Clinical significance of urinary inflammatory biomarkers in patients with IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis, although the definitive markers are unknown. We aimed to investigate the clinical significance of urinary cytokines in patients with IgAN. METHODS: From 2009 to 2018, the patients were divided into three groups: IgAN (n = 191), disease control (n = 53), and normal control (n = 76). We used a multiplex enzyme-linked immunosorbent assay to measure 16 selected urinary inflammatory cytokines, evaluated the correlation between clinical and pathological features following regression analysis on progression. RESULTS: The IgAN group exhibited significantly different levels of urinary cytokines compared to the normal control and disease control groups. Urinary levels of B-cell-activating factor, vascular endothelial growth factor receptor-2, monocyte chemoattractant protein-1, C-X-C motif chemokine 10, C-X-C motif ligand 16, epidermal growth factor (EGF), endocan, endostatin, growth/differentiation factor-15 (GDF-15), interleukin-6 (IL-6), mannose-binding lectin, transferrin receptor, and kidney injury molecule-1 were significantly correlated with both the estimated glomerular filtration rate and urine protein-creatinine ratio. In a multivariate Cox regression analysis, urinary EGF (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.17-0.95, P = 0.04), GDF-15 (HR 2.45, 95% CI 1.01-5.94, P = 0.048), and IL-6 (HR 3.02, 95% CI 1.05-8.64, P = 0.04) were associated with progression in IgAN. CONCLUSIONS: Urinary inflammatory biomarkers may serve as alternative predictive biomarkers in patients with IgAN. Further studies are needed to elucidate the physiological mechanisms and confirm the results.

Cell Type- and Age-Specific Expression of lncRNAs across Kidney Cell Types.

BACKGROUND: Accumulated evidence demonstrates that long non-coding RNAs (lncRNAs) regulate cell differentiation and homeostasis, influencing kidney aging and disease. Despite their versatility, the function of lncRNA remains poorly understood due to the lack of a reference map of lncRNA transcriptome in various cell types. METHODS: In this study, we employed a targeted single-cell RNA sequencing (scRNA-seq) method to enrich and characterize lncRNAs in individual cells. We applied this method to various mouse tissues, including normal and aged kidneys. RESULTS: Through tissue-specific clustering analysis, we identified cell type-specific lncRNAs that showed a high correlation with known cell-type marker genes. Furthermore, we constructed gene regulatory networks (GRNs) to explore the functional roles of differentially expressed lncRNAs in each cell type. In the kidney, we observed dynamic expression changes of lncRNAs during aging, with specific changes in glomerular cells. These cell type- and age-specific expression patterns of lncRNAs provide insights into their potential roles in regulating cellular processes, such as immune response and energy metabolism, during kidney aging. CONCLUSIONS: Our study sheds light on the comprehensive landscape of lncRNA expression and function and provides a valuable resource for future analysis of lncRNAs (https://gist-fgl.github.io/sc-lncrna-atlas/).

Single-cell lineage tracing approaches to track kidney cell development and maintenance.

The kidney is a complex organ consisting of various cell types. Previous studies have aimed to elucidate the cellular relationships among these cell types in developing and mature kidneys using Cre-loxP-based lineage tracing. However, this methodology falls short of fully capturing the heterogeneous nature of the kidney, making it less than ideal for comprehensively tracing cellular progression during kidney development and maintenance. Recent technological advancements in single-cell genomics have revolutionized lineage tracing methods. Single-cell lineage tracing enables the simultaneous tracing of multiple cell types within complex tissues and their transcriptomic profiles, thereby allowing the reconstruction of their lineage tree with cell state information. Although single-cell lineage tracing has been successfully applied to investigate cellular hierarchies in various organs and tissues, its application in kidney research is currently lacking. This review comprehensively consolidates the single-cell lineage tracing methods, divided into 4 categories (clustered regularly interspaced short palindromic repeat [CRISPR]/CRISPR-associated protein 9 [Cas9]-based, transposon-based, Polylox-based, and native barcoding methods), and outlines their technical advantages and disadvantages. Furthermore, we propose potential future research topics in kidney research that could benefit from single-cell lineage tracing and suggest suitable technical strategies to apply to these topics.

