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.
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ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) causes progressive renal damage and is a leading cause of end-stage renal failure. With emerging therapies it is important to devise a method for early detection. We aimed to identify factors from routine clinical data which can be used to distinguish people with a high likelihood of having ADPKD in a primary health care setting. A cross-sectional study was undertaken using data from the Quality Intervention in Chronic Kidney Disease trial extracted from 127 primary care practices in England. The health records of 255 people with ADPKD were compared to the general population. Logistic regression was used to identify clinical features which distinguish ADPKD. These clinical features were used to stratify individual risk using a risk score tool. Renal impairment, proteinuria, haematuria, a diastolic blood pressure over 90 mmHg and multiple antihypertensive medications were more common in ADPKD than the general population and were used to build a regression model (area under the receiver operating characteristic curve; 0.79). Age, gender, haemoglobin and urinary tract infections were not associated with ADPKD. A risk score (range -3 to +10) of ≥0 gave a sensitivity of 70.2% and specificity 74.9% of for detection. Stratification of ADPKD likelihood from routine data may be possible. This approach could be a valuable component of future screening programs although further longitudinal analyses are needed.BMC Nephrology 01/2014; 15:182. DOI:10.1186/1471-2369-15-182 · 1.52 Impact Factor
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ABSTRACT: Renal cyst enlargement is associated with the activation of both the circulating and intra-renal renin-angiotensin (RAS) systems. Angiotensinogen (AGT) is the substrate for renin. The aim of the study was to determine the effect of angiotensinogen inhibition on renal cyst enlargement. An angiotensinogen antisense oligonucleotide (ASO) that selectively inhibits AGT mRNA was injected once weekly in PKD2WS25 mice (an orthologous model of human ADPKD involving mutation of the Pkd2 gene) from 4 to 16 weeks of age. The AGT ASO resulted in a 40% decrease in AGT RNA in the kidney,a 60% decrease in AGT RNA in the liver and a significant decrease in AGT protein in kidney and serum. The AGT ASO resulted in a significant decrease in kidney size, cyst volume density and BUN. The AGT ASO resulted in a significant decrease in TGF-β and interstitial fibrosis in the kidney. Mice treated with the AGT ASO had a significant decrease in the pro-inflammatory cytokines CXCL1 and IL-12 in the kidney. CD36 (Cluster of Differentiation 36), is a scavenger receptor found on tubular cells that can activate the RAS. Administration of a CD36 ASO had no effect on PKD and kidney function suggesting that the effect of the AGT ASO is independent of CD36. In summary, AGT inhibition resulted in significant decrease in kidney size and cyst volume and an improvement in kidney function in PKD mice. The AGT ASO resulted in a decrease in TGF-β, interstitial fibrosis and the pro-inflammatory cytokines CXCL1 and IL-12 in the kidney. Copyright © 2014, American Journal of Physiology - Renal Physiology.American journal of physiology. Renal physiology 12/2014; 308(4):ajprenal.00478.2014. DOI:10.1152/ajprenal.00478.2014 · 3.30 Impact Factor
Nature Reviews Nephrology 12/2014; DOI:10.1038/nrneph.2014.241 · 8.37 Impact Factor