One of the largest controversies in the field of proteinuria/nephrotic syndrome research derives from a 2007 Kidney International paper published by Russo et al. Briefly stated, the authors suggest the paradigm-shifting idea that the glomerulus filters massive amounts of albumin, and that nephrotic syndrome is a defect in tubular reabsorption of albumin. This flies in the face of decades worth of research on proteinuria, which based on a combination of micropuncture and other physiologic experiments in mice and man has led to the conventional model in which albumin is prevented from entering Bowman's space by the charge-selectivity of the glomerular filtration barrier, and nephrotic syndrome results from a breakdown of this barrier. What are we to make of such a debate? Who is right and who is wrong? The following is a (hopefully unbiased) list of the pros and cons of each side of the argument.
Pro: Normal glomeruli filter nephrotic levels of albumin.
The major piece of data in support of this hypothesis comes from the Russo et al paper in which the authors use a relatively new imaging technique, intravital 2-photon microscopy, which enables in vivo imaging of the kidney using injected fluorescent compounds at a resolution previously unachievable. Essentially, the crucial experiment involved injection of a fluorescently-labeled albumin into the vasculature of rats; by quantifying the degree of fluorescence in the plasma compared to Bowman's space, the authors were able to calculate a "sieving coefficient" for albumin. The sieving coefficient they arrived at was about .02--which is orders of magnitude higher than the previous value obtained via the micropuncture method, about .0006. This implies that nephrotic levels of proteinuria are being filtered from normal glomeruli, and the authors postulate a proximal tubular-based mechanism of rapid albumin reclamation. The nature of such a mechanism is unclear, but the authors suggest that vesicles of intact albumin are transcytosed through proximal tubular cells, providing evidence of this by showing an electron micrograph of endogenous albumin within proximal tubular cells. Finally, in a 2008 JASN article by Dr. Wayne Comper, the author sites various methodologic problems with some of the initial experiments used to demonstrate the "charge selectivity" model of the glomerulus. A recent follow-up paper in JASN by Russo et al furthermore suggests that it is an impaired tubular uptake of filtered albumin which accounts for the changes seen in early diabetic nephropathy.
Con: The case against the "tubular proteinuria" model.
Not surprisingly, this newer model has been met with much resistance. In an article by Christensen et al forcefully entitled, "Controversies in nephrology: renal albumin handling, facts, and artifacts!", the authors describe their opposition to the idea that the glomerulus exhibits such large permeability to albumin. First, they point out several methodologic concerns with the technique of 2-photon microscopy, suggesting that the low fluorescent signal they observed is subject to misinterpretation; perhaps some of the "filtered albumin" seen in Bowman's space is fluorescent bleed-through from nearby blood vessels. The authors also point out a very logical question: if massive amounts of protein are retrieved by proximal tubular cells, why haven't we seen evidence of this throughout decades of research in this field? Many veterans of the field have simply not observed proximal tubular cells chock-full of vesicles containing endogenous albumin, and suggest that the published electron micrographs by Russo et al could be fixation artifact. Furthermore, the authors point out that mice lacking megalin function--thought to be a major player in protein uptake in proximal tubular cells--show only a mild degree of proteinuria, not nearly enough to be consistent with the massive amounts of albumin purported to be filtered by the glomerulus. Finally, virtually all of the mutations identified in patients with congenital nephrotic syndrome target genes known to be important in podocyte function: nephrin, podocin, alpha-actinin 4, etc, which would seemingly point to the podocyte, rather than the proximal tubular cell, as the primary player in regulating proteinuria.
So: Who's right and who's wrong? I don't think we know yet, but for now my money is on the conventional explanation--in general, it seems that the "tubular etiology of nephrotic syndrome" is supported predominantly by a new technique, the limitations of which are not yet fully known, and in order to lend it further credence, alternative techniques which support this theory would be necessary. If it does turn out to be true, however, this would really represent a major paradigm shift in nephrology.