Comparison of Humoral Response between Third and Fourth Doses of COVID-19 Vaccine in Hemodialysis Patients.

Dialysis patients are more likely to die or become hospitalized from coronavirus disease 2019 (COVID-19). Currently, only a few studies have evaluated the efficacy of a fourth booster vaccination in hemodialysis (HD) patients and there is not enough evidence to recommend for or against a fourth booster vaccination. This study compared the humoral response and disease severity of patients on HD who received either three or four doses of COVID-19 vaccine. A total of 88 patients were enrolled. Humoral response to vaccination was measured by quantifying immunoglobulin G levels against the receptor binding domain of SARS-CoV-2 (anti-RBD IgG) at five different times and plaque reduction neutralization tests (PRNT) at two different times after vaccination over a period of 18 months. Antibody levels were measured at approximately two-month intervals after the first and second dose, then four months after the third dose, and then one to six months after the fourth dose of vaccine. PRNT was performed two months after the second and four months after the third dose of vaccine. We classified patients into four groups according to the number of vaccine doses and presence of COVID-19 infection. Severe infection was defined as hospital admission for greater than or equal to two weeks or death. There was no difference in antibody levels between naïve and infected patients except after a fourth vaccination, which was effective for increasing antibodies in infection-naïve patients. Age, sex, body mass index (BMI), dialysis vintage, and presence of diabetes mellitus (DM) did not show a significant correlation with antibody levels. Four patients who experienced severe COVID-19 disease tended to have lower antibody levels prior to infection. A fourth dose of SARS-CoV-2 vaccine significantly elevated antibodies in infection-naïve HD patients and may be beneficial for HD patients who have not been previously infected with SARS-CoV-2 for protection against severe infection.

Clinical significance of urinary exosomal microRNAs in patients with IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. The clinical relevance of 11 urinary exosomal microRNAs (miRNAs) was evaluated in patients with IgAN. From January 2009 to November 2018, IgAN (n = 93), disease control (n = 11), and normal control (n = 19) groups were enrolled. We evaluated the expression levels of urinary exosomal miRNAs at the baseline and their relationship with clinical and pathologic features. This study aimed to discriminate statistically powerful urinary exosomal miRNAs for the prognosis of IgAN. Urinary miRNA levels of miR-16-5p, miR-29a-3p, miR-124-3p, miR-126-3p, miR-199a-3p, miR-199b-5p, and miR-335-3p showed significant correlation with both estimated glomerular filtration rate (eGFR) and urine protein-to-creatinine ratio (uPCR). In univariate regression analysis, age, body mass index, hypertension, eGFR, uPCR, Oxford classification E, and three miRNAs (miR-16-5p, miR-199a-3p, and miR-335-3p) were associated with disease progression in patients with IgAN. The area under the curve (AUC) of miR-199a-3p was high enough (0.749) without any other clinical or pathologic factors, considering that the AUC of the International IgAN Risk Prediction Tool was 0.853. Urinary exosomal miRNAs may serve as alternative prognostic biomarkers of IgAN with further research.

Corrigendum: Development and validation of urinary exosomal microRNA biomarkers for the diagnosis of acute rejection in kidney transplant recipients.

[This corrects the article DOI: 10.3389/fimmu.2023.1190576.].

Discordant renal progression of Fabry disease in male monozygotic twins: a case report.

