Abstract
Galactose-deficient IgA1 (Gd-IgA1) and IgA-IgG complexes are known to play an important role in the pathogenesis of IgA nephropathy (IgAN). We aimed therefore to determine the impact of immunosuppression on the serum levels of Gd-IgA1, total IgA1 and IgA-IgG complexes in IgAN patients. In a retrospective study, serum samples from IgAN patients collected before transplantation (t0) and at 3- and 6-month posttransplant (t3 & t6) were used to measure the levels of Gd-IgA1, total IgA1 and IgA-IgG complexes. The area under the curves (AUC) of immunosuppressants was calculated by the plot of plasma trough level or dosage of each immunosuppressant versus time and was interpreted as the extent of drug exposure. Thirty-six out of 64 IgAN patients, who underwent kidney transplantation between 2005 and 2012, were enrolled. From t0 to t3, serum Gd-IgA1 and total IgA1 decreased significantly (24.7 AU (18.6–36.1) to 17.2 (13.1–29.5) (p<0.0001); 4.1 mg/ml (3.6–5.1) to 3.4 (3.0–4.1) (p = 0.0005)), whereas IgA-IgG complexes remained similar. From t3 to t6, Gd-IgA1 and IgA-IgG complexes significantly increased (17.2 AU (13.1–29.5) to 23.9 (16.8–32.0) (p = 0.0143); OD 0.16 (0.06–0.31) to 0.26 (0.14–0.35) (p = 0.0242)), while total IgA1 remained similar. According to median regression analysis, AUC of prednisone t0-6 was significantly associated with the decrease of Gd-IgA1 t0-6 (P = 0.01) and IgA1 t0-6 (p = 0.002), whereas AUC of tacrolimus t0-6 was associated with the decrease of IgA1 t0-6 (p = 0.02). AUC of prednisone t0-3 was associated with the decrease of IgA-IgG complexes t0-3 (p = 0.0036). The association of AUC prednisone t0-6 with Gd-IgA1 t0-6 remained highly significant after adjustment for other immunosuppressants (p = 0.0036). Serum levels of Gd-IgA1, total IgA1 and IgA-IgG in patients with IgAN vary according to the changing degrees of immunosuppression. The exposure to prednisone most clearly influenced the serum levels of Gd-IgA1.
Highlights
One of the most remarkable findings in understanding the pathogenesis of IgA nephropathy (IgAN) is that an excess of poorly galactosylated IgA1 is present both in the serum and in the glomerular immune deposits of patients with IgAN [1, 2]
The exact mechanism of mesangial IgA1 deposition is not yet satisfactorily defined, immune complexes composed of Galactose-deficient IgA1 (Gd-IgA1) and IgG or IgA autoantibodies trigger mesangial cell activation, proliferation and apoptosis [8, 9]
The serum IgA-IgG complexes showed no significant change from t0 to t3 (OD 0.17 (0.08–0.25) (t0) vs. 0.16 (0.06–0.31) (t3), p = 0.6535), increased significantly from t3 to t6 (0.16 (0.06–0.31) (t3) vs. 0.26 (0.14–0.35) (t6), p = 0.0242)
Summary
One of the most remarkable findings in understanding the pathogenesis of IgA nephropathy (IgAN) is that an excess of poorly galactosylated IgA1 is present both in the serum and in the glomerular immune deposits of patients with IgAN [1, 2]. IgA1 has a unique hinge region between the first and second constant-region domains of its heavy chain [3]. This segment undergoes co/post translational modification by the addition of up to six O-glycan chains [4]. These chains comprise N-acetylgalactosamine (GalNAc) in O-linkage with either serine or threonine residues and may be extended by connecting galactose to GalNAc and are completed by adding sialic acid to galactose, GalNAc, or both. The exact mechanism of mesangial IgA1 deposition is not yet satisfactorily defined, immune complexes composed of Gd-IgA1 and IgG or IgA autoantibodies trigger mesangial cell activation, proliferation and apoptosis [8, 9]. Activated mesangial cells release various proinflammatory, proproliferative and profibrogenic mediators and the subsequent inflammation, cellular proliferation, and the synthesis of extracellular matrix lead to the progression of IgAN [10,11,12,13,14,15]
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