Genetics and Immune Predictors for Recurrent Glomerular Diseases in the Kidney Allograft

PROJECT SUMMARY/ABSTRACT The recent development of potent immunosuppressive regimens has led to decreased incidence of acute rejection and increased incidence of non-rejection complications, including recurrent immune-mediated glomerular diseases (GD) which have emerged as leading causes of kidney allograft failure. IgA nephropathy (IgAN), membranous nephropathy (MN), and diffuse podocytopathy (DP) are the most common causes of primary GD in the native kidney and these same GD can recur after transplantation. In the native kidney, it is apparent that immune and genetic factors are important contributors to each of these GD. Although little is known about the pathogenesis of recurrent GD after transplantation, few studies have shown that rigorous donor-recipient HLA matching and steroid-free immunosuppressive regimens are risk factors for recurrent GD. Therefore, we hypothesized that, similar to GD in the native kidney, recurrent GD are mediated by genomic and immune factors. To define the role of genomic and immune factors in recurrent IgAN, MN, and DP, we have begun collecting clinical data, DNA from donor-recipient pairs, recipients’ sera, and kidney allograft biopsies from multiple transplant centers to assemble the largest cohort of transplant patients with recurrent and non-recurrent GD (n=1,035 at least). To ensure adequate power and eliminate the need for replication studies, we are using genetic risk scores (GRS) and serologic studies that has been previously validated in the native kidney. Hence, we developed a research plan composed of three aims that follow parallel approaches. In Specific Aim-1, we will (1) use genome wide SNP arrays to genotype donor-recipient pairs in patients with recurrent and non-recurrent IgAN, generate individual 30-SNP IgAN GRS, and test these GRS as predictors of recurrent disease, (2) test the values of pre-transplant serum levels of galactose-deficient IgA1, IgG anti-glycan antibodies (Ab), and combined IgAN risk scores (which integrate the IgAN GRS with the above pre-transplant serum levels) as predictors for recurrent disease, and (3) compare transcriptomic profiling of different post- transplantation GD to identify immune signals specific for recurrent IgAN. In Specific Aim-2, we will test donor and recipient MN GRS, anti-phospholipase A2 receptor Ab, and combined MN risk scores as predictors for recurrent MN, and identify intra-graft immune signals specific for recurrent MN. In Specific Aim-3, we will test the values of donor and recipient DP GRS and anti-nephrin Ab as predictors for recurrent DP, and use transcriptomic profiling to identify immune signals specific for recurrent disease. Health relatedness of the project: The proposed project will integrate the field of transplantation with novel donor screening technologies and immune monitoring. In the short-term, this proposal promises to define predictors of these relatively rare but clinically relevant recurrent GD. In the long-term, this project has the potential to introduce novel genomic donor-recipient matching and immune monitoring for patients with kidney failure secondary to GD to decrease incidence of recurrent GD, and improve the health of kidney transplant recipients.