Immune-mediated entities of (primary) focal segmental glomerulosclerosis

Abstract

Focal segmental glomerulosclerosis (FSGS) represents a glomerular scar formation downstream of various different mechanisms leading to podocytopathy and podocyte loss. Recently, significant advances were made in understanding genetic factors, podocyte intrinsic mechanisms, and adaptive mechanisms causing FSGS. However, while most cases of nephrotic FSGS are being treated with immunosuppressants, the underlying immune dysregulation, involved immune cells, and soluble factors are only incompletely understood. Thus, we here summarize the current knowledge of proposed immune effector cells, secreted soluble factors, and podocyte response in immune-mediated (primary) FSGS.

Identification of biomarkers and pathways for focal segmental glomerulosclerosis using next generation sequencing data and bioinformatics analysis

“…The GO and REACTOME pathway database contains information on systematic analysis of gene functions, linking genomics with functional information. Pathways include metabolism [42], transport of small molecules [43] and immune system [44] are linked with progression of FSGS. PDK4 [45], ALB (albumin) [46], EGR1 [47], RYR3 [48], APOH (apolipoprotein H) [49], CYP27B1 [50], ESM1 [51], GATA6 [52], PCK1 [53], TET2 [54], AFP (alpha fetoprotein) [55], CACNA1D [56], ATF3 [57], EGF (epidermal growth factor) [58], LPL (lipoprotein lipase) [59], PPARGC1A [60], PLG (plasminogen) [61], NR4A1 [62], STRA6 [63], MLXIPL (MLX interacting protein like) [64], PLA2G6 [65], RGS2 [66], GPS2 [67], SOX5 [68], GLUL (glutamate-ammonia ligase) [69], RYK (receptor like tyrosine kinase) [70], NFKBIA (NFKB inhibitor alpha) [71], LGR4 [72], SPRY2 [73], TRPC1 [74], KL (klotho) [75], GCLC (glutamate-cysteine ligase catalytic subunit) [76], NOX4 [77], CD69 [78], SLC19A2 [79], S100A12 [80], MT1A [81], SORCS1 [82], FKBP5 [83], AFM (afamin) [84], CA3 [85], MAOA (monoamine oxidase A) [86], ND1 [87], ATP6 [88], CHGA (chromogranin A) [89], ICOS (inducible T cell costimulator) [90], DBH (dopamine beta-hydroxylase) [91], CD5 [92], LTA (lymphotoxin alpha) [93], IFNG (interferon gamma) [94], MPO (myeloperoxidase) [95], CD70 [96], CD300E [97], COLEC12 [98], TLR10 [99], LCN2 [100], SLAMF7 [101], TREM2 [102], ITGAL (integrin subunit alpha L) [103], CD27 [104], JAK3 [105], CCR5 [106], FCN1 [107], IL1RN [108], CX3CR1 [109], PDCD1 [110], TRPM2 […”

Kidney organoid systems for studies of immune-mediated kidney diseases: challenges and opportunities

“…Systemic diseases include anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis and systemic lupus erythematosus (SLE) that display renal inflammation in the glomerulus and in the tubulointerstitial compartment but also show extra-renal inflammation (Bohle A 1994 ; Kurts et al 2013 ). In primary glomerulonephritis such as IgA nephropathy, membranous nephropathy, anti-glomerular basement membrane (GBM) nephritis, and primary focal segmental glomerulosclerosis (FSGS), the disease is limited to the kidney (Kopp et al 2020 ; Braun et al 2021 ). While in these diseases, the immune system seems to be the main driver of pathology, it is important to note that leukocytes interact with various parenchymal cells in the kidney.…”

“…Otherwise, transgenic expression of the aforementioned antigens could prime podocytes in iPSC-derived kidney organoids for the subsequent treatment and assessment of the effects of sera derived from membranous nephropathy and anti-GBM patients exert (Petrosyan et al 2019 ). Similar experiments could be envisioned to determine the effects of the proposed circulation permeability factor(s) resulting in the development of primary FSGS (Braun et al 2021 ).…”

Immune-mediated glomerular diseases: new basic concepts and clinical implications

“…Yet another cause of nephrotic syndrome in adults, (primary) focal segmental glomerulosclerosis, remains at the center of attention. In their article “Immune-mediated entities of (primary) focal segmental glomerulosclerosis” ( 2021 in this issue), Braun et al describe the cumulative knowledge of genetics as well as the glomerular and immune cell cross-talk implicated in immune-mediated (primary) focal segmental glomerulosclerosis, fully summarizing the complex interactions of podocytes with soluble factors and leukocytes leading to glomerular scarring.…”