Common variable immunodeficiency with a tnfrsf13b gene mutation in a kidney and pancreas transplant recipient: what should we aim for?

Abstract Background and Aims Common Variable Immune Deficiency (CVID) is a primary immunodeficiency disorder, where genetic defects are commonly present, with hypogammaglobulinemia (typically IgG) and increased susceptibility to recurrent infections, autoimmune disorders, granulomatous diseases and malignancy. It can also potentially lead to nephropathy, with increased risk of proteinuria and metabolic acidosis, higher risk of acute tubular injury caused by Immunoglobulin replacement therapy, and the data available in current literature shows a higher incidence of tubulointerstitial nephritis and membranous glomerulopathy, with IgG deposits on immunofluorescence in most cases. Our aim is to report the challenges of a kidney and pancreas transplant in a recipient with chronic kidney disease and a primary immunodeficiency disorder, to outline an immunosupression strategy with potential alternatives, and to report on the short-term outcomes. Case Report Here-in, we report the case of a 27-year-old patient, with type 1 diabetes mellitus, diagnosed with end-stage chronic kidney disease, who has a history of chronic inflammatory response dysregulation, with chronic monoarthritis, persistent elevation of inflammation markers, recurrent infections and low IgG levels. Genetic screening revealed a heterozygous pathological mutation in TNFRSF13B gene, and a Variant of Uncertain Significance (VOUS) in BACH2 gene. At 24 years-old, she experienced a high-risk pregnancy with HELLP syndrome, and serum creatinine and non-nephrotic proteinuria progressively worsened after postpartum. A native kidney biopsy revealed diabetic nephropathy, with C3 and IgG pseudolinear deposits on immunofluorescence. Eventually, disease progression led to hemodialysis induction. 10 months later, she received a kidney and pancreas cadaveric transplant from a standard criteria donor (SCD). Serum baseline donor creatinine was 0.9 mg/dL, and cause of death was a hemorrhagic stroke. Both donor and receptor had blood group type A (ABO system) and positive cytomegalovirus (CMV) IgG levels. Compatibility analysis showed donor Histocompatibility Leukocyte Antigens (HLA) class I: A 01,32; B08,64; C07,08; and class II: DR 17,07; DQ 02,02; DP 03,45; and receptor HLA class I: A 02,02; B 35,44; C 04,05; and class II: DR 03,04. Flow cytometry showed no receptor class I or class II anti-HLA antibodies. Panel Reactive Antibodies (PRA) test score was 0%, and flow cytometry cross-match (FCCM) was negative. Immunosuppression induction regimen included thymoglobulin, mycophenolate mofetil, tacrolimus and methylprednisolone, with optimal pancreatic graft function. Creatinine at discharge was 2.1 mg/dL. After discharge, maintenance immunosuppression protocol included tacrolimus, mycophenolate mofetil and prednisolone, and pancreas and renal graft function remained successfully stable, with no serious infections until current date. Discussion Common variable immunodeficiency with a heterozygous TNFRSF13B gene mutation is associated with increased risk of hypogammaglobulinemia, lymphoma, gastrointestinal cancer and autoimmunity. The VOUS BACH2 gene is also likely pathological, since there have been BACH2 polymorphisms associated with autoimmune endocrine diseases, including Addison's disease, Graves’ disease and type 1 diabetes mellitus. A hyper-regulated inflammatory state can accelerate kidney function deterioration, but chronic treatment with corticosteroids should be cautious due to the underlying diabetic nephropathy. After transplantation, recipients with CVID are at higher risk of atypical infections, autoimmune complications and disease recurrence with suboptimal long term graft survival. The evidence of current immunosuppression maintenance regimens is weak due to the paucity of CVID cases described in current literature. In the future, we believe that belatacept could offer benefits in terms of reducing the risk of graft loss or the incidence of serious infectious in a transplant recipient with a primary immunodeficiency disorder. Nevertheless, therapy management should be accomplished in a patient-to-patient basis.