A randomized, multicenter, open-label, blinded end point trial comparing the effects of spironolactone to chlorthalidone on left ventricular mass in patients with early-stage chronic kidney disease: Rationale and design of the SPIRO-CKD trial

Abstract

BackgroundChronic kidney disease (CKD) is associated with increased left ventricular (LV) mass and arterial stiffness. In a previous trial, spironolactone improved these end points compared with placebo in subjects with early-stage CKD, but it is not known whether these effects were specific to the drug or secondary to blood pressure lowering.AimThe aim was to investigate the hypothesis that spironolactone is superior to chlorthalidone in the reduction of LV mass while exerting similar effects on blood pressure.DesignThis is a multicenter, prospective, randomized, open-label, blinded end point clinical trial initially designed to compare the effects of 40 weeks of treatment with spironolactone 25 mg once daily to chlorthalidone 25 mg once daily on the co-primary end points of change in pulse wave velocity and change in LV mass in 350 patients with stages 2 and 3 CKD on established treatment with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Because of slow recruitment rates, it became apparent that it would not be possible to recruit this sample size within the funded time period. The study design was therefore changed to one with a single primary end point of LV mass requiring 150 patients. Recruitment was completed on 31 December 2016, at which time 154 patients had been recruited. Investigations included cardiac magnetic resonance imaging, applanation tonometry, 24-hour ambulatory blood pressure monitoring, and laboratory tests. Subjects are assessed before and after 40 weeks of randomly allocated drug therapy and at 46 weeks after discontinuation of the study drug.

Management of Hypertension in Chronic Kidney Disease

“…It is unclear whether this effect is due to BP lowering alone. In order to answer this question, a randomised study comparing spironolactone with the thiazide-like diuretic chlorthalidone in patients with CKD stage 3 has been completed (SPIRO-CKD [Spironolactone in Chronic Kidney Disease]) and results are awaited [ 82 ]. In hypertensive patients without CKD, spironolactone is more effective than bisoprolol or doxazosin at reducing BP when used as a fourth-line add-on therapy [ 83 ].…”

Quantitative Gadolinium-Free Cardiac Fibrosis Imaging in End Stage Renal Disease Patients Reveals A Longitudinal Correlation with Structural and Functional Decline

“…Prior studies using excised tissue 3 , 6 and CMR with gadolinium 4 , 14 established cardiac fibrosis as a potential substrate of arrhythmia and sudden death in ESRD 15 . With contraindications to gadolinium in place, ventricular hypertrophy and cardiac mechanics are often used as surrogate imaging markers of cardiac fibrosis, and are also targets for pharmacological reversal in ESRD 16 – 18 . In this study we used an MT-weighted CMR technique to quantify global ventricular extracellular matrix expansion in patients with ESRD.…”

Spironolactone dose‑dependently alleviates the calcification of aortic rings cultured in hyperphosphatemic medium with or without hyperglycemia by suppressing phenotypic transition of VSMCs through downregulation of Pit‑1

“…Several hours following administration of a single oral dose of 200 mg SPL in men weighing 65–87 kg (mean dose 2.6 mg·kg −1 ), the total serum concentration of SPL and its metabolites reportedly reaches 1,000 ng/ml (45), and a similar result has been reported in another study (46). Nonetheless, the routine dose of SPL for patients with CKD is 25 mg once daily (47). It was hypothesized that SPL may interfere with VC through Pit-1 suppression in a dose-dependent manner, therefore the present study was initiated and 200 ng/ml SPL was set as the low dose, 1,000 ng/ml as the medium dose and 5,000 ng/ml as the high dose.…”