Implementation of the N - terminal proB-type Natriuretic Peptide Test in National Guidelines for Diagnosis of Heart Failure in Croatia

Aim. In this article we aimed to analyze the implications of using new method of determination N - terminal proB - type natriuretic peptide (NT-proBNP) biomarker for rapid diagnosis in Emergency Room of acute heart failure and for prediction of adverse cardiovascular outcome. Methods. Electro-chemiluminescence immunoassay is sandwich principle test with two monoclonal NT-proBNP-specific antibodies. PreciControl Cardiac II level 1 and level 2 with values of 150 ng/L and 4930 ng/L were analyzed by Electro-chemiluminescence immunoassay on Roche Cobas e411, in triplicate for five consecutive days in purpose for calculating within laboratory precision, according to Clinical and Laboratory Standards Institute (CLSI) protocol. Results. According to CLSI protocol we calculated standard deviation and coefficient of variation for repeatability, intermediate precision and within laboratory precision from control results. Calculated coefficient of variation for the within laboratory precision for level 1 was 4,48% and for level 2 was 4,15%. Conclusion. Despite very good curative cardiology, Croatia is still among the countries with high cardiovascular risks and mortality. Through the mutual dialogue and activities between leaders of Croatian Cardiac Society, Croatian Society of Hypertension and Society of Family Physicians, the consensus for the development of the Croatian Guidelines for the Diagnosis of Heart Failure (HF) has been reached

Cognitive impairment prediction in patients with hypertension with Pulse Wave Velocity and arterial stiffness measurement

INTRODUCTION The blood supply of the brain gradually reduces with ongoing age, the cerebral cortex undergoes atrophy, causes cognitive inhibition converting to vascular dementia and Alzheimer’s in later stages. The relation between cognitive impairment (CI) and high blood pressure has been long studied in elderly patients, necessitating for further research and evidence on this topic. AIM To study the parameters of arterial stiffness (AS): central blood pressure (CBP), pulse wave velocity (PWV) in patients with hypertension and determine it’s relationship with vascular CI. METHODS AND MATERIALS A systematic literature review was performed using a standardised published methodology; 25 studies were selected from last 10 years from google search engine, Pubmed central and NCBI with keywords like AS, CBP, PWV, CI. RESULTS PWV was a significant and independently associated with cognitive function when measured with mini mental state examination in an elderly population in Japan. The relationship between high vascular stiffness and CI is explained as the disturbance in regulation of endothelial nitric oxide release. This in turn causes a neuronal energy crisis initiated by cerebral hypoperfusion due to impaired vascular tone and develops CI. As elderly population tend to have an increased risk for arteriosclerosis which is highly predicted by PWV, these patients are highly prone to develop vascular dementia and Alzheimer’s in future. CONCLUSION An inverse relation between AS and cognitive function was found and provided an evidence to vascular hypothesis of vascular dementia and Alzheimer’s. Prospective studies involving these early predictive markers PWV and AS may help in therapeutic intervention and progression of the disease

¿Son la velocidad de la onda del pulso y la rigidez arterial marcadores para evaluar la ateroesclerosis preclínica en pacientes con hipertensión resistente?

Introduction: Pulse wave velocity and arterial stiffness are considered a gold standard for evaluating target organ damage that has arisen subclinically. Endothelial dysfunction is directly proportional to the development of preclinical atherosclerosis. These surrogate markers mentioned above are relatively higher in patients with uncontrolled or resistant hypertension. The objective was to assess whether arterial stiffness and pulse wave velocity are also surrogate markers for the development of preclinical atherosclerosis in patients with resistant hypertension. Methods and materials: A total of 160 patients with resistant hypertension from Croatia and India were included in the study. Central blood pressure and other clinical values were evaluated using a non-invasive device. Results: The statistics of the group were made with gender perspective, the values of the systolic blood pressure (PA-S), the diastolic blood pressure (PA-D), the mean arterial pressure (MAP), the central systolic pressure (PC-S), central diastolic pressure (PC-D), central pulse pressure (cPP) and pulse wave velocity (VOP) have been described.The PA-S values in men / women were 147.26 ± 22.12 / 144.10 ± 21.29; PA-D values in men / women were 94.98 ± 13.36/88.57 ± 12.25 respectively. Conclusions: with the results obtained, it can be concluded that arterial stiffness is an independent marker that is directly proportional to endothelial dysfunction and the development of preclinical atherosclerosis.Introducción: La velocidad de la onda de pulso y la rigidez arterial se considera estándar de oro para evaluar daño a órganos diana que haya surgido subclinicamente. La disfunción endotelial es directamente proporcional al desarrollo de la aterosclerosis preclínica. Estos marcadores sustitutos mencionados anteriormente son relativamente más altos en pacientes con hipertensión no controlada o resistente. El objetivo fue evaluar si la rigidez arterial y la velocidad de la onda del pulso también son marcadores sustitutos del desarrollo de la aterosclerosis preclínica en pacientes con hipertensión resistente. Métodos y materiales: Se incluyeron en el estudio un total de 160 pacientes con hipertensión resistente de Croacia e India. La presión arterial central y otros valores clínicos se evaluaron utilizando un dispositivo no invasivo. Resultados: Las estadísticas del grupo se hicieron con perspectiva de género, los valores de la presión arterial sistólica (PA-S), la presión arterial diastólica (PA-D), la presión arterial media (PAM), la presión central sistólica (PC-S) ,la presión central diastólica ( PC-D), la presión de pulso central (cPP) y la velocidad de la onda de pulso (VOP) han sido descritas. Los valores de PA-S en hombres / mujeres fueron 147.26 ±22.12/ 144.10 ± 21.29; los valores de PA-D en hombres/mujeres fueron 94.98 ± 13.36 / 88.57 ± 12.25 respectivamente. Conclusiones: con los resultados obtenidos se puede concluir que la rigidez arterial es un marcador independiente que es directamente proporcional a la disfunción endotelial y al desarrollo de aterosclerosis preclínica

