Cathepsin S (CTSS) in IgA nephropathy: an exploratory study on its role as a potential diagnostic biomarker and therapeutic target.

Introduction: IgA nephropathy (IgAN), a prevalent form of glomerulonephritis globally, exhibits complex pathogenesis. Cathepsins, cysteine proteases within lysosomes, are implicated in various physiological and pathological processes, including renal conditions. Prior observational studies have suggested a potential link between cathepsins and IgAN, yet the precise causal relationship remains unclear. Methods: We conducted a comprehensive bidirectional and multivariable Mendelian randomization (MR) study using publicly available genetic data to explore the causal association between cathepsins and IgAN systematically. Additionally, immunohistochemical (IHC) staining and enzyme-linked immunosorbent assay (ELISA) were employed to evaluate cathepsin expression levels in renal tissues and serum of IgAN patients. We investigated the underlying mechanisms via gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and immune cell infiltration analysis. Molecular docking and virtual screening were also performed to identify potential drug candidates through drug repositioning. Results: Univariate MR analyses demonstrated a significant link between increased cathepsin S (CTSS) levels and a heightened risk of IgAN. This was evidenced by an odds ratio (OR) of 1.041 (95% CI=1.009-1.073, P=0.012) as estimated using the inverse variance weighting (IVW) method. In multivariable MR analysis, even after adjusting for other cathepsins, elevated CTSS levels continued to show a strong correlation with an increased risk of IgAN (IVW P=0.020, OR=1.037, 95% CI=1.006-1.069). However, reverse MR analyses did not establish a causal relationship between IgAN and various cathepsins. IHC and ELISA findings revealed significant overexpression of CTSS in both renal tissues and serum of IgAN patients compared to controls, and this high expression was unique to IgAN compared with several other primary kidney diseases such as membranous nephropathy, minimal change disease and focal segmental glomerulosclerosis. Investigations into immune cell infiltration, GSEA, and GSVA highlighted the role of CTSS expression in the immune dysregulation observed in IgAN. Molecular docking and virtual screening pinpointed Camostat mesylate, c-Kit-IN-1, and Mocetinostat as the top drug candidates for targeting CTSS. Conclusion: Elevated CTSS levels are associated with an increased risk of IgAN, and this enzyme is notably overexpressed in IgAN patients' serum and renal tissues. CTSS could potentially act as a diagnostic biomarker, providing new avenues for diagnosing and treating IgAN.

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.

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.

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.