Immunoglobulin A nephropathy—novel insights in long-term outcomes and pathophysiology leading to international guideline modification and new emerging therapies

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis, with an estimated incidence of at least 2.5 per 10 000 adults per year. The long-term outcomes remain poor, particularly for patients with proteinuria greater than 0.44 g/g (approximately 500 mg/day) and an estimated glomerular filtration rate (eGFR) decline of more than 1 mL/min/1.73 m2. The recently revised KDIGO guidelines acknowledged the new cutoffs for high-risk patients and proposed lower proteinuria and eGFR-loss goals. New insights into pathophysiology and approval of proteinuria as a surrogate parameter led to a surge in IgAN treatment research. Supportive chronic kidney disease (CKD) care is still considered the basis for every IgAN, and therapies like renin-angiotensinsystem inhibitors (RASi) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) should be established for every patient. Systemic glucocorticoids are still considered first-line treatment for high-risk IgAN and are recommended in current guidelines. However, the prospective data in the TESTING and STOP-IgAN trials are conflicting and more recent retrospective data suggest poor efficacy of glucocorticoids in Caucasian patients. Other immunosuppressive therapies, like Mycophenolate Mofetil (MMF), do seem to lead to better outcomes in Chinese subjects, however, the current data do not support their use in other ethnicities. In conclusion, following the most recent pathophysiology insights, new emerging therapies like TRF-budesonide, ETA-receptor antagonists, B-cell modulation and depletion therapies, and complement inhibitors seem to be quickly replacing current treatment standards. One of the big challenges in the next years will be how to implement new emerging treatments, establishing induction and maintenance protocols, and developing new biomarkers and biopsy criteria to guide the use of novel medications.