Roxadustat on Renal Anemia with Macroinflammation: A Retrospective Cohort Study.

Introduction: Roxadustat, the first-in-class drug for the treatment of renal anemia, has demonstrated efficacy in renal anemia with microinflammation. Additional data are needed regarding the efficacy of roxadustat on renal anemia with systemic macroinflammation. Methods: Three cohorts of renal anemia based on the basic level of high-sensitivity CRP were included. Patients with hsCRP ≤2 mg/L were selected as non-inflammation (NI) group; 2< hsCRP ≤10 mg/L as microinflammation (MI) group; hsCRP≥10 mg/L as macroinflammation (MA) group. Patients received oral roxadustat three times per week for 52 weeks. The primary end point was the hemoglobin level over weeks 12-52. The second end point was the cumulative proportion of patients achieving hemoglobin response by the end of week 12. Results: A total of 107 patients with chronic kidney diseases (CKDs) were enrolled. Overall, the baseline hemoglobin level of patients was 79.99 ± 11.20 g/L. Roxadustat could significantly increase the hemoglobin level in all of the three groups and did not show any significant difference (p > 0.05, respectively). Meanwhile, compared with that of the NI group, there was no significant difference in hemoglobin response rate in the MA group both at week 12 (p = 0.06; 95% confidence interval [CI], 0.9531-13.75) and week 52 (p = 0.37; 95% CI, 0.5080-7.937). Moreover, the hemoglobin response was independent of baseline hsCRP level (p = 0.72, 95% CI, -0.1139 to 0.0794). More importantly, roxadustat significantly reduced ferritin and serum iron levels and increased total iron-binding capacity in the three groups, which showed no significant differences among the three groups (p > 0.05, respectively). Conclusion: Roxadustat significantly improves anemia in CKD patients with systemic macroinflammation.

A Chinese Multi-Specialty Delphi Consensus to Optimize RAASi Usage and Hyperkalaemia Management in Patients with Chronic Kidney Disease and Heart Failure.

Objective: Variations are present in common clinical practices regarding best practice in managing hyperkalaemia (HK), there is therefore a need to establish a multi-specialty approach to optimal renin-angiotensin-aldosterone system inhibitors (RAASi) usage and HK management in patients with chronic kidney disease (CKD) & heart failure (HF).This study aimed to establish a multi-speciality approach to the optimal use of RAASi and how to manage HK in patients with CKD and HF.Methods: A steering expert group of cardiology and nephrology experts from across China convened to discuss challenges to HK management through a nominal group technique (NGT). The group then created a list of 41 statements for a consensus questionnaire, which was distributed for a further survey of in extended panel group of cardiologists and nephrologists across China. Consensus was assessed using a modified Delphi technique, with agreement defined as "strong" (≥75% and <90%) and "very strong" (≥90%). The steering group, data collection, and analysis were aided by an independent facilitator. Results: A total of 150 responses from 21 provinces across China were recruited in the survey. Respondents were comprised of an even split (n=75, 50%) between cardiologists and nephrologists. All 41 statements achieved the 75% consensus agreement threshold, of which 27 statements attained very strong consensus (≥90% agreement) and 14 attained strong consensus (agreement between 75% and 90%). Conclusions: Based on the agreement levels from respondents, the steering group agreed a set of recommendations intended to improve patient outcomes in the use of RAASi therapy and HK management in China.

Erratum: Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury: Erratum.

[This corrects the article DOI: 10.7150/thno.54550.].

CD8 T cells induce the peritubular capillary rarefaction during AKI to CKD transition.

Acute kidney injury (AKI) transformed to chronic kidney disease (CKD) is a critical clinical issue characterized by tubulointerstitial inflammation (TII) and fibrosis. However, the exact mechanism remains largely unclear. In this study, we used single-cell RNA sequencing (scRNA-seq) to obtain a high-resolution profile of T cells in AKI to CKD transition with a mice model of unilateral ischemia-reperfusion injury (uIRI). We found that T cells accumulated increasingly with the progression of AKI to CKD, which was categorized into 9 clusters. A notably increased proportion of CD8 T cells via self-proliferation occurred in the early stage of AKI was identified. Further study revealed that the CD8 T cells were recruited through CXCL16-CXCR6 pathway mediated by macrophages. Notably, CD8 T cells induced endothelial cell apoptosis via Fas ligand-Fas signaling. Consistently, increased CD8 T cell infiltration accompanied with peritubular capillaries (PTCs) rarefaction was observed in uIRI mice. More impressively, the loss of PTCs and renal fibrosis was remarkably ameliorated after the elimination of CD8 T cells. In summary, our study provides a novel insight into the role of CD8 T cells in the transition from AKI to CKD via induction of PTCs rarefaction, which could suggest a promising therapeutic target for AKI.

