Impacto de la inflamación y fibrosis en la función del injerto renal

A pesar de los grandes avances en el campo del trasplante renal (TR), los resultados a largo plazo aún no son óptimos. Varios estudios han demostrado que diversos factores como la inflamación precoz y/o la presencia de fibrosis intersticial (FI) están asociados a un peor pronóstico del injerto, pero todavía se trata de un tema controvertido. En este estudio analizamos el estado inflamatorio (Banff, macrófagos CD68+, fenotipos de macrófagos M1-M2) y la expresión génica de múltiples factores relacionados con la inflamación y FI (TGF-β1, metaloproteinasas, proteínas de matriz extracelular, entre otros) en injertos procedentes de donantes cadáver (DC) y los comparamos con un grupo control de donantes vivos (DV). Así mismo analizamos la potencial asociación de estos factores, ya desde antes de la implantación, con diversas variables clínicas y con la función renal a medio-largo plazo. Entre otros hallazgos, confirmamos que los órganos procedentes de DC presentan un mayor infiltrado intersticial de macrófagos CD68+ y describimos que tanto la expresión génica de varias proteínas pro-inflamatorias como pro-fibróticas se encuentran significativamente incrementadas en los DC incluso antes de la implantación. También observamos un aumento en la expresión génica de proteínas que promueven la infiltración leucocitaria, especialmente macrófagos, en el tejido (MCP-1, ICAM-1), así como de mediadores de inflamación como TNFα, IL1β. También se observó un aumento en la expresión génica de receptores de membrana de los macrófagos que les confiere el fenotipo inflamatorio (M1) así como el antinflamatorio (M2). En los DC también se observó un aumento significativo de los precursores y mediadores de FI. Es de destacar que muchos de estos parámetros (inflamatorios y pro-fibróticos) se asociaron a la función renal estimada (MDRD) en distintos tiempos de seguimiento. El análisis multivariante (regresión lineal múltiple) mostró que tanto la función retrasada del injerto como la expresión génica de TGF-β1 a los cuatro meses fueron predictores independientes de la función del injerto del último control (media 5.8 1.0 años). En conclusión, confirmamos la estrecha interconexión entre inflamación y fibrosis especialmente en el TR de DC, que ésta se inicia ya antes de la implantación y persiste post-TR y que estos factores muy precoces (potencialmente tratables) pueden determinar el pronóstico del injerto a largo plazo.Despite great achievements in the field of renal transplantation (RT), long-term results are still not optimal. Several studies have shown that various factors such as early inflammation and/or the presence of interstitial fibrosis (IF) are associated with a worse graft prognosis, but this issue is still controversial and far from being resolved. In this study, we analyzed the inflammatory state (Banff, CD68 + macrophages, M1-M2 phenotypes, among others) and the gene expression of multiple factors related to both inflammation and IF (TGF-β1, metalloproteinases, extracellular matrix proteins, among others) in grafts from cadaveric donors (CD) and they were compared with a control group from living donors (LD). We also analyzed the potential association of all these factors with several clinical variables with medium and/or long-term renal function. Among other findings, we confirm that organs from CD have a greater CD68+ macrophage infiltration and we describe that the expression of several proinflammatory and and profibrotic molecules is significantly increased in CD even before grafting. We also observed an increased gene expression of proteins related to graft leukocyte infiltration, mainly macrophages, such as MCP-1 or ICAM-1, as well as of inflammatory mediators such as TNFα or IL1β. We also observed an increased gene expression of macrophage membrane cell receptors related to their inflammatory (M1) or anti-inflammatory (M2) phenotype. Finally, we described a significant increase of IF precursors and mediators in CD. It is noteworthy that multiple parameters (both inflammatory and profibrotic) were associated with the estimated glomerular filtration rate (MDRD) at different times. Multiple regression analysis revealed that delayed renal function as well as graft TGF-β1 gene expression four months after RT were independent predictors of the last renal function control during follow-up (5.8 1.0 years). In conclusion, we confirm the existence of an especially close interconnection between inflammation and fibrosis, especially in the CD RT setting, starting before engraftment and progressing after RT, and that these very early (potentially treatable) factors may already devise its long-term graft prognosis

