Slowing the Progression of Diabetic Kidney Disease.

Diabetes is the most frequent cause of kidney disease that progresses to end-stage renal disease worldwide, and diabetic kidney disease is significantly related to unfavorable cardiovascular outcomes. Since the 1990s, specific therapies have emerged and been approved to slow the progression of diabetic kidney disease, namely, renin-angiotensin-aldosterone system blockers (including angiotensin-converting enzyme inhibitors (ACEi) angiotensin receptor blockers (ARBs), the non-steroidal mineralocorticoid receptor antagonist (NS-MRA), finerenone, and sodium-glucose cotransporter-2 (SGLT2) inhibitors). Mechanistically, these different classes of agents bring different anti-inflammatory, anti-fibrotic, and complementary hemodynamic effects to patients with diabetic kidney disease such that they have additive benefits on slowing disease progression. Within the coming year, there will be data on renal outcomes using the glucagon-like peptide-1 receptor agonist, semaglutide. All the aforementioned medications have also been shown to improve cardiovascular outcomes. Thus, all three classes (maximally dosed ACEi or ARB, low-dose SGLT-2 inhibitors, and the NS-MRA, finerenone) form the "pillars of therapy" such that, when used together, they maximally slow diabetic kidney disease progression. Ongoing studies aim to expand these pillars with additional medications to potentially normalize the decline in kidney function and reduce associated cardiovascular mortality.

Effect on cardiac function among patients with type 2 diabetes following high-dose mineralocorticoid receptor antagonist using echocardiography; data from the MIRAD randomized clinical trial.

BACKGROUND: Early heart failure prevention is central in patients with type 2 diabetes, and mineralocorticoid receptor antagonists (MRAs) have shown to improve prognosis. We investigated the effect of high-dose MRA, eplerenone, on cardiac function and structure in patients with type 2 diabetes and established or increased risk of cardiovascular disease but without heart failure. METHODS: In the current randomized, placebo-controlled clinical trial, 140 patients with high-risk type 2 diabetes were randomized to high-dose eplerenone (100-200 mg daily) or placebo as add-on to standard care for 26 weeks. Left ventricular systolic and diastolic function, indexed left ventricular mass (LVMi), and global longitudinal strain (GLS) were assessed using echocardiography at baseline and after 26 weeks of treatment. RESULTS: Of the included patients, 138 (99%) had an echocardiography performed at least once. Baseline early diastolic in-flow velocity (E-wave) indexed by mitral annulus velocity (e') was mean (SD) 11.1 (0.5), with 31% of patients reaching above 12. No effect of treatment on diastolic function was observed measured by E/e' (0.0, 95%CI [-1.2 to 1.2], P = 0.992) or E/A (-0.1, 95%CI [-0.2 to 0.0], P = 0.191). Mean left ventricular ejection fraction (LVEF) at baseline was 59.0% (8.0). No improvement in systolic function was observed when comparing groups after 26 weeks (LVEF: 0.9, 95%CI [-1.1 to 2.8], P = 0.382; GLS: -0.4%, 95%CI [-1.5 to 0.6], P = 0.422), nor in LVMi (-3.8 g/m2 95%CI [-10.2 to 2.7], P = 0.246). CONCLUSION: In the present echo sub-study, no change in left ventricular function was observed following high-dose MRA therapy in patients with type 2 diabetes when evaluated by conventional echocardiography. TRIAL REGISTRATION: Date of registration 25/08/2015 (EudraCT number: 2015-002,519-14).

Patiromer for the management of hyperkalemia in heart failure with reduced ejection fraction: the DIAMOND trial.

