Distal Delivery Research Articles

GLP-1 receptor agonists may enhance the effects of desmopressin in individuals with AVP deficiency: a case series and proposed mechanism

BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) have diverse effects on sodium and water homeostasis. They decrease thirst perception, potentially inhibit arginine vasopressin (AVP) production, and induce natriuresis. We present three cases of AVP deficiency (AVP-D) where GLP-1 RA initiation led to desmopressin dose reduction.CasesThree patients with AVP-D on stable desmopressin therapy started GLP-1 RAs for type 2 diabetes mellitus or obesity. Following weight loss and decreased thirst, all patients reduced their desmopressin dose while maintaining normal thirst and urine output.DiscussionGLP-1 RAs influence sodium and water homeostasis through various mechanisms. In individuals with intact AVP systems, GLP-1 RAs may directly suppress AVP production and induce natriuresis in the kidney leading to increased water excretion. In AVP-D, with exogenous desmopressin replacing endogenous AVP, the osmotic permeability of collecting ducts is primarily influenced by desmopressin dose. Thus, increased distal fluid delivery may allow for lower desmopressin doses to maintain water balance.ConclusionOur findings indicate a potential interaction between GLP-1 RAs and desmopressin in AVP-D. Clinicians should reassess desmopressin dosage upon initiating GLP-1 RA therapy.

Dosimetric characteristics of self-expandable metallic and plastic stents for transpapillary biliary decompression in external beam radiotherapy.

There is little evidence regarding radiation dose perturbation caused by the self-expandable metallic stents (SEMSs) used for transpapillary biliary decompression. We aimed to compare SEMSs with plastic stents (PSs) and clarify their dosimetric characteristics. Fifteen SEMSs (10 braided and 5 lasercut type) and six PSs (diameter: 2.3-3.3mm) were inserted into a water-equivalent solid phantom. In total, 13 SEMSs had radiopaque markers, whereas the other two did not. Using radiochromic films, the dose difference adjacent to the stents at locations proximal, distal, and arc delivery to the radiation source was evaluated based on comparison to measurement of the dose delivery in phantom without any stent in place. The median values of the dose difference for each stent were used to compare the SEMS and PS groups.Results: The dose difference (median (minimum/maximum)) was as follows: proximal, SEMSs + 2.1% (1.8 / 4.7) / PSs + 5.4% (4.1 / 6.3) (p < 0.001); distal, SEMSs -1.0% (-1.6 /-0.4) / PSs -8.9% (-11.7 / -7.4) (p < 0.001); arc delivery, SEMSs 1.2% (0.9 / 2.3) / PSs 2.2% (1.6 / 3.6) (p = 0.005). These results demonstrated that the dose differences of SEMSs were significantly smaller than those of PSs. On the other hand, the dose difference was large at surface of the radiopaque markers for SEMSs: proximal, 10.3% (7.2 / 20.9); distal, -8.4% (-16.3 / -4.2); arc delivery, 5.5% (4.2 / 9.2). SEMSs for biliary decompression can be safely used in patients undergoing radiotherapy, by focusing on the dose distribution around the stents and by paying attention to local changes in the dose distribution of radiopaque markers.

Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2

The renal epithelium is sensitive to changes in blood potassium (K+). We identify the basolateral K+ channel, Kir4.2, as a mediator of the proximal tubule response to K+ deficiency. Mice lacking Kir4.2 have a compensated baseline phenotype whereby they increase their distal transport burden to maintain homeostasis. Upon dietary K+ depletion, knockout animals decompensate as evidenced by increased urinary K+ excretion and development of a proximal renal tubular acidosis. Potassium wasting is not proximal in origin but is caused by higher ENaC activity and depends upon increased distal sodium delivery. Three-dimensional imaging reveals Kir4.2 knockouts fail to undergo proximal tubule expansion, while the distal convoluted tubule response is exaggerated. AKT signaling mediates the dietary K+ response, which is blunted in Kir4.2 knockouts. Lastly, we demonstrate in isolated tubules that AKT phosphorylation in response to low K+ depends upon mTORC2 activation by secondary changes in Cl- transport. Data support a proximal role for cell Cl- which, as it does along the distal nephron, responds to K+ changes to activate kinase signaling.

