Maria-Eleni Roumelioti

The diagnosis and treatment of hyponatremia present challenges to clinicians and opportunities to improve our understanding of body water, sodium and potassium homeostasis and disorders. The first step in the diagnosis of every case of hyponatremia is to categorize it as hypotonic hyponatremia, hypertonic hyponatremia, or pseudohyponatremia. The diagnostic steps that follow the verification of hypotonic hyponatremia include: (a) the identification of the medical condition that caused the hyponatremia; (b) the evaluation of the mechanism of hyponatremia, including the computation of the magnitude of the changes in body water, sodium, and potassium that were responsible for the hyponatremia. Whether the extracellular volume is low, normal, or high provides key information for the determination of the mechanism of hyponatremia and the choice of its treatment method; and (c) the determination of the duration of hyponatremia. Whether hyponatremia is acute or chronic (i.e., lasting more than 48 h) has important implications for its manifestations and management. This perspective reviews the diagnostic categories and various aspects of treatment strategies of hypotonic hyponatremia, including choosing the method(s) for increasing the electrolyte-free renal water clearance, decreasing this clearance during treatment to prevent excessively rapid correction of hyponatremia, determining the type and amount of saline infused for correction of the hyponatremia (choice of isotonic versus hypertonic saline and of the target rise in serum sodium, which determines, along with other parameters, the volume of saline infused), and dialytic methods for correcting hyponatremia. The aim of this perspective is to identify topics that require further research, including diagnostic topics and treatment areas.

Background: Entrustable Professional Activities (EPAs) that transform competencies into distinct, assessable clinical tasks have not yet been developed for US nephrology fellowships. We created and achieved consensus on a set of nephrology-specific EPAs and aligned them with Accreditation Council for Graduate Medical Education (ACGME) competency standards. Methods: This study was conducted within the University of New Mexico nephrology fellowship program. An initial EPA list was generated by the study team using program objectives, a literature review, and clinician insight. Study participants included eight faculty nephrologists and one nephrology fellow, who completed an online-based three-round modified Delphi consensus-building processes. Each EPA was rated on a five-point Likert scale with consensus requiring strict criteria. Finalized EPAs were independently mapped to ACGME nephrology program requirements. Results: Nine study participants (100% response rate) completed all survey rounds. Through iterative consensus, utilizing strict criteria, a final list of 22 distinct EPAs was created, covering 10 core domains of practice including dialysis management, acute kidney injury, chronic kidney disease, electrolyte abnormalities, hypertension, kidney stones, glomerular disease, pregnancy, transplant care, and education. Finalized EPAs were mapped to 38 different ACGME-required sub-competencies, showcasing diversity and applicability to national expectations. Conclusions: We developed the first consensus-based set of EPAs geared for US nephrology fellowship programs, providing a foundation for standardized assessment and curriculum development that could be implemented across nephrology fellowship programs nationally.

Background/Objectives: Hyperglycemic emergencies cause significant losses of body water, sodium, and potassium. This report presents a method for computing the actual losses of water and monovalent cations in these emergencies. Methods: We developed formulas for computing the losses of water and monovalent cations as a function of the presenting serum sodium and glucose levels, the sum of the concentrations of sodium plus potassium in the lost fluids, and body water at the time of hyperglycemia presentation as measured by bioimpedance or in the initial euglycemic state as estimated by anthropometric formulas. The formulas for computing the losses from hyperglycemia were tested in examples of hyperglycemic episodes. Results: The formulas were tested in two patient groups, those with or without known weight loss during the development of hyperglycemia. In the first group, these formulas were applied to estimate the losses of body water and monovalent cations in (a) a previously published case of a boy with diabetic ketoacidosis and known weight loss who, during treatment not addressing his water deficit, developed severe hypernatremia and (b) a comparison of water loss computed by this new method with the reported average fluid gained during treatment of the hyperglycemic hyperosmolar state in a published study. In the second group, the formulas were applied in hypothetical subjects with varying levels of initial body water, serum sodium, and glucose at the time of hyperglycemia and sums of sodium and potassium concentrations in the lost fluids. Conclusions: Losses of body water and monovalent cations, which determine the severity of dehydration and hypovolemia, vary significantly between patients with hyperglycemic emergencies presenting with the same serum glucose and sodium concentrations. These losses can be calculated using estimated or measured body water values. Prospective studies are needed to test this proof-of-concept report.