AIMS: To investigate the impact of patiromer on the serum potassium level and its ability to enable specified target doses of renin-angiotensin-aldosterone system inhibitor (RAASi) use in patients with heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS: A total of 1642 patients with HFrEF and current or a history of RAASi-related hyperkalemia were screened and 1195 were enrolled in the run-in phase with patiromer and optimization of the RAASi therapy [≥50% recommended dose of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, and 50 mg of mineralocorticoid receptor antagonist (MRA) spironolactone or eplerenone]. Specified target doses of the RAASi therapy were achieved in 878 (84.6%) patients; 439 were randomized to patiromer and 439 to placebo. All patients, physicians, and outcome assessors were blinded to treatment assignment. The primary endpoint was between-group difference in the adjusted mean change in serum potassium. Five hierarchical secondary endpoints were assessed. At the end of treatment, the median (interquartile range) duration of follow-up was 27 (13-43) weeks, the adjusted mean change in potassium was +0.03 mmol/l in the patiromer group and +0.13 mmol/l in the placebo group [difference in the adjusted mean change between patiromer and placebo: -0.10 mmol/l (95% confidence interval, CI -0.13, 0.07); P < 0.001]. Risk of hyperkalemia >5.5 mmol/l [hazard ratio (HR) 0.63; 95% CI 0.45, 0.87; P = 0.006), reduction of MRA dose (HR 0.62; 95% CI 0.45, 0.87; P = 0.006), and total adjusted hyperkalemia events/100 person-years (77.7 vs. 118.2; HR 0.66; 95% CI 0.53, 0.81; P < 0.001) were lower with patiromer. Hyperkalemia-related morbidity-adjusted events (win ratio 1.53, P < 0.001) and total RAASi use score (win ratio 1.25, P = 0.048) favored the patiromer arm. Adverse events were similar between groups. CONCLUSION: Concurrent use of patiromer and high-dose MRAs reduces the risk of recurrent hyperkalemia (ClinicalTrials.gov: NCT03888066).

Comparative Safety and Effectiveness of Aldosterone Antagonists Versus Beta-Blockers as Fourth Agents in Patients With Apparent Resistant Hypertension.

BACKGROUND: Limited evidence exists regarding long-term effectiveness and safety of aldosterone antagonists (AAs) versus beta blockers (BBs) as fourth-line antihypertensive agents in patients with resistant hypertension (RH). We evaluated the comparative effectiveness and safety of aldosterone AA versus BB. METHODS: We conducted a real-world retrospective cohort study using IBM MarketScan commercial claims and Medicare Supplemental claims (2007-2019). Patients with RH entered the cohort (ie, index date) when they newly initiated either AA or BB. The effectiveness outcome was major adverse cardiovascular events. Safety outcomes were hyperkalemia, gynecomastia, and kidney function deterioration. Potential confounding was addressed by adjustment for baseline characteristics via stabilized inverse probability of treatment weighting (SIPTW) based on propensity scores. Cox proportional hazards regression with SIPTWs were used to estimate adjusted hazard ratio (aHR) and 95% CI comparing risk for outcomes between AA and BB groups. RESULTS: We identified 80 598 patients with RH (mean age: 61 years, 51% males), of which 6626 initiated AA and 73 972 initiated BB as the fourth antihypertensive agent. Among patients with RH, initiation of AA as a fourth-line antihypertensive agent did not significantly reduce major adverse cardiovascular event risk relative to BB initiation (aHR, 0.77 [95% CI, 0.50-1.19]) but did substantially increase the risk of hyperkalemia (aHR, 3.86 [95% CI, 2.78-5.34]), gynecomastia (aHR, 9.51 [95% CI, 5.69-15.89]), and kidney function deterioration (aHR, 1.63 [95% CI, 1.34-1.99]). CONCLUSIONS: Long-term clinical trials powered to assess major adverse cardiovascular events are necessary to understand the risk-benefit trade-off of AA as fourth-line therapy for RH.

Cardiovascular and kidney outcomes of spironolactone or eplerenone in combination with ACEI/ARBs in patients with diabetic kidney disease.