The Proximal Tubule Response to Low Potassium Is Mediated by mTOR/AKT Activation via Kir4.2

Background: The renal epithelium is highly sensitive to changes in blood potassium (K+) levels. We have a detailed understanding of distal K+-sensitive signaling pathways, yet proximal mechanisms are less well-defined. Results: Mice lacking the basolateral proximal tubule inwardly rectifying K+ channel, Kir4.2, (Kir4.2−/−) demonstrated normal blood and urine electrolytes at baseline. Upon removal of K+ from their diet, Kir4.2−/− animals decompensated as evidenced by increased urinary K+ excretion and development of a proximal renal tubular acidosis compared to control animals (Kir4.2+/+). Potassium wasting in Kir4.2−/− mice was not proximal in origin, but was dependent upon increased ENaC activity along the connecting segment. This was demonstrated by the correction of K+ wasting in knockouts treated with the ENaC inhibitor, amiloride. Using lithium clearance studies, we further demonstrated increased distal sodium delivery in Kir4.2−/− animals due to reduced proximal tubule sodium reabsorption. Optical clearing and three-dimensional confocal imaging reveal Kir4.2−/− mice failed to undergo proximal tubule hypertrophy when fed a low K+ diet, while the distal convoluted tubule response was exaggerated in knockouts compared to control animals. A phosphoproteomics mass spectrometry analysis identified increased mTOR/AKT signaling as mediating the proximal dietary response to K+ depletion in control animals, and changes to mTOR/AKT signaling was blunted in Kir4.2 knockouts. Lastly, we demonstrated in isolated renal tubules that AKT phosphorylation in response to low K+ depended upon mTORC2 activation by secondary reductions in intracellular Cl−. Conclusions: In this work we identify the basolateral inwardly rectifying K+ channel, Kir4.2, as a mediator of the proximal tubule response to K+ deficiency. Kir4.2 knockout mice increase their distal nephron transport burden to maintain electrolyte homeostasis in the face of deficient proximal tubule cell function. Data identify a conserved proximal role for cell Cl− which, as it does along the distal convoluted tubule, responds to extracellular K+ changes to activate intracellular kinase signaling. Along the proximal tubule, mTOR/AKT signaling is essential for the cell response to low K+. Proximal and distal nephron cell Cl− responses work in concert to preserve K+ homeostasis. These studies were supported by NIH grants DP5-OD033412 (AST), DK51265, DK95785, DK62794, DK7569, P30DK114809 (RCH, MZZ), and the Vanderbilt Center for Kidney Disease and Vanderbilt Diabetes Research and Training Center (DK020593) pilot and feasibility grant (JSD). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Nebulized mesenchymal stem cell derived conditioned medium ameliorates Escherichia coli induced pneumonia in a rat model.

Mesenchymal stem cells (MSC) have shown immense therapeutic promise in a range of inflammatory diseases, including acute respiratory distress syndrome (ARDS), and are rapidly advancing through clinical trials. Among their multimodal mechanisms of action, MSCs exert strong immunomodulatory effects via their secretome, which contains cytokines, small molecules, extracellular vesicles, and a range of other factors. Recent studies have shown that the MSC secretome can recapitulate many of the beneficial effects of the MSC itself. We aimed to determine the therapeutic capacity of the MSC secretome in a rat bacterial pneumonia model, especially when delivered directly to the lung by nebulization which is a technique more appropriate for the ventilated patient. Conditioned medium (CM) was generated from human bone marrow derived MSCs in the absence of antibiotics and serum supplements. Post-nebulization lung penetration was estimated through nebulization of CM to a cascade impactor and simulated lung and quantification of collected total protein and IL-8 cytokine. Control and nebulized CM was added to a variety of lung cell culture models and injury resolution assessed. In a rat E. coli pneumonia model, CM was instilled or administered by nebulization and lung injury and inflammation assessed at 48 h. MSC-CM was predicted to have good distal lung penetration and delivery when administered by nebulizer. Both control and nebulized CM reduced NF-κB activation and inflammatory cytokine production in lung cell culture, while promoting cell viability and would closure in oxidative stress and scratch wound models. In a rat bacterial pneumonia model, both instilled and nebulizer delivered CM improved lung function, increasing blood oxygenation and reducing carbon dioxide levels compared to unconditioned medium controls. A reduction in bacterial load was also observed in both treatment groups. Inflammatory cytokines were reduced significantly by both liquid and aerosol CM administration, with less IL-1β, IL-6, and CINC1 in these groups compared to controls. MSC-CM is a potential therapeutic for pneumonia ARDS, and administration is compatible with vibrating mesh nebulization.

