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Understanding predictors and trajectories of increased potassium may inform testing and treatment of hyperkalemia. We examined predictors for repeated hyperkalemia among patients after first-time renin angiotensin system inhibitor (RASi) prescription, chronic kidney disease (CKD), or chronic heart failure (CHF); and we also examined potassium trajectories in these patients after their first hyperkalemia event. We used Danish population-based registries to identify all patients with first-time RASi prescription, incident CKD, or incident CHF (2000–2012). For patients with a first hyperkalemia event, potassium trajectories over the following 6 months were examined. The predictors associated with repeated hyperkalemia were assessed, with repeated hyperkalemia defined as a potassium test >5.0 mmol/L after the first event within 6 months. Overall 262,375 first-time RASi users, 157,283 incident CKD patients, and 14,600 incident CHF patients were included. Of patients with a first hyperkalemia event, repeated hyperkalemia within 6 months occurred in 37% of RASi users, 40% with CKD, and 49% of patients with CHF. Predictors included severe hyperkalemia, low eGFR, diabetes, and spironolactone use. In all cohorts, the median potassium levels declined over 2–4 weeks after a hyperkalemia event for the first time, but reverted to levels higher than before the initial hyperkalemia event in those who had repeated hyperkalemia. Following hyperkalemia, discontinuation of RASi and spironolactone was common in the RASi and CHF cohorts. Repeated hyperkalemia was common among the explored cohorts. The first hyperkalemia event was an indicator of increased median potassium levels. Predictors may identify patients likely to benefit from intensified monitoring and intervention.

IntroductionRenin-angiotensin system inhibitors (RAS) drugs have a proteinuria-reducing effect that could prevent the progression of kidney disease in diabetic patients. Our study aimed to assess the budget impact based on healthcare payer perspective of increasing uptake of RAS drugs into the current treatment mix of standard anti-hypertensive treatments to prevent progression of kidney disease in patient's comorbid with hypertension and diabetes.MethodsA Markov model of a Malaysian hypothetical cohort aged ≥30 years (N = 14,589,900) was used to estimate the total and per-member-per-month (PMPM) costs of RAS uptake. This involved an incidence and prevalence rate of 9.0% and 10.53% of patients with diabetes and hypertension respectively. Transition probabilities of health stages and costs were adapted from published data.ResultsAn increasing uptake of RAS drugs would incur a projected total treatment cost ranged from MYR 4.89 billion (PMPM of MYR 27.95) at Year 1 to MYR 16.26 billion (PMPM of MYR 92.89) at Year 5. This would represent a range of incremental costs between PMPM of MYR 0.20 at Year 1 and PMPM of MYR 1.62 at Year 5. Over the same period, the care costs showed a downward trend but drug acquisition costs were increasing. Sensitivity analyses showed the model was minimally affected by the changes in the input parameters.ConclusionMild impact to the overall healthcare budget has been reported with an increased utilization of RAS. The long-term positive health consequences of RAS treatment would reduce the cost of care in preventing deterioration of kidney function, thus offsetting the rising costs of purchasing RAS drugs. Optimizing and increasing use of RAS drugs would be considered an affordable and rational strategy to reduce the overall healthcare costs in Malaysia.

© 2019 Jun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data on hyperkalemia frequency among chronic kidney disease (CKD) patients receiving renin-angiotensin aldosterone system inhibitors (RAASis) and its impact on subsequent RAASi treatment are limited. This population-based cohort study sought to assess the incidence of clinically significant hyperkalemia among adult CKD patients who were prescribed a RAASi and the proportion of patients with RAASi medication change after experiencing incident hyperkalemia. We conducted a retrospective, population-based cohort study (1 January 2013–30 June 2017) using Australian national general practice data from the NPS MedicineWise’s MedicineInsight program. The study included adults aged 18 years who received 1 RAASi prescription during the study period and had CKD (estimated glomerular filtration rate [eGFR] 6 mmol/L or a record of hyperkalemia diagnosis) and among patients who experienced incident hyperkalemia, the proportion who had RAASi medication changes (cessation or dose reduction during the 210-day period after the incident hyperkalemia event). Among 20,184 CKD patients with a median follow-up of 3.9 years, 1,992 (9.9%) patients experienced an episode of hyperkalemia. The overall incidence rate was 3.1 (95% CI: 2.9–3.2) per 100 person-years. Rates progressively increased with worsening eGFR (e.g. 3.5-fold increase in patients with eGFR

Introduction Renin-angiotensin system (RAS) inhibitors have been increasingly prescribed due to their beneficial effects on end-organ protection. Iatrogenic hyperkalemia is a well-known life-threatening complication of RAS inhibitor use in chronic kidney disease (CKD) patients. We hypothesized that CKD patients treated with RAS inhibitors frequently develop hyperkalemia after hospital discharge even if they were normokalemic during their hospitalization because their lifestyles change substantially after discharge. The present study aimed to examine the incidence of newly diagnosed hyperkalemia, the timing of hyperkalemia, and its risk factors in CKD patients treated with RAS inhibitors at the time of hospital discharge. Methods We retrospectively enrolled patients aged 20 years or older with CKD G3-5 (estimated glomerular filtration rate < 60 mL/min/1.73 m2) and who were treated with RAS inhibitors and discharged from St. Luke’s International Hospital between July 2011 and December 2015. Patients who were under maintenance dialysis or had hyperkalemic events before discharge were excluded. Data regarding the patients’ age, sex, CKD stage, diabetes mellitus status, malignancy status, combined use of RAS inhibitors, concurrent medication, and hyperkalemic events after discharge were extracted from the hospital database. Our primary outcome was hyperkalemia, defined as serum potassium ≥ 5.5 mEq/L. Multiple logistic regression and Kaplan-Meier analyses were performed to identify the risk factors for and the timing of hyperkalemia, respectively. Results Among the 986 patients, 121 (12.3%) developed hyperkalemia after discharge. In the regression analysis, relative to CKD G3a, G3b [odds ratio (OR): 1.88, 95% confidence interval 1.20–2.97] and G4-5 (OR: 3.40, 1.99–5.81) were significantly associated with hyperkalemia. The use of RAS inhibitor combinations (OR: 1.92, 1.19–3.10), malignancy status (OR: 2.10, 1.14–3.86), and baseline serum potassium (OR: 1.91, 1.23–2.97) were also significantly associated with hyperkalemia. The Kaplan-Meier analysis showed that hyperkalemia was most frequent during the early period after discharge, particularly within one month. Conclusion Hyperkalemia was frequent during the early period after discharge among previously normokalemic CKD patients who were treated with RAS inhibitors. Appropriate follow-up after discharge should be required for these patients, particularly those with advanced CKD or malignancy status, such as hematological malignancy or late-stage malignancy, and those who are treated with multiple RAS inhibitors.

Background In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity. Methods We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to

Background Taiwan has the highest renal disease incidence and prevalence in the world. We evaluated the association of statin and renin–angiotensin system inhibitor (RASI) use with dialysis risk in hypertensive patients. Methods Of 248,797 patients who received a hypertension diagnosis in Taiwan during 2001–2012, our cohort contained 110,829 hypertensive patients: 44,764 who used RASIs alone; 7,606 who used statins alone; 27,836 who used both RASIs and statins; and 33,716 who used neither RASIs or statins. We adjusted for the following factors to reduce selection bias by using propensity scores (PSs): age; sex; comorbidities; urbanization level; monthly income; and use of nonstatin lipid-lowering drugs, metformin, aspirin, antihypertensives, diuretics, and beta and calcium channel blockers. The statin and RASI use index dates were considered the hypertension confirmation dates. To examine the dose–response relationship, we categorized only statin or RASI use into four groups in each cohort: 365 cumulative defined daily doses (cDDDs). Results In the main model, PS-adjusted hazard ratios (aHRs; 95% confidence intervals [CIs]) for dialysis risk were 0.57 (0.50–0.65), 0.72 (0.53–0.98), and 0.47 (0.41–0.54) in the only RASI, only statin, and RASI + statin users, respectively. RASIs dose-dependently reduced dialysis risk in most subgroups and in the main model. RASI use significantly reduced dialysis risk in most subgroups, regardless of comorbidities or other drug use (P < 0.001). Statins at >365 cDDDs protected hypertensive patients against dialysis risk in the main model (aHR = 0.62, 95% CI: 0.54–0.71), regardless of whether a high cDDD of RASIs, metformin, or aspirin was used. Conclusion Statins and RASIs independently have a significant dose-dependent protective effect against dialysis risk in hypertensive patients. The combination of statins and RASIs can additively protect hypertensive patients against dialysis risk.

The (pro)renin receptor [(P)RR] is cleaved by furin to generate soluble (P)RR [s(P)RR], which reflects the status of the tissue renin-angiotensin system. Hemodialysis patients have advanced atherosclerosis. The aim of this study was to investigate the relationships between serum s(P)RR levels and background factors, including indices of atherosclerosis, in hemodialysis patients. Serum s(P)RR levels were measured in hemodialysis patients and clearance of s(P)RR through the membrane of the dialyzer was examined. Furthermore, relationships between serum s(P)RR levels and background factors were assessed. Serum s(P)RR levels were significantly higher in hemodialysis patients (30.4 ± 6.1 ng/ml, n = 258) than those in subjects with normal renal function (21.4 ± 6.2 ng/ml, n = 39, P < 0.0001). Clearance of s(P)RR and creatinine were 56.9 ± 33.5 and 147.6 ± 9.50 ml/min, respectively. Serum s(P)RR levels were significantly higher in those with ankle-brachial index (ABI) of < 0.9, an indicator of severe atherosclerosis, than those with ABI of ≥ 0.9 (32.2 ± 5.9 and 30.1 ± 6.2 ng/ml, respectively, P < 0.05). An association between low ABI and high serum s(P)RR levels was observed even after correction for age, history of smoking, HbA1c, and LDL-C. Serum s(P)RR levels were significantly higher in hemodialysis patients when compared with subjects with normal renal function, although s(P)RR is dialyzed to some extent, but to a lesser extent than creatinine. High serum s(P)RR levels may be associated with atherosclerosis independent of other risk factors, suggesting that serum s(P)RR could be used as a marker for atherosclerotic conditions in hemodialysis patients.

Dual renin angiotensin system (RAS) blockade using angiotensin-receptor blockers (ARBs) in combination with angiotensin converting enzyme inhibitors (ACEIs) is reported to improve proteinuria in both diabetic and non-diabetic patients. However, its renoprotective effect and safety remain uncertain in patients with advanced chronic kidney disease (CKD). From January 1, 2000 through June 30, 2009, we enrolled 14,117 pre-dialytic stage 5 CKD patients with serum creatinine >6mg/dL and hematocrit

Background Intra-dialytic hypertension (IDH) is emerging as an important issue in hemodialysis patients. Its risk factors and clinical outcomes are unclear. Methods A total of 73 prevalent hemodialysis patients were enrolled. They included 14 (19.2%) patients with baseline IDH and 59 patients without IDH. Their clinical parameters, laboratory parameters, and mortality were investigated over 78 months. Results The risks factor of IDH included low serum potassium levels, low ultrafiltration, and low arm muscle area. Lower median survival was evident in the IDH group compared to the non-IDH group, but was not significantly different. After adjusting for relevant confounders for age, the IDH group displayed 2.846 times higher mortality rate than the non-IDH Group (adjusted hazard ratio: 2.846; 95% confidence interval: 1.081–7.490; P = 0.034). Conclusion IDH is associated with high mortality in hemodialysis patients. Clinicians should be aware of the risk factors. Future research studies are needed to explore the mechanisms involved in the association between IDH and mortality.

Renin-angiotensin-system (RAS) blockade is thought to slow renal progression in patients with chronic kidney disease (CKD). However, it remains uncertain if the habitual use of RAS inhibitors affects renal progression and outcomes in pre-dialysis patients with advanced CKD. In this multicenter retrospective cohort study, we identified 2,076 pre-dialysis patients with advanced CKD (stage 4 or 5) from a total of 33,722 CKD patients. RAS blockade users were paired with non-users for analyses using inverse probability of treatment-weighted (IPTW) and propensity score (PS) matching. The outcomes were renal death, all-cause mortality, hospitalization for hyperkalemia, and interactive factors as composite outcomes. RAS blockade users showed an increased risk of renal death in PS-matched analysis (hazard ratio [HR], 1.381; 95% CI, 1.071–1.781; P = 0.013), which was in agreement with the results of IPTW analysis (HR, 1.298; 95% CI, 1.123–1.500; P < 0.001). The risk of composite outcomes was higher in RAS blockade users in IPTW (HR, 1.154; 95% CI, 1.016–1.310; P = 0.027), but was marginal significance in PS matched analysis (HR, 1.243; 95% CI, 0.996–1.550; P = 0.054). The habitual use of RAS blockades in pre-dialysis patients with advanced CKD may have a detrimental effect on renal outcome without improving all-cause mortality. Further studies are warranted to determine whether withholding RAS blockade may lead to better outcomes in these patients.

Background Medications aimed at inhibiting the renin–angiotensin system (RAS) have been used extensively for preventing cardiovascular and renal complications in patients with diabetes, but data that compare their clinical effectiveness are limited. We aimed to compare the effects of classes of RAS blockers on cardiovascular and renal outcomes in adults with diabetes. Methods and Findings Eligible trials were identified by electronic searches in PubMed/MEDLINE and the Cochrane Database of Systematic Reviews (1 January 2004 to 17 July 2014). Interventions of interest were angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and direct renin (DR) inhibitors. The primary endpoints were cardiovascular mortality, myocardial infarction, and stroke—singly and as a composite endpoint, major cardiovascular outcome—and end-stage renal disease [ESRD], doubling of serum creatinine, and all-cause mortality—singly and as a composite endpoint, progression of renal disease. Secondary endpoints were angina pectoris and hospitalization for heart failure. In all, 71 trials (103,120 participants), with a total of 14 different regimens, were pooled using network meta-analyses. When compared with ACE inhibitor, no other RAS blocker used in monotherapy and/or combination was associated with a significant reduction in major cardiovascular outcomes: ARB (odds ratio [OR] 1.02; 95% credible interval [CrI] 0.90–1.18), ACE inhibitor plus ARB (0.97; 95% CrI 0.79–1.19), DR inhibitor plus ACE inhibitor (1.32; 95% CrI 0.96–1.81), and DR inhibitor plus ARB (1.00; 95% CrI 0.73–1.38). For the risk of progression of renal disease, no significant differences were detected between ACE inhibitor and each of the remaining therapies: ARB (OR 1.10; 95% CrI 0.90–1.40), ACE inhibitor plus ARB (0.97; 95% CrI 0.72–1.29), DR inhibitor plus ACE inhibitor (0.99; 95% CrI 0.65–1.57), and DR inhibitor plus ARB (1.18; 95% CrI 0.78–1.84). No significant differences were showed between ACE inhibitors and ARBs with respect to all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, angina pectoris, hospitalization for heart failure, ESRD, or doubling serum creatinine. Findings were limited by the clinical and methodological heterogeneity of the included studies. Potential inconsistency was identified in network meta-analyses of stroke and angina pectoris, limiting the conclusiveness of findings for these single endpoints. Conclusions In adults with diabetes, comparisons of different RAS blockers showed similar effects of ACE inhibitors and ARBs on major cardiovascular and renal outcomes. Compared with monotherapies, the combination of an ACE inhibitor and an ARB failed to provide significant benefits on major outcomes. Clinicians should discuss the balance between benefits, costs, and potential harms with individual diabetes patients before starting treatment. Review registration PROSPERO CRD42014014404, In a systematic review with network meta-analyses, Ferrán Catalá-López and colleagues synthesize published and unpublished data from randomized controlled trials of renin-angiotensin system inhibitors., Editors' Summary Background Chronic high blood pressure can damage blood vessels, heart, and kidneys, and cause cardiovascular and kidney (or renal) disease. Diabetes increases the risk for high blood pressure. An estimated two-thirds of adults with diabetes have high blood pressure or take blood-pressure-reducing drugs (also called antihypertensives). Because diabetes itself increases the risk for heart and kidney diseases, controlling blood pressure is important. Several of the drugs commonly prescribed to patients with diabetes target the renin–angiotensin system (RAS), a hormone system that regulates blood pressure and fluid balance. When renal blood flow is low, kidney cells produce renin and secrete it into the blood stream. Renin in the blood generates a protein called angiotensin I. The angiotensin-converting enzyme (ACE) in the lungs subsequently converts angiotensin I to angiotensin II, and angiotensin II docks with its partner, the angiotensin receptor. This then leads to a signaling cascade that causes blood vessels to constrict and the kidneys to secrete water and salt into the blood, resulting in increased blood pressure. Drugs that interrupt different steps in the cascade can lower blood pressure and thereby prevent cardiovascular and renal disease. In addition to their blood-pressure-lowering effects, some RAS blockers have also been shown to protect heart and kidney function through other mechanisms. RAS blockers fall into three main classes: ACE inhibitors block the conversion of angiotensin I into angiotensin II, angiotensin receptor blockers (ARBs) prevent angiotensin II from activating the angiotensin receptor, and direct renin inhibitors inhibit the production of angiotensin I. Why Was This Study Done? As many