BackgroundBlood pressure (BP) control and reduction of urinary protein excretion using agents that block the renin–angiotensin aldosterone system are the mainstay of therapy for chronic kidney disease (CKD). Research has confirmed the benefits in mild CKD, but data on angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) use in advanced CKD are lacking. In the STOP-ACEi trial, we aim to confirm preliminary findings which suggest that withdrawal of ACEi/ARB treatment can stabilize or even improve renal function in patients with advanced progressive CKD.MethodsThe STOP-ACEi trial (trial registration: current controlled trials, ISRCTN62869767) is an investigator-led multicentre open-label, randomized controlled clinical trial of 410 participants with advanced (Stage 4 or 5) progressive CKD receiving ACEi, ARBs or both. Patients will be randomized in a 1:1 ratio to either discontinue ACEi, ARB or combination of both (experimental arm) or continue ACEi, ARB or combination of both (control arm). Patients will be followed up at 3 monthly intervals for 3 years. The primary outcome measure is eGFR at 3 years. Secondary outcome measures include the number of renal events, participant quality of life and physical functioning, hospitalization rates, BP and laboratory measures, including serum cystatin-C. Safety will be assessed to ensure that withdrawal of these treatments does not cause excess harm or increase mortality or cardiovascular events such as heart failure, myocardial infarction or stroke.ResultsThe rationale and trial design are presented here. The results of this trial will show whether discontinuation of ACEi/ARBs can improve or stabilize renal function in patients with advanced progressive CKD. It will show whether this simple intervention can improve laboratory and clinical outcomes, including progression to end-stage renal disease, without causing an increase in cardiovascular events.
At the majority of mutants in the region Glu181‐Val200 incorporating a conserved AsnPheThrΦΦxLys motif cysteine substitution had no effect on sensitivity to ATP, partial agonists, or methanethiosulfonate (MTS) compounds. For the F185C mutant the efficacy of partial agonists was reduced by ∼ 90% but there was no effect on ATP potency or the actions of MTS reagents. At T186C, F188C and K190C mutants ATP potency and partial agonists responses were reduced. The ATP sensitivity of the K190C mutant was rescued towards WT levels by positively charged (2‐aminoethyl)methanethiosulfonate hydrobromide and reduced by negatively charged sodium (2‐sulfonatoethyl) methanethiosulfonate. Both MTS reagents decreased ATP potency at the T186C mutant, and abolished responses at the F195C mutant. 32P‐2‐azido ATP binding to the mutants T186C and K190C was sensitive to MTS reagents consistent with an effect on binding, however binding at F195C was unaffected indicating an effect on gating. The accessibility of the introduced cysteines was probed with (2‐aminoethyl)methanethiosulfonate hydrobromide‐biotin, this showed that the region Thr186‐Ser192 is likely to form a beta sheet and that accessibility is blocked by ATP. Taken together these results suggest that Thr186, Phe188 and Lys190 are involved in ATP binding to the receptor and Phe185 and Phe195 contribute to agonist evoked conformational changes.
Psychosocial conditions in banking activity involving high strain, low social support at work, high effort with low reward and over-commitment may represent possible risk factors for depressive symptoms in bank employees.
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