Protective effect of modified Huangqi Chifeng decoction on immunoglobulin A nephropathy through toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-kappa B signaling pathway.

OBJECTIVE: To examine the nephroprotective mechanism of modified Huangqi Chifeng decoction (, MHCD) in immunoglobulin A nephropathy (IgAN) rats. METHODS: To establish the IgAN rat model, the bovine serum albumin, lipopolysaccharide, and carbon tetrachloride 4 method was employed. The rats were then randomly assigned to the control, model, telmisartan, and high-, medium-, and low-dose MHCD groups, and were administered the respective treatments via intragastric administration for 8 weeks. The levels of 24-h urinary protein, serum creatinine (CRE), and blood urea nitrogen (BUN) were measured in each group. Pathological alterations were detected. IgA deposition was visualized through the use of immunofluorescence staining. The ultrastructure of the kidney was observed using a transmission electron microscope. The expression levels of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-ß1 (TGF-ß1) were examined by immunohistochemistry and quantitative polymerase chain reaction. Levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B (NF-κB) P65, were examined by immunohistochemistry, Western blotting, and quantitative polymerase chain reaction. RESULTS: The 24-h urine protein level in each group increased significantly at week 6, and worsen from then on. But this process can be reversed by treatments of telmisartan, and high-, medium-, and low-dose of MHCD, and these treatments did not affect renal function. Telmisartan, and high-, and medium-dose of MHCD reduced IgA deposition. Renal histopathology demonstrated the protective effect of high-, medium-, and low-dose of MHCD against kidney injury. The expression levels of MCP-1, IL-6, and TGF-ß1 in kidney tissues were downregulated by low, medium and high doses of MHCD treatment. Additionally, treatment of low, medium and high doses of MHCD decreased the protein and mRNA levels of TLR4, MyD88, and NF-κB. CONCLUSIONS: MHCD exerted nephroprotective effects on IgAN rats, and MHCD regulated the expressions of key targets in TLR4/MyD88/NF-κB signaling pathway, thereby alleviating renal inflammation by inhibiting MCP-1, IL-6 expressions, and ameliorating renal fibrosis by inhibiting TGF-ß1 expression.

Composition analysis of Compound Shenhua Tablet, a seven-herb Chinese medicine for IgA nephropathy: evaluation of analyte-capacity of the assays.

Compound Shenhua Tablet, a medicine comprising seven herbs, is employed in treating IgA nephropathy. This study aimed to meticulously analyze its chemical composition. Based on a list of candidate compounds, identified through extensive literature review pertinent to the tablet's herbal components, the composition analysis entailed the systematic identification, characterization, and quantification of the constituents. The analyte-capacity of LC/ESI-MS-based and GC/EI-MS-based assays was evaluated. The identified and characterized constituents were quantified to determine their content levels and were ranked based on the constituents' daily doses. A total of 283 constituents, classified into 12 distinct categories, were identified and characterized in the Compound Shenhua Tablet. These constituents exhibited content levels of 1-10 982 µg·g-1, with daily doses of 0.01-395 µmol·d-1. The predominant constituents, with daily doses of ≥ 10 µmol·d-1, include nine organic acids (citric acid, quinic acid, chlorogenic acid, cryptochlorogenic acid, gallic acid, neochlorogenic acid, isochlorogenic acid C, isochlorogenic acid B, and linoleic acid), five iridoids (specnuezhenide, nuezhenoside G13, nuezhenidic acid, secoxyloganin, and secologanoside), two monoterpene glycosides (paeoniflorin and albiflorin), a sesquiterpenoid (curzerenone), a triterpenoid (oleanolic acid), and a phenylethanoid (salidroside). Additionally, there were 83, 126, and 55 constituents detected in the medicine with daily doses of 1-10, 0.1-1, and 0.01-0.1 µmol·d-1, respectively. The combination of the LC/ESI-MS-based and GC/EI-MS-based assays demonstrated a complementary relationship in their analyte-capacity for detecting the constituents present in the medicine. This comprehensive composition analysis establishes a solid foundation for further pharmacological research on Compound Shenhua Tablet and facilitates the quality evaluation of this complex herbal medicine.