BACKGROUND: Mineralocorticoid receptor antagonist (MRA) when combined with either angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) may provide additional benefits of cardiovascular and kidney disease risk reduction in patients with diabetic kidney disease (DKD) and hypertension. We evaluated the effectiveness of combination therapy (MRAs, either spironolactone or eplerenone, plus ACEI/ARB) compared with monotherapy (ACEI/ARB only) in patients with DKD and hypertension. METHODS: Retrospective cohort study was performed in patients (age ≥ 18 years) with hypertension, diabetes, and albuminuria between 2008 and 2018 within an integrated health system. MRA with ACEI/ARB compared to ACEI/ARB alone was evaluated on composite of cardiovascular events, progression to end-stage kidney disease, or all-cause mortality. Hyperkalemia was compared as a safety outcome. RESULTS: We identified 1282 patients who received MRAs with ACEI/ARBs and 5484 patients who received ACEI/ARBs alone. Median exposure time for combination therapy was 126 days. The rates per 100 person-years of cardiovascular, kidney, or all-cause mortality outcomes were 12.2 and 9.2 for combination therapy and monotherapy, respectively (hazard ratios = 1.24, 95% Confidence Interval (CI):0.94, 1.63). Patients receiving combination therapy had greater reduction in urine albumin-to-creatinine ratio compared with monotherapy (Mean reduction: 823 and 585 mg/g; p < 0.001, respectively). Hyperkalemia was more frequent in combination therapy versus monotherapy (22.3 vs. 10.9 per 100 person-years for combination and monotherapy, respectively; hazard ratios = 1.78, 95%CI: 1.42, 2.24). CONCLUSIONS: Among patients with DKD and hypertension, the short-term use of MRAs, either spironolactone or eplerenone, in combination with ACEI/ARBs, was not associated with lower risk of cardiovascular or kidney outcomes compared with ACEI/ARB monotherapy. The risk of hyperkalemia and the short duration of combination therapy may suggest a real-world clinical challenge for MRA with ACEI/ARB combination therapy.

Patients with acute heart failure treated with the CARRESS-HF diuretic protocol in association with canrenoate potassium: Tolerance of high doses of canrenoate potassium.

BACKGROUND: Oral mineralocorticoid receptor antagonists have failed to prove their efficacy for decongestion and potassium homeostasis in acute heart failure. Intravenous mineralocorticoid receptor antagonists have yet to be studied. AIM: The aim of this study was to confirm the safety of high-dose potassium canrenoate in association with classic diuretics in acute heart failure. METHODS: This retrospective single-centre study included consecutive patients who were hospitalized with acute heart failure between 2013 and 2018. One hundred patients with overload treated with the standardized diuretic protocol from the CARRESS-HF trial were included. There were no exclusion criteria relating to creatinine or kalaemia at the time of admission. Two groups were constituted on the basis of potassium canrenoate posology: a low-dose group (<300mg/day) and a high-dose group (≥300mg/day); the groups were similar in terms of baseline characteristics. RESULTS: Mean daily potassium canrenoate doses were 198mg/day (range 100-280mg/day) in the low-dose group and 360mg/day (range 300-600mg/day) in the high-dose group. There was no significant difference between the high-dose and low-dose groups in terms of mortality, dialysis, renal function, hyperkalaemia, haemorrhage, sepsis or confusion. CONCLUSIONS: Potassium canrenoate at high doses can be used safely in association with standard diuretics in acute heart failure, even in patients with altered renal function. A prospective study is required to evaluate the efficacy of high-dose potassium canrenoate in preventing hypokalaemia and improving decongestion.

Mineralocorticoid Receptor Antagonists for Hypertension Management in Advanced Chronic Kidney Disease: BLOCK-CKD Trial.

