Prophylactic inhibition of soluble epoxide hydrolase delays onset of nephritis and ameliorates kidney damage in NZB/W F1 mice

Epoxy-fatty-acids (EpFAs), cytochrome P450 dependent arachidonic acid derivatives, have been suggested to have anti-inflammatory properties, though their effects on autoimmune diseases like systemic lupus erythematosus (SLE) have yet to be investigated. We assessed the influence of EpFAs and their metabolites in lupus prone NZB/W F1 mice by pharmacological inhibition of soluble epoxide hydrolase (sEH, EPHX2). The sEH inhibitor 1770 was administered to lupus prone NZB/W F1 mice in a prophylactic and a therapeutic setting. Prophylactic inhibition of sEH significantly improved survival and reduced proteinuria. By contrast, sEH inhibitor-treated nephritic mice had no survival benefit; however, histological changes were reduced when compared to controls. In humans, urinary EpFA levels were significantly different in 47 SLE patients when compared to 10 healthy controls. Gene expression of EPHX2 was significantly reduced in the kidneys of both NZB/W F1 mice and lupus nephritis (LN) patients. Correlation of EpFAs with SLE disease activity and reduced renal EPHX gene expression in LN suggest roles for these components in human disease

Angiotensin II type 1 receptor antibodies in childhood kidney transplantation

Angiotensin II type 1 receptor antibodies (AT1 RAb) have emerged as non-HLA Ab present in patients with acute AMR and risk of graft loss. Furthermore, AT1 RAb have been shown to increase angiotensin II sensitivity which may play a role in the development of CVD and hypertension. Data on AT1 RAb in stable transplant recipients are lacking. The aim of this study was to analyze the levels of AT1 RAb in a cohort of stable patients after kidney transplantation (tx) in childhood. A cross-sectional study of 30 children (median age 14, range 3-19 yr, median time since tx five yr) and 28 adults who were transplanted in childhood (median age 26, range 20-40 yr, median time since tx 18 yr) transplanted between 1993-2006 and 1983-2002, respectively, was performed. Healthy controls were 51 healthy children (5-8 yr) and 199 healthy donors (median age 56.5 yr, range 42-83 yr). Plasma AT1 RAb were analyzed by immunoassay. Median total AT1 RAb IgG concentration was significantly higher in the pediatric-tx group as compared to the adult-tx group (40.0 and 10.95 U/mL, p < 0.0001). For both groups, the tx group showed higher levels: the pediatric-tx group vs. control group (40.0 vs. 13.3 U/mL, p = 0.0006) and the adult-tx group vs. adult control group (10.95 vs. 6.5 U/mL, p < 0.0001). Age was the strongest indicator of high levels of AT1 RAb IgG (p = 0.0003). AT1 RAb total IgG levels are significantly higher in a stable pediatric-tx cohort as compared to adult-tx patients and healthy controls of comparable age groups. The relevance of our findings in relation to age, time since tx, previous or future rejection, and CVD risk merits future studies

The XIIIth Banff Conference on Allograft Pathology: The Banff 2015 Heart Meeting Report: Improving Antibody-Mediated Rejection Diagnostics: Strengths, Unmet Needs, and Future Directions.

The 13th Banff Conference on Allograft Pathology was held in Vancouver, British Columbia, Canada from October 5 to 10, 2015. The cardiac session was devoted to current diagnostic issues in heart transplantation with a focus on antibody-mediated rejection (AMR) and small vessel arteriopathy. Specific topics included the strengths and limitations of the current rejection grading system, the central role of microvascular injury in AMR and approaches to semiquantitative assessment of histopathologic and immunophenotypic indicators, the role of AMR in the development of cardiac allograft vasculopathy, the important role of serologic antibody detection in the management of transplant recipients, and the potential application of new molecular approaches to the elucidation of the pathophysiology of AMR and potential for improving the current diagnostic system. Herein we summarize the key points from the presentations, the comprehensive, open and wide-ranging multidisciplinary discussion that was generated, and considerations for future endeavors

High temporal resolution parametric MRI monitoring of the initial ischemia/reperfusion phase in experimental acute kidney injury

Ischemia/reperfusion (I/R) injury, a consequence of kidney hypoperfusion or temporary interruption of blood flow is a common cause of acute kidney injury (AKI). There is an unmet need to better understand the mechanisms operative during the initial phase of ischemic AKI. Non-invasive parametric magnetic resonance imaging (MRI) may elucidate spatio-temporal pathophysiological changes in the kidney by monitoring the MR relaxation parameters T* and T, which are known to be sensitive to blood oxygenation. The aim of our study was to establish the technical feasibility of fast continuous T*/T mapping throughout renal I/R. MRI was combined with a remotely controlled I/R model and a segmentation model based semi-automated quantitative analysis. This technique enabled the detailed assessment of changes in all kidney regions during ischemia and early reperfusion. Significant changes in T* and T were observed shortly after induction of renal ischemia and during the initial reperfusion phase. Our study demonstrated for the first time that continuous and high temporal resolution parametric MRI is feasible for monitoring and characterization of I/R induced AKI in rats. This technique may help in the identification of the timeline of key events responsible for development of renal damage in hypoperfusion-induced AKI

Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection (authors reply inN Engl J Med. 2005 May 12;352(19):2027-8)

BACKGROUND: Antibodies against HLA antigens cause refractory allograft rejection with vasculopathy in some, but not all, patients. METHODS: We studied 33 kidney-transplant recipients who had refractory vascular rejection. Thirteen had donor-specific anti-HLA antibodies, whereas 20 did not Malignant hypertension was present in 16 of the patients without anti-HLA antibodies, 4 of whom had seizures. The remaining 17 patients had no malignant hypertension. We hypothesized that activating antibodies targeting the angiotensin II type 1 (AT1) receptor might be involved. RESULTS: Activating IgG antibodies targeting the AT1 receptor were detected in serum from all 16 patients with malignant hypertension and without anti-HLA antibodies, but in no other patients. These receptor-activating antibodies are subclass IgG1 and IgG3 antibodies that bind to two different epitopes on the second extracellular loop of the AT1 receptor. Tissue factor expression was increased in renal-biopsy specimens from patients with these antibodies. In vitro stimulation of vascular cells with an AT1-receptor-activating antibody induced phosphorylation of ERK 1/2 kinase and increased the DNA binding activity of the transcription factors activator protein 1 (AP-1) and nuclear factor-κB. The AT1 antagonist losartan blocked agonistic AT1-receptor antibody-mediated effects, and passive antibody transfer induced vasculopathy and hypertension in a rat kidney-transplantation model. CONCLUSIONS: A non-HLA, AT1-receptor-mediated pathway may contribute to refractory vascular rejection, and affected patients might benefit from removal of AT 1-receptor antibodies or from pharmacologic blockade of AT 1 receptors

Metal Bioavailability in the Sava River Water

Metals present one of the major contamination problems for freshwater systems, such as the Sava River, due to their high toxicity, persistence, and tendency to accumulate in sediment and living organisms. The comprehensive assessment of the metal bioavailability in the Sava River encompassed the analyses of dissolved and DGT-labile metal species of nine metals (Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, and Zn) in the river water, as well as the evaluation of the accumulation of five metals (Cd, Cu, Fe, Mn, and Zn) in three organs (liver, gills, and gastrointestinal tissue) of the bioindicator organism, fish species European chub (Squalius cephalus L.).This survey was conducted mainly during the year 2006, in two sampling campaigns, in April/May and September, as periods representative for chub spawning and post-spawning. Additionally, metal concentrations were determined in the intestinal parasites acanthocephalans, which are known for their high affinity for metal accumulation. Metallothionein concentrations were also determined in three chub organs, as a commonly applied biomarker of metal exposure. Based on the metal concentrations in the river water, the Sava River was defined as weakly contaminated and mainly comparable with unpolluted rivers, which enabled the analyses of physiological variability of metal and metallothionein concentrations in the chub organs, as well as the establishment of their constitutive levels

Treatment with the immunomodulator FTY720 does not promote spontaneous bacterial infections after experimental stroke in mice

Background: FTY720, an immunomodulator derived from a fungal metabolite which reduces circulating lymphocyte counts by increasing the homing of lymphocytes to the lymph nodes has recently gained interest in stroke research. The aim of this study was to evaluate the protective efficacy of FTY720 in cerebral ischemia in two different application paradigms and to gather first data on the effect of FTY720 on the rate of spontaneous bacterial infections in experimental stroke. Methods: Middle cerebral artery occlusion (MCAO) in C57BL/6 mice (strain J, groups of 10 animals) was performed with two different durations of ischemia (90 min and 3 h) and FTY720 was applied 2 h after vessel occlusion to study the impact of reperfusion on the protective potency of FTY720. Lesion size was determined by TTC staining. Mice treated with FTY720 or vehicle were sacrificed 48 h after 90 min MCAO to determine the bacterial burden in lung and blood. Results: FTY720 1 mg/kg significantly reduced ischemic lesion size when administered 2 h after the onset of MCAO for 3 h (45.4 +/- 22.7 mm3 vs. 84.7 +/- 23.6 mm3 in control mice, p = 0.001) and also when administered after reperfusion, 2 h after the onset of MCAO for 90 min (31.1 +/- 28.49 mm3 vs. 69.6 +/- 27.2 mm3 in control mice, p = 0.013). Bacterial burden of lung homogenates 48 h after stroke did not increase in the group treated with the immunomodulator FTY720 while there was no spontaneous bacteremia 48 h after MCAO in treated and untreated animals. Conclusions: Our results corroborate the experimental evidence of the protective effect of FTY720 seen in different rodent stroke models. Interestingly, we found no increase in bacterial lung infections even though FTY720 strongly reduces the number of circulating leukocytes

The banff 2019 kidney meeting report (I): updates on and clarification of criteria for T cell- and antibody-mediated rejection.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation