Sindrome Uremico-emolitica Atipica: Dalla Patogenesi alla Terapia

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TLR-4 and VEGF polymorphisms in chronic periaortitis

Chronic periaortitis (CP) is a rare disease that is characterised by fibro-inflammatory tissue surrounding the abdominal aorta and has both non-aneurysmal (idiopathic retroperitoneal fibrosis [IRF]) and aneurysmal forms (inflammatory abdominal aortic aneurysm [IAAA]). We investigated whether toll-like receptor 4 (TLR-4) and vascular endothelial growth factor (VEGF) polymorphisms were associated with susceptibility to, and the clinical features of CP

Carriage rate frequencies (%) of VEGF 936 C/T in patients with ^*IRF and ^**IAAA, and VEGF I/D in patients with/without ureteral obstruction, conservative treatment, and deep vein thrombosis^&.

*<p>Idiopathic retroperitoneal fibrosis (IRF);</p>**<p>inflammatory abdominal aortic aneurysms (IAAA);</p>&<p>Values are the number/total number examined (%).</p><p>OR = odds ratio; 95% CI = 95% confidence intervals.</p

Alleles, genotypes and carriage rates frequencies (%) of VEGF I/D, 936 C/T, 634 C/G in patients and control subjects^*.

*<p>Values are the number/total number examined (%).</p><p>OR = odds ratio; 95% CI = 95% confidence intervals.</p

Demographic and clinical characteristics of the 102 patients with chronic periaortitis^*^&.

*<p>Values indicate the percentage of patients unless otherwise indicated.</p>&<p>Some characteristics were not available for all 102 patients.</p>**<p>Atherosclerotic disease: the presence of coronary artery disease, cerebrovascular disease or peripheral arterial disease.</p>§<p>Fever, anorexia, and weight loss.</p><p>ANA = antinuclear antibodies; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein.</p

Serum VEGF levels in 17 patients with chronic periaortitis (CP) and 11 age- and gender-matched healthy controls (HC).

<p><b>VEGF tended to be higher in the CP group, but the difference was not statistically significant (p = 0.081).</b></p

Alleles, genotypes and carriage rate frequencies (%) of the Toll-like receptor (TLR) 4 polymorphism Asp299Gly in patients with chronic periaortitis and control subjects^*.

*<p>Values are the number/total number examined (%).</p><p>OR = odds ratio; 95% CI = 95% confidence interval.</p

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