Risk Factors of Chronic Kidney Disease in Chronic Hepatitis B: A Hospital-based Case-control Study from China.

Background and Aims: Chronic kidney disease (CKD) usually occurs during the chronic infection of hepatitis B virus (HBV). However, the risk factors of CKD in an HBV population have not been completely demonstrated. Our present study aimed to investigate the risk factors of CKD in chronic HBV infection using a hospital based cross-sectional study in the northern area of China. Methods: During January 2013 to December 2017, a total of 94 patients with CKD complicated by chronic HBV infection were consecutively enrolled in the study, as well as 548 age- and sex-matched hepatitis B patients without CKD who were enrolled as controls. Univariate and multivariate regression analyses were used to determine the effects of each variable after adjusting for cofounding factors. Results: Multivariate analysis showed that HBeAg-positive status (odds ratio [OR]=2.099, 95% CI 1.128-3.907), dyslipidemia (OR: 3.025, 95% CI 1.747-5.239), and hypertension (OR: 12.523, 95% CI 6.283-24.958) were independently associated with the incidence of CKD, while duration of HBV infection (≥240 months) (OR: 0.401, 95% CI 0.179-0.894), Log10 HBsAg (OR: 0.514, 95% CI 0.336-0.786), and coronary heart disease (OR: 0.078, 95% CI 0.008-0.768) were protective factors for the incidence of CKD. Duration of HBV infection, Log10 HBsAg, HBeAg-positive status and dyslipidemia remained the risk factors for CKD after adjusting for diabetes mellitus, hypertension, and coronary heart disease. Conclusions: Duration of HBV infection, Log10 HBsAg, HBeAg-positive status and dyslipidemia contributed to the incidence of CKD during chronic HBV infection in a Chinese population.

Hydroxychloroquine alleviates renal interstitial fibrosis by inhibiting the PI3K/Akt signaling pathway.

Renal fibrosis is the ultimate presentation of chronic kidney disease, which progresses to end-stage renal disease. Hydroxychloroquine (HCQ) has been adapted for the treatment of autoimmune diseases; however, the potential mechanism underlying the role of HCQ in renal fibrosis remains unclear. C57BL/6 J mice were randomly divided into three groups (sham group, UUO group, and UUO + HCQ group (20 mg/kg)). HE and Masson staining were performed to assess kidney tissue damage and fibrosis, and western blotting was performed to assess the expression of epithelial-mesenchymal transition (EMT), extracellular matrix (ECM), PI3K/AKT, and NF-κB-related proteins. PCR and TUNEL were adopted to detect inflammatory factors and cell apoptosis. HK-2 cells treated with TGF-ß1 were used for the in vitro experiments. HCQ may potentially have therapeutic effects on renal fibrosis mediated through 122 target genes, and the Kyoto Encyclopedia of Genes and Genomes pathways of these genes were enriched for PI3K/AKT signaling based on network pharmacology. UUO mice that received HCQ demonstrated significantly less tubular damage than the UUO mice. HCQ treatment additionally blunted EMT in UUO kidneys and TGF-ß1-treated renal tubular epithelial cells, and alleviated ECM deposition in kidney tissue. Furthermore, HCQ treatment reduced UUO-induced inflammation and apoptosis. Mechanistically, HCQ treatment suppressed the activation of the PI3K/Akt and NF-kB pathways. This study demonstrated that HCQ ameliorated renal fibrosis by inhibiting the PI3K/AKT and NF-κB signaling pathways to attenuate inflammatory factors and the apoptotic function of renal tubular epithelial cells, thus providing renewed theoretical evidence for HCQ treatment of renal fibrosis.

Nephroprotective Effect of Adropinin Against Streptozotocin-Induced Diabetic Nephropathy in Rats: Inflammatory Mechanism and YAP/TAZ Factor.

