ABSTRACT Background Mineralocorticoid receptor antagonists (MRAs) reduce systolic blood pressure (SBP) and increase serum potassium concentration ([K+]). This indirect comparison investigated any differences in SBP-lowering and hyperkalemia risk between finerenone, a nonsteroidal MRA, and the steroidal MRA spironolactone ± a potassium binder. Methods In FIDELITY (a pooled analysis of FIDELIO-DKD and FIGARO-DKD), a subgroup of patients with treatment-resistant hypertension (TRH) and chronic kidney disease meeting eligibility criteria of the AMBER trial were identified (FIDELITY-TRH). The main outcomes were mean change in SBP, incidence of serum [K+] ≥5.5 mmol/L and hyperkalemia-associated treatment discontinuation. Results at ∼17 weeks were compared with 12 weeks from AMBER. Results In 624 FIDELITY-TRH patients and 295 AMBER patients, the least squares mean change in SBP (mmHg) from baseline was −7.1 for finerenone and −1.3 for placebo {between-group difference −5.74 [95% confidence interval (CI) −7.99 to −3.49], P < .0001} versus −11.7 for spironolactone + patiromer and −10.8 for spironolactone + placebo [between-group difference −1.0 (95% CI −4.4–2.4), P = .58]. The incidence of serum [K+] ≥5.5 mmol/L was 12% for finerenone and 3% for placebo versus 35% with spironolactone + patiromer and 64% with spironolactone + placebo. Treatment discontinuation due to hyperkalemia was 0.3% for finerenone and 0% for placebo versus 7% for spironolactone + patiromer and 23% for spironolactone + placebo. Conclusions In patients with TRH and chronic kidney disease compared with spironolactone with or without patiromer, finerenone was associated with a lower SBP reduction and lower risk of hyperkalemia and treatment discontinuation. Trial Registration: AMBER (NCT03071263), FIDELIO-DKD (NCT02540993), FIGARO-DKD (NCT02545049)

BACKGROUND:The relationship between serum potassium, mortality, and conditions commonly associated with dyskalemias, such as heart failure (HF), chronic kidney disease (CKD), and/or diabetes mellitus (DM) is largely unknown.METHODS:We reviewed electronic medical record data from a geographically diverse population (n = 911,698) receiving medical care, determined the distribution of serum potassium, and the relationship between an index potassium value and mortality over an 18-month period in those with and without HF, CKD, and/or DM. We examined the association between all-cause mortality and potassium using a cubic spline regression analysis in the total population, a control group, and in HF, CKD, DM, and a combined cohort.RESULTS:27.6% had a potassium <4.0 mEq/L, and 5.7% had a value ≥5.0 mEq/L. A U-shaped association was noted between serum potassium and mortality in all groups, with lowest all-cause mortality in controls with potassium values between 4.0 and <5.0 mEq/L. All-cause mortality rates per index potassium between 2.5 and 8.0 mEq/L were consistently greater with HF 22%, CKD 16.6%, and DM 6.6% vs. controls 1.2%, and highest in the combined cohort 29.7%. Higher mortality rates were noted in those aged ≥65 vs. 50-64 years. In an adjusted model, all-cause mortality was significantly elevated for every 0.1 mEq/L change in potassium <4.0 mEq/L and ≥5.0 mEq/L. Diuretics and renin-angiotensin-aldosterone system inhibitors were related to hypokalemia and hyperkalemia respectively.CONCLUSION:Mortality risk progressively increased with dyskalemia and was differentially greater in those with HF, CKD, or DM.

Objective: Recurrent hyperkalemia frequently limits use of renin–angiotensin–aldosterone system inhibitors (RAASi) in chronic kidney disease (CKD) patients with hypertension, diabetes, and/or heart failure. Patiromer is a sodium-free, nonabsorbed potassium (K+)-binding polymer approved by the US Food and Drug Administration for the treatment of hyperkalemia. This post-hoc analysis of OPAL-HK examined the effectiveness and safety of patiromer in reducing serum K+ in hyperkalemic CKD patients on RAASi, with hypertension, receiving diuretic therapy versus those not on diuretics. Methods: Depending on the degree of hyperkalemia at baseline, CKD patients with serum K+ from 5.1 to less than 6.5 mmol/l on RAASi (n = 243) were assigned to a patiromer of total dose 8.4 or 16.8 g, divided twice daily. Changes in serum K+, and tolerability and safety were assessed over 4 weeks in patients on and not on diuretics. Results: At baseline, 132 patients used diuretics and 111 were not on diuretics, mean age was 64.3 and 64.0 years, respectively, and 63 and 51% were men. Similar reductions in serum K+ were seen over 4 weeks in both subgroups. At week 4, serum K+ fell by −0.95 ± 0.04 mmol/l with any diuretic and −1.04 ± 0.05 mmol/l with no diuretic. Patiromer was well tolerated, with mild-to-moderate constipation reported as the most common adverse event (7.6 and 14.4% of patients on any diuretic or no diuretic, respectively). Hypokalemia (s-K+ <3.5 mEq/l) was reported in 2.3% of patients on any diuretic and in 3.7% not on diuretics. Conclusion: The serum K+-lowering efficacy and safety profile of patiromer in hyperkalemia patients with CKD was not compromised by diuretic therapy.

Background: Aldosterone (ALD) plays an important role in the progression of HF and may be increased in HF due to activation of the renin-angiotensin-aldosterone system (RAAS). Hyperkalemia (HK) may also increase ALD and limits the use of RAAS inhibitors (RAASi). Patiromer, a nonabsorbed K+ binder,

Objective: Diuretics, alone or in combination, are frequently prescribed in chronic kidney disease (CKD) and heart failure (HF) patients to reduce volume, blood pressure, and/or for symptom control. Clinicians may also use them to reduce the risk of hyperkalemia, but high doses of diuretics may lead to adverse events from intravascular volume depletion or gout. Patiromer is a non-absorbed K+-binding polymer recently approved by the FDA for the treatment of hyperkalemia (HK). We compared patiromer's effects in RAASi-treated CKD patients with HK on different types of diuretics to patients not receiving diuretics in the treatment phase of OPAL-HK. Design and Method: CKD patients (n = 243) with baseline serum K+ 5.1 to < 6.5 mEq/L on RAASi received patiromer (4.2 or 8.4 g twice daily to start) in the 4-week treatment phase of OPAL-HK. For this post hoc analysis, change in serum-K+ from baseline to week 4 was assessed in patients stratified by baseline diuretic use: 1) loop only, 2) thiazide/thiazide-like only, 3) combination of loop and thiazide/thiazide-like, 4) any (alone or in combination), and 5) none. Subjects receiving aldosterone antagonists alone were allocated to the “No Diuretics” group. Results: Across groups, mean (SD) age ranged from 62.9 (10.5) to 65.4 (8.6) years and % male from 51% to 67%. Mean serum K+ decreased from baseline at week 4 in all subgroups (Table). Reductions in serum K+ did not differ in patients receiving any diuretic vs those not on diuretics. Patiromer was well tolerated; mild-to-moderate constipation was the most common AE (14.4% and 7.6%, respectively, in patients not on diuretics and on any diuretics), with 1 patient in each group discontinuing. Hypokalemia (serum K +< 3.5 mEq/L) was reported in 3.7% and 2.3%, respectively Conclusions: The serum K+-lowering efficacy of patiromer in HK patients was unaffected by concomitant diuretics.

to display brain RAS activation), and Ang II-infused mice. Brain nuclei were homogenized and incubated with excess angiotensinogen to detect AGA, both before and after acid activation of prorenin, with or without the renin inhibitor aliskiren to correct for non-renin-mediated AGA. Renin-dependent (i.e., aliskiren-inhibitable) AGA was readily detectable in brain nuclei, the highest AGA being present in brainstem (u003e thalamus 1⁄4 cerebellum 1⁄4 striatum 1⁄4 midbrain u003e hippocampus 1⁄4 cortex). Brain AGA increased non-significantly after prorenin activation, suggesting that brain prorenin levels are low or absent. Buffer perfusion reduced AGA in all brain areas by u003e60%. Plasma renin (expressed per mL plasma) was 40-800 x higher than brain renin (expressed per g tissue). Plasma prorenin levels resembled plasma renin levels. AGA was undetectable in plasma and brain of renin KO mice, both before and after prorenin activation. DOCA-salt and Ang II suppressed plasma renin, and parallel decreases were observed for brain renin. In summary, brain renin levels (per g tissue) correspond with the amount of renin present in 1-20 mL blood plasma. Brain renin disappears after buffer perfusion, and varies in association with plasma renin. These data indicate that renin detected in brain nuclei represents plasma renin and/or locally activated plasma prorenin. DOCA-salt exposure does not selectively increase brain renin expression.