Non-immunosuppressive treatment for IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerular disease, with approximately 20% to 40% of patients progressing to kidney failure within 25 years. Non-immunosuppressive treatment has become a mainstay in the management of IgAN by improving blood pressure (BP) management, decreasing proteinuria, and avoiding the risks of long-term immunosuppressive management. Due to the slowly progressive nature of the disease, clinical trials are often underpowered, and conflicting information about management with non-immunosuppressive treatment is common. This is an update of a Cochrane review, first published in 2011. OBJECTIVES: To assess the benefits and harms of non-immunosuppressive treatment for treating IgAN in adults and children. We aimed to examine all non-immunosuppressive therapies (e.g. anticoagulants, antihypertensives, dietary restriction and supplementation, tonsillectomy, and herbal medicines) in the management of IgAN. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to December 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of non-immunosuppressive agents in adults and children with biopsy-proven IgAN were included. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed search results, extracted data and assessed study quality. Results were expressed as mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI) using random-effects meta-analysis. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: This review includes 80 studies (4856 participants), of which 24 new studies (2018 participants) were included in this review update. The risk of bias within the included studies was mostly high or unclear for many of the assessed methodological domains, with poor reporting of important key clinical trial methods in most studies. Antihypertensive therapies were the most examined non-immunosuppressive therapy (37 studies, 1799 participants). Compared to placebo or no treatment, renin-angiotensin system (RAS) inhibition probably decreases proteinuria (3 studies, 199 participants: MD - 0.71 g/24 h, 95% CI -1.04 to -0.39; moderate certainty evidence) but may result in little or no difference to kidney failure or doubling of serum creatinine (SCr), or complete remission of proteinuria (low certainty evidence). Death, remission of haematuria, relapse of proteinuria or > 50% increase in SCr were not reported. Compared to symptomatic treatment, RAS inhibition (3 studies, 168 participants) probably decreases proteinuria (MD -1.16 g/24 h, 95% CI -1.52 to -0.81) and SCr (MD -9.37 µmol/L, 95% CI -71.95 to -6.80) and probably increases creatinine clearance (2 studies, 127 participants: MD 23.26 mL/min, 95% CI 10.40 to 36.12) (all moderate certainty evidence); however, the risk of kidney failure is uncertain (1 study, 34 participants: RR 0.20, 95% CI 0.01 to 3.88; very low certainty evidence). Death, remission of proteinuria or haematuria, or relapse of proteinuria were not reported. The risk of adverse events may be no different with RAS inhibition compared to either placebo or symptomatic treatment (low certainty evidence). In low certainty evidence, tonsillectomy in people with IgAN in addition to standard care may increase remission of proteinuria compared to standard care alone (2 studies, 143 participants: RR 1.90, 95% CI 1.45 to 2.47) and remission of microscopic haematuria (2 studies, 143 participants: RR 1.93, 95% CI 1.47 to 2.53) and may decrease relapse of proteinuria (1 study, 73 participants: RR 0.70, 95% CI 0.57 to 0.85) and relapse of haematuria (1 study, 72 participants: RR 0.70, 95% CI 0.51 to 0.98). Death, kidney failure and a > 50% increase in SCr were not reported. These trials have only been conducted in Japanese people with IgAN, and the findings' generalisability is unclear. Anticoagulant therapy, fish oil, and traditional Chinese medicines exhibited small benefits to kidney function in patients with IgAN when compared to placebo or no treatment. However, compared to standard care, the kidney function benefits are no longer evident. Antimalarial therapy compared to placebo in one study reported an increase in a > 50% reduction of proteinuria (53 participants: RR 3.13 g/24 h, 95% CI 1.17 to 8.36; low certainty evidence). Although, there was uncertainty regarding adverse events from this study due to very few events. AUTHORS' CONCLUSIONS: Available RCTs focused on a diverse range of interventions. They were few, small, and of insufficient duration to determine potential long-term benefits on important kidney and cardiovascular outcomes and harms of treatment. Antihypertensive agents appear to be the most beneficial non-immunosuppressive intervention for IgAN. The antihypertensives examined were predominantly angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The benefits of RAS inhibition appear to outweigh the harms in patients with IgAN. The certainty of the evidence of RCTs demonstrating a benefit of tonsillectomy to patients with Japanese patients with IgAN was low. In addition, these findings are inconsistent across observational studies in people with IgAN of other ethnicities; hence, tonsillectomy is not widely recommended, given the potential harm of therapy. The RCT evidence is insufficiently robust to demonstrate efficacy for the other non-immunosuppressive treatments evaluated here.

LPS/TLR4 Pathway Regulates IgA1 Secretion to Induce IgA Nephropathy.

Context: Studies have reported that the incidence and severity of IgA nephropathy (IgAN) are closely related to the imbalance of the intestinal flora. Imbalance of the intestinal flora may cause abnormalities, such as intestinal mucosal immunity or mesenteric B1 lymphocyte subsets. These can lead to an increase in immunoglobulin A (IgA) production and IgA structural changing, which can eventually cause IgA1 deposition in the glomerular mesangial area and nephritis. Objective: The study intended to explore whether the LPS/TLR4 pathway regulates mesenteric B cells, secreting Gd-IgA1 to induce IgA nephropathy. Design: The research team designed an animal study. Setting: The study took place at Department of Nephrology, Minhang Hospital, Fudan University. Animals: The animals were 60 specific pathogen free (SPF) C57BL/6 (B6, H-2b) male mice from that were 6-8 weeks old and weighed 20-25 grams. Intervention: The research team established a mouse model of IgA nephropathy. The team created five groups of mice: (1) the NC group, a normal negative control group without induced nephropathy and with no treatments; (2) the IgA nephropathy (IgAN) group, a positive control group with induced nephropathy and with no treatments; (3) the IgAN+anti-TLR4 group, an intervention group, with induced nephropathy and with a TLR4-antibody (anti-TLR4) treatment; (4) the IgAN+GEC group, an intervention group, with induced nephropathy and with treatment with glutamine enteric-coated capsules (GEC); and (5) the IgAN+anti-TLR4+GEC group, an intervention group, with induced nephropathy and with treatment with anti-TLR4 and GEC. Outcome Measures: The research team collected the blood and urine of all the mice and used an enzyme-linked immunoassay (ELISA) to analyze the levels of blood creatinine, urine protein, and urea nitrogen (BUN). The team also used the ELISA to analyze signal molecules for serum inflammation: interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP-1), cyclooxygenase-2 (COX2), and galactose-deficient IgA1(Gd-IgA1). The team analyzed the distribution and content of IgA+B220+B lymphocytes in the intestinal tissues of all the mice, using tissue immunofluorescence tracking technology, and used hematoxylin-eosin (HE) staining to analyze the pathological damage in the kidney tissue. For analysis of glomerular IgA deposition, the team used a tissue immunofluorescence technique, and for detection of protein expression-toll-like receptor 4 (TLR4), B-cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL)-in mesenteric lymphoid tissues, the team used western blot analysis. Results: For the five groups of mice, the amount or degree of the physiological indicators and inflammatory factors that ELISA detected, the B lymphocytes and IgA sedimentation that immunofluorescence tracing measured, the kidney pathological that HE staining detected, and the expression of immune-related proteins that western blotting measured, all showed a common trend: IgAN group> IgAN+ glomerular endothelial cells (GEC) group> IgAN+anti-TLR4 group> IgAN+anti-TLR4+GEC group> NC group. Conclusions: The TLR4 antibody and GEC for the treatment of the intestinal tract can regulate and repair intestinal function, so that IgAN can also be relieved at the same time. The results supported the hypothesis that a relationship exists between IgAN and the LPS/TLR4 pathway that regulates mesenteric B cells to secrete low-glycosylated poly-IgA1, which provides a new potential therapeutic plan for IgA nephritis.

