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With the ever-increasing burden of kidney disease, the need for developing new therapeutics to manage this disease has never been greater. Extracellular vesicles (EVs) are natural membranous nanoparticles present in virtually all organisms. Given their excellent delivery capacity in the body, EVs have emerged as a frontier technology for drug delivery and have the potential to usher in a new era of nanomedicine for kidney disease. This review is focused on why EVs are such compelling drug carriers and how to release their fullest potentiality in renal therapeutics. We discuss the unique features of EVs compared to artificial nanoparticles and outline the engineering technologies and steps in developing EV-based therapeutics, with an emphasis on the emerging approaches to target renal cells and prolong kidney retention. We also explore the applications of EVs as natural therapeutics or as drug carriers in the treatment of renal disorders and present our views on the critical challenges in manufacturing EVs as next-generation renal therapeutics., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Vascular endothelial growth factor-A (VEGF-A) is a critical angiogenic factor which is mainly secreted from podocytes and epithelial cells in kidney and plays an important role in renal pathophysiology. In recent years, functions of different isoforms of VEGF-A and the new secretion approach via extracellular vesicles (EVs) have been identified. Thus, further understanding are needed for the role of VEGF-A and its isoforms in renal injury and repair. In this review, we summarized the expression, secretion and regulation of VEGF-A, its biological function, and the role of different isoforms of VEGF-A in the development of different renal diseases. Meanwhile, the research progress of VEGF-A as diagnostic marker and therapeutic target for renal diseases were discussed.

Extracellular vesicles (EVs) are lipid bilayer-enclosed structures containing diverse bioactive cargoes that play a major role in intercellular communication in both physiological and pathological conditions. Currently, the field of EV-based therapy has been rapidly growing, and two main therapeutic uses of EVs can be surmised: (i) exploiting stem cell-derived EVs as therapeutic agents; and (ii) employing EVs as natural therapeutic vectors for drug delivery. This review will discuss the recent advances in EV-based therapy in the treatment of renal disease.

Kidney macrophages are central in kidney disease pathogenesis and have therapeutic potential in preventing tissue injury and fibrosis. Recent studies highlighted that kidney macrophages are notably heterogeneous immune cells that fulfill opposing functions such as clearing deposited pathogens, maintaining immune tolerance, initiating and regulating inflammatory responses, promoting kidney fibrosis, and degrading the extracellular matrix. Macrophage origins can partially explain macrophage heterogeneity in the kidneys. Circulating Ly6C + monocytes are recruited to inflammatory sites by chemokines, while self-renewed kidney resident macrophages contribute to kidney repair and fibrosis. The proliferation of resident macrophages or infiltrating monocytes provides an alternative explanation of macrophage accumulation after kidney injury. In addition, dynamic Ly6C expression on infiltrating monocytes accompanies functional changes in handling kidney inflammation and fibrosis. Mechanisms underlying kidney macrophage heterogeneity, either by recruiting monocyte subpopulations, regulating macrophage polarization, or impacting distinctive macrophage functions, may help develop macrophage-targeted therapies for kidney diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wen, Yan, Wang and Liu.)

Under the hypoxic condition, organs or cells trigger a series of reactions or responses to adapt to the physiological requirement. These responses involve a complex regulation at different levels from organs, in particular the kidney (producing erythropoietin), to cells throughout the body. Actually, the responses to hypoxia from adaption to injury largely depend on the degree and time of hypoxia. In the past two decades, with the discovery of hypoxia-inducible factor (HIF), the mechanisms of erythropoiesis regulation were elucidated gradually, which has provided a novel therapeutic strategy for hypoxia-related diseases, especially renal anemia. In this review we focus on the latest advances in oxygen sensing and adaptive mechanism.

Exosomes are increasingly recognized as vehicles of intercellular communication. However, the role of exosome in maintaining cellular homeostasis under stress conditions remained unclear. Here we show that Rab27a expression was upregulated exclusively in tubular epithelial cells (TECs) during proteinuria nephropathy established by adriamycin (ADR) injection and 5/6 nephrectomy as well as in chronic kidney disease patients, leading to the increased secretion of exosomes carrying albumin. The active exosome production promoted tubule injury and inflammation in neighboring and the producing cells. Interferon regulatory factor 1 (IRF-1) was found as the transcription factor contributed to the upregulation of Rab27a. Albumin could be detected in exosome fraction and co-localized with exosome marker CD63 indicating the secretion of albumin into extracellular space by exosomes. Interestingly, inhibition of exosome release accelerated albumin degradation which reversed tubule injury with albumin overload, while lysosome suppression augmented exosome secretion and tubule inflammation. Our findings revealed that IRF-1/Rab27a mediated exosome secretion constituted a coordinated approach to lysosome degradation for albumin handling, which lead to the augment of albumin toxicity as a maladaptive response to maintain cell homeostasis. The findings may suggest a novel therapeutic strategy for proteinuric kidney disease by targeting exosome secretion.

The discovery of hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (PHI) has revolutionized the treatment strategy for renal anemia. However, the presence of multiple transcription targets of HIF raises safety concerns regarding HIF-PHI. Here, we explored the dose-dependent effect of MK-8617 (MK), a kind of HIF-PHI, on renal fibrosis. MK was administered by oral gavage to mice for 12 wk at doses of 1.5, 5, and 12.5 mg/kg. In vitro , the human proximal tubule epithelial cell line HK-2 was treated with increasing doses of MK administration. Transcriptome profiling was performed, and fibrogenesis was evaluated. The dose-dependent biphasic effects of MK on tubulointerstitial fibrosis (TIF) were observed in chronic kidney disease mice. Accordingly, high-dose MK treatment could significantly enhance TIF. Using RNA-sequencing, combined with in vivo and in vitro experiments, we found that Krüppel-like factor 5 (KLF5) expression level was significantly increased in the proximal tubular cells, which could be transcriptionally regulated by HIF-1α with high-dose MK treatment but not low-dose MK. Furthermore, our study clarified that HIF-1α-KLF5-TGF-β1 signaling activation is the potential mechanism of high-dose MK-induced TIF, as knockdown of KLF5 reduced TIF in vivo . Collectively, our study demonstrates that high-dose MK treatment initiates TIF by activating HIF-1α-KLF5-TGF-β1 signaling. These findings provide novel insights into TIF induction by high-dose MK (HIF-PHI), suggesting that the safety dosage window needs to be emphasized in future clinical applications.-Li, Z.-L., Lv, L.-L., Wang, B., Tang, T.-T., Feng, Y., Cao, J.-Y., Jiang, L.-Q., Sun, Y.-B., Liu, H., Zhang, X.-L., Ma, K.-L., Tang, R.-N., Liu, B.-C. The profibrotic effects of MK-8617 on tubulointerstitial fibrosis mediated by the KLF5 regulating pathway.

