Spontaneous Remission of Minimal Change Disease in a Colon Cancer Patient: A Case Report.

Introduction: Minimal change disease (MCD) is most often primary but may occur secondary to other systemic diseases such as malignancy. In secondary MCD, spontaneous remission of nephrotic syndrome after the treatment of related diseases without steroid therapy is rare. Case Presentation: A 78-year-old man visited the outpatient clinic with foamy urine and generalized edema that had persisted for 2 months. The patient had nephrotic syndrome. Before a kidney biopsy, he underwent several tests to determine the secondary cause of the nephrotic syndrome. The serum CEA was slightly elevated, and colon cancer was detected in the sigmoid colon. MCD was diagnosed from a kidney biopsy. He immediately underwent surgery for colon cancer. Complete remission of the MCD was achieved within 2 weeks after surgery. Conclusion: Here, we report a rare case of a patient with secondary MCD who successfully achieved spontaneous remission after colon cancer surgery.

Defining tropism and activity of natural and engineered extracellular vesicles.

Extracellular vesicles (EVs) have important roles as mediators of cell-to-cell communication, with physiological functions demonstrated in various in vivo models. Despite advances in our understanding of the biological function of EVs and their potential for use as therapeutics, there are limitations to the clinical approaches for which EVs would be effective. A primary determinant of the biodistribution of EVs is the profile of proteins and other factors on the surface of EVs that define the tropism of EVs in vivo. For example, proteins displayed on the surface of EVs can vary in composition by cell source of the EVs and the microenvironment into which EVs are delivered. In addition, interactions between EVs and recipient cells that determine uptake and endosomal escape in recipient cells affect overall systemic biodistribution. In this review, we discuss the contribution of the EV donor cell and the role of the microenvironment in determining EV tropism and thereby determining the uptake and biological activity of EVs.

Idiopathic Spontaneous Rupture of a Subcostal Artery in a Patient Undergoing Hemodialysis: A Case Report.

The spontaneous rupture of a subcostal (12th intercostal) artery is exceptionally rare and could be fatal, requiring early diagnosis and treatment. Only one case of intercostal artery (ICA) bleeding in a patient undergoing hemodialysis (HD) has been reported. We additionally describe a 41-year-old man undergoing HD who presented with a spontaneous hemoperitoneum and shock resulting from a subcostal artery rupture. He initially complained of diffuse abdominal pain and dizziness at the emergency room. His abdomen was bloated, and there was tenderness in the right upper quadrant area. Enhanced computed tomography and arteriography revealed a rupture of the right subcostal artery. After the super-selection of the bleeding artery by a microcatheter, embolization was performed using a detachable coil and gelfoam. In a subsequent arteriogram, additional contrast leakage was no longer detected, and his blood pressure was restored to normal. The patient was discharged without any sequelae. He was followed up at our HD center without recurrence of ICA bleeding. To the best of our knowledge, this is the second case in the English literature documenting a spontaneous ICA rupture in a patient undergoing HD. This case indicates that injury to ICA should be suspected when patients undergoing HD complain of abdominal or chest pain and dizziness, although it is very rare.

Defining the activity of pro-reparative extracellular vesicles in wound healing based on miRNA payloads and cell type-specific lineage mapping.

Small extracellular vesicles (EVs) are released by cells and deliver biologically active payloads to coordinate the response of multiple cell types in cutaneous wound healing. Here we used a cutaneous injury model as a donor of pro-reparative EVs to treat recipient diabetic obese mice, a model of impaired wound healing. We established a functional screen for microRNAs (miRNAs) that increased the pro-reparative activity of EVs and identified a down-regulation of miR-425-5p in EVs in vivo and in vitro associated with the regulation of adiponectin. We tested a cell type-specific reporter of a tetraspanin CD9 fusion with GFP to lineage map the release of EVs from macrophages in the wound bed, based on the expression of miR-425-5p in macrophage-derived EVs and the abundance of macrophages in EV donor sites. Analysis of different promoters demonstrated that EV release under the control of a macrophage-specific promoter was most abundant and that these EVs were internalized by dermal fibroblasts. These findings suggested that pro-reparative EVs deliver miRNAs, such as miR-425-5p, that stimulate the expression of adiponectin that has insulin-sensitizing properties. We propose that EVs promote intercellular signaling between cell layers in the skin to resolve inflammation, induce proliferation of basal keratinocytes, and accelerate wound closure.