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

PL-4: INSIGHTS INTO MOLECULAR MECHANISMS OF HYPERTENSION FROM HUMAN GENETICS

Identification and investigation of rare patients with extreme forms of high and low blood pressure has led to the identification of specific genes whose mutation results in these outlier phenotypes. These rare mutations converge on genes that mediate or regulate the renal reabsorption of Na-Cl. Mutations that increase or decrease renal salt reabsorption respectively increase or decrease blood pressure. Mutations that cause hypertension include gain of function mutations in subunits of the epithelial Na+ channel (ENaC) and in any of eight genes that cause constitutive activity of ENaC by its stimulation via its major regulator, the mineralocorticoid receptor, the target of aldosterone signaling; these increase salt reabsorption in the distal nephron. Conversely, mutations that cause hypotension include loss of function mutations in ENaC subunits, but also mutations the thiazide-sensitive Na-Cl cotransporter (NCC) or a K+ channel required for cotransporter function that act in the distal convoluted tubule (DCT), or mutations in the Na-K-2Cl cotransporter as well as K+ and Cl- channels expressed in the thick ascending limb of Henle that are required for normal Na-Cl reabsorption in this nephron segment. ENaC, the Na-Cl cotransporter and the Na-K-2Cl cotransporter, as well as the mineralocorticoid receptor are all commonly used targets for treatment of hypertension and/or diuresis. In addition to these genes, genetic studies also identified a previously unrecognized pathway that regulates the balance between renal salt reabsorption and K+ secretion. Mutations in the kinases WNK1 or WNK4, or genes that mediate their degradation via ubiquitylation, CUL3 and KLHL3 cause hypertension with hyperkalemia. Activity of WNK1 and WNK4 stimulates activation of NCC promoting Na-Cl reabsorption in the DCT, reducing Na-Cl- delivery distally, thereby limiting ENaC activity and limiting K+ secretion in the distal nephron. Conversely, hyperkalemia inhibits WNK activity, promoting distal Na-Cl delivery and maximizing K+ secretion. Angiotensin II signaling promotes WNK activity, increasing Na-Cl reabsorption in the DCT and inhibiting K+ secretion, while hyperkalemia appears to inhibit WNK activity, providing distal Na+ delivery that is used to drive K+ secretion. The importance of this pathway is that it can explain the mechanism by which increased dietary K+ lowers blood pressure. Both reduced dietary salt intake and increased dietary K+ can reduce blood pressure in controlled settings, and recent large population studies have shown that increased dietary K+ and reduced Na-Cl intake not only lower blood pressure but reduce the incidence of cardiovascular disease and death.

RF25 | PMON113 Subarachnoid Hemorrhage Complicated by Nephrogenic and Central Diabetes Insipidus

Abstract Introduction Diabetes insipidus (DI) is a rare complication of subarachnoid hemorrhage (SAH) and associated with worse prognosis and increased mortality. We present a case of combined nephrogenic and central DI together with osmotic diuresis as a result of SAH and discuss the pathophysiology. Case A 63-year-old female without significant past medical history was found unresponsive. CT head followed by angiography confirmed extensive SAH arising from a saccular anterior communicating artery (Acoma) aneurysm. She underwent emergent coil embolization and right frontal external ventriculostomy drain placement. Postoperatively, she developed polyuria (300-400 mL/hour) and hypernatremia (156 mEq/L) concerning for the development of DI. Serum osmolality was elevated at 316 mOsm/kg, urine osmolality inappropriately low relative to serum osmolality at 289 mOsm/kg but also unexpectedly high for complete DI, serum potassium 2.9 mEq/L and urine potassium elevated urine at 9 mEq/L. Serum copeptin was 6 pmol/L and inappropriately low for nephrogenic DI, suggesting a mixed central and peripheral process as well as contribution from osmotic diuresis. Intravenous (IV) desmopressin (DDAVP) only slightly reduced the polyuria. Management was complicated by adypsia and persistent hypokalemia requiring ongoing replacement. IV fluid, which had initially consisted of high-osmolality Plasma-Lyte (294 mOsm/L), matched to urine output, was switched to D5W, leading to a significant decrease in polyuria. On post-operative day 17, DDAVP was discontinued with normalization of sodium (137 mEq/L), potassium (3.8 mEq/L) and urine output. Three months post-operatively, she was asymptomatic with intact pituitary function and no hypokalemia. Discussion Hypokalemia in patients with SAH is thought due to acute intracellular shift of potassium caused by excessive β2-adrenergic activity generated endogenously by the sympathetic nervous system. In our patient, there was also likely contribution from distal tubular delivery of sodium from osmotic diuresis, leading to increased urinary potassium losses and hypokalemia-induced partial nephrogenic DI which was further complicated by partial central DI as suggested by the inappropriately low copeptin level for nephrogenic DI in face of a high serum osmolality and inappropriately low urine osmolality. As the vascular supply to anterior hypothalamus is derived from the Acoma, rupture may compromise perfusion affecting neuronal populations in the lamina terminalis that regulate thirst and AVP secretion in response to hyperosmolarity. Early detection of DI is critical because hypovolemia can predispose to cerebral vasospasm and worsen outcomes. This case also depicts the importance of careful consideration of sources of osmolar loads such as the composition of administered IV fluids, and aggressive potassium replacement to maintain DDAVP sensitivity. Conclusion DI should be considered in polyuria syndrome with hypernatremia after a neurosurgical event. Nephrogenic and central DI and adypsia can manifest following SAH, with sources of iatrogenic osmolar load further complicating the clinical picture. Early recognition and treatment may reduce morbidity and mortality. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:12 p.m. - 1:17 p.m.

Chloride-sensitive signaling turns the potassium switch on

The potassium switch refers to plasma potassium regulation of the sodium-chloride cotransporter (NCC), which controls distal sodium delivery and therefore potassium secretion. Low extracellular potassium activates NCC by relieving chloride inhibition of With-No-Lysine 4 (WNK4). A new mouse model carrying a chloride-insensitive WNK4 mutant still shows NCC activation on low potassium diet. These effects are mediated by WNK4 activation and kelch-like 3 (KLHL3) inhibition and reveal additional chloride-sensitive pathways for NCC activation.

Dual inhibition of SGLT2 and DPP-4 promotes natriuresis and improves glomerular hemodynamic abnormalities in KK/Ta-Ins2Akita mice with progressive diabetic kidney disease

Natriuresis is closely linked to glomerular hemodynamics in diabetic kidney disease (DKD), and is known to be influenced by inhibition of sodium-glucose cotransporter 2 (SGLT2) or dipeptidyl peptidase-4 (DPP-4). In the present study, we investigated whether dual inhibition of SGLT2 and DPP-4 exerts an additive effect on promoting natriuresis and how it ameliorates glomerular hemodynamic abnormalities via the natriuretic effect in DKD. Eight-week-old male KK/Ta-Ins2Akita (KK/Ta-Akita) mice which develop progressive DKD were orally once-daily given either SGLT2 inhibitor empagliflozin (30 mg/kg) alone, DPP-4 inhibitor linagliptin (5 mg/kg) alone or a combination of empagliflozin (30 mg/kg) plus linagliptin (5 mg/kg) for 6 weeks. In vehicle-treated control KK/Ta-Akita mouse group, markedly enhanced glomerular albumin filtration and glomerular filtration rate (GFR) were observed. These renal alterations were dramatically attenuated in KK/Ta-Akita mouse group treated with a combination of empagliflozin plus linagliptin. Notably, the combination therapy provided greater reduction in glomerular albumin filtration and GFR along with higher urinary excretion of sodium and a potential afferent arteriolar vasoconstrictor adenosine than the empagliflozin monotherapy. Significant reduction in urinary excretion levels of a potential afferent arteriolar vasodilator prostaglandin E2 (PGE2) relative to the baseline values was observed after the combination therapy but not the monotherapy. These results suggest that dual inhibition of SGLT2 and DPP-4 highly promotes a distal tubular sodium delivery and thereby contributes to the appropriate modulation of preglomerular arteriolar tone and intraglomerular pressure via an increase in adenosine release and a reduction in PGE2 secretion from macula densa in DKD.

