A New Understanding of Potassium's Influence Upon Human Health and Renal Physiology.

Potassium channels are expressed in virtually all cell types, and their activity is the dominant determinant of cellular membrane potential. As such, potassium flux is a key regulator of many cellular processes including the regulation of action potentials in excitable cells. Subtle changes in extracellular potassium can initiate signaling processes vital for survival (insulin signaling) while more extreme and chronic changes may lead to pathological states (acid-base disturbances and cardiac arrhythmia). While many factors acutely influence extracellular potassium levels, it is principally the role of the kidneys to maintain potassium balance by matching urinary excretion with dietary intake. When this balance is disrupted, human health is negatively impacted. In this review, we discuss evolving views of dietary potassium intake as means of preventing and mitigating diseases. We also provide an update on a molecular pathway called the potassium switch, a mechanism by which extracellular potassium regulates distal nephron sodium reabsorption. Finally, we review recent literature describing how several popular therapeutics influence potassium homeostasis.

Race-Based Equations Delayed Black Patients From Getting Onto Kidney Transplant Lists-An Unprecedented New Policy Seeks to Undo the Damage.

This Medical News article is an interview about new policy from the US Organ Procurement and Transplantation Network to address the harms of race-based kidney function estimation.

Redressing the Harms of Race-Based Kidney Function Estimation.

This Viewpoint emphasizes the urgency of abolishing race-based medical practices and explains how they have unjustly contributed to racial inequities in clinical care and health outcomes.

CNN-assisted SERS enables ultra-sensitive and simultaneous detection of Scr and BUN for rapid kidney function assessment.

Kidney disease is highly prevalent and may result in severe clinical outcomes. Serum creatinine (Scr) and blood urea nitrogen (BUN) are the most widely used biomarkers for kidney function assessment, yet when measured alone, the result can be affected by a variety of parameters such as age, gender, protein consumption, etc. Measuring Scr and BUN simultaneously can eliminate most of the external influences and greatly improve the assessment of kidney function. In this study, a real-time kidney function assessment system based on dual biomarker detection was proposed. Scr and BUN were determined using surface-enhanced Raman scattering (SERS) within the concentration range of 10-1 to 10-6 M and 0.28 to 100 mg dl-1, respectively. A one-dimensional convolutional neural network (1D-CNN) model was employed to quantitatively analyze the concentration of biomarkers from the SERS spectral measurements. Moreover, we simulated a variety of kidney health conditions with 16 groups of mixed Scr and BUN in serum. The proposed CNN-assisted SERS method was used to quantify both biomarkers and provide diagnostic results. The Au core-Ag shell nanoprobes provided ultra-sensitive SERS detection and the CNN model achieved excellent regression results with an R2 of 0.9871 in the testing dataset. The system demonstrated a rapid and robust evaluation for the assessment of kidney function, providing a promising idea for medical diagnosis with the help of spectroscopy and deep learning methods.

Metabolomic Profiling Identifies New Endogenous Markers of Tubular Secretory Clearance.

BACKGROUND: The proximal tubules eliminate protein-bound toxins and drugs through secretion. Measurements or estimates of GFR do not necessarily reflect the physiologically distinct process of secretion. Clinical assessment of this important intrinsic kidney function requires endogenous markers that are highly specific for secretory transport. METHODS: We used metabolomics profiling to identify candidate markers of tubular secretory clearance in 50 participants from a kidney pharmacokinetics study. We measured metabolites in three sequential plasma samples and a concurrent 10-hour timed urine sample using hydrophilic interaction liquid chromatography/high-resolution mass spectrometry. We quantified the association between estimated kidney clearance and normalized plasma peak height of each candidate solute to the clearance of administered furosemide, a protein-bound, avidly secreted medication. RESULTS: We identified 528 metabolites present in plasma and urine, excluding pharmaceuticals. We found seven highly (>50%) protein-bound and 49 poorly bound solutes with clearances significantly associated with furosemide clearance and 18 solute clearances favoring an association with furosemide clearance by the 90th percentile compared with GFR. We also found four highly bound and 42 poorly bound plasma levels that were significantly associated with furosemide clearance. CONCLUSIONS: We found several candidate metabolites whose kidney clearances or relative plasma levels are highly associated with furosemide clearance, an avidly secreted tracer medication of the organic anion transporters, highlighting their potential as endogenous markers of proximal tubular secretory clearance.

Ropinirole involved in a fatal case: blood and urinary concentrations.

PURPOSE: Ropinirole is an antiparkinsonian  drug and has recently been suggested to be effective in amyotrophic lateral sclerosis. It is expected that ropinirole prescriptions will increase in the near future. However, the fatal concentration in blood is unclear at this time. Therefore, we report a fatal case involving ropinirole intoxication and discuss the fatal concentrations with reference to several autopsy cases involving ropinirole. METHODS: Ropinirole was quantified in femoral vein blood, cardiac blood, and urine from five autopsy cases in which ropinirole was detected by drug screening in our laboratory. One is a ropinirole intoxication case (this report) and the others  were non-intoxication cases. Their ropinirole concentrations were compared and discussed. RESULTS: The ropinirole concentration in this case was 100 ng/mL in femoral blood, 160 ng/mL in cardiac blood, and 1840 ng/mL in urine. The ropinirole concentrations in the four non-ropinirole poisoning cases were 7-35 ng/mL (mean: 24 ng/mL) in femoral blood, 13-100 ng/mL (mean: 60 ng/mL) in cardiac blood, and 140-1090 ng/mL (mean: 640 ng/mL) in urine. Cardiac/peripheral ratios were in the range of 1.6-2.1 (mean 1.8). CONCLUSIONS: There were no obvious signs of overdose, and the high cardiac/peripheral blood ratio suggested that postmortem redistribution may have occurred, but the  peripheral blood ropinirole concentration (100 ng/mL) was obviously higher than that reported in the previous fatal case of ropinirole poisoning (64 ng/mL). Based on these results, the cause of death in this case was considered to be shock and fatal arrhythmia due to ropinirole poisoning. This case provides important data on postmortem blood and urinary levels of ropinirole poisoning.

Mathematical modeling of the lower urinary tract: A review.

AIMS: Understand what progress has been made toward a functionally predictive lower urinary tract (LUT) model, identify knowledge gaps, and develop from them a path forward. METHODS: We surveyed prominent mathematical models of the basic LUT components (bladder, urethra, and their neural control) and categorized the common modeling strategies and theoretical assumptions associated with each component. Given that LUT function emerges from the interaction of these components, we emphasized attempts to model their connections, and highlighted unmodeled aspects of LUT function. RESULTS: There is currently no satisfactory model of the LUT in its entirety that can predict its function in response to disease, treatment, or other perturbations. In particular, there is a lack of physiologically based mathematical descriptions of the neural control of the LUT. CONCLUSIONS: Based on our survey of the work to date, a potential path to a predictive LUT model is a modular effort in which models are initially built of individual tissue-level components using methods that are extensible and interoperable, allowing them to be connected and tested in a common framework. A modular approach will allow the larger goal of a comprehensive LUT model to be in sight while keeping individual efforts manageable, ensure new models can straightforwardly build on prior research, respect potential interactions between components, and incentivize efforts to model absent components. Using a modular framework and developing models based on physiological principles, to create a functionally predictive model is a challenge that the field is ready to undertake.

Alzheimer's disease amyloidogenesis is linked to altered lower urinary tract physiology.

AIMS: While most Alzheimer's disease (AD) research emphasizes cognitive and behavioral abnormalities, lower urinary tract symptoms (LUTS) are observed in a third of AD patients, contributing to morbidity, poor quality of life, and need for institutionalization. Alzheimer's disease-associated urinary dysfunction (ADUD) has been assumed to be due to cognitive decline alone. While mouse studies have suggested that bladder innervation and voiding behavior may be altered in AD models, technical challenges precluded voiding reflex assessments. This study seeks to establish a mouse model of ADUD, and it seeks to characterize the noncognitive sequelae involved in AD-pathology associated alterations in the voiding reflex. METHODS: Having developed techniques permitting the assessment of bladder volume, pressure, and flow in mice, we now provide evidence of alterations in involuntary bladder control and increased response heterogeneity in a transgenic amyloidosis mouse model of AD using cystometry and tissue pharmacomyography. Tg-APP/PS1DE9 (PA) mice and their wild-type (WT) littermates (n = 6-8 per group) were used before plaque onset in the PA mice (4-6 months) and after plaque accumulation in the PA mice (8-10 months) in comparison to their WT control littermates. RESULTS: Novel findings include data suggestive of sphincteric discoordination, with pharmacological evidence of altered adrenergic mechanisms. CONCLUSIONS: Together, these data highlight the importance of addressing noncognitive sequelae of AD and offer novel translational insights into the debilitating impact of AD on LUTS and incontinence.

Reduced Glomerular Filtration in Diabetes Is Attributable to Loss of Density and Increased Resistance of Glomerular Endothelial Cell Fenestrations.

BACKGROUND: Glomerular endothelial cell (GEnC) fenestrations are recognized as an essential component of the glomerular filtration barrier, yet little is known about how they are regulated and their role in disease. METHODS: We comprehensively characterized GEnC fenestral and functional renal filtration changes including measurement of glomerular Kf and GFR in diabetic mice (BTBR ob-/ob- ). We also examined and compared human samples. We evaluated Eps homology domain protein-3 (EHD3) and its association with GEnC fenestrations in diabetes in disease samples and further explored its role as a potential regulator of fenestrations in an in vitro model of fenestration formation using b.End5 cells. RESULTS: Loss of GEnC fenestration density was associated with decreased filtration function in diabetic nephropathy. We identified increased diaphragmed fenestrations in diabetes, which are posited to increase resistance to filtration and further contribute to decreased GFR. We identified decreased glomerular EHD3 expression in diabetes, which was significantly correlated with decreased fenestration density. Reduced fenestrations in EHD3 knockdown b.End5 cells in vitro further suggested a mechanistic role for EHD3 in fenestration formation. CONCLUSIONS: This study demonstrates the critical role of GEnC fenestrations in renal filtration function and suggests EHD3 may be a key regulator, loss of which may contribute to declining glomerular filtration function through aberrant GEnC fenestration regulation. This points to EHD3 as a novel therapeutic target to restore filtration function in disease.

Lateralization of bladder function in normal female canines.

This study aimed to identify potential lateralization of bladder function. Electrical stimulation of spinal roots or the pelvic nerve's anterior vesical branch was performed bilaterally in female dogs. The percent difference between the left and right stimulation-induced increased detrusor pressure was determined. Bladders were considered left or right-sided if differences were greater or less than 25% or 10%. Based on differences of 25%, upon stimulation of spinal roots, bladders were left-sided in 17/44 (38.6%), right-sided in 12/44 (27.2%) and bilateral in 15/44 (34.2%). Using ± 10%, 48% had left side dominance (n = 21/44), 39% had right side dominance (n = 17/44), and 14% were bilateral (n = 6/44). With stimulation of the pelvic nerve's anterior vesical branch in 19 dogs, bladders were left-sided in 8 (42.1%), right-sided in 6 (31.6%) and bilateral in 5 (26.3%) using 25% differences and left side dominance in 8 (43%), right sided in 7 (37%) and bilateral in 4 (21%) using 10% differences. These data suggest lateralization of innervation of the female dog bladder with left- and right-sided lateralization occurring at similar rates. Lateralization often varied at different spinal cord levels within the same animal.