High Renal Mast Cell Density Is Associated with Poor Prognosis in Patients with Immunoglobulin A Nephropathy.

INTRODUCTION: This observational cohort study evaluated the prognostic value of mast cells in the pathogenesis and progression of IgA nephropathy. METHODS: A total of 76 adult IgAN patients were enrolled into this study from Jan 2007 and June 2010. Immunohistochemistry and immunofluorescence were used to identify tryptase-positive mast cells in renal biopsy samples. Patients were classified into Tryptasehigh and Tryptaselow groups. Depending on an average of 96-month follow-up, the predictive value of tryptase-positive mast cells in IgAN progression was analyzed. RESULTS: Tryptase-positive mast cells were found frequently in IgAN kidneys while rarely observed in normal kidneys. We also found IgAN patients in Tryptasehigh group presented both severe clinical and pathological renal manifestations. Furthermore, Tryptasehigh group contained more interstitial macrophages and lymphocytes infiltration than Tryptaselow group. Higher tryptase-positive cells density is associated with poor prognosis in patients with IgAN. CONCLUSIONS: High renal mast cells density is associated with severe renal lesions and poor prognosis in patients with Immunoglobulin A nephropathy. High renal mast cells density might be used as a predictor of poor prognosis in patients with IgAN.

Hypercholesterolemia Correlates With Glomerular Phospholipase A2 Receptor Deposit and Serum Anti-Phospholipase A2 Receptor Antibody and Predicts Proteinuria Outcome in Idiopathic Membranous Nephropathy.

Background: The anti-phospholipase A2 receptor (PLA2R) antibody is a non-invasive diagnostic tool and prognosis predictor of idiopathic membranous nephropathy (IMN). Baseline hypercholesterolemia independently predicts proteinuria outcomes in IMN patients. Thus, we investigated whether hyperlipidemia is correlated with anti-PLA2R and pathological indicators. Methods: A total of 495 IMN patients identified by kidney biopsy in Wuhan Tongji Hospital, China, from January 2016 through December 2020 were enrolled in this study. Data on clinical features, pathology findings, and outcomes were collected. Results: Total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were positively related to proteinuria, indicating damage to the renal glomerulus [Spearman's rank correlation coefficient = 0.432, 0.462, 0.315, and 0.289, respectively, P < 0.001 for all]. In univariate logistic regression, low HDL-C [odds ratio (OR): 0.856; 95% CI: 0.778-0.939; P = 0.001] and high TG [OR: 1.025; 95% CI: 1.006-1.044; P = 0.011] were correlated with tubular atrophy, suggesting lesions on tubules. Increased TC [adjusted OR: 1.285; 95% CI: 1.119-1.475; P < 0.001], non-HDL-C [adjusted OR: 1.284; 95% CI: 1.113-1.482; P = 0.001], and LDL-C [adjusted OR: 1.178; 95% CI: 1.009-1.376; P = 0.039] independently predicted glomerular PLA2R deposit; similar results were observed for lipids in predicting the seropositivity of anti-PLA2R antibodies. After treatment, increased HDL-C [adjusted hazard ratio (HR): 1.764; 95% CI: 1.241-2.507; P = 0.002] and decreased non-HDL-C [adjusted HR: 0.884; 95% CI: 0.795-0.983; P = 0.022] independently predicted proteinuria remission. Conclusion: Hypercholesterolemia is a potentially useful biomarker for disease severity, serum anti-PLA2R antibody, glomerular PLA2R deposit, and proteinuria outcome of IMN.

LRG1 Mitigates Renal Interstitial Fibrosis through Alleviating Capillary Rarefaction and Inhibiting Inflammatory and Pro-Fibrotic Cytokines.

