Innate immunity and chronic inflammation are involved in atherosclerosis and atherothrombosis, leading to target organ damage in essential hypertension (EH). However, the role of neutrophils in EH is still elusive. We investigated the association between angiotensin II (Ang II) and neutrophil extracellular traps (NETs) in pathogenesis of EH. Plasma samples, kidney biopsies, and surgical specimens of abdominal aortic aneurysms (AAAs) from patients with EH were used. Cell-based assays, NETs/human aortic endothelial cell cocultures, and in situ studies were performed. Increased plasma levels of NETs and tissue factor (TF) activity were detected in untreated, newly diagnosed patients with EH. Stimulation of control neutrophils with plasma from patients with untreated EH generated TF-enriched NETs promoting endothelial collagen production. Ang II induced NETosis in vitro via an ROS/peptidylarginine deiminase type 4 and autophagy-dependent pathway. Circulating NETs and thrombin generation levels were reduced substantially in patients with EH starting treatment with Ang II receptor blockers, whereas their plasma was unable to trigger procoagulant NETs. Moreover, TF-bearing NETotic neutrophils/remnants accumulated in sites of interstitial renal fibrosis and in the subendothelial layer of AAAs. These data reveal the important pathogenic role of an Ang II/ROS/NET/TF axis in EH, linking thromboinflammation with endothelial dysfunction and fibrosis.

Klotho is a transmembrane protein acting as a co-receptor for FGF-23 and thus exerts clinical actions on mineral metabolism. The association of secreted Klotho with outcomes in CKD patients is unclear. This study examined the relation between plasma Klotho and cardiovascular events in dialysis patients, accounting for common and CKD-MBD related risk factors, arterial stiffness and atherosclerotic burden. Seventy-nine chronic hemodialysis patients were observed for a median follow-up of 5.5 years. Klotho levels as well as carotid–femoral pulse wave velocity (cfPWV) and common carotid intima-media thickness (ccIMT) measurements were performed at baseline. The primary end-point was first occurrence of all-cause death, non-fatal myocardial infarction or non-fatal stroke. Secondary end-points were: (i) all-cause mortality; (ii) cardiovascular mortality; (iii) a combination of cardiovascular death, non-fatal MI, non-fatal stroke, resuscitation after cardiac arrest, coronary revascularization, heart failure hospitalization and atrial fibrillation. Cumulative freedom from the primary endpoint was 31% for the low-Klotho group (≤745 pg/ml) and 53% for the high-Klotho group (logrank p = 0.017); HR: 2.137, 95%CI 1.124–4.065. Cumulative survival was insignificantly lower (44% vs 56%, p = 0.107), but cumulative cardiovascular survival (63% vs 88%, p = 0.029) and cumulative freedom from the cardiovascular composite outcome (18% vs 45%, p = 0.009) were significantly lower in the low-Klotho group. In modelled Cox-regression analysis the association of low Klotho with the primary endpoint remained significant after stepwise adjustment for cFGF3, PTH, Ca x P product, established risk factors (age, dialysis vintage, diabetes, hypertension, smoking, history of cardiovascular disease) as well as cfPWV and ccIMT [Model 6: HR:2.759, 95%CI 1.223–6.224, p = 0.014]. Low Klotho is associated with cardiovascular events in hemodialysis patients, independently from factors associated with mineral-bone disease, common risk factors and intermediate outcomes, such as cfPWV and ccIMT.

Background Cardiovascular morbidity and mortality remains excessive in patients with chronic kidney disease. The association of vascular changes with regulators of extraosseous calcification in this patient population is still under investigation. The aim of the present study was to investigate the associations of the calcification inhibitor fetuin-A, and the anti-osteoclastic factor osteoprotegerin (OPG) with vascular pathology in chronic hemodialysis patients. Methods In this cross-sectional study including 81 stable chronic hemodialysis patients, we measured carotid-to-femoral pulse wave velocity (cfPWV) with applanation tonometry, reflecting arterial stiffness, and common carotid intima-media thickness (ccIMT), a surrogate of early atherosclerosis, as well as serum levels of fetuin-A and OPG. Co-morbidities, traditional cardiovascular risk factors, inflammatory markers and mineral-bone disease serology parameters were also recorded. Results cfPWV correlated inversely with fetuin-A (r=−0.355, p=0.001) and positively with OPG (r=0.584, p<0.001). In multilinear regression analysis including age, gender, diabetes, cardiovascular disease, hypertension, pulse pressure, LDL, logCRP, both fetuin-A and OPG were independently associated with cfPWV (p=0.024 and p=0.041 respectively). ccIMT was negatively associated with fetuin-A (r=−0.312, p=0.005) and positively with OPG (r=0.521, p<0.0001); however these associations lost statistical significance after adjustment for age. Conclusion In chronic hemodialysis patients both fetuin-A and OPG levels are independently associated with arterial stiffness but not with early atherosclerotic vascular changes.

