[Status Quo and Research Progress in Diagnosis and Treatment of Patients With Diabetes Mellitus and Chronic Kidney Disease].

As the incidence of diabetes mellitus is rapidly increasing worldwide,that of related complications,such as diabetic kidney disease(DKD),also increases,conferring a heavy economic burden on the patients,families,society,and government.Diabetes mellitus complicated with chronic kidney disease(CKD)includes DKD and the CKD caused by other reasons.Because of the insufficient knowledge about CKD,the assessment of diabetes mellitus complicated with CKD remains to be improved.The therapies for diabetes mellitus complicated with CKD focus on reducing the risk factors.In clinical practice,DKD may not be the CKD caused by diabetes.According to clinical criteria,some non-diabetic kidney disease may be misdiagnosed as DKD and not be treated accurately.This review summarizes the status quo and research progress in the assessment,diagnosis,and treatment of diabetes mellitus complicated with CKD and predicts the directions of future research in this field.

Serum Sortilin Is Associated with Coronary Artery Calcification and Cardiovascular and Cerebrovascular Events in Maintenance Hemodialysis Patients.

OBJECTIVE: To analyze the role of serum sortilin in coronary artery calcification (CAC) and cardiovascular and cerebrovascular events (CCE) in maintenance hemodialysis (MHD) patients. METHODS: One hundred eleven patients with MHD ≥3 months were included in this study. The general data, clinical features, hematological data, and medication history of the patients were recorded. Eighty-five cases were examined by vascular color Doppler ultrasound, cardiac color Doppler ultrasound, lateral lumbar radiography, and coronary artery calcification score. The patients were followed up for a median time of 45 months. The primary endpoint was CCE or death from a vascular event, and the role of sortilin in this process was analyzed. RESULTS: Among 85 MHD patients, 51 cases (60.00%) had different degrees of CAC. There were significant differences in diabetes, dialysis time, serum phosphorus, calcium-phosphorus product, medical history of phosphate binders, sortilin, and carotid artery plaque between 4 different degrees of calcification groups (p < 0.05). Logistic regression analysis showed that diabetes (OR = 5.475; 95% CI: 1.794-16.71, p = 0.003), calcium-phosphorus product (OR = 2.953; 95% CI: 1.198-7.279, p = 0.019), and sortilin (OR = 1.475 per 100 pg/mL; 95% CI: 1.170-1.858, p = 0.001) were independent risk factors for CAC. During the follow-up, 28 cases of 111 patients (25.23%) suffered from CCE. There were significant differences in CCE between mild, moderate, and severe CAC groups and noncalcification groups (p < 0.05). Cox regression analysis showed that diabetes mellitus (HR 3.424; 95% CI: 1.348-8.701, p = 0.010), CAC (HR 5.210; 95% CI: 1.093-24.83, p = 0.038), and serum sortilin (HR = 8.588; 95% CI: 1.919-38.43, p = 0.005) were independent risk factors for CCE. Besides, we proposed a cutoff value of 418 pg/mL for serum sortilin level, which was able to predict the occurrence of CCE with 75.0% sensitivity and 71.9% specificity. The area under the curve was 0.778 (95% CI: 0.673-0.883). CONCLUSION: Sortilin is newly found to be independently associated with CAC and CCE in MHD patients.

Involvement of hydrogen sulfide in the progression of renal fibrosis.

OBJECTIVE: Renal fibrosis is the most common manifestation of chronic kidney disease (CKD). Noting that existing treatments of renal fibrosis only slow disease progression but do not cure it, there is an urgent need to identify novel therapies. Hydrogen sulfide (H2S) is a newly discovered endogenous small gas signaling molecule exerting a wide range of biologic actions in our body. This review illustrates recent experimental findings on the mechanisms underlying the therapeutic effects of H2S against renal fibrosis and highlights its potential in future clinical application. DATA SOURCES: Literature was collected from PubMed until February 2019, using the search terms including "Hydrogen sulfide," "Chronic kidney disease," "Renal interstitial fibrosis," "Kidney disease," "Inflammation factor," "Oxidative stress," "Epithelial-to-mesenchymal transition," "H2S donor," "Hypertensive kidney dysfunction," "Myofibroblasts," "Vascular remodeling," "transforming growth factor (TGF)-beta/Smads signaling," and "Sulfate potassium channels." STUDY SELECTION: Literature was mainly derived from English articles or articles that could be obtained with English abstracts. Article type was not limited. References were also identified from the bibliographies of identified articles and the authors' files. RESULTS: The experimental data confirmed that H2S is widely involved in various renal pathologies by suppressing inflammation and oxidative stress, inhibiting the activation of fibrosis-related cells and their cytokine expression, ameliorating vascular remodeling and high blood pressure, stimulating tubular cell regeneration, as well as reducing apoptosis, autophagy, and hypertrophy. Therefore, H2S represents an alternative or additional therapeutic approach for renal fibrosis. CONCLUSIONS: We postulate that H2S may delay the occurrence and progress of renal fibrosis, thus protecting renal function. Further experiments are required to explore the precise role of H2S in renal fibrosis and its application in clinical treatment.

