Genetic Defects of the Glomerular Basement Membrane

The glomerular basement membrane is a thin layer of extracellular membrane proteins that is an important part of the filtration barrier, particularly glomerular permselectivity, by preventing proteins from crossing into the filtrate. The major proteins in the GBM are laminin, type IV collagen, nidogen and the heparan sulphate proteoglycan agrin. Interestingly, in the past, I was taught that the highly negative charge on agrin played the major role in mediating charge selectivity. However, recent studies have shown that mutations in the gene encoding agrin, leading to a reduction in charge along the GBM, have no effect of glomerular function in mice. Similarly, deletion of agrin has little effect on permselectivity further suggesting that the role of the proteoglycans in selective filtration is minor at best.

There are two conditions associated with genetic defects in glomerular basement membrane proteins:

Syndrome	Gene(s) affected	Protein	Phenotype
Alports Syndrome	COL4A3 COL4A4 COL4A5	Type IV Collagen, α3, α4, α5 subunits	Initial normal formation of GBM but eventually hematuria, proteinuria and eventual ESRD with characteristic splitting of the GBM. COL4A5 mutations are commonest and are X-linked. Other forms are autosomal.
Pierson Syndrome	LAMB2	Laminin β2	Autosomal recessive disorder with variable phenotype depending on the particular mutation. However, ocular abnormalities (microcoria) are present at birth and the majority of affected individuals progress to ESRD within the first few weeks/months of life. Extrarenal manifestations including hypotonia and neurodevelopmental defects have been reported.

Please see this excellent review in Nature Reviews Nephrology for further information.

Still mysterious: the elusive circulating factor for FSGS

Important new findings were recently published in relation to proteinuria and FSGS, which are definitely of interest to our community.

First, the punch line:

There is new evidence for a “circulating factor” in recurrent FSGS in a fascinating case of a re-transplanted kidney (here)

BUT

There is growing evidence that suPAR is a non-specific marker of kidney disease and therefore not likely to be the “circulating factor.”(here)

In fact, it appears that it is non-specifically found in CKD, and correlates with a declining GFR.

Now for some details:

The re-transplanted kidney

A letter to the NEJM editor (here) describes an amazing case of resolution of recurrent FSGS after re-transplantation. 

A 27 year old patient with primary FSGS receiving a kidney from his healthy 24 year old sister developed proteinuria in the nephrotic range (up to 25 g/day!) within 2 days of transplantation, and had no improvement after plasmapheresis and standard immunosuppressive treatment. A renal biopsy confirmed foot process effacement, the first hallmark of recurrent podocyte damage heralding recurrent FSGS. Incredibly, with all appropriate consents and institutional approval, the transplant team removed the allograft from Patient 1 and re-transplanted it into another patient who had ESRD due to diabetes. Within 3-4 days, the proteinuria resolved and a repeat biopsy showed resolution of foot process effacement and re-establishment of a normal podocyte architecture. Eight months later, Patient 2 is reported to be doing very well, with good allograft function and no proteinuria.

This case demonstrates in a remarkable way that recurrent FSGS results from an elusive “factor” rapidly produced by the recipient (with primary FSGS), and that the allograft itself can remain fully functional if removed from the influence of this “factor” and placed in another patient.

suPAR is not suPER specific

What may have seemed to be exciting news in 2011, namely the notion that soluble uPAR may be predictive of recurrent FSGS (here), appears to be unfortunately evolving into yet another unsuccessful attempt to identify the ever elusive circulating factor.

Recent work published in Kidney International by Maas et al. (here) confirms that suPAR is not able to distinguish between idiopathic FSGS, secondary FSGS or minimal change disease. 

This is actually not surprising, because a closer look at the clinical data in Wei et al. (here) reveals that the admittedly arbitrary cut-off for separating primary FSGS from all other glomerular disease (3000 pg/ml) did not hold up when tested among their patient cohorts with idiopathic, recurrent versus non-recurrent FSGS (all had suPAR> 3000 pg/ml, thus suPAR could not predict the recurrent from the non-recurrent cases). 

The second figure in the Maas et al. paper may help explain this conundrum: they show a negative correlation between suPAR and eGFR, meaning that as GFR drops, suPAR levels rise, which essentially means that suPAR is simply a marker of CKD.

Future work will no doubt continue to address these issues, but the apparent lack of specificity of suPAR for FSGS casts serious doubt on its proposed role as the circulating factor.

So, the search is still on!!!