A heterogenous population of extracellular vesicles mobilize to the alveoli postinjury.

BACKGROUND: Acute lung injury and subsequent resolution following severe injury are coordinated by a complex lung microenvironment that includes extracellular vesicles (EVs). We hypothesized that there is a heterogenous population of EVs recruited to the alveoli postinjury and that we could identify specific immune-relevant mediators expressed on bronchoalveolar lavage (BAL) EVs as candidate biomarkers of injury and injury resolution. METHODS: Mice underwent 30% TBSA burn injury and BAL fluid was collected 4 hours postinjury and compared with sham. Extracellular vesicles were purified and single vesicle flow cytometry (vFC) was performed using fluorescent antibodies to quantify the expression of specific cell surface markers on individual EVs. Next, we evaluated human BAL specimens from injured patients to establish translational relevance of the mouse vFC analysis. Human BAL was collected from intubated patients following trauma or burn injury, EVs were purified, then subjected to vFC analysis. RESULTS: A diverse population of EVs were mobilized to the alveoli after burn injury in mice. Quantitative BAL vFC identified significant increases in macrophage-derived CD44+ EVs (preinjury, 10.8% vs. postinjury, 13%; p < 0.05) and decreases in IL-6 receptor alpha (CD126) EVs (preinjury, 19.3% vs. postinjury, 9.3%, p < 0.05). Bronchoalveolar lavage from injured patients also contained a heterogeneous population of EVs derived from myeloid cells, endothelium, and epithelium sources, with CD44+ EVs being highly detected. CONCLUSION: Injury causes mobilization of a heterogeneous population of EVs to the alveoli in both animal models and injured patients. Defining EV release after injury will be critical in identifying diagnostic and therapeutic targets to limit postinjury acute lung injury.

Role of Kir4.1 Channels in Aminoglycoside-Induced Ototoxicity of Hair Cells.

The Kir4.1 channel, an inwardly rectifying potassium ion (K+) channel, is located in the hair cells of the organ of Corti as well as the intermediate cells of the stria vascularis. The Kir4.1 channel has a crucial role in the generation of endolymphatic potential and maintenance of the resting membrane potential. However, the role and functions of the Kir4.1 channel in the progenitor remain undescribed. To observe the role of Kir4.1 in the progenitor treated with the one-shot ototoxic drugs (kanamycin and furosemide), we set the proper condition in culturing Immortomouse-derived HEI-OC1 cells to express the potassium-related channels well. And also, that was reproduced in mice experiments to show the important role of Kir4.1 in the survival of hair cells after treating the ototoxicity drugs. In our results, when kanamycin and furosemide drugs were cotreated with HEI-OC1 cells, the Kir4.1 channel did not change, but the expression levels of the NKCC1 cotransporter and KCNQ4 channel are decreased. This shows that inward and outward channels were blocked by the two drugs (kanamycin and furosemide). However, noteworthy here is that the expression level of Kir4.1 channel increased when kanamycin was treated alone. This shows that Kir4.1, an inwardly rectifying potassium channel, acts as an outward channel in place of the corresponding channel when the KCNQ4 channel, an outward channel, is blocked. These results suggest that the Kir4.1 channel has a role in maintaining K+ homeostasis in supporting cells, with K+ concentration compensator when the NKCC1 cotransporter and Kv7.4 (KCNQ4) channels are deficient.

Psoralen Alleviates Renal Fibrosis by Attenuating Inflammasome-Dependent NLRP3 Activation and Epithelial-Mesenchymal Transition in a Mouse Unilateral Ureteral Obstruction Model.

The role of psoralen (PS), a major active component extracted from Psoralea corylifolia L. seed, in renal fibrosis is still unclear. Thus, the objective of this study was to evaluate the effects of PS on the development and progression of renal fibrosis induced by unilateral ureteral obstruction (UUO) in a mouse model. Mice were divided into four groups: PS (20 mg/kg, i.g., n = 5), PS + sham (n = 5), UUO (n = 10), and PS + UUO (n = 10). PS was intragastrically administered 24 h before UUO and continued afterwards for 7 days. All mice were killed 7 days post UUO. Severe tubular atrophy, tubular injury, and tubulointerstitial fibrosis (TIF) were significantly developed in UUO mice. A higher expression of transforming growth factor-ß1 (TGF-ß1) was accompanied by elevated levels of α-smooth muscle actin (α-SMA) and phosphorylated Smad2/3 (pSmad2/3) at 7 days post UUO. However, PS treatment reduced tubular injury, interstitial fibrosis, and the expression levels of TGF-ß1, α-SMA, and pSmad2/3. Furthermore, the levels of macrophages (represented by F4/80 positive cells) and the inflammasome, reflected by inflammasome markers such as nucleotide-binding and oligomerization domain-like receptors protein 3 (NLRP3) and cleaved caspase1 (cCASP-1), were significantly decreased by PS treatment. These results suggest that PS merits further exploration as a therapeutic agent in the management of chronic kidney disease (CKD).

