The Role of Tubulointerstitial Inflammation in the Progression of Chronic Renal Failure

There is compelling evidence that interstitial inflammation plays a central role in the loss of renal function in chronic renal disease. The combined effects of interstitial inflammation, oxidative stress and local angiotensin II activity result in the disruption of glomerulus-tubule continuity, the development of pathogenic hypoxia, the generation of myofibroblasts and fibrosis, and the impairment of the protective autoregulation of glomerular blood flow that leads to glomerulosclerosis. The association between proteinuria and progression of chronic kidney disease is firmly established. Proximal tubular cells (PTC) exposed to high concentration of proteins produce proinflammatory and profibrotic factors. The activation of nuclear factor B and the signal transducer and activator of transcription results in the upregulation of a variety of cytokines and chemokines, overexpression of adhesion molecules and interstitial infiltration of inflammatory cells. Fibrosis is promoted by release of transforming growth factor , which induces myofibroblast forPublished online: May 22, 2010 Bernardo Rodríguez-Iturbe Servicio de Nefrología, Hospital Universitario de Maracaibo Ave Goajira s/n Maracaibo 4001-A (Venezuela) Tel. +58 261 751 9610, Fax +58 261 752 4838, E-Mail bernardori @ telcel.net6.ve © 2010 S. Karger AG, Basel 1660–2110/10/1162–0081$26.00/0 Accessible online at: www.karger.com/nec D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /2 3/ 20 17 2 :4 4: 54 A M Rodríguez-Iturbe /García García Nephron Clin Pract 2010;116:c81–c88 c82 nephritis, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis, and membranous nephropathy. Not only were the increments in interstitial volume and fibrosis reported to be correlated with renal functional impairment and worse prognosis, but also the reduction in peritubular capillaries, the morphological changes in tubular epithelia and the intensity of inflammatory infiltration in the interstitium correlated with renal functional deterioration. Why the severity of tubulointerstitial disease should be better correlated with renal function and prognosis is not intuitively obvious. It may be due to the fact that in renal biopsies the tubulointerstitial areas are more representative of the extent of the kidney damage and less subject to sample bias than glomeruli, because segmental changes may be missed in a given glomeruli by the biopsy section. Furthermore, atubular glomeruli may show relative integrity while the disconnected tubule is regularly atrophic and surrounded by inflammatory infiltrate and fibrosis and therefore more indicative of a nonfunctioning nephron. Notwithstanding the considerations of sampling representativeness, and the fact that the association between interstitial inflammation (defined here as the accumulation of immunocompetent cells) and the chronic renal disease of any etiology [3] does not represent a proof of causality, the improvement resulting from therapies that directly or indirectly reduce the inflammatory infiltration strongly suggests a pathogenic role of inflammation in the development of a chronically scarred kidney. ROS Lymphs