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the GLA gene that encodes α-galactosidase A (α-GAL). Clinical phenotypes tend to vary in monozygotic female twins because mutations are located on the X-chromosome, whereas similar phenotypes are found in male monozygotic twins. Here we report the case of male monozygotic twins with FD presenting with distinguishable renal phenotypes. Case: A 49-year-old male patient who visited the hospital with proteinuria 14 years prior was readmitted for the same issue. His monozygotic twin brother had started hemodialysis 6 months prior due to renal failure of unknown origin. The patient's renal function was within the normal range, while his spot urine protein-to-creatinine ratio was 557 mg/g. Echocardiography revealed left ventricular hypertrophy (LVH). The findings of a renal biopsy were consistent with FD. Genetic testing identified a c.656T>C mutation in the GLA gene, and α-GAL activity was significantly decreased. Genetic screening of his family clarified that his mother, older sister, twin brother, and his daughter had the same genetic mutations. The patient received enzyme replacement therapy 34 times. Subsequently, migalastat was initiated that continues today. Renal function and proteinuria remain stable, and the LVH has mildly improved. Conclusion: This is the first case of male monozygotic twins expressing different progressions of FD. Our findings demonstrate the possibility that environmental or epigenetic factors may critically influence genotype-phenotype discordance.

Development and validation of urinary exosomal microRNA biomarkers for the diagnosis of acute rejection in kidney transplant recipients.

Introduction: Acute rejection (AR) continues to be a significant obstacle for short- and long-term graft survival in kidney transplant recipients. Herein, we aimed to examine urinary exosomal microRNAs with the objective of identifying novel biomarkers of AR. Materials and methods: Candidate microRNAs were selected using NanoString-based urinary exosomal microRNA profiling, meta-analysis of web-based, public microRNA database, and literature review. The expression levels of these selected microRNAs were measured in the urinary exosomes of 108 recipients of the discovery cohort using quantitative real-time polymerase chain reaction (qPCR). Based on the differential microRNA expressions, AR signatures were generated, and their diagnostic powers were determined by assessing the urinary exosomes of 260 recipients in an independent validation cohort. Results: We identified 29 urinary exosomal microRNAs as candidate biomarkers of AR, of which 7 microRNAs were differentially expressed in recipients with AR, as confirmed by qPCR analysis. A three-microRNA AR signature, composed of hsa-miR-21-5p, hsa-miR-31-5p, and hsa-miR-4532, could discriminate recipients with AR from those maintaining stable graft function (area under the curve [AUC] = 0.85). This signature exhibited a fair discriminative power in the identification of AR in the validation cohort (AUC = 0.77). Conclusion: We have successfully demonstrated that urinary exosomal microRNA signatures may form potential biomarkers for the diagnosis of AR in kidney transplantation recipients.

Correction: Kim et al. The Medium Cut-Off Membrane Does Not Lower Protein-Bound Uremic Toxins. Toxins 2022, 14, 779.

In the original publication [...].

High physical activity alleviates the adverse effect of higher sedentary time on the incidence of chronic kidney disease.

BACKGROUND: Low physical activity (PA) increases the prevalence of chronic kidney disease (CKD). This study aimed to investigate the effects of PA and sedentary time (ST) on the changes in renal function and the development of CKD in the middle-aged Korean population. METHODS: From the Korean Genome and Epidemiology Study Database, 7988 participants in their 40s and 60s were identified and stratified by (1) PA: high-PA (>24 MET-h/day), moderate-PA (9-24 MET-h/day) and low-PA (<9 MET-h/day); and (2) ST: high-ST (>6 h/day), moderate-ST (3-6 h/day) and low-ST (<3 h/day). Incident CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 following the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS: The mean age of the participants was 52.0 years. The overall incidence of CKD was 16.8 per 1000 person-years over a median of 12 years. The lower the PA and the higher the ST, the lower the baseline eGFR. Relative to the high-PA, the coefficients of the annual eGFR decline were -0.12 (95% confidence interval [CI]: -0.26 to 0.001, P = 0.081) and -0.13 (95% CI: -0.27 to 0.01, P = 0.078) in the moderate- and low-PA groups, respectively. Similarly, relative to the low-ST, the coefficients of annual eGFR decline were -0.07 (59% CI: -0.19 to 0.05, P = 0.236) and -0.14 (95% CI: -0.28 to -0.01, P = 0.039) in the moderate- and high-ST groups, respectively. Incident CKD was higher with lower PA (hazard ratio: high-PA 1.00, moderate-PA 1.13 [1.00, 1.28, P = 0.056] and low-PA 1.25 [1.11, 1.24, P < 0.001]) and higher ST (hazard ratio: low-ST 1.00, moderate-ST 1.04 [0.94, 1.16, P = 0.440] and high-ST 1.19 [1.05, 1.34, P = 0.007]). The high-PA reduced the risk for the CKD development irrespective of the amount of ST. CONCLUSIONS: Low-PA and high-ST are risk factors for the development of CKD in the middle-aged Korean population. High-PA recovers high-ST, inducing a harmful effect on the occurrence of CKD.

