Targeting APRIL in the treatment of glomerular diseases.

A proliferation-inducing ligand (APRIL) is a key member of the tumor necrosis factor superfamily of cytokines and plays a central role in B-cell survival, proliferation, and Ig class switching. Recently, there has been increasing interest in the role of APRIL and the related cytokine B-cell activating factor in several glomerular diseases, because of their importance in the above processes. The therapeutic inhibition of APRIL represents a potentially attractive immunomodulatory approach that may abrogate deleterious host immune responses in autoimmune diseases while leaving other important functions of humoral immunity intact, such as memory B-cell function and responses to vaccination, in contrast to B-cell-depleting strategies. In this review, we describe the physiological roles of APRIL in B-cell development and their relevance to glomerular diseases, and outline emerging clinical trial data studying APRIL inhibition, with a focus on IgA nephropathy where the clinical development of APRIL inhibitors is in its most advanced stage.

Focal Segmental Glomerulosclerosis Patient Baseline Characteristics in the Sparsentan Phase 3 DUPLEX Study.

Introduction: The phase 3 DUPLEX trial is evaluating sparsentan, a novel, nonimmunosuppressive, single-molecule dual endothelin angiotensin receptor antagonist, in patients with focal segmental glomerulosclerosis (FSGS). Methods: DUPLEX (NCT03493685) is a global, multicenter, randomized, double-blind, parallel-group, active-controlled study evaluating the efficacy and safety of sparsentan 800 mg once daily versus irbesartan 300 mg once daily in patients aged 8 to 75 years (USA/UK) and 18 to 75 years (ex-USA/UK) weighing ≥20 kg with biopsy-proven FSGS or documented genetic mutation in a podocyte protein associated with FSGS, and urine protein-to-creatinine ratio (UP/C) ≥1.5 g/g. Baseline characteristics blinded to treatment allocation are reported descriptively. Results: The primary analysis population includes 371 patients (336 adult, 35 pediatric [<18 years]) who were randomized and received study drug (median age, 42 years). Patients were White (73.0%), Asian (13.2%), Black/African American (6.7%), or Other race (7.0%); and from North America (38.8%), Europe (36.1%), South America (12.7%), or Asia Pacific (12.4%). Baseline median UP/C was 3.0 g/g; 42.6% in nephrotic-range (UP/C >3.5 g/g [adults]; >2.0 g/g [pediatrics]). Patients were evenly distributed across estimated glomerular filtration rate (eGFR) categories corresponding to chronic kidney disease (CKD) stages 1 to 3b. Thirty-three patients (9.4% of 352 evaluable samples) had pathogenic or likely pathogenic (P/LP) variants of genes essential to podocyte structural integrity and function, 27 (7.7%) had P/LP collagen gene (COL4A3/4/5) variants, and 14 (4.0%) had high-risk APOL1 genotypes. Conclusions: Patient enrollment in DUPLEX, the largest interventional study in FSGS to date, will enable important characterization of the treatment effect of sparsentan in a geographically broad and clinically diverse FSGS population.

Points of view in nephrology: personalized management of IgA nephropathy, beyond KDIGO.

IgA nephropathy is the most common primary glomerulonephritis worldwide, and an important cause of kidney failure, as 20-40% of patients progress to renal replacement therapy 20-30 years after diagnosis. Its clinical presentation ranges from isolated microscopic hematuria to nephrotic syndrome, and even to a rapidly progressive course. Ethnicity and epigenetics play a key role in its clinical aggressiveness. Selection of patients at risk needing immunosuppressive treatment is a challenge for the nephrologist. Some active and chronic kidney lesions detected on kidney biopsy have been demonstrated to have prognostic value according to the Oxford Classification of IgA nephropathy, later validated by numerous studies. However, KDIGO 2021 guidelines still consider persistent proteinuria > 1 g/24 h to be the most relevant risk factor for the progression of IgA nephropathy and the only one requiring immunosuppressive treatment. KDIGO guidelines have proposed a therapeutic algorithm, but many patients present peculiar characteristics that are not addressed by the current guidelines, pointing to the need for alternative approaches. In these cases, a tailored approach to each patient should be followed in which clinical, histological, laboratory, social and ethical aspects must be considered. In this manuscript we present three cases of IgA nephropathy from different countries, highlighting many of the aspects encountered in clinical practice that illustrate an individualized approach to the treatment of these patients.

Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy.

Targeting the alternative complement pathway is an attractive therapeutic strategy given its role in the pathogenesis of immunoglobulin A nephropathy (IgAN). Iptacopan (LNP023) is an oral, proximal alternative complement inhibitor that specifically binds to Factor B. Our randomized, double-blind, parallel-group adaptive Phase 2 study (NCT03373461) enrolled patients with biopsy-confirmed IgAN (within previous three years) with estimated glomerular filtration rates of 30 mL/min/1.73 m2 and over and urine protein 0.75 g/24 hours and over on stable doses of renin angiotensin system inhibitors. Patients were randomized to four iptacopan doses (10, 50, 100, or 200 mg bid) or placebo for either a three-month (Part 1; 46 patients) or a six-month (Part 2; 66 patients) treatment period. The primary analysis evaluated the dose-response relationship of iptacopan versus placebo on 24-hour urine protein-to-creatinine ratio (UPCR) at three months. Other efficacy, safety and biomarker parameters were assessed. Baseline characteristics were generally well-balanced across treatment arms. There was a statistically significant dose-response effect, with 23% reduction in UPCR achieved with iptacopan 200 mg bid (80% confidence interval 8-34%) at three months. UPCR decreased further through six months in iptacopan 100 and 200 mg arms (from a mean of 1.3 g/g at baseline to 0.8 g/g at six months in the 200 mg arm). A sustained reduction in complement biomarker levels including plasma Bb, serum Wieslab, and urinary C5b-9 was observed. Iptacopan was well-tolerated, with no reports of deaths, treatment-related serious adverse events or bacterial infections, and led to strong inhibition of alternative complement pathway activity and persistent proteinuria reduction in patients with IgAN. Thus, our findings support further evaluation of iptacopan in the ongoing Phase 3 trial (APPLAUSE-IgAN; NCT04578834).

Clinical Practice Patterns in IgA Nephropathy: A Global Questionnaire-Based Survey.

Introduction: IgA nephropathy (IgAN) displays ethnic differences in disease phenotype. We aimed to examine how this common disease is managed worldwide. Methods: An online 2-step questionnaire-based survey was conducted among nephrologists globally focusing on various management strategies used in IgAN. Results: A total of 422 nephrologists responded to the initial survey and 339 to the follow-up survey. Of the nephrologists, 13.7% do not get MEST-C scores in biopsy reports; 97.2% of nephrologists use renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting-enzyme inhibitors (ACEi) / angiotensin receptor blockers (ARB) as initial treatment. Other supportive treatments commonly employed are fish oil (43.6%) and sodium-glucose co-transporter-2 (SGLT2) inhibitors (48.6%) with regional differences. Immunosuppression is generally (92.4%) initiated when proteinuria >1 g/d persists for ≥3 months.Main considerations for initiating immunosuppression are level of proteinuria (87.9%), estimated glomerular filtration rate (eGFR) decline (78.7%), lack of response to RAAS blockade (57.6%) and MEST-C score (64.9%). Corticosteroids (89.1%) are universally used as first-line immunosuppression; mycophenolate mofetil is commonly used in resistant patients (49.3%). Only 30.4% nephrologist enroll patients with persistent proteinuria >1 g/d in clinical trials. Nephrologists in Europe (63.6%), North America (56.5%), and Australia (63.6%) are more likely to do so compared to South America (31.3%) and Asia (17.2%). Only 8.1% nephrologists in lower-middle income countries (LMICs) enroll patients in clinical trials, though 40% of them are aware of such trials in their nations. Conclusion: Although most nephrologists agree on common parameters to assess clinical severity of IgAN, use of RAAS blockade, and blood pressure control, there is heterogeneity in use of other supportive therapies and initiation of immunosuppression. There is reluctance to enroll patients in clinical trials with novel treatments, principally in LMICs.

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. FUNDING: Travere Therapeutics.

