Treatment of IgA Nephropathy: A Rapidly Evolving Field

Abstract

The pivotal event in the pathophysiology of IgA nephropathy is the binding of circulating IgA-containing immune complexes to mesangial cells, with secondary glomerular and tubulointerstitial inflammation and fibrosis. The paramount difficulty in the management of IgA nephropathy is the heterogeneity in its clinical presentation and prognosis, requiring an individualized treatment approach. Goal-directed supportive care remains the bedrock of therapy for all patients, regardless of risk of progression. Sodium-glucose transporter 2 inhibitors and sparsentan should be integral to contemporary supportive care, particularly in patients with chronic kidney damage. Pending the development of reliable biomarkers, it remains a challenge to identify patients prone to progression due to active disease and most likely to derive a net benefit from immunosuppression. The use of clinical parameters, including the degree of proteinuria, the presence of persistent microscopic hematuria, and the rate of eGFR loss, combined with the mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, crescents score, is currently the best approach. Systemic glucocorticoids are indicated in high-risk patients, but the beneficial effects wane after withdrawal and come at the price of substantial treatment-associated toxicity. Therapies with direct effect on disease pathogenesis are increasingly becoming available. While targeted-release budesonide has garnered the most attention, anti-B-cell strategies and selective complement inhibition will most likely prove their added value. We propose a comprehensive approach that tackles the different targets in the pathophysiology of IgA nephropathy according to their relevance in the individual patient.

Trial registration: ClinicalTrials.gov NCT05065970 NCT04578834 NCT03608033 NCT04662723 NCT03188887.

Figure 1

Pathogenesis of IgA nephropathy: the four-hit model. Mucosal IgA is produced within the MALT, more particularly in the GALT, including the Peyer patches, and the NALT, where it plays a key role in the host defense against pathogens. Antigens from the gastrointestinal and respiratory tract are processed by the innate immune system, among which dendritic cells. Class switching of naïve B cells to IgA1(+) B cells occurs via T-cell–dependent (including CD40–CD40L interaction) and T-cell–independent mechanisms, the latter with a critical role for BAFF and APRIL. Both cytokines stimulate B cells via TACI, BCMA, or BAFF-R. IgA1(+) B cells differentiate into IgA1(+) B plasma cells that traffic toward the mucosal surface and produce IgA1, which subsequently enters the lumen. In IgA nephropathy, genetic defects in the enzymes responsible for the galactosylation of IgA1 lead to the formation of Gd-IgA1. The first hit in the pathogenesis of IgA nephropathy is the systemic accumulation of Gd-IgA1, thought to be secreted by gut or respiratory tract-homing Gd-IgA1(+) B cells with spillover from mucosal sites or from B cells that have mishomed to systemic sites. The finding of increased circulating levels of intestinal-activated Gd-IgA1(+) B lymphocytes and Gd-IgA1(+) plasma cells^, also supports this hypothesis. The second hit is the development of autoantibodies directed against the poorly galactosylated region of IgA1. Subsequent circulating immune complex formation consisting of Gd-IgA1 and anti–Gd-IgA1-IgG, IgA, and/or IgM antibodies represents the third hit. The fourth hit entails binding of these immune complexes to mesangial cells, leading to mesangial cell activation. This sets in motion a number of proinflammatory and profibrotic pathways, amplified by complement, RAAS, and ET_A activation. The ultimate result is progressive glomerular and tubulointerstitial injury. APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; BAFF-R, BAFF receptor; BCMA, B-cell maturation antigen; ET_A, endothelin receptor type A; GALT, gut-associated lymphoid tissue; Gd-IgA1, galactose-deficient IgA1; MALT, mucosa-associated lymphoid tissue; NALT, nasopharynx-associated lymphoid tissue; TACI, transmembrane activator and calcium-modulating ligand (CAML) interactor; RAAS, renin–angiotensin–aldosterone system.

Figure 2

Involvement of the complement pathway in IgA nephropathy. The complement system can be activated by the classical, lectin, and alternative pathways, all resulting in the formation of C3 convertases. The classical pathway is initiated by immune complexes that interact with C1q. The lectin pathway is activated by the binding of MBLs and MASP to carbohydrate moieties found primarily on the surface of microbial pathogens. The alternative pathway is capable of autoactivation by a mechanism called “tick-over” of C3. Any of the C3 convertases can cleave C3 to C3a and C3b, producing more C3 convertase in a powerful amplification loop and fully activating the complement system. The terminal complement cascade is initiated by the C5 convertase and ultimately generates the MAC complex. Factor B is the proteolytically active component of the C3 and C5 convertases. The plasma protein properdin stabilizes C3bBb. C3a and C5a are strong anaphylatoxins. Factor H is an important negative regulator of the alternative pathway. Fine-tuning occurs through the factor H–related proteins that compete with factor H and thus prevent deactivation of C3b. In patients with IgA nephropathy, components of the alternative (properdin, factor H, factor H-related proteins and factor B) and lectin (C4d in the absence of C1q, MBL, MASP) pathways are found in the mesangial deposits and correlate with prognosis. The association of circulating factor H–related proteins and disease prevalence/progression,^, the frequent observation of thrombotic microangiopathy lesions in IgA nephropathy relative to other forms of immune-mediated GN,^– and the response of severe forms of IgA nephropathy to C5 inhibition further support a role for complement dysregulation in IgA nephropathy. MAC, membrane attack complex; MASP, mannose-binding lectin-associated serine protease; MBLs, mannose-binding lectins.

Figure 3

Proposal for an individualized treatment approach in patients with IgA nephropathy. CI, contraindication; MMF, mycophenolate mofetil; TRF, targeted-release formulation; SGLT2, sodium–glucose transporter 2.