Patiromer Treatment in Patients With CKD, Hyperkalemia, and Hyperphosphatemia: A Post Hoc Analysis of 3 Clinical Trials.

RATIONALE & OBJECTIVE: Patients with chronic kidney disease (CKD), hyperkalemia (serum potassium [sK+]>5.0 mEq/L), and hyperphosphatemia experience poor clinical outcomes. Patiromer, a potassium binder that uses calcium as the exchange ion, may also reduce serum phosphorus (sP). We characterized the effect of patiromer on sP in patients with CKD, hyperkalemia, and hyperphosphatemia. STUDY DESIGN: A post hoc pooled analysis of individual-level data from the AMETHYST-DN, OPAL-HK, and TOURMALINE trials of patiromer. SETTING & PARTICIPANTS: Patients with CKD and hyperkalemia. EXPOSURE: Patients treated with patiromer (8.4-33.6 g/day). OUTCOME: Mean changes from baseline in sP, sK+, serum calcium (sCa2+), and serum magnesium (sMg2+) after 2 and 4 weeks of treatment. ANALYTICAL APPROACH: Descriptive statistics to summarize pooled data on the study outcomes from the 3 studies. RESULTS: We included 578 patients in the analysis. Of these participants, 86 patients (14.9%) had baseline hyperphosphatemia of whom 75.6% (65 of 86) had CKD stage 4/5 and 31.1% (153 of 492) with sP≤4.5mg/dL had CKD stage 4/5. Among the patients with elevated sP and sK+at baseline, the mean±SD reduction in sP and sK+after 4 weeks of patiromer treatment was-0.62±1.09mg/dL and-0.71± 0.51 mEq/L, respectively. Additionally, the mean±SD reduction in sMg2+in these patients was -0.25±0.23mg/dL while sCa2+remained unchanged. Both sMg2+and sCa2+remained within the normal range. Patiromer was generally well tolerated, and no serious adverse events were considered related to patiromer. LIMITATIONS: These were post hoc analyses, no placebo comparison was performed due to the design of the original studies, and the follow-up period was limited to 4 weeks. CONCLUSIONS: Reductions in sP and sK+to the normal range were observed after 2 weeks of patiromer treatment, and the reduction was sustained during 4 weeks of treatment among patients with non-dialysis-dependent CKD, hyperkalemia, and hyperphosphatemia. Future controlled trials are needed to establish if patiromer is useful to reduce both sK+and sP in hyperkalemic patients with CKD and hyperphosphatemia.

The intersection of mineralocorticoid receptor activation and the FGF23-Klotho cascade: a duopoly that promotes renal and cardiovascular injury.

The nexus of chronic kidney disease (CKD) and cardiovascular disease (CVD) amplifies the morbidity and mortality of CKD, emphasizing the need for defining and establishing therapeutic initiatives to modify and abrogate the progression of CKD and concomitant CV risks. In addition to the traditional CV risk factors, disturbances of mineral metabolism are specific risk factors that contribute to the excessive CV mortality in patients with CKD. These risk factors include dysregulations of circulating factors that modulate phosphate metabolism, including fibroblast growth factor 23 (FGF23) and soluble Klotho. Reduced circulating levels and suppressed renal Klotho expression may be associated with adverse outcomes in CKD patients. While elevated circulating concentrations or locally produced FGF23 in the strained heart exert prohypertrophic mechanisms on the myocardium, Klotho attenuates tissue fibrosis, progression of CKD, cardiomyopathy, endothelial dysfunction, vascular stiffness and vascular calcification. Mineralocorticoid receptor (MR) activation in nonclassical targets, mediated by aldosterone and other ligands, amplifies CVD in CKD. In concert, we detail how the interplay of elevated FGF23, activation of the MR and concomitant reductions of circulating Klotho in CKD may potentiate each other's deleterious effects on the kidney and heart, thereby contributing to the initiation and progression of kidney and cardiac functional deterioration, acting through multipronged, albeit complementary, mechanistic pathways.

Recent advances in pharmacological treatments of hyperkalemia: focus on patiromer.

INTRODUCTION: Hyperkalemia is a common electrolyte disorder, especially among patients with chronic kidney disease (CKD), diabetes mellitus, or heart failure, and is associated with a significantly increased risk for all-cause mortality. Hyperkalemia remains a vexing and challenging problem for clinicians, particularly in the management of patients with chronic kidney disease and congestive heart failure. Several observational and retrospective studies have reported a large gap between recommendations in guidelines and real-world practice in the implementation of RAASi therapies. RAASi treatment regimens are frequently down-titrated or discontinued following hyperkalemia events, with consequent worse outcomes than patients who remain on maximum doses. AREAS COVERED: This review covers the preclinical and clinical studies that led to the approval of patiromer for the treatment of hyperkalemia. A literature search on patiromer was carried out using the PubMed database up to December 2015. EXPERT OPINION: Recently, patiromer was approved by the FDA as the first new potassium binder for the treatment of hyperkalemia in over 50 years. Based on the results of phase II and phase III studies, we conclude that patiromer is a well-tolerated and predictable medication to consistently and safely reduce serum potassium levels and to sustain normokalemia for periods up to 52 weeks in patients with diverse underlying diseases including congestive heart failure, and chronic kidney disease. Future research questions that should be evaluated are: the role of patiromer in treating hyperkalemia and the potential to thereby allow the optimal management of resistant hypertension and the use of high dose MRAs in patients with acute decompensated heart failure. Additional research is also warranted in the potential safety benefits of reducing potassium fluctuations in patients on hemodialysis as a result of treatment of hyperkalemia with patiromer.