Statins may have nephroprotective as well as cardioprotective effects in patients with cardiovascular disease. In the Treating to New Targets (TNT) study (NCT00327691), patients with coronary heart disease (CHD) were randomized to atorvastatin 10 or 80 mg/day and followed for 4.9 years. The relation between intrastudy change in estimated glomerular filtration rate (eGFR) from baseline and the risk of major cardiovascular events (MCVEs, defined as CHD death, nonfatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke) was assessed among 9,500 patients stratified by renal function: improving (change in eGFR more than +2 ml/min/1.73 m(2)), stable (-2 to +2 ml/min/1.73 m(2)), and worsening (less than -2 ml/min/1.73 m(2)). Compared with patients with worsening renal function (1,479 patients, 15.6%), the rate of MCVEs was 28% lower in patients with stable renal function (2,241 patients, 23.6%) (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.60 to 0.87; p = 0.0005) and 64% lower in patients with improving renal function (5,780 patients, 60.8%; HR 0.36; 95% CI 0.30 to 0.43; p <0.0001). For each 1 ml/min/1.73 m(2) increase in eGFR, the absolute reduction in the rate of MCVEs was 2.7% (HR 0.973; 95% CI 0.967 to 0.980; p <0.0001). An absolute MCVE rate reduction per 1 ml/min/1.73 m(2) increase in eGFR of 2.0% was reported with atorvastatin 10 mg and 3.3% with atorvastatin 80 mg. In conclusion, intrastudy stabilization or increase in eGFR in atorvastatin-treated patients with CHD from the TNT study was associated with a reduced rate of MCVEs. Statin-treated CHD patients with progressive renal impairment are at high risk for future cardiovascular events.

BACKGROUND:Improvement in renal function and decreases in serum uric acid (SUA) have been reported following prolonged high-intensity statin (HMG-CoA reductase inhibitor) therapy. This post hoc analysis of the SAGE trial examined the effect of intensive versus less intensive statin therapy on renal function, safety, and laboratory parameters, including SUA, in elderly coronary artery disease (CAD) patients (65-85 years) with or without chronic kidney disease (CKD). METHODS:Patients were randomized to atorvastatin 80 mg/day or pravastatin 40 mg/day and treated for 12 months. Patients were stratified using Modification of Diet in Renal Disease (MDRD) estimated glomerular filtration rates (eGFRs) in CKD (eGFR <60 mL/min/1.73 m(2)) and non-CKD populations. RESULTS:Of the 893 patients randomized, 858 had complete renal data and 418 of 858 (49%) had CKD (99% Stage 3). Over 12 months, eGFR increased with atorvastatin and remained stable with pravastatin (+2.38 vs. +0.18 mL/min/1.73 m(2), respectively; p < 0.0001). MDRD eGFR improved significantly in both CKD treatment arms; however, the increased eGFR in patients without CKD was significantly greater with atorvastatin (+2.08 mL/min/1.73 m(2)) than with pravastatin (-1.04 mL/min/1.73 m(2)). Modest reductions in SUA were observed in both treatment arms, but a greater fall occurred with atorvastatin than with pravastatin (-0.52 vs. -0.09 mg/dL, p < 0.0001). Change in SUA correlated negatively with changes in eGFR and positively with changes in low-density lipoprotein cholesterol. Reports of myalgia were rare (3.6% CKD; 5.7% non-CKD), and there were no episodes of rhabdomyolysis. Elevated serum alanine and aspartate transaminase to >3 times the upper limit of normal occurred in 4.4% of atorvastatin- and 0.2% of pravastatin-treated patients. CONCLUSION:Intensive management of dyslipidemia in older patients with stable coronary heart disease may have beneficial effects on renal function and SUA.

