Determinants of the serum potassium concentration in chronic kidney disease.

BACKGROUND: If Ccr is creatinine clearance, a surrogate for glomerular filtration rate (GFR), the serum potassium concentration (Ks) is the sum of EK/Ccr and TRK/Ccr, which are amounts of potassium excreted and (net) reabsorbed per volume of filtrate (Ks = EK/Ccr + TRK/Ccr). We investigated changes in EK/Ccr, TRK/Ccr, and Ks through the stages of chronic kidney disease (CKD). MATERIALS AND METHODS: We performed a retrospective study of 452 patients with CKD stages G1 - 5. Simultaneous measurements of serum and urine potassium and creatinine concentrations (Ks, Ku, crs, and cru) were used to calculate 1,007 individual values of EK/Ccr and TRK/Ccr as Ku×crs/cru and Ks - EK/Ccr, respectively. Mean values of EK/Ccr and TRK/Ccr were determined in CKD stages G1 - 5. Within each stage, means of the ratios were also ascertained in subsets with hyperkalemia (Ks > 5.1 mmol/L), normokalemia (Ks 3.8 - 5.1 mmol/L), and hypokalemia (Ks < 3.8 mmol/L). RESULTS: In comparison to values in CKD stages G1 - 2, EK/Ccr rose and TRK/Ccr fell in each higher stage. Decrements in TRK/Ccr equaled increments in EK/Ccr in G3a and G3b, and Ks remained stable. In G4 - 5, the ascent of EK/Ccr exceeded the decline in TRK/Ccr, and Ks rose accordingly. Within each CKD stage, EK/Ccr was remarkably similar in the three kalemic subsets; consequently, differences in TRK/Ccr were the sole source of differences in Ks. CONCLUSION: EK/Ccr rises and TRK/Ccr falls through the stages of CKD. Ks remains stable in stages G3a - 3b in association with equal and opposite changes in EK/Ccr and TRK/Ccr. In stages G4 - 5, Ks increases progressively because EK/Ccr rises more than TRK/Ccr falls. Within each CKD stage, differences in TRK/Ccr account entirely for differences in Ks among hyper-, normo-, and hypokalemic subsets. Causes of variability of TRK/Ccr require additional investigation.

Bidirectional locomotion induces unilateral limb adaptations.

Humans can acquire and maintain motor skills throughout their lives through motor learning. Motor learning and skill acquisition are essential for rehabilitation following neurological disease or injury. Adaptation, the initial stage of motor learning, involves short-term changes in motor performance in response to a new demand in the person's environment. Repeated adaptation can improve skill performance and result in long-term skill retention. Locomotor adaptation is extensively studied using split-belt treadmill paradigms. In this study we explored whether bidirectional walking (BDW) on a split-belt treadmill can induce short-term gait adaptations. Twelve healthy volunteers participated in our single session, starting with 2 minutes of normal walking (NW), followed by four 5-minute blocks of BDW with a 1-minute passive rest in between blocks, and ending with another 2-minute of NW. We recorded body kinematics and ground reaction forces throughout the experiment. Participants quickly adapted to BDW with both legs showing decreased step lengths. However, only the backward-walking leg exhibited aftereffects upon returning to NW, indicating short-term adaptation. Notable kinematic changes were observed, particularly in hip extension and pelvis tilt, though these varied among participants. Our findings suggest that BDW induces unilateral adaptations despite bilateral changes in gait, offering new insights into locomotor control and spinal CPG organization.

Epidemiology and Racial Differences of EoE Patients in a U.S. Veterans Population.

BACKGROUND: Eosinophilic esophagitis (EoE) is increasing in prevalence but there is a lack of population-based studies. We sought to determine the prevalence, demographics, and associated atopic diseases in the Veterans Affairs (VA) population. METHODS: A nationwide analysis of data from the VA patient population was done using a Veterans Health Administration database. EoE was identified using ICD9 (530.13) and ICD10 (K20.0) codes from October 2008 to June 2020. Demographic data, smoking status, BMI, treatment, and ICD codes for atopic diagnoses were collected. Two sample proportion z-tests, Chi-square tests, two-sample t tests, and one-way ANOVA were used to assess associations across demographic categories. RESULTS: We identified a total of 11,775 patients with an EoE diagnosis: 91% male, 83% White, 8.6% Black, and 5% were of Hispanic ethnicity. The prevalence of EoE increased over time. At diagnosis, the mean age was 48.5 years overall, 51.6 years for Black patients, 45.3 years for Hispanic patients, and 48.2 years for Whites. Dysphagia was the most common symptom overall, but a higher percentage of Blacks and females were found to report chest pain (p < 0.0001, h = 0.32). With the exception of urticaria and atopic dermatitis, both Blacks and Hispanics had a higher incidence of atopic conditions compared to other races and ethnicities (p < 0.0001). CONCLUSION: While EoE is seen primarily in White males, our study shows that a notable percentage of patients were Black or Hispanic, suggesting that EoE should be considered in non-white patients. The later age of diagnosis in this group could represent a lack of awareness about EoE among non-white patients. More research is needed to study these associations.

Determinants of the serum phosphate concentration in chronic kidney disease.

If Ccr is creatinine clearance and EP and TRP are rates of phosphate excretion and reabsorption, the serum phosphate concentration (Ps) is the sum of EP/Ccr and TRP/Ccr, i.e., the amounts of phosphate excreted and reabsorbed per volume of filtrate. At equilibrium, influx of phosphate into plasma determines EP, and EP/Ccr quantifies the contribution of phosphate influx to Ps. We used data obtained at 688 clinic visits of 387 patients to analyze the evolution of Ps in chronic kidney disease (CKD) stages G1 - 5 (dialysis excluded). EP/Ccr was calculated as (Pu×crs)/cru and TRP/Ccr as Ps-EP/Ccr (where u is urine, s is serum, and cr is creatinine). Means of these parameters were plotted against CKD stages, and correlations among variables were determined with regression analyses. In comparison to values in CKD stages G1 - 2, EP/Ccr rose and TRP/Ccr fell by the same amount in CKD G3a and G3b, and Ps did not change. In stages G4 and G5, EP/Ccr increased sharply, TRP/Ccr fell minimally, and Ps rose significantly. At estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73m2, TRP/Ccr was the principal determinant of Ps at eGFR < 45 mL/min/1.73m2, contributions of EP/Ccr and TRP/Ccr to Ps were comparable. Taken together, our results show that in CKD stages G4 and G5, the effect of phosphate reabsorption on Ps changes negligibly while that of phosphate influx increases dramatically. Because the tubular response to rising EP/Ccr is limited, maintenance of stable Ps in advanced CKD requires extreme reduction of phosphate influx into plasma. TRP/Ccr may define the lowest attainable Ps.

The Impact of Obesity on the Fibrostenosis Progression of Eosinophilic Esophagitis in a U.S. Veterans Cohort.

Whether obesity is protective against progression of EoE is unknown. The aim of this study was to assess factors that alter the progression of EoE and determine if BMI is correlated with reduced disease severity. In this retrospective analysis of the Department of Veterans Affairs electronic health records, patients with EoE who received at least one dilation were identified using ICD and CPT codes. Kaplan-Meier curves determined the relationship between BMI and time to second esophageal dilation as a measurement of severity of disease. Cox proportional hazards models assessed the risk of second dilation adjusted for potential confounders. Of 2890 patients with EoE and at least one dilation, 40% were obese (n = 1165). There were no clinically significant differences in demographics between obese and non-obese patients. Non-obese patients were more likely to be smokers and had a higher mean average of the number of dilation visits compared to obese patients (p < 0.05). When stratified by obesity, non-obese individuals had a median time to next dilation of 6.53 years (95% CI (5.83, 7.79)) compared to 9.24 years for obese individuals (95% CI (7.40, 15.04)). When stratified by six BMI categories, median time to second dilation increased with increasing BMI. The hazard ratio of second dilation for obese individuals was 0.81 (95% CI (0.72-0.92)). EoE patients with a higher BMI were less likely to undergo a second dilation compared to those with a lower BMI. Obesity may have a protective role in EoE or severe strictures may lead to malnourishment. Further research into these possibilities is needed.

Chemical evidence for the tradeoff-in-the-nephron hypothesis to explain secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (SHPT) complicates advanced chronic kidney disease (CKD) and causes skeletal and other morbidity. In animal models of CKD, SHPT was prevented and reversed by reduction of dietary phosphate in proportion to GFR, but the phenomena underlying these observations are not understood. The tradeoff-in-the-nephron hypothesis states that as GFR falls, the phosphate concentration in the distal convoluted tubule ([P]DCT]) rises, reduces the ionized calcium concentration in that segment ([Ca++]DCT), and thereby induces increased secretion of parathyroid hormone (PTH) to maintain normal calcium reabsorption. In patients with CKD, we previously documented correlations between [PTH] and phosphate excreted per volume of filtrate (EP/Ccr), a surrogate for [P]DCT. In the present investigation, we estimated [P]DCT from physiologic considerations and measurements of phosphaturia, and sought evidence for a specific chemical phenomenon by which increased [P]DCT could lower [Ca++]DCT and raise [PTH]. METHODS AND FINDINGS: We studied 28 patients ("CKD") with eGFR of 14-49 mL/min/1.73m2 (mean 29.9 ± 9.5) and 27 controls ("CTRL") with eGFR > 60 mL/min/1.73m2 (mean 86.2 ± 10.2). In each subject, total [Ca]DCT and [P]DCT were deduced from relevant laboratory data. The Joint Expert Speciation System (JESS) was used to calculate [Ca++]DCT and concentrations of related chemical species under the assumption that a solid phase of amorphous calcium phosphate (Ca3(PO4)2 (am., s.)) could precipitate. Regressions of [PTH] on eGFR, [P]DCT, and [Ca++]DCT were then examined. At filtrate pH of 6.8 and 7.0, [P]DCT was found to be the sole determinant of [Ca++]DCT, and precipitation of Ca3(PO4)2 (am., s.) appeared to mediate this result. At pH 6.6, total [Ca]DCT was the principal determinant of [Ca++]DCT, [P]DCT was a minor determinant, and precipitation of Ca3(PO4)2 (am., s.) was predicted in no CKD and five CTRL. In CKD, at all three pH values, [PTH] varied directly with [P]DCT and inversely with [Ca++]DCT, and a reduced [Ca++]DCT was identified at which [PTH] rose unequivocally. Relationships of [PTH] to [Ca++]DCT and to eGFR resembled each other closely. CONCLUSIONS: As [P]DCT increases, chemical speciation calculations predict reduction of [Ca++]DCT through precipitation of Ca3(PO4)2 (am., s.). [PTH] appears to rise unequivocally if [Ca++]DCT falls sufficiently. These results support the tradeoff-in-the-nephron hypothesis, and they explain why proportional phosphate restriction prevented and reversed SHPT in experimental CKD. Whether equally stringent treatment can be as efficacious in humans warrants investigation.

The Relationship of Obesity and OSA to the Development of Sarcoidosis: A Large Retrospective Case-Control US Veterans Administration Analysis.

BACKGROUND: Previous studies have demonstrated an association between BMI and the development of sarcoidosis. We investigated this association and the association between OSA and the development of sarcoidosis in a US Veterans Health Administration database. RESEARCH QUESTIONS: Is the presence of OSA or the BMI associated with the development of sarcoidosis over the subsequent 12 months? STUDY DESIGN AND METHODS: We identified patients with sarcoidosis and OSA through International Classification of Diseases, Ninth and Tenth Revision, codes. We selected a random sample of control participants with no record of sarcoidosis. All patients with sarcoidosis had at least one BMI value recorded in the 12 months before the sarcoidosis diagnosis was made. For the patients without sarcoidosis, the BMI values were obtained over intervals 12 months before a random date. We compared the BMI and the percentage of patients with OSA in the sarcoidosis group and in patients without sarcoidosis. RESULTS: We analyzed 10,512 patients with sarcoidosis and 2,709,884 patients without sarcoidosis. We found no association between BMI and the rate of sarcoidosis developing. Post hoc statistical power calculations verified that these null results were meaningful and not the result of insufficient statistical power. We also found that a diagnosis of OSA was protective of sarcoidosis developing. Using a conditional logistic regression model with strata for age, sex, and BMI in the same 12-month period, a 49.0% lower odds of sarcoidosis was found in patients with OSA compared with patients without a diagnosis of OSA. Although the primary outcomes were assessed at 12 months before the diagnosis of sarcoidosis, these results basically held when examined at 3 and 6 months before the diagnosis was made. INTERPRETATION: These findings suggest that increased BMI is not associated positively with a greater odds of sarcoidosis developing. Furthermore, these results suggest that the presence of OSA lowers the odds of sarcoidosis developing.

miR-146a Dysregulates Energy Metabolism During Neuroinflammation.

Alzheimer's disease (AD) and other neurodegenerative diseases are characterized by chronic neuroinflammation and a reduction in brain energy metabolism. An important role has emerged for small, non-coding RNA molecules known as microRNAs (miRNAs) in the pathophysiology of many neurodegenerative disorders. As epigenetic regulators, miRNAs possess the capacity to regulate and fine tune protein production by inhibiting translation. Several miRNAs, which include miR-146a, are elevated in the brain, CSF, and plasma of AD patients. miR-146a participates in pathways that regulate immune activation and has several mRNA targets which encode for proteins involved in cellular energy metabolism. An additional role for extracellular vesicles (EVs) has also emerged in the progression AD, as EVs can transfer functionally active proteins and RNAs from diseased to healthy cells. In the current study, we exposed various cell types present within the CNS to immunomodulatory molecules and observed significant upregulation of miR-146a expression, both within cells and within their secreted EVs. Further, we assessed the effects of miR-146a overexpression on bioenergetic function in primary rat glial cells and found significant reductions in oxidative phosphorylation and glycolysis. Lastly, we correlated miR-146a expression levels within various regions of the AD brain to disease staging and found significant, positive correlations. These novel results demonstrate that the modulation of miR-146a in response to neuroinflammatory stimuli may mediate the loss of mitochondrial integrity and function in cells, thereby contributing to the progression of beta-amyloid and tau pathology in the AD brain. Multiple inflammatory stimuli can upregulate miRNA-146a expression within neurons, mixed glial cells, and brain endothelial cells, which is either retained within these cells or released from them as extracellular vesicle cargo. The upregulation of miR-146a disrupts cellular bioenergetics in mixed glial cells. This mechanism may play a critical role in the neuroinflammatory response observed during Alzheimer's disease.

Efficacy of metformin monotherapy in US veterans with type 2 diabetes and preexisting chronic kidney disease stage 3.

AIM: To evaluate the glycaemic efficacy of metformin in people with type 2 diabetes (T2D) and stage 3 chronic kidney disease (CKD3). PARTICIPANTS AND METHODS: This was a retrospective study including 145980 US veterans with T2D and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 who initiated metformin monotherapy between November 1999 and July 2017. Propensity-score-matched cohorts were generated based on baseline variables associated with CKD3 (eGFR 30-59 mL/min/1.73 m2 ) to evaluate the independent association between CKD3 and metformin discontinuation, the addition of a second hypoglycaemic agent, and changes in glycated haemoglobin (HbA1c) from baseline in those with and without CKD3. Associations were examined using the Kaplan-Meier method and multivariable regression models, adjusted for baseline and 12-month average metformin dose. RESULTS: The mean age of the entire cohort was 60.7 years, and 95% of the cohort were men, 21% were African American and 9% had CKD3. In the adjusted analyses, patients with CKD3 had a higher risk of metformin discontinuation or addition of a second hypoglycaemic agent, as compared with patients without CKD (hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.19-1.26, and HR 1.26, 95% CI 1.13-1.40, respectively). Among metformin monotherapy users, there were no differences in the average HbA1c reduction from baseline to 12 or 24 months between patients with and without CKD3. CONCLUSIONS: Individuals with CKD3 and T2D were at increased risk of metformin monotherapy failure. However, the HbA1c-lowering efficacy of metformin was similar in patients with and without CKD3, highlighting that metformin is a valuable treatment option for newly treated individuals with T2D and CKD3.

Disruption of metabolic, sleep, and sensorimotor functional outcomes in a female transgenic mouse model of Alzheimer's disease.

Alzheimer's Disease (AD) is the most prevalent form of dementia globally, and the number of individuals with AD diagnosis is expected to double by 2050. Numerous preclinical AD studies have shown that AD neuropathology accompanies alteration in learning and memory. However, less attention has been given to alterations in metabolism, sleep, and sensorimotor functional outcomes during AD pathogenesis. The objective of this study was to elucidate the extent to which metabolic activity, sleep-wake cycle, and sensorimotor function is impaired in APPSwDI/Nos2-/- (CVN-AD) transgenic mice. Female mice were used in this study because AD is more prevalent in women compared to men. We hypothesized that the presence of AD neuropathology in CVN-AD mice would accompany alterations in metabolic activity, sleep, and sensorimotor function. Our results showed that CVN-AD mice had significantly decreased energy expenditure compared to wild-type (WT) mice. An examination of associated functional outcome parameters showed that sleep activity was elevated during the awake (dark) cycle and as well as an overall decrease in spontaneous locomotor activity. An additional functional parameter, the nociceptive response to thermal stimuli, was also impaired in CVN-AD mice. Collectively, our results demonstrate CVN-AD mice exhibit alterations in functional parameters that resemble human-AD clinical progression.