Consenso de expertos sobre recomendaciones basadas en evidencia para el diagnóstico, tratamiento y seguimiento de enfermedad de Fabry en pediatría / Expert Consensus on Evidence-Based Recommendations for the Diagnosis, Treatment, and Follow-Up of Fabry Disease in Pediatric Patients / Consenso de especialistas colombianos sobre recomendações baseadas em evidências para o diagnóstico, tratamento e acompanhamento da doença de Fabry em pediatria

Antecedentes: la enfermedad de Fabry (Ef) es una enfermedad rara ligada a X secundaria al depósito lisosomal de glicoesfingolípidos, debido a la deficiencia de la enzima alfa galactosidasa A (α-Gal A). A pesar de su baja frecuencia, es una condición que afecta la calidad de vida de los pacientes y disminuye su esperanza de vida. Objetivo: generar recomendaciones informadas para el diagnóstico y tratamiento de pacientes pediátricos (menores de 18 años) con Ef. Material y Métodos: revisión de literatura en bases de datos y literatura gris a partir de 2010, incluyendo guías de práctica clínica, revisiones sistemáticas y estudios primarios. La calidad de evidencia se evaluó de acuerdo con el tipo. Las recomendaciones se sometieron a consenso de expertos a través de metodología Delphi modificada. El acuerdo se definió a partir del 80 %. Resultados: A partir del análisis de la evidencia recolectada se formularon un total de 45 recomendaciones para tamización, diagnóstico y tratamiento de paciente pediátrico con Ef. El panel revisor estuvo conformado por once expertos en el tema. Las recomendaciones fueron aprobadas con puntuaciones entre 82.3 % y 100 %. Conclusiones: las recomendaciones resultantes del consenso de expertos permitirán la toma de decisiones clínicas y estandarización de la práctica en la atención de pacientes pediátricos con Ef en el país y la región. El diagnóstico temprano y oportuno garantiza una disminución del impacto en la calidad de vida de los pacientes y sus familiares

Background: Fabry disease (fD) is a rare X-linked disease characterized by the accumulation of glyco- sphingolipids in lysosomes due to the deficiency in the production of alpha-galactosidase A (α-Gal A) enzyme. Despite its low frequency, this disease has a serious impact on the life expectancy and quality. Objective: To make evidence-based recommendations for the diagnosis and treatment of fD in pediatric patients (<18 years of age). Materials and Methods: A study of databases and gray literature was conducted in 2010, including clinical practice guidelines, systematic reviews, and primary research. The type of evidence was used to determine the quality of evidence. The recommendations were submitted to an expert consensus using the modified Delphi process. The agreement was set at 80%. Conclusions: The recommendations emerging from this expert consensus will enable the standardization of care provision for pediatric patients with fD in Colombia and Latin America and clinical decision-making for disease management. Notably, making an early diagnosis ensures a reduction in the impact of this disease on the quality of life of patients and their families

Fundamento: a doença de Fabry (Df) é uma rara doença ligada ao cromossomo X secundária à deposi- ção lisossômica de glicoesfingolipídeos devido à deficiência da enzima alfa galactosidase A (α-Gal A). Apesar de sua baixa frequência, é uma condição que afeta a qualidade de vida dos pacientes e diminui sua expectativa de vida. Objetivo: gerar recomendações baseadas em evidências para o diagnóstico e tratamento de pacientes pediátricos (com menos de 8 anos de idade) com Df. Materais e Métodos: foi realizada uma revisão da literatura em bases de dados e literatura cinza a partir de 2010, incluindo diretrizes de prática clínica, revisões sistemáticas e estudos primários. A qualidade da evidência foi avaliada de acordo com o tipo de evidência. As recomendações foram submetidas ao consenso de especialistas usando a metodologia Delphi modificada. A concordância foi definida a partir de 80%. Resultados: com base na análise das evidências coletadas, foram formuladas um total de 45 recomendações para triagem, diagnóstico e tratamento de pacientes pediátricos com doença de Fabry. O painel de revisão foi composto por onze especialistas no assunto. As recomendações foram aprovadas com pontuações entre 82,3% e 100%. Conclusões: as recomendações resultantes do consenso de especialistas permitirão a tomada de decisão clínica e a padronização da prática no cuidado de pacientes pediátricos com Df em nível nacional e regional; o diagnóstico precoce e oportuno garante a redução do impacto na qualidade de vida dos pacientes e seus familiares.

