Characteristics of Complement Protein Deposition in Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposition.

BACKGROUND: Hypocomplementemia and complement co-deposition with monoclonal immunoglobulins in glomeruli are not rare in proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). Deposition of monoclonal immunoglobulins in glomeruli has been suggested to activate complement and cause kidney injury. However, the profiles of complement activation in PGNMID and their clinical and pathologic significance need to be clarified. METHODS: Forty-six patients with PGNMID were enrolled. Proteomic analysis of glomeruli using laser microdissection and mass spectrometry was performed for ten patients with PGNMID to determine the composition of glomerular deposits. Kidney deposition of complement components was detected by immunohistochemistry and immunofluorescence. Urinary and plasma levels of complement components were measured by an enzyme-linked immunosorbent assay. Group differences were assessed using t tests or Mann-Whitney U tests depending on the distribution. Correlation analysis was performed using Spearman rank correlation or Pearson correlation. RESULTS: Laser microdissection and mass spectrometry-based proteomic analysis showed that complement components were the most enriched proteins deposited in the glomeruli of patients with PGNMID. Glomerular deposition of C3c, C4d, and C5b-9 was detected in most patients. Levels of urinary and plasma C3a, C5a, soluble C5b-9, C4d, Bb, and C1q as well as urinary mannose-binding lectin were significantly higher in patients with PGNMID compared with healthy controls. The intensity of C3c and C4d deposition in glomeruli correlated with serum creatinine and the percentage of crescents, respectively. Furthermore, levels of urinary complement components correlated positively with serum creatinine, urinary protein excretion, percentage of crescents, and global glomerulosclerosis in kidney biopsies, whereas plasma levels of most complement components did not show a significant correlation with clinicopathologic parameters. In multivariable analysis, a higher level of urinary C4d was identified as an independent risk factor of kidney failure. CONCLUSIONS: The complement system was found to be overactivated in PGNMID, and levels of urinary complements correlated with disease severity. A higher level of urinary C4d was identified as an independent risk factor of kidney failure.

Urinary sediment CCL5 messenger RNA as a potential prognostic biomarker of diabetic nephropathy.

BACKGROUND: Urinary sediment messenger RNAs (mRNAs) have been shown as novel biomarkers of kidney disease. We aimed to identify targeted urinary mRNAs in diabetic nephropathy (DN) based on bioinformatics analysis and clinical validation. METHODS: Microarray studies of DN were searched in the GEO database and Nephroseq platform. Gene modules negatively correlated with estimated glomerular filtration rate (eGFR) were identified by informatics methods. Hub genes were screened within the selected modules. In validation cohorts, a quantitative polymerase chain reaction assay was used to compare the expression levels of candidate mRNAs. Patients with renal biopsy-confirmed DN were then followed up for a median time of 21 months. End-stage renal disease (ESRD) was defined as the primary endpoint. Multivariate Cox proportional hazards regression was developed to evaluate the prognostic values of candidate mRNAs. RESULTS: Bioinformatics analysis revealed four chemokines (CCL5, CXCL1, CXLC6 and CXCL12) as candidate mRNAs negatively correlated with eGFR, of which CCL5 and CXCL1 mRNA levels were upregulated in the urinary sediment of patients with DN. In addition, urinary sediment mRNA of CXCL1 was negatively correlated with eGFR (r = -0.2275, P = 0.0301) and CCL5 level was negatively correlated with eGFR (r = -0.4388, P < 0.0001) and positively correlated with urinary albumin:creatinine ratio (r = 0.2693, P = 0.0098); also, CCL5 and CXCL1 were upregulated in patients with severe renal interstitial fibrosis. Urinary sediment CCL5 mRNA was an independent predictor of ESRD [hazard ratio 1.350 (95% confidence interval 1.045-1.745)]. CONCLUSIONS: Urinary sediment CCL5 and CXCL1 mRNAs were upregulated in DN patients and associated with a decline in renal function and degree of renal interstitial fibrosis. Urinary sediment CCL5 mRNA could be used as a potential prognostic biomarker of DN.

Development and External Validation of a Nomogram and a Risk Table for Prediction of Type 2 Diabetic Kidney Disease Progression Based on a Retrospective Cohort Study in China.

Purpose: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. Risk assessment provides information about patient prognosis, contributing to the risk stratification of patients and the rational allocation of medical resources. We aimed to develop a model for individualized prediction of renal function decline in patients with type 2 DKD (T2DKD). Patients and Methods: In a retrospective observational study, we followed 307 T2DKD patients and evaluated the determinants of 1) risk of doubling in serum creatinine (Scr), 2) risk of eGFR<15 mL/min/1.73m2 using potential risk factors at baseline. A prediction model represented by a nomogram and a risk table was developed using Cox regression and externally validated in another cohort with 206 T2DKD patients. The discrimination and calibration of the prediction model were evaluated by the concordance index (C-index) and calibration curve, respectively. Results: Four predictors were selected to establish the final model: Scr, urinary albumin/creatinine ratio, plasma albumin, and insulin treatment. The nomogram achieved satisfactory prediction performance, with a C-index of 0.791 [95% confidence interval (CI) 0.762-0.820] in the derivation cohort and 0.793 (95% CI 0.746-0.840) in the external validation cohort. Then, all predictors were scored according to their weightings. A risk table with the highest score of 11.5 was developed. The C-index of the risk table was 0.764 (95% CI: 0.731-0.797), which was similar to the external validation cohort (0.763; 95% CI: 0.714-0.812). Additionally, the patients were divided into two groups based on the risk table, and significant differences in the probability of outcome events were observed between the high-risk (score >2) and low-risk (score ≤2) groups in the derivation and external validation cohorts (P < 0.001). Conclusion: The nomogram and the risk table using readily available clinical parameters could be new tools for bedside prediction of renal function decline in T2DKD patients.

