Inherited podocytopathies: FSGS and nephrotic syndrome from a genetic viewpoint.

Recent progress in defining the genetic basis of inherited glomerular disease has helped illuminate inadequacies in the way we describe many of these diseases. Too often, we talk about histologic patterns of injury, such as focal and segmental glomerulosclerosis (FSGS), as if they were diseases rather than descriptions of kidney biopsy specimens at particular points in time. Some patients “with FSGS” respond to steroids, some do not; some patients present with nephrotic syndrome (NS), others with mild proteinuria; some present in childhood, some as adults. FSGS can be primary or secondary to other primary processes. Pathologists may further subdivide FSGS (for example, into collapsing nephropathy, glomerular tip lesion, cellular variant). Some, but not all, FSGS recurs in transplanted kidneys. Do these phenotypic differences reflect differences in the underlying biology of the disease? Is the phrase “focal segmental glomerulosclerosis” as a clinical diagnosis very meaningful, or is it too far downstream from the biologically important disease process? Will genetics help us to understand the biologic basis of the similarities and differences between individuals diagnosed with proteinuric disease? Will genetic testing help guide our therapy? These questions are clinically significant. FSGS, broadly defined as a pattern of injury, is a major cause of renal failure and is increasing in frequency (1). We need to know how many biologically distinct diseases cause the histopathology we call FSGS and how best to distinguish these diseases to determine how best to treat patients whose biopsies show this lesion. Certainly FSGS and non-glomerulosclerotic disorders of the podocyte are complex and overlapping phenotypes involving the interplay of genetic and environmental factors. Here we will review recent progress in the understanding of the genetic basis of FSGS and NS. The forms of FSGS we will focus on in our discussion here belong to that subset of patients in whom the FSGS lesion is a downstream response to podocyte injury.