Potassium homeostasis and dyskalemias: the respective roles of renal, extrarenal, and gut sensors in potassium handling.

Integrated mechanisms controlling the maintenance of potassium homeostasis are well established and are defined by the classic "feedback control" of potassium balance. Recently, increasing investigative attention has focused on novel physiological paradigms that increase the complexity and precision of homeostasis. This review briefly considers the classic and well-established feedback control of potassium and then considers subsequent investigations that inform on an intriguing and not widely recognized complementary paradigm: the "feed-forward control of potassium balance." Feed-forward control refers to a pathway in a homeostatic system that responds to a signal in the environment in a predetermined manner, without responding to how the system subsequently reacts (i.e., without responding to feedback). Studies in several animal species, and recently in humans, have confirmed the presence of a feed-forward control mechanism that is capable of mediating potassium excretion independent of changes in serum potassium concentration and aldosterone. Knowledge imparted by this update of potassium homeostasis hopefully will facilitate the clinical management of hyperkalemia in patients with chronic and recurrent hyperkalemia. Awareness of this updated integrative control mechanism for potassium homeostasis is more relevant today when the medical community is increasingly focused on leveraging and expanding established renin-angiotensin-aldosterone system inhibitor treatment regimens and on successfully coping with the challenges of managing hyperkalemia provoked by renin-angiotensin-aldosterone system inhibitors. These new insights are relevant to the future design of clinical trials delineating renal potassium handling.

The Unappreciated Role of Extrarenal and Gut Sensors in Modulating Renal Potassium Handling: Implications for Diagnosis of Dyskalemias and Interpreting Clinical Trials.

In addition to the classic and well-established "feedback control" of potassium balance, increasing investigative attention has focused on a novel and not widely recognized complementary regulatory paradigm for maintaining potassium homeostasis-the "feed-forward control" of potassium balance. This regulatory mechanism, initially defined in rumen, has recently been validated in normal human subjects. Studies are being conducted to determine the location for this putative potassium sensor and to evaluate potential signals, which might increase renal potassium excretion. Awareness of this more updated integrative control mechanism for potassium homeostasis is ever more relevant today, when the medical community is increasingly focused on the challenges of managing the hyperkalemia provoked by renin-angiotensin-aldosterone system inhibitors (RAASis). Recent studies have demonstrated a wide gap between RAASi prescribing guidelines and real-world experience and have highlighted that this gap is thought to be attributable in great part to hyperkalemia. Consequently we require a greater knowledge of the complexities of the regulatory mechanisms subserving potassium homeostasis. Sodium polystyrene sulfonate has long been the mainstay for treating hyperkalemia, but its administration is fraught with challenges related to patient discomfort and colonic necrosis. The current and imminent availability of newer potassium binders with better tolerability and more predictive dose-response potassium removal should enhance the management of hyperkalemia. Consequently it is essential to better understand the intricacies of mammalian colonic K+ handling. We discuss colonic transport of K+ and review evidence for potassium (BK) channels being responsible for increased stool K+ in patients with diseases such as ulcerative colitis.

Atorvastatin does not induce glomerular or tubular dysfunction even at high doses.

The current analyses evaluated the effect of atorvastatin on biomarkers of renal function. Serum creatinine level and markers of tubular and glomerular function, including cystatin C, urine N-acetyl-beta-D-glucosaminidase, urine and serum beta2-microglobulin, and urine albumin, were assessed in osteopenic postmenopausal women with mild dyslipidemia who received atorvastatin 20 mg, atorvastatin 80 mg, or placebo for 1 year. During the study, changes in serum creatinine levels were the same in all 3 treatment groups. Cystatin C levels remained unchanged in all groups at all time points. For the additional markers of renal function, median values at baseline and weeks 26 and 52 in both of the atorvastatin and the placebo groups were similar. Neither moderate- nor high-dose atorvastatin treatment for 1 year altered markers of glomerular and renal tubular function compared with placebo. These data indicate that in this patient population, atorvastatin, even at a high dose, does not interfere with renal tubular reabsorption of protein, induce renal tubular dysfunction, or alter glomerular filtration rate in humans.