Human parietal epithelial cells (PECs) and proteinuria in lupus nephritis: a role for ClC-5, megalin, and cubilin?

BACKGROUND: Parietal epithelial cells are a heterogeneous population of cells located on Bowman's capsule. These cells are known to internalize albumin with a still undetermined mechanism, although albumin has been shown to induce phenotypic changes in parietal epithelial cells. Proximal tubular cells are the main actors in albumin handling via the macromolecular complex composed by ClC-5, megalin, and cubilin. This study investigated the role of ClC-5, megalin, and cubilin in the parietal epithelial cells of kidney biopsies from proteinuric lupus nephritis patients and control subjects and identified phenotypical changes occurring in the pathological milieu. METHODS: Immunohistochemistry and immunofluorescence analyses for ClC-5, megalin, cubilin, ANXA3, podocalyxin, CD24, CD44, HSA, and LTA marker were performed on 23 kidney biopsies from patients with Lupus Nephritis and 9 control biopsies (obtained from nephrectomies for renal cancer). RESULTS: Two sub-populations of hypertrophic parietal epithelial cells ANXA3+/Podocalyxin-/CD44-, both expressing ClC-5, megalin, and cubilin and located at the tubular pole, were identified and characterized: the first one, CD24+/HSA-/LTA- had characteristics of human adult parietal epithelial multipotent progenitors, the second one, CD24-/LTA+/HSA+ committed to become phenotypically proximal tubular cells. The number of glomeruli presenting hypertrophic parietal epithelial cells positive for ClC-5, megalin, and cubilin were significantly higher in lupus nephritis patients than in controls. CONCLUSIONS: Our results may provide further insight into the role of hypertrophic parietal epithelial cells located at the tubular pole and their possible involvement in protein endocytosis in lupus nephritis patients. These data also suggest that the presence of hypertrophic parietal epithelial cells in Bowman's capsule represents a potential resource for responding to protein overload observed in other glomerulonephritis.

Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy.

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

Targeting the Alternative Complement Pathway With Iptacopan to Treat IgA Nephropathy: Design and Rationale of the APPLAUSE-IgAN Study.

Introduction: Targeting the alternative complement pathway (AP) is an attractive therapeutic strategy because of its role in immunoglobulin A nephropathy (IgAN) pathophysiology. Iptacopan (LNP023), a proximal complement inhibitor that specifically binds to factor B and inhibits the AP, reduced proteinuria and attenuated AP activation in a Phase 2 study of patients with IgAN, thereby supporting the rationale for its evaluation in a Phase 3 study. Methods: APPLAUSE-IgAN (NCT04578834) is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 3 study enrolling approximately 450 adult patients (aged ≥18 years) with biopsy-confirmed primary IgAN at high risk of progression to kidney failure despite optimal supportive treatment. Eligible patients receiving stable and maximally tolerated doses of angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) will be randomized 1:1 to either iptacopan 200 mg or placebo twice daily for a 24-month treatment period. A prespecified interim analysis (IA) will be performed when approximately 250 patients from the main study population complete the 9-month visit. The primary objective is to demonstrate superiority of iptacopan over placebo in reducing 24-hour urine protein-to-creatinine ratio (UPCR) at the IA and demonstrate the superiority of iptacopan over placebo in slowing the rate of estimated glomerular filtration rate (eGFR) decline (total eGFR slope) estimated over 24 months at study completion. The effect of iptacopan on patient-reported outcomes, safety, and tolerability will be evaluated as secondary outcomes. Conclusions: APPLAUSE-IgAN will evaluate the benefits and safety of iptacopan, a novel targeted therapy for IgAN, in reducing complement-mediated kidney damage and thus slowing or preventing disease progression.

IgA Nephropathy Patient Baseline Characteristics in the Sparsentan PROTECT Study.

