Coagulation abnormalities in renal pathology are associated with a high thrombotic and hemorrhagic risk. This study aims to investigate the hemostatic abnormalities that are related to the interaction between soluble coagulation factors and blood cells, and the effects of hemodialysis (HD) on it, in end stage renal disease (ESRD) patients. Thirty-two ESRD patients under HD treatment and fifteen healthy controls were included in the study. Whole blood samples from the healthy and ESRD subjects were collected before and after the HD session. Evaluation of coagulation included primary and secondary hemostasis screening tests, proteins of coagulation, fibrinolytic and inhibitory system, and ADAMTS-13 activity. Phosphatidylserine (PS) exposure and intracellular reactive oxygen species (iROS) levels were also examined in red blood cells and platelets, in addition to the platelet activation marker CD62P. Platelet function analysis showed pathological values in ESRD patients despite the increased levels of activation markers (PS, CD62P, iROS). Activities of most coagulation, fibrinolytic, and inhibitory system proteins were within the normal range, but HD triggered an increase in half of them. Additionally, the increased baseline levels of ADAMTS-13 inhibitor were further augmented by the dialysis session. Finally, pathological levels of PS and iROS were measured in red blood cells in close correlation with variations in several coagulation factors and platelet characteristics. This study provides evidence for a complex coagulation phenotype in ESRD. Signs of increased bleeding risk coexisted with prothrombotic features of soluble factors and blood cells in a general hyperfibrinolytic state. Hemodialysis seems to augment the prothrombotic potential, while the persisted platelet dysfunction might counteract the increased predisposition to thrombotic events post-dialysis. The interaction of red blood cells with platelets, the thrombus, the endothelium, the soluble components of the coagulation pathways, and the contribution of extracellular vesicles on hemostasis as well as the identification of the unknown origin ADAMTS-13 inhibitor deserve further investigation in uremia.
Background: The complement system has been recently proposed to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). This study evaluated the value of serum and kidney deposited C3 in predicting renal outcomes in AAV. Methods: This was a retrospective study of 47 patients with AAV, who were categorized according to their serum C3 levels as hypo-or normo-complementemic and to those with positive or negative kidney biopsy immunofluorescence (IF) for C3. Baseline characteristics as well as progression to end-stage renal disease (ESRD) between the 2 groups were compared. Results: In total, 23% (11/47) were hypo-complementemic; these patients were older (74 vs. 65 years, p ¼ 0.013), had higher creatinine levels (4.9 vs. 2.2 mg/dL, p ¼ 0.006), were more often hemodialysis dependent (64% vs. 19%, p ¼ 0.009) and progressed more often to ESRD (55% vs. 11%, p ¼ 0.01) compared to normo-complementemic patients (n ¼ 36). On multivariate analysis, serum creatinine at diagnosis (HR ¼ 16.8, 95%CI: 1.354-208.62, p ¼ 0.028) and low serum C3 (HR ¼ 2.492; 95% CI: 1.537-11.567; p ¼ 0.044) were independent predictors for ESRD. Among 25 patients with an available kidney biopsy, 56% had C3 deposition by IF and displayed more often a mixed histological pattern (72% vs. 27%, p ¼ 0.033), low serum C3 levels (42% vs. 18%, p < 0.001) and serious infections during follow-up (57% vs. 18%, p ¼ 0.047) compared to those with negative (n ¼ 11) IF staining. Conclusion: Almost one of four patients with AAV has low C3 levels at diagnosis which is associated with more severe renal disease and worse renal outcomes (ESRD). This should be taken into account in therapeutic and monitoring strategies.
