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Sequential administration of paricalcitol followed by IL-17 blockade for progressive refractory IgA nephropathy patients.

ABSTRACT: There is no established treatment for progressive IgA nephropathy refractory to steroids and immunosuppressant drugs (r-IgAN). Interleukin 17 (IL-17) blockade has garnered interest in immune-mediated diseases involving the gut-kidney axis. However, single IL-17A inhibition induced paradoxical effects in patients with Crohn's disease and some cases of de novo glomerulonephritis, possibly due to the complete Th1 cell response, along with the concomitant downregulation of regulatory T cells (Tregs). Seven r-IgAN patients were treated with at least six months of oral paricalcitol, followed by the addition of subcutaneous anti-IL-17A (secukinumab). After a mean follow-up of 28 months, proteinuria decreased by 71% (95% CI: 56-87), P < 0.001. One patient started dialysis, while the annual eGFR decline in the remaining patients [mean (95% CI)] was reduced by 4.9 mL/min/1.73 m² (95% CI: 0.1-9.7), P = 0.046. Circulating Th1, Th17, and Treg cells remained stable, but Th2 cells decreased, modifying the Th1/Th2 ratio. Intriguingly, accumulation of circulating Th17.1 cells was observed. This novel sequential therapy appears to optimize renal advantages in patients with r-IgAN and elicit alterations in potentially pathogenic T helper cells.

SUBMITTER: Uriol-Rivera MG

PROVIDER: S-EPMC10902332 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Sequential administration of paricalcitol followed by IL-17 blockade for progressive refractory IgA nephropathy patients.

Uriol-Rivera Miguel G MG Obrador-Mulet Aina A Juliá Maria Rosa MR Daza-Cajigal Vanessa V Delgado-Sanchez Olga O Garcia Alvarez Angel A Gomez-Lobon Ana A Carrillo-Garcia Paula P Saus-Sarrias Carlos C Gómez-Cobo Cristina C Ramis-Cabrer Daniel D Gasco Company Joan J Molina-Infante Javier J

Scientific reports 20240228 1

There is no established treatment for progressive IgA nephropathy refractory to steroids and immunosuppressant drugs (r-IgAN). Interleukin 17 (IL-17) blockade has garnered interest in immune-mediated diseases involving the gut-kidney axis. However, single IL-17A inhibition induced paradoxical effects in patients with Crohn's disease and some cases of de novo glomerulonephritis, possibly due to the complete Th1 cell response, along with the concomitant downregulation of regulatory T cells (Tregs) ...[more]

PMID: 38418932

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Project description:IntroductionRenin-angiotensin system (RAS) blockade using angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) is first-line therapy for IgA nephropathy (IgAN). There is a paucity of information on the predictors and magnitude of response to this treatment.MethodsIn a prospective study, treatment-naive patients with IgAN with urinary protein ≥ 1 g/d and estimated glomerular filtration rate (eGFR) ≥ 30 ml/min per 1.73 m2 received supportive treatment including ACEi (ramipril) or ARB (losartan) in patients intolerant to ACEi, and optimal blood pressure (BP) control to ≤130/80 mm Hg, with a follow-up of 6 months. The primary outcome was remission of proteinuria. Complete remission (CR) was defined as proteinuria < 0.5 g/d and partial remission (PR) as proteinuria < 1g/d with at least a 50% decline from the baseline with stable renal function (≤ 25% reduction in eGFR).ResultsA total of 96 patients were analyzed, with a mean age of 33.3 ± 10.2 years, baseline eGFR 74.0 ± 30.9 ml/min per 1.73 m2, and urinary protein 2.6 ± 1.2 g/d. In all, 71.9% patients received ≥ 75% of the maximum approved dose of ACEi/ARB. Remission was observed in 36.5% (CR, 6.3%) patients at 3 months and in 55.2% (CR, 31.3%) at 6 months. Patients who failed to achieve remission had lower baseline eGFR (P = 0.002) and serum albumin levels (P< 0.001), asymptomatic hyperuricemia (P < 0.001), and higher proteinuria (P = 0.076). E1 (P= 0.053) and T1/T2 (P = 0.009) lesions were more frequent on histology. The ACEi/ARB had to be discontinued in 17 (17.7%) patients. These patients were older (P= 0.085) with lower eGFR (P < 0.002) and serum albumin levels (P = 0.001) and more E1 (P = 0.012) and T1/T2 (P = 0.001) lesions on histology.ConclusionMeticulous supportive therapy with optimal use of ACEi/ARB achieved remission in half of IgAN patients in this study. Increasing the treatment duration to 6 months improved remission rates. Patients with severe clinical and histological disease were less likely to tolerate and respond to treatment with RAS blockade.