Spironolactone, a steroidal mineralocorticoid receptor antagonist, is recommended as add-on therapy for treatment-resistant/uncontrolled hypertension. However, caution is advised in patients with advanced chronic kidney disease (CKD) due to an increased risk for hyperkalemia. KBP-5074 is a nonsteroidal mineralocorticoid receptor antagonist under investigation for the treatment of treatment-resistant and uncontrolled hypertension in patients with moderate-to-severe CKD. BLOCK-CKD is a phase 2, international, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of KBP-5074, on top of current therapy, in patients with stage 3B/4 CKD (estimated glomerular filtration rate ≥15 and ≤44 mL/[min·1.73 m2]) and resistant hypertension (trough cuff seated systolic blood pressure ≥140 mm Hg, despite treatment with maximally tolerated doses of 2 or more antihypertensive medicines with complementary mechanisms). Patients (n=240) will be randomized 1:1:1 to once-daily treatment with KBP-5074 0.25 mg, KBP-5074 0.5 mg, or placebo, stratified by estimated glomerular filtration rate (≥30 versus <30 mL/[min·1.73 m2]) and systolic blood pressure (≥160 versus <160 mm Hg). Approximately 30% of enrolled patients should have an estimated glomerular filtration rate of 15 to 29 mL/(min·1.73 m2). The primary efficacy analysis is the change in trough cuff seated systolic blood pressure from baseline to day 84 for the KBP-5074 doses compared with placebo. Changes in urinary albumin-creatinine ratio will be assessed along with changes in serum potassium/incidence of hyperkalemia and changes in estimated glomerular filtration rate and serum creatinine. BLOCK-CKD will determine whether the addition of KBP-5074 will effectively lower blood pressure without an increased risk of hyperkalemia in patients who are not candidates for steroidal mineralocorticoid receptor antagonists due to advanced CKD. Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT03574363.

Salt intake in mineralocorticoid receptor antagonist-treated primary aldosteronism: foe or ally?

Mild hyperkalemia is a common side effect of mineralocorticoid receptor antagonist (MRA) treatment of patients with primary aldosteronism (PA), which can be worsened by instructions to minimize salt intake. Our objective was to evaluate the effect of salt consumption on serum potassium levels and mean, mean minimal, and mean maximal systolic and diastolic blood pressure (BP) in MRA-treated hyperkalemic PA patients under relative salt restriction. Seventeen consecutive mildly hyperkalemic MRA-treated PA patients aged 66.3 ± 8.37 years were recruited. Body mass index (BMI) and BP were assessed, and serum and 24-h urinary sodium and potassium levels, plasma renin, and serum aldosterone were measured, while patients followed a relatively salt-restricted diet, after 1 month of controlled salt supplementation (usual salt-restricted diet plus 4 g salt/day) and after 6 months on instructions for free dietary salt consumption. Baseline salt consumption was additionally evaluated in two more patient groups (normotensive subjects and normokalemic MRA-treated PA patients). One month of controlled salt supplementation (24-h urine sodium (median, min, max): 195.2 (120.30-275.20) vs 110.13 (34.30-139.20) mEq/day, p < 0.001) resulted in increased kaliuresis (62.25 (40.69-97.0) vs 54.0 (23.28-79.60) mEq/day, p = 0.001) and a decrease of serum potassium (5.2 (5-5.70) vs 4.6 (3.8-5.1) mEq/L, p < 0.001), while serum sodium (139 (133-141) vs 1 39 (135-144) mEq/L) and mean systolic (130 (105-141 vs. 130 (106-141) mmHg) and diastolic (76 (53-85) vs75 (53-84) mmHg) BP remained stable. These findings were unchanged after 6 months of free salt consumption. BMI remained constant, while plasma renin and serum aldosterone decreased following salt repletion. Adequate salt consumption attenuates MRA-induced hyperkalemia in relatively salt-restricted PA patients without affecting BP or BMI.

Effect of the mineralocorticoid receptor antagonist eplerenone on liver fat and metabolism in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial (MIRAD trial).