Background and Aims The role of plasmapheresis in the overall and renal survival of patients with ANCA-associated vasculitis (AAV) has not been fully elucidated. The aim of this study is to address whether plasmapheresis is associated with improvement in renal function and survival at 12 months in patients with severe manifestations of AAV and to record the indications, adverse events and treatment characteristics. Method Retrospective, descriptive study of 28 patients with AAV diagnosed over the last five years in a tertiary center. Patients were included if they had received therapeutic plasmapheresis adjunctive to conventional therapy (steroids and immunosuppressants) for the first episode of AAV or in relapse. Results 12 patients (75% male) were enrolled with average age at diagnosis 78.5±6.14 years. The patients were followed for a median period of 20 months. In 75% of the patients MPO-ANCA was positive, in 17% ANCA negative and in 8% double positive anti-GBM/ANCA. On admission, all patients had abnormal renal function with average serum creatinine 5mg/dl±2.12 and the majority of patients (9/12) were dialysis dependent. Indications for plasmapheresis were: alveolar hemorrhage in 33%, renal impairment in 25% and combination of the two above in 42%. 11 patients received plasmapheresis for the first episode of AAV and 1 patient for relapse. Plasmapheresis was performed using filtration and fresh frozen plasma as replacement fluid. The mean number of plasmapheresis treatment was 8 (range 1 to 19 days) and the average internal time between admission and first plasmapheresis treatment was 3 days. One patient had a severe allergic reaction resulting in early discontinuation and no episodes of severe infection or death were recorded during plasmapheresis. As far as treatment all patients received concomitant immunosuppressive therapy with cyclophosphamide (CYC) and corticosteroids while Rituximab (RTX) was added in 3 patients (3/12). Alveolar hemorrhage was resolved in all patients (100%). After one year, 75% of the patients had renal recovery (cre=5mg/dl±2.12 vs cre=2.6mg/dl±1.6, p=0.06) and 67% of the patients who required hemodialysis at the time of diagnosis, during the first year became independent of dialysis (75% vs 33%, p=0.5). Finally, survival at the end of the first year was 83% with cancer and ischaemic heart disease being the cause of death. Conclusion Plasmapheresis is quite often used in daily clinical practice with remarkable results in dialysis independence and survival, without serious complications. The actual role of plasmapheresis in ANCA-vasculitis therapeutic algorithm will be determined shortly with the expected results of a randomized multicenter study.
BACKGROUND AND AIMS Transforming growth factor-β1 (TGF-β1) has long been considered as a potent, multifunctional cytokine that is involved in the pathogenesis of fibrosis and inflammation, which acts through Smad signaling in renal pathology. We intended to investigate the expression of TGF-β1/Smad3 signaling in glomerulonephritis (GN) and to assess its role as risk factor for progression to chronic kidney disease (CKD). METHOD We evaluated the immunohistochemical expression of TGF-β1, phosphorylated Smad3 (pSmad3) and Smad7 semiquantitatively and quantitatively using computerized image analysis program in different compartments of 50 renal biopsies with GN and the results were statistically analyzed with clinicopathological parameters. We also examined the associations among their expressions, the impact of their co-expression and their role in progression to CKD. RESULTS TGF-β1 expression correlated positively with segmental glomerulosclerosis (P = .025) and creatinine level at diagnosis (p = .002), while pSmad3 expression with interstitial inflammation (P = .024). In glomerulus, we recorded different expression patterns of pSmad3 in crescents, while concomitant expressions of strong Smad7 and moderate pSmad3 were observed to be correlated with renal inflammation, such as cellular crescent (P = .011), intense interstitial inflammation (P = .029) and lower serum complement 3 (P = .028) and complement 4 (P = .029). We also reported a significant preferable expression between pSmad3 and glomerular endothelial cells of proliferative GN (P = .045) and podocytes of non-proliferative GN (P = .005). Finally, on multivariate Cox-regression analysis, TGF-β1 expression (HR = 5.08; 95% CI 1.133–22.78; P = .034) was emerged as independent predictor for CKD. CONCLUSION TGF-β1/Smad3 dependent signaling is upregulated, especially in proliferative GN, with specific characteristics in different forms of GN. TGF-β1 expression is indicated as independent risk factor for progression to CKD, while specific co-expression pattern of pSmad3 and Smad7 in glomerulus is correlated with renal inflammation.
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