IgA nephropathy with minimal change disease associated with primary Sjögren's syndrome: A case report.

RATIONALE: Only 1 case of IgA nephropathy (IgAN) with minimal change disease (MCD) associated with primary Sjögren's syndrome (SS) has been reported. We additionally describe IgAN with MCD associated with primary SS. PATIENT CONCERNS: A 80-year-old woman visited our hospital complaining of generalized edema that had started 4 weeks prior. She reported a sense of thirst and dry eye for the last 5 years. DIAGNOSES: Her initial laboratory findings were compatible with nephrotic syndrome; both the antinuclear antibody (1:80) and anti-SS-A (Ro) antibody (200 U/mL) tests were positive. A salivary gland scan revealed markedly decreased uptake for both the parotid and submandibular glands. The Schirmer test was positive. The random urine protein/creatinine ratio was 10 mg/mg. Renal biopsy was compatible with IgAN with superimposed MCD. INTERVENTIONS: Furosemide was intravenously administered with intermittent albumin infusion for her edema control. She was started on prednisone 40mg daily for 6 weeks, which was tapered to 5 mg for another 6 months after starting prednisolone. OUTCOMES: Over the next 6 months, her edema improved and the proteinuria decreased significantly. LESSONS: Physician should suspect IgA with MCD when patient with SS clinically showed nephrotic syndrome, and perform renal biopsy for pathologically diagnosis and appropriate treatment.

Molecular characterization and functionality of rumen-derived extracellular vesicles using a Caenorhabditis elegans animal model.

The rumen fluids contain a wide range of bacteria, protozoa, fungi, and viruses. The various ruminal microorganisms in the rumen provide nutrients by fermenting the forage they eat. During metabolic processes, microorganisms present in the rumen release diverse vesicles during the fermentation process. Therefore, in this study, we confirmed the function of rumen extracellular vesicles (EVs) and their interaction with the host. We confirmed the structure of the rumen EVs by transmission electron microscope (TEM) and the size of the particles using nanoparticle tracking analysis (NTA). Rumen EVs range in size from 100 nm to 400 nm and are composed of microvesicles, microparticles, and ectosomes. Using the Caenorhabditis elegans smart animal model, we verified the interaction between the host and rumen EVs. Exposure of C. elegans to rumen EVs did not significantly enhance longevity, whereas exposure to the pathogenic bacteria Escherichia coli O157:H7 and Staphylococcus aureus significantly increased lifespan. Furthermore, transcriptome analysis showed gene expression alterations in C. elegans exposed to rumen EVs, with significant changes in the metabolic pathway, fatty acid degradation, and biosynthesis of cofactors. Our study describes the effect of rumen EV interactions with the host and provides novel insights for discovering biotherapeutic agents in the animal industry.

Melanin Treatment Effect of Vacuoles-Zinc Oxide Nanoparticles Combined with Ascorbic Acid.

Currently, ascorbic acid (AA) is widely used as a skin whitening material, but, AA, an unstable hydrophilic molecule, cannot penetrate the skin easily, due to the hydrophobic character of the stratum corneum. Therefore, we conjugated AA with hydrated zinc oxide-an inorganic matrix with positive surface charge, to improve the stability of AA. The metal-conjugated-ascorbic acid (ZnAA) was then combined with yeast vacuole through the vacuolar membrane proteins that relate to metal transportation to create an enhanced vacuole that contained ZnAA. The characteristics of vacuole with ZnAA (ZnAA_Vac) were next examined by various tests that included X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Field emission scanning electron microscopy (FE-SEM), and energy-dispersive X-ray (EDX) analysis. Furthermore, the ability of ZnAA_Vac to degrade melanin was confirmed in both melanoma cell line B16F10, and the artificial human skin MelanoDerm. The results showed that ZnAA_Vac possessed a higher depigmenting effect than the wild-type vacuole or ascorbic acid by reducing 75% of melanin color. Interestingly, ZnAA_Vac was found to be harmless, and did not cause any cytotoxicity to the cells. Overall, ZnAA_Vac is expected to provide a robust, harmless, and effective whitening agent for the skin.