BACKGROUND: Diabetic Nephropathy remains a major cause of morbidity and mortality in patients suffering from renal dysfunction. This study accessed the nephroprotective role of Adropinin against streptozotocin (STZ) induced diabetic nephropathy in rats and scrutinizes the possible mechanism of action. METHODS: STZ (45 mg/kg) dose was used for inducing diabetic nephropathy (DN) and rats were divided into different groups and received the dose-dependent treatment of Adropinin. Blood glucose level, body weight, tissue weight, antioxidant, renal, hepatic parameters, and cytokines were determined. At the end of the experimental study, renal histopathology was performed. RESULTS: Adropinin significantly (P<0.001) boosted plasma insulin levels and reduced the blood glucose level. Adropinin considerably increased body weight and reduced kidney weight and kidney hypertrophy. Adropinin significantly (P<0.001) reduced urine outflow, microalbumin, total protein, blood urea nitrogen (BUN), uric acid and increased the creatinine, creatinine clearance. Adropinin significantly (P<0.001) reduced the indole sulfate level in the serum, kidney and reduced in the urine. Adropinin significantly (P<0.001) reduced the total cholesterol, triglyceride, low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL) and increased the level of high-density lipoprotein (HDL). Adropinin significantly (P<0.001) increased the level of antioxidant enzymes such as glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and reduced the level of malonaldehyde (MDA), 8-hydroxy-2' -deoxyguanosine (8-OHdG). Adropinin significantly (P<0.001) reduced the level of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), transforming growth factor beta (TGF-ß) and increased the level of interleukin-10 (IL-10), respectively. Adropinin treatment showed improvement in renal histopathology. CONCLUSION: We can say that Adropinin showed the nephroprotective effect against the STZ-induced diabetic nephropathy rats via inflammatory and antioxidant pathway.

IDO1 as a new immune biomarker for diabetic nephropathy and its correlation with immune cell infiltration.

INTRODUCTION: Indoleamine 2,3-dioxygenase 1(IDO1) has complicated roles in immune-inflammatory response regulation, but its correlation with immune cell infiltration in diabetic nephropathy (DN) remains unknown. METHODS: Gene expression data were extracted from the GEO database. Differentially expressed genes (DEGs) were identified and functional correlation analysis was performed. The immune hub gene was screened using Maximal Clique Centrality, and verified in DN model mice via western blotting, immunohistochemistry, and immunofluorescence analysis. CIBERSORTx was used to assign values to immune cell infiltration in DN and determine a correlation with the hub gene. The prognostic significance of the hub gene was then validated. RESULTS: The 330 screened DEGs from the GEO dataset were most enriched in GO functions and KEGG pathways associated with immune inflammation. IDO1 was identified as a hub immune gene, with upregulated expression in DN model mice. IDO1 expression was positively correlated with M1 macrophages (R = 0.58, P < 0.001) and monocytes (R = 0.44, P = 0.049), and was negatively correlated with resting memory CD4 T cells (R = -0.51, P = 0.019). IDO1 expression was upregulated in peritoneal macrophages after high glucose stimulation, and inflammatory factor production was reversed by IDO1 inhibition. Higher IDO1 expression was associated with worse prognosis in DN patients via multivariate survival analysis (P < 0.001). CONCLUSIONS: IDO1 was identified as a diagnostic and prognostic biomarker for DN and shown to play a vital role in immune cell infiltration in DN, ascertained using microarray data and CIBERSORTx for the first time.

Association of Complement and Inflammatory Biomarkers with Diabetic Nephropathy.

OBJECTIVE: To investigate the association between complement and inflammatory biomarkers with diabetic nephropathy (DN) in type 2 diabetes mellitus (T2DM). METHODS: Plasma and urinary complement and inflammatory biomarkers were measured in 115 T2DM patients assigned to one of two groups: with DN (n=48) and without DN (n=67). RESULTS: The plasma and urinary levels of C3a, C4d, C5a, sC5b-9 and MBL (mannan-binding lectin) were significantly higher in T2DM patients with DN compared to T2DM patients without DN. The plasma levels of IL-10 and INF-γ, as well as the urinary levels of INF-γ and TNF-α in T2DM patients with DN, were significantly higher than T2DM patients without DN. Both urinary MBL and INF-γ were independent risk factors for DN within T2DM patients (OR, 2.35 (95% CI 2.28-2.64) and 1.17 (95% CI 1.15-1.18); P=0.000 and 0.016, respectively). The area under the receiver-operating-characteristic-curve for urinary MBL was 0.89, with sensitivity 91% and specificity 83% for DN. The area under the receiver-operating-characteristic-curve for INF-γ was 0.84, with sensitivity 86% and specificity 79% based on cutoff values of 1.42 ng/mg and 5.15 pg/mg, respectively. CONCLUSION: This study suggests that urinary INF-γ and MBL levels are independent risk factors with a high predictive power for DN in T2DM patients.