Background and Purpose— Higher low-density lipoprotein cholesterol is associated with more rapid chronic kidney disease progression; reduction in cholesterol with statins, in conjunction with statins’ pleiotropic effects, such as decreasing inflammation, may be renoprotective. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial assessed the effect of statin treatment on the risk of nonfatal and fatal stroke in subjects with a noncardioembolic stroke or transient ischemic attack, no known coronary heart disease, and low-density lipoprotein cholesterol between 2.6 and 4.9 mmol/L (100–190 mg/dL). Methods— We explored the effect of randomization to atorvastatin 80 mg/d or placebo on the change in estimated glomerular filtration rate (eGFR; using the 4-component Modification of Diet in Renal Disease Study equation) in SPARCL subjects (n=4731) with (eGFR, <60 mL/min per 1.73 m 2 ; n=3119) and without (eGFR, ≥60 mL/min per 1.73 m 2 ; n=1600) chronic kidney disease overall and by glycemic status at baseline. Results— Mean baseline eGFR was similar between treatment groups (65.5±0.26 versus 65.6±0.26 mL/min per 1.73 m 2 atorvastatin versus placebo; 33% versus 34% had chronic kidney disease, respectively; P =0.55). After 60 months, eGFR increased 3.46±0.33 mL/min per 1.73 m 2 in those randomized to atorvastatin versus 1.42±0.34 mL/min per 1.73 m 2 in those randomized to placebo ( P <0.001) independent of baseline renal function. In the subgroup with diabetes mellitus at randomization, eGFR increased 1.12±0.92 mL/min per 1.73 m 2 in the atorvastatin group and decreased 1.69±0.92 mL/min per 1.73 m 2 in placebo group during a period of 60 months ( P =0.016). Conclusions— This post hoc analysis suggests that atorvastatin treatment may improve renal function in patients with prior stroke or transient ischemic attack with and without chronic kidney disease, and that atorvastatin treatment may prevent eGFR decline in patients with stroke and diabetes mellitus. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00147602.

Impaired kidney function often accompanies heart failure (HF) and is associated with a worse prognosis. This post hoc analysis of the Treating to New Targets (TNT) trial examined whether the observed decrease in HF hospitalizations with high- compared to low-dose atorvastatin could be related to improvements in kidney function. Of 10,001 TNT participants, 9,376 had estimated glomerular filtration rate (eGFR) measurements at baseline and 1 year and were included in this analysis. The association of change in year-1 eGFR and subsequent HF hospitalization was examined using Cox regression models. In total 218 participants developed subsequent HF hospitalization. Little change in eGFR occurred over 1 year in the atorvastatin 10-mg group, whereas eGFR improved in the 80-mg group by 1.48 ml/min/1.73 m(2) (95% confidence interval 1.29 to 1.67, p <0.0001). Subsequent HF was preceded by a decrease in eGFR over 1 year compared to modest improvement in those without subsequent HF (-0.09 +/- 7.89 vs 0.81 +/- 6.90 ml/min/1.73 m(2), p = 0.0015). After adjusting for baseline eGFR, each 5-ml/min/1.73 m(2) increase in eGFR at 1 year was associated with a lower risk of subsequent HF hospitalization (hazard ratio 0.85, 95% confidence interval 0.77 to 0.94, p = 0.002). This relation was independent of treatment effect or change in low-density lipoprotein cholesterol level at 1 year. In conclusion, treatment with high- compared to low-dose atorvastatin was associated with improvement in eGFR at 1 year, which was related to a decrease in subsequent HF hospitalization. This suggests that improvement in kidney function may be related to the beneficial effect of high-dose atorvastatin on HF hospitalization. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;109:1761-1766)

Background: Renal impairment often accompanies heart failure (HF) and is a recognized independent risk factor for morbidity and mortality in HF patients. In TNT, a dose-dependent improvement in renal function and reduction in hospitalization for congestive HF (hCHF) in CHD patients with dyslipidemia treated with 10 mg or 80 mg of atorvastatin (A) was demonstrated. The purpose of this post hoc TNT sub-analysis is to examine the predictive value of change in eGFR at 1 year (yr) on subsequent hCHF.