Introduction: Sparsentan is a novel single-molecule dual endothelin angiotensin receptor antagonist with hemodynamic and anti-inflammatory properties and is not an immunosuppressant. The ongoing phase 3 PROTECT trial examines sparsentan in adults with IgA nephropathy (IgAN). Methods: The PROTECT trial (NCT03762850) is a multicenter, international, randomized, double-blind, parallel-group, active-controlled study. The efficacy and safety of sparsentan versus the active control irbesartan is being evaluated in adults with biopsy-proven IgAN and proteinuria ≥1.0 g/d despite maximized treatment with an angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin receptor blocker (ARB) for at least 12 weeks. Blinded and aggregated baseline characteristics are reported descriptively and compared to contemporary phase 3 trials with patients with IgAN. Results: The primary analysis population includes 404 patients who were randomized and received study drug (median age, 46 years). Enrolled patients were from Europe (53%), Asia Pacific (27%), and North America (20%). Baseline median urinary protein excretion was 1.8 g/d. The range of estimated glomerular filtration rate (eGFR) was broad with the largest proportion of patients (35%) in chronic kidney disease (CKD) stage 3B. Before transitioning to study medication, mean systolic/diastolic blood pressure was 129/82 mm Hg, with the majority of patients (63.4%) receiving the maximum labeled ACEi or ARB dose. Patients in Asian versus non-Asian regions included a higher percentage of females, had lower blood pressures, and included lower proportions of patients with a history of hypertension and baseline antihypertensive treatment. Conclusions: Patient enrollment in PROTECT, with differing racial backgrounds and across CKD stages, will allow for important characterization of the treatment effect of sparsentan in patients with IgAN with proteinuria at high risk of kidney failure.

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 <60 mL/min per 1·73 m2 and ≥60 mL/min per 1·73 m2) and urine protein excretion at screening (≤1·75 g/day and >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.

Safety and effectiveness of COVID-19 SPUTNIK V vaccine in dialysis patients / Seguridad y efectividad de vacuna COVID-19 SPUTNIK V en pacientes en diálisis

Abstract Introduction: Given the vulnerability of chronic kidney disease individuals to SARS-CoV-2, nephrology societies have issued statements calling for prioritization of these patients for vaccination. It is not yet known whether COVID-19 vaccines grant the same high level of protection in patients with kidney disease compared to the non-dialysis population. The aims of this study were to evaluate the safety - measured by the adverse events potentially attributed to vaccines (ESAVI) - and the effectiveness - evaluated by the presence of antibodies - in dialysis patients immunized with the COVID-19 Sputnik V vaccine. Methods: multicenter, ob servational and analytical study of a prospective cohort of hemodialysis patients from the Ciudad Autónoma de Buenos Aires participating in an official vaccination program. Dialysis requiring individuals older than 18 years, who received both components of the COVID-19 vaccine were included. Results: Data from 491 patients were included in the safety analysis. ESAVI with either the first or second component was detected in 186 (37.9%, 95% CI 33.6%-42.3%). Effectiveness analysis measuring antibodies levels against SARS-CoV-2 were performed in 102 patients; 98% presented these IgG antibodies at day 21 after the second component. In patients with COVID-19 prior to vaccination, antibodies at day 21 after the first component reached almost the highest levels compared to patients without previous COVID-19, but IgG rise among patients with previous COVID-19 was lower than in those without this previous disease. Conclusion: The Sputnik V vaccine has been shown to be safe and effective in this patient's population.

