The bioactivity of plasma factors in focal segmental glomerulosclerosis.

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Abstract

Focal segmental glomerulosclerosis (FSGS) is a devastating form of nephrotic syndrome, often leading to end-stage renal failure after the failure of a succession of highly toxic therapies. It has long been thought to be caused by a circulating factor(s) that may be produced by cells of the immune system. Much research has focused on identifying such factor(s), including the development of a promising in vitro assay, which estimates glomerular permeability based on the swelling of isolated glomeruli in response to patients' plasma. This assay has also been used as the basis of testing plasma fractions for permeability activity, with no specific factor yet identified. Other studies have attempted to replicate proteinuria in whole animals, by injecting plasma or plasma fractions from focal segmental glomerulosclerosis patients, with inconsistent results. More recently there has been evidence that there may be either inhibitory or missing factor(s) in plasma, with respect to permeability. An additional major biological advance is a growing appreciation of the podocyte as the target cell in this disease, and an understanding of the key molecules involved. Putting together this knowledge, with the latest technological advances in protein identification, provides promising avenues towards finally solving the basis of this enigmatic disease.

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TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function.

Jochen Reiser, Krishna Polu, Clemens Möller … (2005)

Progressive kidney failure is a genetically and clinically heterogeneous group of disorders. Podocyte foot processes and the interposed glomerular slit diaphragm are essential components of the permeability barrier in the kidney. Mutations in genes encoding structural proteins of the podocyte lead to the development of proteinuria, resulting in progressive kidney failure and focal segmental glomerulosclerosis. Here, we show that the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm. We identified five families with autosomal dominant focal segmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 on chromosome 11q. Two of the TRPC6 mutants had increased current amplitudes. These data show that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function.

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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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Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis.

V Savin, R. Sharma, M. Sharma … (1996)

Heavy proteinuria and progressive renal injury recur after transplantation in up to 40 percent of patients with renal failure caused by idiopathic focal segmental glomerulosclerosis. A circulating factor may be responsible for this recurrence. To determine whether patients with focal segmental glomerulosclerosis have a circulating factor capable of causing glomerular injury, we tested serum samples from 100 patients with the disorder in an in vitro assay of glomerular permeability to albumin. Of the 56 patients who had undergone renal transplantation, 33 had recurrences. Sixty-four patients, many of whom had undergone transplantation, were being treated with dialysis. Thirty-one patients with other renal diseases and nine normal subjects were also studied. The 33 patients with recurrent focal segmental glomerulosclerosis after transplantation had a higher mean (+/-SE) value for permeability to albumin (0.47+/-0.06) than the normal subjects (0.06+/-0.07) or the patients who did not have recurrences (0.14+/-0.06). After plasmapheresis in six patients with recurrences, the permeability was reduced (from 0.79+/-0.06 to 0.10+/-0.05, P = 0.008), and proteinuria was significantly decreased. Patients with corticosteroid-sensitive nephrotic syndrome or with membranous nephropathy after transplantation had low levels of serum activity. The circulating factor bound to protein A and hydrophobic-interaction columns and had an apparent molecular mass of about 50 kd. A circulating factor found in some patients with focal segmental glomerulosclerosis is associated with recurrent disease after renal transplantation and may be responsible for initiating the renal injury.