Background: Polarized macrophage populations can orchestrate both inflammation of the kidney and tissue repair during CKD. Proinflammatory M1 macrophages initiate kidney injury, but mechanisms through which persistent M1-dependent kidney damage culminates in fibrosis require elucidation. Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor that suppresses inflammatory signals, is an essential regulator of macrophage polarization in adipose tissues, but the effect of myeloid KLF4 on CKD progression is unknown., Methods: We used conditional mutant mice lacking KLF4 or TNF α (KLF4's downstream effector) selectively in myeloid cells to investigate macrophage KLF4's role in modulating CKD progression in two models of CKD that feature robust macrophage accumulation, nephrotoxic serum nephritis, and unilateral ureteral obstruction., Results: In these murine CKD models, KLF4 deficiency in macrophages infiltrating the kidney augmented their M1 polarization and exacerbated glomerular matrix deposition and tubular epithelial damage. During the induced injury in these models, macrophage-specific KLF4 deletion also exacerbated kidney fibrosis, with increased levels of collagen 1 and α -smooth muscle actin in the injured kidney. CD11b + Ly6C hi myeloid cells isolated from injured kidneys expressed higher levels of TNF α mRNA versus wild-type controls. In turn, mice bearing macrophage-specific deletion of TNF α exhibited decreased glomerular and tubular damage and attenuated kidney fibrosis in the models. Moreover, treatment with the TNF receptor-1 inhibitor R-7050 during nephrotoxic serum nephritis reduced damage, fibrosis, and necroptosis in wild-type mice and mice with KLF4-deficient macrophages, and abrogated the differences between the two groups in these parameters., Conclusions: These data indicate that macrophage KLF4 ameliorates CKD by mitigating TNF-dependent injury and fibrosis., (Copyright © 2019 by the American Society of Nephrology.)

Although glucocorticoids are the mainstays in the treatment of renal diseases for decades, the dose dependent side effects have largely restricted their clinical use. Microvesicles (MVs) are small lipid-based membrane-bound particles generated by virtually all cells. Here we show that RAW 264.7 macrophage cell-derived MVs can be used as vectors to deliver dexamethasone (named as MV-DEX) targeting the inflamed kidney efficiently. Methods : RAW macrophages were incubated with dexamethasone and then MV-DEX was isolated from the supernatants by centrifugation method. Nanoparticle tracking analysis, transmission electron microscopy, western blot and high-performance liquid chromatography were used to analyze the properties of MV-DEX. The LC-MS/MS was applied to investigate the protein compositions of MV-DEX. Based on the murine models of LPS- or Adriamycin (ADR)-induced nephropathy or in-vitro culture of glomerular endothelial cells, the inflammation-targeting characteristics and the therapeutic efficacy of MV-DEX was examined. Finally, we assessed the side effects of chronic glucocorticoid therapy in MV-DEX-treated mice. Results : Proteomic analysis revealed distinct integrin expression patterns on the MV-DEX surface, in which the integrin α L β 2 (LFA-1) and α 4 β 1 (VAL-4) enabled them to adhere to the inflamed kidney. Compared to free DEX treatment, equimolar doses of MV-DEX significantly attenuated renal injury with an enhanced therapeutic efficacy against renal inflammation and fibrosis in murine models of LPS- or ADR-induced nephropathy. In vitro , MV-DEX with about one-fifth of the doses of free DEX achieved significant anti-inflammatory efficacy by inhibiting NF-κB activity. Mechanistically, MV-DEX could package and deliver glucocorticoid receptors to renal cells, thereby, increasing cellular levels of the receptor and improving cell sensitivity to glucocorticoids. Notably, delivering DEX in MVs significantly reduced the side effects of chronic glucocorticoid therapy (e.g., hyperglycemia, suppression of HPA axis). Conclusion : In summary, macrophage-derived MVs efficiently deliver DEX into the inflamed kidney and exhibit a superior capacity to suppress renal inflammation and fibrosis without apparent glucocorticoid adverse effects. Our findings demonstrate the effectiveness and security of a novel drug delivery strategy with promising clinical applications., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

316: F1006-F1015, 2019. First published March 6, 2019; doi: 10.1152/ajprenal.00413.2018 .-Experimental studies have shown that pharmacological activation of calcium-sensing receptor (CaSR) attenuates renal fibrosis in some animal models beyond modification of bone and mineral homeostasis; however, its underlying mechanisms remain largely unknown. Since excessive collagen deposition is the key feature of fibrosis, the present study aimed to examine whether CaSR was involved in the regulation of collagen expression in rats with adenine diet-induced renal fibrosis and in profibrotic transforming growth factor (TGF)-β 1 -treated renal proximal tubular epithelial cells (PTECs). The results showed that the CaSR agonist cinacalcet significantly attenuated renal collagen accumulation and tubular injury in adenine diet-fed rats. Additionally, the in vitro experiment showed that profibrotic TGF-β 1 significantly increased the expression of collagen and decreased CaSR expression at the mRNA and protein levels in a concentration- and time-dependent manner. Furthermore, the CaSR CRISPR activation plasmid and cinacalcet partially abrogated the upregulation of collagen induced by TGF-β 1 treatment. Blockade of CaSR by the CRISPR/Cas9 KO plasmid or the pharmacological antagonist Calhex231 further enhanced TGF-β 1 -induced collagen expression. Mechanistic experiments found that Smad2 phosphorylation and Snail expression were markedly increased in PTECs treated with TGF-β 1 , whereas the CaSR CRISPR activation plasmid and cinacalcet substantially suppressed this induction. In summary, this study provides evidence for a direct renal tubular epithelial protective effect of CaSR activation in renal fibrosis, possibly through suppression of collagen expression in PTECs.

