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Abstract Background Observational studies have demonstrated the alterations of gut microbiota composition in diabetic nephropathy (DN), however, the correlation between gut microbiota and DN remains unclear. Methods A two-sample Mendelian randomization (MR) analysis was designed to estimate the association between gut microbiota and DN. The summary statistics of gut microbiota from phylum level to genus level were obtained from a large-scale, genome-wide association study involving 18,340 individuals, and the data at the species level was derived from the study of TwinsUK Registry, including 1126 twin pairs. The summary statistics of DN were originated from the latest release data of FinnGen (R7, 299623 participants). The MR estimation was calculated using inverse variance weighted, weighted median, MR-Egger regression, and MR-PRESSO. Heterogeneity was assessed using Cochrane’s Q test. Results Inverse variance weighted results indicated that the order Bacteroidetes and its corresponding class and phylum [odds ratio (OR), 1.58; 95% confidence interval (CI), 1.15–2.17], the family Verrucomicrobiaceae and its corresponding class and order (OR, 1.46; 95% CI, 1.14–1.87), the genera Akkermansia (OR, 1.46; 95% CI, 1.14–1.87) and Catenibacterium (OR, 1.33; 95% CI, 1.07–1.66) might be associated with a higher risk of DN; whereas the genera Coprococcus2 (OR, 0.68; 95% CI, 0.51–0.91) and Eubacterium_coprostanoligenes_group (OR, 0.69; 95% CI, 0.52–0.92) might play protective roles in DN. Conclusions This MR study suggested that several gut bacteria were potentially associated with DN, further studies are required to validate these findings.

Abstract Background The aim of this study was to investigate the association between systemic immune‐inflammation index (SII) and all‐cause mortality in individuals with chronic kidney disease (CKD). Patients and Methods This prospective cohort study was carried out among 9303 participants with CKD from the National Health and Nutrition Examination Survey cycles spanning 1999 to 2018. The mortality data were ascertained by linking participant records to the National Death Index up to December 31, 2019. Complex sampling‐weighted multivariate Cox proportional hazards models were employed to estimate the association between SII level and all‐cause mortality, providing hazard ratios (HR) and 95% confidence intervals (CI). A restricted cubic spline analysis was conducted to explore potential nonlinear correlation. Subgroup analyses and sensitivity analyses were also conducted. Results During a median follow‐up period of 86 months, 3400 (36.54%) all‐cause deaths were documented. A distinctive “J”‐shaped relationship between SII level and all‐cause mortality was discerned among individuals with CKD, with the nadir observed at an SII level of 478.93 within the second quartile. After adjusting for potential covariates, the risk of all‐cause mortality escalated by 13% per increment of one standard deviation of SII, once SII exceeded 478.93 (HR = 1.13; 95% CI = 1.08–1.18). An elevated SII was associated with an increased risk of all‐cause mortality among patients with CKD (Q4 vs. Q2: HR = 1.23; 95% CI = 1.01–1.48). Subgroup analyses indicated that the correlation between SII and CKD mortality was particularly pronounced among participants over 60 years old and individuals with diabetes. Sensitivity analyses revealed a linear positive association between SII and all‐cause mortality after removing the extreme 5% outliers of SII. Conclusions A distinctive “J”‐shaped relationship between SII level and all‐cause mortality was identified among individuals with CKD. Further research is warranted to validate and expand upon these findings.

