Pathophysiology of renal tubular obstruction: Therapeutic role of synthetic RGD peptides in acute renal failure

Abstract

In his famous work On the Natural Faculties, Galen of Pergamum introduced the idea of [δλκηζ] as the principal mode of kidney function: the attraction of blood to the kidney, he claimed, results in the production of urine [1]. Though unproven in Galen's ancient times and entirely rejected by the later generations as a mechanistic explanation of renal function, the concept of attraction has not only survived, albeit in a modified form, but has become one of the cornerstone principles of modern physiology and our current understanding of the pathophysiology of processes as diverse as platelet aggregation, metastases, immune recognition and wound healing, to name a few, all of which are governed by adhesion molecules. Here we review the role of adhesion molecules in the pathophysiology of tubular obstruction, focusing on the integrins and their newly recognized function in it. The importance of renal tubular obstruction in the pathogenesis of acute renal failure (ARF) was brought to center stage by a series of elegant microdissection studies by Oliver, MacDowell and Tracy [2]. Using servo-null pressure monitoring of the proximal tubular pressure in diverse models of ARF, investigators have provided solid evidence for the elevation in hydrostatic intratubular pressure concomitant with the unchanged stop-flow and estimated glomerular capillary pressures, further confirming the tubulo-obstructive component of this syndrome [3–5]. It has been concluded, therefore, that tubular obstruction and elevated proximal tubular pressure equilibrate glomerular filtration pressure, thus leading to the persisting oliguria. Necrotic epithelial cells have been postulated to provide the matrix for casts obstructing the tubular lumen. Recent findings of viable epithelial cells in the urine of patients and experimental animals with ARF, however, cast doubt on the postulated schema and suggest the possibility of epithelial cell detachment as an important contributor to the development of tubular obstruction [6–8]. In the following discussion we develop this theme, providing data on the possible mechanism(s) of tubular obstruction in ischemic ARF, and on the therapeutic strategies in and benefits of inhibiting tubular obstruction, and suggest some future directions of this fledgling field of investigations.