Extracellular vesicles (EVs) are released to maintain cellular homeostasis as well as to mediate cell communication by spreading protective or injury signals to neighbour or remote cells. In kidney, increasing evidence support that EVs are signalling vesicles for different segments of tubules, intra-glomerular, glomerular-tubule and tubule-interstitial communication. EVs released by kidney resident and infiltrating cells can be isolated from urine and were found to be promising biomarkers for kidney disease, reflecting deterioration of renal function and histological change. We have here summarized the recent progress about the functional role of EVs in kidney disease as well as challenges and future directions involved., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Renal fibrosis is the common pathological pathway of progressive CKD. The commonly used biomarkers in clinical practice are not optimal to detect injury or predict prognosis. Therefore, it is crucial to develop novel biomarkers to allow prompt intervention. Urine serves as a valuable resource of biomarker discovery for kidney diseases. Owing to the rapid development of omics platforms and bioinformatics, research on novel urinary biomarkers for renal fibrosis has proliferated in recent years. In this chapter, we discuss the current status and provide basic knowledge in this field. We present novel promising biomarkers including tubular injury markers, proteins related to activated inflammation/fibrosis pathways, CKD273, transcriptomic biomarkers, as well as metabolomic biomarkers. Furthermore, considering the complex nature of the pathogenesis of renal fibrosis, we also highlight the combination of biomarkers to further improve the diagnostic and prognostic performance.

The renal tubules are the major component of the kidney and are vulnerable to a variety of injuries including ischemia, proteinuria, toxins, and metabolic disorders. It has long been believed that tubules are the victim of injury. In this review, we shift this concept to renal tubules as a driving force in the progression of kidney disease. In response to injury, tubular epithelial cells (TECs) can synthesize and secrete varieties of bioactive molecules that drive interstitial inflammation and fibrosis. Innate immune-sensing receptors on the TECs also aggravate immune responses. Necroinflammation, an auto-amplification loop between tubular cell death and interstitial inflammation, leads to the exacerbation of renal injury. Furthermore, TECs also play an active role in progressive renal injury via mechanisms associated with the conversion into collagen-producing fibroblast phenotype, cell cycle arrest at both G1/S and G2/M checkpoints, and metabolic disorder. Thus, a better understanding the mechanisms by which tubular injury drives AKI and CKD is necessary for the development of therapeutics to halt the progression of CKD.

Extracellular vesicles (EVs) are small lipid-based membrane-bound vesicles secreted by most cells under both physiological and pathological conditions. A key function of EVs is to mediate cell-cell communication via transferring mRNAs, miRNAs and proteins from parent cells to recipient cells. These unique features of EVs have spurred a renewed interest in their utility for therapeutics. Given the growing evidence for EV-mediated renal diseases, strategies that could block the release or uptake of pathogenic EVs will be discussed in this review. Then, the therapeutic potential of EVs predominantly from stem cells in renal diseases will be outlined. Finally, we will focus on the specific application of EVs as a novel drug delivery system and highlight the challenges of EVs-based therapies for renal diseases.

Nephrotic syndrome (NS) is characterized by proteinuria, hypoalbuminemia and edema. The disorder of sodium and water metabolism is a critical mechanism regulating the origination and progression of NS. Zhen-wu-tang (ZWT) has been traditionally used to treat edema disease in China and Japan. The present study was carried out to assess the protective effect of ZWT in Adriamycin-induced (ADR) NS rats and investigate the potential anti-NS mechanisms of ZWT. We found that ZWT treatment ameliorate impaired kidney function and regulate water balance of kidney. Importantly, ZWT increased the expression of Aquaporin-2 (AQP2) which play key roles in maintaining body water homeostasis. Additionally, we determined miRNAs expression patterns in NS rats. Using bioinformatics prediction and miR-92b mimic or inhibitor in vitro, we identified miR-92b as a possible modulator of AQP2. Also we found that ZWT can decrease the expression of miR-92b and reverse the effect of miR-92b on AQP2 in vitro. We further demonstrated that miR-92b directly regulated AQP2 expression by targeting 3'-UTR of AQP2. These finding suggest that ZWT may reduce renal edema in Adriamycin-induced nephropathy via regulating AQP2 and miR-92b., (Copyright © 2018. Published by Elsevier Masson SAS.)

Renal anemia, mainly caused by the deficiencies of erythropoietin (EPO) and iron metabolism disorder, is one of the most common complications of chronic kidney disease. Hypoxia-inducible factor (HIF) is a class of transcription factors responsible for maintaining homeostasis during oxygen deprivation. In normoxia, HIF is degraded by prolyl hydroxylase (PHD). While under hypoxic conditions, the hydroxylation activity of PHD is inhibited, and the cellular concentration of HIF is elevated, resulting in an increase in endogenous EPO production and iron absorption. Therefore, this regulating pathway, also termed as the HIF-PHD axis, has become a promising therapeutic target of treating renal anemia. Several innovative drugs acting as selective HIF-PHD inhibitors have been successfully developed in the past years, and some of them are undergoing clinical trials. In this review, we will introduce the definition and regulatory mechanism of HIF-PHD axis, as well as current insights into its physiologic and therapeutic role in renal anemia.

