Advances in the biology and genetics of the podocytopathies implications for diagnosis and therapy

In the past few years, an increased number of podocyte-expressed genes have been identified, stimulating a growing interest in studying their role in the development of proteinuria and glomerular disease. Substantial progress has been made not only in clarifying the mechanisms of podocyte injury as a major cause of proteinuria, but also in organizing this new knowledge and integrating it in new classification schemes where morphology, etiology, and mechanisms of podocyte injury are the variables that define each glomerulopathy. Here, we describe how one such schema relates to the pathogenesis of the various lesions. Podocytes are highly specialized postmitotic cells with different structural and metabolic functions, including maintaining the filtration barrier and the normal structure of the glomerular tuft, remodeling the glomerular basement membrane (GBM), performing endocytosis of filtered proteins, and counteracting the intracapillary hydrostatic pressure.1 Podocytes are formed by a cell body containing the nucleus, primary processes, and foot processes, which adhere to the GBMs and are connected to each other by the slit diaphragms (SDs). The complex structure of the cell may be altered at any level: podocyte injury may derive from abnormalities of transcription factors in the nucleus, altered energy production by mitochondria in the cytoplasm, altered intracellular Ca+ homeostasis or aberrant lysosomal activity, abnormalities of proteins residing in the luminal (facing the urinary space) or abluminal (facing the GBM) surface of the cell membranes, and abnormalities of proteins that are part of the SD complex, and therefore participate in maintaining the integrity of the filtration barrier, or that are part of the actin-based cytoskeleton. In addition, podocyte pathologic changes may derive from abnormal immune system activation or direct viral infection of podocytes. Abnormal cell function may reflect primary, intrinsic damage of the podocytes, sometimes genetically determined, or may be the result of extrinsic factors that interfere with the normal molecular anatomy and biology of the cell. In response to these stimuli and according to the developmental state at the time of the injury, podocytes may react in different ways: (1) they can modify their phenotype and undergo foot process effacement, a phenomenon that is not associated with alteration of the number of podocytes per glomerulus; (2) they can undergo apoptosis, an event that may occur as result of intrinsic or extrinsic damage; (3) under certain circumstances, podocytes may undergo developmental arrest and resemble immature precursors, a phenomenon generally accompanied by mild proliferative activity; and (4) adult podocytes can dedifferentiate and reenter the cell cycle to actively proliferate and, under specific circumstances, express a dysregulated phenotype. A recently proposed taxonomy of podocytopathies identifies 4 patterns of glomerular injury that appear to result from these 4 pathways that injured podocytes may take: (1) minimal change nephropathy (MCN), if the number of podocytes per glomerulus is unchanged; (2) focal segmental glomerulosclerosis (FSGS), if there is podocytopenia; (3) diffuse mesangial sclerosis (DMS), where low proliferative index has been described; or (4) collapsing glomerulopathy (CG), if there is marked proliferation (Figures 1 and ​and22).1 Figure 1 Injured podocytes may take 4 different pathways. Under certain circumstances, injured podocytes undergo foot process effacement without significant change in podocyte number. When this occurs, the glomeruli generally appear normal on light microscopy ... Figure 2 Podocytopathies: morphologic patterns. A, No changes are seen in minimal change nephropathy (MCN), with the exception of foot process effacement on ultrastructural analysis. B, On the contrary, in focal segmental glomerulosclerosis (FSGS), by definition ... We propose that the 4 pathways of response to podocyte injury can result from multiple pathogenic stimuli. Here, we describe how recent advances in podocyte biology present paradigms of podocytopathic injury. Each of these relates to specific functions of the podocyte.