Objectives The small GTPase Rac1 (RAC1) has been linked to podocyte disorders and steroid-sensitive nephrotic syndrome (SSNS). The aim of this study was to explore and validate the potential causal association between circulating RAC1 and SSNS.Methods The association between circulating RAC1 and SSNS at both gene expression and proteomic levels was investigated using Mendelian randomization analysis, and further validated by single-cell RNA-sequencing, proteomic analysis, and experimental studies. The genetic instruments comprised cis-expression quantitative trait loci (cis-eQTLs) associated with RAC1 gene expression and protein QTLs correlated with plasma RAC1 protein levels. Causal associations were estimated utilizing the inverse variance weighted and MR-PRESSO methods. Validation of RAC1 expression was conducted through single-cell RNA-sequencing of peripheral blood mononuclear cells from patients with SSNS and healthy controls. Proteomic analysis was performed among patients with minimal change nephrotic syndrome. Experimental validation was conducted using a puromycin aminonucleoside (PAN)-induced nephrosis model.Results Increased expression of RAC1 was associated with a higher risk of SSNS (gene expression level: odds ratio [OR], 1.53; 95% confidence interval [CI], 1.02–2.28; protein level: OR, 1.82; 95% CI, 1.05–3.17). The results of MR-PRESSO were consistent (gene expression level: OR, 1.49; 95% CI, 1.17–1.92; protein level: OR, 1.81; 95% CI, 1.16–2.85). Single-cell RNA sequencing and proteomic analysis confirmed elevated RAC1 expression in patients with SSNS compared to healthy controls. Experimental data further supported increased RAC1 expression in PAN-induced nephropathy.Conclusions Increased expression of RAC1 might be causally associated with SSNS, suggesting that targeting RAC1 might represent a potential therapeutic strategy for SSNS.

Background Systemic Immune-Inflammation Index (SII) is a novel inflammatory biomarker closely associated with the inflammatory response and chronic kidney disease. Klotho is implicated as a pathogenic factor in the progression of kidney disease, and supplementation of Klotho may delay the progression of chronic kidney disease by inhibiting the inflammatory response. Our aim is to investigate the potential relationship between SII and Klotho in adult patients in the United States and explore the differences in the populations with and without albuminuria.Methods We conducted a cross-sectional study recruiting adult participants with complete data on SII, Klotho, and urine albumin-to-creatinine ratio (ACR) from the National Health and Nutrition Examination Survey from 2007 to 2016. SII was calculated as platelet count × neutrophil count/lymphocyte count, with abnormal elevation defined as values exceeding 330 × 10^9/L. Albuminuria was defined as ACR >30 mg/g. Weighted multivariable regression analysis and subgroup analysis were employed to explore the independent relationship between SII and Klotho.Results Our study included a total of 10,592 individuals. In all populations, non-albuminuria population, and proteinuria population with ACR ≥ 30, participants with abnormally elevated SII levels, as compared to those with SII less than 330 × 10^9/L, showed a negative correlation between elevated SII levels and increased Klotho, which persisted after adjusting for covariates.Conclusions There is a negative correlation between SII and Klotho in adult patients in the United States. This finding complements previous research but requires further analysis through large prospective studies.

Background Renal impairment has been previously linked to peripheral eosinophil count (PEC), prompting an investigation into its potential relationship with chronic kidney disease (CKD). This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES 1999–2018) to comprehensively explore the association between PEC and CKD.Methods Survey-weighted generalized multivariate linear regression was employed to evaluate the associations between PEC, urinary albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR), with meticulous adjustment for potential covariates. To assess non-linear correlations, a restricted cubic spline analysis was conducted. Sensitivity analysis was performed to test the stability of results.Results The study included a total of 9224 participants with non-dialysis CKD. In the multivariate linear regression model, after comprehensive adjustment for potential covariates, PEC showed a negative association with eGFR (β per 100 cells/uL increase in PEC, −0.71; 95% CI, −1.04, −0.37), while demonstrating a positive trend with UACR (β per 100 cells/uL increase in PEC, 10.21; 95% CI, 1.37, 19.06). The restrictive cubic spline curve analysis suggested that these associations occurred within the range of 0 to 400 cells/uL for PEC. Sensitivity analysis supported the stability of the observed results.Conclusions Circulating eosinophil levels are negatively correlated with eGFR and demonstrate a positive trend with UACR, when PEC falls within the range of less than 400 cells/uL among adults with CKD. Further research is warranted to validate these findings.