Identification of stable reference genes for relative quantification of long RNA expression in urinary extracellular vesicles.

Urinary extracellular vesicles (uEVs) are rich in valuable biomolecule information which are increasingly recognized as potential biomarkers for various diseases. uEV long RNAs are among the critical cargos capable of providing unique transcriptome information of the source cells. However, consensus regarding ideal reference genes for relative long RNAs quantification in uEVs is not available as of date. Here we explored stable reference genes through profiling the long RNA expression by RNA-seq following unsupervised analysis and validation studies. Candidate reference genes were identified using four algorithms: NormFinder, GeNorm, BestKeeper and the Delta Ct method, followed by validation. RNA profile showed uEVs contained abundant long RNAs information and the core transcriptome was related to cellular structures, especially ribosome which functions mainly as translation, protein and RNA binding molecules. Analysis of RNA-seq data identified RPL18A, RPL11, RPL27, RACK1, RPSA, RPL41, H1-2, RPL4, GAPDH, RPS27A as candidate reference genes. RT-qPCR validation revealed that RPL41, RPSA and RPL18A were reliable reference genes for long RNA quantification in uEVs from patients with diabetes mellitus (DM), diabetic nephropathy (DN), IgA nephropathy (IgAN) and prostate cancer (PCA). Interestingly, RPL41 also outperformed traditional reference genes in renal tissues of DN and IgAN, as well as in plasma EVs of several types of cancers. The stable reference genes identified in this study may facilitate development of uEVs as novel biomarkers and increase the accuracy and comparability of biomarker studies.

Podocyte-derived soluble RARRES1 drives kidney disease progression through direct podocyte and proximal tubular injury.

Retinoic acid receptor responder protein-1 (RARRES1) is a podocyte-enriched transmembrane protein whose increased expression correlates with human glomerular disease progression. RARRES1 promotes podocytopenia and glomerulosclerosis via p53-mediated podocyte apoptosis. Importantly, the cytopathic actions of RARRES1 are entirely dependent on its proteolytic cleavage into a soluble protein (sRARRES1) and subsequent podocyte uptake by endocytosis, as a cleavage mutant RARRES1 exerted no effects in vitro or in vivo. As RARRES1 expression is upregulated in human glomerular diseases, here we investigated the functional consequence of podocyte-specific overexpression of RARRES1 in mice in the experimental focal segmental glomerulosclerosis and diabetic kidney disease. We also examined the effects of long-term RARRES1 overexpression on slowly developing aging-induced kidney injury. As anticipated, the induction of podocyte overexpression of RARRES1 (Pod-RARRES1WT) significantly worsened glomerular injuries and worsened kidney function in all three models, while overexpression of RARRES1 cleavage mutant (Pod-RARRES1MT) did not. Remarkably, direct uptake of sRARRES1 was also seen in proximal tubules of injured Pod-RARRES1WT mice and associated with exacerbated tubular injuries, vacuolation, and lipid accumulation. Single-cell RNA sequence analysis of mouse kidneys demonstrated RARRES1 led to a marked deregulation of lipid metabolism in proximal tubule subsets. We further identified matrix metalloproteinase 23 (MMP23) as a highly podocyte-specific metalloproteinase and responsible for RARRES1 cleavage in disease settings, as adeno-associated virus 9-mediated knockdown of MMP23 abrogated sRARRES1 uptake in tubular cells in vivo. Thus, our study delineates a previously unrecognized mechanism by which a podocyte-derived protein directly facilitates podocyte and tubular injury in glomerular diseases and suggests that podocyte-specific functions of RARRES1 and MMP23 may be targeted to ameliorate glomerular disease progression in vivo.