AIM: To investigate whether the mineralocorticoid receptor antagonist eplerenone has beneficial effects on liver fat and metabolism in patients with type 2 diabetes (T2D), the mineralocorticoid receptor antagonist in type 2 diabetes (MIRAD) trial. MATERIAL AND METHODS: In this 26-week, double-blind, randomized, placebo-controlled trial, we enrolled 140 patients with T2D and high risk of cardiovascular disease. Patients were randomized 1:1 to either eplerenone with a target dose of 200 mg/day for patients with estimated glomerular filtration rate (eGFR) of 60 mL/min per 1.73 m2 or more and 100 mg/day for patients with eGFR between 41 and 59 mL/min per 1.73 m2 or placebo. The primary outcome measure was change in liver fat by proton magnetic resonance spectroscopy at week 26 from baseline; secondary outcomes were changes in metabolism, and safety by incident hyperkalaemia. RESULTS: No changes in liver fat in the eplerenone group 0.91% (95% CI -0.57 to 2.39) or the placebo group -1.01% (-2.23 to 0.21) were found. The estimated absolute treatment difference was 1.92% (-3.81 to 0.01; P = 0.049). There was no beneficial impact on supporting secondary outcome variables of metabolism as fat mass distribution, lipid metabolism or insulin resistance. Despite a high dosage of eplerenone 164 versus 175 mg in patients treated with placebo (P = 0.228), the number of patients with incident hyperkalaemia (≥5.5 mmol/L) was low, with six in the eplerenone versus two in the placebo group (P = 0.276). CONCLUSION: The addition of high doses of eplerenone to background antidiabetic and antihypertensive therapy does not show beneficial effects on liver fat and metabolism in patients with T2D.

Clinical efficacy of Unani medicine Renax for treatment of Urolithiasis.

Stone formation occurs most commonly in acute and chronic renal failure. A kidney stone is a solid lump made up of crystals that separate from the urine and build up on the inner surfaces of the kidney. The current study was conducted to investigate the clinical efficacy of Unani medicine Renax in comparison with allopathic medicine (Spironolactone + Furosemide) to treat urolithiasis. The study was conducted in District Dera Ghazi Khan, South Punjab region. This was case control, randomized, double blind clinical study. All patients were examined by the Physician and given either herbal or allopathic medicine for Urolithiasis. The patients were divided "into two groups" a control group and test groups. A Total of 24 patients were completely cured out of 50 by use of Renax while a total of 9 patients was cured out of 50 with allopathic medicine (Spironolactone + Furosemide). This study validated the claim of traditional healer for use of Unani medicine in the treatment of urolithiasis.

Future drug discovery in renin-angiotensin-aldosterone system intervention.

INTRODUCTION: Renin-angiotensin-aldosterone system inhibitors (RAASIs), including angiotensin-converting enzyme inhibitors, angiotensin AT1 receptor blockers and mineralocorticoid receptor antagonists (MRAs), are the cornerstone for the treatment of cardiovascular and renal diseases. Areas covered: The authors searched MEDLINE, PubMed and ClinicalTrials.gov to identify eligible full-text English language papers. Herein, the authors discuss AT2-receptor agonists and ACE2/angiotensin-(1-7)/Mas-receptor axis modulators, direct renin inhibitors, brain aminopeptidase A inhibitors, biased AT1R blockers, chymase inhibitors, multitargeted drugs, vaccines and aldosterone receptor antagonists as well as aldosterone synthase inhibitors. Expert opinion: Preclinical studies have demonstrated that activation of the protective axis of the RAAS represents a novel therapeutic strategy for treating cardiovascular and renal diseases, but there are no clinical trials supporting our expectations. Non-steroidal MRAs might become the third-generation of MRAs for the treatment of heart failure, diabetes mellitus and chronic kidney disease. The main challenge for these new drugs is that conventional RAASIs are safe, effective and cheap generics. Thus, the future of new RAASIs will be directed by economical/strategic reasons.

Effects of combined low-dose spironolactone plus vitamin E vs vitamin E monotherapy on insulin resistance, non-invasive indices of steatosis and fibrosis, and adipokine levels in non-alcoholic fatty liver disease: a randomized controlled trial.

The beneficial effects of mineralocorticoid receptor blockade by spironolactone have been shown in animal models of non-alcoholic fatty liver disease (NAFLD). The aim of the present 52-week randomized controlled trial was to compare the effects of low-dose spironolactone and vitamin E combination with those of vitamin E monotherapy on insulin resistance, non-invasive indices of hepatic steatosis and fibrosis, liver function tests, circulating adipokines and hormones in patients with histologically confirmed NAFLD. Homeostasis model of assessment of insulin resistance (HOMA-IR) and non-invasive indices of steatosis and fibrosis were calculated. Analysis was intention-to-treat. NAFLD liver fat score, an index of steatosis, decreased significantly in the combination treatment group (P = .028), but not in the vitamin E group, and the difference for group*time interaction was significant (P = .047). Alanine aminotransferase-to-platelet ratio index, an index of fibrosis, did not change. Insulin levels and HOMA-IR decreased significantly only within the combination group (P = .011 and P = .011, respectively). In conclusion, the combined low-dose spironolactone plus vitamin E regimen significantly decreased NAFLD liver fat score. Larger-scale trials are needed to clarify the effect of low-dose spironolactone on hepatic histology.

