Editorial

Preventing renal disease progression: Can complete renin-angiotensin-aldosterone blockade work?

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Perhaps the most daunting challenge for any primary care physician, nephrologist, or other internal medicine specialist is how to prevent the progression of chronic kidney disease.

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A MAJOR HEALTH CARE CRISIS

Ten to 20 million people in the United States have chronic kidney disease, with diabetic nephropathy and arterial hypertension accounting for two-thirds of cases. In 2007, the US Renal Data System1 reported that, at the end of 2005, 341,319 patients were receiving dialysis and another 143,693 had received renal transplants.

The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiatives2 has raised the level of awareness of chronic kidney disease among physicians and the general public. We have become more adept at diagnosing chronic kidney disease, in particular by calculating the estimated glomerular filtration rate, and we are starting to learn how to sort out the patients designated as having chronic kidney disease by this calculation but without “true” kidney disease. Nevertheless, the medical profession is still struggling to determine the best way to prevent progression in chronic kidney disease, and no single innovative approach currently exists. Should the emphasis be on the blood pressure target, the level of proteinuria reduction, the classes of medications to be used, or on other factors such as lipid control, vitamin D repletion,3 or glycemic control?

WHY INHIBIT THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM?

Over the last 20 years, investigators have devoted much effort to controlling the adverse effects of the renin-angiotensin-aldosterone system on the renal vasculature and parenchyma. We now understand that this system is a complex cascade and that angiotensin II plays a key role.

Angiotensin II enhances the vascular tone of both the afferent and the efferent glomerular arterioles, helps regulate intraglomerular pressure and glomerular filtration, and stimulates the adrenal cortex to release aldosterone. In addition, it has several nonhemodynamic effects. In particular, it may alter the selective permeability of the glomerular capillary barrier by influencing podocyte morphology and by directing a reorganization of its actin cytostructure.

Podocytes are highly differentiated pericyte-like cells that are essential for normal kidney function, but they have limited regenerative ability. Angiotensin II stimulation can lead to podocyte injury via mechanical stress due to increased intraglomerular pressure or an increase in cytosolic calcium,4 formation of bridging between the parietal basement membrane and the glomerular basement membrane,5 and extension of the extracapillary disease process to the glomerular-proximal tubular junction.6 These alterations can result in progressive atrophy, cell death, subsequent fibrosis, and irreversible loss in functioning renal parenchyma.

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