CPK served as a specialist to Relypsa, Inc

CPK served as a specialist to Relypsa, Inc., Sanofi-Aventis U.S. observed even in serum potassium ranges that are often not considered targets for therapeutic interventions. The heightened risk of mortality associated with hyperkalemia is present in all individual populations, even those in whom hyperkalemia occurs normally rarely, such as individuals with normal kidney function. 2014;10:653C662.8 The pivotal role of RAASis in engendering hyperkalemia was summarized by the findings of 2 meta-analyses that examined clinical trials of single versus dual RAAS blockade. One of these recognized 33 randomized controlled trials with 68,405 patients, and reported that dual RAAS blockade was associated, among other factors, with a 55% increase in the relative risk of hyperkalemia.22 The second meta-analysis examined studies conducted in patients with FadD32 Inhibitor-1 CKD, identifying 59 randomized controlled trials with a NOS3 total of 4975 participants. This analysis reported that dual RAAS blockade resulted in an increase in serum potassium concentrations and a 3.4% increase in the absolute rate of hyperkalemia.23 Compared to observational studies, clinical trials offer several advantages when evaluating the incidence and the risk factors of hyperkalemia: typically, they have few missed measurements of serum potassium, and the protocol-driven nature of serum potassium monitoring lessens bias by indication when detecting hyperkalemia. Furthermore, in FadD32 Inhibitor-1 clinical trials assessing the effects of RAASis there is a concerted effort to maintain patients on the study intervention, and hence discontinuation rates caused by milder hyperkalemia events (which are probably substantially affecting observational studies) are less common. Due to these considerations, information from clinical trials is more likely to provide an unbiased assessment of the likelihood of hyperkalemia in patients receiving RAASis. However, the select nature of the clinical trial populations may lessen the generalizability of these findings; thus the reported incidence of hyperkalemia, and the RAASi discontinuation rates caused by hyperkalemia, tend to be significantly higher in everyday clinical practice.24, 25 Outcomes associated with hyperkalemia Hyperkalemia has been associated with increased mortality FadD32 Inhibitor-1 in patients with normal kidney function and in patients along the entire spectrum of CKD severity. In a large cohort of patients hospitalized with acute myocardial infarction, serum potassium levels showed a U-shaped association with adverse outcomes, with incrementally higher mortality observed with serum potassium levels above 4.0 mEq/l, and with higher risk of ventricular fibrillation associated with serum potassium levels 5.0 mEq/l.26 Similar U-shaped associations between serum potassium and long-term mortality were present in patients with nonCdialysis-dependent CKD5, 27, 28 and in patients receiving chronic hemodialysis.6, 29, 30 In the latter studies the lowest mortality was seen in patients with serum potassium levels of approximately 4.0 to 5.0 mEq/l.5, 6, 28 In patients receiving peritoneal dialysis, hyperkalemia and serum potassium variability were associated with higher 1-year mortality but not longer-term mortality. 31 The presence of short-term adverse effects associated with hyperkalemia was also explained in a study of FadD32 Inhibitor-1 245,808 hospitalized US veterans, in whom serum potassium levels 5.5 mEq/l were associated with a significant increase in 1-day mortality,2 corroborating the hypothesis that the higher mortality associated with hyperkalemia may be caused by malignant arrhythmias.32, 33 This study also compared the relative risk of 1-day mortality associated with hyperkalemia in patients with and without CKD. Interestingly, the risk associated with similar levels of hyperkalemia was much higher in patients with normal kidney function and gradually decreased in those with increasingly severe CKD (odds ratios of 1-day mortality associated with serum potassium 6.0 vs.? 5.5 mEq/l in patients with normal eGFR and in those with CKD stages 3, 4, and 5 were 31.64, 19.52, 11.56, and 8.02, respectively). These findings suggest that patients with more.