Background Pulmonary function has been reported to be associated with chronic kidney disease. However, the relationship between lung function and rapid kidney function decline remains unclear.Methods Participants aged ≥45 years with complete data from the 2011 and 2015 interviews of the China Health and Retirement Longitudinal Study (CHARLS) were included. Lung function, assessed by peak expiratory flow (PEF), and kidney function, assessed by estimated glomerular filtration rate (eGFR), were tested at the baseline and endpoint surveys. Rapid kidney function decline was defined as a decrease in eGFR ≥3 mL/min/1.73 m²/year, and ΔeGFR represented the difference between baseline and endpoint eGFR. Multivariate logistic regression models and linear regression models were employed to evaluate the association between PEF and the risk of rapid eGFR decline, as well as the correlation between PEF and ΔeGFR.Results A total of 6159 participants were included, with 1157 (18.78%) individuals experiencing a rapid decline in eGFR. After adjusting for potential covariates, higher baseline PEF (Quartile 4 vs Quartile 1, OR=0.95, 95% CI 0.92 to 0.98) and elevated PEF % predicted (OR=0.96, 95% CI 0.94 to 0.99) were found to be associated with a lower risk of rapid eGFR decline. ΔeGFR decreased by 0.217 and 0.124 mL/min/1.73 m² for every 1 L/s increase in baseline PEF (β (95% CI): −0.217 (−0.393 to –0.042)) and 10% increase in PEF % predicted (β (95% CI): −0.124 (−0.237 to –0.011)), respectively. During the follow-up period, ΔeGFR decreased as PEF increased over time among participants in Quartile 1 (β per 1 L/s increase in ΔPEF=−0.581, 95% CI −1.003 to –0.158; β per 10% increase in ΔPEF % predicted=−0.279, 95% CI −0.515 to –0.043).Conclusions Higher PEF was associated with a slower longitudinal eGFR decline in middle-aged and older adults.

BackgroundGut microbiota has been reported to play an important role in diabetic kidney disease (DKD), however, the alterations of gut bacteria have not been determined.MethodsStudies comparing the differences of gut microbiome between patients with DKD and non-DKD individuals using high-throughput sequencing technology, were systematically searched and reviewed. Outcomes were set as gut bacterial diversity, microbial composition, and correlation with clinical parameters of DKD. Qualitative data were summarized and compared through a funnel R script, and quantitative data were estimated by meta-analysis.ResultsA total of 15 studies and 1640 participants were included, the comparisons were conducted between DKD, diabetes mellitus (DM), non-diabetic kidney disease (NDKD), and healthy controls. There were no significant differences of α-diversity between DKD and DM, and between DKD and NDKD, however, significant lower microbial richness was found in DKD compared to healthy controls. Different bacterial compositions were found between DKD and non-DKD subjects. The phylum Actinobacteria were found to be enriched in DKD compared to healthy controls. At the genus level, we found the enrichment of Hungatella, Bilophila, and Escherichia in DKD compared to DM, patients with DKD showed lower abundances of Faecalibacterium compared to those with NDKD. The genera Butyricicoccus, Faecalibacterium, and Lachnospira were depleted in DKD compared to healthy controls, whereas Hungatella, Escherichia, and lactobacillus were significantly enriched. The genus Ruminococcus torques group was demonstrated to be inversely correlated with estimated glomerular filtration rate of DKD.ConclusionsGut bacterial alterations was demonstrated in DKD, characterized by the enrichment of the genera Hungatella and Escherichia, and the depletion of butyrate-producing bacteria, which might be associated with the occurrence and development of DKD. Further studies are still needed to validate these findings, due to substantial heterogeneity.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022340870.

