The Increased Clinical and Economic Burden of Hyperkalemia in Medicare Patients Admitted to Long-Term Care Settings.

INTRODUCTION: Older patients are at increased risk for hyperkalemia (HK). This study describes the prevalence, recurrence, and clinical and economic burden of HK in Medicare patients admitted to a long-term care (LTC) setting. METHODS: Retrospective cohort study using 100% Medicare Fee-for-Service (FFS) claims identified patients aged ≥ 65 years with index admission between 2017 and 2019 to a LTC setting (skilled nursing, home health, inpatient rehabilitation, or long-term acute care). Beneficiaries were required to have 12 months continuous medical and pharmacy coverage prior to index LTC admission and ≥ 30 days after LTC discharge (follow-up). Patient characteristics, healthcare resource utilization, and costs were assessed. HK was defined as ICD-10 diagnosis code E87.5 in any claim position or Medicare Part D fill for oral potassium binder. RESULTS: Of 4,562,231 patients with a LTC stay, the prevalence of HK was 14.7% over the full study period (pre-index, index stay, and follow-up). Excluding those with HK only during the follow-up period resulted in 4,081,103 patients. Of these, 290,567 (7.1%) had HK and 3,790,536 (92.9%) did not have HK during or within 14 days prior to index LTC stay. The HK recurrence rate during index stay and follow-up was 48.3%. Unmatched HK versus non-HK patients were more often male (43.0% vs. 35.4%), Black (13.5% vs. 8.0%), dual eligible for Medicaid (34.2% vs. 25.0%), with higher mean Charlson Comorbidity Index scores (6.2 vs. 3.9) (all p < 0.0001). After propensity matching, HK patients were 2.2 times more likely to be hospitalized, with higher mortality (30.8% vs. 21.5%) and higher total healthcare costs during both index stay (US$26,520 vs. $18,021; p < 0.0011) and follow-up ($57,948 vs. $41,744 (p < 0.0011) versus matched non-HK patients. CONCLUSION: Prevalence and recurrence of HK was high among LTC patients, and HK was associated with significantly greater clinical and economic burden during and post-LTC.

Hyperkalemia is a serious medical condition commonly occurring in nursing home residents. It is characterized by abnormally high blood levels of potassium that if untreated can be life-threatening. High levels of potassium can be the result of kidney disease and inability to remove potassium from the bloodstream; eating foods high in potassium; and/or taking medications that interfere with the kidney's ability to remove potassium from the bloodstream. Older patients who have chronic kidney disease, heart failure, diabetes, and high blood pressure are at particularly high risk for hyperkalemia. Management is difficult as it requires reducing intake of foods high in potassium, adjusting medications that cause hyperkalemia, and potentially treating with oral potassium binders to reduce potassium blood levels. This study focused on the clinical outcomes, healthcare services use, and costs incurred by Medicare beneficiaries 65 years and older admitted to long-term care, where the occurrence of hyperkalemia is often high yet unrecognized. Patients with a diagnosis of hyperkalemia immediately before and during admission to long-term care or after discharge had an increased rate of death compared with patients without a hyperkalemia diagnosis. Hyperkalemia patients also had more hospitalizations and visits to the Emergency Department and outpatient facilities, resulting in higher total medical costs. Total costs for hyperkalemia patients were highest for those with chronic kidney disease, heart failure, and diabetes.

Bipolar II compared with bipolar I disorder: baseline characteristics and treatment response to quetiapine in a pooled analysis of five placebo-controlled clinical trials of acute bipolar depression.

