Hydroxychloroquine sulfate for IgA nephropathy: mechanisms and therapeutic potential in improving proteinuria and alleviating disease progression - a literature review

Abstract

IgA nephropathy (IgAN), the most common form of glomerulonephritis worldwide, often progresses to chronic kidney failure within 10 to 15 years. Despite its clinical importance, effective disease-modifying therapies for IgAN remain limited. Proteinuria is well recognized as both a prognostic biomarker and a modifiable therapeutic target in IgAN. Several randomized controlled trials conducted among Chinese patients with IgAN have demonstrated the efficacy of hydroxychloroquine (HCQ) in reducing proteinuria. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines also suggest that HCQ may exert potential therapeutic effects in IgAN. However, the molecular mechanisms underlying the renoprotective effects of HCQ remain incompletely understood. This review synthesises current evidence on HCQ's therapeutic mechanisms in IgAN, highlighting its multifaceted roles in: (1) suppressing pathogenic galactose-deficient IgA1 synthesis through modulation of mucosal immunity, Toll-like receptor (TLR) signaling, IL-6 pathways, and complement activation; (2) inhibiting autophagy-mediated antigen presentation via major histocompatibility complex class II (MHC-II) molecules; (3) modulating non-canonical autophagy pathways to attenuate human mesangial cells (HMCs) proliferation and protect podocytes; and (4) demonstrating antithrombotic effects. Collectively, HCQ demonstrates multifaceted mechanisms for proteinuria reduction in IgAN while maintaining a favorable safety profile.

Keywords: Galactose-deficient IgA1; Hydroxychloroquine; IgA nephropathy; Mechanism; Proteinuria.

Fig. 1

“Four-hit” hypothesis and mucosal immunity. Antigens stimulate mucosal immunity, including the tonsils and intestinal mucosa. Naïve B cells encounter antigens in the inductive sites of mucosal immunity. IgA-specific CSR occurs via T-cell-dependent and T-cell-independent pathways. In the T-cell-dependent pathway, CSR is induced by TGF-β1, IL-6, and IL-10. CD40 on B cells binds to CD40L on activated CD4 + T cells, providing a costimulatory signal for B cell activation and IgA CSR. In the T-cell-independent pathway, CSR is mediated directly by TGF-β, IL-6, IL-10, BAFF, and APRIL. In IgAN, the first hit involves elevated circulating levels of Gd-IgA1. The second hit is the production of anti-Gd-IgA1 autoantibodies. The third hit occurs when these autoantibodies bind Gd-IgA1, forming circulating ICs. These ICs deposit in the glomerular mesangium (fourth hit), activating HMCs and complement, ultimately leading to renal injury. IgAN, IgA nephropathy; CSR, class-switch recombination; BAFF, B cell activation factor; APRIL, a proliferation-inducing ligand; Gd-IgA1, galactose-deficient IgA1; ICs immune complexes; HMCs, human mesangial cells