adults with diabetes are prescribed RAS blockers and likely need to take them or related drugs for the rest of their lives, the question of which drug (or drug combination) has the best results and the least side effects is important. Data from many randomized controlled trials (RCTs, which are the most rigorous clinical tests) have generated results that address this question. Their combined analysis, however, is complicated because the trials often don’t compare all treatments directly, don’t use the exact same treatments in patients with the exact same conditions, or don’t measure the exact same outcomes. Nonetheless, scientists have developed methods to analyze such complex data, including a method called network meta-analysis, which helps to integrate and synthesize diverse results to determine the relative merits of multiple treatments. Here the researchers apply network meta-analysis to all available data from RCTs in which adults with diabetes were given RAS blockers, alone or in combination with other high blood pressure treatments, and that measured cardiovascular or renal outcomes. What Did the Researchers Do and Find? The researchers started with a systematic search of the medical literature for RCTs that tested RAS blockers alone or in combination in adults with diabetes. They also contacted the sponsors of many studies to find out whether they had additional data that were not included in the published reports. They included all trials that had at least 100 participants, followed the participants for at least 12 months, and reported cardiovascular or renal outcomes. In all, 71 trials that tested a total of 14 different treatment regimens in 103,120 participants met these criteria. With network meta-analysis, the researchers were able to summarize the results of all these trials in a meaningful way. They did this by integrating direct comparisons of RAS blockers within the same trial (where those were available) with indirect comparisons across all trials. The primary endpoints in their analysis were major cardiovascular outcome (a composite of cardiovascular mortality, nonfatal heart attack, and nonfatal stroke) and progression of renal disease (a composite of end-stage renal disease, doubling of serum creatinine [a marker of reduced kidney function], and all-cause mortality). They also analyzed the individual cardiovascular or renal outcomes separately, but these results carried more uncertainty because fewer patients had the individual, compared with the combined, outcomes. The researchers found no significant differences in the risk of major cardiovascular outcome between ACE inhibitors and either ARBs or a combination of an ACE inhibitor plus an ARB. Similarly, for the risk of progression of renal disease, no significant differences were detected between ACE inhibitors and any of the remaining therapies, such as ARBs or a combination of an ACE inhibitor plus an ARB. They also found that no RAS blocker strategy was superior to ACE inhibitors with respect to all-cause mortality, cardiovascular mortality, heart attacks, strokes, end-stage renal disease, or doubling of serum creatinine. Overall, any single ACE inhibitor or ARB was equally effective as any other, and just as effective as any drug combination. What Do These Findings Mean? The findings reinforce North American and European guidelines that recommend ACE inhibitors and ARBs for antihypertensive therapy in patients with diabetes. The fact that combinations of two drugs had outcomes no better than those of a single ACE inhibitor or ARB—together with results from other studies that reported increased adverse effects in patients who took drug combinations—cautions against the use of combination therapy. The findings also contradict earlier reports suggesting that ARBs may increase the risk of cardiovascular outcomes. There were not enough data comparing direct renin inhibitors (a drug class that was developed more recently and therefore has been studied less) with ACE inhibitors or ARBs to allow strong conclusions; additional research might therefore be warranted. The analyses here did not consider the costs of any particular drug, or any side effects that were not relevant to the outcomes measured. These factors, together with the results here and a patient’s specific situation, should be taken into account when doctors and their patients discuss and decide appropriate treatments. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001971. The MedlinePlus has links to information on diabetes The American Diabetes Association provides information on kidney disease, heart disease, and high blood pressure The European Society of Cardiology has guidelines on diabetes, heart disease, and high blood pressure The UK National Institute for Health and Care Excellence has guidelines on renin–angiotensin system drugs