The association of normal-range serum phosphorus with immunoglobulin A nephropathy progression: a retrospective cohort study.

PURPOSE: The relationship between serum phosphorus and immunoglobulin A (IgA) nephropathy progression remains uncertain, especially normal-range serum phosphorus. Therefore, we herein examined the relationship between the normal-range serum phosphorus and the progression of IgA nephropathy. METHODS: One hundred sixty-two patients with primary IgA nephropathy were divided into three groups according to tertiles of baseline serum phosphorus (first tertile: 0.73-1.04 mmol/L; second tertile: 1.04-1.21 mmol/L; third tertile: 1.21-1.60 mmol/L). Estimated glomerular filtration rate (eGFR) was calculated using the chronic kidney disease epidemiology collaboration. The composite outcome was defined as a decrease of at least 50% in eGFR from baseline or end-stage kidney disease (ESKD). The association of serum phosphorus with IgA nephropathy progression was estimated using Cox proportional hazards models, adjusting for potential confounders. RESULTS: During a median 16 month follow-up period, 15 patients reached a composite outcome. In the crude Cox proportional hazard model, baseline serum phosphorus as a continuous variable was associated with increased risk for adverse renal outcomes [hazard ratio (HR) = 63.510, 95% confidence interval (CI) = 3.953-1020.284, P = 0.003], and the high tertile of serum phosphorus group had an increased risk of the composite outcome by using the low tertile group as the reference (HR = 11.895, 95% CI = 1.522-92.993, P = 0.018). After adjustment for traditional risk factors, the high tertile of serum phosphorus group was significantly related to IgA nephropathy progression compared with the low tertile group (HR = 9.424, 95% CI = 1.019-87.165, P = 0.048). CONCLUSIONS: Relatively higher serum phosphorus levels within the normal range were significantly associated with the progression of IgA nephropathy.

[State-of-the-art paradigm of corticosteroid therapy for immune-mediated inflammatory kidney diseases].

Since 1950's corticosteroids (CS) have remained the cornerstone of immunosuppressive therapy for immune-mediated kidney diseases. However multiple adverse events, associated with the prolonged CS therapy, became the basis for the development of novel treatment approaches. Current evidence supports the implementation of the steroid-sparing regimens for the treatment of different types of glomerulonephritis. Randomised controlled trial PEXIVAS demonstrated the efficacy and safety of early steroid tapering, starting from the second week of therapy, in patients with ANCA-associated vasculitis with kidney involvement. Several trials showed the efficacy of oral prednisolone 0.3-0.5 mg/kg/daily as a part of multitarget therapy for severe proliferative lupus nephritis. A combination of calcineurin inhibitors and low-dose CS are effective for remission induction in membranous nephropathy, as well as the steroid-free rituximab regimen for the patients with moderate risk of disease progression. Medium dose CS showed promising effect in patients with IgA-nephropathy. Long-term high dose CS remain the standard-of-care for the treatment of minimal change disease and focal segmental glomerulosclerosis, however patients with steroid-dependent and relapsing disease tacrolimus and rituximab can help to achieve steroid-sparing effect. The role of CS pulse-therapy is currently debated, nevertheless it remains a compulsory treatment in several conditions. Thus, overall trend is directed towards the minimization of the maximal doses of CS and/or treatment duration. However, to implement this approach morphological verification of the diagnosis and personalized assessment of the potential risk and benefit are required.

Dioscin Mediated IgA Nephropathy Alleviation by Inhibiting B Cell Activation In Vivo and Decreasing Galactose-Deficient IgA1 Production In Vitro.