INTRODUCTION: Increasing evidence has demonstrated that loss of peritubular capillaries plays a critical role in renal interstitial fibrosis. Leucine-rich α2-glycoprotein-1 (LRG1) has been observed promoting angiogenesis in the ocular disease mouse model and myocardial infarction model. We aimed to explore the role of LRG1 in renal interstitial fibrosis. METHODS: We analyzed the expression of LRG1 in the plasma and kidney of CKD patients by ELISA and immunohistochemistry. Relationships between the expression of LRG1 in plasma and kidney and renal fibrosis and inflammation were analyzed. Tube formation assay was used to detect the angiogenesis in the human umbilical vein endothelial cell lines (HUVECs). And real-time PCR was used to detect the mRNA expression of LRG1, inflammatory factors, renal tubular injury indicators, pro-fibrotic cytokines, and CD31. We examined the effects of genetic ablation of LRG1 on renal fibrosis induced by unilateral ureteral obstruction (UUO) mice model at day 7. RESULTS: We demonstrated that the expression of LRG1 in renal tissues and plasma samples was upregulated in CKD patients. And the expression of LRG1 was elevated in human renal tubular epithelial cell line (HK-2) cells in response to the stimulation of TNF-α in vitro, and in kidney after UUO in vivo. The deficiency of the LRG1 gene aggravated renal fibrosis, inflammatory cells infiltration, and capillary rarefaction after UUO. In vitro, LRG1 promoted the tube formation of HUVEC cells. LRG1 inhibits fibronectin secretion induced by TGF-ß1 in HK-2 and overexpression of LRG1 in HK-2 cells decreased fibronectin secretion. CONCLUSION: LRG1 may prevent renal fibrosis by inhibiting the secretion of inflammatory and pro-fibrotic cytokines and promoting angiogenesis.

Characteristics and Prognostic Value of Tertiary Lymphoid Organs in Membranous Nephropathy: A Retrospective Study.

BACKGROUND: Tertiary lymphoid organs play an essential role in the inflammation of the kidney. The clinical association between TLOs and membranous nephropathy (MN) is not clear yet. METHODS: Consecutive patients with the histologically confirmed membranous nephropathy in Tongji Hospital from July 19, 2012, to September 26, 2019, were included in this study. TLOs in renal biopsy tissues were detected by periodic acid-Schiff-stained and immunohistochemistry. Logistic regression was performed to evaluate the correlations of TLOs and clinical features of patients with MN. Kaplan-Meier analysis was utilized to examine the relationship between TLOs and remission of proteinuria. RESULTS: A total of 442 patients with MN were included in this study, of which the average age was 46.4 years old, and 58.8% were male. Moreover, 33% of patients with MN had TLOs in this study. The median value of proteinuria among patients with MN with TLOs was 4.9 g/24 h, which was much greater than no-TLOs ones (3.2 g/24 h, p < 0.001). Moreover, the patients with TLOs had higher serum creatinine and lower serum albumin. The severity of clinical features among the patients with MN aggravated with the increase in the grade of TLOs. In addition, the patients who had TLOs were more likely to be positive of anti-phospholipase A2 receptor autoantibodies. Meanwhile, the patients without TLOs showed significantly higher complete remission and total remission of proteinuria. CONCLUSION: In this study, we demonstrated that TLOs were common among patients with MN. Moreover, the patients with MN with TLOs showed a worse clinical manifestation and an outcome compared with the patients without TLOs.

Clinical and pathological findings of SARS-CoV-2 infection and concurrent IgA nephropathy: a case report.

BACKGROUND: Since the Coronavirus Disease 2019 (COVID-19) outbreak, there is accumulating data on the clinical characteristics, treatment strategies and prognosis of COVID-19 in patients with concurrent renal disease. Postmortem investigations reveal renal involvement in COVID-19, and most recently, several biopsy researches reveal that acute tubular injury, as well as glomerular nephropathy such as collapsing glomerulopathy were common histological findings. However, to our best knowledge, there is limited data regarding IgA nephropathy in the setting of COVID-19. CASE PRESENTATION: In the present case, we report a 65-year old Chinese woman who presented with dark-colored urine, worsening proteinuria and decreased renal function after COVID-19 infection. She received a renal biopsy during COVID-19 infection. The renal biopsy revealed IgA nephropathy without any evidence for SARS-Cov-2. The findings suggest that the renal abnormalities were a consequence of exacerbation of this patient's underlying glomerular disease after COVID-19 infection. After a regimen of 3-day course of glucocorticoid and angiotensin II receptor blocker therapy, the patient recovered and remained stable upon follow-up. CONCLUSIONS: It is important to consider the underlying glomerular disease exacerbation as well as virus induced injury when dealing with renal abnormalities in patients with COVID-19. A kidney biopsy may be indicated to exclude a rapidly progressive glomerular disease.

Plasma chemokine CXC motif-ligand 16 as a predictor of renal prognosis in immunoglobulin A nephropathy.