BACKGROUND: Bipolar I and II represent the most common and severe subtypes of bipolar disorder. Although bipolar I disorder is relatively well studied, the clinical characteristics and response to treatment of patients with bipolar II disorder are less well understood. METHODS: To compare the severity and burden of illness of patients with bipolar II versus bipolar I disorder, baseline demographic, clinical, and quality of life data were examined in 1900 patients with bipolar I and 973 patients with bipolar II depression, who were enrolled in five similarly designed clinical placebo-controlled trials of quetiapine immediate-release and quetiapine extended-release. Acute (8 weeks) response to treatment was also compared by assessing rating scale scores, including Montgomery-Åsberg depression rating scale, Hamilton rating scale for anxiety, Young mania rating scale, and clinical global impression-severity scores, in the bipolar I and II populations in the same pooled database. RESULTS: Patients with bipolar I and bipolar II depression were similar in demographics, baseline rating scale scores (depression, anxiety, mania, and quality of life), and mood episode histories. Symptom improvements in response to quetiapine were greater versus comparators (lithium, paroxetine, and placebo) at 4 and 8 weeks in both bipolar I and II patients. Patients with the bipolar II subtype initially showed slower responses to all treatments, but, by 8 weeks, attained similar symptom improvement as patients with bipolar I depression. CONCLUSIONS: Pooled analysis of five clinical trials of quetiapine demonstrated that patients with bipolar II depression have a similar burden of illness and quality of life to patients with bipolar I. Bipolar II patients consistently showed a slower response to treatments than bipolar I patients, but, after 8 weeks of treatment with quetiapine, symptom improvements were similar between bipolar I and II disorder subtypes.

Age-dependent changes in Ca2+ homeostasis in peripheral neurones: implications for changes in function.

Calcium ions represent universal second messengers within neuronal cells integrating multiple cellular functions, such as release of neurotransmitters, gene expression, proliferation, excitability, and regulation of cell death or apoptotic pathways. The magnitude, duration and shape of stimulation-evoked intracellular calcium ([Ca2+]i) transients are determined by a complex interplay of mechanisms that modulate stimulation-evoked rises in [Ca2+]i that occur with normal neuronal function. Disruption of any of these mechanisms may have implications for the function and health of peripheral neurones during the aging process. This review focuses on the impact of advancing age on the overall function of peripheral adrenergic neurones and how these changes in function may be linked to age-related changes in modulation of [Ca2+]i regulation. The data in this review suggest that normal aging in peripheral autonomic neurones is a subtle process and does not always result in dramatic deterioration in their function. We present studies that support the idea that in order to maintain cell viability peripheral neurones are able to compensate for an age-related decline in the function of at least one of the neuronal calcium-buffering systems, smooth endoplasmic reticulum calcium ATPases, by increased function of other calcium-buffering systems, namely, the mitochondria and plasmalemma calcium extrusion. Increased mitochondrial calcium uptake may represent a 'weak point' in cellular compensation as this over time may contribute to cell death. In addition, we present more recent studies on [Ca2+]i regulation in the form of the modulation of release of calcium from smooth endoplasmic reticulum calcium stores. These studies suggest that the contribution of the release of calcium from smooth endoplasmic reticulum calcium stores is altered with age through a combination of altered ryanodine receptor levels and modulation of these receptors by neuronal nitric oxide containing neurones.

Glutamate-induced protease-mediated loss of plasma membrane Ca2+ pump activity in rat hippocampal neurons.

Ca2+ dysregulation is a hallmark of excitotoxicity, a process that underlies multiple neurodegenerative disorders. The plasma membrane Ca2+ ATPase (PMCA) plays a major role in clearing Ca2+ from the neuronal cytoplasm. Here, we show that the rate of PMCA-mediated Ca2+ efflux from rat hippocampal neurons decreased following treatment with an excitotoxic concentration of glutamate. PMCA-mediated Ca2+ extrusion following a brief train of action potentials exhibited an exponential decay with a mean time constant (tau) of 8.8 +/- 0.2 s. Four hours following the start of a 30 min treatment with 200 microm glutamate, a second population of cells emerged with slowed recovery kinetics (tau = 16.5 +/- 0.3 s). Confocal imaging of cells expressing an enhanced green fluorescent protein (EGFP)-PMCA4b fusion protein revealed that glutamate treatment internalized EGFP and that cells with reduced plasma membrane fluorescence had impaired Ca2+ clearance. Treatment with inhibitors of the Ca2+-activated protease calpain protected PMCA function and prevented EGFP-PMCA internalization. PMCA internalization was triggered by activation of NMDA receptors and was less pronounced for a non-toxic concentration of glutamate relative to one that produces excitotoxicity. PMCA isoform 2 also internalized following exposure to glutamate, although the Na+/K+ ATPase did not. These data suggest that glutamate exposure initiated protease-mediated internalization of PMCAs with a corresponding loss of function that may contribute to the Ca2+ dysregulation that accompanies excitotoxicity.

