Rosanna Coppo

Background: KDIGO and IPNA guidelines indicate a target of proteinuria 90 days (CSR). Aim of the study was to investigate clinical and histological factors associated with CSR and the value on long-term eGFR decline. Results: The study enrolled 709 children with different ethnicities (White, Chinese, and Japanese). The median age at biopsy was 12.9 years, eGFR 95.7 ml/min/1.73 m2 and proteinuria 1.2 g/day/1.73 m2. MEST-C scoring detected M1 in 57% of the cases, E1 in 41.3%, S1 in 53.3%, T1-2 in 13.6% and C1-2 in 46.7%. CSR occurred in 395 children (55.7%) after time-averaged observation of 0.7 years (0.4–1.3 years) and was maintained throughout follow-up in 47.3% of the cases. In a sensitivity analysis, children who achieved CSR had significant protection from eGFR decline at 4 and 5-years (P = 0.026 and P = 0.004, respectively). During follow-up, 74.4% were treated with renin-angiotensin system blockers (RASB) and 67.4% with immunosuppressors (IS). In a Cox proportional multivariate model including time-dependent RASB and IS treatment, a significant association with CSR was detected for younger age (P = 0.009), higher eGFR (P = 0.002), absence of segmental sclerosis (P < 0.001) and RASB treatment (P < 0.001). The model including ethnicity showed a strong effect of Japanese and Chinese ethnicity (both P < 0.001) and a significant association of CSR with age, absence of S1 (P < 0.001) and T1-2 (P = 0.016) and RASB and IS treatment (both P < 0.01). Conclusions: The observational study showed that the achievement of CSR in children with IgAN was associated with better eGFR outcome.

Immunoglobulin A nephropathy (IgAN) is an immune-mediated disease of B-cell origin and the most common primary glomerulonephritis worldwide, which often progresses to kidney failure within 10–20 years of diagnosis. Microscopic hematuria is frequently observed in IgAN; it is thought to result from damage to the glomerular filtration barrier caused by pathogenic immune complex deposits, allowing red blood cells to leak into the urinary space. Emerging evidence suggests that microscopic hematuria in IgAN may be linked to active glomerular inflammation, poorer disease prognosis and progressive kidney function decline. Despite this, it remains an underutilized biomarker for IgAN because of a lack of standardization (which can lead to preanalytical errors), challenging logistical considerations in large multicenter trials and non-glomerular hematuria as a confounding factor. The “proteinuria-centric” approach by the nephrology community may overlook that active forms of glomerulonephritis manifest with both proteinuria and hematuria, in contrast to primary podocytopathies where proteinuria is the main feature. When properly assessed, microscopic hematuria is a prognostically relevant biomarker in IgAN that may improve risk stratification and assessment of therapeutic response when evaluated alongside traditional biomarkers. This review evaluates the methods of assessment, pathophysiology and clinical utility of microscopic hematuria in IgAN.

IgA nephropathy (IgAN) is a leading cause of kidney failure with diverse clinical presentations and treatment responses, particularly to corticosteroids, with conflicting evidence. Due to potentially severe side effects and heterogenous responses more individualized approaches are needed. We developed a causal machine learning framework for predicting individualized treatment effects of corticosteroids in IgAN by integrating clinical variables, histopathological scores, and deep learning-based biomarkers from digitized kidney biopsies (pathomics) of 1,022 patients from eight retrospective international cohorts. At the cohort-level, corticosteroids showed no significant effect on five-year kidney survival. However, the framework identified subpopulations with and without significant treatment benefit, improving progression-free kidney survival and also reducing overtreatment in low-benefit patients. Pathomics highlighted tubulointerstitial inflammation and glomerular tuft deformation as predictors of corticosteroid response. Our framework offers a blueprint for precision therapy in IgAN, supporting clinical decision-making in the era of emerging targeted treatments.