Project description:Purpose of the reviewImmunoglobulin A (IgA) nephropathy (IgAN) is the most common primary glomerular kidney disease. Children and adults are presumed to have the same disease and are treated similarly. However, there are differences between childhood IgAN and adult IgAN that may require unique treatment considerations, even after transition to adult nephrology services. A narrative review was conducted to compare childhood and adult IgAN and to describe the distinct characteristics of childhood IgAN. Reframing childhood IgAN can inform guideline recommendations unique to childhood IgAN, the development of targeted therapies, and clinical trial design.Sources of informationMedline and Embase were searched for reports on children and adults with IgAN published between January 2013 and December 2023 (updated May 2024). The search was not restricted by age group, outcomes reported, language, or study design. Randomized controlled trials (RCTs), observational studies, review articles, and nephrology conference abstracts were included. A total of 3104 reports were retrieved. Forty-seven reports (37 primary studies and 10 reviews) were included in the review. Two RCTs and 35 observational studies included a total of 45 085 participants (9223 children and 35 862 adults).MethodData were extracted for primary IgAN and not for IgA vasculitis-associated nephritis. Findings were described with no statistical comparisons due to variations in interventions and outcome definitions.Key findingsGross hematuria was the obvious clinical difference between childhood IgAN and adult (60-88% vs 15-20%). Nephrotic syndrome was more common in children, approaching up to 44%, while <18% of adults had nephrotic syndrome. Children were biopsied sooner (6 vs 15 months) and had more inflammatory kidney lesions (mesangial hypercellularity: 41-82% vs 38-64%; endocapillary hypercellularity: 39-58% vs 17-34%). Chronic kidney lesions were more prevalent in adults (segmental sclerosis: 62-77% vs 8-51%; interstitial fibrosis/tubular atrophy: 34-37% vs 1-18%). The use of immunosuppressive therapy was higher in children (46-84% vs 35-56%). Children were started on immunosuppressive therapy sooner than adults. Adults were more likely to be optimized with renin-angiotensin system inhibitors (87-94% vs 49-75%). Children had better kidney function than adults at diagnosis (estimated glomerular filtration rate of 90-128 vs 50-88 ml/min/1.73 m2), and children also had better kidney survival, with kidney failure of 3.1% vs 13.4% at 5 years. Children had more risk alleles for IgAN and higher levels of mannose-binding lectin than adults.LimitationsMost studies were retrospective and observational, with limited data on children and disease mechanisms. Data were not pooled for analysis because of important differences in definitions and measurements of baseline characteristics and outcomes. Data from countries with established urine screening programs were different compared to countries without urine screening programs. Some observed differences may be due to practice variation and delayed diagnosis in adults (lead-time bias). Well-designed prospective studies and standardized measures for kidney function assessment and outcomes can reduce heterogeneity and improve results from reviews.ConclusionInherent differences between childhood IgAN and adult IgAN may be due to distinct disease mechanisms. Approaching childhood IgAN as a separate condition could lead to the discovery of targeted therapies and improve management during childhood and after the transition to adult care.

Dataset Information

Sequential administration of paricalcitol followed by IL-17 blockade for progressive refractory IgA nephropathy patients.

Publications

Sequential administration of paricalcitol followed by IL-17 blockade for progressive refractory IgA nephropathy patients.

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