Prognostic significance of glomerular and tubulointerstitial morphometry in idiopathic membranous nephropathy

The purpose of our study was to investigate the prognostic value of clinical and pathological, in particular glomerular and tubulointerstitial morphometric variables in idiopathic membranous nephropathy (IMN). We prospectively followed 60 Caucasian patients diagnosed with idiopathic membranous nephropathy for at least 2 years or until primary outcome (≥50% permanent decrease in estimated glomerular filtration rate or death). Glomerular and tubulointerstitial morphometric variables at the time of renal biopsy were analyzed with respect to this outcome. Univariate analysis revealed that significant negative prognostic factors for this outcome were higher cholesterol and smaller albumin concentrations, higher creatinine and maximal 24-h proteinuria, higher grade of nephroangiosclerosis, higher glomerular basement membrane thickness and glomerulopathy index, higher interstitial fibrosis and tubular atrophy percentage and higher injury score. In multivariate analysis, only the maximal 24-h proteinuria and interstitial fibrosis and tubular atrophy percentage were independent predictors of this outcome. The results suggest that morphometric analysis, mainly quantitative measurement of interstitial fibrosis and tubular atrophy percentage, injury score, glomerular basement membrane thickness and glomerulopathy index could be used as an additional method for risk stratification of patients with idiopathic membranous nephropathy

Cysteamine-colon and cysteamine-duodenum lesions in rats. Attenuation by gastric pentadecapeptide BPC 157, cimetidine, ranitidine, atropine, omeprazole, sulphasalazine and methylprednisolone

Recently, we showed cysteamine-duodenal lesions without gastric acid, since they were induced also in gastrectomized rats, as in naive rats, and they were inhibited by the novel stomach pentadecapeptide BPC 157 as well as standard antiulcer drugs (i.e. cimetidine, ranitidine, omeprazole, bromocriptine, atropine). Therefore, as an advantage of considering cysteamine as a directly acting cytotoxic agent and mentioned agents as direct cytoprotective agents, the present focus was on the ulcerogenic effect of cysteamine and protective effect of gastroduodenal antiulcer agents outside upper gastrointestinal tract (i.e. in colon). Intrarectal administration of the cysteamine (200 or 400 mg/kg b.w) produced severe colon lesions (i.e. transmural inflammation with serosal involvement) in rats (30 min–72h-experimental period), apparently distinctive from smaller lesions after non-specific irritant enema [diluted HCl solution, pH 3.8 (adjusted to pH of cysteamine solution (pH 3.8)]. All of the tested antiulcer agents were applied simultaneously with cysteamine enema (8 cm from the anus, in a volume of the 1.0 ml/rat) intraperitoneally (i.p.), intragastrically (i.g.) or intrarectally (i.r.). Pentadecapeptide BPC 157 (10 mg or 10 ng/kg b.w.), given in either regimen, previously shown to have, besides others, a particular beneficial activity just in the intestinal mucosa, inhibited these cysteamine colon lesions (assessed after 30 min, 60 min, 180 min, 24 h, 48 h, 72 h following cysteamine in a dose of either 200 or 400 mg/kg i.r.). Cysteamine-colon lesions were also attenuated by standard antiulcer agents (mg/kg b.w.), given i.p., i.g., or i.r., such as ranitidine (10), cimetidine (50), omeprazole (10), atropine (10), together with methylprednisolone (1), and sulphasalazine (50, i.r.), assessed 30 min following application of 200 mg of cysteamine. Finally, standard cysteamine duodenal lesions (assessed 24 h after a subcutaneous application of 400 mg/kg of cysteamine) were also attenuated by these agents application (given in the same doses, i.p., 1 h before cysteamine), with only exception to sulphasalazine. Thus, the extended cysteamine specific ulcerogenic effect, cysteamine colon/duodenum lesion-link and an extenuation of agents protection from upper to lower part of gastrointestinal tract (i.e. stomach pentadecapeptide BPC 157, standard antiulcer agents, cimetidine, ranitidine, atropine, omeprazole) and vice versa (remedies for inflammatory bowel disease) evidenced in the present study may be potentially important for both further experimental and clinical research

Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

BackgroundSparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis.MethodsPROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850.FindingsBetween Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m2 per year versus −3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m2 per year versus −3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals.InterpretationOver 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics