Targeted therapeutic options based on the pathogenesis of IgA nephropathy

ABSTRACT Immunoglobulin A nephropathy (IgAN) remains the leading cause of primary glomerular disease globally. The disease often results in progressive chronic kidney disease and eventual kidney failure, and has a poor prognosis, significantly increasing the global healthcare burden. The pathogenesis of IgAN is extremely intricate, involving the formation of circulating IgA immune complexes. These immune complexes have unique chemical and biological characteristics that facilitate their deposition in mesangial cells and the reactive accumulation of underglycosylated IgA1 in mesangial cells, ultimately leading to tissue damage in glomerular sclerosis and renal interstitial fibrosis. Although IgAN has been widely recognized as a separate disease entity, specific treatments for the disease have not been available until recently. Contemporary standard-of-care regimens remain centred on comprehensive supportive management, encompassing lifestyle modifications and targeted blockade of the renin–angiotensin–aldosterone system. In recent years, however, as further elucidating the molecular mechanisms underlying the pathogenesis of IgAN and acceptance of surrogate endpoints has accelerated the drug approval process, a number of novel investigational drug trials targeting IgAN have emerged. With the development of these drugs, we hope to achieve a comprehensive multipronged treatment strategy: on the one hand, to target the consequences of persistent nephron loss, and on the other hand, to suppress glomerular inflammation, antagonize pro-fibrotic signalling pathways within glomerular and tubulointerstitial compartments and curtail the synthesis of pathogenic IgA molecules. This review summarizes recent advances and updates in IgAN treatment strategies and highlights important findings that may provide hope for future research.