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BACKGROUND: For long Epstein-Barr virus (EBV) has been suspected to be involved in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to verify the association between EBV, cell-free DNA (cfDNA) and kidney disease in SLE. METHODS: Blood samples were obtained from 43 SLE patients and 50 healthy individuals. EBV load was measured via real-time PCR assay. Sizing and quantification of plasma cfDNA was performed on Bioanalyzer. We proposed that the uniformity of cfDNA fragmentation can be described using cfDNA fragmentation index. RESULTS: SLE patients with chronic kidney disease (CKD +) had higher EBV load compared to CKD(-) patients (P = 0.042). Patients with high cfDNA level had higher EBV load (P = 0.041) and higher cfDNA fragmentation index (P < 0.001) compared to patients with low cfDNA level. Among patients with high cfDNA level, EBV load was higher in CKD(+) group compared to CKD(-) group (P = 0.035). EBV load was positively correlated with the fragmentation index in all SLE patients (P = 0.028, R2 = 0.13), and the correlation was even more pronounced in CKD (+) patients (P < 0.001, R2 = 0.20). CONCLUSIONS: We showed that EBV load was associated with non-uniform cfDNA fragmentation, higher cfDNA levels, and kidney disease in SLE patients. Although the causality of this relationship could not be determined with the current study, it brings rationale for further investigations on the role of EBV and cfDNA interplay in SLE pathogenesis.

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BACKGROUND: Increased level of cell-free DNA (cf-DNA) is associated with systemic lupus erythematosus (SLE) and might be related to disease activity. The aim of this study was to evaluate whether cfDNA integrity, size distribution and concentration of different cfDNA fractions is associated with lupus activity and kidney involvement. METHODS: Blood samples were collected from 43 SLE patients and 50 healthy controls. Nuclear and mitochondrial fractions of cfDNA and intracellular DNA were quantified by real-time qPCR. Sizing and quantification of total cfDNA level was performed on Bioanalyzer. RESULTS: We determined four parameters that characterized cfDNA profile: fragmentation index, ratio of intra- to extracellular mtDNA copy number, cfDNA concentration, and presence of 54-149 bp and 209-297 bp fragments. Patients with healthy-like cfDNA profile had higher eGFR (P = 0.009) and more often no indications for kidney biopsy or less advanced lupus nephritis (LN) (P = 0.037). In contrary, SLE patients with distinct cfDNA profile (characterized by increased cfDNA concentration and fragmentation, higher discrepancy between intra- to extracellular mtDNA copy number, and the presence of 54-149 bp and 209-297 bp fragments) had lower eGFR (P = 0.005) and more often advanced LN or history of renal transplantation (P = 0.001). CONCLUSIONS: We showed that cfDNA profiling may help to distinguish SLE patients with renal involvement and severe disease course from patients with more favorable outcomes. We suggest cfDNA profile a promising SLE biomarker.

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The aim of this study was to determine the co-occurrence of heterotopic ossifications (HO) and elevated bone biomarkers level (urine type I collagen cross-linked C-telopeptide - CTX-1, serum alkaline phosphatase - ALP) and assess the effectiveness of pharmacological prophylaxis of HO. The study group consisted of (N=54) patients qualified for total hip arthroplasty. In N=19 (35%) patients new HO were formed (48th week vs to baseline). On baseline, the mean CTX-1 value in the HO (-) patients was 8.60+/-5.37 ug/mmol vs HO (+) 11.73+/-6.02 ug/mmol (p<0,05). On the 5th day after the surgery, the mean value in HO (-) patients was 8.45+/-4.04 ug/mmol vs HO (+)14.46+/- 5.91 ug/mmol (p<0,05). The mean increase in CTX-1 levels in HO (+) patients' vs HO (-) compared to the initial value was 21% vs 47%. Correlation between CTX-1 concentration on the 5th day and the appearance of new ossifications (r=0.48, p<0.05) was demonstrated. In group covered by prophylaxis diclofenac 150 mg for 6 weeks, HO assessment in Brooker's scale was on average 0.78 points lower than in the group without prophylaxis and 0.89 points lower than in the group without prophylaxis and no risk factors of HO (p<0,05). The study also reported a correlation between the corrected ALP concentration in the 12th week and HO (r=0.59, p<0.05).

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MicroRNAs play multiple roles in the regulation of blood pressure (BP). Nevertheless, to date, no study has assessed the association between microRNA plasma expression and BP control in chronic kidney disease (CKD) patients. Given this background, we evaluated the plasma expression of miR-155-5p, a translational inhibitor of angiotensin receptor type I, in CKD patients, to determine the association between miR-155-5p level and BP control. In this single-center cross-sectional study, we analyzed the miR-155-5p concentration by quantitative reverse transcriptase polymerase chain reaction using the U6 snRNA as a reference gene and 24-hour ambulatory blood pressure monitoring in CKD patients (stage ≥2) in relation to a control group of healthy age-matched and gender-matched individuals, with normal BP proven by the ambulatory blood pressure monitoring. We enrolled a total of 105 patients with CKD (stages 2-5, including 33 kidney renal transplant recipients), aged 59 ± 14 years; 47% males and 26 healthy volunteers (aged 55 ± 13, 50% male). Within the study group, a total of 36 patients (40%) presented with an average 24-hour systolic BP (SBP) ≥130 mm Hg and 41 patients (45%) presented nocturnal hypertension (NHT; SBP ≥120 mm Hg or diastolic BP ≥ 70 mm Hg). miRNA-155-5p was increased in plasma of CKD patients with median expression relative to control subjects equal to 2.92 (1.34-5.58). Interestingly, the plasma miRNA-155-5p expression was significantly higher in patients with NHT: 4.04 (2.92-10.8) versus 2.01 (1.21-3.07), P = .001 and its expression maintained an independent association with the average nocturnal SBP (coefficient B = 4.368, P = .047) by a multivariate regression analysis adjusted for confounders. The miR-155-5p was increased among CKD patients and further increased among subjects presenting with NHT. Further studies are warranted to determine the role of this non-coding RNA as a potential novel biomarker and therapeutic target in the non-dipping CKD individuals, characterized by increased cardiovascular risk.

