Focal segmental glomerulosclerosis (FSGS) is a clinicopathologic syndrome that could be idiopathic(primary) or secondary(genetic, infectious like HIV & parvo B19, drug induced IFN-alpha, pamidronate, lithium, Reflux nephropathy, hyperfiltration, HTN, obesity, Sickle cell etc). Clinically, it manifests as proteinuria with patients being asymptomatic to nephrotic. Proteinuria is non selective. Other features are HTN, Hematuria. with normal serological tests & complement levels. FSGS accounts for up to 1/3 of idiopathic nephrotic syndrome in adults and is the most common cause of nephrotic syndrome in african americans. Left untreated it frequently progresses to ESRD (End stage Renal disease.
While the management of secondary FSGS is directed at treating the cause when applicable, treatment of primary or idiopathic FSGS usually is nonspecific and targeted towards decreasing proteinuria, controlling BP, lipid control and low protein diet. In severe cases treatment is with steroids (tapering dose for at least 6 months) and for those who develop complications or are intolerant cytotoxic therapies like cyclosporine, tacrolimus, mycophenolate or cyclophosphamide. There are experimental therapies that include plasmapheresis.
It has long been speculated that there is a permeability factor playing a major role in the pathogenesis of idiopathic FSGS.
Recently it has been found out that suPAR (Soluble urokinase plasminogen activator receptor) is elevated in up to 2/3 of patients with primary FSGS. Evidence that higher SuPAR levels correlate with increased risk for recurrent FSGS after transplantation in patients with FSGS further supports the theory of this circulating factor in the pathogenesis of this condition. Importantly, molecular studies have also shown that the molecular size of suPAR is very close to the predicted molecular size of the “permeability factor” that has been considered to play a major role in the pathogenesis of idiopathic FSGS.
How does suPARwork?
suPar activates the podocyte beta 3 integrin (necessary for anchoring the podocyte foot processes to the glomerular basement membrane & also maintain cellular structure) causing foot process effacement, proteinuria & glomerulopathy. Since it plays a major role, removing this factor by plasmapheresis or interfering SuPAR- beta 3 integrin interaction through antibodies will abrogate the pathogenesis of this disease
This opens up the therapy of plasmapheresis for such patients. It not only potentially keeps patients away from renal replacement therapy, but also may inhibit the progression of the disease at early stages to prevent its complications. However, It has to be noted that plasmapheresis has been shown to be effective in some patients with recurrent FSGS in a renal allograft, but not in patients with FSGS in their native kidneys. Could this be explained by presence of more than one such circulating factors or could it be due to patient selection?
For now, it is exciting to know more and more “idiopathic” glomerulopathies have prospects of entering the ‘treatable’ category of kidney diseases