HIGHER PREVALENCE OF CV-RELATED COMORBIDITIES IN US ADULTS WITH STAGE IIIB CKD SUPPORTS A MODIFICATION TO THE EXISTING NKF/KDIGO CLASSIFICATION OF CKD Daniel Wilson, Andreas Kuznik, Jack Mardekian, Lisa Tarasenko Pfizer Inc, New York, NY, USA Some clinicians have recommended revision of the current NKF/KDIGO classification of CKD and establishing Stages IIIa and IIIb CKD because of perceived differences in CV risk profiles in Stage III. CKD is often associated with CV target organ damage and CHD risk equivalents. In this analysis of a nationally representative database, we quantified the prevalence of CVD and CHD risk equivalents in US adults by CKD stage, utilizing the suggested modification of Stage III CKD, in an attempt to determine if such a revision is warranted. Data from NHANES 2001–2008 were stratified by CKD stage; eGFR was calculated using the 4-variable MDRD Study equation. CKD staging used modified NKF criteria: Stage III CKD was subdivided into Stage IIIa (eGFR >45–<60 mL/min/1.73m) and Stage IIIb (eGFR 30– <45 mL/min/1.73m). CVD history was self reported; DM was identified by self report, use of diabetic medications, or fasting glucose ≥126 mg/dL. Of the NHANES participants with valid renal data, 12% had CKD. The prevalence of CV-related comorbidities increased with progressive renal impairment (Table). Prevalence of CVD, CHD and stroke increased markedly between CKD Stage IIIa and IIIb. Prevalence of DM was notably higher in Stage IV versus Stage I CKD. CKD Stage CVD* CHD Stroke DM Normal 5.9% 4.2% 1.9% 7.8% I 10.9% 7.2% 2.8% 33.7% II 24.3% 17.6% 6.5% 30.9% IIIa 25.6% 19.1% 7.9% 20.4% IIIb 48.7% 33.6% 23.5% 33.1% IV 60.1% 42.6% 33.2% 49.1% *Composite of CHD, stroke and CHF Persons with CKD, especially those with advanced renal impairment, have a high prevalence of concomitant CVD. Our analysis supports the proposed revision of the current NKF/KDIGO classification of CKD, as the prevalence of specific CV comorbidities and CHD risk equivalents was substantially higher in Stage IIIb versus IIIa CKD.

Using data from the 2001-2002, 2003-2004, and 2005-2006 National Health and Nutrition Examination Surveys, we generated current estimates of the prevalence and overlap of cardiovascular comorbidities among older US adults (aged ≥ 65 years) with dyslipidemia, stratified by lipid-lowering medication use. We estimated that among the 32.5 million older US adults, 67% (21.8 million) are dyslipidemic. Among these subjects, the prevalence of congestive heart failure (CHF) is 9.9% (2.2 million); coronary heart disease (CHD): 27.0% (5.9 million); history of stroke: 10.4% (2.3 million); diabetes: 26.5% (5.8 million); and ≥ 1 of these comorbidities: 51.2% (11.1 million). Among dyslipidemic subjects who are receiving lipid-lowering medication (10.4 million), these figures are CHF: 10.1% (1.0 million); CHD: 29.6% (3.1 million); history of stroke: 12.3% (1.3 million); diabetes: 31.5% (3.3 million); and ≥ 1 of these comorbidities: 55.3% (5.7 million); compared with those who are not receiving lipid-lowering medication (11.4 million), CHF: 9.8% (1.1 million); CHD: 24.7% (2.8 million); history of stroke: 8.6% (1 million); diabetes: 21.9% (2.5 million); and ≥ 1 of these comorbidities: 47.5% (5.4 million). Among older US adults with dyslipidemia, 51.2% have ≥ 1 of the cardiovascular conditions studied. Among those who are receiving lipid-lowering medication, 55.3% report having comorbidities that put them at high risk for new or recurring cardiovascular events. Even more noteworthy is that 47.5% of dyslipidemic older adults who are not taking statins also have significant comorbidities. This highlights a critical unmet medical need for this growing population, which, solely based on age, is more likely to be at risk for cardiovascular events.