Tim-3 aggravates podocyte injury in diabetic nephropathy by promoting macrophage activation via the NF-κB/TNF-α pathway.

OBJECTIVE: Macrophage-mediated inflammation plays a significant role in the development and progression of diabetic nephropathy (DN). However, the underlying mechanisms remain unclear. Studies suggest that T cell immunoglobulin domain and mucin domain-3 (Tim-3) has complicated roles in regulating macrophage activation, but its roles in the progression of DN are still completely unknown. METHODS: We downregulated Tim-3 expression in kidney (intrarenal injection of Tim-3 shRNA expressing lentivirus or global Tim-3 knockout mice) and induced DN by streptozotocin (STZ). We analyzed the degree of renal injury, especially the podocyte injury induced by activated macrophages in vitro and in vivo. Then, we transferred different bone marrow derived macrophages (BMs) into STZ-induced Tim-3 knockdown mice to examine the effects of Tim-3 on macrophages in DN. RESULTS: First, we found that Tim-3 expression on renal macrophages was increased in patients with DN and in two diabetic mouse models, i.e. STZ-induced diabetic mice and db/db mice, and positively correlated with renal dysfunction of DN patients. Tim-3 deficiency ameliorated renal damage in STZ-induced diabetes with concurrent increase in protein levels of Nephrin and WT-1. Similar effects were observed in mice with Tim-3 knockdown diabetic mice. Second, adoptive transfer of Tim-3-expressing macrophages, but not Tim-3 knockout macrophages, accelerated diabetic renal injury in DN mice, suggesting a key role for Tim-3 on macrophages in the development of DN. Furthermore, we found NF-κB activation and TNF-α excretion were upregulated by Tim-3 in diabetic kidneys, and podocyte injury was associated with the Tim-3-mediated activation of the NF-κB/TNF-α signaling pathway in DN macrophages both in vivo and in vitro. CONCLUSIONS: These results suggest that Tim-3 functions as a key regulator in renal inflammatory processes and serves as a potential therapeutic target for renal injury in DN.

Protective effect of calcitriol on podocytes in spontaneously hypertensive rat.

BACKGROUND: Hypertension is a major global public health issue. Uncontrolled hypertension leads to organ damage, especially renal damage. Calcitriol is used to treat osteoporosis, promote bone formation, and increase bone mass. Previous studies have demonstrated that 1,25(OH)2D3, in addition to its classic role, also has multiple immune regulation and renoprotective functions and inhibits the activity of the renin-angiotensin-aldosterone system (RASS). The aim of the current study was to investigate the renoprotective effects of calcitriol in a spontaneously hypertensive rat (SHR) model. METHODS: A total of 18 SHRs and 8 age-matched normal Wistar rats were enrolled. SHRs were randomly divided into a hypertensive nephropathy group (H), a hypertensive nephropathy treated with calcitriol group (D) and a control group (NS). The rats were sacrificed after 16 weeks of treatment. The blood pressure (BP) of rats were measured one time every 4 weeks. The levels of serum albumin, serum creatinine, blood calcium, serum Vitamin D and 24-h urinary protein were measured after 16 weeks treatment. The protein level of WT1, nephrin and vitamin D receptor (VDR) was examined by Western blotting and immunohistochemical staining. RESULTS: There were no notable changes in blood pressure or serum creatinine in group H and D compared with group NS. The albumin, calcium and vitamin D serum levels in group H were significantly decreased compared with group NS and significantly increased in group D compared with group H. The level of 24-h urine protein significantly increased in group H compared with group NS and significantly decreased in group D compared with group H. The expression of VDR, WT1 and nephrin in the kidney were all significantly decreased in group H compared with group NS and significantly increased in group D compared with group H. CONCLUSION: The present results indicated that there was injury of podocytes in hypertensive nephropathy, which can be ameliorated by calcitriol in SHR, but there was no significant anti-hypertensive effect. Vitamin D/VDR decreased proteinuria perhaps by increasing expression of nephrin and WT1 protein in podocyte of SHRs.

Correlation between endothelial dysfunction and left ventricular remodeling in patients with chronic kidney disease.

BACKGROUND/AIMS: To investigate the role of endothelial dysfunction on left ventricular remodeling in patients with chronic kidney disease and to evaluate the correlation between endothelial dysfunction and left ventricular remodeling. METHODS: Seventy-three patients with chronic kidney disease as study-group and thirty healthy volunteers as control-group were enrolled in the present study. All patients in both groups had echocardiography examination. The concentration of endothelin-1, nitric oxide, and inducible nitric oxide synthase of serum of all patients and healthy volunteers was measured. The incidence of cardiac structural abnormalities in patients with chronic kidney disease, and the relationship between endothelial dysfunction and cardiac structural abnormalities were analyzed. RESULTS: The incidence of left ventricular hypertrophy, left ventricular concentric remodeling, and left ventricular systolic dysfunction was 65%, 8.33%, and 16.67%, respectively. The level of endothelin-1 and nitric oxide increased in study-group, and the concentration of inducible nitric oxide synthase decreased. There was significant positively relationship between plasma endothelin-1 and left ventricular mass index, interventricular septal thickness, left ventricular diastolic diameter. There was negatively relationship between the level of serum nitric oxide and the maximum flow velocity at the mitral in left ventricular diastolic stage. There was not any correlation between inducible nitric oxide synthase with left ventricular remodeling. CONCLUSIONS: The results showed that there was a higher incidence of left ventricular hypertrophy in patients with chronic kidney disease. Endothelin-1 and nitric oxide played an important role on the development of left ventricular hypertrophy.

Oligomeganephronia: case report and literature review.

INTRODUCTION: Oligomeganephronia (OMN) is one of rare congenital kidney disease. The number of nephrons reduces and the volume of glomerulus increases. The incidence of OMN is uncertain because it is difficult to diagnose. There are no any special clinical manifestations of OMN. Renal pathology is the only way to diagnose OMN, so missed diagnosis always happens without renal pathology. CASE OUTLINE: A 26-year-old male was diagnosed OMN associated with proteinuria and increased serum creatinine. The size of both kidneys on ultrasound was smaller than normal. Pathological features involved a reduced number of greatly enlarged glomeruli indicating OMN. CONCLUSION: OMN is a rare disease and it has been rarely reported. The exact mechanism is not clear. The diagnosis mainly depends on pathological findings. For patients with OMN, proteinuria and renal dysfunction are often the main cause to visit a doctor. Early diagnosis is important.

Relationship between psychiatric disorders and quality of life in nondialysis patients with chronic kidney disease.

BACKGROUND: The aim of this study was to investigate the relationship between psychiatric disorders (anxiety and depression) and quality of life (QOL) in nondialysis patients with chronic kidney disease (CKD). METHODS: QOL was evaluated in a sample of 57 nondialysis patients with CKD using the 36-item Short Form Health Survey questionnaire comprising 8 scales, including the physical component summary and mental component summary measures. Depression and anxiety were estimated using the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale, respectively. RESULTS: Depression and anxiety scores were negatively correlated with 7 of the 8 scales of the Short Form 36 questionnaire, and with the physical component summary and mental component summary scores, despite 38.6% patients with depression and 54.4% with anxiety, whereas QOL in the depression group, the anxiety group, and the anxiety and depression comorbid group was lower than that for those without the corresponding psychiatric disorders (P < 0.05). CONCLUSIONS: This study demonstrates that depression and anxiety, commonly encountered in patients with CKD, could be a risk factor for QOL in these patients.