Answer. Yes. Many patients who have large urinary protein losses have a condition known as the nephrotic syndrome. In addition to urinary protein, this syndrome is characterized by elevated cholesterol levels, hypoalbuminemia (low serum albumin levels) and edema. The elevated serum cholesterol level is felt to be secondary to the decrease in serum albumin. Albumin is a vital protein that helps balance blood pressure forces and prevents edema. When the body senses that the pressure forces are abnormal, it triggers genes in the liver to stimulate the production of a variety of proteins in addition to albumin. Some of these other proteins carry cholesterol around the body.1

This fascinating process is complicated, but its consequences are significant. Through a twist of fate, the VLDL (very low-density lipoproteins) and LDL (low density lipoproteins), both “bad cholesterols” are increased. However, the HDL (high-density lipoprotein) or “good cholesterol” unfortunately is not. This leads to accelerated heart disease because LDL and cholesterol accumulation in blood vessel walls promote hardening of the arteries (atherosclerosis). The amount of any protein or other substance in the blood depends on how fast it is produced and how rapidly it is broken down. An enzyme known as lipoprotein lipase is responsible for the break down of VLDL. Since protein production by the liver causes an increased demand for amino acid building blocks, there are fewer building blocks available for the production of enzymes such as lipoprotein lipase. Without this “breakdown” enzyme, there is an accumulation of this bad lipid carrying protein.

Complicated proteins such as LDL gain entry into cells through receptors. The number of receptors on a given cell is heavily regulated, and thus receptors act as gateways for cell entry. In patients with proteinuria the LDL receptor is reduced, thus more LDL, having been refused entry into liver cells, remains in the blood stream where it can promote blood vessel wall damage. Another enzyme that is depressed interferes with HDL’s ability to take cholesterol out of blood vessels and transport it back to the liver where it can be eliminated in the bile. Paradoxically, an enzyme that interferes with the feedback mechanism that turns off excess cholesterol synthesis is increased. Consequently, the major enzyme responsible for the synthesis of cholesterol (HMG-Co A reductase) is increased.2 This is the enzyme inhibited by the popular anticholesterol “statins.”

While in situations such as the nephrotic syndrome, proteinuria directly promotes a lipid disorder, there are other conditions where proteinuria is a marker before reaching the point of being a cause of cardiovascular disease. The risk of cardiovascular disease starts with the earliest detection of tiny amounts of protein in the urine, microalbuminuria. Microalbuminuria is a known cardiovascular risk factor for it indicates early blood vessel damage.3 Since the glomerular filter is composed of blood vessels, it is logical that the kidney would serve as an early warning system for impending blood vessel disease. Substances such as angiotensin II cause blood vessels to constrict and stimulate inflammation, oxidation, abnormal growth and other mediators of vascular damage in the kidney as well as all over the body.4

The treatment should always be to try to eliminate the underlying disease. In patients who present with very early proteinuria (microalbuminuria) secondary to diabetes or hypertension, aggressive treatment can result in a lower microalbumin levels and decreased blood vessel damage.5 In many patients, there is not a cure for the underlying disease. Thus, management of factors that promote proteinuria, especially blood pressure, should be the focus. Products such as the angiotensin receptor blockers and converting enzyme inhibitors are the current mainstay of treatment. Other pharmaceuticals currently under investigation have as their primary effect a reduction of urinary proteinuria. They show great promise.6

Finally, therapy should be directed toward prevention of potential complications. Management of hyperlipidemia with the statin class of drugs and other proven cholesterol agents may be indicated. The use of agents that block angiotensin have been shown to reduce the progression of kidney disease toward failure.7, 8

Answer provided by Stephen Z. Fadem, MD, FACP, who serves as a member of AAKP’s Medical Advisory Board and the AAKP Board of Directors. Dr. Fadem is a practicing nephrologist in Houston, Texas.

References:

1. Marsh JB. Lipoprotein metabolism in experimental nephrosis.  Proc Soc Exp Biol Med 1996; 213:178-86.
2. Vaziri ND. Molecular mechanisms of lipid disorders in  nephrotic syndrome. Kidney Int 2003; 63:1964-76.
3. Rowley K, O’Dea K, Best JD. Association of albuminuria and the metabolic syndrome. Curr Diab Rep 2003; 3:80-6.
4. Hsueh WA, Quinones MJ. Role of endothelial dysfunction in insulin resistance. Am J Cardiol 2003; 92:10J-17J.
5. Goldstein BJ. Insulin resistance: from benign to type 2 diabetes mellitus. Rev Cardiovasc Med 2003; 4 Supply 6:S3-10.
6. Solini A, Vergnani L, Ricci F, Crepaldi G. Glycosaminoglycans delay the progression of nephropathy in NIDDM. Diabetes Care 1997; 20:819-23.
7. Parving HH, Hovind P, Rossing K, Andersen S. Evolving strategies for renoprotection: diabetic nephropathy. Curr Opin Nephrol Hypertens 2001; 10:515-22.
8. Schwarz A. New aspects of the treatment of nephrotic syndrome. J Am Soc Nephrol 2001; 12 Suppl 17:S44-7.

The American Association of Kidney Patients presents Ask the Doctor, an opportunity for readers to submit kidney related health questions to healthcare professionals who specialize in an area of concern. The answers are not to be construed as a diagnosis and therefore, alterations in current healthcare should not occur until the patient’s physician is consulted.

This article originally appeared in the March/April 2004 issue of Kidney Beginnings: The Magazine, Vol. 3, No. 1.

Back