The OSCAR for cardiovascular disease prevention in chronic kidney disease goes to blood pressure control

Nephropathy progression is slowed and cardiovascular events reduced in patients with stage 3 or higher chronic kidney disease when blood pressure is controlled using combinations of renin–angiotensin system (RAS) blockers with dihydropyridine calcium channel blockers or diuretics. We discuss a trial comparing high-dose RAS blockade with lower-dose RAS blockade combined with a dihydropyridine calcium channel blocker. The primary outcome was cardiovascular events. The combination group had better blood pressure control and fewer total events

Novel non‐steroidal mineralocorticoid receptor antagonists in cardiorenal disease

Mineralocorticoid receptor antagonists (MRAs) are key agents in guideline-oriented drug therapy for cardiovascular diseases such as chronic heart failure with reduced ejection fraction and resistant hypertension. Currently available steroidal MRAs are efficacious in reducing morbidity and mortality; however, they can be associated with intolerable side effects including hyperkalaemia in everyday clinical practice. Recently, a new class of non-steroidal MRAs (including esaxerenone, AZD9977, apararenone, KBP-5074 and finerenone) have been developed with an improved benefit-risk profile and a novel indication for finerenone for diabetic kidney disease. To better understand the non-steroidal MRAs, this review provides information on the molecular pharmacology as well as relevant current preclinical and clinical data on cardiorenal outcomes. A comparative review of all compounds in the class is discussed with regard to clinical efficacy and safety as well as a perspective outlining their future use in clinical practice. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issueto

Differential effects of calcium channel blockers on size selectivity of proteinuria in diabetic glomerulopathy

Differential effects of calcium channel blockers on size selectivity of proteinuria in diabetic glomerulopathy.BackgroundCalcium channel blockers (CCBs) are known to have differential effects on both changes in proteinuria as well as progression of diabetic nephropathy. No clinical study, however, has evaluated whether the differential antiproteinuric effects of CCBs may be explained by their effect on glomerular membrane permeability. We, therefore, tested the hypothesis that certain subclasses of CCBs reduce proteinuria by changing size selectivity of the glomerular membrane, hence changing its permeability.MethodsTwenty-one patients with type 2 diabetes and the presence of nephropathy with hypertension were randomized to receive either diltiazem CD or nifedipine GITS after baseline data for mean systolic and diastolic pressure, urinary protein excretion, glomerular filtration rate, renal plasma flow, neutral dextran and IgG clearances were obtained. Glomerular filtration rate, renal plasma flow, neutral dextran and IgG clearance were measured every three months, arterial pressure and heart rate every month. Patients were followed for 21months.ResultsAt 21months, both patient groups had similar levels of blood pressure control, however, only the diltiazem group had a change in proteinuria (4 ± 10%Δ, nifedipine vs. -57 ± 18%Δ, diltiazem; P < 0.001) with improvement in glomerular size selectivity and change in IgG clearance.ConclusionsThese data support the hypothesis that CCBs that provide sustained reductions in proteinuria do so, in part, by improving glomerular size permselectivity

Differential effects of calcium antagonist subclasses on markers of nephropathy progression

Differential effects of calcium antagonist subclasses on markers of nephropathy progression.BackgroundNumerous studies suggest that the dihydropyridine calcium antagonists (DCAs) and nondihydropyridine calcium antagonists (NDCAs) have differential antiproteinuric effects. Proteinuria reduction is a correlate of the progression of renal disease. In an earlier systematic review, calcium antagonists were shown as effective antihypertensive drugs, but there was uncertainty about their renal benefits in patients with proteinuria and renal insufficiency.MethodsA systematic review was conducted to assess the differential effects of DCAs and NDCAs on proteinuria in hypertensive adults with proteinuria, with or without diabetes, and to determine whether these differential effects translate into altered progression of nephropathy. Studies included in the review had to be randomized clinical trials with at least 6months of treatment, include a DCA or NDCA treatment arm, have one or more renal end points, and have been initiated after 1986. Summary data were extracted from 28 studies entered into two identical but separate databases, which were compared and evaluated by independent reviewers. The effects of each drug class on blood pressure (N = 1338) and proteinuria (N = 510) were assessed.ResultsAfter adjusting for sample size, study length, and baseline value, there were no statistically significant differences in the ability of either class of calcium antagonist to decrease blood pressure. The mean change in proteinuria was +2% for DCAs and -30% for NDCAs (95% CI, 10% to 54%, P = 0.01). Consistently greater reductions in proteinuria were associated with the use of NDCAs compared with DCAs, despite no significant differences in blood pressure reduction or presence of diabetes.ConclusionThis analysis supports (1) similar efficacy between subclasses of calcium antagonists to lower blood pressure, and (2) greater reductions in proteinuria by NDCAs compared to DCAs in the presence or absence of diabetes. Based on these findings, NDCAs, alone or in combination with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), are suggested as preferred agents to lower blood pressure in hypertensive patients with nephropathy associated with proteinuria