Resumen Introducción: Dada la vulnerabilidad al SARS-CoV-2 de las personas con enfermedad renal crónica, las sociedades de nefrología han emitido declaraciones pidiendo priorizar a estos pacientes para la vacunación. Aún no se sabe si las vacunas COVID-19 confieren el mismo nivel de protección en pacientes con enfermedad renal. Los objetivos de este estudio fueron evaluar la seguridad, medida por eventos supuestamente atribuidos a las vacunas (ESAVI) y la efectividad, evaluada por la presencia de anticuerpos en pacientes en diálisis inmuniza dos con la vacuna COVID-19 Sputnik V. Métodos: estudio multicéntrico, observacional y analítico de una cohorte prospectiva de pacientes en hemodiálisis, en la Ciudad Autónoma de Buenos Aires, con plan de vacunación. Se incluyeron pacientes mayores de 18 años en diálisis que recibieron ambos componentes de la vacuna COVID-19. Resultados: 491 pacientes fueron incluidos en el análisis de seguridad. Se detectó ESAVI con el primer o el segundo componente en 186 (37.9% IC 95%: 33.6%-42.3%). La efectividad medida por presencia de anticuerpos IgG contra SARS-Cov-2 se realizó en 102 pacientes, 98% presentaba IgG contra SARS-CoV-2, 21 días después del segundo componente. En pacientes con COVID-19 previo a la vacunación, los anticuerpos al día 21 del primer componente alcanzaron niveles casi mayores que en aquellos que no habían sufrido COVID-19, aunque el aumento de los niveles a los 21 días del segundo componente fue menor que en los pacientes sin COVID-19 previo. Conclusión: Los pacientes en diálisis constituyen una población vulnerable para la infección por SARS-CoV-2, por lo tanto, más allá de las recomendaciones implementadas por las unidades de diálisis, la vacunación completa es mandatoria. Se ha demostrado que la vacuna Sputnik V es segura y eficaz en esta población de pacientes.

Corticosteroids and mycophenolic acid analogues in immunoglobulin A nephropathy with progressive decline in kidney function.

Background: A randomized controlled trial demonstrated a beneficial effect of corticosteroids (CS) + cyclophosphamide followed by azathioprine in progressive immunoglobulin A nephropathy (IgAN). Although treatment with CS and mycophenolic acid analogues (MPAAs) remains controversial in IgAN, there is no information about their effects in progressive IgAN. Methods: Patients with progressive IgAN, defined by a decrease in estimated glomerular filtration rate (eGFR) of at least 10 mL/min/1.73 m2 in the 12 months prior to the start of treatment, proteinuria ≥0.75 g/24 h despite maximum tolerated doses of renin-angiotensin system blockers, and persistent haematuria who had received treatment with CS + MPAA were included in this retrospective study. The main outcome was the difference between the eGFR slope from the start of treatment with CS + MPAA to the last visit with this treatment with respect to the eGFR slope during the 12 months prior to the start of treatment. Results: A total of 25 patients were included in the study. The mean duration of CS + MPAA treatment was 24.7 ± 15.2 months. In the 12 months prior to treatment the median rate of kidney function decline was 23 mL/min/1.73 m2/year [interquartile range (IQR) -32 to -16]. After the onset of treatment, the median eGFR slope was 5 mL/min/1.73 m2/year (IQR 3-9; P = 0.001 with respect to the 12 months prior to treatment). Proteinuria decreased from 1.8 g/day (IQR 1.0-2.5) at baseline to 0.6 g/day (IQR 0.3-1.2) at the end of treatment (P = 0.01) and haematuria disappeared in 40% of patients. There were no serious adverse effects requiring treatment discontinuation. Conclusions: CS + MPAA is an effective treatment in IgAN patients with a sustained decline in kidney function accompanied by persistent proteinuria and haematuria despite optimized conservative treatment. Prospective studies are needed to confirm these results.

Downregulation of megalin, cubilin, ClC-5 and podocin in Fabry nephropathy: potential implications in the decreased effectiveness of enzyme replacement therapy.

Fabry disease is an X-linked disorder due to mutations in α-galactosidase A, resulting in the accumulation of enzyme substrates and cell malfunction. Kidney involvement is frequent, affecting all native kidney cell types. Podocyte damage results in proteinuria and chronic kidney disease. End-stage kidney disease is the rule in middle-aged males and some females with the classic phenotype. In podocytes and kidney proximal tubular cells, megalin is one of the molecules involved in enzyme replacement therapy (ERT) cellular absorption. After podocyte damage, podocin concentration is decreased and contributes to progressive proteinuria. We report in a male and a female patient the decreased expression of megalin, cubilin, ClC-5 and podocin compared to controls and chronic kidney disease (CKD) biopsies. Moreover, the decrease in ClC-5, a molecule engaged in endosomal-lysosomal acidification, could also affect ERT. These findings may partially explain some of the dysfunctions described in Fabry nephropathy and could highlight possible alterations in the pharmacokinetics of the delivered enzyme.

