Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion

Complement synthesis in cells of origin is strongly linked to the pathogenesis and progression of renal disease. Multiple studies have examined local C3 synthesis in renal disease and elucidated the contribution of local cellular sources, but the contribution of infiltrating inflammatory cells remains unclear. We investigate the relationships among C3, macrophages and Th17 cells, which are involved in interstitial fibrosis. Here, we report that increased local C3 expression, mainly by monocyte/macrophages, was detected in renal biopsy specimens and was correlated with the severity of renal fibrosis (RF) and indexes of renal function. In mouse models of UUO (unilateral ureteral obstruction), we found that local C3 was constitutively expressed throughout the kidney in the interstitium, from which it was released by F4/80+macrophages. After the depletion of macrophages using clodronate, mice lacking macrophages exhibited reductions in C3 expression and renal tubulointerstitial fibrosis. Blocking C3 expression with a C3 and C3aR inhibitor provided similar protection against renal tubulointerstitial fibrosis. These protective effects were associated with reduced pro-inflammatory cytokines, renal recruitment of inflammatory cells, and the Th17 response. in vitro, recombinant C3a significantly enhanced T cell proliferation and IL-17A expression, which was mediated through phosphorylation of ERK, STAT3, and STAT5 and activation of NF-kB in T cells. More importantly, blockade of C3a by a C3aR inhibitor drastically suppressed IL-17A expression in C3a-stimulated T cells. We propose that local C3 secretion by macrophages leads to IL-17A-mediated inflammatory cell infiltration into the kidney, which further drives fibrogenic responses. Our findings suggest that inhibition of the C3a/C3aR pathway is a novel therapeutic approach for obstructive nephropathy

History of kidney stones and risk of chronic kidney disease: a meta-analysis

Background Although the relationship between a history of kidney stones and chronic kidney disease (CKD) has been explored in many studies, it is still far from being well understood. Thus, we conducted a meta-analysis of studies comparing rates of CKD in patients with a history of kidney stones. Methods PubMed, EMBASE, and the reference lists of relevant articles were searched to identify observational studies related to the topic. A random-effects model was used to combine the study-specific risk estimates. We explored the potential heterogeneity by subgroup analyses and meta-regression analyses. Results Seven studies were included in this meta-analysis. Pooled results suggested that a history of kidney stones was associated with an increased adjusted risk estimate for CKD [risk ratio (RR), 1.47 95% confidence interval (CI) [1.23–1.76])], with significant heterogeneity among these studies (I2 = 93.6%, P < 0.001). The observed positive association was observed in most of the subgroup analyses, whereas the association was not significant among studies from Asian countries, the mean age ≥50 years and male patients. Conclusion A history of kidney stones is associated with increased risk of CKD. Future investigations are encouraged to reveal the underlying mechanisms in the connection between kidney stones and CKD, which may point the way to more effective preventive and therapeutic measures

T Follicular Helper Cells in Tertiary Lymphoid Structure Contribute to Renal Fibrosis by IL-21

Tertiary lymphoid structure (TLS) represents lymphocyte clusters in non-lymphoid organs. The formation and maintenance of TLS are dependent on follicular helper T (TFH) cells. However, the role of TFH cells during renal TLS formation and the renal fibrotic process has not been comprehensively elucidated in chronic kidney disease. Here, we detected the circulating TFH cells from 57 IgAN patients and found that the frequency of TFH cells was increased in IgA nephropathy patients with renal TLS and also increased in renal tissues from the ischemic-reperfusion-injury (IRI)-induced TLS model. The inducible T-cell co-stimulator (ICOS) is one of the surface marker molecules of TFH. Remarkably, the application of an ICOS-neutralizing antibody effectively prevented the upregulation of TFH cells and expression of its canonical functional mediator IL-21, and also reduced renal TLS formation and renal fibrosis in IRI mice in vivo. In the study of this mechanism, we found that recombinant IL-21 could directly promote renal fibrosis and the expression of p65. Furthermore, BAY 11-7085, a p65 selective inhibitor, could effectively alleviate the profibrotic effect induced by IL-21 stimulation. Our results together suggested that TFH cells contribute to TLS formation and renal fibrosis by IL-21. Targeting the ICOS-signaling pathway network could reduce TFH cell infiltration and alleviate renal fibrosis

Prevalence and Risk Factors of Reduced Bone Mineral Density in Systemic Lupus Erythematosus Patients: A Meta-Analysis

Background. We aimed to conduct a meta-analysis concerning the frequency and risk factors of reduced bone mineral density (BMD) in systemic lupus erythematosus (SLE) with evidence from published studies. Methods. A comprehensive literature search was conducted based on the EMBASE, Web of Science, PubMed, and Cochrane Library databases up to March 5th, 2017. Eligible studies reported any prevalence of reduced BMD in SLE patients. All risk factors with odds ratios or risk ratios associated with reduced BMD were extracted. Results. 71 reports with 33527 SLE patients were included. Low BMD, osteopenia, and osteoporosis at any site were presented, respectively, in 45%, 38%, and 13% of the SLE patients. The prevalence of osteoporosis increased with the advancing of age, while U-shaped associations between age and the prevalence of low BMD and osteopenia were found. Lumbar spine was indicated to have higher prevalence of osteoporosis. Age, disease duration, drugs use, and many other factors were identified as predictors of reduced BMD. Conclusion. Low BMD, osteoporosis, and osteopenia appeared to be prevalent in patients with SLE. Risk factors of reduced BMD were various