The increase of circulating galactose-deficient IgA1 (Gd-IgA1) is caused by excessive activation of IgA-positive secretory cells in the process of mucosal immune responses, which is a critical link in the pathogenesis of IgA nephropathy (IgAN). Peyer's patch, the prominent place where B lymphocytes are transformed into IgA-secreting plasma cells, is the primary source of IgA. In addition, the lower expression of core 1ß-1,3-galactosyltransferase (C1GalT1) and its molecular chaperone, C1GalT1-specific molecular chaperone (Cosmc), is related to abnormal glycosylation of IgA1 in IgAN patients. Our clinical experience shows that Dioscoreae Nipponicae Rhizoma's (DNR) herbal medicine can relieve proteinuria and hematuria and improve renal function in IgAN patients. Dioscin (DIO) is one of the main active ingredients of DNR, which has various pharmacological activities. This study explores DIO's possible mechanism in treating IgAN.The IgAN model mouse was established by mucosal immune induction. The mice were divided into the control, model, and DIO gavage groups. The glomerular IgA deposition in mice, renal pathological changes, and B cell markers CD20 and CXCR5 expression in Peyer's patch were detected by immunofluorescence and immunohistochemistry. After lipopolysaccharide (LPS) stimulation, DIO's effects on DAKIKI cells proliferation, IgA and Gd-IgA1 secretion, C1GalT1, and Cosmc expression were studied by cell counting kit-8 (CCK-8) assay, enzyme-linked immunosorbent assay (ELISA) test, quantitative real-time polymerase chain reaction (QRT-PCR), and western blotting (WB). In in vivo studies, IgA deposition accompanied by glomerular mesangial hyperplasia and increased expression of CD20 and CXCR5 in Peyer's patch in the IgAN model mouse was alleviated by DIO. In vitro studies showed 0.25 µg/mL to 1.0 µg/mL DIO inhibited LPS-induced DAKIKI cell proliferation, IgA and Gd-IgA1 secretion, and up-regulated the mRNA and protein expression of C1GalT1 and Cosmc. This study demonstrates that DIO may reduce Gd-IgA1 production by inhibiting excessive activation of IgA-secreting cells and up-regulating C1GALT1/Cosmc expression.

[Notoginsenoside R_1 interferes with renal oxidative stress and Nrf2/HO-1 signaling pathway to alleviate kidney injury in mice with IgA nephropathy and its mechanism].

The purpose of this study was to investigate the effect of notoginsenoside R_1(NGR_1) on alleviating kidney injury by regulating renal oxidative stress and the Nrf2/HO-1 signaling pathway in mice with IgA nephropathy(IgAN) and its mechanism. The mouse model of IgAN was established using a variety of techniques, including continuous bovine serum albumin(BSA) gavage, subcutaneous injections of carbon tetrachloride(CCl_4) castor oil, and tail vein injections of lipopolysaccharide(LPS). After successful modeling, mice with IgAN were randomly separated into a model group, low, medium, and high-dose NGR_1 groups, and a losartan group, and C57BL6 mice were utilized as normal controls. The model and normal groups were given phosphate buffered saline(PBS) by gavage, the NGR_1 groups were given varying dosages of NGR_1 by gavage, and the losartan group was given losartan by gavage for 4 weeks. The 24-hour urine of mice was collected after the last administration, and serum and kidney tissues of mice were taken at the end of the animal experiment. Then urine red blood cell count(URBCC), 24-hour urine protein(24 h protein), serum creatinine(Scr), and blood urea nitrogen(BUN) levels were measured. The enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of galactose-deficient IgA1(Gd-IgA1), kidney injury molecule 1(Kim-1), and neutropil gelatinase-associated lipocalin(NGAL) in the mouse serum. The assay kits were used to detect the levels of malondialdehyde(MDA) and superoxide dismutase(SOD), and immunofluorescence(IF) was used to detect the expression level of glutathione peroxidase 4(GPX4) in the mesangial region. Western blot was used to detect the protein expression of nuclear transcription factor E2 related factor 2(Nrf2)/heme oxygenase 1(HO-1) signaling pathway in the renal tissue. Hematoxylin-eosin(HE) staining was used to observe pathological alterations in the glomerulus of mice. The results revealed that, as compared with the model group, the serum Gd-IgA1 level, URBCC, 24 h protein level, renal damage markers(Kim-1 and NGAL) in the high-dose NGR_1 group decreased obviously and renal function indicators(BUN, Scr) improved significantly. The activity of SOD activity and expression level of GPX4 increased significantly in the high-dose NGR_1 group, whereas the expression level of MDA reduced and protein expression levels of Nrf2 and HO-1 increased. Simultaneously, HE staining of the renal tissue indicated that glomerular damage was greatly decreased in the high-dose NGR_1 group. In conclusion, this study has clarified that NGR_1 may alleviate the kidney injury of mice with IgAN by activating the Nrf2/HO-1 signaling pathway, improving antioxidant capacity, and reducing the level of renal oxidative stress.

Effects and mechanisms of Chinese herbal medicine on IgA nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN), is the main cause of end-stage renal disease, that causes serious physical and psychological burden to patients worldwide. Some traditional treatment measures, such as blocking the renin-angiotensin-aldosterone system, controlling blood pressure, and following a low-protein diet, may not achieve satisfactory results. Therefore, more effective and safe therapies for IgAN are urgently needed. PURPOSE: The aim of this review is to summarize the clinical efficacy of Chinese herbal medicines (CHMs) and their active ingredients in the treatment and management of IgAN based on the results of clinical trials, systematic reviews, and meta-analyses, to fully understand the advantages and perspectives of CHMs in the treatment of IgAN. STUDY DESIGN AND METHODS: For this review, the following electronic databases were consulted: PubMed, ResearchGate, Science Direct, Web of Science, Chinese National Knowledge Infrastructure and Wanfang Data, "IgA nephropathy," "traditional Chinese medicine," "Chinese herbal medicine," "herb," "mechanism," "Meta-analysis," "systematic review," "RCT" and their combinations were the keywords to search the relevant literature. Data were collected from 1990 to 2022. RESULTS: This review found that the active ingredients of CHMs commonly act on multiple signaling pathways in the clinical treatment of IgAN, mainly with antioxidant, anti-inflammatory and anti-fibrosis effects, and regulation of autophagy. CONCLUSION: Compared with the single-target therapy of modern medicine, CHMs can regulate the corresponding pathways from the aspects of anti-inflammation, anti-oxidation, anti-fibrosis and autophagy to play a multi-target treatment of IgAN through syndrome differentiation and treatment, which has good clinical efficacy and can be used as the first choice or alternative therapy for IgAN treatment. This review provides evidence and research direction for a comprehensive clinical understanding of the protective effect of Chinese herbal medicine on IgAN.