Protection of Hearing Loss in Ototoxic Mouse Model Through SPIONs and Dexamethasone-Loaded PLGA Nanoparticle Delivery by Magnetic Attraction.

Background: Ototoxicity currently has no available treatment other than medication withdrawal as soon as toxicity is suspected. The human inner ear organs have little potential for regeneration; thus, ototoxicity-induced hair cell injury is deemed permanent. Dexamethasone (Dexa) is a synthetic steroid analog that has significant potential for otoprotection in the treatment of various inner ear diseases; however, its low absorption into the inner ear prevents significant recovery of function. Nanoparticles facilitate targeted drug delivery, stabilize drug release, and increase half-life of the drug. Methods: This study aimed to develop poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded superparamagnetic iron oxide nanoparticles (SPIONs) and Dexa (PSD-NPs) to control localized drug delivery by magnetic attraction in the treatment of ototoxicity-induced hearing loss. PSD-NPs and without SPIONs (PD-NPs) were prepared using a nanoprecipitation method. Results: Using an inner ear simulating system, we confirmed that PSD-NPs has an otoprotective effect in organotypic culture that is enhanced by magnetic attraction. PSD-NPs delivered via intrabullar injection in a magnetic field penetrated the inner ear and prevented hearing loss progression to a greater degree than equivalent doses of Dexa or PSD-NPs alone (day 28: ototoxic: 80.0 ± 0.0 dB; Dexa 100: 60.0 ± 15.5 dB; PSD 100: 50.0 ± 8.2 dB; PSD 100 with magnet: 22.5 ± 5.0 dB; P < 0.05). The protective effects were confirmed in various in vivo and in vitro models of ototoxicity. Conclusion: Our findings suggest that SPIONs with Dexa and magnetic field application prevent the progression of ototoxicity-induced hearing loss through anti-apoptotic mechanisms in the inner ear.

Serpin-loaded extracellular vesicles promote tissue repair in a mouse model of impaired wound healing.

Chronic metabolic diseases such as diabetes are characterized by delayed wound healing and a dysregulation of the inflammatory phase of wound repair. Our study focuses on changes in the payload of extracellular vesicles (EVs) communicating between immune cells and stromal cells in the wound bed, which regulate the rate of wound closure. Adoptive transfer of EVs from genetically defined mouse models are used here to demonstrate a functional and molecular basis for differences in the pro-reparative biological activity of diabetic (db/db) vs. wildtype EVs in wound healing. We identify several members of the Serpin family of serine protease inhibitors that are absent in db/db EVs, then we overexpress Serpin A1, F2 and G1 in EVs to evaluate their effect on wound healing in db/db mice. Serpins have an important role in regulating levels of elastase, plasmin and complement factors that coordinate immune cell signaling in full thickness wounds in a diabetic model. Here, we establish a novel therapeutic approach by engineering the payload of EVs based on proteomic analysis. Serpin-loaded EVs were used to rescue the Serpin deficiency identified by proteomics and promote wound healing in db/db mice, as well as evaluated how EVs affected extracellular matrix remodeling and the resolution of tissue injury. Therefore, we propose that the identification of EV payloads that are downregulated in diabetic wounds can be systematically analyzed for their functional activity and potential as a therapeutic, based on whether their re-expression in engineered EVs restores normal kinetics of tissue repair in chronic wounds.

The neutrophil-to-lymphocyte ratio may indicate when to start hemodialysis.

