Efficacy and safety of prophylactic anticoagulation in patients with primary nephrotic syndrome: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Nephrotic syndrome (NS) is associated with an increased incidence of venous thromboembolism (VTE), approximately 10%. We performed a systematic review to evaluate the efficacy and safety of prophylactic anticoagulation in patients with NS. METHODS: Studies evaluating prophylactic anticoagulation in NS were identified by an electronic search of MEDLINE and EMBASE databases until December 2021. Weighted mean proportion and 95% confidence intervals (CIs) of thromboembolic and haemorrhagic events were calculated using a fixed-effects and a random-effects model. The differences in the outcomes among groups were estimated as pooled odds ratio (OR) and corresponding 95% CI. Statistical heterogeneity was evaluated using the I2 statistic. RESULTS: Five cohort studies, for a total of 414 adult patients, were included. Only two studies had a control group. The weighted mean incidence of pulmonary embolism (PE) and deep vein thrombosis in patients who received VTE prophylaxis was 1.8% (95% CI: 0.6-3.5%; I2 : 4.4%) and 0.9% (95% CI: 0.2-2.2%; I2 : 43.4%) respectively. The weighted mean incidence of major bleeding in patients who received VTE prophylaxis was 2.3% (95% CI: 1-4.2%; I2 : 25.4%). Patients with NS that received VTE prophylaxis had a non-significant reduced risk of PE (OR: 0.63 (95% CI: 0.03-14.8; I2 : 64.4%)) and an increased risk of major bleeding (OR: 2.08 (95% CI: 0.41-10.45; I2 : 0%)) compared to patients with NS that did not receive VTE prophylaxis. CONCLUSIONS: Our findings suggest that prophylactic anticoagulation in adult patients with primary NS may reduce the risk of VTE, even if it may be associated with a not negligible bleeding risk.

Danger-associated molecular pattern molecules and the receptor for advanced glycation end products enhance ANCA-induced responses.

OBJECTIVES: The pro-inflammatory activities of the calgranulins and HMGB1 can be counteracted by sRAGE, the soluble form of their shared receptor. To understand the role of these molecules in AAV and their potential as therapeutic targets we have studied (i) the relationship between these DAMPS and disease activity; (ii) the expression of RAGE and sRAGE in biopsy tissue and peripheral blood; and (iii) the effect of these molecules on ANCA-mediated cytokine production. METHODS: We examined circulating levels of calgranulins (S100A8/A9 and S100A12), HMGB1 and sRAGE by ELISA. RAGE was examined in AAV kidney and lung biopsies by immunohistochemistry and RAGE expression was monitored in peripheral blood by qPCR. In vitro, the effect of co-stimulating PBMC with ANCA and S100A8/A9 on cytokine production was studied by ELISA. RESULTS: We found significantly raised levels of calgranulins and HMGB1 in active AAV regardless of clinical phenotype (PR3+/MPO+ AAV). Levels of calgranulins showed significant correlations with each other. RAGE protein and message was raised in peripheral blood and in cells infiltrating kidney and lung biopsy tissue, while sRAGE was lowered. Furthermore, ANCA-mediated production of IL-8 from PBMC was significantly enhanced by the presence of S100A8/A9 in a RAGE/TLR4-dependent manner. CONCLUSIONS: Raised circulating calgranulins provide a good marker of disease activity in AAV and are unlikely to be counteracted by sRAGE. Increased RAGE expression in AAV indicates receptor stimulation in active disease that may exacerbate ANCA-induced cytokine production. Targeting the RAGE pathway may provide a useful therapeutic approach in AAV.

Excessive neutrophil extracellular trap formation in ANCA-associated vasculitis is independent of ANCA.

Neutrophil extracellular traps (NETs) are auto-antigenic strands of extracellular DNA covered with myeloperoxidase (MPO) and proteinase3 (PR3) that can be a source for the formation of anti-neutrophil cytoplasmic autoantibodies (ANCAs). The presence of NETs was recently demonstrated in renal tissue of patients with ANCA-associated vasculitis (AAV). NET formation was enhanced in AAV, suggesting that MPO-ANCA could trigger NET formation, supporting a vicious circle placing NETs in the center of AAV pathogenesis. Here we investigated NET formation in 99 patients with AAV by a novel highly sensitive and automated assay. There was a significant excess of ex vivo NET formation in both MPO-ANCA- and PR3-ANCA-positive patients with AAV compared to healthy individuals. Excessive NET formation did not correlate with serum ANCA levels. Likewise, immunoglobulin G depletion had no effect on excessive NET formation in patients with AAV, indicating an ANCA-independent process. Next, we explored the relation of excessive NET formation to clinical disease in ten patients with AAV and showed that excessive NET formation was predominantly found during active disease, more so than during remission. Excessive NET formation was found in patients with AAV hospitalized for disease relapse but not during severe infection. Thus, excessive NET formation in AAV is independent of ANCA, and an excess of ex vivo NET formation was related to active clinical disease in patients with AAV and a marker of autoimmunity rather than infection.

Alport syndrome and pregnancy: a case series and literature review.

