Potassium Secretion Research Articles

Klotho is highly expressed in the chief sites of regulated potassium secretion, and it is stimulated by potassium intake

Klotho regulates many pathways in the aging process, but it remains unclear how it is physiologically regulated. Because Klotho is synthesized, cleaved, and released from the kidney; activates the chief urinary K+ secretion channel (ROMK) and stimulates urinary K+ secretion, we explored if Klotho protein is regulated by dietary K+ and the potassium-regulatory hormone, Aldosterone. Klotho protein along the nephron was evaluated in humans and in wild-type (WT) mice; and in mice lacking components of Aldosterone signaling, including the Aldosterone-Synthase KO (AS-KO) and the Mineralocorticoid-Receptor KO (MR-KO) mice. We found the specific cells of the distal nephron in humans and mice that are chief sites of regulated K+ secretion have the highest Klotho protein expression along the nephron. WT mice fed K+-rich diets increased Klotho expression in these cells. AS-KO mice exhibit normal Klotho under basal conditions but could not upregulate Klotho in response to high-K+ intake in the K+-secreting cells. Similarly, MR-KO mice exhibit decreased Klotho protein expression. Together, i) Klotho is highly expressed in the key sites of regulated K+ secretion in humans and mice, ii) In mice, K+-rich diets increase Klotho expression specifically in the potassium secretory cells of the distal nephron, iii) Aldosterone signaling is required for Klotho response to high K+ intake.

Renal potassium regulation in a pig model of therapeutic hypothermia

Therapeutic hypothermia is increasingly utilized clinically to reduce tissue metabolism and protect against neurological damage in cases of cardiac arrest, traumatic brain injury or perinatal hypoxic ischemia. With even mild exposure to hypothermia, hypokalemia develops purportedly due to transcellular potassium shifts resulting in decreased circulating potassium levels. Renal dysfunction with body temperature cooling has also been postulated to potentially contribute to development of sustained hypokalemia. In this study, we used a pig model of controlled acute hypothermia without confounding hypotension and hypoxemia, to test the hypothesis that renal handling of potassium remains intact in hypothermia and is not the cause of decreased circulating plasma potassium seen with body cooling. Anesthetized, mechanically ventilated Duroc cross young pigs (n=25, body weight = 10.0 ± 0.4 kg, male or female) were catheterized for hemodynamic monitoring, regional blood flow assessment via colored microspheres, and urine collection. After baseline values were obtained, pigs were divided into a control normothermia group (n=12) with body temperature maintained at 38.4 ± 0.1 oC or a hypothermia group (n=13) with core body temperature cooled to 34.5 ± 0.1 oC and hypothermia sustained for 2 hours. Hypothermia reduced tissue metabolism as indicated by a decrease in oxygen consumption (VO2= 5.2 ± 0.2 ml/kg in normothermia vs 3.7 ± 0.3 ml/kg in hypothermia. Mean arterial pressure (68± 3 mm Hg) and cardiac output (199 ± 21 ml/min/kg) were not different between groups. Even with the short duration of cold exposure, plasma potassium was lower (p<0.05) within 2 hours of hypothermia (4.1 ± 0.1 mEq/L) vs control (4.8 ± 0.1 mEq/L). Cold exposure caused redistribution of blood flow to the small intestines from other internal organs. Renal blood flow tended to decrease with cold, but glomerular filtration rate was suffcient to maintain urine flow, sodium excretion and free water clearance. Potassium clearance, however, was lower (p<0.05) in hypothermia (0.70 ± 0.07 ml/min/kg) than in normothermia (1.04 ± 0.07 ml/min/kg), with lower potassium excretion (hypothermia = 2997 ± 331 mEq/min vs control = 4784 ± 393 mEq/min, p<0.05) and fractional excretion of potassium. Reduced renal potassium excretion is consistent with renal compensation for lower circulating potassium induced by hypothermia. Interestingly, with relatively higher blood flow to the small intestines compared to decreased blood flow of other internal organs, potassium secretion in the early colon may contribute to further potassium wasting in hypothermia. The rapid initiation of decreased potassium circulating levels with hypothermia supports the thesis of temperature sensitive cell membrane potassium channels affecting extracellular to intracellular shifts of potassium. Results of this study indicate that renal potassium regulation is maintained in hypothermia and functions to decrease urinary potassium loss in the face of hypokalemia. The views expressed are those of the authors and do not necessarily reflect the offcial policy or position of the Defense Health Agency, Department of the Army, Department of Defense, or the U.S. Government. 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.