Long non-coding RNA HOTAIR knockdown alleviates gouty arthritis through miR-20b upregulation and NLRP3 downregulation.

This study aimed to determine the mechanism underlying the regulation of gout by the HOX transcript antisense RNA (HOTAIR) long non-coding RNA (lncRNA). The expression levels of HOTAIR, miR-20b, and Nlrp3 were estimated by qRT-PCR and western blotting. The methylation level of HOTAIR was detected by methylation-specific PCR. The recruitment of DNA methyltransferase 1 (DNMT1) to the lncRNA HOTAIR promoter was confirmed by a ChIP assay. RNA immunoprecipitation and RNA pull-down assays were used to confirm the interaction between HOTAIR and miR-20b. LncRNA HOTAIR and Nlrp3 expression was upregulated, and that of miR-20b was downregulated in synovial fluid mononuclear cells (SFMCs) collected from patients with gouty arthritis and monosodium urate (MSU)-stimulated THP-1 cells. Interleukin (IL)-1ß level increased substantially upon stimulation by MSU crystals. The methylation percentage of HOTAIR was reduced in SFMCs from patients with gouty arthritis and MSU-stimulated THP-1 cells. DNMT1 expression was downregulated in MSU-stimulated THP-1 cells, and DNMT1 knockdown increased lncRNA HOTAIR expression. In addition, the interaction of HOTAIR with miR-20b was confirmed. HOTAIR knockdown suppressed Nlrp3 expression and the secretion of inflammatory cytokines via miR-20b regulation. Finally, in vivo experiments showed that HOTAIR knockdown alleviated ankle swelling in a mouse model of gouty arthritis. These findings suggest that lncRNA HOTAIR knockdown suppresses inflammatory cytokine secretion by upregulating miR-20b and downregulating NLRP3, thereby alleviating ankle swelling in gouty arthritis.

The chronic kidney disease and acute kidney injury involvement in COVID-19 pandemic: A systematic review and meta-analysis.

BACKGROUND: Currently, the SARS-CoV-2 promptly spread across China and around the world. However, there are controversies about whether preexisting chronic kidney disease (CKD) and acute kidney injury complication (AKI) are involved in the COVID-19 pandemic. MEASUREMENTS: Studies reported the kidney outcomes in different severity of COVID-19 were included in this study. Standardized mean differences or odds ratios were calculated by employing Review Manager meta-analysis software. RESULTS: Thirty-six trials were included in this systematic review with a total of 6395 COVID-19 patients. The overall effects indicated that preexisting CKD (OR = 3.28), complication of AKI (OR = 11.02), serum creatinine (SMD = 0.68), abnormal serum creatinine (OR = 4.86), blood urea nitrogen (SMD = 1.95), abnormal blood urea nitrogen (OR = 6.53), received continuous renal replacement therapy (CRRT) (OR = 23.63) were significantly increased in severe group than that in nonsevere group. Additionally, the complication of AKI (OR = 13.92) and blood urea nitrogen (SMD = 1.18) were remarkably elevated in the critical group than that in the severe group. CONCLUSIONS: CKD and AKI are susceptible to occur in patients with severe COVID-19. CRRT is applied frequently in severe COVID-19 patients than that in nonsevere COVID-19 patients. The risk of AKI is higher in the critical group than that in the severe group.

[Clinical and Pathological Characteristics of Related-Renal Damage in Patients with POEMS Syndrome].

OBJECTIVE: To investigated the clinical and pathological characteristics of related-renal damage in patients with POEMS syndrome. METHODS: Five patients diagnosed as POEMS syndrome in our hospital were selected. Their clinical manifestation, pathological characteristics of kidney and laboratory examination were analyzed retrospectively. Among the 5 patients, three males and two females with a median age of 50 years old. The mean interval before diagnosis was 13.0±7.2 months. RESULTS: All the patients showed neuropathy, endocrinopathy, monoclonal plasma cell-proliferative disorder, skin changes and extravascular volume overload, in which 4 patients showed organomegaly. Proteinuria was found in 5 patients, and microhematuria was found in 4 patients. Moreover, 4 patients showed an elevated blood urea, while 2 patients showed creatinine elevation. 1 patient at chronic kidney disease (CKD)-G1 stage, 2 patients at CKD-G2 stage, and 1 patient at CKD-G3b stage, moreover, 1 patient at CKD-G5 stage. Endothelial injury and mesangial lesion were the main characteristics of renal pathology. 3 patients were pathologically diagnosed as thrombotic microangiopathy kidney damage, while 2 patients as light chain amyloidosis. CONCLUSION: POEMS syndrome is a multi-systemic disease with complex clinical manifestations. 5 patients had different degrees of renal insufficiency. Endothelial injury and mesangial lesion are the main features of renal pathology.