External Validation of International Risk-Prediction Models of IgA Nephropathy in an Asian-Caucasian Cohort.

INTRODUCTION: Two prediction models for IgA nephropathy (IgAN) using clinical variables and the Oxford MEST scores were developed and validated in 2 multiethnic cohorts. Additional external validation is required. METHODS: Biopsy-proven Chinese and Argentinian patients with IgAN were included. The primary outcome was defined as a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage renal disease. C-statistics and stratified analyses were used for model discrimination, coefficient of determination (R2 D) for model fit, and calibration plots for model calibration. Baseline survival function was also evaluated. RESULTS: A total of 1275 patients were enrolled, with a mean age of 34 (interquartile range: 27-42) years, 50% of whom (638 of 1275) were men. Use of renin-angiotensin system blockers was higher than in previously reported cohorts, whereas other variables were comparable. The C-statistic of the models was 0.81, and R2 D was higher than reported. Survival curves in the subgroups (<16th, ∼16th to <50th, ∼50th to <84th, and ≥84th percentiles of linear predictor) were well separated. Most of the predictor variables, including hazard ratio, predicted 5-year risk, and eGFR decline slope, were worse with risk increasing. The baseline survival function was comparable in our cohort and the reported cohorts. The calibration was acceptable for the full model without race. However, the risk probability over 3 years was overestimated in the full model with race included. CONCLUSION: The prediction models showed good performance on personalized risk assessment, which may be used as drug-specific, precision-medicine approaches to treatment decisionmaking.

Des-resucitación en la sobrecarga de fluidos asociada a la lesión renal aguda / Des-resuscitation in the overload of fluids associated with acute kidney injury

Los resultados generales del tratamiento de la lesión renal aguda en los últimos años han mejorado casi de manera constante, aunque sin una comprensión completa de su fisiopatología. La respuesta a este interrogante radicaría en la comprensión del rol proactivo en lo que hace a la administración / remoción de los fluidos, abarcando todo el proceso de reanimación de los pacientes críticos, es decir no limitándose a la administración sino también al momento oportuno de la remoción de los mismos, buscando como principal objetivo mejorar la perfusión tisular. Se discute entre otros el papel clave que ejerce la integridad vascular en la sobrecarga de fluidos, haciendo hincapié en el papel del glicocálix endotelial. Las maniobras de des-resucitación activa con diuréticos o con terapias de soporte renal, podrían ser instrumentos cada vez más reconocidos en la aplicación de la sobrecarga de fluidos, en particular en aquellos pacientes con lesión renal aguda.

In the last few years the general results in the treatment of acute kidney injury has improved constantly, without a complete comprehension of its pathophysiology. With this paradigm in mind, in these last few years we have seen an evolving comprehension of the possible answers that may be based on recognizing the more proactive role of fluid management in the resuscitation of critical patients, not limited only to the delivery of fluids, but also to their active removal, having as the principal objective the improvement of tissue perfusion. The key role of vascular integrity in fluid overload is discussed, emphasizing the role of the endothelial glycocalyx. Active des-resuscitation maneuvers with diuretics or with renal support therapies could be increasingly recognized instruments in the management of fluid overload, particularly in those patients with acute kidney injury.

Clinical parameters, LysoGb3, podocyturia, and kidney biopsy in children with Fabry disease: is a correlation possible?

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase enzyme deficiency. We present clinical, biochemical, and histologic findings in children with classical phenotypic presentation of Fabry disease. METHODS: A retrospective analysis was performed using charts from 14 children with confirmed diagnosis. Clinical parameters were evaluated. Globotriaosylsphingosine -lysoGb3- detection in plasma, podocyturia, and kidney biopsy were carried out in all cases. RESULTS: All patients except one demonstrated at least one symptom of Fabry disease. LysoGb3 levels were above the normal range in all patients. Podocyturia was documented in all patients. Kidney biopsy revealed glomerular, interstitial, vascular, and tubular changes on light microscopy in nearly all patients. Electron microscopy showed podocyte inclusions in all patients. CONCLUSIONS: No difference in symptomatology was discernible between boys and girls. Podocyturia was detectable in children serving as a possible early marker of kidney injury. LysoGb3 was elevated in all cases, emphasizing the importance for diagnosis especially in female patients with normal αGal A activity. A possible association between lysoGb3 and symptom severity and histological involvement in kidney biopsy should be assessed in prospective studies with enough statistical power to determine if lysoGb3 can be used to predict nephropathy in children with Fabry disease.

