Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy.

SIGNIFICANCE STATEMENT: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.

Macrophage Migration Inhibitory Factor (MIF) as a Stress Molecule in Renal Inflammation.

Renal inflammation is an initial pathological process during progressive renal injury regardless of the initial cause. Macrophage migration inhibitory factor (MIF) is a truly proinflammatory stress mediator that is highly expressed in a variety of both inflammatory cells and intrinsic kidney cells. MIF is released from the diseased kidney immediately upon stimulation to trigger renal inflammation by activating macrophages and T cells, and promoting the production of proinflammatory cytokines, chemokines, and stress molecules via signaling pathways involving the CD74/CD44 and chemokine receptors CXCR2, CXCR4, and CXCR7 signaling. In addition, MIF can function as a stress molecule to counter-regulate the immunosuppressive effect of glucocorticoid in renal inflammation. Given the critical position of MIF in the upstream inflammatory cascade, this review focuses on the regulatory role and molecular mechanisms of MIF in kidney diseases. The therapeutic potential of targeting MIF signaling to treat kidney diseases is also discussed.

Effect of the Combination of Hemodialysis and Hemoperfusion on Clearing Advanced Glycation End Products: A Prospective, Randomized, Two-Stage Crossover Trial in Patients Under Maintenance Hemodialysis.

Advanced glycation end products (AGEs) are protein-bound uremic toxins and are elevated in patients with the end-stage of renal disease. The present study sought to develop an effective method to remove the circulating AGEs from patients using the combination of hemodialysis (HD) and hemoperfusion (HP). Thirty-six patients undergoing maintenance HD for 3 months were randomly divided into two groups. Patients in Group 1 received HD, followed by the combined HP + HD treatment once, whereas patients in Group 2 were first treated with HP + HD and then they received the HD treatment alone. Patients treated with HD alone did not alter higher levels of serum AGEs. In contrast, patients treated with the combined HP + HD exhibited significantly lower levels of serum AGEs and TNF-α. Results from this study demonstrate that the combination of HD + HP treatment may be an effective and better approach to remove the protein-bound uremic toxins and inflammatory cytokines.

Clinical characteristics and antibiotic treatment of peritoneal dialysis-associated peritonitis caused by Pseudomonas species: a review of 15 years' experience from southern China.

Pseudomonas can lead to peritoneal dialysis-associated peritonitis, which is characterized by a poor prognosis, such as a substantial failure rate and a high death rate. This study aimed to provide an overview of Pseudomonas peritonitis's clinical features, the regimens of antibiotic, antibiotic resistance, and outcomes in peritoneal dialysis (PD) patients. This study observed patients with Pseudomonas peritonitis in two large PD centers in South China from January 2008 to December 2022. The demographics, symptomatology, antibiotics regimens, resistance to common antibiotics, and clinical outcomes of all included patients were reviewed. A total of 3,459 PD patients were included, among them 57 cases of peritonitis caused by Pseudomonas, including 48 cases (84.2%) of Pseudomonas aeruginosa. The incidence rate of Pseudomonas peritonitis was 0.0041 episode per patient-year. Of them, 28.1% (16 cases) of the patients were accompanied by exit site infection (ESI), and all had abdominal pain and turbid ascites at the time of onset. The most commonly used antibiotic combination was ceftazidime combined with amikacin. Approximately 89% of Pseudomonas species were sensitive to ceftazidime, and 88% were sensitive to amikacin. The overall primary response rate was 28.1% (16 patients), and the complete cure rate was 40.4% (23 patients). There was no significant difference in the complete cure rate of peritonitis using three and other antibiotic treatment regimens (44.8% vs 46.4%; P = 0.9). The successful treatment group had higher baseline albumin level (35.9 ± 6.2; P = 0.008) and residual urine volume (650.7 ± 375.5; P = 0.04). Although the incidence of peritonitis caused by Pseudomonas was low, the symptoms were serious, and prognosis was very poor. Pseudomonas was still highly susceptible to first-line antibiotics currently in use against Gram-negative bacteria. Patients with successful treatment had higher albumin levels and higher urine output. IMPORTANCE: Although the incidence of peritoneal dialysis-associated peritonitis caused by Pseudomonas is very low, it seriously affects the technique survival of peritoneal dialysis patients. However, there are few studies and reports on Pseudomonas peritonitis in the Chinese mainland area. Therefore, the purpose of this study is to describe the clinical characteristics, the regimens of antibiotic, drug resistance, and outcome of peritoneal dialysis patients in southern China in the past 15 years and summarize the clinical experience in the treatment of Pseudomonas peritonitis.

Advanced glycation end-products induce tubular CTGF via TGF-beta-independent Smad3 signaling.