Contrast-induced acute kidney injury and adverse clinical outcomes risk in acute coronary syndrome patients undergoing percutaneous coronary intervention: a meta-analysis

Abstract Background Recent studies have shown associations between contrast-induced acute kidney injury (CI-AKI) and increased risk of adverse clinical outcomes in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI); however, the estimates are inconsistent and vary widely. Therefore, this meta-analysis aimed to evaluate the precise associations between CI-AKI and adverse clinical consequences in patients undergoing PCI for ACS. Methods EMBASE, PubMed, Web of Science™ and Cochrane Library databases were systematically searched from inception to December 16, 2016 for cohort studies assessing the association between CI-AKI and any adverse clinical outcomes in ACS patients treated with PCI. The results were demonstrated as pooled risk ratios (RRs) with 95% confidence intervals (CI). Heterogeneity was explored by subgroup analyses. Results We identified 1857 articles in electronic search, of which 22 (n = 32,781) were included. Our meta-analysis revealed that in ACS patients undergoing PCI, CI-AKI significantly increased the risk of adverse clinical outcomes including all-cause mortality (18 studies; n = 28,367; RR = 3.16, 95% CI 2.52–3.97; I2 = 56.9%), short-term all-cause mortality (9 studies; n = 13,895; RR = 5.55, 95% CI 3.53–8.73; I2 = 60.1%), major adverse cardiac events (7 studies; n = 19,841; RR = 1.49, 95% CI: 1.34–1.65; I2 = 0), major adverse cardiovascular and cerebrovascular events (3 studies; n = 2768; RR = 1.86, 95% CI: 1.42–2.43; I2 = 0) and stent restenosis (3 studies; n = 130,678; RR = 1.50, 95% CI: 1.24–1.81; I2 = 0), respectively. Subgroup analyses revealed that the studies with prospective cohort design, larger sample size and lower prevalence of CI-AKI might have higher short-term all-cause mortality risk. Conclusions CI-AKI may be a prognostic marker of adverse outcomes in ACS patients undergoing PCI. More attention should be paid to the diagnosis and management of CI-AKI

Interleukin 17 receptor A modulates monocyte subsets and macrophage generation in vivo.

Interleukin (IL)-17A signaling via Interleukin 17 receptor A (Il17ra) contributes to the inflammatory host response by inducing recruitment of innate immune cells, but also plays a role in homeostatic neutrophilic granulocyte regulation. Monocytes, the other main innate immune cell, have a longer life span and can pursue multiple differentiation pathways towards tissue macrophages. Monocytes are divided into two subpopulations by expression of the Ly6C/Gr1 surface marker in mice. We here investigated the role of Il17ra in monocyte homeostasis and macrophage generation. In Il17ra(-/-) and in mixed bone marrow chimeric wt/Il17ra(-/-) mice, the concentrations of circulating Il17ra(-/-) Gr1(low) monocytes were significantly decreased compared to wt cells. Pulmonary, splenic and resident peritoneal Il17ra(-/-) macrophages were significantly fewer than of wt origin. Bone marrow progenitor and monocyte numbers were equal, but the proportion of Il17ra(-/-) Gr1(low) monocytes was already decreased at bone marrow level. After monocyte depletion, initial Gr1(high) and Gr1(low) monocyte regeneration of Il17ra(-/-) and wt cells was very similar. However, Il17ra(-/-) Gr1(low) counts were not sustained. After labeling with either fluorescent beads or BrdU, Il17ra(-/-) Gr1(high) monocyte transition to Gr1(low) cells was not detectable unlike wt cells. Monocyte recruitment in acute peritonitis, which is known to be largely due to Gr1(high) cell migration, was unaffected in an identical environment. Unilateral ureteral obstruction induces a less acute inflammatory and fibrotic kidney injury. Compared to wt cells in the same environment, Il17ra(-/-) macrophage accumulation in the kidney was decreased. In the absence of Il17ra on all myeloid cells, renal fibrosis was significantly attenuated. Our data show that Il17ra modulates Gr1(low) monocyte counts and suggest defective Gr1(high) to Gr1(low) monocyte transition as an underlying mechanism. Lack of Il17ra altered homeostatic tissue macrophage formation and diminished renal inflammation and fibrosis. Il17ra appears to be a novel modulator of monocyte phenotype and possible therapeutic target in renal fibrosis