Clinicopathological Characteristics and Outcomes of Immunoglobulin A Nephropathy with Different Types of Dyslipidemia: A Retrospective Single-Center Study.

INTRODUCTION: Immunoglobulin A nephropathy (IgAN) is one of the most common glomerulonephritic diseases in the world. Several lines of evidence have suggested that dyslipidemia is related to the disease progression and prognosis of IgAN. However, the study is scarce on the clinicopathological characteristics and outcomes of IgAN with dyslipidemia. METHODS: This study retrospectively analyzed 234 patients with biopsy-proven idiopathic IgAN at the Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, between January 2015 and June 2021. The participants were divided into dyslipidemia (n = 119) and non-dyslipidemia (n = 115), and the dyslipidemia group was also divided into the following 4 groups: hypertriglyceridemia group, hypercholesterolemia group, mixed hyperlipidemia group, and low high-density lipoprotein cholesterol group. The estimated glomerular filtration rate (eGFR) was estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS: The prevalence of dyslipidemia in IgAN patients in our center was 50.9% (119/234). The patients with dyslipidemia presented with higher systolic blood pressure (BP), diastolic BP, serum creatinine, uric acid, hemoglobin, proteinuria, and eGFR (p < 0.05). Proportions of males, hypertension, and chronic kidney disease stage 2∼5 were also higher in the dyslipidemia group (p < 0.05). Similarly, the pathological characteristics performed were worse in the dyslipidemia group. Most dyslipidemia patients had a higher percentage of mesangial hypercellularity (M1) and tubular atrophy/interstitial fibrosis (T1∼2) in the Oxford Classification's scoring system (p < 0.05). Multivariate logistic regression analysis revealed that male gender (odds ratio [OR] = 2.397, 95% confidence interval [CI]: 1.051-5.469, p = 0.038) and proteinuria (OR = 1.000, 95% CI: 1.000-1.001, p = 0.035) were possible risk factors for dyslipidemia. A total of 13 patients (13.8%) in the dyslipidemia group had an endpoint event, of which 6 patients (6.4%) had a ≥50% decrease in eGFR from baseline and 7 patients (7.4%) reached the end-stage renal disease stage. Kaplan-Meier survival curve analysis showed that patients in the dyslipidemia group had a worse outcome than those in the non-dyslipidemia group (log-rank test, p = 0.048). CONCLUSIONS: IgAN patients with dyslipidemia presented more severe clinicopathological characteristics. Male gender and proteinuria are significantly associated with the occurrence of dyslipidemia in IgAN patients. Patients in the dyslipidemia group had a worse prognosis than those in the non-dyslipidemia group, which may be essential for the disease management of IgAN and help identify the high-risk patients.

Clinicopathological features and long-term prognosis of glomerular diseases associated with mercury-containing cosmetics.

OBJECTIVE: The pathological types and long-term prognosis of glomerular diseases related to mercury exposure are unclear. This study retrospectively examined 41 cases of glomerulonephropathy caused by mercury-containing cosmetics. METHODOLOGY: Forty-one subjects with glomerular diseases presumably caused by mercury-containing cosmetics were selected. Clinical features, kidney biopsy, treatment, and follow-up data were collected. RESULTS: All patients were female with an average age of 39.4 ± 6.6 years at diagnosis. Median time of exposure to mercury-containing cosmetics was six months, and average urine mercury level was 66.80 ± 38.55ug/(g·Cr). Most patients presented with nephrotic syndrome. Renal histopathology showed membranous nephropathy in 22 patients (53.65%), minimal change disease in 13 patients (31.71%), IgA nephropathy with minimal change disease in 5 patients (12.20%), and focal segmental glomerulosclerosis in 1 patient. Median time of exposure to mercury was longer and the proportion of patients with autoantibodies (mainly antinuclear antibodies) was higher in patients with membranous nephropathy. Both blood phospholipase A2 receptor -Ab and kidney tissue phospholipase A2 receptor were negative. Thirty-six patients received glucocorticosteroids and/or immunosuppressants. Five patients were treated with an angiotensin receptor blocker, and nine patients were treated with chelation therapy. The median follow-up time was 40 months (range 27-94). All patients achieved complete remission, and the median time to complete remission was one month. They all successfully discontinued the drugs without relapsing; withdrawal time was 26 months. CONCLUSION: Membranous nephropathy was the most common pathological type in mercury-induced glomerular disease. Patients were sensitive to glucocorticosteroids and immunosuppressants and achieved complete remission quickly. Contrary to primary glomerulonephritides, patients with mercury-induced glomerular diseases had no relapses after withdrawal of the mercury containing cosmetics.

Clinical efficacy of supplementing qi dispelling wind and activating blood circulation method in the treatment of IgA nephropathy: A meta-analysis.