Urine Exosomal bkv-miR-B1-5p and BK Virus Nephropathy in Kidney Transplant Recipients.

BACKGROUND: Urine exosomal bkv-miR-B1-5p is associated with BK virus (BKV) nephropathy (BKVN); however, its posttransplantation changes and predictability for BKVN have not been determined in kidney transplant recipients (KTRs). METHODS: Urine exosomal bkv-miR-B1-5p and urine and plasma BKV DNA were measured at 2 weeks and 3, 6, and 12 months posttransplant in 83 KTRs stratified into biopsy-proven or presumptive BKVN, BKV viruria, and no evidence of BKV reactivation. Joint model, multivariable Cox model and receiver operating characteristic curve (ROC) were used to investigate the association of each assay with the following events: a composite of biopsy-proven or presumptive BKVN, and biopsy-proven BKVN. RESULTS: Urine exosomal bkv-miR-B1-5p and urine and plasma BKV DNA showed similar posttransplant time-course changes. Joint models incorporating serial values demonstrated significant associations of all assays with the events, and Cox analyses using single time point values at 2 weeks posttransplant showed that only urine exosomal bkv-miR-B1-5p was significantly associated with the events, although it did not outperform urine BKV DNA in ROC analyses. CONCLUSIONS: Urine exosomal bkv-miR-B1-5p was associated with BKVN as were urine and plasma BKV DNA loads on serial follow-up, and might have potential as a predictive marker for BKVN during the early posttransplant period. CLINICAL TRIALS REGISTRATION: Clinical Research Information Service (https://cris.nih.go.kr/cris/), KCT0001010.

The Medium Cut-Off Membrane Does Not Lower Protein-Bound Uremic Toxins.

The accumulation of protein-bound uremic toxins (PBUT) is associated with increased cardiovascular outcomes in patients on dialysis. However, the efficacy of PBUT removal for a medium-cutoff (MCO) membrane has not been clarified. This study was designed to assess the efficacy of PBUT clearance according to dialysis modalities. In this prospective and cross-over study, we enrolled 22 patients who received maintenance hemodiafiltration (HDF) thrice weekly from three dialysis centers. The dialysis removal of uremic toxins, including urea, beta 2-microglobulin (B2MG), lambda free light chain (λ-FLC), indoxyl sulfate (IS), and p-cresyl sulfate (pCS), was measured in the 22 patients on high-flux HD (HF-HD), post-dilution online HDF (post-OL-HDF), and MCO-HD over 3 weeks. The average convection volume in post-OL-HDF was 21.4 ± 1.8 L per session. The reduction rate (RR) of B2MG was higher in post-OL-HDF than in MCO-HD and HF-HD. The RR of λ-FLC was the highest in MCO-HD, followed by post-OL-HDF and HF-HD. The dialysate albumin was highest in MCO-HD, followed by post-OL-HDF and HF-HD. Post-dialysis plasma levels of IS and pCS were not statistically different across dialysis modalities. The total solute removal and dialytic clearance of IS and pCS were not significantly different. The clearance of IS and pCS did not differ between the HF-HD, post-OL-HDF, and MCO-HD groups.

Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Response After Heterologous Immunizations With ChAdOx1/BNT162b2 in End-Stage Renal Disease Patients on Hemodialysis.

