The role of the kallikrein-kinin and renin-angiotensin-aldosterone systems in the development of hypertension in glomerulonephritis

A total of 74 patients with various clinicomorphological variants of glomerulonephritis (GN) were examined. Only a high activity of the enzyme kinase-1 that destroys kinins and the kallikrein inhibitors alpha 1-antitrypsin, alpha 2-macroglobulin is a contribution of the kallikrein-kinin system made to the general antihypertensive "armoury" of the body, as shown by the study. The correlation between the kallikrein activity and the active renin/total renin ratio predetermines that kallikrein may participate in endogenous plasma renin activation in GN patients. In this case, the vasoconstrictive effect of renin may limit the antihypertensive action of kallikrein and kinins by a feedback mechanism.     

The usage of the laser induced fluorescence in laparoscopy

Optic biopsy (the laser-induced fluorescence) was applied in laparoscopic surgery in 14 patients with colonic malignancy. There were investigated 66 lymph nodes. Trustworthiness of the laser induced fluorescence was 80.7%.     

Novel management strategy for patients with suspected pulmonary embolism.

AIMS: A simple management strategy is required for patients with acute pulmonary embolism which allows a rapid and reliable diagnosis in order to start timely and appropriate treatment. METHODS AND RESULTS: Two hundred and four consecutive patients with suspected pulmonary embolism were managed according to a standardized protocol based on the clinical pretest probability and the initial haemodynamic presentation (shock index=heart rate divided by systolic blood pressure). Patients with a high pretest probability and a positive shock index (> or =1) (n=21) underwent urgent transthoracic echocardiography. Based on the presence or absence of right ventricular dysfunction, reperfusion treatment was initiated immediately. Patients with a negative shock index (<1) (n=183) underwent diagnostic evaluation including pretest probability, D-dimer, and spiral computed tomography (CT) as first-line tests. Echocardiography was performed only when a central pulmonary embolism was found in the spiral CT(n=33). According to our strategy, 98 patients met the diagnostic criteria of pulmonary embolism: 75 patients (all shock index <1) were treated with heparin alone, 16 (seven had a shock index > or =1) with thrombolysis, four (all shock index > or =1) with catheter fragmentation, and three (all shock index > or =1) with surgical embolectomy. The all-cause mortality rate at 30 days was 5%, and at 6 months 11%. Right ventricular dysfunction on baseline echocardiography was not associated with a higher mortality rate at 6 months (logrank 2.4, P=0.12). CONCLUSIONS: The novel management strategy for patients with suspected pulmonary embolism resulted in a rapid diagnosis and treatment with a low 30-day mortality. In patients with pulmonary embolism and a positive shock index, time-consuming imaging tests can be avoided to reduce the risk of sudden death and not to delay reperfusion therapy.     

Regulation of Na+ excretion and arterial blood pressure by purinergic signalling intrinsic to the distal nephron: consequences and mechanisms

Discretionary control of Na⁺ excretion is a key component of the regulation of arterial blood pressure in mammals. Sodium excretion is fine‐tuned in the aldosterone‐sensitive distal nephron by the activity of the epithelial Na⁺ channel (ENaC). Here, ENaC functions as a final effector of the renin–angiotensin–aldosterone system (RAAS) during negative feedback control of blood pressure. Mutations affecting ENaC activity and abnormal regulation of this channel affect blood pressure through pathological changes to Na⁺ excretion. Recent evidence demonstrates that powerful signalling pathways function in parallel with the RAAS to modulate ENaC activity and blood pressure. An inclusive paradigm is emerging with respect to regulation of blood pressure where ENaC serves as a critical point of convergence for several important signalling systems that affect renal Na⁺ excretion. A robust inhibitory purinergic signalling system intrinsic to the distal nephron dynamically regulates ENaC through paracrine ATP signalling via the metabotropic P2Y₂ purinergic receptor to properly match urinary Na⁺ excretion to dietary Na⁺ intake. This enables blood pressure to be maintained within a normal range despite broad changes in dietary Na⁺ consumption. Loss of purinergic inhibition of ENaC increases blood pressure by causing inappropriate Na⁺ excretion. In contrast, stimulation of the P2Y₂ receptor promotes natriuresis and a decrease in blood pressure. Such observations identify purinergic signalling in the distal nephron as possibly causative, when dysfunctional, for certain forms of elevated blood pressure, and as a possible therapeutic target for the treatment of elevated blood pressure particularly that associated with salt sensitivity.     

Intravenous immunoglobulin significantly reduces exposure of concomitantly administered anti‐C5 monoclonal antibody tesidolumab

Awareness of drug‐drug interactions is critical in organ transplant recipient management. However, biologic agents interfering with monoclonal antibodies is not widely considered. We report the effect of high‐dose intravenous immunoglobulin (IVIg) on safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the human anti‐C5 monoclonal antibody tesidolumab (LFG316) in end‐stage renal disease patients awaiting kidney transplant. In this single‐center, phase 1, open‐label, parallel‐group study, 8 patients were assigned to receive either single‐dose tesidolumab + IVIg or tesidolumab alone, with 56‐day follow‐up. Within‐group PK parameters were consistent. Mean tesidolumab exposure decreased 34%, clearance increased 63%, and half‐life decreased 41% comparing tesidolumab + IVIg to tesidolumab alone. IVIg influence on tesidolumab elimination was most evident in the first 3 weeks. Complete suppression of both total and alternative complement activities was maintained for 4 weeks in the tesidolumab alone group and for 2 weeks in the tesidolumab + IVIg group. Tesidolumab was well tolerated. IVIg infused before tesidolumab affected tesidolumab PK and PD, resulting in a shortened period of full complement activity inhibition. These findings suggest a clinically relevant impact of IVIg on monoclonal antibody clearance and indirectly hint at an IVIg mechanism of action in treating autoimmune diseases and allosensitization by accelerating pathogenic IgG antibody degradation. Trial registration number: NCT02878616.