Abnormal coagulation and enhanced fibrinolysis due to lysinuric protein intolerance associates with bleeds and renal impairment

Introduction: Lysinuric protein intolerance (LPI), a rare autosomal recessive transport disorder of cationic amino acids lysine, arginine and ornithine, affects intestines, lungs, liver and kidneys. LPI patients may display potentially life-threatening bleeding events, which are poorly understood. Aims: To characterize alterations in haemostatic and fibrinolytic variables associated with LPI. Methods: We enrolled 15 adult patients (8 female) and assessed the clinical ISTH/ SSC-BAT bleeding score (BS). A variety of metabolic and coagulation assays, including fibrin generation test derivatives, clotting time (CT) and clot lysis time (CLT), thromboelastometry (ROTEM), and PFA-100 and Calibrated Automated Thrombogram (CAT), were used. Results: All patients had mild-to-moderate renal insufficiency, and moderate bleeding tendency (BS 4) without spontaneous bleeds. Mild anaemia and thrombocytopenia occurred. Traditional clotting times were normal, but in contrast, CT in fibrin generation test, and especially ROTEM FIBTEM was abnormal. The patients showed impaired primary haemostasis in PFA, irrespective of normal von Willebrand factor activity, but together with lowered fibrinogen and FXIII. Thrombin generation (TG) was reduced in vitro, according to CAT-derived endogenous thrombin potential, but in vivo TG was enhanced in the form of circulating prothrombin fragment 1 and 2 values. Very high D-dimer and plasmin-alpha 2-antiplasmin (PAP) complex levels coincided with shortened CLT in vitro. Conclusions: Defective primary haemostasis, coagulopathy, fibrin abnormality (FIBTEM, CT and CLT), low TG in vitro and clearly augmented fibrinolysis (PAP and D-dimer) in vivo were all detected in LPI. Altered fibrin generation and hyperfibrinolysis were associated with the metabolic and renal defect, suggesting a pathogenetic link in LPI.Peer reviewe

Renal fibrosis

Renal fibrosis, characterized by tubulointerstitial fibrosis and glomerulosclerosis, is the final manifestation of chronic kidney disease. Renal fibrosis is characterized by an excessive accumulation and deposition of extracellular matrix components. This pathologic result usually originates from both underlying complicated cellular activities such as epithelial-to-mesenchymal transition, fibroblast activation, monocyte/macrophage infiltration, and cellular apoptosis and the activation of signaling molecules such as transforming growth factor beta and angiotensin II. However, because the pathogenesis of renal fibrosis is extremely complicated and our knowledge regarding this condition is still limited, further studies are needed

Plasmin is not protective in experimental renal interstitial fibrosis1

Plasmin is not protective in experimental renal interstitial fibrosis.BackgroundThe plasminogen-plasmin system has potential beneficial or deleterious effects in the context of renal fibrosis. Recent studies have implicated plasminogen activators or their inhibitors in this process.MethodsThe development of renal interstitial fibrosis was studied in mice genetically deficient in plasminogen (plg-/- mice) and littermate controls (plg+/+ mice) by inducing unilateral ureteric obstruction (UUO) by ligating the left ureter.ResultsCollagen accumulation in the kidney was decreased in plg-/- mice at 21 days compared with plg+/+ mice by hydroxyproline assay (plg+/+ 19.0 ± 1.2 μg collagen/mg tissue, plg-/- 15.6 ± 0.5 μg collagen/mg tissue, P = 0.04). Macrophage accumulation in plg-/- mice was reduced at 21 days, consistent with a role for plasmin in macrophage recruitment in this model. Myofibroblast accumulation, assessed by the expression of α-smooth muscle actin (α-SMA), was similar in both groups at both time points. Endogenous plasmin played a role in the activation of transforming growth factor-β (TGF-β), as plg-/- mice had lower ratios of βig-h3:TGF-β1 mRNA than plg+/+ mice. Matrix metalloproteinase (MMP)-9 activity was unchanged in the absence of plasmin, but MMP-2 activity was decreased.ConclusionPlasminogen, the key proenzyme in the plasminogen-plasmin system, does not protect mice from experimental interstitial fibrosis and may have significant pathogenetic effects. These findings, together with other recently published studies in the biology of renal fibrosis, imply that effects of proteins such as plasminogen activator inhibitor-1 (PAI-1), tissue-type plasminogen activator (tPA), and urokinase-type plasminogen activator receptor (uPAR) on renal fibrosis occur independently from the generation of plasmin

Intrarenal Antigens Activate CD4+ Cells via Co-stimulatory Signals from Dendritic Cells

Dendritic cells in the kidney take up antigens, but little is known about their role in providing co-stimulatory signals for the activation of CD4+ cells. This study examined the phenotype of dendritic cells in the renal interstitium and in the lymph node draining the kidney before and after intrarenal ovalbumin injection. After intrarenal injection of the antigen, expression of the co-stimulatory molecules CD86 and programmed cell death ligand 1 (PD-L1) increased on renal dendritic cells, whereas expression of only CD86 increased on dendritic cells of the draining lymph node. The activation and proliferation of antigen-specific CD4+ cells in the lymph node were assessed by transfer of naïve, fluorescently labeled ovalbumin-specific T cell receptor transgenic cells to mice before antigen administration. Blocking both CD86 and CD80 profoundly inhibited CD4+ cell proliferation, but CD86 was the dominant CD28 ligand in the early proliferative response of CD4+ cells. Conversely, activation of PD-1, the receptor expressed on CD4+ cells that binds PD-L1 and PD-L2, reduced the proliferation of CD4+ cells in the draining lymph node. Comparing subcutaneous and intrarenal administration of antigen, it was found that CD4+ cell activation was slower and the effects of combined CD80 and CD86 blockade were more profound when antigen was presented via the kidney compared with the skin. In summary, renal dendritic cells take up antigen and participate in the control of antigen-specific CD4+ cell proliferation by upregulating co-stimulatory molecules such as CD86 that stimulate CD4+ cell proliferation and by signaling through PD-1, which prevents an inappropriately exuberant immune response