Oxidative stress as a culprit in diabetic kidney disease.

Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease (ESRD), and the prevalence of DKD has increased worldwide during recent years. DKD is associated with poor therapeutic outcomes in most patients, but there is limited understanding of its pathogenesis. This review suggests that oxidative stress interacts with many other factors in causing DKD. Highly active mitochondria and NAD(P)H oxidase are major sources of oxidants, and they significantly affect the risk for DKD. Oxidative stress and inflammation may be considered reciprocal causes of DKD, in that each is a cause and an effect of DKD. Reactive oxygen species (ROS) can act as second messengers in various signaling pathways and as regulators of metabolism, activation, proliferation, differentiation, and apoptosis of immune cells. Epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNAs can modulate oxidative stress. The development of new technologies and identification of new epigenetic mechanisms may provide novel opportunities for the diagnosis and treatment of DKD. Clinical trials demonstrated that novel therapies which reduce oxidative stress can slow the progression of DKD. These therapies include the NRF2 activator bardoxolone methyl, new blood glucose-lowering drugs such as sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists. Future studies should focus on improving early diagnosis and the development of more effective combination treatments for this multifactorial disease.

Identification of diagnostic gene biomarkers and immune infiltration in patients with diabetic kidney disease using machine learning strategies and bioinformatic analysis.

Objective: Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease worldwide. Early diagnosis is critical to prevent its progression. The aim of this study was to identify potential diagnostic biomarkers for DKD, illustrate the biological processes related to the biomarkers and investigate the relationship between them and immune cell infiltration. Materials and methods: Gene expression profiles (GSE30528, GSE96804, and GSE99339) for samples obtained from DKD and controls were downloaded from the Gene Expression Omnibus database as a training set, and the gene expression profiles (GSE47185 and GSE30122) were downloaded as a validation set. Differentially expressed genes (DEGs) were identified using the training set, and functional correlation analyses were performed. The least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), and random forests (RF) were performed to identify potential diagnostic biomarkers. To evaluate the diagnostic efficacy of these potential biomarkers, receiver operating characteristic (ROC) curves were plotted separately for the training and validation sets, and immunohistochemical (IHC) staining for biomarkers was performed in the DKD and control kidney tissues. In addition, the CIBERSORT, XCELL and TIMER algorithms were employed to assess the infiltration of immune cells in DKD, and the relationships between the biomarkers and infiltrating immune cells were also investigated. Results: A total of 95 DEGs were identified. Using three machine learning algorithms, DUSP1 and PRKAR2B were identified as potential biomarker genes for the diagnosis of DKD. The diagnostic efficacy of DUSP1 and PRKAR2B was assessed using the areas under the curves in the ROC analysis of the training set (0.945 and 0.932, respectively) and validation set (0.789 and 0.709, respectively). IHC staining suggested that the expression levels of DUSP1 and PRKAR2B were significantly lower in DKD patients compared to normal. Immune cell infiltration analysis showed that B memory cells, gamma delta T cells, macrophages, and neutrophils may be involved in the development of DKD. Furthermore, both of the candidate genes are associated with these immune cell subtypes to varying extents. Conclusion: DUSP1 and PRKAR2B are potential diagnostic markers of DKD, and they are closely associated with immune cell infiltration.

Roxadustat for the treatment of anemia in patients with chronic kidney diseases: a meta-analysis.

BACKGROUND: Anemia is a common complication of chronic kidney disease (CKD). Treating renal anemia with erythropoiesis-stimulating agents (ESAs) or erythropoietin analogs is effective but has side effects. Therefore, we performed a meta-analysis to assess the efficacy and safety of roxadustat in treating CKD-induced anemia. METHODS: We searched publications online and conducted a meta-analysis and calculated relative risks with 95% confidence intervals (CIs) for dichotomous data and mean differences (MD) with 95% CIs for continuous data. RESULTS: Of 110 articles, nine were included that contained 12 data sets and 11 randomized control trials on roxadustat. In the non-dialysis-dependent (NDD) high-dose/low-dose subgroups, the change in hemoglobin (Hb) levels was significantly higher in the roxadustat group than in the placebo group (P<0.0001, P=0.001, respectively). The Hb response rate of the roxadustat is higher in the NDD subgroup than in the placebo group (P<0.00001, MD=6.92, 95% CI: 4.03, 11.89). However, in the dialysis-dependent subgroup, there was no significant difference in the change in Hb levels or the Hb response rate between the roxadustat and ESA groups. There was no change in the mortality in the roxadustat group compared to that in the placebo/ESA group. Hyperkalemia may be a side effect of roxadustat. CONCLUSIONS: Roxadustat elevated the serum Hb levels in a manner similar to that observed for ESAs. Roxadustat raised the Hb levels more significantly than the placebo and showed a higher Hb response rate than the placebo group in NDD patients. Roxadustat is a safe and effective drug for anemia in CKD patients.