A randomized controlled study of finerenone versus placebo in Japanese patients with type 2 diabetes mellitus and diabetic nephropathy.

AIMS: Finerenone (BAY 94-8862) is a novel non-steroidal mineralocorticoid receptor antagonist. The aim of this study was to compare the efficacy and safety of seven once-daily oral doses of finerenone (1.25-20mg) and placebo in 96 patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) receiving a RAS blocker. METHODS: ARTS-DN Japan was a multicenter, randomized, double-blind, placebo-controlled, phase 2b study. RESULTS: Analysis of the urinary albumin-to-creatinine ratio (UACR) at day 90 relative to baseline indicated a nominally significant effect of finerenone. The UACR at day 90 relative to baseline for each finerenone treatment group was numerically reduced compared with placebo. No serious adverse events (AEs) or deaths were reported and no patients experienced treatment-emergent AEs resulting in discontinuation of study drug. Small mean increases in serum potassium level were observed in the finerenone treatment groups (0.025-0.167mmol/L) compared with the placebo group (-0.075mmol/L); no patients developed hyperkalemia. CONCLUSION: When given in addition to a RAS inhibitor, finerenone reduced albuminuria without adverse effects on serum potassium levels or renal function in Japanese patients with T2DM and DN.

Spot urine sodium excretion as prognostic marker in acutely decompensated heart failure: the spironolactone effect.

INTRODUCTION: Loop diuretic resistance characterized by inefficient sodium excretion complicates many patients with acutely decompensated heart failure (ADHF). Mineralocorticoid receptor antagonists (MRAs) in natriuretic doses may improve spot urine sodium excretion and outcomes. OBJECTIVE: Our primary aim was to assess the association of high-dose spironolactone with short-term spot urine sodium excretion, and our secondary aim was to determine if this higher short-term spot urine sodium excretion is associated with reduction in the composite clinical outcome (of cardiovascular mortality and/or ADHF hospitalization) event rate at 180 days. METHODS: Single-centre, non-randomized, open-label study enrolling 100 patients with ADHF. Patients were treated with standard ADHF therapy alone (n = 50) or oral spironolactone 100 mg/day plus standard ADHF therapy (n = 50). Spot urine samples were collected at day 1 and day 3 of hospitalization. RESULTS: Spironolactone group had significantly higher spot urine sodium levels compared to standard care group at day 3 (84.13 ± 28.71 mmol/L vs 70.74 ± 34.43 mmol/L, p = 0.04). The proportion of patients with spot urinary sodium <60 mmol/L was lower in spironolactone group at day 3 (18.8 vs 45.7, p = 0.01). In multivariate analysis, spironolactone was independently associated with increased spot urinary sodium and urinary sodium/potassium ratio of >2 at day 3 (both, p < 0.05). Higher spot urine sodium levels were associated with a lower event rate [HR for urinary sodium >100 mmol/L = 0.16 (0.06-0.42), p < 0.01, compared to <60], and provided a significant prognostic gain measured by net reclassification indexes. CONCLUSION: Spot urinary sodium levels >60 mmol/L and urinary sodium/potassium ratio >2 measured at day 3 of hospitalization for ADHF are associated with improved mid-term outcomes. Spironolactone is associated with increased spot urinary sodium and sodium/potassium ratio >2.

Randomized, double-blind, placebo-controlled trial of spironolactone for hypokalemia in continuous ambulatory peritoneal dialysis patients.

