Kidneys Inc.

medicine and nephrology updates and interesting cases by a practicing nephrologist in USA

Archive for the category “glomerular diseases”

Idiopathic(primary) FSGS and suPAR(soluble urokinase Plasminogen Activator Receptor)

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


Idiopathic membranous nephropathy, not idiopathic anymore

Idiopathic membranous nephropathy (IMN) was just that, idiopathic. No causative agent or etiology identified in patients. Like most other things in medicine, idiopathic only means, ‘not yet discovered’. A 2009 NEJM article changed the way we look at IMN and glomerulonephritis in general. Antibodies to M-type phospholipase (A2) receptor was found to be highly specific and sensitive in evaluation of patients with IMN. PLA2R is expressed in podocytes, and IgG4 antibodies co-localized in the glomerular deposits in patients with IMN. Anti-PLA2R Abs found positive in 70-80% of patients with IMN. Serum titers of anti-PLA2R antibodies also correlated with disease activity.  Recently in ‘correspondence’ in NEJM, there was an interesting perspective regarding the limitations of relying only on the circulating anti-PLA2R antibodies for detection.

Now there is more coming up as another genetic locus has been discovered for this unique disease. This in fact may fill the gap from the previous discoveries.

While the PLA2R has been located on 2q24, genome wide studies of single nucleotide polymorphism have shown HLA DQ1 (class2 alpha chain 1) as another focus on 6p21 (long arm of Chromosome 6).. This gene is associated with immune modulation and associated with type 1 diabetes, celiac disease and organ transplant rejection. In case of IMN, it seems to  facilitate the autoimmune response to PLA2R in the glomeruli. Homozygosity for both risk alleles gave an odds ratio of about 78.5. (CI 34.6- 178.2). However, this study included only French, Dutch and British groups, essentially, caucasian population. Looking forward to see more on this.

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