We evaluated whether the neutrophil-to-lymphocyte ratio (NLR) could aid dialysis decision-making in combination with the clinical presentation and biochemical findings. We retrospectively evaluated the medical records of 279 patients who commenced chronic maintenance hemodialysis. We compared the laboratory findings at 6 months before dialysis to those at dialysis initiation. NLR cutoffs and risk factors for each of six uremic symptoms were determined. Mean age was 60.7 years and mean estimated glomerular filtration rate (eGFR) was 5.7 ± 2.5 mL/min/1.73 m2 at the time of hemodialysis and 7.7 ± 3.8 mL/min/1.73 m2 6 months earlier (p < 0.001). The mean NLR increased significantly from 2.5 ± 1.0 to 4.9 ± 2.8 (p < 0.001). The NLR was positively correlated with the C-reactive protein level (r = 0.202, p = 0.009) and negatively correlated with those of albumin (r = -0.192, p = 0.001) and total CO2 (r = -0.134, p = 0.023). The NLR cutoffs for neurological and gastrointestinal symptoms as determined using receiver operator curve analysis were 2.4 (area under the curve [AUC] 0.976; 95% confidence interval [CI] 0.960-0.993; sensitivity 92.2%; specificity 94.7%) and 3.6 (AUC 0.671; 95% CI 0.588-0.755; sensitivity 68.1%; specificity 63.5%), respectively. On multiple linear regression analysis of neurological symptoms, the NLR was a significant predictor (ß = -0.218, p = 0.017), as was age (ß = 0.314, p = 0.037). In conclusion, the NLR may serve as a supplementary marker predicting uremic symptoms and a need for hemodialysis in stage 5 CKD patients.

Page kidney following spontaneous subcapsular hematoma immediately after kidney transplantation: a case report.

BACKGROUND: Page kidney (PK) is the occurrence of kidney hypoperfusion and ischemia due to pressure on the kidney by a subcapsular hematoma (SH), a mass, or fluid collection. SH after renal transplantation may result in kidney ischemia and graft loss. CASE PRESENTATION: We present a rare case of early spontaneous SH in an allograft kidney that led to a decrease in renal function. A 56-year-old male patient underwent deceased donor kidney transplantation. After declamping, appropriate renal perfusion and immediate diuresis were observed, with no evidence of SH. However, his urinary output abruptly decreased 6 h postoperatively. Abdominal ultrasonography showed 28 mm deep SH on transplant and the resistive index (RI) increased to 0.98-1 and diastolic flow reversal was observed. Surgical interventions were performed 2 days after transplantation, following a further decrease in urinary output. Serum creatinine decreased to 2.2 mg/dL, urinary output increased to an average of 200 cc per hour and the RI value was decreased to 0.7 on POD 7. CONCLUSION: In patients with abrupt decreased renal function after transplantation, SH should be suspected and the presence of PK should be determined using Doppler USG. In these cases, surgical intervention may avoid allograft dysfunction.

Acute kidney injury due to direct infiltration by lymphoplasmacytic lymphoma secreting IgG paraproteins: A case report.

INTRODUCTION: Waldenström's macroglobulinemia is a lymphoplasmacytic lymphoma (LPL) associated with a monoclonal immunoglobulin M protein. Although acute kidney injury (AKI) due to immunoglobulin M paraprotein infiltration into the renal interstitium has been reported, there has been no report of AKI with invasion of the immunoglobulin G paraprotein into the renal interstitium in a patient with LPL. PATIENT CONCERNS: A 65-year-old male was admitted to our hospital with fatigue and decreased renal function. He complained of a 3-kg weight loss in the last 3 months. DIAGNOSIS: The initial blood urea nitrogen and serum creatinine levels were 55.9 and 1.83 mg/dL, respectively. Serum protein electrophoresis revealed a monoclonal component (3.5 g/dL) in the gamma region and immunofixation electrophoresis showed an immunoglobulin G kappa monoclonal protein. Renal pathology revealed that CD3-CD20+ CD138+ lymphoid cells had infiltrated the renal interstitium. A bone marrow biopsy was compatible with LPL. INTERVENTIONS: Intravenous methylprednisolone (1 mg/kg) was administered after confirming the renal pathological findings. OUTCOMES: Serum creatinine decreased to 0.8 mg/dL 14 days after treatment. CONCLUSIONS: Physicians should recognize LPL secreting various immunoglobulins as a possible cause of AKI when renal failure of unknown etiology and serum immunoglobulin paraprotein is present. A kidney biopsy should be performed for definitive diagnosis and appropriate management.

Impact of phase angle and sarcopenia estimated by bioimpedance analysis on clinical prognosis in patients undergoing hemodialysis: A retrospective study.