Extracellular vesicles (EVs) are nanosized, membrane-bound vesicles released from different cells. Recent studies have revealed that EVs may participate in renal tissue damage and regeneration through mediating inter-nephron communication. Thus, the potential use of EVs as therapeutic vector has gained considerable interest. In this review, we will discuss the basic characteristics of EVs and its role in nephron cellular communication. Then, the application of EVs as therapeutic vector based on its natural content or as carriers of drug, in acute and chronic kidney injury, was discussed. Finally, perspectives and challenges of EVs in therapy of kidney disease were described., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Renal fibrosis is a common pathological pathway of progressive chronic kidney disease (CKD). However, kidney function parameters are suboptimal for detecting early fibrosis, and therefore, novel biomarkers are urgently needed. We designed a 2-stage study and constructed a targeted microarray to detect urinary mRNAs of CKD patients with renal biopsy and healthy participants. We analysed the microarray data by an iterative random forest method to select candidate biomarkers and produce a more accurate classifier of renal fibrosis. Seventy-six and 49 participants were enrolled into stage I and stage II studies, respectively. By the iterative random forest method, we identified a four-mRNA signature in urinary sediment, including TGFβ1, MMP9, TIMP2, and vimentin, as important features of tubulointerstitial fibrosis (TIF). All four mRNAs significantly correlated with TIF scores and discriminated TIF with high sensitivity, which was further validated in the stage-II study. The combined classifiers showed excellent sensitivity and outperformed serum creatinine and estimated glomerular filtration rate measurements in diagnosing TIF. Another four mRNAs significantly correlated with glomerulosclerosis. These findings showed that urinary mRNAs can serve as sensitive biomarkers of renal fibrosis, and the random forest classifier containing urinary mRNAs showed favourable performance in diagnosing early renal fibrosis.

Renal fibrosis is a histological outcome of chronic kidney disease (CKD) progression. However, the noninvasive detection of renal fibrosis remains a challenge. Here we constructed a renal fibrosis target mRNA array and used it to detect urinary mRNAs of CKD patients for investigating potential noninvasive biomarkers of renal fibrosis. We collected urine samples from 39 biopsy-proven CKD patients and 11 healthy controls in the training set. Urinary mRNA profiles of 86 genes showed a total of 21 mRNAs that were differentially expressed between CKD patients and controls (P < 0.05), and vimentin (VIM) mRNA demonstrated the highest change fold of 9.99 in CKD vs. controls with robust correlations with decline of renal function and severity of tubulointerstitial fibrosis. Additionally, VIM mRNA further differentiated patients with moderate-to-severe fibrosis from none-to-mild fibrosis group with an area of the curve of 0.796 (P = 0.008). A verification of VIM mRNA in the urine of an additional 96 patients and 20 controls showed that VIM is not only well correlated with renal function parameters but also correlated with proteinuria and renal fibrosis scores. Multiple logistic regression and receiver-operating characteristics analysis further showed that urine VIM mRNA is the best predictive parameter of renal fibrosis compared with estimated glomerular filtration rate, serum creatinine, and blood urea nitrogen. In addition, there is no improved predictive performance for the composite biomarkers to predict renal fibrosis severity compared with a single gene of VIM. Overall, urinary VIM mRNA might serve as a novel independent noninvasive biomarker to monitor the progression of kidney fibrosis., (Copyright © 2015 the American Physiological Society.)

Aims: Podocyte injury plays an important role in the pathogenesis of kidney disease. Urinary exosomes are microvesicles released by tubular epithelial cells and podocytes containing information of their originated cells. This study investigated for the first time whether podocyte related mRNA in urinary exosome could serve as novel biomarkers for kidney disease., Methods: Urine samples were collected from 32 patients of kidney disease who underwent kidney biopsy and 7 controls. CD2AP, NPHS2 and synaptopodin were detected by real-time RT-PCR on RNA isolated from urinary exosome., Results: The pellet microvesicles were positively stained with exosome and podocyte marker, AQP2, CD9 and nephrin. CD2AP mRNA was lower (p=0.008) in kidney disease patients compared with controls and decreased with the increasing severity of proteinuria (p=0.06). CD2AP correlated with serum creatinine (r=-0.373, p=0.035), BUN (r=-0.445, p=0.009) and eGFR (r=0.351, p=0.046). Neither NPHS2 nor synaptopodin correlated with parameters of renal function. CD2AP mRNA correlated negatively with 24 hour urine protein (r=-0.403, p=0.022), severity of tubulointerstitial fibrosis (r=-0.394, p=0.026) and glomerulosclerosis (r=-0.389, p=0.031) and could discriminate kidney disease from controls with AUC of 0.821 (p=0.008)., Conclusions: Urinary exosome mRNA of CD2AP might be a non-invasive tool for detecting both renal function and fibrosis of kidney disease., (© 2013 Elsevier B.V. All rights reserved.)

Unlabelled: The present study aimed to investigate the effects of Cordyceps sinensis on renal fibrosis and its possible mechanisms. Sprague-Dawley rats were randomly divided into three groups: sham operation (SHAM) group, 5/6 subtotal nephrectomy (SNx) untreated group, and 5/6 subtotal nephrectomy treated with C. sinensis (2.0 g/kg d) (CS) group. Rats were studied 12 weeks after the surgery, and the CS group presented with significantly lower proteinuria, and better renal function compared with the SNx group (p<0.05). Pathological study showed that the glomerulosclerosis tubulointerstitial injury score was significantly reduced in the CS group compared with the SNx group. Furthermore, the mRNA expression of TGF-β1, Smad2 and Smad3 and the protein expression of TGF-β1, TβRI, TβRII and p-Smad2/3 were attenuated by the C. sinensis treatment. In constrast, the mRNA and protein expression of Smad7 was upregulated. Furthermore, the expression of α-SMA and FSP1 was also significantly attenuated, accompanied by the increasing expression of E-cadherin, suggesting the inhibition of the epithelial-mesenchymal transition (EMT)., In Conclusion: C. sinensis exerted its antifibrotic effect on the SNx rats through the inhibition of the TGF-β1/Smad pathway., (Copyright © 2013. Published by Elsevier Ltd.)