Endovascular treatment of penetrating atherosclerotic ulcers of the arch and thoracic aorta: In-hospital and 5-year outcomes

ObjectiveThoracic endovascular aortic repair (TEVAR) is the treatment of choice for thoracic aorta diseases including penetrating aortic ulcer (PAU). The objective of this study was to analyze the results of TEVAR for the treatment of PAU in our population. MethodsFrom January 1999 to January 2019, 830 patients with type B aortic syndromes were treated with TEVAR in our institution. Of these we selected 73 patients treated for a PAU. Clinical and radiologic follow-up was performed in all patients. ResultsMean age of our population was 72 ± 8 years. Fifteen patients (20.5%) were treated in an emergency setting. The proximal landing zone was in arch zone 2 in 22 patients (30.1%). In-hospital mortality was 6.8% and was associated with acute presentation (P = .005). Distal arch delivery of the endograft was unrelated to mortality (Fisher exact test, P = .157). Survival at 1 and 5 years was 81.7% and 67.3%, respectively. Sixteen patients underwent reintervention of the thoracic aorta. Patients who underwent emergency surgery and older patients had a shorter survival (log rank test, P < .001). No difference in survival was shown according to the proximal landing zone (log rank P = .292) or the dimension of the thoracic aorta (log rank P = .067). In multivariable Cox regression analysis, only age older than 75 years was associated with 5-year mortality (hazard ratio, 6.60; 95% CI, 2.12-20.56); P < .001). ConclusionsThe use of TEVAR for treatment of aortic PAU is a safe procedure in an elective setting despite necessity of arch stent grafting. An early intervention performed at smaller aortic diameters of <55 mm might be beneficial in selected patients to improve late survival.

The Future Is Now: Preparing Sport Management Graduates in Times of Disruption and Change.

COVID-19 disrupted the world, and the impacts have been experienced in many areas, including sport and higher education. Sport management academicians need to reflect on the past two years' experience, determine what worked and what did not work, and avoid the temptation of automatically returning to past practices. The authors of this manuscript applied the disruption literature and propose transformative changes in what sport management academicians teach (e.g., greater emphasis on innovation, entrepreneurship, automation, critical thinking skills to facilitate working in flexible environments and across areas), how colleagues teach (e.g., heightened integration of technology, blended learning models) and where colleagues teach (on-campus and distal delivery modes, asynchronous and synchronous delivery to students on campus and across regions/countries). Examples of start-up companies and entrepreneurial ventures are offered to help illustrate the changing sports landscape and the emerging opportunities for current and future students, graduates, and professors. Sport management professors are offered some suggestions to assist them in seizing this opportunity.

Does the early aldosterone-induced SGK1 play a role in early Kaliuresis?