ABSTRACT: Bioimpedance analysis (BIA) has been widely used in the evaluation of body composition in patients undergoing maintenance hemodialysis. We conducted this study to evaluate impact of phase angle (PA) and sarcopenia measured by BIA on clinical prognosis in these patients.This longitudinal retrospective study enrolled patients who underwent hemodialysis between January 2016 and March 2019. The patients were stratified into higher (> 4°) and lower (≤ 4.0°) PA groups. Sarcopenia was defined when the appendicular skeletal muscle mass was < 20 kg in men and < 15 kg in women.Of the 191 patients, 63.4% were men. The mean age was 64.2 ±â€Š12.4 years. The lower PA group was older, had a higher proportion of women, a lower body mass index, lower albumin, cholesterol, uric acid, and phosphorus levels, and a higher incidence of history of coronary artery disease than the higher PA group. Linear regression analysis revealed that PA was significantly associated with body mass index (B = 0.18, P = .005), serum albumin (B = 0.23, P = .001), and creatinine levels (B = 0.32, P < .001). During a median follow-up of 16.7 months, 14.1% (n = 27) of patients experienced major adverse cardiovascular events and 11.0% (n = 21) died. Kaplan-Meier survival analysis showed that the higher PA group had significantly better survival, regardless of sarcopenia. Multivariate Cox analyses revealed that lower PA (0.51 [0.31-0.85], P = .010), higher IDWG (1.06 [1.01-1.12], P = .028) and C-reactive protein level (1.01 [1.01-1.02], P < .001), and a history of coronary artery disease (3.02 [1.04-8.77], P = .042) were significantly related to all-cause mortality after adjusting for other covariates.PA measured by BIA was an independent factor in the prediction of mortality in maintenance hemodialysis patients, regardless of sarcopenia. Intervention studies are needed to confirm if the improvement in PA is associated with better clinical outcome.

Intrahepatic inflammatory IgA+PD-L1high monocytes in hepatocellular carcinoma development and immunotherapy.

BACKGROUND: IgA neutralizes pathogens to prevent infection at mucosal sites. However, emerging evidence shows that IgA contributes to aggravating inflammation or dismantling antitumor immunity in human diseased liver. The aim of this study was to elucidate the roles of inflammation-induced intrahepatic inflammatory IgA+ monocytes in the development of hepatocellular carcinoma (HCC). METHODS: Patient cohorts including steatohepatitis cohort (n=61) and HCC cohort (n=271) were established. Patients' surgical and biopsy specimens were analyzed using immunohistochemistry. Multicolor flow cytometry was performed with a subset of patient samples. Single-cell RNA-Seq analysis was performed using Gene Expression Omnibus (GEO) datasets. Additionally, we performed in vitro differentiation of macrophages, stimulation with coated IgA, and RNA sequencing. Hepa1-6 cells and C57BL/6N mice were used to obtain HCC syngeneic mouse models. RESULTS: Serum IgA levels were associated (p<0.001) with fibrosis progression and HCC development in patients with chronic liver diseases. Additionally, immunohistochemical staining of inflamed livers or HCC revealed IgA positivity in monocytes, with a correlation between IgA+ cell frequency and IgA serum levels. Compared with IgA- monocytes, intrahepatic IgA+ monocytes expressed higher levels of programmed death-ligand 1 (PD-L1) in inflamed livers and in HCC tumor microenvironment. Single-cell RNA sequencing using NCBI GEO database indicated an upregulation in inflammation-associated genes in the monocytes of patients whose plasma cell IGHA1 expression was greater than or equal to the median value. Bulk RNA sequencing demonstrated that in vitro stimulation of M2-polarized macrophages using coated IgA complex induced PD-L1 upregulation via YAP-mediated signaling. In vivo blockade of IgA signaling decreased the number of tumor-infiltrating IgA+PD-L1high macrophages and increased the number of CD69+CD8+ T cells to enhance antitumor effects in HCC mice models. CONCLUSIONS: Overall, the findings of this study showed that serum IgA levels was correlated with intrahepatic and intratumoral infiltration of inflammatory IgA+PD-L1high monocytes in chronic liver diseases and HCC, providing potential therapeutic targets.

Incidence, risk factors, and prognosis of acute kidney injury in hospitalized patients with acute cholangitis.

