We seek to be a participating clinical center (PCC) in the RFA entitled """"""""Polycystic Kidney Disease Clinical Trials Network."""""""" Hypertension is common, occurs early, and is associated with a faster progression to renal failure in ADPKD. We have shown activation of the systemic renin-angiotensin-aldosterone system (RAAS) in hypertension associated with ADPKD prior to loss of renal function, and that intrarenal activation of RAAS is present. We have demonstrated that angiotensin converting enzyme inhibition alone (ACEI) has beneficial effects by reducing proteinuria and regression of left ventricular hypertrophy as well as improving effective renal plasma flow, and this may relate to filtration fraction. In contrast to other kidney diseases, ACEI has not been as successful in preventing loss of renal function. This may relate to study design issues, sample size, inclusion of low risk individuals not progressing, and less than maximal blockade of RAAS. Therefore, we propose to assess the effect of combination therapy, i.e. ACEI, angiotensin receptor blockade (ARB), and aldosterone antagonism (spironolactone) in the setting of rigorous blood pressure control (<125/75 mm Hg) on the rate of loss of renal function in ADPKD while controlling for other potential contributors to loss of renal function. ADPKD children with hypertension demonstrate a greater increase in renal volume than other ADPKD children in the setting of normal renal function. Using MRI, we have shown decreased renal blood flow in ADPKD as compared to age and gender-matched children suggesting that activation of RAAS occurs early in ADPKD children. We propose to study a special population of ADPKD subjects (children) throughout adolescence to determine the safety and efficacy of ACE/ARB combination therapy in the acute and chronic setting on renal blood flow, and the rate of renal cyst and total renal growth. Taken together, these studies will determine if maximal inhibition of RAAS prevents loss of renal function in ADPKD adults and if combination ACEI/ARB therapy maintains renal blood flow while slowing renal and cyst growth in ADPKD children. Ultimately these studies should demonstrate slowing or halting progression of ADPKD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK062408-03
Application #
6707567
Study Section
Special Emphasis Panel (ZDK1-GRB-3 (M1))
Program Officer
Flessner, Michael Francis
Project Start
2002-08-15
Project End
2009-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
3
Fiscal Year
2004
Total Cost
$589,985
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Cornec-Le Gall, Emilie; Chebib, Fouad T; Madsen, Charles D et al. (2018) The Value of Genetic Testing in Polycystic Kidney Diseases Illustrated by a Family With PKD2 and COL4A1 Mutations. Am J Kidney Dis 72:302-308
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Torres, Vicente E; Abebe, Kaleab Z; Schrier, Robert W et al. (2017) Dietary salt restriction is beneficial to the management of autosomal dominant polycystic kidney disease. Kidney Int 91:493-500
Irazabal, María V; Abebe, Kaleab Z; Bae, Kyongtae Ty et al. (2017) Prognostic enrichment design in clinical trials for autosomal dominant polycystic kidney disease: the HALT-PKD clinical trial. Nephrol Dial Transplant 32:1857-1865
Porath, Binu; Gainullin, Vladimir G; Cornec-Le Gall, Emilie et al. (2016) Mutations in GANAB, Encoding the Glucosidase II? Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease. Am J Hum Genet 98:1193-1207
Heyer, Christina M; Sundsbak, Jamie L; Abebe, Kaleab Z et al. (2016) Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol 27:2872-84

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