Urinary K+ potassium excretion rapidly increases after a potassium‐rich meal. The early aldosterone‐induced sgk1 gene (encoding serum and glucocorticoid‐induced kinase 1), activates potassium clearance, but the role of this kinase in the early activation of K+ secretion has not been clearly defined. Here, we challenged inducible renal‐tubule‐specific Sgk1Pax8 / LC1 knockout mice with an acute high‐potassium load (HK:5%K+) and compared the physiological and molecular responses to control mice. We observe that urinary excretion after a K+ load over the first 3 h is not dependent on SGK1 but is coincident with the rapid dephosphorylation of the Na+,Cl−‐cotransporter (NCC) to increase distal salt delivery. Molecular analyses indicate that whereas SGK1‐mediated phosphorylation of the ubiquitin‐protein ligase NEDD4‐2 begins to increase by 3h, SGK1‐dependent proteolytic activation of ENaC only becomes detectable after 6 h of HK intake. Consistent with SGK1‐dependent ENaC activation via inhibition of NEDD4‐2‐mediated ubiquitylation, Sgk1Pax8 / LC1 mice are unable to efficiently inhibit NEDD4‐2 or increase ENaC cleavage after 6 h of HK. Nevertheless, no defect in acute K+ balance was detected in the mutant mice after 6 h of HK. Moreover, we found that Sgk1Pax8 / LC1 mice reduce NCC phosphorylation and NCC‐mediated salt absorption to a greater extent than control mice after a K+ load, promoting increased amiloride‐sensitive Na+‐reabsorption via ENaC to maintain adequate kaliuresis. Together, these data indicate that: (a) during the early 3 h of HK intake, K+ excretion is SGK1‐independent even under an extreme K+ challenge, (b) shortly after, SGK1 inhibits NEDD4‐2 and activates ENaC to stimulate K+‐secretion, (c) SGK1‐dependent phosphorylation of NCC occurs, acting more likely as a brake pedal to prevent excessive K+ loss.

Distal Intracoronary Delivery of Epinephrine versus Verapamil to Prevent No-Reflow During Primary Percutaneous Coronary Intervention: A Randomized, Open-Label, Trial

Background: Previous trials showed a promising potential use of epinephrine in the treatment of no-reflow phenomenon (the no-reflow phenomenon is multiple pathogenetic processes, which may be attributed to ischemic injuries, distal atherothrombotic embolization, coronary-microcirculation susceptibility to injury, and reperfusion injuries (6)). This study aimed to compare the safety and efficacy of distal intracoronary delivery of epinephrine versus verapamil to prevent no-reflow during primary percutaneous coronary intervention (PPCI). Materials and Methods: We conducted a randomized, open-label, trial on patients undergoing PPCI. Patients were randomized to one of three groups: group I who received distal intracoronary administration of epinephrine; group II who received verapamil; and group III who served as a control group. The primary endpoint in our study was the incidence of no-reflow, defined as a post-procedural (Thrombolysis in Myocardial Infarction) TIMI flow grade (TFG) is &lt; 3 or, in the case of a TFG of 3, when TIMI myocardial perfusion grade (TMPG) is 0 or 1. Results: A total of 120 patients were randomized. The angiographic flow and perfusion parameters were significantly improved in group I and II versus the control group, with better results in epinephrine group only TMPG3 was significantly higher with epinephrine (77.5%) than verapamil (55%) (p = 0.037) and TMPG2 was higher in verapamil (32.5%) than epinephrine (7.5%) (p = 0.003). No reflow is lower with epinephrine than verapamil (25% vs 27.5%); however, with no statistically significant difference (P=0.785). Patients in the three groups has no statistical significant difference in (MACE) or heart failure hospitalization. Conclusion: Epinephrine and verapamil are safe and effective in managing patients with no-reflow during PPCIs. Further studies with a larger sample and a longer duration of follow-up are required to confirm these findings

Proton and Heavy Particle Intracranial Radiosurgery.

