis, to cells, apoptosis, axonal damage and peroxidation were reduced in the RGCs of the NAC group and p-p38 levels were decreased in the RGCs of the NADPH group, while in stimulated Müller cells cultured individually or cocultured with RGCs, gliosis and p38/MAPK, rather than JNK/MAPK, activation were inhibited. The results were more synergistic in the rat model, where either NADPH or NAC showed crossover effects on inhibiting peroxidation and p38/MAPK pathway activation. Moreover, the combination of NADPH and NAC ameliorated RGC electrophysiological function and prevented Müller cell gliosis to the greatest extent. These data illustrated conjoined mechanisms in glaucomatous RGC injury and Müller cell gliosis and suggested that NADPH and NAC collaborate as a neuroprotective and anti-inflammatory combination treatment for glaucoma and other underlying human neurodegenerative diseases.

PTEN: an emerging target in rheumatoid arthritis?

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a critical tumor suppressor protein that regulates various biological processes such as cell proliferation, apoptosis, and inflammatory responses by controlling the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PI3K/AKT) signaling pathway. PTEN plays a crucial role in the pathogenesis of rheumatoid arthritis (RA). Loss of PTEN may contribute to survival, proliferation, and pro-inflammatory cytokine release of fibroblast-like synoviocytes (FLS). Also, persistent PI3K signaling increases myeloid cells' osteoclastic potential, enhancing localized bone destruction. Recent studies have shown that the expression of PTEN protein in the synovial lining of RA patients with aggressive FLS is minimal. Experimental upregulation of PTEN protein expression could reduce the damage caused by RA. Nonetheless, a complete comprehension of aberrant PTEN drives RA progression and its interactions with other crucial molecules remains elusive. This review is dedicated to promoting a thorough understanding of the signaling mechanisms of aberrant PTEN in RA and aims to furnish pertinent theoretical support for forthcoming endeavors in both basic and clinical research within this domain.

Insight into the status of plasma renin and aldosterone measurement: findings from 526 clinical laboratories in China.

OBJECTIVES: Accurate measurements of renin and aldosterone levels play an important role in primary aldosteronism screening, which is of great importance in the management and categorization of hypertension. The objective of this study is to investigate the current status of plasma renin and aldosterone measurements in China, which is achieved by analyzing the results of 526 clinical laboratories nationwide for three pooled fresh plasma samples derived from more than 2,000 patients. METHODS: Renin and aldosterone in three pooled plasma samples were measured four times in 526 laboratories employing various measurement systems. The inter- and intra-laboratory %CV were calculated and compared. To determine the source of the substantial inter-laboratory %CV, laboratories were categorized according to the measurement systems they are using, and both the inter- and intra-measurement-system %CV were calculated and compared. RESULTS: Regarding renin, the majority of laboratories use four primary commercial immunoassays. However, for aldosterone, in addition to commercial immunoassays, laboratory-developed liquid chromatography-tandem mass spectrometry (LC-MS) methods are also used by laboratories. The median values of intra-laboratory %CVs, intra-measurement-system %CVs, inter-laboratory %CVs, and inter-measurement systems %CVs varied between 1.6 and 2.6 %, 4.6 and 14.9 %, 8.3 and 25.7 %, and 10.0 and 34.4 % for renin, respectively. For aldosterone, these values ranged from 1.4 to 2.2 %, 2.5-14.7 %, 9.9-31.0 %, and 10.0-35.5 %, respectively. CONCLUSIONS: The precision within laboratories and measurement systems for plasma renin and aldosterone measurements is satisfactory. However, the comparability between laboratories using different measurement systems remains lacking, indicating the long way to achieve standardization and harmonization for these two analytes.

Inhibition of inflammation by berberine: Molecular mechanism and network pharmacology analysis.

