Gustavo Andres Useche Bonilla

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: 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. FUNDING: Travere Therapeutics.

Background: Several studies highlight the relevance of convective transport versus diffusive transport in the elimination of substances of higher molecular weight with great advantages in the prevention of chronic complications. Convective techniques improve them substantially. Among them, on-line hemodiafiltration (HDF-OL) is the one that eliminates more medium and high molecular weight toxins, although high-flux hemodialysis with high permeability dialyzers comes close to the advantages offered by HDF-OL. The aim of the present study is to estimate whether there are differences in the different parameters between high-flux hemodialysis (HD-FH) and OL-HDF. Methods: Multicenter, retrospective, descriptive study, analyzing the evolution in one year in both techniques. Variables of interest: demographics, Charlson comorbidity index, Karnofsky index, analytical parameters (urea kinetics, nutrition, inflammation, bone-mineral metabolism, anemia, dyslipidemia), interdialysis weight gain, diabetes, arterial hypertension and hospitalization among others. Results: A total of 1674 in OL-HDF and 889 in HD-HF. No differences in: sex, diabetes, etiology of nephropathy, physical activity, smoking, months on dialysis, dry weight, interdialysis gain. There were statistically significant differences in favor of OL-HDF in: KtV, ß2-microglobulin, hemoglobin levels and PTH. In favor of HDF-HF-HDF: albumin and aluminum. The proportion of hospitalized patients was higher in the OL-HDF group (41%) compared to the high-flow HD group (37%) (p 0.044). Conclusion: These results highlight the complexity of choosing the optimal dialysis technique, which must be customized according to the patient's specific needs and clinical situation. Although OL-HDF offers advantages in the removal of larger toxins, which is crucial to prevent chronic complications, the observed hospitalization rate suggests the need for vigilance. Funding: Other NIH Support - Diaverum Renal Services, SL, Other U.S. Government Support

Background: Extended hemodialysis (HDx) combines diffusive and convective transport using cut-off membranes. Considering its potential as an alternative to online hemodiafiltration (OL-HDF), we conducted a comparative study between the two techniques. Methods: A retrospective analysis in 10 outpatient dialysis centers during 2024. Patients on HDx or OL-HDF for at least 360 days, with 90 recorded treatments, were included. Patients on incremental or palliative hemodialysis were excluded. Demographic, clinical, and laboratory variables (at baseline, 6 and 12 months), emergency hospitalizations, and annual consumption of dialysis medications (sodium heparin, erythropoiesis-stimulating agents [ESA], iron, paricalcitol, etecalcetide) were collected. The comparative analysis used Propensity Score Matching (PSM) and Inverse Probability of Treatment Weighting (IPTW) with Doubly Robust Estimation, using R (v4.4.3). The final cohort included 40 patients on HDx and 253 on OL-HDF. Results: After adjusting for age, gender, time on dialysis, diabetes, hypertension, vascular access, Charlson and Karnofsky indices, frequency and duration of sessions, and average annual blood flow (Qb), statistically significant differences were found: hemoglobin levels and transferrin saturation index (TSI) were higher in HDx, and serum potassium was lower. No differences were observed in albumin, β2-microglobulin, or the risk of urgent hospitalization. Regarding medication use, HDx showed significantly lower use of iron sucrose and etecalcetide and higher use of sodium heparin. The trend toward lower use of AEE and paricalcitol in HDx did not reach statistical significance Conclusion: Although differences in hemoglobin, IST, and potassium were identified, these are not considered clinically relevant. In our experience, HDx and HDF-OL showed comparable efficacy in median solute clearance and analytical parameters with no differences in urgent hospitalization events. HDx may offer additional advantages, such as reduced consumption of certain drugs and potential water savings compared to HDF-OL.