Variations of plasma sodium levels (mmol/L) and plasma vasopressin levels (pg/ml) during the osmotic challenge in responders and non-responders.

<p>Measurements were performed 15 mins before (P0) and then 15 (P1), 45 (P2), 75 (P3), and 105 (P4) mins after the beginning of saline hypertonic infusion. During osmotic challenge, changes in plasma sodium levels did not differ between the two groups. Values are expressed as median with interquartile range.</p

Variations of heart rate (beats/min), mean arterial pressure (MAP) (mmHg) and systolic arterial pressure (SAP) (mmHg) during the osmotic challenge in responders and non-responders.

<p>During osmotic challenge, changes in heart rate, SAP, MAP, and plasma levels of BNP did not differ between the two groups Values are expressed as median with interquartile range.</p

Change in thirst (cm on VAS) during the osmotic challenge in responders and non-responders.

<p>Thirst was comparable between the two groups at baseline but was significantly greater in responders at end of test Values are expressed as median with interquartile range.</p

Urinary ammonium excretion rates after acute acid load in patients with a normal acid-base status, according to the urinary acidification defect.

<p>All urinary pH values measured within the 6 hours after the acid load are plotted against all the corresponding NH₄⁺ excretion rates (logarithmic value). Patients were classified in four subgroups according to the minimal pH value and to the maximal NH₄⁺ excretion rate obtained within this 6 hours: <b>idiopathic hypocitraturia (green):</b> min. urine pH < 5.3, max. NH₄⁺ ≥ 33 μEq/min.; <b>high U. pH, high U. NH</b>_<b>4</b> <b>(blue):</b> min. urine pH ≥ 5.3, max. NH₄⁺ ≥ 33 μEq/min.; <b>high U. pH, low U. NH</b>_<b>4</b> (<b>purpura):</b> min. urine pH ≥5.3, max. NH₄⁺ < 33 μEq/min.; <b>low U. pH, low U. NH</b>_<b>4</b> <b>(red):</b> min. urine pH < 5.3, max. NH₄⁺ < 33 μEq/min. The thick line represents the regression line and the thin lines the 95% confidence intervals of the idiopathic hypocitraturia group (reference group). The horizontal dotted line is the NH₄⁺ excretion rate cut-off set at 33 μEq/min. The vertical dotted line is the urinary pH cut-off set at 5.3.</p

Demographic and medical characteristics of the patients.

<p>Demographic and medical characteristics of the patients.</p

Biological characteristics of the 67 patients.

<p>Biological characteristics of the 67 patients.</p

Demographic and biological characteristics of the 56 patients with normal baseline plasma HCO₃^- undergoing the acute acid load test.

<p>Demographic and biological characteristics of the 56 patients with normal baseline plasma HCO₃^- undergoing the acute acid load test.</p

Study results flow chart.

<p>Subgroups classifications: <b>idiopathic hypocitraturia</b>: min. urine pH < 5.3, max. NH₄⁺ ≥ 33 μEq/min.; <b>high U. pH, high U. NH</b>_<b>4</b>: min. urine pH ≥ 5.3, max. NH₄⁺ ≥ 33 μmol/min.; <b>high U. pH, low U. NH</b>_<b>4</b>: min. urine pH ≥5.3, max. NH₄⁺ < 33 μEq/min.; <b>low U. pH, low U. NH</b>_<b>4</b>: min. urine pH < 5.3, max. NH₄⁺ < 33 μEq/min. AE1: chloride bicarbonate exchanger; AI: autoimmune disease; E161K: missense polymorphism (p.Glu161Lys) of the ATP6V1B1 gene; H+-ATPase: B1 and a4-subunits of the apical H+-ATPase, including missense polymorphism (p.Glu161Lys) of the <i>ATP6V1B1</i> gene; HCO3-: plasma bicarbonate; NH4Cl: ammonium chloride. AI diseases are allocated as follows: <b>"idiopathic hypocitraturia"</b>: spondyloarthritis (N = 1), rheumatic polyarthritis (N = 1); "<b>high U.pH, high U.NH4"</b>: Gougerot-Sjögren disease (N = 1), spondylarthritis (N = 1), primary biliary cirrhosis (N = 1); <b>"high U.pH, low U.NH</b>_<b>4</b>^<b>+</b><b>"</b>: Crohn’s disease (N = 1).</p

Urinary response to an acute acid load in patients with a normal acid-base status.

<p>A) Subdivision in 2 subgroups, according to the ability of the patients to decrease urinary pH below 5.3 (upper panel) or not (lower panel). B) Subdivision into four subgroups according the ability of the subjects to decrease urinary pH below 5.3 and to reach maximal urinary ammonium excretion (U.NH₄⁺) to 33 μEq/min. Green: idiopathic hypocitraturia defined to both appropriate adaptation of both pH and U.NH₄⁺). Blue: appropriate maximal urinary ammonium excretion in spite of insufficient urinary acidification (high U. pH, high U.NH₄⁺ group); Purpura: Inappropriate urinary acidification but appropriate U.NH₄⁺ (high U. pH, low U.NH₄⁺ group); Red: Appropriate urinary acidification and U.NH₄⁺ (low U. pH, low U.NH₄⁺ group). Points represent the median value, whiskers represent the interquartile range.</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