Evaluation of the angiotensin II receptor blocker azilsartan medoxomil in African-American patients with hypertension

The efficacy and safety of azilsartan medoxomil (AZL-M) were evaluated in African-American patients with hypertension in a 6-week, double-blind, randomized, placebo-controlled trial, for which the primary end point was change from baseline in 24-hour mean systolic blood pressure (BP). There were 413 patients, with a mean age of 52years, 57% women, and baseline 24-hour BP of 146/91mmHg. Treatment differences in 24-hour systolic BP between AZL-M 40mg and placebo (-5.0mmHg; 95% confidence interval, -8.0 to -2.0) and AZL-M 80mg and placebo (-7.8mmHg; 95% confidence interval, -10.7 to -4.9) were significant (P.001 vs placebo for both comparisons). Changes in the clinic BPs were similar to the ambulatory BP results. Incidence rates of adverse events were comparable among the treatment groups, including those of a serious nature. In African-American patients with hypertension, AZL-M significantly reduced ambulatory and clinic BPs in a dose-dependent manner and was well tolerated

Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl

Background: A phase 3 randomized clinical trial was designed to test whether bardoxolone methyl, a nuclear factor erythroid-2–related factor 2 (Nrf2) activator, slows progression to end-stage renal disease in patients with stage 4 chronic kidney disease and type 2 diabetes mellitus. The trial was terminated because of an increase in heart failure in the bardoxolone methyl group; many of the events were clinically associated with fluid retention.&lt;p&gt;&lt;/p&gt; Methods and Results: We randomized 2,185 patients with type 2 diabetes mellitus (T2DM) and stage 4 chronic kidney disease (CKD) (estimated glomerular filtration rate 15 to &lt;30 mL min−1 1.73 m−2) to once-daily bardoxolone methyl (20 mg) or placebo. We used classification and regression tree analysis to identify baseline factors predictive of heart failure or fluid overload events. Elevated baseline B-type natriuretic peptide and previous hospitalization for heart failure were identified as predictors of heart failure events; bardoxolone methyl increased the risk of heart failure by 60% in patients with these risk factors. For patients without these baseline characteristics, the risk for heart failure events among bardoxolone methyl– and placebo-treated patients was similar (2%). The same risk factors were also identified as predictors of fluid overload and appeared to be related to other serious adverse events.&lt;p&gt;&lt;/p&gt; Conclusions: Bardoxolone methyl contributed to events related to heart failure and/or fluid overload in a subpopulation of susceptible patients with an increased risk for heart failure at baseline. Careful selection of participants and vigilant monitoring of the study drug will be required in any future trials of bardoxolone methyl to mitigate the risk of heart failure and other serious adverse events.&lt;p&gt;&lt;/p&gt

ACE inhibition or angiotensin receptor blockade: Impact on potassium in renal failure

ACE inhibition or angiotensin receptor blockade: Impact on potassium in renal failure.BackgroundInhibition of the renin-angiotensin system is known to raise serum potassium [K+] levels in patients with renal insufficiency or diabetes. No study has evaluated the comparative effects of an angiotensin-converting enzyme (ACE) inhibitor versus an angiotensin receptor blocker (ARB) on the changes in serum [K+] in people with renal insufficiency.MethodsThe study was a multicenter, randomized, double crossover design, with each period lasting one month. A total of 35 people (21 males and 14 females, 19 African Americans and 16 Caucasian) participated, with the mean age being 56 ± 2 years. Mean baseline serum [K+] was 4.4 ± 0.1 mEq/L. The glomerular filtration rate (GFR) was 65 ± 5 mL/min/1.73 m2, and blood pressure was 150 ± 2/88 ± 1 mm Hg. The main outcome measure was the difference from baseline in the level of serum [K+], plasma aldosterone, and GFR following the initial and crossover periods.ResultsFor the total group, serum [K+] changes were not significantly different between the lisinopril or valsartan treatments. The subgroup with GFR values of ≤60 mL/min/1.73 m2 who received lisinopril demonstrated significant increases in serum [K+] of 0.28 mEq/L above the mean baseline of 4.6 mEq/L (P = 0.04). This increase in serum [K+] was also accompanied by a decrease in plasma aldosterone (P = 0.003). Relative to the total group, the change in serum [K+] from baseline to post-treatment in the lisinopril group was higher among those with GFR values of ≤60 mL/min/1.73 m2. The lower GFR group taking valsartan, however, demonstrated a smaller rise in serum [K+], 0.12 mEq/L above baseline (P = 0.1), a 43% lower value when compared with the change in those who received lisinopril. This blunted rise in [K+] in people taking valsartan was not associated with a significant decrease in plasma aldosterone (P = 0.14).ConclusionsIn the presence of renal insufficiency, the ARB valsartan did not raise serum [K+] to the same degree as the ACE inhibitor lisinopril. This differential effect on serum [K+] is related to a relatively smaller reduction in plasma aldosterone by the ARB and is not related to changes in GFR. This study provides evidence that increases in serum [K+] are less likely with ARB therapy compared with ACE inhibitor therapy in people with renal insufficiency