Fig. 2

Mucosal Immunity in IgAN and the Role of HCQ. In patients with IgAN, accumulated uremic toxins promote the release of inflammatory substances, alter intestinal permeability, and impair intestinal epithelial tight junctions. Consequently, pathogens have an increased likelihood of crossing the intestinal mucosal barrier. LPS on the bacterial surface specifically activates the TLR4 signaling pathway, which generates IL-6, IFN-α, and IFN-β via the MyD88-NF-κB and MyD88-IRF7 pathways. Intracellular TLRs TLR9 and TLR7 are also present. The endoplasmic reticulum synthesizes intact TLR9/7 molecules. TLR9/7 exit the endoplasmic reticulum, traverse the Golgi apparatus, and reach the lysosome. In the lysosome, their ectodomains are cleaved and hydrolyzed, forming signaling-competent TLR9/7 molecules. Upon activation by ligands, TLR9 engages two signaling pathways, MyD88-NF-κB and MyD88-IRF7. In contrast, TLR7 activation leads to IL-6 production exclusively through the MyD88-NF-κB signaling pathway. IL-6 up-regulates APRIL, promotes Th17 cells production and inhibits the Cosmc gene expression. In the presence of Cosmc, C1GALT1 transfers β-galactose to 1,3-GalNAc via the UDP-galactose transporter, facilitating IgA1 formation. However, LPS and IL-6 inhibit Cosmc expression and decrease expression and activity of C1GALT1, decreasing the transfer of β-galactose to 1,3-GalNAc on IgA1. This results in an elevated level of Gd-IgA1, exacerbating the immune response and establishing a vicious cycle. HCQ repairs intestinal epithelial tight junctions, safeguards the junctional proteins ZO-1 and Occludin, and restricts pathogen translocation across the intestinal barrier. Additionally, HCQ inhibits lysosomal acidification, blocking the cleavage of the ectodomains of TLR9/7. It also prevents the binding of TLR9/7 to their ligands. At a concentration of 30 µM, HCQ completely suppresses the TLR-MyD88-NF-κB and TLR-MyD88-IRF7 signaling pathways. IgAN, IgA nephropathy; HCQ, hydroxychloroquine; Gd-IgA1, galactose-deficient IgA1; LPS, lipopolysaccharides; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor kappa-B; IRF7; interferon regulatory factor 7; Cosmc, core β1,3GalT-specific molecular Chaperone; C1GALT1, core-1 β1-3galactosyltransferase; TLR, Toll-like receptor; CpG-ODN, class c CpG oligodeoxynucleotides

Fig. 3

The complement system and the role of HCQ. The complement cascade can be activated via three distinct pathways: the classical pathway, the lectin pathway, and the alternative pathway. The activation of C3 represents the pivotal step in complement activation. In the lectin pathway, the production of acute-phase proteins, such as MBL, bind to microbes, activating MASPs to form C4b2a (a C3 convertase). Conversely, the alternative pathway undergoes continuous low-level self-activation. In the presence of factors B and D, this process leads to the generation of C3b. All three pathways culminate in the formation of C5 convertase (C3bBb3b and C4b2a3b), which cleaves C5. This cleavage releases C5b and the potent anaphylatoxin C5a. C5adesArg is a derivative of C5a. Additionally, C5b initiates the sequential assembly of the lytic membrane attack complex (C5b-9), inducing cell and tissue damage and promoting inflammation. HCQ inhibits both MBL-dependent activation and the alternative pathway. HCQ, hydroxychloroquine; MBL, mannose-binding lectin; MASPs, mannose-binding-lectin-associated serine proteases

Fig. 4

HCQ inhibits autophagy. By alkalizing the lysosome, HCQ disrupts the fusion of autophagosomes with lysosomes. This interference halts autophagic flow and inhibits autophagic flux. Through alkalinization, HCQ impedes post-translational modifications of newly synthesized proteins within the endoplasmic reticulum or trans-Golgi network vesicles. Consequently, HCQ blocks the cleavage of MHC-II invariant chains. Moreover, HCQ suppresses the mitochondrial antioxidant system. This suppression mediates the generation of ROS, leading to excessive ROS production. This inhibits activation-induced autophagic flux, causes autophagosome accumulation, and induces proliferation defects in CD4 + T cells. Cumulatively, these effects inhibit MHC-II autoantigen presentation, thereby suppressing the downstream IgA CRS. HCQ, hydroxychloroquine; MHC-II, major histocompatibility complex class II; ROS, reaction oxidative stress; CRS, class-switch recombination

Fig. 5

HCQ induces non-canonical autophagy. Facilitated by V-ATPase, HCQ modifies the extracellular tonicity, inducing osmotic imbalance. Subsequently, endocytosis triggers osmotic swelling of endolysosomal compartments, which in turn elicits non-canonical autophagy. V-ATPase, vacuolar-type H⁺-ATPase; HCQ, hydroxychloroquine