The Derivative of Tripterygium wilfordii Hook F-Kunxian Capsule, Attenuated Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.

The study aimed to explore the efficacy and safety of Kunxian Capsule (KXC) in the treatment of rheumatoid arthritis (RA). The randomized controlled trials (RCTs) comparing the effects of KXC in patients with RA were included in this study. Weighted mean differences (MDs) were calculated for net changes by employing Review Manager meta-analysis software. Nine RCTs were included in the systematic review with a total of 747 patients. The overall effects showed that KXC alone or combined with disease-modifying antirheumatic and drugs decreased tender joint counts (P=0.02, MD = -1.07, 95% CI: -1.95 to -0.18), shortened duration of morning stiffness (P < 0.0001, MD = -9.01, 95% CI: -13.08 to -4.93), lowered erythrocyte sedimentation rate (P < 0.00001, MD = -5.27, 95% CI: -6.78 to -3.77), and reduced C-reactive protein (P < 0.0001, MD = -5.04, 95% CI: -7.28 to -2.80). The most common adverse events were gastrointestinal disturbances and abnormal liver function. These results suggest that KXC is likely to be a more effective and safe candidate for treating RA compared with conventional therapies.

Proteomic profiling of fetal esophageal epithelium, esophageal cancer, and tumor-adjacent esophageal epithelium and immunohistochemical characterization of a representative differential protein, PRX6.

AIM: To understand the molecular mechanism of esophageal cancer development and provide molecular markers for screening high-risk populations and early diagnosis. METHODS: Two-dimensional electrophoresis combined with mass spectrometry were adopted to screen differentially expressed proteins in nine cases of fetal esophageal epithelium, eight cases of esophageal cancer, and eight cases of tumor-adjacent normal esophageal epithelium collected from fetuses of different gestational age, or esophageal cancer patients from a high-risk area of esophageal cancer in China. Immunohistochemistry (avidin-biotin-horseradish peroxidase complex method) was used to detect the expression of peroxiredoxin (PRX)6 in 91 cases of esophageal cancer, tumor-adjacent normal esophageal tissue, basal cell hyperplasia, dysplasia, and carcinoma in situ, as well as 65 cases of esophageal epithelium from fetuses at a gestational age of 3-9 mo. RESULTS: After peptide mass fingerprint analysis and search of protein databases, 21 differential proteins were identified; some of which represent a protein isoform. Varying degrees of expression of PRX6 protein, which was localized mainly in the cytoplasm, were detected in adult and fetal normal esophageal tissues, precancerous lesions, and esophageal cancer. With the progression of esophageal lesions, PRX6 protein expression showed a declining trend (P < 0.05). In fetal epithelium from fetuses at gestational age 3-6 mo, PRX6 protein expression showed a declining trend with age (P < 0.05). PRX6 protein expression was significantly higher in well-differentiated esophageal cancer tissues than in poorly differentiated esophageal cancer tissues (P < 0.05). CONCLUSION: Development and progression of esophageal cancer result from interactions of genetic changes (accumulation or superposition). PRX6 protein is associated with fetal esophageal development and cancer differentiation.

The Effects of Modified Simiao Decoction in the Treatment of Gouty Arthritis: A Systematic Review and Meta-Analysis.

The modified Simiao decoctions (MSD) have been wildly applied in the treatment of gouty arthritis in China. However, the evidence needs to be evaluated by a systematic review and meta-analysis. After filtering, twenty-four randomised, controlled trials (RCTs) comparing the effects of MSD and anti-inflammation medications and/or urate-lowering therapies in patients with gouty arthritis were included. In comparison with anti-inflammation medications, urate-lowering therapies, or coadministration of anti-inflammation medications and urate-lowering therapies, MSD monotherapy significantly lowered serum uric acid (p < 0.00001, mean difference = -90.62, and 95% CI [-128.38, -52.86]; p < 0.00001, mean difference = -91.43, and 95% CI [-122.38, -60.49]; p = 0.02, mean difference = -40.30, and 95% CI [-74.24, -6.36], resp.). Compared with anti-inflammation medications and/or urate-lowering therapies, MSD monotherapy significantly decreased ESR (p < 0.00001; mean difference = -8.11; 95% CI [-12.53, -3.69]) and CRP (p = 0.03; mean difference = -3.21; 95% CI [-6.07, -0.36]). Additionally, the adverse effects (AEs) of MSD were fewer (p < 0.00001; OR = 0.08; 95% CI [0.05, 0.16]). MSD are effective in the treatment of gouty arthritis through anti-inflammation and lowering urate. However, the efficacy of MSD should be estimated with more RCTs.