HIF-1α and adaptor protein LIM and senescent cell antigen-like domains protein 1 axis promotes tubulointerstitial fibrosis by interacting with vimentin in angiotensin II-induced hypertension.

BACKGROUND AND PURPOSE: Activation of the renin-angiotensin system, as a hallmark of hypertension and chronic kidney diseases (CKD) is the key pathophysiological factor contributing to the progression of tubulointerstitial fibrosis. LIM and senescent cell antigen-like domains protein 1 (LIMS1) plays an essential role in controlling of cell behaviour through the formation of complexes with other proteins. Here, the function and regulation of LIMS1 in angiotensin II (Ang II)-induced hypertension and tubulointerstitial fibrosis was investigated. EXPERIMENTAL APPROACH: C57BL/6 mice were treated with Ang II to induce tubulointerstitial fibrosis. Hypoxia-inducible factor-1α (HIF-1α) renal tubular-specific knockout mice or LIMS1 knockdown AAV was used to investigate their effects on Ang II-induced renal interstitial fibrosis. In vitro, HIF-1α or LIMS1 was knocked down or overexpressed in HK2 cells after exposure to Ang II. KEY RESULTS: Increased expression of tubular LIMS1 was observed in human kidney with hypertensive nephropathy and in murine kidney from Ang II-induced hypertension model. Tubular-specific knockdown of LIMS1 ameliorated Ang II-induced tubulointerstitial fibrosis in mice. Furthermore, we demonstrated that LIMS1 was transcriptionally regulated by HIF-1α in tubular cells and that tubular HIF-1α knockout ameliorates LIMS1-mediated tubulointerstitial fibrosis. In addition, LIMS1 promotes Ang II-induced tubulointerstitial fibrosis by interacting with vimentin. CONCLUSION AND IMPLICATIONS: We conclude that HIF-1α transcriptionally regulated LIMS1 plays a central role in Ang II-induced tubulointerstitial fibrosis through interacting with vimentin. Our finding represents a new insight into the mechanism of Ang II-induced tubulointerstitial fibrosis and provides a novel therapeutic target for progression of CKD.

Maximizing the Value of Real-World Data and Real-World Evidence to Accelerate Healthcare Transformation in China: Summary of External Advisory Committee Meetings.

Use of real-world data (RWD) is gaining wide attention. To bridge the gap between diverse healthcare stakeholders and to leverage the impact of Chinese real-world evidence (RWE) globally, a multi-stakeholder External Advisory Committee (EAC) and EAC meetings were initiated, aiming to elucidate the current and evolving RWD landscape in China, articulate the values of RWE in ensuring Chinese patients' equitable access to affordable medicines and solutions, and identify strategic opportunities and partnerships for expansion of RWE generation in China. Chinese and international experts who are clinicians and academic researchers were selected as EAC members based on their professional background and familiarity with RWD/RWE. Three EAC meetings were held quarterly in 2023. Various topics were presented and discussed for insights and suggestions. Nine experts from China, one from South Korea, and two from Europe were selected as EAC members and attended these meetings. Experts' presentations were summarized by theme, including the RWD landscape and RWE enablement in China, as well as global development of a patient-centric ecosystem. Experts' insights and suggestions on maximizing the RWD/RWE value to accelerate healthcare transformation in China were collected. We concluded that though data access, sharing, and quality are still challenging, RWD is developing to support evidence generation in the medicinal product lifecycle, inform clinical practice, and empower patient management in China. RWD/RWE creates value, accelerates healthcare transformation, and improves patient outcomes. Fostering a patient-centric ecosystem across healthcare stakeholders and maintaining global partnerships and collaboration are essential for unlocking the power of RWD/RWE.

HIPK2 C-terminal domain inhibits NF-κB signaling and renal inflammation in kidney injury.