Stereotactic radiosurgery (SRS) involves the delivery of a highly conformal ablative dose of radiation to both benign and malignant targets. This has traditionally been accomplished in a single fraction; however, fractionated approaches involving five or fewer treatments have been delivered for larger lesions, as well as lesions in close proximity to radiosensitive structures. The clinical utilization of SRS has overwhelmingly involved photon-based sources via dedicated radiosurgery platforms (e.g., Gamma Knife® and Cyberknife®) or specialized linear accelerators. While photon-based methods have been shown to be highly effective, advancements are sought for improved dose precision, treatment duration, and radiobiologic effect, among others, particularly in the setting of repeat irradiation. Particle-based techniques (e.g., protons and carbon ions) may improve many of these shortcomings. Specifically, the presence of a Bragg Peak with particle therapy at target depth allows for marked minimization of distal dose delivery, thus mitigating the risk of toxicity to organs at risk. Carbon ions also exhibit a higher linear energy transfer than photons and protons, allowing for greater relative biological effectiveness. While the data are limited, utilization of proton radiosurgery in the setting of brain metastases has been shown to demonstrate 1-year local control rates >90%, which are comparable to that of photon-based radiosurgery. Prospective studies are needed to further validate the safety and efficacy of this treatment modality. We aim to provide a comprehensive overview of clinical evidence in the use of particle therapy-based radiosurgery.

Balloon-based drug coating delivery to the artery wall is dictated by coating micro-morphology and angioplasty pressure gradients

Paclitaxel coated balloon catheters (PCB) were developed as a polymer-free non-implantable alternative to drug eluting stents, delivering similar drug payloads in a matter of minutes. While PCB have shown efficacy in treating peripheral arterial disease in certain patient groups, restenosis rates remain high and there is no class effect. To help further optimize these devices, we developed a scanning electron microscopy (SEM) imaging technique and computational modeling approach that provide insights into the coating micromorphology dependence of in vivo drug transfer and retention. PCBs coated with amorphous/flaky or microneedle coatings were inflated for 60 sec in porcine femoral arteries. Animals were euthanized at 0.5, 24 and 72 h and treated arteries processed for SEM to image endoluminal coating distribution followed by paclitaxel quantification by mass spectrometry (MS). Endoluminal surfaces exhibited sparse coating patches at 0.5 h, predominantly protruding (13.71 vs 0.59%, P < 0.001), with similar micro-morphologies to nominal PCB surfaces. Microneedle coating covered a 1.5-fold endoluminal area (16.1 vs 10.7%, P = 0.0035) owing to higher proximal and distal delivery, and achieved 1.5-fold tissue concentrations by MS (1933 vs 1298 μg/g, P = 0.1745) compared to amorphous/flaky coating. Acute longitudinal coating distribution tracked computationally predicted microindentation pressure gradients (r = 0.9, P < 0.001), with superior transfer of the microneedle coatings attributed to their amplification of angioplasty contact pressures. By 24 h, paclitaxel concentration and coated tissue areas both declined by >93% even as nonprotruding coating levels were stable between 0.5 and 72 h, and 2.7-fold higher for microneedle vs flaky coating (0.64 vs 0.24%, P = 0.0195). Tissue retained paclitaxel concentrations at 24–72 h trended 1.7-fold higher post treatment with microneedle coating compared to the amorphous/flaky coating (69.9 vs 39.9 μg/g, P = 0.066). Thus, balloon based drug delivery is critically dependent on coating micromorphologies, with superior performance exhibited by micromorphologies that amplify angioplasty pressures.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i): renal implications

Type 2 diabetes mellitus (DM2) is a chronic condition that affects more than 400 million individuals worldwide. In DM2 patients, an appropriate glycemic control slows the onset and delays the progression of all its micro and macrovascular complications. Even though there are several glucose-lowering drugs, only approximately half of patients achieve glycemic control, while undesirable adverse effects (e.g., low serum glucose) normally affect treatment. Therefore, there is a need for new types of treatments. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have just been developed for treating DM2. Renal hyperfiltration as a marker of increased intraglomerular pressure in diabetic patients, and the role of renin-angiotensin-aldosterone system (RAAS) in this phenomenon have been studied. Nevertheless, RAAS blockade does not completely reduce hyperfiltration or diabetic renal damage. In this sense, the contribution of renal tubular factors to the hyperfiltration state, including sodium-glucose cotransporter (SGLT), has been currently studied. SGLT2i reduce proximal tubular sodium reabsorption, therefore increasing distal sodium delivery to the macula densa, causing tubule-glomerular feedback activation, afferent vasoconstriction, and reduced hyperfiltration in animal models. In humans, SGLT2i was recently shown to reduce hyperfiltration in normotensive, normoalbuminuric patients suffering from type 1 diabetes mellitus. In DM2 clinical trials, SGLT2 is associated with significant hyperfiltration and albuminuria reduction. The aim of this article is to compile the information regarding SGLT2i drugs, emphasizing its mechanism of renal repercussion.