BACKGROUND: Traditional Chinese Medicine (TCM), renowned for its holistic approach with a 2000-year history of utilizing natural remedies, offers unique advantages in disease prevention and treatment. Berberine, found in various Chinese herbs, has been employed for many years, primarily for addressing conditions such as diarrhea and dysentery. Berberine has recently become a research focus owing to its pharmacological activities and benefits to human bodies. However, little is known about the anti-inflammatory mechanism of berberine. PURPOSE: To summarize recent findings regarding the pharmacological effects and mechanisms of berberine anti-inflammation and highlight and predict the potential therapeutic effects and systematic mechanism of berberine. METHODS: Recent studies (2013-2023) on the pharmacological effects and mechanisms of berberine anti-inflammation were retrieved from Web of Science, PubMed, Google Scholar, and Scopus up to July 2023 using relevant keywords. Network pharmacology and bioinformatics analysis were employed to predict the therapeutic effects and mechanisms of berberine against potential diseases. RESULTS: The related pharmacological mechanisms of berberine anti-inflammation include the inhibition of inflammatory cytokine production (e.g., IL-1ß, IL-6, TNF-α), thereby attenuating the inflammatory response; Inhibiting the activation of NF-κB signaling pathway and IκBα degradation; Inhibiting the activation of MAPK signaling pathway; Enhancing the activation of the STAT1 signaling pathway; Berberine interacts directly with cell membranes through a variety of pathways, thereby influencing cellular physiological activities. Berberine enhances human immunity and modulates immune system function, which is integral to addressing certain autoimmune and tumour-related health concerns. CONCLUSION: This study expounds on the correlation between berberine and inflammatory diseases, encapsulating the mechanisms through which berberine treats select typical inflammatory ailments. Furthermore, it delves into a deeper understanding of berberine's effectiveness by integrating network pharmacology and molecular docking techniques in the context of treating inflammatory diseases. It provides guidance and reference for berberine's subsequent revelation of the modern scientific connotation of Chinese medicine.

Continuous flow aerobic granular sludge: recent developments and applications.

Aerobic granular sludge (AGS) in continuous-flow reactors (CFRs) has attracted significant interest, with notable progress in research and application over the past two decades. Cumulative studies have shown that AGS-CFRs exhibit comparable morphology, settleability, and pollutant removal efficiency to AGS cultivated in sequencing batch reactors, despite their smaller particle sizes. Shear force and selection pressure are the primary drivers of granulation. While not mandatory for granulation, feast/famine conditions play a crucial role in ensuring long-term stability and nutrient removal. Additionally, bioaugmentation can facilitate the granulation process. Furthermore, this paper comprehensively assesses the application of AGS-CFRs in full-scale wastewater treatment plants (WWTPs). Currently, AGS-CFRs have been implemented in nine WWTPs, encompassing two distinct processes. Hydrocyclone-based densified activated sludge significantly enhances sludge density, settleability, and biological phosphorus removal efficiency, thus increasing treatment capacity. The microaerobic-aerobic configuration with internal separators can induce granulation, ensuring long-term stability, eliminating the need for external clarifiers, and reducing land and energy requirements. This review demonstrates the high potential of AGS-CFRs for intensifying existing WWTPs with minimal retrofitting needs. However, further research is required in granulation mechanisms, long-term stability, and nutrient removal to promote the widespread adoption of AGS.

Kidney Failure Attributed to Focal Segmental Glomerulosclerosis: A USRDS Retrospective Cohort Study of Epidemiology, Treatment Modalities, and Economic Burden.

Rationale & Objective: This study describes the epidemiology, characteristics, and clinical outcomes of patients with focal segmental glomerulosclerosis (FSGS)-attributed kidney failure in the US Renal Data System (USRDS) during 2008-2018, and health care resource utilization and costs among those with Medicare-linked data. Study Design: This was a retrospective cohort study. Setting & Population: Patients with FSGS-attributed kidney failure in the USRDS were enrolled in the study. Outcomes: The outcomes were as follows: Prevalence and incidence, clinical and demographic characteristics, time to kidney transplant or death, health care resource utilization, and direct health care costs. Analytical Approach: Patients with FSGS as the primary cause of kidney failure were followed from USRDS registration (index date) until death or data end. Prevalence and incidence were calculated per 1,000,000 US persons. Patient characteristics at index and treatment modalities during follow-up were described. Time to kidney transplant or death was assessed with Kaplan-Meier and competing risk analyses. Health care resource utilization and costs were reported among patients with 1 year Medicare Part A+B coverage postindex, including (Medicare Coverage subgroup) or excluding (1-year Medicare Coverage subgroup) those who died. Results: The FSGS cohort and Medicare Coverage and 1-year Medicare Coverage subgroups included 25,699, 6,340, and 5,575 patients, respectively. Mean annual period prevalence and incidence rates of FSGS-attributed kidney failure were 87.6 and 7.5 per 1,000,000 US persons, respectively. Initial treatment for most patients was in-center hemodialysis (72.1%), whereas 7.3% received kidney transplant. Accounting for competing risk of death, year 1 and 5 kidney transplant rates were 15% and 34%, respectively. In the Medicare Coverage and 1-year Medicare Coverage subgroups, 76.6% and 74.2% required inpatient admission, 69.9% and 67.3% visited the emergency room, and mean monthly health care costs were $6,752 and $5,575 in the year postindex, respectively. Limitations: Drug costs may be underestimated because Medicare Part D coverage was not required; kidney acquisition costs were not available. Conclusions: FSGS-attributed kidney failure is associated with substantial clinical and economic burden, prompting the need for novel therapies for FSGS to delay kidney failure.