Balancing sodium and potassium: Implication of mTORC2-mediated ENaC activation in DCT2 and early CNT for potassium balance in high dietary potassium

Background: The activity of the epithelial sodium ion channel, ENaC, and ENaC-dependent potassium (K+) secretion through ROMK are influenced by both aldosterone-dependent and independent mechanisms in response to dietary potassium (K+). While ENaC activity in the late connecting tubule (CNT) and cortical collecting duct (CCD) depends on aldosterone, it is aldosterone-independent in the late distal convoluted tubule (DCT2) and early CNT (eCNT). Aldosterone-stimulated ENaC activity relies on SGK1, transcriptionally upregulated by aldosterone and subsequently phosphorylated and activated by mTOR complex-2 (mTORC2). Recent evidence suggests that high potassium can rapidly activate mTORC2/SGK1 signaling to stimulate ENaC. In this study, we explore mTORC2’s role in K+ secretion and aldosterone-independent ENaC regulation. Methods: Rictor, a core component of mTORC2, was selectively knocked out (KO'd) in DCT2, CNT and CD by utilizing Calbindin as Cre-driver (CRKO mice) or late CNT and CD, by employing AQP2 as the Cre-driver (ARKO mice). Both wild-type (WT) and KO mice were subjected to a high potassium (HK) diet for short-term (4 hours) or medium-term (48 hours) periods, enabling the monitoring of both the early response and prolonged adaptation to the HK diet. Parameters assessed include urinary and blood electrolyte levels, renal transporter expression, activity and localization, and mTORC2 target phosphorylation. Results: On a normal K+ diet, both KO mice maintained Na+ and K+ balance but CRKO mice had elevated aldosterone levels. After short-term (4-hour) HK intake, CRKO mice had disrupted Na+ and K+ balance, reduced K+ excretion and hyperkalemia. In contrast, ARKO mice maintained Na+ and K+ balance with elevated aldosterone. On a prolonged HK diet (48 hours), CRKO mice had severe hyperkalemia, reduced GFR and significantly elevated aldosterone level. Immunofluorescence studies indicated markedly reduced apical localization of active ENaC in DCT2/eCNT of CRKO mice. Conversely, ENaC apical localization in the late CNT and CCD was mostly unaffected. Phosphorylation of mTORC2 targets involved in ENaC regulation, such as SGK1, and SGK1’s target, Nedd4-2, was also reduced in CRKO mice. ARKO mice maintained ion balance with normal K+ levels but significantly increased aldosterone levels and maintained ENaC apical localization in the late CNT and CCD. Conclusions: The data suggest that high aldosterone can compensate mTORC2 deficiency and maintain ENaC activity in the late CNT and CCD. However, mTORC2 activity is crucial for maintaining ENaC activity in the late DCT and early CNT (aldosterone-independent) and preserving potassium balance during high dietary potassium intake. National Institutes of Health (R01- DK56695), James Hilton Manning and Emma Austin Manning Foundation. 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.

Aldosterone's impact on kidney health: exploring the benefits of mineralocorticoid receptor antagonists for renal protection.

Aldosterone, a hormone synthesized by the adrenal cortex, plays a crucial role in regulating sodium and potassium levels in the kidneys through interaction with the mineralocorticoid receptor (MR) in the distal tubules and collecting ducts. While aldosterone aids in maintaining fluid balance by promoting sodium reabsorption and potassium secretion, elevated levels can lead to inflammation, oxidative stress, and organ damage. Experimental evidence highlights aldosterone's involvement in renal inflammation, collagen deposition, and fibrosis, often exacerbating the effects of therapies like angiotensin-converting enzyme inhibitors (ACEIs) by increasing proteinuria and vascular damage. Conversely, mineralocorticoid receptor antagonists (MRAs) show promise in mitigating these harmful effects. This review integrates current knowledge on aldosterone and MRAs, emphasizing their roles in renal health from both clinical and experimental perspectives. Additionally, the novel drug finerenone has shown favorable renal and cardiovascular outcomes in patients with diabetes and chronic kidney disease (CKD), warranting exploration of its potential use in other disease populations in future research.

Postnatal development of salivary phosphate, sodium and potassium secretion in calves.