Treatment with patiromer decreases aldosterone in patients with chronic kidney disease and hyperkalemia on renin-angiotensin system inhibitors

Elevated serum aldosterone can be vasculotoxic and facilitate cardiorenal damage. Renin-angiotensin system inhibitors reduce serum aldosterone levels and/or block its effects but can cause hyperkalemia. Patiromer, a nonabsorbed potassium binder, decreases serum potassium in patients with chronic kidney disease on renin-angiotensin system inhibitors. Here we examined the effect of patiromer treatment on serum aldosterone, blood pressure, and albuminuria in patients with chronic kidney disease on renin-angiotensin system inhibitors with hyperkalemia (serum potassium 5.1–6.5 mEq/l). We analyzed data from the phase 3 OPAL-HK study (4-week initial treatment phase of 243 patients; 8-week randomized withdrawal phase of 107 patients). In the treatment phase, the (mean ± standard error) serum potassium was decreased concordantly with the serum aldosterone (−1.99 ± 0.51 ng/dl), systolic/diastolic blood pressure (−5.64 ± 1.04 mm Hg/−3.84 ± 0.69 mm Hg), and albumin-to-creatinine ratio (−203.7 ± 54.7 mg/g), all in a statistically significant manner. The change in the plasma renin activity (−0.44 ± 0.63 μg/l/hr) was not significant. In the withdrawal phase, mean aldosterone levels were sustained with patiromer (+0.23 ± 1.07 ng/dl) and significantly increased with placebo (+2.78 ± 1.25 ng/dl). Patients on patiromer had significant reductions in mean systolic/diastolic blood pressure (−6.70 ± 1.59/−2.15 ± 1.06 mm Hg), whereas those on placebo did not (−1.21 ± 1.89 mm Hg/+1.72 ± 1.26 mm Hg). Significant changes in plasma renin activity were found only in the placebo group (–3.90 ± 1.41 μg/l/hr). Thus, patiromer reduced serum potassium and aldosterone levels independent of plasma renin activity in patients with chronic kidney disease and hyperkalemia on renin-angiotensin system inhibitors

Baseline characteristics and enrichment results from the SONAR trial

Aim: The SONAR trial uses an enrichment design based on the individual response to the selective endothelin receptor antagonist atrasentan on efficacy (the degree of the individual response in the urinary albumin‐to‐creatinine ratio [UACR]) and safety/tolerability (signs of sodium retention and acute increases in serum creatinine) to assess the effects of this agent on major renal outcomes. The patient population and enrichment results are described here. Methods: Patients with type 2 diabetes with an estimated glomerular filtration rate (eGFR) within 25 to 75 mL/min/1.73 m2 and UACR between 300 and 5000 mg/g were enrolled. After a run‐in period, eligible patients received 0.75 mg/d of atrasentan for 6 weeks. A total of 2648 responder patients in whom UACR decreased by ≥30% compared to baseline were enrolled, as were 1020 non‐responders with a UACR decrease of &lt;30%. Patients who experienced a weight gain of &gt;3 kg and in whom brain natriuretic peptide exceeded ≥300 pg/mL, or who experienced an increase in serum creatinine &gt;20% (0.5 mg/dL), were not randomized. Results: Baseline characteristics were similar for atrasentan responders and non‐responders. Upon entry to the study, median UACR was 802 mg/g in responders and 920 mg/g in non‐responders. After 6 weeks of treatment with atrasentan, the UACR change in responders was −48.8% (95% CI, −49.8% to −47.9%) and in non‐responders was −1.2% (95% CI, −6.4% to 3.9%). Changes in other renal risk markers were similar between responders and non‐responders except for a marginally greater reduction in systolic blood pressure and eGFR in responders. Conclusions: The enrichment period has successfully identified a population with a profound UACR reduction without clinical signs of sodium retention in whom a large atrasentan effect on clinically important renal outcomes is possible. The SONAR trial aims to establish whether atrasentan confers renal protection