Hyperkalemia: pathophysiology, risk factors and consequences.

There have been significant recent advances in our understanding of the mechanisms that maintain potassium homoeostasis and the clinical consequences of hyperkalemia. In this article we discuss these advances within a concise review of the pathophysiology, risk factors and consequences of hyperkalemia. We highlight aspects that are of particular relevance for clinical practice. Hyperkalemia occurs when renal potassium excretion is limited by reductions in glomerular filtration rate, tubular flow, distal sodium delivery or the expression of aldosterone-sensitive ion transporters in the distal nephron. Accordingly, the major risk factors for hyperkalemia are renal failure, diabetes mellitus, adrenal disease and the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or potassium-sparing diuretics. Hyperkalemia is associated with an increased risk of death, and this is only in part explicable by hyperkalemia-induced cardiac arrhythmia. In addition to its well-established effects on cardiac excitability, hyperkalemia could also contribute to peripheral neuropathy and cause renal tubular acidosis. Hyperkalemia—or the fear of hyperkalemia—contributes to the underprescription of potentially beneficial medications, particularly in heart failure. The newer potassium binders could play a role in attempts to minimize reduced prescribing of renin–angiotensin inhibitors and mineraolocorticoid antagonists in this context.

Potassium acts through mTOR to regulate its own secretion.

Potassium (K+) secretion by kidney tubule cells is central to electrolyte homeostasis in mammals. In the K+ secretory "principal" cells of the distal nephron, electrogenic Na+ transport by the epithelial sodium channel (ENaC) generates the electrical driving force for K+ transport across the apical membrane. Regulation of this process is attributable in part to aldosterone, which stimulates the gene transcription of the ENaC-regulatory kinase, SGK1. However, a wide range of evidence supports the conclusion that an unidentified aldosterone-independent pathway exists. We show here that in principal cells, K+ itself acts through the type 2 mTOR complex (mTORC2) to activate SGK1, which stimulates ENaC to enhance K+ excretion. The effect depends on changes in K+ concentration on the blood side of the cells, and requires basolateral membrane K+-channel activity. However, it does not depend on changes in aldosterone, or on enhanced distal delivery of Na+ from upstream nephron segments. These data strongly support the idea that K+ is sensed directly by principal cells to stimulate its own secretion by activating the mTORC2-SGK1 signaling module, and stimulate ENaC. We propose that this local effect acts in concert with aldosterone and increased Na+ delivery from upstream nephron segments to sustain K+ homeostasis.

Effect of Macronutrient Type and Gastrointestinal Release Site on PYY Response in Normal Healthy Subjects.

Enteroendocrine L cells release satiety inducing hormones in response to stimulation by luminal macronutrients. We sought to profile the differential effect of macronutrient type and site of release on circulating concentrations of the L cell-derived enteroendocrine hormone peptide tyrosine tyrosine (amino acids 1 to 36) (PYY). Eight healthy volunteers were recruited to a randomized, double-blinded, six-way crossover study. At each visit, the participants consumed a 500-kcal drink containing carbohydrate, protein, or fat in either gastric or small intestinal release formulations. Plasma PYY concentrations and hunger ratings were assessed for 3 hours after consumption of the test drink. The food intake was recorded thereafter at an ad libitum lunch. Microcapsular formulations targeting the distal small intestinal delivery of fat, but not carbohydrate or protein, markedly enhance PYY release relative to macronutrient delivery in gastric release formulations. Food intake at an ad libitum meal was lowest after consumption of the formulation releasing fat at the distal small intestine. Targeting of fat to the distal small intestine in delayed release microcapsules enhanced PYY release and was associated with reductions in food intake.