The transition of young lambs and calves from a non-ruminating to a ruminating animal include substantial, developmental changes to alter saliva production. Due to the simultaneous development of the forestomach system, the salivary glands must transfer more and more substances such as bicarbonate and phosphate (Pi), but also sodium (Na), into saliva in order to create and to maintain optimal environmental conditions for microbial metabolism. The objective of the present study was to characterize the effects of different dietary energy levels on the ability of the salivary glands to concentrate minerals in young ruminants in more detail during the first 7 weeks of life. Blood and saliva samples were collected from twelve female calves of the German Holstein breed fed different levels of milk replacer. Plasma and saliva samples were collected over 7 weeks postpartum and Na, Pi and potassium (K) concentrations were measured. Salivary Na and Pi concentrations (p < 0.001) increased as a function of time and were not affected by varying energy intake, while K concentration (p < 0.001) decreased over the developmental period and was also not affected by energy intake. This suggests that the ability to specifically concentrate minerals such as Na and Pi in saliva follows a genetic program in the salivary glands rather than being influenced by dietary factors such as energy intake in young ruminants.

Diuretic Effect of Combination of Watercress (Nasturtium officinale) and Purslane (Portulaca oleraceae)

Watercress (Nasturtium officinale) and purslane (Portulaca oleracea) are used to increase urination.This preclinical study aims to prove the diuretic effect of a combination of watercress and purslaneextracts. Simplisia of watercress and purslane herbs mixed with various combinations A (1:9), B(1:3) and C (1:1), then extracted in 50% ethanol. The animals were divided into five groups: control,furosemide 3.6 mg/kgBW, A 38 mg/kgBW, B 28 mg/kgBW, and C 10 mg/kgBW. Diuretic assay wascarried out using the modified Lipschitz method with the parameters observed were cumulative urinevolume for 6 and 24 hours, and potassium levels in 24-hour urine. The results showed the onset ofdiuretic effect of furosemide at 60 minutes, A at 150 minutes, B at 240 minutes and C at 90 minutes.Percent effectiveness of the diuretic in the furosemide was 718%, A 212%, B 231%, and C 368% whencompared to the controls. All combinations of extracts increased sodium and potassium secretion whencompared to controls, but this effect was not as strong as furosemide. All combinations of watercressand purslane herbs have a diuretic effect but weakly saluretic when compared to furosemide and thecombination that gives the best effect is combination C.

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

Steroidal or non-steroidal MRAs: should we still enable RAASi use through K binders?

Renin-angiotensin-aldosterone system inhibitors (RAASi) and mineralocorticoid receptor antagonists (MRAs) are important interventions to improve outcomes in patients with chronic kidney disease and heart failure, but their use is limited in some patients by the development of hyperkalemia. The risk of hyperkalemia may differ between agents, with one trial showing lower risk of hyperkalemia with the novel non-steroidal MRA finerenone compared with steroidal MRA spironolactone. Novel potassium binders, including patiromer and sodium zirconium cyclosilicate, are available interventions to manage hyperkalemia and enable continuation of RAASi and MRAs in patients who could benefit from these treatments. These agents bind free potassium ions in the lumen of the gastrointestinal tract to prevent the absorption of dietary potassium and increase potassium secretion. Several studies showed that potassium binders are effective compared with placebo for preventing hyperkalemia or steroidal MRA discontinuation, but none has evaluated whether this strategy impacts clinically important endpoints such as cardiovascular events. Due to this and other limitations related to cost, clinical availability, pill burden and patient selection, alternative potential strategies to mitigate hyperkalemia may be more practical. Conservative strategies include increased monitoring and use of loop or thiazide diuretics to increase urinary potassium excretion. Non-steroidal MRAs may have a lower risk of hyperkalemia than steroidal MRAs and have stronger anti-inflammatory and anti-fibrotic effects with resultant reduced risk of kidney disease progression. Sodium-glucose cotransporter-2 inhibitors also decrease hyperkalemia risk in patients on MRAs and decrease cardiovascular events and kidney disease progression. These may be better first-line interventions to obviate the need for potassium binders and offer additional benefits.

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.

A quantitative systems pharmacology model of plasma potassium regulation by the kidney and aldosterone.