This study of patients in the US Renal Data System observed increasing prevalence and fluctuating incidence of focal segmental glomerulosclerosis (FSGS)-attributed kidney failure from 2008 to 2018. Patients experienced a high clinical burden, including more than 3 years of treatment with dialysis, one-third receiving a kidney transplant, and one-third dying during follow-up. In the first year after US Renal Data System registration, three-quarters of patients with Medicare coverage required hospitalization, and more than two-thirds visited the emergency room. The total annual health care costs were >$68,000 per patient with FSGS-attributed kidney failure, underscoring the high economic burden of this disorder and the treatments required to sustain life. Novel therapies for FSGS are needed to delay or ideally prevent the need dialysis and transplantation after kidney failure.

Lactobacillus johnsonii Improves Intestinal Barrier Function and Reduces Post-Weaning Diarrhea in Piglets: Involvement of the Endocannabinoid System.

Probiotic intervention is a well-established approach for replacing antibiotics in the management of weaning piglet diarrhea, which involves a large number of complex systems interacting with the gut microbiota, including the endocannabinoid system; nevertheless, the specific role of the endocannabinoid system mediated by probiotics in the piglet intestine has rarely been studied. In this study, we used antibiotics (ampicillin) to perturb the intestinal microbiota of piglets. This resulted in that the gene expression of the intestinal endocannabinoid system was reprogrammed and the abundance of probiotic Lactobacillus johnsonii in the colon was lowered. Moreover, the abundance of Lactobacillus johnsonii was positively correlated with colonic endocannabinoid system components (chiefly diacylglycerol lipase beta) via correlation analysis. Subsequently, we administered another batch of piglets with Lactobacillus johnsonii. Interestingly, dietary Lactobacillus johnsonii effectively alleviated the diarrhea ratio in weaning piglets, accompanied by improvements in intestinal development and motility. Notably, Lactobacillus johnsonii administration enhanced the intestinal barrier function of piglets as evidenced by a higher expression of tight junction protein ZO-1, which might be associated with the increased level in colonic diacylglycerol lipase beta. Taken together, the dietary Lactobacillus johnsonii-mediated reprogramming of the endocannabinoid system might function as a promising target for improving the intestinal health of piglets.

Kidney Failure Attributed to Immunoglobulin A Nephropathy: A USRDS Retrospective Cohort Study of Epidemiology, Treatment Modalities, and Economic Burden.