Background: The non-hemodynamic effects of angiotensin receptor blocker (ARB) in the delay of progression of chronic kidney disease (CKD) remain unclear. In this study, we investigated the influence of irbesartan on the urinary excretion of cytokines in patients with CKD., Methods: In this randomized perspective clinical trial, different doses of irbesartan (150 mg/d and 300 mg/d) were given to two groups of patients in a cross-over design. Blood pressure (BP), creatinine clearance (Ccr) and 24-hour proteinuria were examined. Urinary excretion of cytokines was determined by human inflammatory cytokine antibody array. A two-fold change in spot intensity was considered significant., Results: Urinary excretion of cytokines (granulocyte colony stimulating factor (GCSF), intercellular cell adhesion molecule-1 (ICAM-1), interferon γ (IFN-γ), interleukin 1β (IL-1b), IL-2, IL-6, IL-8, IL-11, IL-15 and macrophage inflammatory protein 1d (MIP-1d)) in group B (irbesartan 300 mg/d) was significantly decreased in comparison to group A (irbesartan 150 mg/d) after 8-week treatment. In group A, 8 weeks of treatment induced a two- to nine-fold reduction in urinary cytokine levels (GCSF, GM-CSF, IFN-γ, IL-1a, IL-11, IL-12p40, MCP-2, MIP-1a), while increasing the dosage to 300 mg/d further decreased the excretion of GCSF, GM-CSF, IL-12p40, MCP-2 and MIP-1a by week 18. There was no significant difference in BP or Ccr between the two groups. However, 24-hour proteinuria was significantly reduced in both groups, and in group A the reduction was dose dependent., Conclusion: Irbesartan offers additional renoprotection in a dose-dependent manner by reducing pro-inflammatory cytokines excretion in the urine of CKD patients.

Background: Patients with chronic kidney disease (CKD) are more likely to have complications due to cardiovascular disease (CVD). This study was performed to investigate the prevalence of chronic kidney disease (CKD) and the relation of CKD and number of stenosed coronary vessels in patients who had undergone coronary angiography with suspected coronary artery disease (CAD)., Methods: The data of 1,010 consecutive patients who underwent coronary angiography for suspected CAD in Zhongda Hospital were analyzed. Estimated glomerular filtration rate (eGFR) was calculated with the abbreviated Modified Diet in Renal Disease (MDRD) Study equation. CKD was defined as presence of eGFR <60 ml/min per 1.73 m(2) and/or proteinuria. Luminal narrowing with at least 1 lesion =50% in the main branches of the coronary artery was considered as CAD. The number of stenotic arteries was recorded (1- to 3-vessel disease [VD]). A significant stenosis in the left main trunk was scored as 2-VD., Results: Patients with CAD had a significantly higher prevalence of CKD compared with patients without CAD (18.8% vs. 5.4%, p<0.001). CKD was significantly associated with CAD, 2-VD and 3-VD, versus without CAD (0-VD) (odds ratio [OR] = 2.163; 95% confidence interval [95% CI], 1.296-3.611; OR=2.478; 95% CI, 1.288-4.766; OR=2.504; 95% CI, 1.271-4.933; respectively) after adjustment for covariates., Conclusions: There was a higher prevalence of CKD in patients with CAD diagnosed by coronary angiography, and it increased with the number of stenosed coronary vessels. CKD is a critical risk factor for CAD, especially 3-VD.

Objective: To retrospectively investigate the prevalence and distribution of chronic kidney disease (CKD) in hospitalized Chinese adult patients., Methods: The medical histories of 13,383 adult patients hospitalized in Zhongda Hospital from September 2004 to August 2005, 6215 males and 7168 female, aged (51 +/- 19) (18 - 103), were reviewed. The blood pressure, serum creatinine, proteinuria were investigated. CKD was defined and classified according to the NKF/DOQI guideline. Glomerular filtration rate (GFR) was estimated by using the simplified modification of diet in renal disease study (MDRD) equation. eGFR = 186.3 x serum creatinine(-1.154) x age(-0.203) x (0.742 for women) ml.min(-1).(1.7 3 m2)(-1)., Results: The prevalence rate of CKD was 14.82% in this group, and the prevalence rates of CKD of stage 1 to 5 were 3.33%, 2.49%, 7.07%, 1.08%, and 0.86% respectively. 53.07% of the CKD patients were elderly patients (age > 65) with a CKD prevalence rate of 29.47%, significantly higher than that of the middle-aged and young patients (9.49%, P < 0.01). The eGFR levels of 9.01% of the hospitalized patients were below 60 ml.min(-1).(1.73 m2)(-1). The prevalence rate of proteinuria was 8.87%. 39.06% of the patients at stages 1 - 3 failed to be diagnosed as with CKD during their hospitalization. The most common causes of CKD were hypertension (29.49%), diabetes (11.64%), and primary glomerulonephritis (4.39%). Hypertension, diabetes and being elderly were main risk factors for CKD., Conclusion: CKD is a very common disease among the hospitalized patients in China. With the increasing number of aging populations, elderly people will be the highest risk group for CKD. More strategies have to be made for its early detection and prevention.

Aims: Emerging evidence suggests that the urinary excretion of cytokines is associated with the progression of chronic kidney disease (CKD). However, detection of urinary cytokines in high throughput is still a problem in clinical practice. In this cross-sectional study, we applied a novel proteomic technology, antibody array, to analyze urinary cytokine profiles in patients with CKD., Methods: A total of 10 subjects including 7 CKD patients and 3 normal controls were studied. These patients with CKD were divided into two groups according to the levels of estimated glomerular filtration rate (eGFR): group A (eGFR >or=80 ml/min/1.73 m(2), n = 3) and group B (eGFR

Complement factor B (CFB) variants have been described to play a causative role in auto-immune associated C3 glomerulopathy (C3G) and/or atypical hemolytic uremic syndrome (aHUS) by affecting the dysregulations of alternative pathway activation. However, CFB variant concomitant with COL4A5 variant is scarce. Here, we depict two intriguing cases with concurrent novel heterozygosity for CFB c.2054_2057del (p.Ser687Profs∗16) variant and a previous reported COL4A5 c.2999G > T (p.Gly1000Val) variant in a pair of siblings. The clinical feature of either paternal CFB variant or maternal COL4A5 variant is just mild microscopic hematuria. Interestingly, their two children with paternal CFB c.2054_2057del (p.Ser687Profs∗16) variant and maternal COL4A5 c.2999G > T (p.Gly1000Val) variant presented with massive proteinuria, hematuria, and progressive renal failure with poor treatment response. Moreover, complement pathway activation in renal tissue further supports and strengthens the pathogenic role of CFB variant in the development of renal injury in the presence of COL4A5 variant. In conclusion, the rare sibling cases highlight that the extension of genetic analyses in the proband is helpful for the diagnosis and understanding of some family cluster renal diseases. [ABSTRACT FROM AUTHOR]