The incidence of hypokalemia in continuous ambulatory peritoneal dialysis (CAPD) patients is about 15-60%, leading to significant complications. There is no standard treatment other than potassium supplement in this setting. The aim of this study was to evaluate effect of spironolactone 25 mg/day in CAPD patients who have a history of hypokalemia. This is a randomized, double-blind, placebo-controlled, cross-over study in CAPD patients who had a history of hypokalemia. Study intervention is 4 weeks of oral spironolactone 25 mg/day or placebo, cross-over after a 2-week wash-out period. The primary outcome was the difference of serum potassium before and after 4 weeks of spironolactone treatment. Serum potassium was measured every 2 weeks, serum magnesium, urine and peritoneal fluid potassium measured before and after each treatment period. We enrolled 24 patients, and 20 completed the cross-over study. Ten patients were anuric. The total doses of potassium supplement were the same during the study period. Serum potassium levels before and after study intervention were not significantly different in both groups (4.23 ± 0.64 vs. 3.90 ± 0.59 mEq/L for spironolactone P = 0.077 and 3.84 ± 0.62 vs. 3.91 ± 0.52 for placebo P = 0.551). Total 24-h potassium, magnesium, sodium excretion, urine volume and ultrafiltration volume were not affected by spironolactone or placebo. There was one episode of hyperkalemia (5.6 mEq/L) during the spironolactone treatment period. Spironolactone 25 mg/day does not have a significant effect on serum potassium or urine and peritoneal excretion rate in CAPD patients who have a history of hypokalemia.

Predictors of hyperkalemia risk after hypertension control with aldosterone blockade according to the presence or absence of chronic kidney disease.

BACKGROUND/AIMS: Aldosterone antagonists have been proven to be efficient in the management of hypertension and the reduction of proteinuria; however, they are not widely used because of the risk of hyperkalemia. We assessed the predictors of hyperkalemia risk following hypertension control using aldosterone blockade in the presence or absence of chronic kidney disease (CKD). METHODS: A total of 6,575 patients with hypertension treated between January 1, 2000, and November 30, 2012, were evaluated for the safety of an aldosterone-blocking agent (spironolactone) added to preexisting blood pressure-lowering regimens. Hyperkalemia was defined as a serum potassium level ≥5.0 mEq/l. All patients used 3 mechanistically complementary antihypertensive agents, including a diuretic and a RAAS blocker. Patients were evaluated after 4 and 8 weeks of treatment. The incidence of hyperkalemia, significant renal dysfunction [a reduction of the estimated glomerular filtration rate (eGFR) ≥30%], and adverse effects was assessed. RESULTS: The incidence of hyperkalemia in the presence or absence of CKD was 50.4 and 42.6% after 4 weeks (p = 0.001) and 3.8 and 3.0% after 8 weeks, respectively (p = 0.371). A logistic regression analysis revealed that medication, CKD, basal hyperkalemia, reduction in eGFR, and diabetes were all predictive of a hyperkalemia risk following spironolactone use. CONCLUSION: Spironolactone was well tolerated by selected CKD patients. The risk of serious hyperkalemia or a significant reduction of eGFR appears to be low. Strict monitoring over the first month of treatment followed by standard surveillance for angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers is suggested.

The positive predictive value of a hyperkalemia diagnosis in automated health care data.

PURPOSE: Our objectives were to determine performance of coded hyperkalemia diagnosis at identifying (1) clinically evident hyperkalemia and (2) serum potassium>6 mmol/L. METHODS: This retrospective observational study included 8722 patients with diabetes within an integrated healthcare system who newly initiated an angiotensin converting enzyme inhibitor, angiotensin receptor blocker, or spironolactone. The primary outcome was first hyperkalemia-associated event (hospitalization, emergency department visit or death within 24 hours of coded diagnosis and/or potassium≥6 mmol/L) during the first year of therapy. Medical records were reviewed. RESULTS: Among a random sample of 99 patients not coded as having hyperkalemia, none had hyperkalemia upon record review. Among all 64 patients identified as having hyperkalemia, all had hospitalization or emergency department visit associated with coded diagnosis or elevated potassium. Of 55 with coded diagnosis, 42 (PPV 76%) had clinically evident hyperkalemia; 32 (PPV 58%) had potassium≥6. Of 9 identified using only potassium≥6, 7 (PPV 78%) had clinically evident hyperkalemia. CONCLUSIONS: Nearly one-fourth of patients with coded diagnosis do not have clinically evident hyperkalemia and nearly one-half do not have potassium≥6. Because both false positives and negatives occur with coded diagnoses, medical record validation of hyperkalemia-associated outcomes is necessary.