PURPOSE: To assess pregnancy outcome in women with Alport syndrome and the impact of pregnancy on the disease progression. METHODS: We describe one of the largest series of pregnancies in Alport syndrome. Seven pregnancies of six women were monitored by a multidisciplinary team of nephrologists and gynecologists. After delivery, patients were followed for at least 3 years. We compare our results with those in the literature. RESULTS: Pregnancy course was uneventful in the patient with isolated microscopic hematuria. In the other cases, all presenting mild proteinuria at conception, some complications occurred. Proteinuria worsened during the last trimester, reaching nephrotic ranges in five out of six pregnancies and was associated with fluid overload leading to hospitalizations and early delivery. The majority of the newborns had a low birth weight. The two patients with arterial hypertension at conception and twin pregnancy developed pre-eclampsia and renal function deterioration persisted after delivery. The one with pre-pregnancy renal dysfunction reached end-stage renal disease. In the other patients, in which renal function and blood pressure were and remained normal, proteinuria improved after delivery and no signs of disease progression were recorded at last observation. CONCLUSIONS: Our observations suggest that Alport syndrome should be considered a potential risk factor for pregnancy in proteinuric patients due to the development of pre-eclampsia, renal function deterioration, and/or full-blown nephrotic syndrome that results in anasarca, slowing of fetal growth and pre-term delivery. Thus, all women with Alport syndrome should receive pre-conceptional counseling and be kept in close follow-up during pregnancy.

Low-dose rituximab is poorly effective in patients with primary membranous nephropathy.

BACKGROUND: The optimal dosing and the efficacy of rituximab for primary membranous nephropathy (PMN) has not been established. This multicentric prospective study evaluates the efficacy and safety of low-dose rituximab (RTX) therapy in patients with PMN in clinical practice. METHODS: Thirty-four consecutive patients with PMN and nephrotic syndrome were included and received RTX (375 mg/m2) once (18 patients) or twice (16 patients). RTX was the first-line therapy for 19 (56%) and the second line for 15 (44%) patients. All patients were followed for 12 months after RTX and 24 for at least 18 months (mean 23.9 ± 18.6 months). RESULTS: At 12 months, 5 patients (14.7%) achieved complete response, 10 (29.4%) partial and 19 (55.8%) no response. Response occurred ∼6 months after RTX. At 24 months, the clinical situation was unchanged: two non-responders achieved partial response and two responders relapsed. Responders had significantly higher baseline GFR and lower anti-PLA2R antibodies compared with non-responders. Outcome was similar between one or two doses of RTX (non-responders 55.5 versus 56%, respectively) and between patients who had received previous therapy versus those receiving RTX as first-line therapy (non-responders 40 versus 68%, respectively). In the 15 patients already treated, the response to RTX was comparable to that of previous therapies. CONCLUSION: Low-dose RTX obtains remission in <50% of PMN patients. Probably, higher doses and longer treatments are needed to induce and maintain a response. The balance between the costs and benefits should guide the selection of the patient and the optimal dosage.

Glomerular Autoimmune Multicomponents of Human Lupus Nephritis In Vivo (2): Planted Antigens.

Glomerular planted antigens (histones, DNA, and C1q) are potential targets of autoimmunity in lupus nephritis (LN). However, the characterization of these antigens in human glomeruli in vivo remains inconsistent. We eluted glomerular autoantibodies recognizing planted antigens from laser-microdissected renal biopsy samples of 20 patients with LN. Prevalent antibody isotypes were defined, levels were determined, and glomerular colocalization was investigated. Renal and circulating antibodies were matched, and serum levels were compared in 104 patients with LN, 84 patients with SLE without LN, and 50 patients with rheumatoid arthritis (RA). Autoantibodies against podocyte antigens (anti-α-enolase/antiannexin AI) were also investigated. IgG2 autoantibodies against DNA, histones (H2A, H3, and H4), and C1q were detected in 50%, 55%, and 70% of biopsy samples, respectively. Anti-DNA IgG3 was the unique non-IgG2 anti-DNA deposit, and anti-C1q IgG4 was mainly detected in subepithelial membranous deposits. Anti-H3, anti-DNA, and anti-C1q IgG2 autoantibodies were also prevalent in LN serum, which also contained IgG3 against the antigen panel and anti-C1q IgG4. Serum and glomerular levels of autoantibodies were not strictly associated. High serum levels of all autoantibodies detected, including anti-α-enolase and antiannexin AI, identified LN versus SLE and RA. Anti-H3 and anti-α-enolase IgG2 levels had the most remarkable increase in LN serum and represented a discriminating feature of LN in principal component analysis. The highest levels of these two autoantibodies were also associated with proteinuria>3.5 g/24 hours and creatinine>1.2 mg/dl. Our findings suggest that timely autoantibody characterization might allow outcome prediction and targeted therapies for patients with nephritis.

[Role of vitamin D in the pathogenesis of chronic kidney disease]. / Ruolo della vitamina D nei pazienti con malattia renale cronica.