IgA nephropathy (IgAN) is an inflammatory glomerular disease caused by the production of galactose-deficient IgA1 (Gd-IgA1), which induces the formation of autoantibodies and IgA immune complexes (IgAICs) that are ultimately deposited in the mesangium. This event triggers mesangial cell proliferation, cytokine release and complement activation, and both glomerular and interstitial damage, eventually leading to kidney function decline. Persisting proteinuria is the most relevant marker of disease progression. Systemic corticosteroids (CSs), a powerful anti-inflammatory approach, have shown kidney protective effects in early trials involving patients with IgAN at risk of progression with persistent proteinuria. However, later studies raised concerns regarding severe adverse events associated with high doses of methylprednisolone and questioned the long-term benefits. As a result, the KDIGO 2021 guidelines recommended limiting CS therapy to selected patients who accepted the high risk of adverse events. The treatment landscape shifted when reduced doses of methylprednisolone, combined with Pneumocystis pneumonia prophylaxis, demonstrated similar kidney protection compared to full methylprednisolone doses with fewer adverse events. An innovative approach involves a targeted budesonide formulation acting on Peyer’s patches, the main site of Gd-IgA1 production. This treatment showed benefits comparable to systemic CSs, with valuable limitations of adverse events. Several new drugs targeting key pathogenetic events of IgAN are under investigation, with promising results published in recent months. These new therapies target B cell activation (and subsequent Gd-IgA1 production), the complement cascade triggered by IgAIC deposition and the endothelin system, a key amplifier of kidney damage that contributes to the chronicity of IgAN.

IgA nephropathy (IgAN) is an inflammatory glomerular disease due to production of galactose-deficient IgA1 (Gd-IgA1) which induces formation of autoantibodies and IgA immune complexes (IgAIC) finally deposited in the mesangium. This event triggers mesangial cell proliferation, cytokine release and complement activation, glomerular and interstitial damage leading to kidney function decline. Persisting proteinuria is the most relevant marker of disease progression. The powerful anti-inflammatory approach with systemic corticosteroids (CS) in patients with IgAN at risk of progression with persistent proteinuria provided kidney function protection in early trials. However, subsequent studies raised alarm on severe adverse events associated with high doses of methylprednisolone doses or reported limited long-term benefits. This led to KDIGO 2021 guidelines conclusion to limit CS to selected patients who accepted the high risk of adverse events. The scenario changed when reduced doses of methylprednisolone associated with Pneumocystis prophylaxis reported benefits on kidney function like methylprednisolone full doses and limited adverse events. Finally, an innovative approach to steroid therapy in IgAN was offered by a budesonide formulation targeting the Peyer’s patches, major site of production of Gd-IgA1. The benefits were like those obtained with systemic CS administration, with valuable limitations of adverse events. A series of new drugs targeting the pathogenetic events of IgAN are under investigation and exciting reports have been published over the last months. The new targets include B cell activation with production of Gd-IgA1, the complement cascade triggered by deposited IgAIC and the endothelin system, a multipotential kidney damage amplifier system perpetuating chronicity of IgAN.

IgA nephropathy in children has a potential progression risk over decades of adult life. For this reason, pediatric nephrologists tend to treat the disease from the onset, aiming at halting the pathogenetic processes, based on expert opinion and general confidence with steroids for the lack of large pediatric controlled studies. Glucocorticosteroids are widely used, although without full comprehension of the fine molecular effects on IgAN, mostly based on trials performed in adults. In this review, a critical analysis of adult data is provided for extrapolating information useful for children, with a parallel evaluation of the results of the TESTING Trial, employing oral methylprednisolone, and of the NEFIgArd Trial, using enteric release budesonide. Patients’ characteristics and the scheme of the two studies are surprisingly similar: Nefecon and methylprednisolone showed 40–50% proteinuria reduction from baseline, with a fast effect of methylprednisolone (3–6 months) and a similar effect on renal function decline. Large genome-wide studies, above-risk alleles, also discovered risk loci targetable by multiple drugs particularly those involved in the modulation of the mucosal immunity priming of B-cells toward the production of galactose deficient IgA1 (Gd-IgA1). The new KDIGO 2024 guidelines under public review in recent months will lower the proteinuria threshold for treatment to 0.5 mg/mg and consider the value of Nefecon in reducing the levels of Gd-IgAI1. The choice between old and new corticosteroids in treating children with IgAN is approaching. In the near future, the genetic data, complemented by blood and urine biomarkers, could be included in tools to guide therapeutic choices and monitoring. Graphical Abstract