Atypical hemolytic uremic syndrome and acute tubular necrosis induced by complement factor B gene (CFB) mutation: A case report.

RATIONALE: Atypical hemolytic uremic syndrome (aHUS) is an uncommon and serious disease that manifests hemolytic anemia, thrombocytopenia, and acute kidney injury. Genetic complement abnormalities have been shown to be responsible. Compared with the aHUS caused by other mutated genes, aHUS secondary to CFB mutation in adults is extremely rare. We report an adult with CFB mutation developing aHUS. PATIENT CONCERNS: A 56-year-old man was admitted for 4-day history of nausea and fatigue, anuria for 2 days, and unconsciousness for 10 hours. DIAGNOSES: The patient presented with life-threatening anemia, thrombocytopenia, acute kidney injury, and nervous system abnormalities. The patient had schistocytes on the peripheral blood smear, increased lactate dehydrogenase (LDH), and plasma-free hemoglobin levels. The patient was later found to harbor a pathogenic variant in the CFB gene (C.1598A>G), and was diagnosed with aHUS and acute kidney injury. INTERVENTION: The patient was treated by plasmapheresis, continuous renal replacement therapy, blood transfusion, and anti-infective and antihypertensive treatment. OUTCOMES: After the treatment, the patient's consciousness returned to normal, and the hemoglobin, platelet, and serum creatinine recovered. The disease activity remained quiescent during the follow-up. LESSONS: A rare heterozygous variant c.1598A>G p.Lys 533Arg in the CFB gene, which was associated with adult-onset aHUS, was described and successfully treated. This case can help in understanding the early diagnosis and effective therapies of this rare disease.

Clinicopathologic correlations of renal biopsy findings from northeast China: A 10-year retrospective study.

Renal biopsy is the cornerstone of diagnostic approaches in nephrology, as they provide invaluable diagnostic information. In this study, we analyzed and reported renal biopsy results from northeast China from the past 10 years to describe the epidemiological trend.We analyzed clinical features, indications, and histological diagnoses of renal biopsies collected between January 1, 2007, and December 31, 2016.There were 2725 identified cases (with a mean age of 41.24 ±â€Š15.18 years, 55% male) during the study period. The main clinical indication was nephrotic syndrome (59.9%). Membranous nephropathy (29.1%) was the most common pathological finding in the entire study population, followed by IgA nephropathy (23.4%), minimal change disease (12.7%), and mesangio-proliferative glomerulonephritis (7.4%).We divided the study period into 2 subperiods: 2007 to 2011 (period 1) and 2012 to 2016 (period 2). Membranous nephropathy and minimal change disease were more frequent in period 2 than in period 1. Conversely, IgAN and non-IgA mesangio-proliferative glomerulonephritis were less frequent in period 2 than in period 1. Cases of Henöch-Schönlein purpura nephritis and lupus nephritis were observed less over time, while cases of nephroangiosclerosis increased significantly over time. Finally, there was a significant increase in the number of tubulointerstitial diseases observed over time, while there was a significant decrease in glomerulosclerosis and unclassified findings over time.Membranous nephropathy was the most common pathological finding from renal biopsy and the prevalence has increased significantly in recent years in northeast China.

Kimura's disease with membranoproliferative glomerulonephritis: a case report with literature review.

BACKGROUND: Kimura's disease is a rare disease and its etiology is still unclear. Here we reported a case with lymphadenopathy complicated with secondary membranoproliferative glomerulonephritis. CASE PRESENTATION: A 46-year-old Chinese man presented with bilateral tumor-like nodules over his neck during the past 6 months and developed edema for 15 days. His blood pressure was 145/90 mmHg, multiple 1 × 1 cm masses were found over bilateral post-auricular and submandibular areas, along with trace edema of the lower extremities. Laboratory data showed an increased peripheral eosinophil count at 3.66 × 109/L (50% of total leukocytes), with a 24-hour urine total protein of 8 g and a serum albumin of 19 g/L, and serum IgE of 2930 IU/ml (<100 IU/ml). The patient underwent renal biopsy, which revealed membranoproliferative glomerulonephritis with eosinophilic infiltration of the interstitium. Lymph node biopsy showed eosinophilic lymphoid follicular granuloma. Bone marrow biopsy showed no abnormalities. A diagnosis of Kimura's disease was then established. We started him on prednisone 60 mg/day (1 mg/kg), and tapered the dose to 55 mg/day 2 months later, followed by a gradual reduction of 2.5 mg every 2 weeks. Valsartan was given for blood pressure control. His neck nodules shrank after 2 weeks of treatment and complete renal remission was achieved 3 months later. No relapse occurred after follow-up for 31 months. CONCLUSION: Kimura's disease can present with bilateral neck nodules and nephrotic syndrome (membranoproliferative glomerulonephritis), and prednisone can be a suitable choice of treatment.

Roles of 12-Lipoxygenase and Its Interaction with Angiotensin II on p21 and p27 Expression in Diabetic Nephropathy.

BACKGROUND: 12-Lipoxygenase (12-LO) and angiotensin II (Ang II) are involved in the development of diabetic renal hypertrophy, in which cyclin-kinase inhibitors, p21 and p27 play pivotal roles. Here, we study the effects of 12-LO and its interaction with Ang II on glomerular p21 and p27 expression in diabetic conditions. METHODS: Models used in the current study include glomerular mesangial cells (MCs); and glomeruli from (1) type 2 diabetic db/db mice; (2) type 2 diabetic rats induced by high-fat diet feeding followed by streptozotocin injection; (3) 12-LO knockout (12-LOKO) mice; and (4) normal rats infused with Ang II or 12(S)-hydroxyeicosatetraenoic acid (12[S]-HETE, arachidonic acid metabolite of 12-LO). RESULTS: The protein expression levels of p21 and p27 were increased in high glucose-stimulated MCs and in glomeruli isolated from db/db mice. In type 2 diabetic rats, cinnamyl-3,4-dihydroxy-α-cynanocinnamate (inhibitor of 12-LO) attenuated the increases in glomerular p21 and p27 protein expression, while in normal rats, 12(S)-HETE injection increased glomerular p21 and p27 expression. 12(S)-HETE and Ang II were mutually stimulated in glomeruli. Glomerular p21 and p27 expression were decreased in 12-LOKO mice compared to levels in control mice, and Ang II stimulation increased the protein expression of p27 in control but not 12-LOKO mice. Ang II stimulation had no effect on p21 protein expression in 12-LOKO mice. CONCLUSION: 12-LO is involved in diabetic renal hypertrophy via the induction of p21 and p27 protein expression and interacts with Ang II to induce p27 upregulation in diabetes. The current results suggest a potential amplifying loop in the pathogenesis of diabetic nephropathy.

Decreased α7nAChR mRNA levels in peripheral blood monocytes are associated with enhanced inflammatory cytokine production in patients with lupus nephritis.

The cholinergic anti-inflammatory pathway modulates cytokine release by activating alpha-7 nicotinic acetylcholine receptors (α7nAChR) in monocytes/macrophages. We aimed to determine the role of α7nAChR in lupus nephritis (LN). We enrolled 36 inactive and 35 active LN patients, 34 primary glomerulonephritis patients, and 35 healthy controls. Peripheral blood monocytes were isolated, and mRNA expression of α7nAChR, interleukin (IL)-1ß, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α) in monocytes was measured. α7nAChR and IL-10 mRNA levels were significantly decreased, but IL-6 was increased, in LN patients compared with healthy controls or glomerulonephritis patients (all P < 0.01). Interestingly, α7nAChR mRNA levels were negatively correlated to SLEDAI (r = -0.68, P < 0.01), anti-dsDNA (r = -0.38, P < 0.05), and proteinuria (r = -0.49, P < 0.01) levels, and positively correlated to serum complement C3 levels (r = 0.38, P < 0.05) in patients with active LN. Furthermore, α7nAChR mRNA levels were negatively correlated to TNF-α (r = -0.50, P < 0.01), IL-1ß (r = -0.42, P < 0.05), IL-6 (r = -0.69, P < 0.01) mRNA levels, and positively correlated to IL-10 (r = 0.45, P < 0.01). TNF-α, IL-1ß, and IL-6 protein levels in the supernatant of cultured monocytes from active LN patients were significantly higher, while IL-10 was lower, than that of healthy controls. PNU-282987, an α7nAChR agonist, significantly decreased TNF-α, IL-1ß, and IL-6 but increased IL-10 in the monocyte culture supernatant of active LN patients, which were abolished by an α7nAChR antagonist methyllycaconitine. The effects of PNU-282987 were confirmed in lipopolysaccharides-stimulated monocytes. Taken together, these findings suggest that decrease in α7nAChR mRNA levels may play a role in LN and that activation of α7nAChR may inhibit inflammation in LN.

Smoking as a risk factor for diabetic nephropathy: a meta-analysis.

BACKGROUND: Previous studies have investigated the connection between diabetic nephropathy and smoking, and reported widely varying rates. This study aimed to systematically analyze the impact of smoking on diabetic nephropathy. METHODS: We searched the PubMed and EMBASE electronic databases to identify relevant English-language studies published up to March 2016. Eligible studies were selected using inclusion and exclusion criteria. Data for each study were extracted independently by two authors. The homogeneity of the effect size across the studies was tested. Odds ratio (OR) was calculated by using the random-effect model. Sensitivity analysis was performed to reduce heterogeneity, and publication biases were examined. RESULTS: A total of 21 eligible studies were selected and pooled analyzed. No significant differences in demographic characteristics were found between patients with diabetic nephropathy and those with non-diabetic nephropathy. Significant heterogeneity across studies was found except those of diabetes mellitus controls. The aggregate OR of smoking in the patients with diabetic nephropathy in comparison with those with non-diabetic nephropathy was 1.70 (95% confidence interval 1.48-1.95). No evidence of publication bias was found. CONCLUSION: Our findings indicate that smoking is a significant risk factor for diabetic nephropathy in diabetic patients.

Effect of peritoneal dialysis versus hemodialysis on renal anemia in renal in end-stage disease patients: a meta-analysis.

The aim of this meta-analysis was to evaluate the effect of peritoneal dialysis (PD) and hemodialysis (HD) on renal anemia (RA) in renal disease patients by a meta-analysis. Relevant studies published before June 2015 were searched. Pooled odds ratio (OR) with 95% confidence interval (CI) was used to evaluate the effect of HD and PD on RA based on five indexes: hemoglobin, ferritin, transferrin saturation index, serum albumin, and parathyroid hormone. Sensitivity analysis and publication bias assessment were conducted to evaluate the stability and reliability of our results. A total of fourteen eligible studies with 1103 cases underwent HD and 625 cases underwent PD were used for this meta-analysis. There were no significant difference for levels of hemoglobin (SMD = -0.23, 95% CI: -0.74 to 0.28), ferritin (SMD = 0.01, 95% CI: -0.59 to 0.62), parathyroid hormone (SMD = 0.11, 95% CI: -1.53 to 1.75) and transferrin saturation index (SMD = -0.06, 95% CI: -0.67 to 0.56) between HD and PD group. However, the content of serum albumin in HD group was much more than that in PD group (SMD = 1.58, 95% CI: 0.35 to 2.81). Neither of the included studies could reverse the pooled side effect and Egger's test demonstrated no publication bias. Both of the two dialysis strategies have a similar effect on RA in renal disease patients.

Prediction of the molecular mechanisms and potential therapeutic targets for diabetic nephropathy by bioinformatics methods.

In this study, we aimed to explore the molecular mechanisms of and genetic factors influencing diabetic nephropathy (DN). Gene expression profiles associated with DN were obtained from the GEO database (Accession no. GSE20844). The differentially expressed genes (DEGs) between diabetic mice and non-diabetic mice were screened. Subsequently, the DEGs were subjected to functional and pathway analysis. The protein-protein interaction (PPI) network was constructed and the transcription factors (TFs) were screened among the DEGs. A total of 92 upregulated and 118 downregulated genes were screened. Pathway analysis revealed that the p53 signaling pathway, the transforming growth factor (TGF)-ß signaling pathway and the mitogen-activated protein kinase (MAPK) signaling pathway were significantly enriched by upregulated genes. Serpine1 (also known as plasminogen activator inhibitor-1), early growth response 1 (Egr1) and Mdk were found to be significant nodes in the PPI network by three methods. A total of 12 TFs were found to be differentially expressed, of which nuclear receptor subfamily 4, group A, member 1 (Nr4a1) and peroxisome proliferator-activated receptor gamma (Pparg) were found to have multiple interactions with other DEGs. We demonstrated that the p53 signaling pathway, the TGF-ß signaling pathway and the MAPK signaling pathway were dysregulated in the diabetic mice. The significant nodes (Serpine1, Egr1 and Mdk) and differentially expressed TFs (Nr4a1 and Pparg) may provide a novel avenue for the targeted therapy of DN.