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Hyperglycemia results in the activation of tissue angiotensin II. Angiotensin II stimulates the synthesis of ECM proteins and causes a decrease activity of proteolytic enzymes. The aim of this study was to assess the impact of multilevel blocking of the RAAS, cathepsin B activity, and fibronectin accumulation in the glomerular in the rats diabetes model. Sixty male Wistar rats were initially included. Diabetes was induced by intravenous administration of streptozotocin. The animals were randomized to six groups of ten rats in group. Rats in the four groups were treated with inhibitors of the RAAS: enalapril (EN), losartan (LOS), enalapril plus losartan (EN + LOS), and spironolactone (SPIR); another group received dihydralazine (DIH) and the diabetic rats (DM) did not receive any drug. After six weeks, we evaluated blood pressure, 24 h urine collection, and blood for biochemical parameters and kidneys. In this study, fluorometric, ELISA, and immunohistochemical methods were used. Administration of EN + LOS increased activity of cathepsin B in homogenates of glomeruli compared to DM. Losartan treatment resulted in reduction of the ratio kidney weight/body weight compared to untreated diabetic rats. SPIR resulted in the increase activity of cathepsin B in the homogenate of glomeruli. The values of cathepsin B in the plasma of rats in all studied groups were similar and showed no tendency.

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The strategic location of the liver and its metabolic activity make it a key organ regulating homeostasis. Our purpose was to examine its participation in removal of cytokines: interleukin-6 (Il-6), tumor necrosis factor-alpha (TNF-α), hepatocyte growth factor (HGF), and transforming growth factor-beta (TGF-ß) from the portal circulation in human. 20 liver donors and 20 patients with end-stage liver failure were included in the study. Their blood was collected during liver transplantation from the portal, hepatic, and peripheral vein, and the hepatic artery and cytokines' concentrations were determined. Using the results the mathematical model of cytokine elimination by the liver was developed. In donors significantly lower levels of IL-6, TNF-α, HGF, and TGF-ß were detected in portal blood compared to hepatic vein. In patients with cirrhosis there were no significant differences of IL-6, TNF-α, and TGF-ß levels between portal and hepatic veins. Significantly higher level of HGF in hepatic compared to portal vein was observed. In healthy liver elimination of the cytokines prevailed over their synthesis, as reflected by the positive values of the elimination ratios. In the cirrhotic liver elimination ratios of Il-6, HGF, and TGF-ß were negative indicating the prevalence of intrahepatic synthesis of cytokines over their removal.

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CONTEXT: Machine perfusion improves graft survival. Histopathologic analysis reveals a lower incidence of chronic rejection and interstitial fibrosis in kidneys preserved with machine perfusion. Ischemic/reperfusion injury may help to explain these findings. OBJECTIVE: To assess the activation of genes correlated with ischemic/reperfusion injury in kidneys preserved under different conditions before transplant. DESIGN/PATIENTS: Between 2005 and 2006, 69 kidney biopsy specimens were collected and patients were followed up for 5 years after that.Intervention-Before transplant, kidneys were preserved with machine perfusion or cold storage. Donors from the machine perfusion and cold storage groups did not differ with regard to age, sex, or hemodynamic status. Recipients were divided into 5 groups: expanded criteria donor-machine perfusion (n = 16), standard criteria donor-machine perfusion (n = 10), expanded criteria donor-cold storage (n = 9), and standard criteria donor-cold storage (n = 27); 7 kidneys were retrieved from living related donors. MAIN OUTCOME MEASURES: Biopsies were done 30 minutes after reperfusion. Interleukin-1ß, vascular endothelial growth factor, heme oxygenase-1, and hypoxia-inducible factor-1 gene expression levels were analyzed. RESULTS: Mean expression levels of hypoxia-inducible factor-1α were significantly higher in the cold storage groups, and lower in the machine perfusion and living-related donor groups. Five-year graft survival was significantly (P< .05) lower in the expanded criteria donor-cold storage group (66%) than in the standard criteria donor-machine perfusion group (90%). Machine perfusion influences gene expression related to hypoxia during reperfusion and may improve the long-term results of kidney transplant.

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Liver fibrosis is one of the most compound pathological process occurred as the answer to risen inflammation factor. It is characterized by balance disorders between syntesis and degradation ECM (Extracellular Matrix) by myofibroblasts. This appears when activated by inflammation factor HSC cells transform in myofibroblasts. Among major causes of the chronic liver inflammation, with parenchymal cells destruction and replace of connective tissue, are: hepatotropic viruses (HCV, HBV), alcohol, autoimmunologic disorders.

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Fibrosis is characterized by balance disorders between syntesis and degradation ECM (Extracellular Matrix) by myofibroblasts. Activated by inflammation factor HSC cells transform in myofibroblasts. This changes are caused and assisted by number of mediators: cytokines, growth factors, kinases. All this stimulus we call fibrosis factors. This paper compose second part of object-article: Liver fibrosis and cirrhosis - causes.

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