Advanced glycation end-products (AGEs) can induce expression of connective tissue growth factor (CTGF), which seems to promote the development of diabetic nephropathy, but the exact signaling mechanisms that mediate this induction are unknown. Here, AGEs induced CTGF expression in tubular epithelial cells (TECs) that either lacked the TGF-beta1 gene or expressed dominant TGF-beta receptor II, demonstrating independence of TGF-beta. Furthermore, conditional knockout of the gene encoding TGF-beta receptor II from the kidney did not prevent AGE-induced renal expression of CTGF and collagen I. More specific, AGEs induced CTGF expression via the receptor for AGEs-extracellular signal-regulated kinase (RAGE-ERK)/p38 mitogen-activated protein kinase-Smad cross-talk pathway because inhibition of this pathway by several methods (anti-RAGE antibody, specific inhibitors, or dominant negative adenovirus to ERK1/2 and p38) blocked this induction. Overexpressing Smad7 abolished AGE-induced Smad3 phosphorylation and CTGF expression, demonstrating the necessity for activation of Smad signaling in this process. More important, knockdown of either Smad3 or Smad2 demonstrated that Smad3 but not Smad2 is essential for CTGF induction in response to AGEs. In conclusion, AGEs induce tubular CTGF expression via the TGF-beta-independent RAGE-ERK/p38-Smad3 cross-talk pathway. These data suggest that overexpression of Smad7 or targeting Smad3 may have therapeutic potential for diabetic nephropathy.

[Association of plasma level of advanced oxidation protein products with Framingham risk score in type 2 diabetic patients without vascular diseases].

OBJECTIVE: To explore the association of plasma level of advanced oxidation protein products (AOPPs) with Framingham risk score in type 2 diabetic patients without vascular diseases. METHDOS: This cross-sectional study was conducted among type 2 diabetic patients without vascular diseases recruited from 3 affiliated hospitals of Southern Medical University between March, 2010 and May, 2011, with age- and gender-matched healthy individuals as the control group. The demographic data were collected from all the participants, and the biochemical indexes and plasma levels of AOPPs were examined. The risk of cardiovascular disease in 10 years was assessed for all the participants based on their Framingham risk scores. RESULTS: A total of 112 diabetic patients and 49 healthy subjects were enrolled in this study. The diabetic patients had significantly higher body mass index (BMI), blood glucose, triglyceride, low-density lipoprotein (LDL), plasma AOPPs and Framingham risk score but lower high-density lipoprotein level than the control subjects. Spearman correlation analysis showed that plasma level of AOPPs was positively correlated with the Framingham risk score (r=-0.44, P<0.001), and further multiple linear regression analysis suggested that plasma AOPPs level was independently correlated with the Framingham risk score (ß0.305, P<0.001). CONCLUSION: Type 2 diabetic patients without vascular diseases have significantly higher plasma levels of AOPPs and are at a greater risk of cardiovascular events in 10 years than healthy individuals. Plasma AOPPs are positively correlated with the Framingham risk score, suggesting the value of plasma AOPPs level in predicting the risk of cardiovascular events in these patients.

Evidence for vascular macrophage migration inhibitory factor in destabilization of human atherosclerotic plaques.

OBJECTIVE: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine and has been shown to play a role in pathogenesis of atherosclerosis. The aim of this study is to investigate the potential role of MIF in the destabilization of atherosclerotic plaques by stimulation of vascular MMP-1 expression. METHODS: MIF and matrix metalloproteinase protein-1 (MMP-1) expression in human atherosclerotic plaques were determined by immunohistochemistry. The functional activity of MIF was examined by its ability to induce MMP-1 expression in vascular smooth muscle cells (VSMCs) in vitro. RESULTS: Two-color immunohistochemistry demonstrated that MIF was strongly upregulated in vulnerable, but not in fibrous plaques. Upregulation of vascular MIF was associated with macrophage accumulation (p<0.01), strong expression of vascular MMP-1 (p<0.001), and collagenolysis in vulnerable atheromatous plaques, but not in the fibrous lesions. Co-expression of MIF and MMP-1 in vulnerable atheromatous plaques appeared to contribute to the weakening of fibrous caps and plaque disruption. The role of MIF in vascular MMP-1 expression was demonstrated by the ability of MIF to directly stimulate VSMCs to express MMP-1 mRNA and protein, and to increase MMP-1 activity in a dose- and time-dependent manner, which was blocked by a neutralizing MIF antibody (p<0.001). CONCLUSIONS: MIF and MMP-1 are markedly upregulated in vulnerable atheromatous plaques and are associated with the weakening of the fibrous cap. The ability of MIF to induce MMP-1 expression and collagenolytic activity in VSMCs suggests that MIF may play a role in the destabilization of human atherosclerotic plaques.

Macrophage migration inhibitory factor induces MMP-9 expression: implications for destabilization of human atherosclerotic plaques.