Podocyturia: Potential applications and current limitations.

Chronic kidney disease is a prevalent condition that affects millions of people worldwide and is a major risk factor of cardiovascular morbidity and mortality. The main diseases that lead to chronic kidney disease are frequent entities as diabetes mellitus, hypertension and glomerulopathies. One of the clinical markers of kidney disease progression is proteinuria. Moreover, the histological hallmark of kidney disease is sclerosis, located both in the glomerular and in the interstitial compartments. Glomerulosclerosis underscores an irreversible lesion that is clinically accompanied by proteinuria. In this regard, proteinuria and glomerular sclerosis are linked by the cell that has been conserved phylogenetically not only to prevent the loss of proteins in the urine, but also to maintain the health of the glomerular filtration barrier: The podocyte. It can then be concluded that the link between proteinuria, kidney disease progression and chronic kidney disease is mainly related to the podocyte. What is this situation due to? The podocyte is unable to proliferate under normal conditions, and a complex molecular machinery exists to avoid its detachment and eventual loss. When the loss of podocytes in the urine, or podocyturia, is taking place and its glomerular absolute number decreased, glomerulosclerosis is the predominant histological feature in a kidney biopsy. Therefore, tissular podocyte shortage is the cause of proteinuria and chronic kidney disease. In this regard, podocyturia has been demonstrated to precede proteinuria, showing that the clinical management of proteinuria cannot be considered an early intervention. The identification of urinary podocytes could be an additional tool to be considered by nephrologists to assess the activity of glomerulopathies, for follow-up purposes and also to unravel the pathophysiology of podocyte detachment in order to tailor the therapy of glomerular diseases more appropriately.

In IgA Nephropathy, Glomerulosclerosis Is Associated with Increased Urinary CD80 Excretion and Urokinase-Type Plasminogen Activator Receptor-Positive Podocyturia.

BACKGROUND: Podocyturia may determine the evolution to podocytopenia, glomerulosclerosis, and renal failure. According to the Oxford classification of IgA nephropathy (IgAN), the S1 lesion describes glomerulosclerosis. Urokinase-type plasminogen activator receptor (uPAR) participates in podocyte attachment, while CD80 increases in glomerulosclerosis. We measured uPAR-positive urinary podocytes and urinary CD80 (uCD80) in controls and in IgAN subjects with M1E0S0T0 and M1E0S1T0 Oxford scores to assess a potential association between podocyturia, inflammation, and glomerulosclerosis. METHODS: The groups were as follows: controls (G1), n = 20 and IgAN group (G2), n = 39, subdivided into M1E0S0T0 (G2A), n = 21 and M1E0S1T0 (G2B), n = 18. Among the included variables, we determined uPAR-positive podocytes/gram of urinary creatinine (gUrCr) and uCD80 ng/gUrCr. Biopsies with interstitial fibrosis and tubular atrophy <10% were included. RESULTS: Groups were not different in age and gender; urinary protein-creatinine (uP/C) ratio, Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation, uPAR-positive podocytes/gUrCr, and uCD80 were significantly increased in G2 versus G1. G2A and G2B were not different in age, gender, hypertension, and follow-up. G2B displayed significantly higher uP/C, uPAR-positive podocytes, uCD80, and lower CKD-EPI versus G2A. Strong significant correlations were encountered between uCD80 and podocyturia in G2A and G2B. However, when G1 was compared to G2A and G2B separately, the differences with respect to uP/C, uPAR-positive podocytes, and podocyturia were significantly stronger versus G2B than versus G2A. CONCLUSIONS: IgAN presents elevated uCD80 excretion and uPAR-positive podocyturia, while CD80 correlates with podocyturia. Glomerulosclerosis (S1) at the time of biopsy is associated with higher uP/C, lower renal function, increased uPAR-positive podocyturia, and CD80 excretion, and is independent of M1. In IgAN, uPAR may participate in podocyte detachment.