BACKGROUND: IgA nephropathy (IgAN) is a common primary glomerular disease, and supplementing qi dispelling wind and activating blood is commonly used as a treatment method in Chinese medicine. However, the existing studies have small sample sizes. This study aimed to use a meta-analysis to explore the clinical efficacy of this method and to systematically introduce this effective treatment. METHODS: We searched for randomized controlled trial studies on supplementing qi dispelling wind and activating blood circulation methods for IgAN indexed in the China National Knowledge Infrastructure, Wanfang Data, Chongqing VIP, SinoMed, PubMed, EMBASE, and Web of Science databases, which were interrogated from database inception to January 2022. Combining the inclusion and exclusion criteria to screen the literature, we included a total of 15 eligible studies; the quality of the included studies was evaluated using the risk of bias assessment tool of the Cochrane System Revies Manual 5.4. The outcome indexes were extracted, and a meta-analysis was performed using Review Manager 5.4 software. RESULTS: Fifteen articles were included in this review. A meta-analysis of the results led to the conclusion that supplementing qi dispelling wind and activating blood circulation prescription has beneficial effects on the total effective rate [odds ratios = 3.95, 95% confidence interval (CI) 2.76-5.67], and can reduce 24-hour urinary protein quantity (mean deviation = -0.35, 95% CI -0.54 to -0.16) and serum creatinine (mean deviation = -15.41,95% CI -28.39 to -2.44) without impact normal level of alanine transaminase, hemoglobin, and serum albumin. CONCLUSIONS: Supplementing qi dispelling wind and activating blood can significantly improve renal function and reduce 24-hour urinary protein quantity levels in patients with IgAN compared to the use of non-Chinese medicine treatment. This finding provides a rationale for using this method in the clinical treatment of IgAN.

Effects of modified Huangqi Chifeng decoction on the IL-17 signaling pathway in an IgA nephropathy rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: Immunoglobulin A nephropathy (IgAN) is an immune-related primary glomerular disease prevalent worldwide, with complicated clinical manifestations and an unclear pathogenesis. IgAN is the main cause of chronic renal failure and places a significant burden on patients and society. The modified Huangqi Chifeng decoction (MHCD) is an effective prescription for the clinical treatment of IgAN while its specific mechanism remains to be further elucidated. AIM OF THE STUDY: Based on the findings of previous network pharmacology-related method-based studies, this study aimed to further explore the mechanism of action of MHCD for IgAN treatment. MATERIALS AND METHODS: IgAN rat model was established by bovine serum protein + carbon tetrachloride + lipopolysaccharide. After successful modeling, the rats in the original model group were divided into 5 group: model group, telmisartan group, and MHCD high-, medium- and low-dose groups by random number table (n = 10 respectively). The corresponding drugs were applied for 8 weeks, and the experiment lasted for 21 weeks. At the end of the experiment, 24h urine protein quantification, serum biochemistry and IL-6 and IL-17A levels were measured. The pathological changes of kidney were observed by light microscope, immunofluorescence microscope and the changes of glomerular ultrastructure were observed by transmission electron microscope. The expression levels of IL-17 signaling pathway related proteins (HSP90, MMP9, NF-κB P65 and p-NF-κB P65) were detected by Western Blot and immunohistochemistry. RESULT: Telmisartan and MHCD treatment can reduce the 24h urinary protein level and improved blood stasis states of IgAN rats, alleviate the renal pathological injury, decrease the serum levels of IL-6, IL-17A and the expression levels of HSP90, MMP9 and p-NF-κB P65 related proteins in IL-17 signaling pathway. CONCLUSION: MHCD can down-regulate the expression of IL-17 signaling pathway-related factors in IgAN model rats, improve the state of blood stasis, and alleviate the pathological damage of kidney in rats.

Mechanism of Yiqi Yangying Heluo Formula in the Treatment of IgA Nephropathy by Affecting Gd-IgA1 Based on BAFF Molecular Level and T Lymphocyte Immunity.

Background: Galactose-deficient IgA1 (Gd-IgA1) is a critical initiating factor in the pathogenesis of IgA nephropathy (IgAN), which plays an important role in the diagnosis and evaluation of this disease. Moreover, the whole pathogenesis process has an intimate association with the immune response of T and B lymphocytes and their inflammatory factors. There is no specific therapy for IgAN at present. Yiqi Yangyin Formula can significantly reduce urinary protein and hematuria in patients with IgAN. Yiqi Yangying Heluo Formula (YYHF) is optimized on the basis of the above prescription, but its specific mechanism remains to be further studied. Methods: The effect of YYHF on urinary protein and urinary red blood cell count in patients with IgAN was observed by a self-controlled clinical study before and after treatment. On this basis, flow cytometry was used to detect the proportion of T lymphocyte subsets in peripheral blood of patients with IgAN before and after treatment and healthy controls. Meanwhile, the levels of Gd-IgA1, B cell activation factor (BAFF), and their cytokines (IL-4, IL-6, and IL-17) in peripheral blood were detected by enzyme-linked immunosorbent assay. The changes in mechanism-related indicators of the two groups were observed and subject to correlation analysis. Results: (1) Compared with the levels before treatment, 24-hour urinary protein content decreased by 47.7% and urinary red blood cell number decreased by 67% in patients with IgAN intervened by YYHF after 48 weeks of follow-up. (2) Compared with the healthy control group, patients with IgAN showed a significantly increased proportion of Th1 cells, Th17 cells, Th1/Th2, Th1/Treg, Th2/Treg, and Th17/Treg, obviously reduced proportion of Th2 cells and Treg cells, and evidently elevated levels of Gd-IgA1, BAFF, and their cytokines (IL-4, IL-6, and IL-17) in the peripheral blood. (3) Following 48 weeks of follow-up after intervention treatment with YYHF, the levels of Gd-IgA1, BAFF, IL-6, and IL-17 were significantly lower, but the level of IL-4 was higher in peripheral blood of patients with IgAN than those before treatment and after 24 weeks of treatment; simultaneously, the proportion of Th1 cells, Th17 cells, Th1/Th2, Th1/Treg, Th2/Treg, and Th17/Treg decreased while that of Th2 cells and Treg cells increased after 48 weeks of follow-up compared with that before treatment in peripheral blood of patients with IgAN. (4) The results of correlation analysis revealed that the level of Gd-IgA1 in peripheral blood of patients with IgAN was positively correlated with the level of BAFF, as well as the proportion of Th1 cells, Th17 cells, Th1/Th2, IL-6, and IL-17 levels, and negatively correlated with the proportion of Treg cells. In addition, the level of Gd-IgA1 in peripheral blood was positively correlated with proteinuria, yet without correlation with hematuria. Conclusion: YYHF can reduce the quantitative level of 24 h urinary protein and urinary red blood cell count in patients with IgAN. Patients with IgAN have obvious T cell immune imbalance. YYHF can significantly reduce the level of Gd-IgA1 in patients with IgAN, and its mechanism may be explained by the reduced level of BAFF in peripheral blood and improved immune balance of T cells.

