Effects of Hydroxychloroquine on Proteinuria in Immunoglobulin A Nephropathy

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Abstract

Background: Hydroxychloroquine (HCQ) is a well-known immunomodulator that is useful as in the treatment for lupus because of its inhibitory effect on toll-like receptors and cytokines, which are speculated to play a role in the pathogenesis of Immunoglobulin A (IgA) nephropathy (IgAN). However, there was only one study that investigated the effect of HCQ on proteinuria in patients with IgAN. Methods: Ninety patients with IgAN who received HCQ in addition to optimized dosage of renin-angiotensin-aldosterone system inhibitors (RAASi) were recruited for this study, and 90 matched historical controls who received RAASi alone were selected from our registry by the propensity score matching method. Their clinical data were compared at baseline and during follow-up till the termination of HCQ or addition of immunosuppressive agents. Results: The median baseline proteinuria level of the 90 patients who received HCQ was comparable with the RAASi-alone group (1.5 [1.2, 2.1] vs. 1.5 [1.2, 1.9] g/day, p = 0.74). At 6 months post-study initiation, the median proteinuria level in the HCQ group was lower than that in the RAASi-alone group (0.8 [0.7, 1.2] vs. 1.2 [0.8, 1.8] g/day, p = 0.02). The percentage by which proteinuria was reduced in the HCQ group was significantly higher than that in the RAASi-alone group (–43% [–57, –12] vs. –19% [–46, 17], p = 0.01). No serious adverse effects were documented during treatment with HCQ. Conclusion: The addition of HCQ to RAASi resulted in a significant and safe reduction in proteinuria in patients with IgAN.

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Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells.

Hiromichi Ishikawa, H Tezuka, Masayuki Matsushita … (2007)

Immunoglobulin-A has an irreplaceable role in the mucosal defence against infectious microbes. In human and mouse, IgA-producing plasma cells comprise approximately 20% of total plasma cells of peripheral lymphoid tissues, whereas more than 80% of plasma cells produce IgA in mucosa-associated lymphoid tissues (MALT). One of the most biologically important and long-standing questions in immunology is why this 'biased' IgA synthesis takes place in the MALT but not other lymphoid organs. Here we show that IgA class-switch recombination (CSR) is impaired in inducible-nitric-oxide-synthase-deficient (iNOS-/-; gene also called Nos2) mice. iNOS regulates the T-cell-dependent IgA CSR through expression of transforming growth factor-beta receptor, and the T-cell-independent IgA CSR through production of a proliferation-inducing ligand (APRIL, also called Tnfsf13) and a B-cell-activating factor of the tumour necrosis factor (TNF) family (BAFF, also called Tnfsf13b). Notably, iNOS is preferentially expressed in MALT dendritic cells in response to the recognition of commensal bacteria by toll-like receptor. Furthermore, adoptive transfer of iNOS+ dendritic cells rescues IgA production in iNOS-/- mice. Further analysis revealed that the MALT dendritic cells are a TNF-alpha/iNOS-producing dendritic-cell subset, originally identified in mice infected with Listeria monocytogenes. The presence of a naturally occurring TNF-alpha/iNOS-producing dendritic-cell subset may explain the predominance of IgA production in the MALT, critical for gut homeostasis.

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The role of antimalarial agents in the treatment of SLE and lupus nephritis.

Joanne Bargman, Alice W. Lee, Earl Silverman (2011)

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that affects various organs. Lupus nephritis is one of the most common, and most important, serious manifestations of SLE. Antimalarial agents are part of the immunomodulatory regimen used to treat patients with SLE; however, their role in the treatment of patients with lupus nephritis in particular is less well recognized, especially by nephrologists. Not all antimalarial agents have been used in the treatment of lupus; this Review will focus on studies using chloroquine and hydroxychloroquine. In addition, this Review will briefly describe the history of antimalarial drug use in patients with SLE, the theorized mechanisms of action of the agents chloroquine and hydroxychloroquine, their efficacy in patients with SLE and those with lupus nephritis, their use in pregnancy, and potential adverse effects. The Review will also cover the latest recommendations regarding monitoring for hydroxychloroquine-associated or chloroquine-associated retinopathy. Overall, antimalarial drugs have numerous beneficial effects in patients with SLE and lupus nephritis, and have a good safety profile.

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Previous antimalarial therapy in patients diagnosed with lupus nephritis: influence on outcomes and survival.

A Sisó, Antonio Plaza, Valdemiro P. Brito … (2008)

The aim of this study was to analyze the effect of exposure to antimalarial drugs at diagnosis of lupus nephritis on the outcome of the disease, especially renal failure, comorbid processes, and survival. We analyzed a cohort of 206 consecutive patients with biopsy-proven lupus nephritis. Renal biopsies were categorized according to the classification proposed by the ISN/RPS in 2003. Exposure to antimalarial drugs (chloroquine and hydroxychloroquine) was defined as the use of these drugs before the diagnosis of lupus nephritis independent of dose and duration. Fifty-six (27%) patients had received antimalarials before the diagnosis of lupus nephritis. During the follow-up, these patients had a lower frequency of creatinine values >4 mg/dL (2% vs 11%, P = 0.029) and end-stage renal failure (2% vs 11%, P = 0.044) in comparison with those never treated with antimalarials. Patients exposed to antimalarials also had a lower frequency of hypertension (32% vs 50%, P = 0.027), infections (11% vs 29%, P = 0.006), and thrombotic events (5% vs 17%, P = 0.039). Twenty patients (10%) died during the study period. Patients exposed to antimalarials had a lower mortality rate at the end of the follow-up (2% vs 13% for those not exposed to antimalarials, P = 0.029). Multivariate analysis identified thrombosis and infections as statistically significant independent variables. Kaplan-Meier plots showed a lower rate of end-stage renal failure (log rank = 0.04) in patients exposed to antimalarials. In conclusion, exposure to antimalarials before the diagnosis of lupus nephritis was negatively associated with the development of renal failure, hypertension, thrombosis and infection, and with a better survival rate at the end of the follow-up. This, together with other published data, suggests that antimalarials should be considered a mandatory therapeutic option in all patients diagnosed with systemic lupus erythematosus.