Can patiromer allow for intensified renin-angiotensin-aldosterone system blockade with losartan and spironolactone leading to decreased albuminuria in patients with chronic kidney disease, albuminuria and hyperkalaemia?:An open-label randomised controlled trial: MorphCKD

INTRODUCTION: Chronic kidney disease (CKD) is associated with significantly increased morbidity and mortality. No specific treatment of the underlying condition is available for the majority of patients, but ACE-inhibitors (ACE-I) and angiotensin II-receptor blockers (ARB) slows progression in albuminuric CKD. Adding a mineralocorticoid receptor-antagonist (MRA) like spironolactone has an additive effect. However, renin–angiotensin–aldosterone system (RAAS)-blockade increases the risk of hyperkalaemia which is exacerbated by the presence of CKD. Thus, hyperkalaemia may prevent optimal use of RAAS-blockade in some patients. This project hypothesises that adding a potassium binder (patiromer) allows for improved RAAS-blockade including the use of MRA, thereby reducing albuminuria in patients with albuminuric CKD where full treatment is limited by hyperkalaemia. If successful, the study may lead to improved treatment of this subgroup of patients with CKD. Furthermore, the study will examine the feasibility of potassium binders in patients with CKD. METHODS AND ANALYSIS: An open-label, randomised controlled trial including 140 patients with estimated glomerular filtration rate (eGFR) 25–60 mL/min/1.73 m(2), a urinary albumin/creatinine ratio (UACR) >500 mg/g (or 200 mg/g if diabetes mellitus) and a current or two previous plasma-potassium >4.5 mmol/L. Patients who develop hyperkaliaemia >5.5 mmol/L during a run-in phase, in which RAAS-blockade is intesified with the possible addition of spironolactone, are randomised to 12-month treatment with maximal tolerated ACE-I/ARB and spironolactone with or without patiromer. The primary endpoint is the difference in UACR measured at randomisation and 12 months compared between the two groups. Secondary endpoints include CKD progression, episodes of hyperkalaemia, blood pressure, eGFR, markers of cardiovascular disease, diet and quality of life. ETHICS AND DISSEMINATION: This study is approved by The Central Denmark Region Committees on Health Research Ethics (REFNO 1-10-72-110-20) and is registered in the EudraCT database (REFNO 2020-001595-15). Results will be presented in peer-reviewed journals, at meetings and at international conferences

Short and Long-Term Effects of the Angiotensin II Receptor Blocker Irbesartan on Intradialytic Central Hemodynamics:A Randomized Double-Blind Placebo-Controlled One-Year Intervention Trial (the SAFIR Study)

Little is known about the tolerability of antihypertensive drugs during hemodialysis treatment. The present study evaluated the use of the angiotensin II receptor blocker (ARB) irbesartan.Randomized, double-blind, placebo-controlled, one-year intervention trial.Eighty-two hemodialysis patients with urine output >300 mL/day and dialysis vintage <1 year.Irbesartan/placebo 300 mg/day for 12 months administered as add-on to antihypertensive treatment using a predialytic systolic blood pressure target of 140 mmHg in all patients.Cardiac output, stroke volume, central blood volume, total peripheral resistance, mean arterial blood pressure, and frequency of intradialytic hypotension.At baseline, the groups were similar regarding age, comorbidity, blood pressure, antihypertensive medication, ultrafiltration volume, and dialysis parameters. Over the one-year period, predialytic systolic blood pressure decreased significantly, but similarly in both groups. Mean start and mean end cardiac output, stroke volume, total peripheral resistance, heart rate, and mean arterial pressure were stable and similar in the two groups, whereas central blood volume increased slightly but similarly over time. The mean hemodynamic response observed during a dialysis session was a drop in cardiac output, in stroke volume, in mean arterial pressure, and in central blood volume, whereas heart rate increased. Total peripheral resistance did not change significantly. Overall, this pattern remained stable over time in both groups and was uninfluenced by ARB treatment. The total number of intradialytic hypotensive episodes was (placebo/ARB) 50/63 (P = 0.4). Ultrafiltration volume, left ventricular mass index, plasma albumin, and change in intradialytic total peripheral resistance were significantly associated with intradialytic hypotension in a multivariate logistic regression analysis based on baseline parameters.Use of the ARB irbesartan as an add-on to other antihypertensive therapy did not significantly affect intradialytic hemodynamics, neither in short nor long-term, and no significant increase in hypotensive episodes was seen.Clinicaltrials.gov NCT00791830

Consort flow diagram.