The Korean government decided to schedule heterologous vaccinations on dialysis patients for early achievement of immunization against Coronavirus disease 2019(COVID-19). However, the effects of heterologous immunizations in hemodialysis (HD) patients are unclear. One hundred (HD) patients from Gangdong Kyung Hee University Hospital and Kyung Hee Medical Center and 100 hospital workers from Gangdong Kyung Hee University Hospital were enrolled in this study. The HD patients received the mixing schedule of ChAdOx1/BNT162b2 vaccinations at 10-week intervals, while hospital workers received two doses of ChAdOx1 vaccines at 12-week intervals. Serum IgG to a receptor-binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2 was measured 1 month after the first dose, 2 months and 4 months after the second dose. The median [interquartile range] anti-RBD IgG was 82.1[34.5, 176.6] AU/ml in HD patients and 197.1[124.0, 346.0] AU/ml in hospital workers (P < 0.001) after the first dose. The percentage of positive responses (IgG > 50 AU/ml) was 65.0% and 96.0% among the both group, respectively (P < 0.001). The anti-RBD IgG levels increased significantly by 2528.8 [1327.6, 5795.1] AU/ml with a 100.0% positive response rate in HD patients 2 months after the second dose, which was higher than those in hospital workers 981.4[581.5, 1891.4] AU/ml (P < 0.001). Moreover, anti-RBD IgG remains constantly high, and positive response remains 100% in HD patients 4 months after the second dose. This study suggests that heterologous vaccinations with ChAdOx1/BNT162b2 can be an alternative solution on HD patients for early and strong induction of humoral response.

Three-Dimensional Visualization With Tissue Clearing Uncovers Dynamic Alterations of Renal Resident Mononuclear Phagocytes After Acute Kidney Injury.

Traditional histologic methods are limited in detecting dynamic changes in immune cells during acute kidney injury (AKI). Recently, optical tissue clearing combined with multiphoton microscopy (MPM) or light sheet fluorescence microscopy (LSFM) has become an emerging method for deep tissue evaluation and three-dimensional visualization. These new approaches have helped expand our understanding of tissue injury and repair processes, including tracing the changes in immune cells. We designed this study to investigate the morphological and functional alterations of renal mononuclear phagocytes (MNPs) in lipopolysaccharide (LPS)-induced AKI using renal clearing in CD11c-YFP mice. We also evaluated the effect of the NLRP3 inhibitor MCC950 to determine whether NLRP3 inhibition attenuates the activation of CD11c+ cells in an LPS-induced AKI model. Transverse sectioned whole mouse kidney imaging by LSFM showed that CD11c+ cells were mainly distributed in the cortex, especially the tubulointerstitial area. The number of CD11c+ cells was significantly more densely interspersed, particularly in periglomerular and perivascular lesions, in the saline-treated LPS-exposed kidney than in the control kidney. Deep imaging of the kidney cortex by MPM demonstrated an increased number of CD11c+ cells in the saline-treated LPS group compared with the control group. This quantitative alteration of CD11c+ cells in AKI was accompanied by morphological changes at high resolution, showing an increased number and level of dendrites. These morphological and behavioral changes in the saline-treated LPS group were accompanied by increased MHC class II and CD86 on CD11c-YFP+ cells. MCC950 attenuated the activation of CD11c+ cells after AKI and improved renal function. In conclusion, wide and deep three-dimensional visualization using MPM or LSFM combined with kidney clearing uncovers dynamic changes of renal MNPs, which are directly linked to renal function in AKI.

Midbody plays an active role in fibroblast-myofibroblast transition by mediating TGF-ß signaling.

The transition of fibroblasts into myofibroblasts is a crucial step in kidney fibrosis. However, the biological processes involved in this transdifferentiation are incompletely understood. In this study, we discovered that the midbody plays a role in the fibroblast-myofibroblast transition by mediating TGF-ß/Smad signaling. Combining bulk RNA-seq, histology, and the western blot of unilateral ureteral obstruction kidneys, we demonstrated that the pathway related to microtubules is implicated in kidney fibrosis, and the blocking of microtubule dynamics by colchicine improved kidney fibrosis. Subsequently, to explore microtubule-based organelles in detail, we cultured NRK-49F (rat kidney fibroblast cell line) and HKC-8 (human proximal tubule cell line) under transforming growth factor-ß1 (TGF-ß1) stimulation, which caused deciliation in both cell lines during epithelial-mesenchymal and fibroblast-myofibroblast transition. We identified another microtubule-based organelle, the midbody, whose formation is promoted by TGF-ß1 in fibroblasts as a result of proliferation in contrast to tubular cells. Notably, TGF-ß receptors were present in the midbody of both cell lines. In TGF-ß1-treated fibroblasts, colchicine or Hedgehog pathway inhibitor 4 impaired the midbody formation, and attenuated the upregulation of canonical TGF-ß/Smad signaling and α-SMA expression. These findings offer novel insight into the midbody as an active organelle involved in fibroblast-myofibroblast transition by mediating TGF-ß/Smad signaling, which could be a potential therapeutic target.

Risk of malignancy in kidney transplant recipients: a nationwide population-based cohort study.

BACKGROUND: Post-transplant malignancy is major morbidity complicated in kidney transplantation (KT). In Korea, a few studies have investigated the sex- and age-dependent risk for post-transplant malignancy among KT recipients on a large scale. METHODS: We utilized a national health insurance database in Korea to investigate the relative risk of post-transplant malignancy in 12,634 KT recipients between 2007 and 2017. The same number of patients with acute appendicitis was included as a control group. The relative risk of malignancy was estimated using a multivariable-adjusted Cox model, and interaction analysis was performed to investigate age- and sex-predominant patterns. RESULTS: KT recipients had an overall 1.8-fold higher risk for post-transplant malignancy with an increased risk for 14 of 29 cancer types, among which Kaposi's sarcoma, non-Hodgkin's lymphoma, kidney, uterus, and bladder/urinary tract cancers were most prominent. Although the overall risk for post-transplant malignancy was similar between male and female KT recipients, head and neck cancer had a higher risk among male KT recipients, whereas non-Hodgkin's lymphoma and bladder/urinary tract cancer had a higher risk among female KT recipients. Overall, the young (< 50 years) KT recipients had a higher risk for post-transplant malignancy than older ones (≥ 50 years), whose pattern was most prominent in non-Hodgkin's lymphoma. In contrast, breast and nonmelanoma skin cancer showed a higher risk among older KT recipients. CONCLUSION: KT recipients had an increased risk for a wide range of cancer types, some of which showed differential risk patterns with age and sex. Our result suggests that focused screening for predominant post-transplant malignancies may be an effective strategy for selected KT recipients.

PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans.

Intracranial aneurysm (IA) rupture leads to subarachnoid hemorrhage, a sudden-onset disease that often causes death or severe disability. Although genome-wide association studies have identified common genetic variants that increase IA risk moderately, the contribution of variants with large effect remains poorly defined. Using whole-exome sequencing, we identified significant enrichment of rare, deleterious mutations in PPIL4, encoding peptidyl-prolyl cis-trans isomerase-like 4, in both familial and index IA cases. Ppil4 depletion in vertebrate models causes intracerebral hemorrhage, defects in cerebrovascular morphology and impaired Wnt signaling. Wild-type, but not IA-mutant, PPIL4 potentiates Wnt signaling by binding JMJD6, a known angiogenesis regulator and Wnt activator. These findings identify a novel PPIL4-dependent Wnt signaling mechanism involved in brain-specific angiogenesis and maintenance of cerebrovascular integrity and implicate PPIL4 gene mutations in the pathogenesis of IA.

The role of inflammation in diabetic kidney disease.

Diabetic kidney disease (DKD) has been the leading cause of chronic kidney disease for over 20 years. Yet, over these two decades, the clinical approach to this condition has not much improved beyond the administration of glucose-lowering agents, renin-angiotensin-aldosterone system blockers for blood pressure control, and lipid-lowering agents. The proportion of diabetic patients who develop DKD and progress to end-stage renal disease has remained nearly the same. This unmet need for DKD treatment is caused by the complex pathophysiology of DKD, and the difficulty of translating treatment from bench to bed, which further adds to the growing argument that DKD is not a homogeneous disease. To better capture the full spectrum of DKD in our design of treatment regimens, we need improved diagnostic tools that can better distinguish the subgroups within the condition. For instance, DKD is typically placed in the broad category of a non-inflammatory kidney disease. However, genome-wide transcriptome analysis studies consistently indicate the inflammatory signaling pathway activation in DKD. This review will utilize human data in discussing the potential for redefining the role of inflammation in DKD. We also comment on the therapeutic potential of targeted anti-inflammatory therapy for DKD.

A Cell-Penetrating Peptide That Blocks Toll-Like Receptor Signaling Protects Kidneys against Ischemia-Reperfusion Injury.

Renal ischemia-reperfusion injury (IRI) is involved in the majority of clinical conditions that manifest as renal function deterioration; however, specific treatment for this type of injury is still far from clinical use. Since Toll-like receptor (TLR)-mediated signaling is a key mediator of IRI, we examined the effect of a multiple-TLR-blocking peptide named TLR-inhibitory peptide 1 (TIP1), which exerts the strongest action on TLR4, on renal IRI. We subjected C57BL/6 mice to 23 min of renal pedicle clamping preceded by intraperitoneal injection with a vehicle or TIP1. Sham control mice underwent flank incision only. Mouse kidneys were harvested after 24 h of reperfusion for histology, western blot, RT-PCR, and flow cytometry analysis. Pretreatment with TIP1 lowered the magnitude of elevated plasma creatinine levels and attenuated tubular injury. TIP1 treatment also reduced mRNA expression of inflammatory cytokines and decreased apoptotic cells and oxidative stress in post-ischemic kidneys. In kidneys pretreated with TIP1, the infiltration of macrophages and T helper 17 cells was less abundant than those in the IRI only group. These results suggest that TIP1 has a potential beneficial effect in attenuating the degree of kidney damage induced by IRI.

Clinical Decision Support System Based on Hybrid Knowledge Modeling: A Case Study of Chronic Kidney Disease-Mineral and Bone Disorder Treatment.

Clinical decision support systems (CDSSs) represent the latest technological transformation in healthcare for assisting clinicians in complex decision-making. Several CDSSs are proposed to deal with a range of clinical tasks such as disease diagnosis, prescription management, and medication ordering. Although a small number of CDSSs have focused on treatment selection, areas such as medication selection and dosing selection remained under-researched. In this regard, this study represents one of the first studies in which a CDSS is proposed for clinicians who manage patients with end-stage renal disease undergoing maintenance hemodialysis, almost all of whom have some manifestation of chronic kidney disease-mineral and bone disorder (CKD-MBD). The primary objective of the system is to aid clinicians in dosage prescription by levering medical domain knowledge as well existing practices. The proposed CDSS is evaluated with a real-world hemodialysis patient dataset acquired from Kyung Hee University Hospital, South Korea. Our evaluation demonstrates overall high compliance based on the concordance metric between the proposed CKD-MBD CDSS recommendations and the routine clinical practice. The concordance rate of overall medication dosing selection is 78.27%. Furthermore, the usability aspects of the system are also evaluated through the User Experience Questionnaire method to highlight the appealing aspects of the system for clinicians. The overall user experience dimension scores for pragmatic, hedonic, and attractiveness are 1.53, 1.48, and 1.41, respectively. A service reliability for the Cronbach's alpha coefficient greater than 0.7 is achieved using the proposed system, whereas a dependability coefficient of the value 0.84 reveals a significant effect.