Humoral permeability factors in the nephrotic syndrome: a compendium and prospectus.
The concept that increased glomerular albumin permeability in steroid-resistant nephrotic syndrome is induced by circulating humoral factors is not new. Zimmermann (1) was among the first to demonstrate that serum from a renal transplant patient with recurrent focal segmental glomerulosclerosis (FSGS) could provoke increased albumin excretion when infused in the aorta of intact rats. Unfortunately, the experiment was not easily reproducible, and the possibility that human serum could induce serum sickness in rats was a serious limitation of the original experiment. We now know that inhibitors of permeability activity are present in both normal human and rat serum (see below), which explains the difficulty in replicating the disease in intact animals. In 1974 Shalhoub (2) theorized that a disordered clone of T lymphocytes, present in both minimal change disease and FSGS, secreted a circulating lymphokine "toxic" to the glomerular barrier. In support of this hypothesis, Koyama et al (3) formed hybridomas from T cells from four patients with minimal change disease and three control subjects. The hybridomas of the patients produced a substance that induced proteinuria when injected intravenously into normal rats. However, the study utilized stimulated and not quiescent T cells, and therefore the relevance to the pathogenesis of FSGS is unknown. Hoyer and colleagues first described recurrence of idiopathic nephrotic syndrome after renal transplantation in 1972 (4). Numerous subsequent reports have established the rate of recurrence as being about 30%. Timely plasmapheresis associated with aggressive immunosuppression resolves the proteinuria and disease progression in a large proportion of cases (5). FSGS not only recurs after renal transplantation, but the diseased kidney can also recover when kept protected from the pathological milieu. Rea et al (6) demonstrated that kidneys from a donor with FSGS transplanted into two uremic recipients were free from proteinuria, and that renal function was normal after one year. Ethical and legal considerations aside, recurrence of FSGS after transplantation is strong evidence supporting the role of a humoral factor in the pathogenesis of the disease.
Musante
L
L
Unit and Laboratory of Nephrology, G. Gaslini Children Hospital, Genoa, Italy.
Candiano
G
G
Zennaro
C
C
Bruschi
M
M
Carraro
M
M
Artero
M
M
Ghiggeri
G M
GM
D000818:Animals; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism; D006801:Humans; D009404:Nephrotic Syndrome / Q000378:metabolism*; D010539:Permeability; D000091402:Prohibitins; D011507:Proteinuria / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism
C000717331:PHB2 protein, human; D000091402:Prohibitins; D012709:Serum Albumin