BACKGROUND: The association between acute cholangitis (AC) and acute kidney injury (AKI) remains unclear. We investigated the incidence, and clinical course of AKI in patients with AC, and the long-term prognosis. METHODS: We performed a single-center retrospective study of patients hospitalized with AC in a tertiary care center from January 2011 to December 2017. The risk factors for AKI were evaluated, and AKI severity was analyzed using the Systemic Inflammatory Response System (SIRS), quick sequential organ failure assessment (qSOFA) score, and 2018 Tokyo Guidelines (TG) grade. To calculate the relative risk of death based on AKI, hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained using Cox's proportional hazard models. RESULTS: A total of 1,438 patients with AC were included, of whom 18.2% (n = 261) developed AKI. AKI patients were older, and had a lower systolic blood pressure and more comorbidities including hypertension (HT), chronic kidney disease, and cardiovascular accidents. Disease severity (as assessed by SIRS, qSOFA, and the Tokyo Guidelines grade) was higher in the AKI group, as was the in-hospital mortality rate. Multivariate analysis revealed that age, HT, SIRS and qSOFA scores ≥ 2, and TG grade of III were significant risk factors for AKI. Kaplan-Meier analysis revealed significantly higher mortality in the AKI than non-AKI group. AKI (HR = 1.853; 95% CI: 1.115-3.079) and TG grade III (HR = 2.139; 95% CI: 1.190-3,846) were independent predictors of all-cause AC mortality, even after adjusting for all covariates. The annual rate of decline in the estimated glomerular filtration rate was faster in the AKI than non-AKI group (2.9 ± 6.7 vs. 0.5 ± 5.3 mL/min/1.73 m2/year, p < 0.001). CONCLUSIONS: AKI development increased AC severity and mortality. Our results suggest that clinicians should monitor AKI status and perform appropriate management as soon as possible.

Renoprotective Effect of KLF2 on Glomerular Endothelial Dysfunction in Hypertensive Nephropathy.

Kruppel-like factor 2 (KLF2) regulates endothelial cell metabolism; endothelial dysfunction is associated with hypertension and is a predictor of atherosclerosis development and cardiovascular events. Here, we investigated the role of KLF2 in hypertensive nephropathy by regulating KLF2 expression in human primary glomerular endothelial cells (hPGECs) and evaluating this expression in the kidney tissues of a 5/6 nephrectomy mouse model as well as patients with hypertension. Hypertension-mimicking devices and KLF2 siRNA were used to downregulate KLF2 expression, while the expression of KLF2 was upregulated by administering simvastatin. After 4 mmHg of pressure was applied on hPGECs for 48 h, KLF2 mRNA expression decreased, while alpha-smooth muscle actin (αSMA) mRNA expression increased. Apoptosis and fibrosis rates were increased under pressure, and these phenomena were aggravated following KLF2 knockdown, but were alleviated after simvastatin treatment; additionally, these changes were observed in angiotensin II, angiotensin type-1 receptor (AT1R) mRNA, and interleukin-18 (IL-18), but not in angiotensin type-2 receptor mRNA. Reduced expression of KLF2 in glomerular endothelial cells due to hypertension was found in both 5/6 nephrectomy mice and patients with hypertensive nephropathy. Thus, our study demonstrates that the pressure-induced apoptosis and fibrosis of glomerular endothelial cells result from angiotensin II, AT1R activation, and KLF2 inhibition, and are associated with IL-18.

Impact of DBP on all-cause and cardiovascular mortality: results from the National Health and Nutrition Examination survey, 1999-2014.

INTRODUCTION: Hypertension is common and has a significant effect on cardiovascular morbidity and death. However, despite the development of several guidelines to manage SBP, there is little research or guidance on the evaluation and management of DBP or isolated diastolic hypertension (IDH). METHOD: To determine the association of DBP with all-cause and cardiovascular mortality, we used NHANES data from 1999 to 2014 and included adults aged at least 18 years. The relationship between DBP, IDH and all-cause, cardiovascular mortality was evaluated. RESULTS: Of the 35 109 participants, all-cause death occurred in 10.6%, and cardiovascular death occurred in 2.1% over a median follow-up of 7.2 years. Multivariate Cox regression analysis revealed that the risk of all-cause mortality was significantly higher in the lowest (≤56.9 mmHg) DBP groups than in the reference group (DBP 74-76.9 mmHg). However, the risk of cardiovascular mortality was significantly higher in the lowest and highest (≥83 mmHg) DBP group than in the reference group. The risk of all-cause mortality was higher for most groups with SBP at least 140 mmHg than for the reference group with DBP 74-76.9 mmHg and SBP 100-139.9 mmHg. Both the 2018 ESC/NICE and the 2017 AHA/ACC-defined IDH was not significantly associated with all-cause mortality. CONCLUSION: DBP and all-cause mortality had an inverse relationship, whereas DBP and cardiovascular mortality had a U-shaped relationship, with the DBP reference group having the lowest risk for all-cause and cardiovascular mortality. There was no significant relationship between IDH and death.