BackgroundRecent data indicate the importance of gut-kidney axis in the pathogenesis of Immunoglobulin A nephropathy (IgAN). Growing evidence suggests the alterations of diversity and composition of gut microbiome among patients with IgAN, however, the details are not yet fully understood.MethodsEligible studies comparing the gut microbiome between patients with IgAN and non-IgAN individuals were systematically searched from PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, and ClinicalTrials.gov. The primary outcomes were alpha- and beta-diversity, and the differences in gut microbiota composition between patients with IgAN and non-IgAN persons. Qualitative analysis and meta-analysis were performed according to available data.ResultsEleven cross-sectional studies, including 409 patients with IgAN and 243 healthy controls, were enrolled. No significant differences in the diversity and enrichment of gut bacteria were found between IgAN and healthy individuals, whereas the beta-diversity consistently showed significant microbial dissimilarities among the two groups. Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia were the dominant phyla, however, no significant differences were found between IgAN patients and healthy controls at the phylum level. The genera, Streptococcus and Paraprevotella showed a higher proportion in patients with IgAN compared to healthy individuals, whereas Fusicatenibacter showed a lower abundance according to meta-analysis. Qualitative analyses suggested that Escherichia-Shigella might be increased in IgAN patients; the genera, Clostridium, Prevotella 9,and Roseburia, members of Ruminococcaceae and Lachnospiraceae families, were likely to have decreased abundances in patients with IgAN compared to healthy individuals.ConclusionGut microbiota dysbiosis was demonstrated in IgAN, which might be involved in the pathogenesis of IgAN. Further studies are needed to confirm the findings of this study, due to the substantial heterogeneity.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier PROSPERO (CRD42022304034).

Podocyte is also called glomerular epithelial cell, which has been considered as the final gatekeeper of glomerular filtration barrier (GFB). As a major contributor to proteinuria, podocyte injury underlies a variety of glomerular diseases and becomes the challenge to patients and their families in general. At present, the therapeutic methods of podocyte injury mainly include angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, steroid and immunosuppressive medications. Nevertheless, the higher cost and side effects seriously disturb patients with podocyte injury. Promisingly, traditional Chinese medicine (TCM) has received an increasing amount of attention from different countries in the treatment of podocyte injury by invigorating spleen and kidney, clearing heat and eliminating dampness, as well enriching qi and activating blood. Therefore, we searched articles published in peer-reviewed English-language journals through Google Scholar, PubMed, Web of Science, and Science Direct. The protective effects of active ingredients, herbs, compound prescriptions, acupuncture and moxibustion for treatment of podocyte injury were further summarized and analyzed. Meanwhile, we discussed feasible directions for future development, and analyzed existing deficiencies and shortcomings of TCM in the treatment of podocyte injury. In conclusion, this paper shows that TCM treatments can serve as promising auxiliary therapeutic methods for the treatment of podocyte injury.

Background: The efficacy and safety of immunosuppressive monotherapy agents were evaluated for immunoglobulin A nephropathy (IgAN) using a network meta-analysis approach.Methods: Randomized controlled trials (RCTs) published prior to October 1, 2019, using immunosuppressive agents for treating IgAN, were systematically searched in PubMed, Embase, Cochrane Library, and Web of Science databases. Relative risks (RRs) or standard mean differences with 95% confidence intervals (CIs) were estimated using the random-effects model. The primary outcomes were clinical remission, end-stage renal disease (ESRD), and serious adverse events (SAEs). The secondary outcomes were urinary protein excretion and serum creatinine.Results: Twenty-five RCTs with 2,005 participants were deemed eligible. Six medications were evaluated: corticosteroids, mycophenolate mofetil (MMF), tacrolimus (TAC), cyclosporine, leflunomide, and hydroxychloroquine (HCQ). Steroids (RR 1.50, 95% CI 1.17–1.93), MMF (RR 2.05, 95% CI 1.15–3.65), TAC (RR 3.67, 95% CI 1.06–12.63), and HCQ (RR 3.25, 95% CI 1.05–10.09) significantly improved clinical remission rates compared to supportive care alone. Only steroids reduced the risk of ESRD (RR 0.35, 95% CI 0.12–0.98); however, there were significantly more SAEs than in the control group (RR 2.90, 95% CI 1.37–6.13). No significantly different effects in serum creatinine levels were found among the therapies. MMF showed no significant improvement in remission when excluding studies with a follow-up of fewer than 2 years in the sensitivity analysis (RR 1.41, 95% CI 0.40–4.92). The effect of TAC in the decrease of proteinuria was reversed after discontinuing medication for 3 months; the long-term effects of HCQ could not be evaluated due to the short follow-up duration.Conclusion: Corticosteroids might induce remission and increase renal survival in IgAN; however, adverse reactions should be taken into consideration. MMF, TAC, and HCQ might improve the remission of proteinuria when treating IgAN, but showed no superiority compared to steroids, and the long-term effects require further study.