BACKGROUND: There are few non-invasive biomarkers that have been identified to improve the risk stratification of patients with IgA nephropathy (IgAN). CXCL16 has been shown to play a key role as a chemoattractant, adhesion, and fibrosis factor in inflammatory disease. This study evaluated the potential for CXCL16 plasma as a potential biomarker in patients with IgAN. METHODS: Plasma CXCL16 was measured in 230 patients with renal biopsied IgAN enrolled from 2012 to 2014. The patients were followed for 41.3 months, with a 50% reduction in estimated glomerular filtration rate or end-stage renal disease as endpoints. RESULTS: The plasma CXCL16 levels in IgAN patients were strongly correlated with the uric acid, estimated glomerular filtration rate and tubular atrophy/interstitial fibrosis score in multivariate analysis. Furthermore, counts of CD4+ T cells, CD8+ T cells, and CD20+ B cells in renal biopsies of IgAN patients were significantly correlated with the plasma CXCL16 levels, but not CD68+ macrophage. Lastly, we concluded that patients with higher levels of plasma CXCL16 had an increased risk of poor renal outcome compared to those with lower levels. There was no association between the polymorphisms and clinical parameters of CXCL16, including the levels and prognosis of plasma CXCL16. CONCLUSIONS: Plasma CXCL16 levels were associated with clinical parameters; pathological damage; CD4+ T cell, CD8+ T cell, and CD20+ B cell infiltration in renal tissue; and renal outcome in IgAN patients. Plasma CXCL16 might be a potential prognosis predictor in Chinese IgAN patients.

Plasma fractalkine levels are associated with renal inflammation and outcomes in immunoglobulin A nephropathy.

BACKGROUND: A recognized noninvasive biomarker to improve risk stratification of immunoglobulin A nephropathy (IgAN) patients is scarce. Fractalkine has been shown to play a key role in glomerular disease as chemoattractant, adhesion and even fibrosis factor. The current study assessed the possibility of plasma fractalkine as a novel biomarker in IgAN patients. METHODS: Plasma fractalkine was measured in 229 patients with renal biopsy consistent IgAN from 2012 to 2014, and clinical, pathological and prognostic relationships were analyzed. RESULTS: The plasma fractalkine levels in IgAN patients were significantly correlated with the creatinine level and 24-h urine protein by both univariate and multivariate analysis. Mesangial hypercellularity was still significantly correlated with the plasma fractalkine levels even after adjustment for other potential predictor variables by multivariate analysis. In addition, the counts of CD20+ B cells or CD68+ macrophage in renal biopsies of IgAN patients were significantly correlated with the plasma fractalkine levels, but not CD4+ and CD8+ T cells. Finally, we concluded that patients with higher plasma fractalkine levels had higher risk of poor renal outcome compared with those with lower plasma fractalkine levels. No association was observed between the CX3CR1 polymorphisms and clinical parameters including plasma fractalkine levels and prognosis. Recombinant fractalkine induced mesangial cells extracellular matrix synthesis and promoted the migration of microphage cells RAW264.7. CONCLUSIONS: Plasma fractalkine levels were associated with creatinine level, 24-h urine protein, mesangial hypercellularity pathological damage, the CD68+ macrophage and CD20+ B cell infiltration in renal tissue and renal outcome in IgAN patients. Plasma fractalkine might be a potential prognosis novel predictor in Chinese patients with IgAN.

Soluble Urokinase Receptor Levels Are Correlated with Focal Segmental Glomerulosclerosis Lesions in IgA Nephropathy: A Cohort Study from China.

BACKGROUND: Soluble urokinase receptor (suPAR) may be involved in the pathological mechanisms of focal segmental glomerulosclerosis (FSGS) changes. However, it remains unclear whether suPAR is correlated with the FSGS-like lesions in IgA nephropathy (IgAN). METHODS: We measured the plasma suPAR levels in 138 patients with IgAN, and then their clinical and pathological relationships were analyzed. RESULTS: We found that the plasma suPAR levels were significantly correlated with age and renal function by both univariate and multivariate analysis in our IgAN patient cohort. Female had higher plasma suPAR levels and no significant correlation was observed between plasma suPAR levels and 24-h urine protein and highly sensitive C-reaction protein with multivariate analysis. In our cohort, sixty of these IgAN patients could be diagnosed with a type of FSGS lesions. The plasma suPAR levels were higher in the IgAN patients with FSGS lesions than in the IgAN patients without FSGS lesions by univariate (P < 0.0001) and multivariate (P < 0.001) analysis adjusting for other predictor variables, which might be helpful to differentiate the pathological changes with and without FSGS lesions. And the optimal cutoff value was 1806 pg/ml in this study. The plasma suPAR concentrations were also associated with the degree of tubular atrophy/interstitial fibrosis in both univariate and multivariate analysis. In multivariate analysis, the plasma suPAR levels were correlated with the percentage of crescents, not global sclerosis and arterial lesions. CONCLUSIONS: Our study suggested that the plasma suPAR levels were associated with age, gender, renal function, the degree of tubular atrophy/interstitial fibrosis and the percentage of crescent formation. The plasma suPAR might be a potential predictor for the presence of FSGS pathological lesions in Chinese patients with IgAN.

