Abstract. The development of renal interstitial fibrosis (RIF) represents an important step in the progression of chronic proteinuric nephropathies. The Munich Wistar Frömter (MWF) rat represents a valuable model to study the progression in proteinuric renal disease. MWF animals demonstrate a significant increase of urinary albumin excretion (UAE) and RIF compared with the spontaneously hypertensive rat (SHR) with low UAE. The aim of this study was to analyze the genetic basis and the relation between UAE and RIF by genetic linkage and quantitative trait loci (QTL) mapping analysis. The authors generated a backcross population between MWF and SHR including 215 male animals. UAE was determined in young backcross animals at 8 wk, and at 14 and 24 wk of age, respectively. RIF was evaluated by Sirius red staining of kidney sections and quantified by computer-assisted image analysis at 24 wk. Total genome scan analysis identified in total eight QTL linked to UAE and a major locus on chromosome 6. At this locus, homozygosity for the MWF allele exhibited a strong effect on UAE levels (threefold elevation) and displayed significant linkage already at 8 wk (logarithm of odds [LOD] ϭ 4.3) with increasing significance at 14 and 24 wk (LOD ϭ 7.8 and 10.1, respectively). In addition, this was the only QTL that was linked to the amount of RIF (P ϭ 0.0009, LOD ϭ 2.4). These data establish a genetic link between early onset albuminuria and progression of RIF at the QTL on RNO6. This study demonstrates the power of genetic linkage analysis for the dissection of physiologic pathways involved in renal disease progression.The Munich Wistar Frömter (MWF) rat represents a valuable experimental model for the investigation of progressive glomerular injury and the progression of proteinuric renal disease (1,2). Previous investigations in this model demonstrated that molecular mechanisms leading to functional impairment of intrinsic properties of the glomerular wall rather than structural changes must be responsible for abnormal permeability of the glomerular capillary barrier to proteins (1,3). This results in an early increase of urinary albumin excretion (UAE) in young MWF animals (4). A large body of experimental evidence obtained in MWF and other animal models of proteinuric renal disease documented a pathophysiologic link among progressive proteinuria, tubulointerstitial damage, and renal scarring (5). The data indicate that progression of chronic proteinuric nephropathies to end-stage renal disease follows a final common pathway despite the heterogenous nature of the initial insults in the glomerulus (6). The development of tubulointerstitial damage and renal interstitial fibrosis (RIF) are important steps in this pathway, and RIF may correlate with disease prognosis and organ survival (7-9). The pivotal first step, however, is the impairment of glomerular permeability to proteins with subsequent excessive filtration and presentation of these macromolecules to the proximal tubule. The progressive accumulation of RIF is a detriment...