The HALT Polycystic Kidney Disease Trials: Design and Implementation
ABSTRACT Two HALT PKD trials will investigate interventions that potentially slow kidney disease progression in hypertensive autosomal dominant polycystic kidney disease (ADPKD) patients. Studies were designed in early and later stages of ADPKD to assess the impact of intensive blockade of the renin-angiotensin-aldosterone system and level of BP control on progressive renal disease. Design, settings, participants, and measurements: PKD-HALT trials are multicenter, randomized, double-blind, placebo-controlled trials studying 1018 hypertensive ADPKD patients enrolled over 3 yr with 4 to 8 yr of follow-up. In study A, 548 participants, estimated GFR (eGFR) of >60 ml/min per 1.73 m(2) were randomized to one of four arms in a 2-by-2 design: combination angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) therapy versus ACEi monotherapy at two levels of BP control. In study B, 470 participants, eGFR of 25 to 60 ml/min per 1.73 m2 compared ACEi/ARB therapy versus ACEi monotherapy, with BP control of 120 to 130/70 to 80 mmHg. Primary outcomes of studies A and B are MR-based percent change kidney volume and a composite endpoint of time to 50% reduction of baseline estimated eGFR, ESRD, or death, respectively.
This report describes design issues related to (1) novel endpoints such as kidney volume, (2) home versus office BP measures, and (3) the impact of RAAS inhibition on kidney and patient outcomes, safety, and quality of life.
HALT PKD will evaluate potential benefits of rigorous BP control and inhibition of the renin-angiotensin-aldosterone system on kidney disease progression in ADPKD.
Conference Paper: Adaptive robust constrained matched filter and subspace detection[Show abstract] [Hide abstract]
ABSTRACT: A minimax methodology for formulating adaptively robust and sensitive matched filter and subspace detectors is provided, where the signal and interference of structured noise are partially known. The signal and interference subspaces are assumed to reside in conical regions of the measurement space, and the gain parameters can have bounded magnitude. It is shown that the minimax approach permits the design of a rich variety of matched filter and subspace detectors that vary in the degree of robustness and sensitivity.Signals, Systems and Computers, 2002. Conference Record of the Thirty-Sixth Asilomar Conference on; 12/2002
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ABSTRACT: Hypertension is common and occurs in a majority of autosomal dominant polycystic kidney disease (ADPKD) patients before the loss of kidney function. Hypertension relates to progressive kidney enlargement and is a significant independent risk factor for progression to ESRD. The pathogenesis of hypertension in ADPKD is complex and dependent on many factors that influence each other. Pkd1 and Pkd2 expression levels are highest in the major vessels and are present in the cilia of endothelial cells and in vascular smooth muscle cells. Decreased or absent polycystin 1 or 2 expression is associated with abnormal vascular structure and function. Pkd1/Pkd2 deficiency results in reduced nitric oxide (NO) levels, altered endothelial response to shear stress with attenuation in vascular relaxation. Ten percent to 20% of ADPKD children show hypertension and the majority of adults are hypertensive before any loss of kidney function. Cardiac abnormalities such as left ventricular hypertrophy and carotid intimal wall thickening are present before the development of hypertension in ADPKD. The activation of the renin-angiotensin-aldosterone system occurs in ADPKD because of decreased NO production as well as bilateral cyst expansion and intrarenal ischemia. With increasing cyst size, further activation of the RAAS occurs, blood pressure increases, and a vicious cycle ensues with enhanced cyst growth and hypertension ultimately leading to ESRD. The inhibition of the angiotensin aldosterone system is possible with angiotensin converting enzyme inhibitors and angiotensin receptor blockers. However, interventional studies have not yet shown benefit in slowing progression to renal failure in ADPKD. Currently, large multicenter studies are being performed to determine the beneficial effects of RAAS inhibition both early and late in ADPKD.Advances in chronic kidney disease 03/2010; 17(2):153-63. DOI:10.1053/j.ackd.2010.01.001 · 1.94 Impact Factor
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ABSTRACT: More frequent utilization and continuous improvement of imaging techniques has enhanced appreciation of the high phenotypic variability of autosomal dominant polycystic kidney disease, improved understanding of its natural history, and facilitated the observation of its structural progression. At the same time, identification of the PKD1 and PKD2 genes has provided clues to how the disease develops when they (genetic mechanisms) and their encoded proteins (molecular mechanisms) are disrupted. Interventions designed to rectify downstream effects of these disruptions have been examined in animal models, and some are currently tested in clinical trials. Efforts are underway to determine whether interventions capable to slow down, stop, or reverse structural progression of the disease will also prevent decline of renal function and improve clinically significant outcomes.Advances in chronic kidney disease 03/2010; 17(2):190-204. DOI:10.1053/j.ackd.2010.01.006 · 1.94 Impact Factor