Antiarrhythmic and nonantiarrhythmic drugs for sudden cardiac death prevention.

Life-threatening ventricular arrhythmias such as sustained ventricular tachycardia and ventricular fibrillation are responsible for two thirds of sudden cardiac deaths annually in the United States. Implantable cardioverter-defibrillator (ICD) therapy prevents mortality from arrhythmic death but is expensive and has some associated morbidity from proarrhythmia and mechanical malfunction. Furthermore, ICDs treat ventricular arrhythmias but do not prevent them. Antiarrhythmic drugs (AADs) can be used for acute or chronic therapy to prevent ventricular arrhythmias and sudden cardiac deaths. AADS are often used in patients with an ICD who have recurrent ICD shocks resulting from ventricular arrhythmias. Class I AADs are contraindicated in patients with structural heart disease. Other than amiodarone, all Class III drugs have either a neutral or deleterious effect on mortality. Dronedarone, a new Class III drug, may reduce mortality, but more information is needed to be sure. A class of drugs that do not qualify as an AAD can modify cardiovascular remodeling processes and have a delayed and indirect antiarrhythmic effect. These so-called "nonantiarrhythmic drugs" such as drugs acting on the renin-angiotensin-aldosterone system, fish oil, and statins can reduce the likelihood of future ventricular tachycardia/ventricular fibrillation in patients with coronary artery disease or congestive heart failure. The role of AADs for chronic therapy for primary and secondary prevention of sudden cardiac death is problematic because of proarrhythmia and adverse side effects. Because these nonantiarrhythmic drugs are well tolerated and have no proarrhythmic actions, their benefits should outweigh risks.

Diabetes and drug-associated hyperkalemia: effect of potassium monitoring.

BACKGROUND: Renin-angiotensin-aldosterone system (RAAS) inhibitors are associated with hyperkalemia, but there is little evidence demonstrating patients who receive potassium monitoring have a lower rate of hyperkalemia. OBJECTIVE: To evaluate the association between potassium monitoring and serious hyperkalemia-associated adverse outcomes among patients with diabetes newly initiating RAAS inhibitor therapy. DESIGN: Retrospective observational study. PARTICIPANTS: Patients with diabetes without end-stage renal disease initiating RAAS inhibitor therapy between 2001 and 2006 at three integrated health care systems. MEASUREMENTS: Potassium monitoring and first hyperkalemia-associated adverse event during the initial year of therapy. Hyperkalemia-associated adverse events included hospitalizations, emergency department visits or deaths within 24 h of hyperkalemia diagnosis and/or diagnostic potassium >or=6 mmol/l. Incidence rates were calculated in person-years (p-y). We used inverse probability propensity score weighting to adjust for differences between patients with and without monitoring; Poisson regression was used to obtain adjusted relative risks. RESULTS: A total of 19,391 of 27,355 patients (71%) received potassium monitoring. Serious hyperkalemia-associated events occurred at an incidence rate of 10.2 per 1,000 p-y. Compared to patients without monitoring, adjusted relative risk of hyperkalemia-associated adverse events among all patients with monitoring was 0.50 (0.37, 0.66); in the subset of patients who also had chronic kidney disease (n = 2,176), adjusted relative risk was 0.29 (0.18, 0.46). CONCLUSIONS: Patients prescribed RAAS inhibitors who have both diabetes and chronic kidney disease and receive potassium monitoring are less likely to experience a serious hyperkalemia-associated adverse event compared to similar patients who did not receive potassium monitoring. This evidence supports existing consensus-based guidelines.