A Personalized Update on IgA Nephropathy: A New Vision and New Future Challenges

Abstract

IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world among patients undergoing renal biopsy. Approximately 30% of patients with IgAN develop end-stage kidney disease 20 years after renal biopsy. It is a glomerulopathy with a very broad clinical presentation, making it difficult to stratify and treat. IgAN is characterized by dysregulation of the immune system, which causes an abnormal synthesis of IgA1 that is deglycosylated causing its mesangial deposition. IgAN pathogenesis is incompletely understood; the current multi-hit hypothesis of IgAN pathogenesis does not explain the range of glomerular inflammation and renal injury associated with mesangial IgA deposition. Although associations between IgAN and glomerular and circulating markers of complement activation are established, the mechanism of complement activation and contribution to glomerular inflammation and injury are not defined. On the other hand, the renal-gut connection can also play an important role in the pathogenesis of IgAN with possible therapeutic implications. In order to standardize the histological findings, the Oxford Classification has allowed clarifying renal lesions that confer potential risk of progression. Currently, except for the blockade of the renin-angiotensin-aldosterone system, no other therapies are available in clinical setting for the treatment of IgAN, although the range of new drugs under investigation is extensive. The incorporation in the next trials of clinical parameters such as the amount of hematuria and histological lesions may allow more personalized therapeutic approaches. To summarize, in recent years, several important efforts have taken place in the understanding of IgAN, but still, further studies are warranted to elucidate the best therapeutic strategies according to the risk to improve the prognosis of this entity.

The mucosal immune system and IgA nephropathy

“…The study performed by Liu et al tested oral HCQ in IgAN patients receiving maximal supportive treatment, including RAAS inhibitor therapy and blood pressure control. A significant decrease in proteinuria (48.4%) was showed in the HCQ group compared to a 10% increase in the placebo group without differences in the percentage of change of eGFR after only 6 months of follow-up [99,101].…”

“…Indeed, the HCQ, inhibiting the mucosal and intrarenal TLRs signaling, is able to reduce the cytokine and chemokine production as well as to suppress the presentation of autoantigens, thus exercising immunomodulatory and antiinflammatory actions [98,99].…”

Gene Expression as a Guide to the Development of Novel Therapies in Primary Glomerular Diseases

“…IgA-secreting plasma cells migrate to mucosa, releasing dimeric IgA into the lumen, whereas misdirected cells are released to systemic circulation, secreting poorly O-galactosylated IgA1. Circulating galactose-deficient IgA1 forms immune complexes with specific antibodies, resulting in immune-complex deposition or in situ formation in the mesangium, inducing mesangial cell proliferation and increased production of mesangial matrix [ 38 , 39 ]. Despite improvements in understanding the pathogenesis of IgAN, this multiple-hit hypothesis model does not explain kidney injury associated with mesangial IgA deposition.…”

IgA and FcαRI: Versatile Players in Homeostasis, Infection, and Autoimmunity

“…188 The release of pro-inflammatory cytokines such as TNF-α, IL-6, and TGF-β by mesangial cells after IgA immune complex binding was suggested to induce inflammation and glomerulosclerosis. 187,189 In mice, gd-IgA1 immune complexes were not cleared from the circulation and deposited in the kidney. Shedding of FcαRI in transgenic mice however resulted in the deposition of soluble FcαRI-IgA immune complexes in the mesangium, which induced glomerular and interstitial macrophage infiltration, hematuria, mesangial matrix expansion, and mild proteinuria.…”