Fluorofenidone attenuates oxidative stress and renal fibrosis in obstructive nephropathy via blocking NOX2 (gp91phox) expression and inhibiting ERK/MAPK signaling pathway.

BACKGROUND/AIMS: We evaluated the therapeutic effects of fluorofenidone (AKF-PD), a novel pyridone agent, targeting oxidative stress and fibrosis in obstructive nephropathy. METHODS: AKF-PD was used to treat renal interstitial fibrosis in unilateral ureteral obstruction (UUO) obstructive nephropathy in rats. The expression of NOX2 (gp91phox), fibronectin and extracellular signal regulated kinase (ERK) were detected by western blot. A level of Malondialdehyde (MDA), an oxidative stress marker, was measured by ELISA. In addition, ROS and the expressions of NOX2, collagen I (a1), fibronectin and p-ERK were measured in angiotensin (Ang) II-stimulated rat proximal tubular epithelial cells (NRK-52E) in culture. RESULTS: In NRK-52E cells, AKF-PD reduced AngII induced expressions of ROS, NOX2, fibronectin, collagen I (a1) and p-ERK. In UUO kidney cortex, AKF-PD attenuated the degree of renal interstitial fibrosis, which was associated with reduced the expressions of collagen I (a1) and fibronectin. Furthermore, AKF-PD downregulated the expressions of NOX2, MDA and p-ERK. CONCLUSION: AKF-PD treatment inhibits the progression of renal interstitial fibrosis by suppressing oxidative stress and ERK/MAPK signaling pathway.

Fluorofenidone protects against renal fibrosis by inhibiting STAT3 tyrosine phosphorylation.

Signaling through the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, especially JAK2/STAT3, is involved in renal fibrosis. Fluorofenidone (FD), a novel pyridone agent, exerts anti-fibrotic effects in vitro and in vivo. Herein, we sought to investigate whether FD demonstrates its inhibitory function through preventing JAK2/STAT3 pathway. In this study, we examined the effect of FD on activation of rat renal interstitial fibroblasts, glomerular mesangial cells (GMC), and expression of JAK2/STAT3. Moreover, we explored the histological protection effects of FD in UUO rats, db/db mice, and phosphorylation of JAK2/STAT3 cascade. Our studies found that pretreatment with FD resulted in blockade of activation of fibroblast and GMC manifested by fibronectin (FN) and α-smooth muscle actin (α-SMA) protein expression and decline of STAT3 tyrosine phosphorylation induced by IL-6 or high glucose. In unilateral ureteral obstruction rats and a murine model of spontaneous type 2 diabetes (db/db mice), treatment with FD blocked the expression of FN and α-SMA, prevented renal fibrosis progression, and attenuated STAT3 activation. However, FD administration did not interfere with JAK2 activation both in vivo and in vitro. In summary, the molecular mechanism by which FD exhibits renoprotective effects appears to involve the inhibition of STAT3 phosphorylation.

Fluorofenidone inhibits nicotinamide adeninedinucleotide phosphate oxidase via PI3K/Akt pathway in the pathogenesis of renal interstitial fibrosis.