Pregnancy Outcomes in Chinese Patients with Systemic Lupus Erythematosus (SLE): A Retrospective Study of 109 Pregnancies.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that primarily affects women during their reproductive years. The interaction between SLE and pregnancy remains debated. The objective of this study was to analyze the fetal and maternal outcomes of Chinese women with SLE. A total of 109 pregnancies in 83 SLE patients from June 2004 to June 2014 at a tertiary university hospital were reviewed retrospectively. Patients' characteristics, clinical and laboratory data during pregnancy were obtained from electronic medical records. After exclusion of elective abortions, the live birth rate was 61.5%. Significantly, APS (antiphospholipid syndrome), disease activity, hypertension, hypocomplementemia, thrombocytopenia, and anemia during pregnancy were more commonly observed in fetal loss pregnancies than in live birth pregnancies. Compared to the 64 women with a history of SLE, 19 women with new-onset lupus during pregnancy had worse pregnancy outcome. Furthermore, the 64 patients with a history of SLE were divided into lupus nephritis group and SLE group (non-renal involvement). We found that the lupus nephritis group had worse maternal outcome than the SLE group. We conclude that new-onset lupus during pregnancy predicts both adverse maternal and fetal outcomes, while a history of lupus nephritis predicts adverse maternal outcomes. It is essential to provide SLE women with progestational counseling and regular multispecialty care during pregnancy

Kidney disease is associated with in-hospital death of patients with COVID-19

In December 2019, a coronavirus 2019 (COVID-19) disease outbreak occurred in Wuhan, Hubei Province, China, and rapidly spread to other areas worldwide. Although diffuse alveolar damage and acute respiratory failure were the main features, the involvement of other organs needs to be explored. Since information on kidney disease in patients with COVID-19 is limited, we determined the prevalence of acute kidney injury (AKI) in patients with COVID-19. Further, we evaluated the association between markers of abnormal kidney function and death in patients with COVID-19. This was a prospective cohort study of 701 patients with COVID-19 admitted in a tertiary teaching hospital that also encompassed three affiliates following this major outbreak in Wuhan in 2020 of whom 113 (16.1%) died in hospital. Median age of the patients was 63 years (interquartile range, 50-71), including 367 men and 334 women. On admission, 43.9% of patients had proteinuria and 26.7% had hematuria. The prevalence of elevated serum creatinine, elevated blood urea nitrogen and estimated glomerular filtration under 60 ml/min/1.73m2 were 14.4, 13.1 and 13.1%, respectively. During the study period, AKI occurred in 5.1% patients. Kaplan-Meier analysis demonstrated that patients with kidney disease had a significantly higher risk for in-hospital death. Cox proportional hazard regression confirmed that elevated baseline serum creatinine (hazard ratio: 2.10, 95% confidence interval: 1.36-3.26), elevated baseline blood urea nitrogen (3.97, 2.57-6.14), AKI stage 1 (1.90, 0.76-4.76), stage 2 (3.51, 1.49-8.26), stage 3 (4.38, 2.31-8.31), proteinuria 1+ (1.80, 0.81-4.00), 2+∼3+ (4.84, 2.00-11.70), and hematuria 1+ (2.99, 1.39-6.42), 2+∼3+ (5.56,2.58- 12.01) were independent risk factors for in-hospital death after adjusting for age, sex, disease severity, comorbidity and leukocyte count. Thus, our findings show the prevalence of kidney disease on admission and the development of AKI during hospitalization in patients with COVID-19 is high and is associated with in-hospital mortality. Hence, clinicians should increase their awareness of kidney disease in patients with severe COVID-19

Chronic Kidney Disease and the Risk of New-Onset Atrial Fibrillation: A Meta-Analysis of Prospective Cohort Studies

<div><p>Objective</p><p>Recent epidemiological evidence indicates an association between chronic kidney disease (CKD) and the risk of new-onset atrial fibrillation (AF), but the results are inconclusive. This meta-analysis examined the association between CKD and new-onset AF.</p><p>Methods</p><p>PubMed, EMBASE, the Cochrane Collaboration and the reference lists of relevant articles were searched to identify eligible studies. The random effect model was used to calculate the overall multivariable-adjusted hazard ratio (HR) with its corresponding 95% confidence interval (CI). Associations were tested in subgroups of study characteristics and study quality criteria. We also performed sensitivity analyses and assessments of publishing bias.</p><p>Results</p><p>Seven prospective cohort studies (n = 400,189 participants) were included in this meta-analysis. Pooled results suggested that CKD was associated with an increased adjusted risk estimate for new-onset AF (HR, 1.47; 95% CI, 1.21–1.78), with significant heterogeneity between these studies (I² = 79.7%, P<0.001). Results were not different in any subgroup except sample size. Stratified analyses found that the diagnostic method of CKD and eGFR (estimated glomerular filtration rate), the number of confounders adjusted for, and study quality explained little of the variation between studies. Sensitivity analysis further demonstrated the results to be robust.</p><p>Conclusions</p><p>CKD is associated with an increased risk of incident AF. Further research is needed to investigate the biological association between CKD and AF and identify a preventive strategy to decrease the incidence of AF in CKD patients.</p></div