Rationale & Objective: This study describes the epidemiology, characteristics, and outcomes of patients with immunoglobulin A nephropathy (IgAN)-attributed kidney failure in the US Renal Data System (USRDS) from 2008 to 2018, including health care resource utilization and costs among patients with Medicare-linked data. Study Design: Retrospective cohort study. Setting & Population: Patients with IgAN-attributed kidney failure in the USRDS. Outcomes: Prevalence/incidence, clinical/demographic characteristics, time to kidney transplant, and health care resource utilization and costs. Analytical Approach: Patients with IgAN as primary cause of kidney failure (IgAN cohort) were followed from USRDS registration (index date) until data end/death. Prevalence/incidence were calculated per 1,000,000 US persons. Demographic and clinical characteristics at index and treatment modality during follow-up were summarized. Time from index to kidney transplant was assessed using Kaplan-Meier and competing risk analyses. Health care resource utilization and health care costs were reported among patients with 1 year Medicare Part A+B coverage postindex, including or excluding those who died (Medicare Coverage and 1-year Medicare Coverage subgroups, respectively). Results: The IgAN cohort, Medicare Coverage, and 1-year Medicare Coverage subgroups included 10,101, 1,696, and 1,510 patients, respectively. Mean annual period prevalence and incidence of IgAN-attributed kidney failure were 39.3 and 2.9 per 1,000,000 US persons, respectively. Initial treatment was in-center hemodialysis (63.1%) or kidney transplant (15.1%). Year 1 and 5 kidney transplant rates were 5% and 17%, respectively, accounting for competing risk of death. In the Medicare Coverage and 1-year Medicare Coverage subgroups, 74.4% and 72.3%, respectively, required inpatient admission, 67.3% and 64.4%, respectively, visited the emergency room, and mean total health care costs were $6,293 (SD: $6,934) and $5,284 ($3,455), respectively, per-patient-per-month in the year postindex. Limitations: Drug costs may be underestimated as Medicare Part D coverage was not required; kidney acquisition costs were unavailable. Conclusions: IgAN-attributed kidney failure is associated with substantial clinical and economic burdens. Novel therapies for IgAN that delay kidney failure are needed.

This study of patients in the United States Renal Data System (USRDS) observed fluctuating incidence and increasing prevalence of immunoglobulin A nephropathy (IgAN)-attributed kidney failure from 2008 to 2018. Patients experienced a high clinical burden, with 63% receiving in-center dialysis and over 15% receiving transplantation as initial therapy. In the first year after USRDS registration, nearly three-quarters of patients with Medicare coverage required hospitalization, and around two-thirds visited the emergency room. The total annual health care costs were >$63,000 per patient with IgAN-attributed kidney failure, underscoring the high economic burden of this disorder and currently available treatments. Novel therapies for IgAN are needed to delay or prevent the need for costly dialysis and transplantation after kidney failure.

Preparation of eGaIn NDs/TPU Composites for X-ray Radiation Shielding Based on Electrostatic Spinning Technology.

Thermoplastic polyurethane (TPU) composites with eutectic gallium (Ga) and indium (In) (eGaIn) fillings of 0 wt%-75 wt% were prepared using the electrostatic spinning method. Field emission scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier-transform infrared (FTIR) spectroscopy were used to characterize the eGaIn NDs/TPU composites. To evaluate their X-ray shielding properties, Phy-X/PSD and WinXCom were employed to calculate the mass attenuation coefficients, linear attenuation coefficients, half-value layers, tenth value layers, mean free paths, and adequate atomic numbers of the eGaIn NDs/TPU composites. The SEM results indicated that the eGaIn nanodroplets were evenly distributed throughout the TPU fibers, and the flowable eGaIn was well-suited for interfacial compatibility with the TPU. A comparison of the eGaIn NDs/TPU composites with different content levels showed that the composite with 75 wt% eGaIn had the highest µm at all the evaluated energies, indicating a superior ability to attenuate X-rays. This non-toxic, lightweight, and flexible composite is a potential material for shielding against medical diagnostic X-rays.

Clinical Characteristics and Histopathology in Adults With Focal Segmental Glomerulosclerosis.