Transient rise in intracellular calcium produces a long-lasting increase in plasma membrane calcium pump activity in rat sensory neurons.

The plasma membrane Ca2+ ATPase (PMCA) plays a major role in clearing Ca2+ from the neuronal cytoplasm. Calmodulin stimulates PMCA activity and for some isoforms this activation persists following clearance of Ca2+ owing to the slow dissociation of calmodulin. We tested the hypothesis that PMCA-mediated Ca2+ efflux from rat dorsal root ganglion (DRG) neurons in culture would remain stimulated following increases in intracellular Ca2+ concentration ([Ca2+]i). PMCA-mediated Ca2+ extrusion was recorded following brief trains of action potentials using indo-1-based photometry in the presence of cyclopiazonic acid. A priming stimulus that increased [Ca2+]i to 506 +/- 28 nm (>15 min) increased the rate constant for [Ca2+]i recovery by 47 +/- 3%. Ca2+ clearance from subsequent test stimuli remained accelerated for up to an hour despite removal of the priming stimulus and a return to basal [Ca2+]i. The acceleration depended on the magnitude and duration of the priming [Ca2+]i increase, but was independent of the source of Ca2+. Increases in [Ca2+]i evoked by prolonged depolarization, sustained trains of action potentials or activation of vanilloid receptors all accelerated Ca2+ efflux. We conclude that PMCA-mediated Ca2+ efflux in DRG neurons is a dynamic process in which intense stimuli prime the pump for the next Ca2+ challenge.

Modulating Ca2+ clearance from neurons.

Neurons are exquisitely sensitive to the duration, amplitude and localization of transient increases in intracellular Ca2+ concentration ([Ca2+]i). Modulation of Ca2+ uptake into the mitochondrion and endoplasmic reticulum, and efflux via the plasma membrane Ca2+ pump and Na+/Ca2+ exchange profoundly affect the shape of [Ca2+]i signals. Ca2+ clearance mechanisms are modulated by other signaling pathways, are sensitive to metabolic state and have a memory of the recent history of cell activation. We present here examples of pharmacologic and endogenous regulation of Ca2+ sequestration and efflux in neurons. Ca2+ clearance mechanisms differentially shape [Ca2+]i signals based on their affinity, capacity and location; their modulation alters specific neuronal functions. The increasingly apparent diversity of the molecular entities that make up the [Ca2+]i regulatory system reveals new sites for modulation. Specialized Ca2+ clearance mechanisms participate in unique cellular functions and thus, are important targets for pharmacological and physiological regulation of the neuron.

Aging and calcium buffering in adrenergic neurons.

The aging process at the cellular, organ and whole organism levels is in many respects a mystery. A common bias among those who study aging is that cellular homeostasis "generally falls apart". The assumption of a general deterioration in cellular homeostasis does not take into account that many individuals age quite well maintaining even robust physiological and mental functions. One facet of aging studies that has come to the forefront is the impact of age on the control of the ion messenger, calcium. Emerging evidence suggests that despite age-related declines in any one component or multiple components of the calcium buffering systems, compensatory mechanisms may be able to maintain overall calcium homeostasis. This brief review focuses specifically on the ability of peripheral neurons to maintain control of the ion messenger calcium with advancing age. In addition, the idea that the impact of age on calcium homeostasis may be more subtle due to complex and integrated mechanisms that control this ion is discussed.