Immunoglobulin A (IgA) nephropathy, in the presence of myeloid bodies, has been reported in Fabry disease (FD). In this case, we excluded the diagnosis of FD by demonstrating the absence of mutation in the α-galactosidase A（ GLA ）gene. Our patient also denied any history of use of cationic amphiphilic drugs. Interestingly, we identified a novel missense mutation for Coenzyme Q2（COQ2） , which is known to cause COQ2 mutation-associated nephropathy. We also found heteromorphic mitochondria and good treatment response in our patient following coenzyme Q10 supplementation. In light of our findings, our patient was diagnosed with COQ2 nephropathy and IgA nephropathy. To our knowledge, this is the first case report of COQ2 nephropathy with pathologic manifestations of myeloid bodies in podocytes. [ABSTRACT FROM AUTHOR]

Integrins are transmembrane receptors that function as noncovalent heterodimers that mediate cellular adhesion and migration, cell to cell communication, and intracellular signaling activation. In kidney, latency associated peptide-transforming growth factor β (TGF-β) and soluble urokinase plasminogen activator receptor (suPAR) were found as the novel ligands of integrins that contribute to renal interstitial fibrosis and focal segmental glomerular sclerosis glomerulosclerosis (FSGS). Interestingly, recent studies revealed that integrins are the compositional cargo of exosomes. Increasing evidence suggested that exosomal integrin played critical roles in diverse pathophysiologic conditions such as tumor metastasis, neurological disorders, immunology regulation, and other processes. This review will focus on the biology and function of exosomal integrin, emphasizing its potential role in kidney disease as well as its implications in developing novel therapeutic and diagnosis approaches for kidney disease. [ABSTRACT FROM AUTHOR]

Background: The lack of consensus criteria of acute on chronic kidney injury (ACKI) affects the judgment for its clinical prognosis.Methods: In this study, we analyzed the data from 711,615 hospitalized adults who had at least 2 serum creatinine (SCr) tests within 30 days. We estimated the reference change value (RCV) of SCr given initial SCr level in adults without known risks of acute kidney injury other than chronic kidney disease (CKD). We proposed a criterion for ACKI based on the RCV of SCr (cROCK), which defined ACKI as a ≥25% increase in SCr in 7 days. We validated cROCK by its association with the risks of in-hospital mortality, death after discharge, and CKD progression in a large cohort of patients with CKD stage 3.Results: In 21,661 patients with CKD stage 3, a total of 3,145 (14.5%), 1,512 (7.0%), and 221 (1.0%) ACKI events were detected by both cROCK and Kidney Disease Improving Global Outcomes (KDIGO), cROCK only, and KDIGO only, respectively. cROCK detected 40% more ACKI events than KDIGO. Compared with patients without ACKI by both definitions, those with cROCK- but not KDIGO-defined ACKI had a significantly increased risk of in-hospital mortality (hazard ratio [HR] 5.53; 95% CI 3.75-8.16), death after discharge (HR 1.51; 95% CI 1.21-1.83), and CKD progression (OR 5.65; 95% CI 3.05-10.48).Conclusions: RCV-based criterion (cROCK) for ACKI is clinically valid in that it has a substantially improved sensitivity in identifying patients with high risk of adverse outcomes. [ABSTRACT FROM AUTHOR]

Background/Aims: Chronic kidney disease (CKD) is a worldwide public health problem. Regardless of the underlying primary disease, CKD tends to progress to end-stage kidney disease, resulting in unsatisfactory and costly treatment. Its common pathogenesis, however, remains unclear. The aim of this study was to provide an unbiased catalog of common gene-expression changes of CKD and reveal the underlying molecular mechanism using an integrative bioinformatics approach. Methods: We systematically collected over 250 Affymetrix microarray datasets from the glomerular and tubulointerstitial compartments of healthy renal tissues and those with various types of established CKD (diabetic kidney disease, hypertensive nephropathy, and glomerular nephropathy). Then, using stringent bioinformatics analysis, shared differentially expressed genes (DEGs) of CKD were obtained. These shared DEGs were further analyzed by the gene ontology (GO) and pathway enrichment analysis. Finally, the protein-protein interaction networks(PINs) were constructed to further refine our results. Results: Our analysis identified 176 and 50 shared DEGs in diseased glomeruli and tubules, respectively, including many transcripts that have not been previously reported to be involved in kidney disease. Enrichment analysis also showed that the glomerular and tubulointerstitial compartments underwent a wide range of unique pathological changes during chronic injury. As revealed by the GO enrichment analysis, shared DEGs in glomeruli were significantly enriched in exosomes. By constructing PINs, we identified several hub genes (e.g. OAS1, JUN, and FOS) and clusters that might play key roles in regulating the development of CKD. Conclusion: Our study not only further reveals the unifying molecular mechanism of CKD pathogenesis but also provides a valuable resource of potential biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: There are limited data on the trends of incidence or prevalence of end stage renal disease (ESRD) in China. To assist in future planning for the ESRD program, the trends of incidence, prevalence and health care costs were analyzed and forecasted to the year 2025 by modeling of historical data from 2004 through 2014.Methods: Nanjing urban employee basic medical insurance (NJUEBMI) data were obtained from the Nanjing Medical Insurance Information System from 2004 to 2014. The time series forecasting system in SAS 9.4 was used. Each variable was independently forecasted by the fittest model, which was selected automatically or manually.Results: The forecasting models demonstrated mean percent errors of -2.49 to 5.62 %, relative to the observed values. The R-square values for the forecasting models ranged from 0.756 to 0.997. On the basis of trends in the historical data, the models projected that the average annual increase in the NJUEBMI population was 4.77 %, with forecasted values of 5,029,270 in 2025 (95 % CI, 4,960,423-5,098,117). The incidence and prevalence of ESRD were projected to increase by 1.19 and 1.95 % annually and were expected to reach 250.5 pmp (95 % CI, 247.7-253.3) and 1505 pmp(95 % CI, 1450-1560) by 2025. Additionally, the costs associated with ESRD were forecasted to increase at a growth rate of 5.80 % for healthcare costs and 7.25‰ for per capita medical expenses, with forecasted values of ¥600.3 million ($92.4 million) (95 % CI, 541.8-658.9) and ¥99.0 thousand ($15.2 thousand) (95 % CI, 98.6-99.3), respectively, by 2025. The incidence and prevalence of kidney transplantation were projected to decrease by 6.58 and 9.79 % annually.Conclusions: These projections suggest that the incidence, prevalence, healthcare costs, and per capita medical expenses of ESRD would increase in the NJUEBMI population. They provide a basis for discussing the trends of ESRD in China and facing the challenges from the ESRD program. [ABSTRACT FROM AUTHOR]