Telmisartan protects 5/6 Nx rats against renal injury by enhancing nNOS-derived NO generation via regulation of PPARγ signaling.

A 5/6 nephrectomized (Nx) rat model was employed to address the impact of telmisartan on CKD related renal injury and the underlying molecular mechanisms. It was noted that telmisartan provided protection for rats against 5/6 Nx induced lethality. Telmisartan treated 5/6 Nx rats manifested improved renal function as characterized by the higher GFR but lower urinary albumin, BUN and Scr as compared with that of control rats. Telmisartan treatment also significantly decreased systolic blood pressure and alleviated glomerulosclerosis and interstitial fibrosis. Mechanistic studies revealed that telmisartan possesses the capability to increase NO generation in the kidney. Further studies demonstrated that telmisartan promotes PPARγ expression, by which it specifically enhances nNOS expression in the kidneys after 5/6 Nx insult. Particularly, blockade of PPARγ signaling by GW9662 abolished the protective effect conferred by telmisartan, indicating that telmisartan induction of renal nNOS expression along with NO generation is dependent on PPARγ signaling. Together, our data support that telmisartan could be a promising drug for treatment of chronic kidney diseases in diverse clinical settings.

Glucocorticoid receptor agonist dexamethasone attenuates renal ischemia/reperfusion injury by up-regulating eNOS/iNOS.

The aim of this study was to determine the effect of dexamethasone (DEX) on renal ischemia/reperfusion injury (IRI). C57BL/6 mice were randomly divided into Sham group, IRI group and DEX group. The mice in IRI and DEX groups subjected to renal ischemia for 60 min, were treated with saline or DEX (4 mg/kg, i.p.) 60 min prior to I/R. After 24 h of reperfusion, the renal function, renal pathological changes, activation of extracellular signal-regulated kinase (ERK) and glucocorticoid receptor (GR), and the levels of iNOS and eNOS were detected. The results showed DEX significantly decreased the damage to renal function and pathological changes after renal IRI. Pre-treatment with DEX reduced ERK activation and down-regulated the level of iNOS, whereas up-regulated the level of eNOS after renal IRI. DEX could further promote the activation of GR. These findings indicated GR activation confers preconditioning-like protection against acute IRI partially by up-regulating the ratio of eNOS/iNOS.

TJ0711, a novel vasodilatory ß-blocker, protects SHR rats against hypertension induced renal injury.

Previous studies suggested that ß-blockers with adjunctive α1-blocking activities warrant renoprotective function other than the therapeutic effect on hypertension. The current report is designed to dissect the role of TJ0711, a novel ß-blocker with a 1:1 ratio for the ß1/α1 blocking activities, in renoprotection in SHR rats. It was noted that TJ0711 possesses similar potency for control of blood pressure as that of Carvedilol. However, TJ0711 is much more potent in terms of protecting SHR rats against hypertension induced renal injury. Specifically, SHR rats treated with 20mg/kg/day of TJ0711 manifested significantly lower levels for urine albumin and total protein. In line with these result, TJ0711 treated rats displayed much less severe pathological changes in the kidneys. Mechanistic studies revealed that TJ0711 improves kidney perfusion during the course of hypertensive insult by enhancing eNOS expression through suppressing inflammatory cytokine secretion. TJ0711 also attenuates Vasohibin-1 expression to prevent HIF-1α from signal-induced degradation, and by which it promotes HO-1 expression to protect SHR rats against oxidative stress induced by hypertension in the kidneys. Together, our data suggest that TJ0711 possesses higher potency for renoprotection while manifesting the similar effect on hypertension therapy as Carvedilol.