Rationale & Objective: Few data are available regarding histological features at the time of focal segmental glomerulosclerosis (FSGS) diagnosis among diverse real-world populations. This study describes clinical and histological characteristics and correlates of histological disease severity in adults with FSGS who underwent a clinical kidney biopsy. Study Design: Real-world cohort study with data derived from health records. Setting & Participants: Adults with FSGS by kidney biopsies from Arkana Laboratories from January 1, 2016 to May 31, 2020. Exposure: Race, chronic kidney disease stage, nephrotic proteinuria, age, sex, and hypertension. Outcomes: Severe histological disease, defined as global glomerulosclerosis in >50% of glomeruli and >25% interstitial fibrosis and tubular atrophy (IFTA). Analytical Approach: Demographic, clinical, and histological characteristics were compared between race groups. Correlates of severe disease were analyzed using multiple logistic regression. Results: Among 2,011 patients with FSGS, 40.6% were White, and 23.6% Black. White patients were older (52.8 vs 45.5 years, P < 0.001) with a higher estimated glomerular filtration rate (eGFR) than Black patients (53.5 vs 43.1 mL/min/1.73 m2, P < 0.001). A higher proportion of Black patients had global glomerulosclerosis ≥50% (32.1% vs 14.6%, P < 0.001) or IFTA >50% (34.6% vs 14.7%, P < 0.001). Severe histological disease was more likely in Black patients (OR, 2.46; 95% CI, 1.59-3.79; P < 0.001). A higher proportion of patients with nephrotic than nonnephrotic proteinuria exhibited diffuse foot process effacement. Limitations: Unequal representation across United States regions, missing demographic and clinical data, and lack of data on primary versus secondary FSGS, treatments, or outcomes. Conclusions: Black patients were more frequently diagnosed at younger age with lower eGFR and more severe histological disease compared with White patients. Timelier identification of FSGS could increase the opportunity for therapeutic intervention, especially for high-risk patients, to mitigate disease progression and complications. Plain-Language Summary: Focal segmental glomerulosclerosis (FSGS) accounts for around one-quarter of diagnoses derived from clinical kidney biopsies in the United States. Limited data are available regarding the classes and distribution of histological features at FSGS diagnosis among diverse real-world populations. Analyzing data from US patients who underwent kidney biopsy and were diagnosed with FSGS, we showed that up to half of patients had features of severe histological disease. Of this overall population, Black patients were more frequently diagnosed at a younger age but with more severe histological disease than White patients. The work highlights the need for timelier diagnosis of FSGS to enable intervention at an earlier disease stage.

Corrigendum to "Clinicopathological Characteristics of Adult IgA Nephropathy in the United States" [Kidney International Reports Volume 8, Issue 9, September 2023, Pages 1792-1800].

[This corrects the article DOI: 10.1016/j.ekir.2023.06.016.].

Development and material characteristics of glaucoma surgical implants.

Background: Glaucoma is the leading cause of irreversible blindness worldwide. The reduction of intraocular pressure has proved to be the only factor which can be modified in the treatment, and surgical management is one of the important methods for the treatment of glaucoma patients. Main text: In order to increase aqueous humor outflow and further reduce intraocular pressure, various drainage implants have been designed and applied in clinical practice. From initial Molteno, Baerveldt and Ahmed glaucoma implants to the Ahmed ClearPath device, Paul glaucoma implant, EX-PRESS and the eyeWatch implant, to iStent, Hydrus, XEN, PreserFlo, Cypass, SOLX Gold Shunt, etc., glaucoma surgical implants are currently undergoing a massive transformation on their structures and performances. Multitudinous materials have been used to produce these implants, from original silicone and porous polyethylene, to gelatin, stainless steel, SIBS, titanium, nitinol and even 24-carat gold. Moreover, the material geometry, size, rigidity, biocompatibility and mechanism (valved versus nonvalved) among these implants are markedly different. In this review, we discussed the development and material characteristics of both conventional glaucoma drainage devices and more recent implants, such as the eyeWatch and the new minimally invasive glaucoma surgery (MIGS) devices. Conclusions: Although different in design and materials, these delicate glaucoma surgical implants have widely expanded the glaucoma surgical methods, and improved the success rate and safety of glaucoma surgery significantly. However, all of these glaucoma surgical implants have various limitations and should be used for different glaucoma patients at different conditions.

Gut microbiota-mediated IL-22 alleviates metabolic inflammation.

Low-grade chronic inflammation, also known as metabolic inflammation, promotes the development of metabolic diseases. Increasing evidence suggests that changes in gut microbes and metabolites disrupt the integrity of the gut barrier and exert significant effects on the metabolism of various tissues, including the liver and adipose tissue, thereby contributing to metabolic inflammation. We observed that IL-22 is a key signaling molecule that serves as a bridge between intestinal microbes and the host, effectively alleviating metabolic inflammation by modulating the host immunomodulatory network. Here, we focused on elucidating the underlying mechanisms by which the gut microbiota and their metabolites reduce inflammation via IL-22, highlighting the favorable impact of IL-22 on metabolic inflammation. Furthermore, we discuss the potential of IL-22 as a therapeutic target for the management of metabolic inflammation and related diseases.

Comparison Between Two Types of Viral-Induced Anterior Uveitis In Vitro and In Vivo: A Stronger Response in Herpes Simplex Virus Type 1 Than in Murine Cytomegalovirus.

