RESistance of IgA Nephropathy to Conventional and Newly-approved Therapies: an Observational, Real-life Study (RESIGAN)

IgA Nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally, diagnosed by detecting mesangial IgA deposits in the kidneys, often accompanied by IgG and C3. The disease's pathophysiology remains unclear despite its commonality. Prognosis can vary widely, from benign hematuria to rapidly progressive forms leading to end-stage renal disease within months. The MEST-C classification provides histological prognostic factors that enhance prognosis assessment and facilitate the development of integrated scoring systems. However, these scores are limited in predicting treatment responses and lack validation for IgA vasculitis nephritis.

Given the disease's heterogeneity, treatment strategies for IgAN are contentious. Nephroprotective approaches focusing on reducing intraglomerular pressure through RAS blockade play a significant role in management. Steroids are suggested for rapidly progressive disease, but their effectiveness in persistent proteinuria, despite optimized nephroprotection, is debated. Other treatments, including B cell-targeting therapies and complement inhibition, are under investigation. Recent advances in nephroprotection, such as SGLT2 inhibitors and endothelin-1 receptor antagonists, could significantly reshape future therapeutic strategies. While these treatments are widely available in Europe, their real-world effectiveness remains to be evaluated. Identifying factors linked to persistent proteinuria and renal dysfunction despite optimized strategies is a pressing unmet need.

This study hypothesizes that new nephroprotective strategies will influence the risk of persistent proteinuria and renal dysfunction in a real-life cohort of IgAN patients.

Primary Objective: To identify clinical, biological, and histological risk factors for persistent proteinuria and renal dysfunction in IgAN patients.

Secondary Objectives include:

Identifying risk factors for steroid therapy response. Evaluating responses to nephroprotective therapies, including SGLT2 inhibition. Analyzing responses to immunosuppressive therapies at various time points post-diagnosis.

Assessing risk factors for persistent proteinuria and renal dysfunction in patients with related conditions or IgA vasculitis.

Identifying risk factors for adverse events following nephroprotection or immunosuppressive therapies.

Describing treatment trajectories since IgAN diagnosis. Validating the International IgA Nephropathy prediction tool. Developing a cohort of IgAN patients will facilitate reliable epidemiological data collection and allow for the evaluation of responses to contemporary treatments, identifying patients with treatment resistance in real-life scenarios. This identification is critical for establishing early, efficient therapeutic strategies for IgAN patients at risk of progression.

Study Design: A prospective and retrospective observational cohort study.

Inclusion Criteria:

Adult patients aged ≥ 18 years. Renal biopsy after 2017 confirming IgA deposits for IgAN diagnosis (index date).

Informed consent from patients who do not object to data use. Non-inclusion Criteria: None.

Cohort Details:

Retrospective Cohort: Expected 600 patients, inclusion from 01/01/2017 to study start date.

Prospective Cohort: 200 participants over 2 years, followed for 2 years, totaling 4 years of research.

For retrospective data collection, information notes will be mailed to patients, allowing data use after one month without opposition. Prospective patients will receive study information during clinic visits, with data used if there is no objection. Data will be extracted from medical records, including clinical, histological, and laboratory results, collected by clinical research assistants or investigators. Patient Health Information (PHI) will be stored securely, with only month and year of birth recorded for privacy.

Analysis: For primary outcomes, univariable analysis will utilize logistic regression to explore the association of risk factors with outcomes. A multivariable model may be developed based on expert knowledge and univariable results. The model's performance will be assessed via the area under the curve (AUC) and R², with bootstrap validation to evaluate for overfitting.

Total Research Duration: 4 years, with a recruitment period of 2 years and a follow-up period of 2 years. The retrospective data will cover at least 2 years post-IgAN diagnosis, potentially extending up to 12 years based on the biopsy date (from 2017).

• Proportion of patients with persistent proteinuria (>1 g/g) and/or renal dysfunction (>20% eGFR decline) at 6 months from diagnosis [Time frame: month 6 from diagnosis]
• Proportion of patients with persistent proteinuria (>1 g/g) and/or renal dysfunction (>20% eGFR decline) at twenty-four months from diagnosis. [Time frame: month 24 from diagnosis]
• Proportion of patients with persistent proteinuria (>1 g/g) and/or renal dysfunction (>20% eGFR decline) at the end of follow-up. [Time frame: At the end of follow-up, that is at least 2 years from inclusion]
• Proportion of patients experiencing a Major Adverse Renal Event (MARE) by month 12, defined as the initiation of dialysis, receipt of a kidney transplant, or onset of renal failure [Time frame: month 12 from diagnosis]
• Proportion of patients experiencing a Major Adverse Renal Event (MARE) by month 6, defined as the initiation of dialysis, receipt of a kidney transplant, or onset of renal failure [Time frame: month 6 from diagnosis]
• Proportion of patients with absence of response to steroids therapy defined as persistent proteinuria or renal dysfunction at the end of steroids treatment [Time frame: At the end of steroids treatment, that is on average at 6 months from inclusion]
• Proportion of patients with severe hyperkalemia (>6mM/l) evaluated at each visit [Time frame: Baseline, Month 3, Month 6, Month 12, Month 24, and then each year until the end of follow-up]
• Proportion of patients with severe acute renal failure (KDIGO stage 3) at each visit until the end of follow-up [Time frame: Baseline, Month 3, Month 6, Month 12, Month 24, and then each year until the end of follow-up]
• Proportion of patients with 50% decline in eGFR or end-stage kidney disease at any time during follow-up [Time frame: Baseline, Month 3, Month 6, Month 12, Month 24, and then each year until the end of follow-up]