Intestinal microbiota-derived membrane vesicles (MVs) play essential roles in immunomodulation and maintenance of the intestinal micro-ecosystem. The relationship between MVs and chronic kidney disease (CKD) has remained undefined. This review provides a survey of the structure and biological function of different vesicle types and summarizes the possible pathogenic mechanisms mediated by MVs, which may be of great clinical significance in the diagnosis and treatment of chronic kidney disease. • Gram-negative bacteria as well as gram-positive bacteria can release membrane vesicles to promote cell-to-cell communication. • Intestinal microbiota-derived membrane vesicles are mediate inflammation, pyroptosis, immunomodulation, and disease development. • The cause of membrane vesicles related kidney diseases may be inflammation, cytokines activation, or intestine-kidney axis. • Intestinal microbiota-derived membrane vesicles may be a proposing therapeutic tool for the chronic kidney disease. [ABSTRACT FROM AUTHOR]

Aim:FTY720, a new immunomodulatory drug with low cytotoxicity, is currently used to treat multiple sclerosis. In this study, we investigated the effects of FTY720 on inflammatory cell infiltration in albumin overload-induced nephropathy of rats.Methods:Male Wistar rats were subjected to right-side nephrectomy and divided into 3 groups. One week after the surgery, albumin overload (AO) group was treated with BSA (5 g·kg−1·d−1, ip) for 9 weeks; AO+FTY720 group was given BSA (5 g·kg−1·d−1, ip) plus FTY720 (0.5 g·kg−1·d−1, ip) for 9 weeks; and control group received daily ip injection of equivalent volume of saline. All rats were killed 9 weeks after nephrectomy.Results:AO rats exhibited gradually increased urinary protein excretion accompanied by elevated urinary N-acetyl-β-O-glucosaminidase activity, and both reached their peak values at week 7. Furthermore, AO significantly increased lymphocytes and monocytes in circulation and the inflammatory cells recruited to tubulointerstitium, and the expression of inflammatory cytokines MCP-1, TNF-α and IL-6, as well as sphingosine 1-phosphate (S1P) receptors S1pr1 and S1pr3, and S1P-synthesizing enzyme sphingosine kinase 1 (Sphk1) in the kidney. Concomitant administration of FTY720 significantly attenuated all the AO-induced pathological changes.Conclusion:FTY720 alleviates tubulointerstitium inflammation in an AO rat model of nephropathy via down-regulation of the Sphk1 pathway. [ABSTRACT FROM AUTHOR]

Aim:Proteinuria is not only a common marker of renal disease, but also involved in renal tubulointerstitial inflammation and fibrosis. The aim of this study was to investigate the mechanisms underlying the protective effects of enalapril, an ACEI, against nephropathy in rats.Methods:Wistar rats underwent unilateral right nephrectomy, and then were treated with BSA (5 g·kg−1·d−1, ip), or BSA plus enalapril (0.5 g·kg−1·d−1, po) for 9 weeks. The renal lesions were evaluated using histology and immunohistochemistry. The expression of NLRP3, caspase-1, IL-1β and IL-18 was analyzed using immunohistochemistry, RT-PCR and Western blot.Results:BSA-overload resulted in severe proteinuria, which peaked at week 7, and interstitial inflammation with prominent infiltration of CD68+ cells (macrophages) and CD3+ cells (T lymphocytes), particularly of CD20+ cells (B lymphocytes). BSA-overload markedly increased the expression of NLRP3, caspase-1, IL-1β and IL-18 in the proximal tubular epithelial cells, and in inflammatory cells as well. Furthermore, the expression of IL-1β or IL-18 was significantly correlated with proteinuria (IL-1β: r=0.757; IL-18: r=0.834). These abnormalities in BSA-overload rats were significantly attenuated by concurrent administration of enalapril.Conclusion:Enalapril exerts protective effects against BSA-overload nephropathy in rats via suppressing NLRP3 inflammasome expression and tubulointerstitial inflammation. [ABSTRACT FROM AUTHOR]

Background: We investigated whether urinary mRNA of connective tissue growth factor (CCN2) and nephroblastoma overexpressed gene (CCN3) can provide clinical insight into the management of patients with nondiabetic CKD. Methods: Urinary mRNA expression of CCN2 and CCN3 were measured by Real-time PCR in 35 CKD patients and 12 controls. Results: Urinary mRNA of CCN2 and CCN3 were distinctively greater in CKDs than healthy controls. Urinary CCN3/CCN2 mRNA ratio correlated to the degree of glomerular histological changes in those who received renal biopsy. Conclusion: Urinary CCN3/CCN2 mRNA ratio may be a useful noninvasive biomarker for evaluating patients with nondiabetic CKD prior to renal biopsy. [ABSTRACT FROM AUTHOR]

