Dietary Manipulation Modifies Protein Linked to Nephrotic Syndrome

Kidneys affected by nephrotic syndrome have small pores in the podocytes, large enough to permit proteinuria (and subsequently hypoalbuminemia, since some of the protein albumin has gone from the blood to the urine) but not large enough to allow cells through (hence no hematuria).

Common causes of NS include diabetic nephropathy, minimal change disease (the most common cause of NS in children under 10 years of age), focal and segmental glomerulosclerosis, and membranous nephropathy. It also can be caused by infections, certain drugs, cancer, genetic disorders, immune disorders, or diseases that affect multiple body systems including lupus, multiple myeloma, and amyloidosis. Treatment for NS is usually based on glucocorticoids, for example prednisone, and other immunosuppressive drugs that can have significant toxicity, especially after prolonged use or repeated cycles of treatment.

Investigators at the University of Alabama (Birmingham, USA) worked with a transgenic rat model that mimicked human minimal change disease. They reported in the December 12, 2010 online edition of the journal Nature Medicine that these mice demonstrated highly elevated expression of the secreted glycoprotein angiopoietin-like-4 (Angptl4). Overexpression of Angptl4 in rat kidney tissue induced nephrotic disease-like, selective proteinuria (over 500-fold increase in albuminuria), loss of glomerular basement membrane (GBM) charge and foot process effacement, while transgenic expression specifically in adipose tissue resulted in increased circulating Angptl4, but no proteinuria.

Close examination at the molecular level revealed that the Angptl4 secreted from podocytes from rats with nephrotic syndrome lacked the normal number of attached sialic acid residues. In an attempt to increase the amount of sialic acid in Angpt14, the investigators fed the rats the sialic acid precursor N-acetyl-D-mannosamine (ManNAc). They found that this treatment increased the sialylation of Angptl4 and decreased albuminuria by more than 40%.

"This is a major breakthrough in understanding the development and treatment of kidney disease associated with proteinuria, the leakage of protein in the urine," said senior author Dr. Sumant Singh Chugh, MD, associate professor of medicine at the University of Alabama. "These findings, at present, most directly relate to minimal change disease, a form of nephrotic syndrome commonly seen in children, but are also likely to be relevant to common causes of proteinuria and nephrotic syndrome in adults, including those with diabetes."

"The major known toxicity of sialic acid therapy observed by other investigators in a mouse model of the human muscle disease, hereditary inclusion body myopathy, was the development of ovarian cysts at very high doses," said Dr. Chugh. "These doses are approximately 20-fold higher than those used to reduce proteinuria in rats in the current study; knowing that, we believe sialic acid repletion has potential in the future treatment of minimal change disease and some other forms of nephrotic syndrome."

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