Macrophage migration inhibitory factor (MIF) has been shown to participate in both experimental and human atherogenesis. Expression of MMP-9 has been shown to play a role in the instability of atherosclerotic plaque. Thus, we hypothesize that MIF may participate in the destabilization of atherosclerotic plaques by stimulating MMP-9 expression. This hypothesis was investigated by examining the expression of MIF and MMP-9 in human atherosclerotic plaques using two-color immunostaining and by determining the potential role of MIF in the induction of MMP-9 expression in vascular smooth muscle cells (VSMC) and macrophages in vitro. Two-color immunohistochemistry demonstrated that MIF was strongly upregulated by macrophages and VSMCs. This was associated with marked increase in MMP-9 expression in vulnerable atheromatous plaques, but not in the fibrous lesions. Upregulation of MIF and MMP-9 in vulnerable atheromatous plaques was associated with the weakening of fibrous caps. The role of MIF in MMP-9 expression was demonstrated by the ability of MIF to directly induce MMP-9 mRNA and protein expression in macrophages and in VSMCs in a dose and time-dependent manner, which was blocked by a neutralizing MIF antibody. In conclusion, MIF and MMP-9 are markedly upregulated in vulnerable atheromatous plaques. The ability of MIF to induce MMP-9 expression in VSMCs and macrophages suggests that MIF may play a role in the destabilization of human atherosclerotic plaques.

[Value of plasma brain natriuretic peptide detection in cardiac function assessment in hemodialysis patients].

OBJECTIVE: To detect plasma brain natriuretic peptide (BNP) changes in hemodialysis patients with chronic renal failure (CRF) and assess the diagnostic value of BNP for cardiac function. METHODS: Plasma BNP concentration was measured in 93 hemodialysis patients with CRF and 52 healthy control subjects. In the 93 patients, echocardiographic examinations were performed to determine the relationship between BNP and cardiac function. RESULTS: The median plasma BNP levels in 52 normal controls were 3.35 pg/ml (1.00-9.73 pg/ml), and 146.5 pg/ml (56.2-546.9 pg/ml) and 90.0 pg/ml (18.3-310.5 pg/ml) in 93 patients before and after hemodialysis, respectively, showing significant difference among those 3 groups (P<0.001). The plasma BNP levels in patients with CRF complicated by heart failure (LVEF<50%) before and after hemodialysis were 686.0 pg/ml (334.5-1319.3 pg/ml) and 248.0 pg/ml (80.3-814.5 pg/ml) respectively, significantly higher than 62.8 pg/ml (22.0-321.6 pg/ml) and 20.7 pg/ml (1.0-200.9 pg/ml) in patients with normal cardiac function (LVEF > or = 50%) (P=0.002). The plasma BNP levels in patients with dilated left ventricle before and after hemodialysis were 609.0 pg/ml (254-1152.0 pg/ml) and 310.0 pg/ml (28.3-839.6 pg/ml) respectively, significantly higher than 62.8 pg/ml (23.2-192.5 pg/ml) and 22.4 pg/ml (1.0-80.7 pg/ml) in patients with normal left ventricle. Multiple linear regression analysis for left ventricular diastolic dimension, LVEF and plasma BNP level before hemodialysis showed that high BNP level was significantly correlated with dilated left ventricle and poor cardiac function (P<0.01). CONCLUSIONS: Plasma BNP levels in hemodialysis patients with CRF are significantly higher than those in healthy controls, and are significantly lowered after hemodialysis but still remain higher than the normal level. Plasma BNP levels in hemodialysis patients with dilated left ventricle or heart failure are significantly higher than those in patients with normal left ventricle or cardiac function, and high plasma BNP level is significantly correlated with dilated left ventricle and poor cardiac function.

[Continuous renal replacement therapy for severe acute renal failure].

OBJECTIVE: To estimate the clinical value of continuous renal replacement therapy (CRRT) in the treatment of severe acute renal failure (ARF) and identify the factors influencing the patients' prognosis. METHODS: The clinical characteristics, disease severity and prognosis were retrospectively studied in 116 patients with severe ARF undergoing CRRT from January, 1998 to May, 2004, in comparison with those in 102 such patients treated with intermittent hemodialysis (IHD). RESULTS: The mean score of Acute Physiology and Chronic Health Evaluation II (APACHE II) was 27.0+/-7.5 in patients receiving CRRT, of whom 56 (48%) had a score no less than 29, 36 (31%) between 24 to 29 and 24 (21%) less than 24. The mean APACHE II score was 21.9+/-5.2 in patients with IHD, and none of them had a score over 29, 44 (43%) had a score between 24 to 29 and 58 (57%) less than 24. The mean APACHE II score of CRRT group was significantly higher than that of IHD group (t=4.769, P=0.000), suggesting that most of the patients treated with CRRT were in critical condition. The patients' survival rate, however, did not differ significantly between the two groups, being 37% (43/116) in CRRT group and 48/ (49/102) in IHD group (X2=2.678, P=0.101 8). When only the patients with a score no less than 24 were compared, the survival rate of CRRT group was significantly higher than that of IHD group (24% vs 9%, X2=4.229, P=0.039 7), demonstrating better effect of CRRT than IHD in the management of critical ARF cases. In patients treated with CRRT, the patients in fatal cases had significantly older age, more critical condition (indicated by APACHE II score) and greater dependence on mechanical ventilation or vasoactive support than those who survived (P<0.05). CONCLUSIONS: CRRT is one of the effective methods for management of severe ARF patients, especially in those with critical conditions, with better effect than that of IHD. The prognosis of severe ARF patients treated with CRRT can be influenced by the patients' age and disease severity, and the need of vasoactive drugs or mechanical ventilation may help predict the patients' prognosis.