A Low-Protein, Plant-Dominant Gluten-Free Diet for Immunoglobulin A Nephropathy and Focal Segmental Glomerulosclerosis.

Immunoglobulin A nephropathy is the most common glomerulonephritis syndrome in the world, yet there is currently no cure. While blood pressure control, renin-angiotensin-aldosterone system inhibition, and immunosuppression may slow disease progression, low-protein diets, defined as a daily dietary protein intake of 0.6 to 0.8 g/kg body weight, may also decrease immune complex deposition and disease severity, as evidenced in animal models. The link between secondary immunoglobulin A nephropathy and celiac disease has also led to the rise of gluten-free diets and zinc supplementation as potential lifestyle modifications to help manage common immunoglobulin A nephropathy symptoms such as proteinuria and hematuria. In addition, case reports and prospective studies suggest that patients with focal segmental glomerulosclerosis, which manifests as steroid-resistant nephrotic syndrome may also benefit from a gluten-free diet. We highlight the example of a gluten-free, plant-dominant low-protein diet (a different type of low-protein diet that addresses both protein quantity and quality) for patients with immunoglobulin A nephropathy or focal segmental glomerulosclerosis.

Unraveling the Mechanism of Zhibaidihuang Decoction against IgA Nephropathy Using Network Pharmacology and Molecular Docking Analyses.

Zhibaidihuang Decoction (ZBDHD) is a traditional Chinese medicine with immense potential to treat IgA nephropathy. However, its core ingredients and representative mechanism remain unclear. In this study, we uncovered the key component and underlying mechanisms of ZBDHD for IgA nephropathy by applying network pharmacology and molecular docking approaches. This was done by first identifying the active ingredients and, subsequently, their corresponding gene targets in ZBDHD with the help of the Traditional Chinese Medicine Systems Pharmacology and analysis platform (TCMSP) database, thereby constructing the drug-compound-target network. The IgA nephropathy-associated genes were then identified using GeneCards, Drugbank, and OMIM databases. The overlapped targets were later obtained to establish Protein-Protein Interaction (PPI) networks, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, we performed molecular docking among active compounds and hub genes, and thereby verified the key compound of ZBDHD. The drug-compound-gene network consisted of 289 nodes and 1,113 edges. The top four active ingredients were beta-sitosterol, kaempferol, quercetin and stigmasterol. The top five hub genes in the PPI network were AKT1, ILB1, IL-6, TNF, and TP53. Molecular docking results could demonstrate that there was high affinity among active compounds and the core targets, while quercetin may possibly be the key compound of ZBDHD. We first identified the positive compound and the candidate molecular mechanisms of ZBDHD in an IgA nephropathy treatment and discovered that quercetin might be the core compound of ZBDHD in the treatment of IgA nephropathy.

Guben Tongluo Formula Protects LPS-induced Damage in Lamina Propria B Lymphocytes Through TLR4/MyD88/NF-κB Pathway.

OBJECTIVE: The main pathological feature of immunoglobulin A nephropathy (IgAN), an autoimmune kidney disease, is the deposition of IgA immune complexes, accompanied by mesangial cell proliferation and elevated urine protein. The Guben Tongluo formula (GTF) is a traditional Chinese medicine prescription, which has predominant protective effects on IgAN. However, the therapeutic mechanism of the GTF in IgAN remains elusive. The present study aimed to determine the effects of GTF in treating IgAN via regulating the TLR4/MyD88/NF-κB pathway. METHODS: In the present study, lamina propria B lymphocytes were treated with different concentrations of lipopolysaccharide (LPS) (0, 1, 5, 10 and 20 ng/mL). Flow cytometry was used to define positive CD86+CD19+ cells. CCK-8 assay was used to examine cell proliferation. RNAi was used to induce TLR4 silencing. qRT-PCR and Western blotting were used to determine gene expression. RESULTS: It was found that the LPS dose-dependently increased the content of IgA and galactose-deficient IgA1 (Gd-IgA), the levels of TLR4, Cosmc, MyD88 and phosphorylated (p)-NF-κB, and the ratio of CD86+CD19+ and IgA-producing B cells. However, the TLR4 knockdown reversed the role of LPS. This suggests that TLR4 mediates the effects of LPS on lamina propria B lymphocytes. Furthermore, the GTF could dose-dependently counteract the effects of LPS and TLR4 overexpression on lamina propria B lymphocytes through the TLR4/MyD88/NF-κB pathway. CONCLUSION: Collectively, these results demonstrate that the GTF can regulate the TLR4/MyD88/NF-κB pathway to treat IgAN model lamina propria B lymphocytes stimulated by LPS.