<p>This figure is reused from our previous publication [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126882#pone.0126882.ref026" target="_blank">26</a>]. Inclusion and exclusion criteria have been published previously [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126882#pone.0126882.ref025" target="_blank">25</a>]. Briefly, the main inclusion criteria were urine output >300 mL/day, dialysis vintage <1 year and left ventricular ejection fraction >30%. Absence of an AV-fistula was not an exclusion criterion since most patients were expected to obtain an AV-fistula during the study. Moreover, blood pressure and IDH episodes were monitored in all patients regardless of access modality. Time of dropout was not significantly different as previously reported [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126882#pone.0126882.ref026" target="_blank">26</a>].</p

Pre- and postdialytic blood pressures.

<p>Fig 2A-B is reused from our previous publication but is slightly modified compared to the original. Image reproduced under a CC-BY licence from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126882#pone.0126882.ref026" target="_blank">26</a>] with permission from Nature Publishing group. PreHD: Predialytic blood pressure (BP); PostHD: Postdialytic BP; Δ: PostHD-PreHD difference; *) 0.05><i>P</i>≥0.01 vs. baseline within the placebo or ARB group; †) 0.05><i>P</i> ≥0.01 placebo vs. ARB; ↕†) in Figs 2C-D indicates that parallel curves were assumed (Model 2). The constant mean differences (placebo-ARB) with 95% confidence interval were 6.2(0.5–11)mmHg; <i>P</i> = 0.03 (Δ(PostHD-PreHD)Systolic BP) and 3.0(0.1–6.0)mmHg; <i>P</i> = 0.04 (Δ(PostHD-PreHD)Diastolic BP). Note that Fig 2A shows all predialytic BP values recorded between baseline and 12 months, whereas the <i>P</i>-values given in 2A were based on values obtained at baseline, 1 week, 3 months, 6 months, 9 months, and 12 months, respectively from multivariate repeated meaurements analysis (xtmixed). Mean values from these time points are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126882#pone.0126882.t002" target="_blank">Table 2</a>.</p

Change (∆) between baseline and 12 months for selected parameters.

<p>Change baseline-12 months (Δ) for selected parameters. Values are given as means with 95% confidence intervals (95% CI). Estimates and <i>P</i>-values were based on multivariate repeated measurements model (xtmixed) Model 1 assuming different development over time in the two groups (placebo and ARB).</p><p>a) HD-time and additional antihypertensive drugs besides placebo/ARB could not be analyzed with xtmixed due to many identical values. Differences within/between groups were therefore analyzed with paired/unpaired Student’s t-test. HD_START: Measurements performed within the first 30 minutes of the HD-session; HD_END: Measurements performed within the last 30 minutes of the HD-session; DDD: Defined daily doses; Ang2: Angiotensin II Hemoglobin conversion factor from g/dL to mmol/L is x 0.6206.</p><p>Change (∆) between baseline and 12 months for selected parameters.</p

Baseline characteristics.

<p>Data are presented as mean ± standard deviation or as median with range.</p><p>‡) Cardiovascular disease was defined as ≥ 1 known conditions (placebo/ARB): Ischemic heart disease (9/8); arrhythmia (6/5); valvular disease (6/3); heart failure (0/1); LV: Left ventricular;</p><p>#)Tx: Kidney transplantation;</p><p>§) Charlson comorbidity index score range 0–37; 0 = low, 3+ = high; DDD = Defined daily doses; EPO: erythropoetin;</p><p>a) n = 39 (Placebo group);</p><p>b) n = 36 (Placebo group);</p><p>GFR: glomerular filtration rate based on the mean of urinary creatinine and urea clearance as previously described [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126882#pone.0126882.ref025" target="_blank">25</a>]; bpm: beats per minute; HDF: hemodiafiltration; HD: hemodialysis;</p><p>c) Three patients in the placebo group and two patients in the ARB group had dialysis vintage > one year and four patients (two in each group) had urine output < 300 mL/day due to delay after inclusion/screening.</p><p>Baseline characteristics.</p