Phosphatonin fibroblast growth factor-23 (FGF-23) is involved in phosphate (P) excretion and vitamin D metabolism. Recently, FGF-23 has been suggested to be responsible for the hypophosphatemia and inappropriately low calcitriol levels observed after renal transplantation. We performed a prospective study to investigate FGF-23 levels in patients with end-stage renal disease before and after renal transplantation and their probable association with markers of bone and mineral metabolism. Intact FGF-23 levels were determined before and at 3, 6, and 12 months posttransplantation in 18 renal transplant recipients. Intact parathyroid hormone (iPTH), calcium (Ca), P, 25(OH)VitD, and 1,25VitD levels were measured at the same time periods. Renal threshold phosphate concentration (/GFR) was also calculated at 3, 6, and 12 months posttransplantation. The results showed that FGF-23 levels decreased by 89% 3 months posttransplantation (346 146 versus 37 9 pg/mL, ) and remained stable throughout the study period. iPTH and P levels also decreased significantly after renal transplantation, while Ca and 1,25VitD increased. Pretransplantation FGF-23 was significantly correlated with P levels at 3 months posttransplantation (). In conclusion, FGF-23 levels decrease dramatically after successful renal transplantation. Pre-transplantation FGF-23 correlate with P levels 3 months posttransplantation.

Aims: Diagnosis of primary membranous nephropathy (PMN) is mainly based on immunofluorescence/immunohistochemistry findings. However, assessment of specific features on optical microscopy can help to estimate the severity of the disease, guide treatment and predict the response. The aim of this study was to identify, classify and grade the precise histological findings in PMN to predict renal function outcome and guide treatment.Methods and results: Histological parameters, including focal segmental sclerosis (FSGS), tubular atrophy (TA), interstitial fibrosis (IF) and vascular hyalinosis (VH), were re‐evaluated in 752 patients with PMN. Their predictive value was estimated separately, and also in a combination score (FSTIV) graded from 0 to 4. Finally, the impact of histology was assessed in the response to immunosuppressive treatment. Mean age of patients was 53.3 (15–85) years and most presented with nephrotic syndrome. FSGS was present in 32% and VH in 51% of the patients, while TA and IF were graded as stage ≥1 in 52% and 51.4%, respectively. The follow‐up period was 122.3 (112–376) months. FSGS, TA and IF and VH were associated with impaired renal function at diagnosis (P = 0.02, P < 0.0001, P = 0.001 and P = 0.02, respectively) and at the end of follow‐up (P = 0.004, P < 0.0001, P < 0.0001 and P = 0.04, respectively). In multiple regression and binary logistic analysis, the presence of FSGS and degree of TA were the most significant parameters predicting renal function outcome, defined either by eGFR (end), FSGS (r = 0.6, P < 0.0001) and TA (r = 0.6, P < 0.0001), or by the endpoint of >50% eGFR reduction, FSGS (P = 0.001) and TA (P = 0.02). Also, patients presented with FSGS, IF, VH and/or with FSTIV > 1 could benefit from immunosuppression, regardless of clinical presentation.Conclusions: The presence and degree of four histological indices, FSGS, VH, TA and IF, assessed separately or in combination, and FSTIV score not only predict renal function outcome after long‐term follow‐up, but can also help in the choice of appropriate treatment. Decisions concerning immunosuppressive treatment can be guided by pathology regardless of clinical findings.

The term cardiorenal syndrome refers to the interaction between the heart and the kidney in disease and encompasses five distinct types according to the initial site affected and the acute or chronic nature of the injury. Type 4, or chronic renocardiac syndrome, involves the features of chronic renal disease (CKD) leading to cardiovascular injury. There is sufficient epidemiologic evidence linking CKD with increased cardiovascular morbidity and mortality. The underlying pathophysiology goes beyond the highly prevalent traditional cardiovascular risk burden affecting renal patients. It involves CKD-related factors, which lead to cardiac and vascular pathology, mainly left ventricular hypertrophy, myocardial fibrosis, and vascular calcification. Risk management should consider both traditional and CKD-related factors, while therapeutic interventions, apart from appearing underutilized, still await further confirmation from large trials.