Impacto de la inflamación y fibrosis en la función del injerto renal

A pesar de los grandes avances en el campo del trasplante renal (TR), los resultados a largo plazo aún no son óptimos. Varios estudios han demostrado que diversos factores como la inflamación precoz y/o la presencia de fibrosis intersticial (FI) están asociados a un peor pronóstico del injerto, pero todavía se trata de un tema controvertido. En este estudio analizamos el estado inflamatorio (Banff, macrófagos CD68+, fenotipos de macrófagos M1-M2) y la expresión génica de múltiples factores relacionados con la inflamación y FI (TGF-β1, metaloproteinasas, proteínas de matriz extracelular, entre otros) en injertos procedentes de donantes cadáver (DC) y los comparamos con un grupo control de donantes vivos (DV). Así mismo analizamos la potencial asociación de estos factores, ya desde antes de la implantación, con diversas variables clínicas y con la función renal a medio-largo plazo. Entre otros hallazgos, confirmamos que los órganos procedentes de DC presentan un mayor infiltrado intersticial de macrófagos CD68+ y describimos que tanto la expresión génica de varias proteínas pro-inflamatorias como pro-fibróticas se encuentran significativamente incrementadas en los DC incluso antes de la implantación. También observamos un aumento en la expresión génica de proteínas que promueven la infiltración leucocitaria, especialmente macrófagos, en el tejido (MCP-1, ICAM-1), así como de mediadores de inflamación como TNFα, IL1β. También se observó un aumento en la expresión génica de receptores de membrana de los macrófagos que les confiere el fenotipo inflamatorio (M1) así como el antinflamatorio (M2). En los DC también se observó un aumento significativo de los precursores y mediadores de FI. Es de destacar que muchos de estos parámetros (inflamatorios y pro-fibróticos) se asociaron a la función renal estimada (MDRD) en distintos tiempos de seguimiento. El análisis multivariante (regresión lineal múltiple) mostró que tanto la función retrasada del injerto como la expresión génica de TGF-β1 a los cuatro meses fueron predictores independientes de la función del injerto del último control (media 5.8 1.0 años). En conclusión, confirmamos la estrecha interconexión entre inflamación y fibrosis especialmente en el TR de DC, que ésta se inicia ya antes de la implantación y persiste post-TR y que estos factores muy precoces (potencialmente tratables) pueden determinar el pronóstico del injerto a largo plazo.Despite great achievements in the field of renal transplantation (RT), long-term results are still not optimal. Several studies have shown that various factors such as early inflammation and/or the presence of interstitial fibrosis (IF) are associated with a worse graft prognosis, but this issue is still controversial and far from being resolved. In this study, we analyzed the inflammatory state (Banff, CD68 + macrophages, M1-M2 phenotypes, among others) and the gene expression of multiple factors related to both inflammation and IF (TGF-β1, metalloproteinases, extracellular matrix proteins, among others) in grafts from cadaveric donors (CD) and they were compared with a control group from living donors (LD). We also analyzed the potential association of all these factors with several clinical variables with medium and/or long-term renal function. Among other findings, we confirm that organs from CD have a greater CD68+ macrophage infiltration and we describe that the expression of several proinflammatory and and profibrotic molecules is significantly increased in CD even before grafting. We also observed an increased gene expression of proteins related to graft leukocyte infiltration, mainly macrophages, such as MCP-1 or ICAM-1, as well as of inflammatory mediators such as TNFα or IL1β. We also observed an increased gene expression of macrophage membrane cell receptors related to their inflammatory (M1) or anti-inflammatory (M2) phenotype. Finally, we described a significant increase of IF precursors and mediators in CD. It is noteworthy that multiple parameters (both inflammatory and profibrotic) were associated with the estimated glomerular filtration rate (MDRD) at different times. Multiple regression analysis revealed that delayed renal function as well as graft TGF-β1 gene expression four months after RT were independent predictors of the last renal function control during follow-up (5.8 1.0 years). In conclusion, we confirm the existence of an especially close interconnection between inflammation and fibrosis, especially in the CD RT setting, starting before engraftment and progressing after RT, and that these very early (potentially treatable) factors may already devise its long-term graft prognosis

The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy

International audienc

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

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