Purpose: To observe the similarities and differences between herpes simplex virus type 1 (HSV-1) and murine cytomegalovirus (MCMV)-induced viral anterior uveitis (VAU), both in vitro and in vivo. Methods: Primary rat trabecular meshwork cells (RTMCs) were infected by HSV-1 or MCMV to clarify the pattern of virus replication and the effect on cells. In vivo, intracameral injection of HSV-1 or MCMV was performed to establish the VAU rat models. The clinical manifestation, intraocular pressure (IOP), histological characteristics, ultrastructural changes, and the expression of inflammatory cytokines in the anterior segment were observed and compared between these two types of VAU models. Results: Both viruses could infect the RTMCs but HSV-1 exhibited an earlier and greater cytopathic effect in vitro. In vivo, both VAU rats showed typical acute VAU signs, and the IOP elevation seemed to be correlated with the inflammatory progression. Histopathological findings and ultrastructural changes revealed tissue damage and cell infiltration in the anterior chamber angle. In both models, similar proinflammatory cytokines were upregulated. HSV-1 and MCMV viral particles were identified under transmission electron microscopy. Conclusions: HSV-1 and MCMV infection share certain similarities but have significant differences both in vitro and in vivo. HSV-1 usually has a stronger anterior segment inflammation with a longer duration compared with MCMV in VAU models. Our results provided a valuable animal model for investigating pathogenesis and exploring therapeutic strategies for clinical VAU.

Implications of Complete Proteinuria Remission at any Time in Focal Segmental Glomerulosclerosis: Sparsentan DUET Trial.

Introduction: Focal segmental glomerulosclerosis (FSGS) is a rare glomerular disease with high unmet clinical need. Interest in proteinuria as a surrogate end point for regulatory approval of novel treatments has increased. We assessed the relationship between achieving complete remission (CR) of proteinuria at least once during follow-up and long-term kidney outcomes. Methods: This post hoc analysis included all patients enrolled in the DUET trial of sparsentan in FSGS and the open-label extension (OLE). Evaluations occurred every 12 weeks, including blood pressure (BP), edema, proteinuria, and kidney function. CR was defined as a urine protein/creatinine ratio ≤0.3g/g in a first morning urine sample. Results: A total of 108 patients who received ≥1 sparsentan dose were included in this study. During a median follow-up of 47.0 months, 46 patients (43%) experienced ≥1 CR, 61% occurring within 12 months of starting sparsentan. There was an increased likelihood of CR with a higher sparsentan dose or baseline subnephrotic-range proteinuria. Achieving ≥1 CR was associated with significantly slower rate of estimated glomerular filtration rate (eGFR) decline versus non-CR patients (P < 0.05). Use of immunosuppressive agents was more frequent in patients who achieved a CR. However, the antiproteinuric effect of sparsentan was additive to that achieved with concomitant immunosuppressive treatment. No unanticipated adverse events occurred. Conclusion: We conclude that sparsentan can be safely administered for extended periods and exerts a sustained antiproteinuric effect. Achievement of CR at any time during follow-up, even if it is not sustained, may be an indicator of a favorable response to treatment and a predictor of improved kidney function outcomes.

Clinicopathological Characteristics of Adult IgA Nephropathy in the United States.

Introduction: IgA nephropathy (IgAN) is a progressive autoimmune kidney disease and a leading cause of glomerular disease that can result in kidney failure (KF). The median age at diagnosis is 35 to 37 years and approximately 50% of patients will progress to KF within 20 years. We aimed to enhance the understanding of renal histology and chronic kidney disease (CKD) stage at the time of IgAN diagnosis using a large real-world biopsy cohort. Methods: This retrospective cohort study evaluated biopsy data and clinical characteristics from adult patients within the US who were diagnosed with IgAN between January 1, 2016 to May 31, 2020. Descriptive statistics were summarized and relationship(s) between each Oxford Classification (MEST-C) component score with 24-hour proteinuria or CKD stage were examined using regression analysis. Results: A total of 4375 patients (mean age 47.7 years, 62.7% male) met eligibility criteria. Mild to moderate mesangial hypercellularity (47.3%), segmental sclerosis (65.0%), tubular atrophy ≥25% (57.4%), and crescents (18.5%) were identified; and 74.6% of patients were at CKD stage ≥3. Proteinuria ≥1 g/d was associated with higher MEST-C scores, and the odds of mesangial hypercellularity, segmental sclerosis, tubular atrophy, and crescents increased with CKD stage. Conclusion: Most patients with IgAN in our US cohort were diagnosed at CKD stage ≥3 and had high MEST-C scores and proteinuria that are suggestive of significant disease burden at the time of kidney biopsy. Strategies are required to raise awareness and promote earlier detection of asymptomatic urinary abnormalities before extensive irreversible kidney damage has occurred.

Inhibition of cGAS-STING pathway alleviates neuroinflammation-induced retinal ganglion cell death after ischemia/reperfusion injury.

Acute glaucoma is a vision-threatening disease characterized by a sudden elevation in intraocular pressure (IOP), followed by retinal ganglion cell (RGC) death. Cytosolic double-stranded DNA (dsDNA)-a damage-associated molecular pattern (DAMP) that triggers inflammation and immune responses-has been implicated in the pathogenesis of IOP-induced RGC death, but the underlying mechanism is not entirely clear. In this study, we investigated the effect of the inflammatory cascade on dsDNA recognition and examined the neuroprotective effect of the cyclic GMP-AMP (cGAMP) synthase (cGAS) antagonist A151 on a retinal ischemia/reperfusion (RIR) mouse model. Our findings reveal a novel mechanism of microglia-induced neuroinflammation-mediated RGC death associated with glaucomatous vision loss. We found that RIR injury facilitated the release of dsDNA, which initiated inflammatory responses by activating cGAS-stimulator of interferon genes (STING) pathway. Correspondingly, elevated expressions of cGAS and STING were found in retinal samples from human glaucoma donors. Furthermore, we found that deletion or inhibition of cGAS or STING in microglia transfected with poly(dA:dT) specifically decreased microglia activation and inflammation response. We also observed that A151 treatment promoted poly(dA:dT)--stimulated changes in polarization from the M1 to the M2 phenotype in microglia. Subsequently, A151 administered to mice effectively inhibited the cGAS-STING pathway, absent in melanoma 2 (AIM2) inflammasome and pyroptosis-related molecules. Furthermore, A151 administration significantly reduced neuroinflammation, ameliorated RGC death and RGC-related reductions in visual function. These findings provide a unique perspective on glaucomatous neuropathogenesis and suggest cGAS as an underlying target of retinal inflammation to provide a potential therapeutic for acute glaucoma.

Keratin8 Deficiency Aggravates Retinal Ganglion Cell Damage Under Acute Ocular Hypertension.

Purpose: Keratin 8/18 (KRT8/18), paired members of the intermediate filament family, have shown vital functions in regulating physiological activities more than supporting the mechanic strength for cells and organelles. However, the KRT8/18 presence in retinal ganglion cells (RGCs) and functions on neuroprotection in a mouse model of acute ocular hypertension (AOH) are unknown and worthy of exploration. Methods: We identified the existence of KRT8/18 in normal human and mouse retinas and primary RGCs. KRT8/18 levels were detected after AOH modeling. The adeno-associated virus (AAV) system was intravitreally used for selective KRT8 knockdown in RGCs. The histological changes, the loss and dysfunction of RGCs, and the gliosis in retinas were detected. The markers of cell apoptosis and MAPK pathways were investigated. Results: KRT8/18 existed in all retinal layers and was highly expressed in RGCs, and they increased after AOH induction. The KRT8 knockdown in RGCs caused no histopathological changes and RGC loss in retinas without AOH modeling. However, after the KRT8 deficiency, AOH significantly promoted the loss of whole retina and inner retina thickness, the reduction, apoptosis, and dysfunction of RGCs, and the glial activation. Besides, downregulated Bcl-2 and upregulated cleaved-Caspase 3 were found in the AOH retinas with KRT8 knockdown, which may be caused by the increased phosphorylation level of MAPK pathways (JNK, p38, and ERK). Conclusions: The KRT8 deficiency promoted RGC apoptosis and neurodegeneration by abnormal activation of MAPK pathways in AOH retinas. Targeting KRT8 may serve as a novel treatment for saving RCGs from glaucomatous injuries.