Thymoma-associated nephrotic syndrome: report of seven cases

Background: Thymoma is often associated with a series of paraneoplastic syndromes. Among them, thymoma-related nephrotic syndrome is much rare. Methods: This retrospective study collected data from patients with thymoma and renal involvement in Xiangya Hospital, Central South University in a period of 5 years to investigate the clinical characteristics of thymoma-associated nephrotic syndrome. Results: Seven patients were studied (age: 51.1±21.4 years old; male/female ratio: 5/2). Among them, thymic pathology revealed 2 cases of type A and 1 case of type B3, myasthenia gravis (MG) was found in 1 out of 7 cases. Renal pathology showed 2 cases of FSGS and 1 case of IgA nephropathy. 2 out of 7 cases who received combined therapy of steroid and immunosuppressive drugs achieved complete remission. Despite 3 out of 7 cases received surgical excision of thymoma, 2 of them experienced treatment failure in nephrotic syndrome. Conclusions: nephrotic syndrome can be associated with thymoma. The FSGS is the most frequent thymoma-associated glomerular lesion in this study. IgA nephropathy may be another pathological type in thymoma-associated NS. Despite after surgical excision, long treatment periods with high dosage of steroid combined with immunosuppressants were needed to achieve complete remission.

the induction of nephropathy.

1.
Clinical data: including gender, age at diagnosed with NS, renal biopsy and thymoma, histological type, clinical stage, therapeutic schedule, and whether thymoma is accompanied by other paraneoplastic syndrome.
Davison's study found that about 40% of patients with NS are often preceded the diagnosis of malignancy [12] . Due to small number of cases enrolled, only 1 patient with NS prior to thymoma was found in this study. As NS is often characterized by hypoproteinemia and edema of bilateral lower limbs, it is more likely to be discovered. Therefore, it is particularly necessary to perform chest CT scan when screening and diagnosing the etiology of NS.
Abnormal thymic tissue can lead to regulatory disorders produced by T cells: AIRE deficiency, decreased MHC II expression, decreased Tregs, autoantibodies against I interferons, abnormally high CD8 + CD45RA + T cells and cytokines for age were the possible underlying mechanism [13; 14] . On the other hand, the occurrence of thymoma itself can alter the thymic architecture, which may disrupt regional immune microenvironment, and lead to immature autoactive T cell activation which can escape negative selection in the thymus and further evade peripheral tolerance mechanism [15] . This autoimmune response and immune compounds can thereby increase the permeability of glomeruli, leading to the occurrence of NS [3] .
Previous studies have shown that minimal-change nephropathy is the most common nephropathy caused by thymoma, followed by membranous nephropathy, and also includes focal segmental glomerular sclerosis [3] . Posner first reported a case of thymic carcinoma with membranous glomerulonephritis in 1980 [16] . Jhaveri's study found that membranous nephropathy is a common type of renal pathology associated with solid tumors [2] . In our study, 2 of the 3 patients with biopsy were   [17] . With the same study area of Karras' study, Simon's study showed that the most common primary glomerular diseases was also IgAN (2.4/1000, 3.6/1000 in males and 1.3/1000 in females) in 898 patients in a region of France [18] . While, in Karras' study, there is no case of IgA, which may be associated with bias or renal pathology related to thymic pathology type. This study demonstrated for the first time that IgA nephropathy may be a new pathological type in thymoma-associated NS.
There is no standard treatment protocol about the dosage and duration of steroid and/or immunosuppressants of thymoma-associated NS. Adequate duration of steroids combined with immunosuppressants are more effective than steroids only in treating NS, whether or not the thymus is removed. In karras's study, 11 out of 13 patients presented with MCD or FSGS were initially treated with steroids, the effective rate was 84% (54% CR, 30%PR) [3] , but in our study, even by combining steroid, immunosuppressants and thymectomy, the effective rate is only 57% (4/7).
Immunosupressive drugs, such as cyclosporine, cyclophosphamide, chlorambucil, and azathioprine, are the common choice [3; 19] . In our study, we chose tacrolimus, a more powerful and new immunosuppressive agents, to suppress the immune function, and the patients (2/2) achieved partial remission. and anterior thymomectomy, the patient achieved complete remission, and no signs of recurrence of thymoma and NS were observed after that [20] . For those who underwent surgical excision in our study, only case 3 achieved CR, but for those who did not undergo surgical excision, the treatment in 3 out of 4 patients were effective. With limited data, we were unable to identify the absolute correlation between thymomectomy and the remission of NS, but we can ascertain that combination therapy (combing steroids, immunosuppressants and thymectomy) may be effective way to reduce proteinuria.
In the course of the treatment of NS, most patients were admitted into our department because of lower extremity edema, anemia and infection. In the routine examination after admission, we found thymoma occasionally. Due to the existence of infection, severe hypoalbuminemia, perinephric effusion, or with the use of steroid and /or immunosuppressants, it will increase the possibility of infection, severely postpone the operation of thymoma. It also explained why the cases of thymectomy were less in this study.

Conclusion
In conclusion, in this study, we demonstrated that FSGS is the most frequent thymoma-associated glomerular lesion. IgA nephropathy may be a new pathological type in thymoma-associated NS. Combination therapy may be an effective way to achieve complete remission for both thymoma and NS. The effect of thymectomy upon renal symptoms is difficult to ascertain. Standardized, unified and effective treatment protocol should be exerted to relieve misery of these patients.