Effect of PD solutions on <i>P. aeruginosa</i> and CNS planktonic cells.

<p>Mean log CFU/mL after 24 h exposure to PD solutions was used for the generation of the heat map. The strains are indicated on the right (Pa, P. aeruginosa; Se, S. epidermidis, Scc, S. caprae/capitis; Sha, S. haemolyticus; Sho, S. hominis). Strains derived from catheters of patients with infection are indicated with an asterisk. Main strains clusters are identified as group 1 (G1) and group 2 (G2). The conventional and biocompatible (bicarbonate, bicarbonate/lactate, icodextrin) PD solutions are indicated on the bottom, as well as the growth controls: positive (C+, TSB culture medium) and negative (C-, saline). The initial inoculum concentration was of ~1 × 107 CFU/mL (7 log CFU/mL). Dendrograms across the top and left of the heat map show the relationship between PD solutions and strains, respectively. Distance values are depicted by the gradient colour ranging from green (lowest value) to red (highest value).</p

Clinic and epidemiologic characteristics of the study population.

<p>Clinic and epidemiologic characteristics of the study population.</p

Effect of PD solutions on <i>P. aeruginosa</i> and CNS biofilm cells (A) and biomass, cells and extracellular matrix (B).

<p>Mean log CFU/cm2 (A) and Abs570nm/cm2 (B) after 24 h exposure to PD solutions were used for the generation of the heat maps. The strains are indicated on the right (Pa, <i>P. aeruginosa</i>; Se, S. epidermidis, Scc, S. caprae/capitis; Sha, S. haemolyticus; Sho, S. hominis). Strains derived from catheters of patients with infection are indicated with an asterisk. Main strains clusters are identified as group 1 (G1) and group 2 (G2). The conventional and biocompatible (bicarbonate, bicarbonate/lactate, icodextrin) PD solutions are indicated on the bottom, as well as the growth controls: positive (C+, TSB culture medium) and negative (C-, saline). Dendrograms across the top and left of the heat map show the relationship between PD solutions and strains, respectively. Distance values are depicted by the gradient colour ranging from green (lowest value) to red (highest value).</p

PD catheters.

<p>Schematic diagram of the catheter segments including the silicone based segments: external <b>(a)</b> and intraperitoneal <b>(d)</b> and the cuffs: subcutaneous <b>(b)</b> and deep <b>(c)</b> (left). The different segments were cultured separately. Therefore, a Venn diagram (right) illustrates the possible relationships among them (external segment in red, subcutaneous cuff in yellow, deep cuff in blue and intraperitoneal segment in green) <b>(A)</b>. The representation of the distribution and overlap of positive segment cultures in catheters removed from patients with (left) and without infection (right) <b>(B)</b>. Values represent the number of catheters with a specific catheter colonization pattern. Four patients had growth on all catheter segments—with refractory and fungal (n = 3) and catheter-related peritonitis (n = 1); 2 patients had growth on the catheter subcutaneous and deep cuffs—with relapsing peritonitis (n = 1) and chronic catheter infection (n = 1); 3 patients had growth only on the catheter deep cuff—with relapsing peritonitis (n = 1) and chronic catheter infection (n = 2); 2 patients had growth on the catheter deep cuff and intraperitoneal segment—with chronic catheter infection; 3 patients had growth on the catheter subcutaneous and deep cuffs and intraperitoneal segment—with catheter-related peritonitis (n = 1), chronic catheter infection (n = 2). At the time of removal, ^§2 and *, 1 catheter did not present subcutaneous cuff.</p

Microbial yield on PD catheters external (A) and intraperitoneal (B) segments and subcutaneous (C) and deep (D) cuffs in patients with and without infection.

<p>Data is presented as colony-forming units (CFU)/segment with the corresponding microorganisms represented by specific symbols. dot, coagulase negative Staphylococci (including Staphylococcus epidermidis, S. haemolyticus, S. caprae/ capitis, S. hominis, S. auricularis); diamond filled, <i>Staphylococcus aureus</i>; square filled, Corynebacterium spp.; down-pointing triangle filled, Micrococcus luteus; up-pointing triangle filled, Enterococcus faecalis; hexagon filled, Streptococcus spp.; right-pointing triangle filled, Bacillus spp.; circle, Pseudomonas <i>aeruginosa</i>; square, Sphingomonas spp.; diamond, Alcaligenes faecalis; down-pointing triangle, Serratia marcescens; up-pointing triangle, Burkholderia sp.; left-pointing triangle, Stenotrophomonas maltophilia; right-pointing triangle, Escherichia coli; crossed out circle, Enterobacter aerogenes; star, Candida parapsilosis; asterisk, Candida glabrata; circle quartered, non-identified microorganism. Absence of microorganisms is represented by, vertical line. Polymicrobial cultures are identified with a half tick-up line. In the group “infection” the cause of removal is indicated as alpha, for refractory peritonitis; beta, for relapsing peritonitis; gamma, fungal peritonitis; delta, for catheter-related peritonitis and epsilon, for chronic catheter infections. The dashed line indicates the culture method detection limit.</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

Background Sparsentan, 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. Methods PROTECT, 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. Findings Between 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. Interpretation Over 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.</p