HIPK2 is a multifunctional kinase that acts as a key pathogenic mediator of chronic kidney disease and fibrosis. It acts as a central effector of multiple signaling pathways implicated in kidney injury, such as TGF-ß/Smad3-mediated extracellular matrix accumulation, NF-κB-mediated inflammation, and p53-mediated apoptosis. Thus, a better understanding of the specific HIPK2 regions necessary for distinct downstream pathway activation is critical for optimal drug development for CKD. Our study now shows that caspase-6-mediated removal of the C-terminal region of HIPK2 (HIPK2-CT) lead to hyperactive p65 NF-κB transcriptional response in kidney cells. In contrast, the expression of cleaved HIPK2-CT fragment could restrain the NF-κB transcriptional activity by cytoplasmic sequestration of p65 and the attenuation of IκBα degradation. Therefore, we examined whether HIPK2-CT expression can be exploited to restrain renal inflammation in vivo. The induction of HIPK2-CT overexpression in kidney tubular cells attenuated p65 nuclear translocation, expression of inflammatory cytokines, and macrophage infiltration in the kidneys of mice with unilateral ureteral obstruction and LPS-induced acute kidney injury. Collectively, our findings indicate that the HIPK2-CT is involved in the regulation of nuclear NF-κB transcriptional activity and that HIPK2-CT or its analogs could be further exploited as potential antiinflammatory agents to treat kidney disease.

Therapeutic role of miR-26a on cardiaorenal injury in mice model of angiotensin-II induced chronic kidney disease through inhibition of LIMS1/ILK pathway.

BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated a microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t-test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS: Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.

Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects.

Direct tubular injury caused by several medications, especially chemotherapeutic drugs, is a common cause of AKI. Inhibition or loss of cyclin-dependent kinase 12 (CDK12) triggers a transcriptional elongation defect that results in deficiencies in DNA damage repair, producing genomic instability in a variety of cancers. Notably, 10-25% of individuals developed AKI after treatment with a CDK12 inhibitor, and the potential mechanism is not well understood. Here, we found that CDK12 was downregulated in the renal tubular epithelial cells in both patients with AKI and murine AKI models. Moreover, tubular cell-specific knockdown of CDK12 in mice enhanced cisplatin-induced AKI through promotion of genome instability, apoptosis, and proliferative inhibition, whereas CDK12 overexpression protected against AKI. Using the single molecule real-time (SMRT) platform on the kidneys of CDK12RTEC+/- mice, we found that CDK12 knockdown targeted Fgf1 and Cast through transcriptional elongation defects, thereby enhancing genome instability and apoptosis. Overall, these data demonstrated that CDK12 knockdown could potentiate the development of AKI by altering the transcriptional elongation defect of the Fgf1 and Cast genes, and more attention should be given to patients treated with CDK12 inhibitors to prevent AKI.

Mitochondrial fumarate promotes ischemia/reperfusion-induced tubular injury.

AIM: Mitochondrial dysfunction, a characteristic pathological feature of renal Ischemic/reperfusion injury (I/RI), predisposes tubular epithelial cells to maintain an inflammatory microenvironment, however, the exact mechanisms through which mitochondrial dysfunction modulates the induction of tubular injury remains incompletely understood. METHODS: ESI-QTRAP-MS/MS approach was used to characterize the targeted metabolic profiling of kidney with I/RI. Tubule injury, mitochondrial dysfunction, and fumarate level were evaluated using qPCR, transmission electron microscopy, ELISA, and immunohistochemistry. RESULTS: We demonstrated that tubule injury occurred at the phase of reperfusion in murine model of I/RI. Meanwhile, enhanced glycolysis and mitochondrial dysfunction were found to be associated with tubule injury. Further, we found that tubular fumarate, which resulted from fumarate hydratase deficiency and released from dysfunctional mitochondria, promoted tubular injury. Mechanistically, fumarate induced tubular injury by causing disturbance of glutathione (GSH) hemostasis. Suppression of GSH with buthionine sulphoximine administration could deteriorate the fumarate inhibition-mediated tubule injury recovery. Reactive oxygen species/NF-κB signaling activation played a vital role in fumarate-mediated tubule injury. CONCLUSION: Our studies demonstrated that the mitochondrial-derived fumarate promotes tubular epithelial cell injury in renal I/RI. Blockade of fumarate-mediated ROS/NF-κB signaling activation may serve as a novel therapeutic approach to ameliorate hypoxic tubule injury.

Measurement of urinary exosomal phospholipase A2 receptor is a sensitive method for diagnosis of PLA2R-associated membranous nephropathy.