Key Points: Patients treated with maintenance hemodialysis report a higher symptom burden on the days they receive hemodialysis treatment, compared with non-hemodialysis days. The severity of physical, cognitive, and mood symptoms can vary diurnally, and the pattern of this variation may differ between hemodialysis and non-hemodialysis days. Ecological momentary assessment can provide insights into the complex, dynamic symptom experiences of patients on hemodialysis. Background: Patients with ESKD on hemodialysis experience a high symptom burden, which is compounded by unpredictable fluctuations in symptom severity. Few studies have used ecological momentary assessment to determine how symptoms vary over time. This study aimed to characterize the diurnal and day-to-day variability in symptoms among patients receiving hemodialysis. Methods: Patients enrolled in the Technology-Assisted Collaborative Care trial rated the intensity of physical, cognitive, and mood symptoms using an automated telephone-administered version of the Daytime Insomnia Symptom Scale at four time points (morning, early afternoon, late afternoon, evening) for seven consecutive days at baseline. Confirmatory factor analysis was used to verify the original four-factor solution for the Daytime Insomnia Symptom Scale: sleepiness/fatigue (SF), alert cognition (AC), positive mood (PM), and negative mood (NM). Symptom domain scores were calculated for each time point, and mixed modeling with random patient effects was used to examine differences in daily symptoms at daily time points between hemodialysis and non-hemodialysis days after controlling for age, sex, race, and comorbidity burden. Results: One hundred sixty patients were enrolled (mean±SD age 58±14 years, 45% women, 52% White). Diurnal symptom variation existed; trends were nonlinear and differed by hemodialysis versus non-hemodialysis days. Day-to-day symptom variation also existed; patients endorsed better physical, cognitive, and mood states (i.e., higher AC and PM) as well as lower symptom burden (i.e., lower SF and NM) on non-hemodialysis days compared with hemodialysis days at all time points. The greatest day-to-day mean differences (MDs) were observed in the early afternoon for all symptom domains: AC (MD=0.17 P < 0.001), PM (MD=0.28, P < 0.001), SF (MD=−0.66, P < 0.001), and NM (MD=−0.26, P < 0.001). Conclusions: Patients with ESKD demonstrate diurnal variation in symptoms and greater symptom burden on hemodialysis days compared with non-hemodialysis days, with the most extreme differences in symptom severity occurring in the early afternoon. Clinical Trial registration number: ClinicalTrials.gov NCT03440853.

In hyperglycemia, the serum sodium concentration ([Na]_S) receives influences from (a) the fluid exit from the intracellular compartment and thirst, which cause [Na]_S decreases; (b) osmotic diuresis with sums of the urinary sodium plus potassium concentration lower than the baseline euglycemic [Na]_S, which results in a [Na]_S increase; and (c), in some cases, gains or losses of fluid, sodium, and potassium through the gastrointestinal tract, the respiratory tract, and the skin. Hyperglycemic patients with hypernatremia have large deficits of body water and usually hypovolemia and develop severe clinical manifestations and significant mortality. To assist with the correction of both the severe dehydration and the hypovolemia, we developed formulas computing the fractional losses of the body water and monovalent cations in hyperglycemia. The formulas estimate varying losses between patients with the same serum glucose concentration ([Glu]_S) and [Na]_S but with different sums of monovalent cation concentrations in the lost fluids. Among subjects with the same [Glu]_S and [Na]_S, those with higher monovalent cation concentrations in the fluids lost have higher fractional losses of body water. The sum of the monovalent cation concentrations in the lost fluids should be considered when computing the volume and composition of the fluid replacement for hyperglycemic syndromes.

Chronic insomnia is common in patients undergoing in-center hemodialysis, yet there is limited evidence on effective treatments for this population. To compare the effectiveness of cognitive behavioral therapy for insomnia (CBT-I), trazodone, and placebo for insomnia in patients undergoing long-term hemodialysis. Randomized, multicenter, double-blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT03534284). 26 dialysis units in Albuquerque, New Mexico, and Seattle, Washington. Patients with Insomnia Severity Index (ISI) score of 10 or greater, with sleep disturbances on 3 or more nights per week for 3 or more months. Participants were randomly assigned to 6 weeks of CBT-I, trazodone, or placebo. The primary outcome was the ISI score at 7 and 25 weeks from randomization. A total of 923 patients were prescreened, and of the 411 patients with chronic insomnia, 126 were randomly assigned to CBT-I (n = 43), trazodone (n = 42), or placebo (n = 41). The change in ISI scores from baseline to 7 weeks with CBT-I or trazodone was no different from placebo: CBT-I, -3.7 (95% CI, -5.5 to -1.9); trazodone, -4.2 (CI, -5.9 to -2.4); and placebo, -3.1 (CI, -4.9 to -1.3). There was no meaningful change in ISI scores from baseline to 25 weeks: CBT-I, -4.8 (CI, -7.0 to -2.7); trazodone, -4.0 (CI, -6.0 to -1.9); and placebo, -4.3 (CI, -6.4 to -2.2). Serious adverse events (SAEs), particularly serious cardiovascular events, were more frequent with trazodone (annualized cardiovascular SAE incidence rates: CBT-I, 0.05 [CI, 0.00 to 0.29]; trazodone, 0.64 [CI, 0.34 to 1.10]; and placebo, 0.21 [CI, 0.06 to 0.53]). Modest sample size and most participants had mild or moderate insomnia. In patients undergoing hemodialysis with mild or moderate chronic insomnia, there was no difference in the effectiveness of 6 weeks of CBT-I or trazodone compared with placebo. The incidence of SAEs was higher with trazodone. National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases.

Diabetes mellitus (DM) and chronic kidney disease (CKD) are common in middle aged and older adult individuals. DM may accelerate the aging process, and the age-related declines in the estimated glomerular filtration rate (eGFR) can pose a challenge to diagnosing diabetic kidney disease (DKD) using standard diagnostic criteria especially with the absence of severe albuminuria among older adults. In the presence of CKD and DM, older adult patients may need multidisciplinary care due to susceptibility to various health issues, e.g., cognitive decline, auditory or visual impairment, various comorbidities, complex medical regimens, and increased sensitivity to medication adverse effects. As a result, it can be challenging to apply recent therapeutic advancements for the general population to older adults. We review the evidence that the benefits from these newer therapies apply equally to older and younger patients with CKD and diabetes type 2 and propose a comprehensive management. This framework will address nonpharmacological measures and pharmacological management with renin angiotensin system inhibitors (RASi), sodium glucose co-transporter 2 inhibitors (SGLT2i), non-steroidal mineralocorticoids receptor antagonists (MRAs), and glucagon like peptide 1 receptor agonists (GLP1-RAs).

Diabetes mellitus (DM) and chronic kidney disease (CKD) are common in middle aged and elderly individuals. DM may accelerate the aging process, and the age-related declines in the estimated Glomerular Filtration Rate (eGFR), can pose a challenge to diagnose diabetic kidney disease (DKD) using standard diagnostic criteria especially with absence of severe albuminuria among the elderly. In the presence of CKD and DM, elderly patients may need multidisciplinary care due to susceptibility to various health issues e.g., cognitive decline, auditory or visual impairment, various comorbidities, complex medical regimens, and increased sensitivity to medication adverse effects. As a result, it can be challenging to apply recent therapeutic advancements for the general population to the elderly. We review the evidence that the benefits from these newer therapies apply equally to elderly and non-elderly patients and propose a framework for the management of DKD by discussing the nonpharmacological measures and pharmacological management with renin angiotensin system inhibitors (RASi), Sodium Glucose Co-Transporter two inhibitors (SGLT2i), non-steroidal mineralocorticoids receptor antagonists (MRAs), and Glucagon Like Peptide 1 Receptor Agonists (GLP1-RAs).

Key Points: Lower neighborhood walkability was associated with higher depressive symptoms and fatigue and younger age with depressive symptoms. Depressive symptoms, pain, and fatigue were frequently reported, often occurred together, and were often not all already treated. Patients with a higher symptom burden and men may be more likely to be ready to seek treatment for depressive symptoms, pain, or fatigue. Background: Patients on hemodialysis (HD) often experience clinically significant levels of pain, fatigue, and depressive symptoms. We explored potential sociodemographic differences in symptom burden, current treatment, and readiness to seek treatment for these symptoms in patients screened for the TĀCcare trial. Methods: In-center HD patients from Pennsylvania and New Mexico were screened for fatigue (≥5 on 0–10-point Likert scale), pain (Likert scale ≥4), depressive symptoms (≥10 Patient Health Questionnaire-9), and readiness to seek treatment (5–item Stages of Behavior Change questionnaire). Symptom burden and treatment status by sociodemographic factors were evaluated using chi square, Fisher exact tests, and logistic regression models. Results: From March 2018 to December 2021, 506 of 896 (57%) patients screened met eligibility criteria and completed the symptom screening (mean age 60±13.9 years, 44% female, 17% Black, 25% American Indian, and 25% Hispanics). Of them, 77% screened positive for ≥1 symptom and 35% of those were receiving treatment for ≥1 of these symptoms. Pain, fatigue, and depressive symptom rates were 52%, 64%, and 24%, respectively. Age younger than 65 years was associated with a higher burden of depressive symptoms, pain, and reporting ≥1 symptom (PP$60,000/yr: odds ratio [OR]=0.16, confidence interval [CI]=0.03 to 0.76) and living in less walkable neighborhoods with more depressive symptoms (OR= 5.34, CI=1.19 to 24.05) and fatigue (OR= 5.29, CI=1.38 to 20.33). Conclusions: Pain, fatigue, and depressive symptoms often occurred together, and younger age, less neighborhood walkability, and lower income were associated with a higher burden of symptoms in HD patients. Male patients were less likely to be receiving treatment for symptoms. These findings could inform priority HD patient symptom identification and treatment targets.

Pseudohyponatremia remains a problem for clinical laboratories. In this study, we analyzed the mechanisms, diagnosis, clinical consequences, and conditions associated with pseudohyponatremia, and future developments for its elimination. The two methods involved assess the serum sodium concentration ([Na]_S) using sodium ion-specific electrodes: (a) a direct ion-specific electrode (ISE), and (b) an indirect ISE. A direct ISE does not require dilution of a sample prior to its measurement, whereas an indirect ISE needs pre-measurement sample dilution. [Na]_S measurements using an indirect ISE are influenced by abnormal concentrations of serum proteins or lipids. Pseudohyponatremia occurs when the [Na]_S is measured with an indirect ISE and the serum solid content concentrations are elevated, resulting in reciprocal depressions in serum water and [Na]_S values. Pseudonormonatremia or pseudohypernatremia are encountered in hypoproteinemic patients who have a decreased plasma solids content. Three mechanisms are responsible for pseudohyponatremia: (a) a reduction in the [Na]_S due to lower serum water and sodium concentrations, the electrolyte exclusion effect; (b) an increase in the measured sample’s water concentration post-dilution to a greater extent when compared to normal serum, lowering the [Na] in this sample; (c) when serum hyperviscosity reduces serum delivery to the device that apportions serum and diluent. Patients with pseudohyponatremia and a normal [Na]_S do not develop water movement across cell membranes and clinical manifestations of hypotonic hyponatremia. Pseudohyponatremia does not require treatment to address the [Na]_S, making any inadvertent correction treatment potentially detrimental.