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Prognostic Value of Serum Biomarkers of Autoimmunity for Recurrence of IgA Nephropathy after Kidney Transplantation.

ABSTRACT: A prognostic biomarker for IgA nephropathy (IgAN) recurrence after renal transplant is lacking. We followed 96 consecutive first renal transplant recipients with native kidney IgAN (79 men; 92 deceased donors; mean age =48.1 years) on calcineurin inhibitor-based immunosuppression over 10 years for death, allograft failure, and clinicopathologic recurrence (CPR; clinically evident and biopsy-proven). Using time-dependent Cox regression analysis and receiver operating characteristic curves, we assessed prognostic significance of levels of galactose-deficient IgA1 (Gd-IgA1; autoantigen) and Gd-IgA1-specific IgG and IgA autoantibodies in serum obtained at time of transplant or native-kidney IgAN diagnosis (30 patients only). Overall, 13 patients died, 34 kidneys failed (17 due to CPR), and 34 patients developed CPR after a mean interval of 5.8 years. Compared with healthy controls (n=30), patients had significantly elevated serum Gd-IgA1 levels at diagnosis and transplant, but levels did not associate with any outcome. Patients also had significantly elevated levels of normalized (but not total) serum Gd-IgA1-specific IgG autoantibodies at diagnosis and transplant, and the level at transplant associated with higher risk of CPR (relative risk, 2.68; 95% confidence interval, 1.26 to 5.71; P=0.01; area under the receiver operating characteristic curve, 0.62; 95% confidence interval, 0.51 to 0.74; P=0.05). Normalized Gd-IgA1-specific IgG autoantibody level remained an independent risk factor for CPR in multivariate analysis. Serum Gd-IgA1-specific IgA autoantibody level did not change between diagnosis and transplant or predict outcome. This study emphasizes post-transplant prognostic value of normalized serum IgG antiglycan autoantibody level in patients with IgAN.

SUBMITTER: Berthoux F

PROVIDER: S-EPMC5461789 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IgA nephropathy (IgAN), the most frequent primary glomerulonephritis, affects young patients and is associated with a high risk of progression to end-stage renal disease. Consequently, patients with IgAN constitute an important proportion of candidates for kidney transplantation. Several studies showed a significant risk of IgAN recurrence on kidney graft, but the risks factors for recurrence remain to be accurately evaluated. Indeed, early identification of at risk patients may allow the optimization of treatment and the reduction of recurrence rate on the graft. In the present work, we studied the relationship between post-transplant serum IgA (sIgA) levels and the risk of IgAN recurrence after kidney transplantation. Recipients with IgAN had higher levels of sIgA as compared to patients with other nephropathies (p<0.05). The prevalence of IgAN recurrence was 20.8% during the period of analysis (mean follow-up of 6 ± 3.2 years). Serum IgA levels at M6, M12 and M24 post-transplant were significantly higher in patients with IgAN recurrence as compared to those without (p = 0.009, p = 0.035 and p = 0.029, respectively). Using receiver operating curve (ROC), sIgA at M6 and M12 post-transplant were significantly associated with IgAN recurrence (AUC = 0.771, p = 0.004 and AUC = 0.767, p = 0.016, respectively), while serum creatinine and proteinuria were not. Serum IgA level at month 6 was significantly associated with the occurrence of post-transplant IgA recurrence, whether it was analyzed as a continuous or a categorical variable. After successive adjustment on age, gender and proteinuria, sIgA remained a significant risk factor of post-transplant IgAN recurrence. Finally, survival free of IgAN recurrence was significantly better in patients with sIgA<222 mg/dL at month 6 as compare to IgAN patients with sIgA≥222 mg/dL (p = 0.03). Thus, the present work supports a link between post-transplant sIgA levels and IgAN recurrence and suggests that sIgA may be a valuable predictive biomarker of IgAN recurrence in kidney transplant recipients.

Project description:Background: The complement system activation and regulation have been linked to post-transplant pathologies including chronic antibody mediated rejection (cAMR) and the recurrence of IgA nephropathy (ReIgAN) but distinct mechanisms remain to be elucidated. Methods: In this retrospective single center study, the outcome of kidney transplantation was studied in 150 patients with late histological diagnosis to be either cAMR or ReIgAN, 14 stable kidney grafts at 3 months and finally 11 patients with native kidney IgAN nephropathy. To study a role of complement cascade and regulation in cAMR and ReIgAN, the RNA was extracted from available frozen kidney biopsy samples and using RT-qPCR transcripts of 11 target genes along with clinical data were determined and compared with stable grafts at 3 months protocol biopsies or IgAN native kidney nephropathy. Immunohistologically, CD46 (MCP), and C5 proteins were stained in biopsies. Results: Interestingly, there were no differences in kidney graft survival between cAMR and ReIgAN since transplantation. cAMR was associated with significantly higher intragraft transcripts of C3, CD59, and C1-INH as compared to ReIgAN (p < 0.05). When compared to normal stable grafts, cAMR grafts exhibited higher C3, CD55, CD59, CFH, CFI, and C1-INH (p < 0.01). Moreover, ReIgAN was associated with the increase of CD46, CD55, CD59 (p < 0.01), and CFI (p < 0.05) transcripts compared with native kidney IgAN. Rapid progression of cAMR (failure at 2 years after biopsy) was observed in patients with lower intrarenal CD55 expression (AUC 0.77, 78.6% sensitivity, and 72.7 specificity). There was highly significant association of several complement intrarenal transcripts and the degree of CKD regardless the diagnosis; C3, CD55, CFH, CFI, and C1-INH expressions positively correlated with eGFR (for all p < 0.001). Neither the low mRNA transcripts nor the high mRNA transcripts biopsies were associated with distinct trend in MCP or C5 proteins staining. Conclusions: The intrarenal complement system transcripts are upregulated in progressively deteriorated kidney allografts.

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Prognostic Value of Serum Biomarkers of Autoimmunity for Recurrence of IgA Nephropathy after Kidney Transplantation.

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