The origin of albuminuria remains controversial owing to difficulties in quantifying the actual amount of albumin filtered by the kidney. Here we use fluorescently labeled albumin, together with the powerful technique of intravital 2-photon microscopy to show that renal albumin filtration in non-proteinuric rats is approximately 50 times greater than previously measured and is followed by rapid endocytosis into proximal tubule cells (PTCs). The endocytosed albumin appears to undergo transcytosis in large vesicles (500 nm in diameter), identified by immunogold staining of endogenous albumin by electron microscopy, to the basolateral membrane where the albumin is disgorged back to the peritubular blood supply. In nephrotic rats, the rate of uptake of albumin by the proximal tubule (PT) is decreased. This is consistent with reduced expression of clathrin, megalin, and vacuolar H(+)-ATPase A subunit, proteins that are critical components of the PT endocytotic machinery. These findings strongly support the paradigm-shifting concept that the glomerular filter normally leaks albumin at nephrotic levels. Albuminuria does not occur as this filtered albumin load is avidly bound and retrieved by PTCs. Dysfunction of this retrieval pathway leads to albuminuria. Thus, restoration of the defective endocytotic and processing function of PT epithelial cells might represent an effective strategy to limit urinary albumin loss, at least in some types of nephrotic syndrome.
Globotriaosylceramide accumulation in the Fabry kidney is ance was more limited than that observed in other cell types. cleared from multiple cell types after enzyme replacement therapy.No evidence of immune complex disease was found by immuno-Background. Fabry disease, a lysosomal storage disease caused fluorescence despite circulating anti-r-h␣GalA IgG antibodies. by deficient lysosomal ␣-galactosidase A activity, is character-Conclusions. These findings indicate a striking reversal of ized by globotriaosylceramide (GL-3) accumulation in multiple renal glycosphingolipid accumulation in the vasculature and in cell types, particularly the vasculature, leading to end organ other renal cell types, and suggest that long-term treatment failure. Accumulation in the kidney is responsible for progreswith r-h␣GalA may halt the progression of pathology and sive decline in renal function in male patients with the classical prevent renal failure in patients with Fabry disease. phenotype, resulting in renal failure in their third to fifth decades of life. With the advent of recombinant protein synthesis technology, enzyme replacement therapy has become a viable alternative to dialysis or renal transplantation, previously the Fabry disease is an X-linked recessive disorder in which only available treatment options for end-stage renal disease.affected males are deficient in the lysosomal enzyme Methods. The pre-and post-treatment renal biopsies were ␣-galactosidase A. This deficiency leads to accumulation analyzed from fifty-eight Fabry patients enrolled in a Phase 3 double-blind, randomized, placebo-controlled trial followed by
We hypothesize that an epidemic of ESRD has occurred in people with diabetes in the United States population over the last two decades. The nature of the factor responsible for the epidemic and the reasons it affects patients with type 2 diabetes particularly are unknown. Research efforts to identify the putative factor deserve high priority, as does a commitment of resources to provide care for the burgeoning number of patients with ESRD and type 2 diabetes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.