Minimal change disease and idiopathic FSGS: manifestations of the same disease

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Abstract

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the key histological findings in patients with idiopathic nephrotic syndrome (INS). Although MCD and idiopathic FSGS are often considered to represent separate entities based on differences in their presenting characteristics, histology and outcomes, little evidence exists for this separation. We propose that MCD and idiopathic FSGS are different manifestations of the same progressive disease. The gradual development of FSGS in patients with non-remitting or relapsing INS has been well documented. Moreover, FSGS is the uniform result of substantial podocyte loss in animal models, and a common feature of virtually all progressive human glomerulopathies. As evidence suggests a common aetiology, the pathogenesis of MCD and idiopathic FSGS should be studied together. In clinical trials, idiopathic FSGS should be considered to represent an advanced stage of disease progression that is less likely to respond to treatment than the earlier stage of disease, which is usually defined as MCD.

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Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis.

J M Kaplan, S. H. Kim, K N North … (2000)

Focal and segmental glomerulosclerosis (FSGS) is a common, non-specific renal lesion. Although it is often secondary to other disorders, including HIV infection, obesity, hypertension and diabetes, FSGS also appears as an isolated, idiopathic condition. FSGS is characterized by increased urinary protein excretion and decreasing kidney function. Often, renal insufficiency in affected patients progresses to end-stage renal failure, a highly morbid state requiring either dialysis therapy or kidney transplantation. Here we present evidence implicating mutations in the gene encoding alpha-actinin-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS. In vitro, mutant alpha-actinin-4 binds filamentous actin (F-actin) more strongly than does wild-type alpha-actinin-4. Regulation of the actin cytoskeleton of glomerular podocytes may be altered in this group of patients. Our results have implications for understanding the role of the cytoskeleton in the pathophysiology of kidney disease and may lead to a better understanding of the genetic basis of susceptibility to kidney damage.

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Pathogenesis of lipoid nephrosis: a disorder of T-cell function.

J Shalhoub (1974)

Clinical observations suggest that lipoid nephrosis is produced by a systemic abnormality of T-cell function resulting in the secretion of a circulating chemical mediator toxic to an immunologically innocent glomerular basement membrane. The lack of evidence of a humoral antibody response, remission induced by measles which modifies cell-mediated immunity, the therapeutic benefits of steroids and cyclophosphamide which also abate cell-mediated responses, and the occurrence of this syndrome in Hodgkin's disease support this hypothesis. The susceptibility of untreated patients to pneumococcal infections may be of primary or secondary pathogenetic importance. Taken together, the data suggest that this syndrome is a clinical expression of a self-limited primary immune-deficiency disease.

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Induction of B7-1 in podocytes is associated with nephrotic syndrome.

Anne Davidson, J Kreidberg, Katsuhiko Asanuma … (2004)

Kidney podocytes and their slit diaphragms form the final barrier to urinary protein loss. This explains why podocyte injury is typically associated with nephrotic syndrome. The present study uncovered an unanticipated novel role for costimulatory molecule B7-1 in podocytes as an inducible modifier of glomerular permselectivity. B7-1 in podocytes was found in genetic, drug-induced, immune-mediated, and bacterial toxin-induced experimental kidney diseases with nephrotic syndrome. The clinical significance of our results is underscored by the observation that podocyte expression of B7-1 correlated with the severity of human lupus nephritis. In vivo, exposure to low-dose LPS rapidly upregulates B7-1 in podocytes of WT and SCID mice, leading to nephrotic-range proteinuria. Mice lacking B7-1 are protected from LPS-induced nephrotic syndrome, suggesting a link between podocyte B7-1 expression and proteinuria. LPS signaling through toll-like receptor-4 reorganized the podocyte actin cytoskeleton in vitro, and activation of B7-1 in cultured podocytes led to reorganization of vital slit diaphragm proteins. In summary, upregulation of B7-1 in podocytes may contribute to the pathogenesis of proteinuria by disrupting the glomerular filter and provides a novel molecular target to tackle proteinuric kidney diseases. Our findings suggest a novel function for B7-1 in danger signaling by nonimmune cells.