Chronic kidney disease (CKD) is a relevant health problem due to its worldwide increasing prevalence and the morbidity and mortality linked to its complications. Since the early stages of CKD, although patients are completely asymptomatic, important mineral homeostasis disorders occur. These disorders, involving serum levels of calcium, phosphorus, parathyroid hormone, and vitamin D, have a striking impact on patient prognosis as they affect the cardiovascular system. The new term of Chronic Kidney Disease-Mineral Bone Disease (CKD-MBD) was introduced to label bone disease during CKD as a systemic disorder tightly linked to cardiovascular calcifications and disabilities. Vitamin D deficiency has a main role in the pathogenesis of CKD-MBD, throughout the pleiotropic actions of this hormone. Vitamin D receptors (VDRs) are ubiquitous and their activation has shown protective effects against secondary hyperparathyroidism development and anti-hypertensive, anti-inflammatory, anti-fibrotic, immunomodulating, anti-proliferative, anti-diabetic and anti-proteinuric properties. These mechanisms explain, at least in part, vitamin D status influence in avoiding and delaying cardiovascular disease and CKD progression. These findings strongly support the importance of an early diagnosis of mineral homeostasis disorders in CKD and the need for correction of vitamin D deficiency to prevent related disabilities and major events.

The role of monocytes in ANCA-associated vasculitides.

The anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are a heterogeneous group of diseases causing inflammation in small blood vessels and linked by the presence of circulating ANCA specific for proteinase 3 (PR3) or myeloperoxidase (MPO). These antigens are present both in the cytoplasmic granules and on the surface of neutrophils, and the effect of ANCA on neutrophil biology has been extensively studied. In contrast, less attention has been paid to the role of monocytes in AAV. These cells contain PR3 and MPO in lysosomes and can also express them at the cell surface. Monocytes respond to ANCA by producing pro-inflammatory and chemotactic cytokines, reactive-oxygen-species and by up-regulating CD14. Moreover, soluble and cell surface markers of monocyte activation are raised in AAV patients, suggesting an activated phenotype that may persist even during disease remission. The presence of monocyte-derived macrophages and giant cells within damaged renal and vascular tissue in AAV also attests to their role in pathogenesis. In particular, their presence in the tertiary lymphoid organ-like granulomas of AAV patients may generate an environment predisposed to maintaining autoimmunity. Here we discuss the evidence for a pathogenic role of monocytes in AAV, their role in granuloma formation and tissue damage, and their potential to both direct and maintain autoimmunity. ANCA-activation of monocytes may therefore provide an explanation for the relapsing-remitting course of disease and its links with infections. Monocytes may thus represent a promising target for the treatment of this group of life-threatening diseases.

Congenital anomalies of superior vena cava and their implications in central venous catheterization.

Congenital anomalies of superior vena cava (SVC) are generally discovered incidentally during central venous catheter (CVC) insertion, pacemaker electrode placement, and cardiopulmonary bypass surgery. Persistent left SVC (PLSVC) is a rare (0.3%) anomaly in healthy subjects, usually asymptomatic, but when present and undiagnosed, it may be associated with difficulties and complications of CVC placement. In individuals with congenital heart anomalies, its prevalence may be up to 10 times higher than in the general population.In this perspective, awareness of the importance of the incidental finding of PLSV during CVC placement is crucial. To improve knowledge of this rare but potentially dangerous condition, we describe the embryological origin of SVC, its normal anatomy, and possible congenital anomalies of the venous system and of the heart, including the presence of a right to left cardiac shunt. Diagnosis of PLSVC as well as the clinical complications and technical impact of SVC congenital anomalies for CVC placement are emphasized.

Which cannulation technique for which patient.

Cannulation of arteriovenous (AV) access is a crucial part of vascular access management in hemodialysis patients. It can significantly affect survival of the AV access, and consequently, it probably influences patient survival. The best type of cannulation technique, rotating site versus constant site (or buttonhole), is currently debated, but the increase in infectious complications observed with the buttonhole technique suggests a prudent use of this technique, restricting it to specific patients. Even in cases with a specific indication, the balance between advantages of the constant site needling and the potentially severe consequences of access related systemic infection should be considered. Educational efforts in improving cannulation skills of dialysis staff are important for improving outcomes, as the proper use of the rotating site technique might still be the best approach to cannulation.

Dialysis central venous catheter types and performance.

The choice of both short-term (nontunneled) and long-term (tunneled) central venous catheters (CVCs) for hemodialysis is a difficult one, due to the large number of available catheters, with very different characteristics and cost.CVC-related complications (in particular infections, thrombosis and inefficient dialysis) can determine ominous consequences and death, with extremely elevated costs due to prolonged hospitalization and expensive procedures. Thus, the correct balance between cost and quality of CVC is required when deciding which kind of CVC should be adopted.In this regard, the design of CVCs has become a very active area of industrial and clinical research, with the ultimate goal of improving the long-term function of the catheter and of reducing complication rates, because even small improvements in the complication or reintervention rates have a positive impact on individual patient care and cost to society. In this article we review the general features of CVCs, including differences between tunneled and nontunneled CVCs, materials and their compatibility with lock solutions, the implications of straight versus precurved design in nontunneled CVCs, lumen and tip features with their clinical implications, catheter coatings and their effect on infection and thrombosis.