Background: The discovery of phospholipase A2 receptor (PLA2R) and its antibody (aPLA2Rab) has paved the way for diagnosing PLA2R-associated membranous nephropathy (PLA2R-MN) with a high specificity of 98%. However, the sensitivity was only 40% to 83.9%, and there is ongoing discussion around determining the optimal threshold for diagnosis. Recent advancements in the use of exosomes, a novel form of "liquid biopsy," have shown great promise in identifying markers for various medical conditions. Methods: Protein mass spectrometry and western blot were applied to verify the existence of PLA2R antigen in the urine exosome. We then evaluated the efficacy of urinary exosomal PLA2R antigen alone or combined with serum aPLA2Rab level to diagnose PLA2R-MN. Results: The urinary exosomes contained a high abundance of PLA2R antigen as evidenced by protein mass spectrometry and western blot in 85 PLA2R-MN patients vs the disease controls (14 secondary MN patients, 22 non-MN patients and 4 PLA2R-negative MN patients) and 20 healthy controls. Of note, urinary exosomal PLA2R antigen abundance also had a good consistency with the PLA2R antigen level in the renal specimens of PLA2R-MN patients. The sensitivity of urinary exosomal PLA2R for diagnosing PLA2R-MN reached 95.4%, whereas the specificity was 63.3%. Combining detection of the urinary exosomal PLA2R and serum aPLA2Rab could develop a more sensitive diagnostic method for PLA2R-MN, especially for patients with serum aPLA2Rab ranging from 2 to 20 RU/mL. Conclusions: Measurement of urinary exosomal PLA2R could be a sensitive method for the diagnosis of PLA2R-MN.

Safety and effectiveness of HSK21542 for hemodialysis patients: a multiple ascending dose study.

Background: HSK21542, a novel selective peripherally-restricted κ-opioid receptor agonist has been proven to be a safe and effective analgesic and antipruritic drug in both in vitro and in vivo studies. We aimed to evaluate its safety, pharmacokinetics and efficacy in hemodialysis patients over a 1-week treatment period, and to establish the optimal dosage for a further 12-week stage 2 trial. Methods: In this multiple ascending dose study, hemodialysis patients were randomly assigned to receive HSK21542 (0.05-0.80 µg/kg), or a placebo three times within 2.5 h at the end of each dialysis session for 1 week. Safety evaluations included reports of treatment-emergent adverse events (TEAEs); pharmacokinetics and efficacy outcomes were also assessed. Results: Among the 44 screened patients, 41 were enrolled and completed the trial. The overall incidence of TEAEs was higher in the HSK21542 group compared to the placebo group, with an incidence of 75.0%, 50.0%, 75.0%, and 88.9% in the range of 0.05-0.80 µg/kg. All TEAEs were grade 1 or 2 in severity. HSK21542 exhibited linear pharmacokinetics characteristics within the dose range 0.05-0.80 µg/kg, without drug accumulation after multiple-doses. Compared to the placebo, a significant decrease of the weekly mean Worst Itching Intensity Numerical Rating Scale was found in the HSK21542-0.30 µg/kg group (p = 0.046), but without significant improvement in the Skindex-16 score. Conclusion: HSK21542 was well tolerated in the dose range 0.05-0.80 µg/kg in hemodialysis patients. HSK21542-0.3 µg/kg exhibited promising efficacy in patients with moderate to severe pruritus and warrants a further Stage 2 trial. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT04470154.

Elevated serum FGF21 is an independent predictor for adverse events in hemodialysis patients from two large centers: a prospective cohort study.

Introduction: We explored the relationship and the predictive value of serum fibroblast growth factor 21 (FGF21) with all-cause mortality, major adverse cardiovascular events (MACEs) and pneumonia in hemodialysis (HD) patients.Methods: A total of 388 Chinese HD patients from two HD centers were finally enrolled in this prospective cohort study (registration number: ChiCTR 1900028249) between January 2018 and December 2018. Serum FGF21 was detected. Patients were followed up with a median period of 47 months to record the MACEs and pneumonia until death or 31 December 2022.Results: The incidence of all-cause mortality, MACEs and pneumonia in HD patients were 20.6%, 29.6%, and 34.8%, respectively. The optimal cutoffs for FGF21 to predict all-cause mortality, MACEs and pneumonia were 437.57 pg/mL, 216.99 pg/mL and 112.79 pg/mL. Multivariate Cox regression analyses showed that FGF21, as a categorical variable, was an independent predictor for all-cause mortality, MACEs and pneumonia (HR, 3.357, 95% CI, 2.128-5.295, p < 0.001; HR, 1.575, 95% CI, 1.046-2.371, p = 0.029; HR, 1.784; 95% CI, 1.124-2.830; p = 0.014, respectively). The survival nomogram, MACEs-free survival nomogram and pneumonia-free survival nomogram based on FGF21 constructed for individualized assessment of HD patients had a high C-index with 0.841, 0.706 and 0.734.Conclusion: Higher serum FGF21 is an independent predictor of all-cause mortality, MACEs and pneumonia in HD patients.