AIM: Oxidative stress plays an important role in the progression of renal interstitial fibrosis. The nicotinamide adeninedinucleotide phosphate (NADPH) oxidase (Nox) family is considered one of the major sources of reactive oxygen species (ROS). In the present study, we investigated the inhibitory effects of a novel anti-fibrotic agent, Fluorofenidone (AKF-PD), upon Nox-mediated oxidative stress and deposition of extracellular matrix (ECM) in the development of renalinterstitial fibrosis. METHODS: AKF-PD was used to treat renal fibrosis in unilateral ureteral obstruction (UUO) obstructive nephropathy in rats. The expression of Nox homologues, p-Akt, collagen I and III were detected by immunoblotting or immunohistochemistry. Levels of 8-iso prostaglandin F2alpha (8-Iso PGF2a) was measured by enzyme linked immunosorbent assay. In addition, ROS and the expression of collagen I (1a), Nox subunits and p-Akt was measured in angiotensin (Ang) II-stimulated rat proximal tubular epithelial (NRK-52E) cells in culture. RESULTS: AKF-PD treatment significantly attenuated tubulo-interstitial injury, ECM deposition and oxidative stress in fibrotic rat kidneys. In addition, AKF-PD inhibited the expression of ROS, Collagen I (1a), Nox2, p-Akt in Ang II-stimulated NRK-52E cells. CONCLUSION: AKF-PD attenuates the progression of renal interstitial fibrosis partly by suppressing NADPH oxidase and ECM deposition via the PI3K/Akt signalling pathway, suggesting AKF-PD is a potential novel therapeutic agent against renal fibrosis.

Fluorofenidone attenuates diabetic nephropathy and kidney fibrosis in db/db mice.

BACKGROUND/AIMS: Fluorofenidone [1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone, AKF-PD], a novel pyridone agent, showed potent antifibrotic properties. The aim of the present study was to investigate the effects of AKF-PD on diabetic nephropathy and kidney fibrosis, and to obtain an insight into its mechanisms of action. METHODS: We administered AKF-PD to diabetic db/db mice for 12 weeks. Moreover, we performed in vitro cultures using murine mesangial cells exposed to high ambient glucose concentrations. RESULTS: AKF-PD reduced renal hypertrophy, mesangial matrix expansion and albuminuria in the db/db mice. The upregulated expression of α1(I)- and α1(IV)-collagen and fibronectin mRNAs, transforming growth factor-ß1 (TGF-ß1), α-smooth muscle actin (α-SMA), and tissue inhibitors of metalloproteinase 1 (TIMP-1) mRNAs and proteins was inhibited by AKF-PD treatment in the renal cortex of db/db mice. The maximal effective dose of AKF-PD was about 500 mg/kg body weight. AKF-PD inhibited the upregulated expression of α1(I)- and α1(IV)-collagens, TGF-ß1, TIMP-1 and α-SMA induced by high glucose concentrations in cultured mesangial cells. CONCLUSIONS: Our data indicate that AKF-PD diminishes the abnormal accumulation of mesangial matrix through the inhibition of upregulated expression of TGF-ß target genes in kidneys of db/db mice, resulting in attenuation of renal fibrosis and amelioration of renal dysfunction despite persistent hyperglycemia. Therefore, AKF-PD, a potent antifibrotic agent, holds great promise in the treatment of diabetic nephropathy.

Fluorofenidone attenuates renal interstitial fibrosis in the rat model of obstructive nephropathy.

Fluorofenidone (FD) is a novel pyridone agent with significant antifibrotic effects in vitro. The purpose of this study is to investigate the effects of FD on renal interstitial fibrosis in rats with obstructive nephropathy caused by unilateral ureteral obstruction (UUO). With pirfenidone (PD, 500 mg/kg/day) and enalapril (10 mg/kg/day) as the positive treatment controls, the rats in different experimental groups were administered with FD (500 mg/kg/day) from day 4 to day 14 after UUO. The tubulointerstitial injury, interstitial collagen deposition, and expression of type I and type III collagen, transforming growth factor-ß(1) (TGF-ß(1)), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), α-smooth muscle actin (α-SMA), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were assessed. FD treatment significantly attenuated the prominently increased scores of tubulointerstitial injury, interstitial collagen deposition, and protein expression of type I and type III collagen in ureter-obstructed kidneys, respectively. As compared with untreated rats, FD also significantly reduced the expression of α-SMA, TGF-ß(1), CTGF, PDGF, and inhibitor of TIMP-1 in the obstructed kidneys. Fluorofenidone attenuates renal interstitial fibrosis in the rat model of obstructive nephropathy through its regulation on fibrogenic growth factors, tubular cell transdifferentiation, and extracellular matrix.