Background: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD) in the world. Emerging evidence has shown that urinary mRNAs may serve as early diagnostic and prognostic biomarkers of DKD. In this article, we aimed to first establish a novel bioinformatics-based methodology for analyzing the "urinary kidney-specific mRNAs" and verify their potential clinical utility in DKD.Methods: To select candidate mRNAs, a total of 127 Affymetrix microarray datasets of diabetic kidney tissues and other tissues from humans were compiled and analyzed using an integrative bioinformatics approach. Then, the urinary expression of candidate mRNAs in stage 1 study (n = 82) was verified, and the one with best performance moved on to stage 2 study (n = 80) for validation. To avoid potential detection bias, a one-step Taqman PCR assay was developed for quantification of the interested mRNA in stage 2 study. Lastly, the in situ expression of the selected mRNA was further confirmed using fluorescent in situ hybridization (FISH) assay and bioinformatics analysis.Results: Our bioinformatics analysis identified sixteen mRNAs as candidates, of which urinary BBOX1 (uBBOX1) levels were significantly upregulated in the urine of patients with DKD. The expression of uBBOX1 was also increased in normoalbuminuric diabetes subjects, while remained unchanged in patients with urinary tract infection or bladder cancer. Besides, uBBOX1 levels correlated with glycemic control, albuminuria and urinary tubular injury marker levels. Similar results were obtained in stage 2 study. FISH assay further demonstrated that BBOX1 mRNA was predominantly located in renal tubular epithelial cells, while its expression in podocytes and urothelium was weak. Further bioinformatics analysis also suggested that tubular BBOX1 mRNA expression was quite stable in various types of kidney diseases.Conclusions: Our study provided a novel methodology to identify and analyze urinary kidney-specific mRNAs. uBBOX1 might serve as a promising biomarker of DKD. The performance of the selected urinary mRNAs in monitoring disease progression needs further validation. [ABSTRACT FROM AUTHOR]

Background: Increased plasma level of lipoprotein(a) (Lpa) is a risk factor of cardiovascular diseases. This study aimed to explore the role of Lpa in the progression of atherosclerosis in patients with end-stage renal disease (ESRD) and to investigate whether its potential mechanism is mediated by CXC chemokine ligand 16 (CXCL16) and low-density lipoprotein receptor (LDLr).Methods: This is a retrospective clinical study. From January 2015 to April 2016, forty-six ESRD patients from Danyang First People's Hospital were investigated. The patients were grouped according to their plasma Lpa levels: control group (Lpa < 300 mg/l, n = 23) and high Lpa group (Lpa ≥ 300 mg/l, n = 23). ESRD Patients with acute infective diseases, cancer, and/or chronic active hepatitis were excluded. Biochemical indexes and lipid profiles of the patients were measured. Surgically removed tissues from the radial arteries of ESRD patients receiving arteriovenostomy were used for the preliminary evaluation of atherosclerosis. Haematoxylin-eosin (HE) and filipin staining were used to observe foam cell formation. Protein expression levels of Lpa, CXCL16, and LDLr were detected by immunohistochemistry staining and immunofluorescent staining.Results: There was more foam cell formation and cholesterol accumulation in the radial arteries of the high Lpa group than in those of the control group. Furthermore, the expression levels of Lpa, CXCL16, and LDLr were significantly increased in the radial arteries of the high Lpa group. Correlation analyses showed that the protein expression levels of Lpa (r = 0.72, P < 0.01), LDLr (r = 0.54, P < 0.01), and CXCL16 (r = 0.6, P < 0.01) in the radial arteries of ESRD patients were positively correlated with the plasma Lpa levels. Further analyses showed that the co-expression of Lpa with LDLr or CXCL16 was increased in the high Lpa group.Conclusions: High plasma Lpa levels accelerated the progression of atherosclerosis in ESRD through inducing Lpa accumulation in the arteries, which was associated with LDLr and CXCL16. These two lipoproteins could both be major lipoprotein components that regulate the entry of Lpa into arterial cells. [ABSTRACT FROM AUTHOR]

Dysfunctional mitochondria participate in the progression of chronic kidney disease (CKD). Pirfenidone is a newly identified anti-fibrotic drug. However, its mechanism remains unclear. Mitochondrial dysfunction is an early event that occurs prior to the onset of renal fibrosis. In this context, we investigated the protective effect of pirfenidone on mitochondria and its relevance to apoptosis and oxidative stress in renal proximal tubular cells. A remnant kidney rat model was established. Human renal proximal tubular epithelial cells (HK2) using rotenone, a mitochondrial respiratory chain complex Ι inhibitor were further investigated in vitro to examine the mitochondrial protective effect of pirfenidone. Pirfenidone protected mitochondrial structures and functions by stabilizing the mitochondrial membrane potential, maintaining ATP production and improving the mitochondrial DNA (mtDNA) copy number. Pirfenidone decreased tubular cell apoptosis by inhibiting the mitochondrial apoptotic signaling pathway. Pirfenidone also reduced oxidative stress by enhancing manganese superoxide dismutase (Mn-SOD) and inhibiting intracellular reactive oxygen species (ROS) generation, which suggested that the anti-oxidant effects occurred at least partially via the mitochondrial pathway. Pirfenidone may be effective prior to the onset of renal fibrosis because this drug exerts its anti-fibrotic effect by protection of mitochondria in renal proximal tubular cells. [ABSTRACT FROM AUTHOR]

Significance: The disturbance of the hypoxia response system is closely related to human diseases, because it is essential for the maintenance of homeostasis. Given the significant role of the hypoxia response system in human health, therapeutic applications targeting prolyl hydroxylase-hypoxia-inducible factor (HIF) signaling have been attempted. Thus, systemically reviewing the hypoxia response-based therapeutic strategies is of great significance. Recent Advances: Disturbance of the hypoxia response is a characteristic feature of various diseases. Targeting the hypoxia response system is, thus, a promising therapeutic strategy. Interestingly, several compounds and drugs are currently under clinical trials, and some have already been approved for use in the treatment of certain human diseases. Critical Issues: We summarize the molecular mechanisms of the hypoxia response system and address the potential therapeutic implications in kidney diseases. Given that the effects of hypoxia response in kidney diseases are likely to depend on the pathological context, specific cell types, and the differences in the activation pattern of HIF isoforms, the precise application is critical for the treatment of kidney diseases. Although HIF-PHIs (HIF-PHD inhibitors) have been proven to be effective and well tolerated in chronic kidney disease patients with anemia, the potential on-target consequence of HIF activation and some outstanding questions warrant further consideration. Future Direction: The mechanism of the hypoxia response system disturbance remains unclear. Elucidation of the molecular mechanism of hypoxia response and its precise effects on kidney diseases warrants clarification. Considering the complexity of the hypoxia response system and multiple biological processes controlled by HIF signaling, the development of more specific inhibitors is highly warranted. Antioxid. Redox Signal. 37, 936–955. [ABSTRACT FROM AUTHOR]