Computed tomography-determined skeletal muscle density predicts 3-year mortality in initial-dialysis patients in China.

BACKGROUND: Skeletal muscle mass and quality assessed by computed tomography (CT) images of the third lumbar vertebra (L3) level have been established as risk factors for poor clinical outcomes in several illnesses, but the relevance for dialysis patients is unclear. A few studies have suggested a correlation between CT-determined skeletal muscle mass and quality at the first lumbar vertebra (L1) level and adverse outcomes. Generally, chest CT does not reach beyond L1. We aimed to determine whether opportunistic CT scan (chest CT)-determined skeletal muscle mass and quality at L1 are associated with mortality in initial-dialysis patients. METHODS: This 3-year multicentric retrospective study included initial-dialysis patients from four centres between 2014 and 2017 in China. Unenhanced CT images of the L1 and L3 levels were obtained to assess skeletal muscle mass [by skeletal muscle index, (SMI), cm2 /m2 ] and quality [by skeletal muscle density (SMD), HU]. Skeletal muscle measures at L1 were compared with those at L3. The sex-specific optimal cutoff values of L1 SMI and L1 SMD were determined in relation to all-cause mortality. The outcomes were all-cause death and cardiac death. Cox regression models were applied to investigate the risk factors for death. RESULTS: A total of 485 patients were enrolled, of whom 257 had both L1 and L3 images. Pearson's correlation coefficient between L1 and L3 SMI was 0.84 (P < 0.001), and that between L1 and L3 SMD was 0.90 (P < 0.001). No significant association between L1 SMI and mortality was observed (P > 0.05). Low L1 SMD (n = 280, 57.73%) was diagnosed based on the optimal cutoff value (<39.56 HU for males and <33.06 HU for females). Multivariate regression analysis revealed that the low L1 SMD group had higher risks of all-cause death (hazard ratio 1.80; 95% confidence interval 1.05-3.11, P = 0.034) and cardiac death (hazard ratio 3.74; 95% confidence interval 1.43-9.79, P = 0.007). CONCLUSIONS: In initial-dialysis patients, there is high agreement between the L1 and L3 measures for SMI and SMD. Low SMD measured at L1, but not low SMI, is an independent predictor of both all-cause death and cardiac death.

Activation of HIF-1α C-terminal transactivation domain protects against hypoxia-induced kidney injury through hexokinase 2-mediated mitophagy.

The transcription factor hypoxia-inducible factor-1α (HIF-1α), as a master regulator of adaptive responses to hypoxia, possesses two transcriptional activation domains [TAD, N-terminal (NTAD), and C-terminal (CTAD)]. Although the roles of HIF-1α NTAD in kidney diseases have been recognized, the exact effects of HIF-1α CTAD in kidney diseases are poorly understood. Here, two independent mouse models of hypoxia-induced kidney injury were established using HIF-1α CTAD knockout (HIF-1α CTAD-/-) mice. Furthermore, hexokinase 2 (HK2) and mitophagy pathway are modulated using genetic and pharmacological methods, respectively. We demonstrated that HIF-1α CTAD-/- aggravated kidney injury in two independent mouse models of hypoxia-induced kidney injury, including ischemia/reperfusion-induced kidney injury and unilateral ureteral obstruction-induced nephropathy. Mechanistically, we found that HIF-1α CTAD could transcriptionally regulate HK2 and subsequently ameliorate hypoxia-induced tubule injury. Furthermore, it was found that HK2 deficiency contributed to severe renal injury through mitophagy inhibition, while mitophagy activation using urolithin A could significantly protect against hypoxia-induced kidney injury in HIF-1α C-TAD-/- mice. Our findings suggested that the HIF-1α CTAD-HK2 pathway represents a novel mechanism of kidney response to hypoxia, which provides a promising therapeutic strategy for hypoxia-induced kidney injury.

Quercetin alleviates tubulointerstitial inflammation by inhibiting exosomes-mediated crosstalk between tubular epithelial cells and macrophages.

BACKGROUND: Tubulointerstitial inflammation (TII) is a critical pathological feature of kidney disease leading to renal fibrosis, and its treatment remains a major clinical challenge. We sought to explore the role of quercetin, a potential exosomes inhibitor, in exosomes release and TII. METHODS: The effects of quercetin on exosomes release and TII were examined by two TII mouse models: the unilateral ureteral obstruction (UUO) models and the LPS-induced mouse models. In vitro, exosomes-mediated crosstalk between tubular epithelial cells (TECs) and macrophages was performed to investigate the mechanisms by which quercetin inhibited exosomes and TII. RESULTS: In this study, we found that exosomes-mediated crosstalk between TECs and macrophages contributed to the development of TII. In vitro, exosomes released from LPS-stimulated TECs induced increased expression of inflammatory cytokines and fibrotic markers in Raw264·7 cells and vice versa. Interestingly, heat shock protein 70 (Hsp70) or Hsp90 proteins could control exosomes release from TECs and macrophages both in vivo and in vitro. Importantly, quercetin, a previously recognized heat shock protein inhibitor, could significantly reduce exosomes release in TII models by down-regulating Hsp70 or Hsp90. Quercetin abrogated exosomes-mediated intercellular communication, which attenuated TII and renal fibrosis accordingly. CONCLUSION: Quercetin could serve as a novel strategy for treatment of tubulointerstitial inflammation by inhibiting the exosomes-mediated crosstalk between tubules and macrophages.

Comprehensive analysis of the roles of fatty acid transport related proteins in clear cell renal cell carcinoma.

OBJECTIVE: This study aimed to explore the clinical significance of fatty acid transport-related protein (FATRP) in patients with clear cell renal cell carcinoma(ccRCC). METHODS: RNA-seq data and corresponding clinical data of ccRCC were obtained from TCGA data portal. Seventeen key FATRP genes were comprehensively investigated using bioinformatics approaches to systematically investigate their expression patterns in ccRCC. In addition, the correlation between the expression levels of these genes and clinicopathological features in ccRCC was further explored. RESULTS: Among the 17 key FATRP genes, only FABP5, FABP6, and FABP7 could be regarded as ideal biomarkers for ccRCC, as they were highly expressed in ccRCC tumor tissues, and positively correlates with tumor progression and poor prognosis. FABP6 had the highest copy number variations (CNV) events (63.07 %), and ccRCC patients with FABP6 amplification had a better prognosis than the unaltered group. DNA methylation levels of FABP6 and FABP7 were downregulated in ccRCC tumor tissues compared to those in normal tissues. FABP5 showed the opposite results. Moreover, a novel four FATRP gene (FABP1, FABP5, FABP7, FATP2) and three clinical parameter (age, stage, and grade) prediction model was constructed and that comprised a significant independent prognostic signature. CONCLUSIONS: Only a few FATRP genes are upregulated in ccRCC tumor tissue, and positively correlate with tumor progression and poor prognosis. The accuracy of a single gene of these FATRP genes as predictors of progression and prognosis of ccRCC is limited. The performance of the novel prediction model proposed by this study was much better than that of any single gene.

An update on renal fibrosis: from mechanisms to therapeutic strategies with a focus on extracellular vesicles.

The increasing prevalence of chronic kidney disease (CKD) is a major global public health concern. Despite the complicated pathogenesis of CKD, renal fibrosis represents the most common pathological condition, comprised of progressive accumulation of extracellular matrix in the diseased kidney. Over the last several decades, tremendous progress in understanding the mechanism of renal fibrosis has been achieved, and corresponding potential therapeutic strategies targeting fibrosis-related signaling pathways are emerging. Importantly, extracellular vesicles (EVs) contribute significantly to renal inflammation and fibrosis by mediating cellular communication. Increasing evidence suggests the potential of EV-based therapy in renal inflammation and fibrosis, which may represent a future direction for CKD therapy.