Mechanism for the therapeutic effect of Tripterygium wilfordii Hook. f. preparations on IgA nephropathy. / é›·å ¬è—¤åˆ¶å‰‚æ²»ç–—IgAè‚¾ç— çš„ä½œç”¨æœºåˆ¶.

Tripterygium wilfordii Hook. f. is a traditional Chinese herbal medicine. The bioactive compounds from Tripterygium wilfordii Hook. f. have unique immunosuppressive and anti-inflammatory effects, and can exert their pharmacological effects through multi-target and multi-channel. Tripterygium wilfordii Hook. f. preparations have been used in IgA nephropathy (IgAN) for many years and are well accepted for good curative effects. However, the underlying mechanisms are still unclear. It is valuable to summarize the current progress in clinical application of Tripterygium wilfordii Hook. f. preparations in IgAN and other kidney diseases. We discussed the component characteristics, efficacies in reducing urinary protein levels and protecting renal function, as well as the side effects. As for the mechanisms, we should focus on all links of IgAN pathogenesis, including reducing the production of pathogenic IgA, decreasing renal inflammation and fibrosis, and protecting podocytes. As a representative drugs with clear efficacy and potential toxicity, Tripterygium wilfordii Hook. f. preparations need more in-depth basic and clinical research to improve their efficacy and safety.

Effectiveness and safety of KunXian capsule for the treatment of IgA nephropathy.

BACKGROUND: Tripterygium Wilfordii Hook F (TwHF) preparation has been widely used in the treatments of IgA nephropathy (IgAN) in China. However, the effectiveness and safety of the new generation of TwHF preparation, KuxXian capsule, on the treatment of IgAN remains unknown. METHODS: Here, we retrospectively describe our experience treating 55 consecutive IgAN patients with KunXian. We defined complete remission as proteinuria < 0.5 g/24 h and partial remission as proteinuria < 1 g/24 h, each also having > 50% reduction in proteinuria from baseline. RESULTS: At first follow-up after KunXian treatment (5.7 weeks, IQR 4.7-7.9), all but two patients (96%) showed a reduction in proteinuria. The overall median proteinuria decreased from 2.23 g/day at baseline to 0.94 g/day (P < 0.001) at the first follow-up. During a median follow-up of 28 weeks after KunXian administration, 25(45.5%) patients achieved complete remission, 34 (61.8%) patients achieved complete/partial remission. Of the 12 patients discontinued KunXian treatment during the follow-up, the median proteinuria was increased from 0.97 g/24 h to 2.74 g/24 h after a median of 10.9 weeks (P = 0.004). Multivariable Cox models showed that female, treatment switching from previous generation of TwHF preparation, lower initial KunXian dosage, and higher proteinuria at baseline were independently associated proteinuria remission. Of the 20 pre-menopausal females, 12 of them developed oligomenorrhea or menstrual irregularity and ten of them developed amenorrhea. CONCLUSION: KunXian is effectiveness and safety for the treatment of IgA nephropathy. Woman of childbearing age to be informed of the risk of ovarian failure after being treated with TwHF preparations.

Dyslipidemia may be a risk factor for progression in children with IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is often chronically progressive and commonly accompanied by dyslipidemia. However, the intrinsic relationship between dyslipidemia and IgAN remains to be elucidated. This study aimed to investigate the impact of different types of dyslipidemia on clinical and pathological characteristics in children with IgAN. METHODS: In our retrospective cohort study from January 2006 to January 2021, 276 children with IgAN were ultimately included in the baseline analysis, and 169 were included in the follow-up analysis. The clinical and pathological features of different types of dyslipidemia and their effect on kidney prognosis were analyzed. RESULTS: Children in the dyslipidemia group had more severe clinical characteristics (higher blood urea nitrogen, serum uric acid, and 24-h proteinuria; higher proportion of hypertension; and lower serum albumin and estimated glomerular filtration rate) and pathological changes (higher proportion of Lee grades IV-V and E1, S1, and C2 in MEST-C). Furthermore, the clinical and pathological characteristics were worse in the mixed hyperlipidemia group. Multivariate logistic analysis showed that hypertension, steroid treatment, lower serum albumin, severe proteinuria, and segmental glomerulosclerosis were independent risk factors for dyslipidemia in children with IgAN. The Kaplan-Meier analysis revealed that the probability of kidney survival in children with dyslipidemia was lower than that in those without dyslipidemia, with a median follow-up of 5.9 years. CONCLUSIONS: Children with IgAN and dyslipidemia, especially mixed hyperlipidemia, are prone to more severe clinical and pathological changes. Our study provides further insight into dyslipidemia as a potential risk factor in children with IgAN. A higher resolution version of the Graphical abstract is available as Supplementary information.