Chronic renal failure (CRF) is a major cause of morbidity and morality, primarily due to its relentless progression to end stage renal disease. Recent studies suggest that the chronic functional and structural compensatory adaptations of the normal or minimally diseased remnant nephrons are central to the progressive nature of renal disease. The timing and mechanisms which initiate and ultimately lead to these adaptations, however, are not well understood.
The specific aims of this study are to test the hypothesis that 1) the adjustments in nephron function occur in a rather specific time related sequence, instead of simultaneously after nephron loss, 2) the modulation of remnant nephron function over the first day is influenced by the intrarenal hormonal environment and partly by the hypertrophic response which itself alters over time, and 3) the loss of resetting of renal autoregulation seen in rats with CRF may be the consequence of hormonal influences rather than the hypertrophy, per se. To evaluate this hypothesis studies will be conducted in Munich-Wistar rats to document the magnitude and sequence of the functional and structural compensatory adaptations of the glomeruli and tubules of remnant nephrons at 60 min, 1 day and 7 days after nephron loss. The second phase of this investigation will be an analysis of the mechanisms for and rate at which renal autoregulation is impaired in remnant nephrons during the first week after nephron loss. These studies will evaluate both components of renal autoregulation, the tubuloglomerular feedback mechanism and the myogenic component. During the last phase of this study a regulatory role of endogenous hormonal systems in the control of glomerular and tubular function of remnant nephrons will be ascertained during the first week after reduction in nephron number. These investigations require application of a variety of physiological, morphological, metabolic and biochemical techniques including glomerular and tubular micropuncture, light and electron microscopy, as well as DNA, RNA, and humoral-hormonal assays. The significance of our studies is that the pathophysiologic mechanisms involved in the adaptations of remnant nephrons will be further defined and that our basic understanding for progressive kidney disease will be improved.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK037706-04
Application #
3236757
Study Section
General Medicine B Study Section (GMB)
Project Start
1986-02-01
Project End
1994-01-31
Budget Start
1989-02-01
Budget End
1990-01-31
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045