Plasma potassium regulation within a narrow range is vital for life. The risk for hyperkalemia increases when kidney function is impaired and with therapeutic interventions such as mineralocorticoid receptor antagonists (MRAs). The kidney maintains potassium homeostasis by matching potassium intake and excretion, in part through the action of aldosterone. A mechanistic mathematical model was developed and used to investigate the effect of renal impairment and MRAs on plasma potassium levels. The model describes renal potassium filtration, reabsorption, and secretion along the nephron; potassium-aldosterone regulatory feedbacks; whole body potassium balance; and the pharmacologic effects of MRAs. The model was calibrated by fitting (1) the plasma potassium and aldosterone response to potassium infusion in humans on high/low potassium diets, and (2) the acute potassium excretion response to spironolactone. The model was validated by predicting steady-state plasma potassium with sustained spironolactone treatment in hyperaldosteronism patients. The model was then used to demonstrate that (1) declining renal function alone has a small effect on plasma potassium for GFR > 30ml/min, but an increasing effect as GFR approaches end stage renal disease (GFR ~ 15ml/min) (2) the effect of increasing potassium intake has minimal effect at normal GFRs but increasing effect on plasma potassium as GFR declines, and 3) MRAs have a minor effect on plasma potassium when GFR is normal, but cause larger increases as GFR falls below 60ml/min. This model provides a quantitative framework for investigating integrated impacts of diseases and therapies in this complex system.

Directed search for diuretics among 6-substituted pteridine-2,4,7(1H,3H,8H)-triones

Directed search for biologically active compounds among heterocycles still remains a relevant area of medical chemistry. Among the significant number of heterocyclic compounds, pteridines deserve special attention. Among the above-mentioned ones the drugs with antitumor, antimicrobial, antiviral, diuretic and other types of biological action are known. Nevertheless, 6-substituted pteridine-2,4,7(1H,3H,8H)-triones, which are structurally similar to triamterene (6-phenylpteridine-2,4,7-triamine) – a diuretic with potassium-sparing action are interesting objects for search for diuretics. All the more, they are characterized by prototropic tautomerism, able to form hydrogen and donor-acceptor bonds with various ligands, and it is likely that these structural features will provide their diuretic effect. The aim of the study is the directed search for diuretics among 6-substituted pteridine-2,4,7(1H,3H,8H)-triones using in silico and in vivo methodology and elucidation of the probable mechanism of action. 1-methyl-3-R-6- (2-oxo-2-aryl- (hetaryl-) ethyl) pteridine-2,4,7(1H,3H,8H)-triones were selected to study the effect on renal excretory function. and 1-methyl-3-R-6- (2-hydroxy-2-aryl- (hetaryl-) ethyl) pteridine-2,4,7(1H,3H,8H)-triones. Directed search for compounds that affect the excretory function of the kidneys of rats was conducted by the conventional method of E.B. Berkhin with water load. The content of creatinine, sodium, potassium and chlorides in blood and urine plasma was determined by biochemical methods using standard test kits of NPV "Philisit-Diagnostics" (Ukraine) and calculations were performed according to generally accepted methods. Research of the probable mechanism was conducted by flexible molecular docking, as an approach of finding molecules with affinity to a specific biological target. Macromolecular data were downloaded from the Protein Data Bank (PDB) namely, the crystal structures of Human carbonic anhydrase II (PDB ID – 3HS4) and epithelial sodium channel (ENaC) (PDB ID – 4NTX). Studies of the effect of the synthesized compounds on the excretory function of the kidneys of rats showed that 1-methyl-3-R-6- (2-oxo-2-aryl- (hetaryl-) ethyl) pteridine-2,4,7(1H,3H,8H)-triones containing 4-fluorophenyl, 2,4-difluorophenyl, 4-chlorophenyl fragments in the molecule increase diuresis by the second hour by 27.3-70.1% compared with the control group. According to the results of the impact on daily diuresis, it was found that the most active was 1-methyl-6- (2-oxo-2-phenyl) ethyl) pteridine-2,4,7(1H,3H,8H)-triones, which increased daily diuresis by 168.1%, exceeding the effect of Hydrochlorothiazide (41.8%) and Triamterene (49.1%). However, substituted 1-methyl-3-R-6- (2-hydroxy-2-aryl- (hetaryl-) ethyl) pteridine-2,4,7(1H,3H,8H)-triones are inactive compounds. In-depth studies using biological tests and molecular docking have suggested that 1-methyl-6- (2-oxo-2-aryl) ethyl) pteridine-2,4,7(1H,3H,8H)-triones 2.1, 2.5 and 2.6) probable mechanisms of diuretic action are disruption of sodium transport in the distal convoluted tubules, causing sodium excretion and water loss and possibly inhibition of epithelial sodium channels that promote sodium uptake and potassium secretion in the distal convolutions and tubules, which implements potassium-sparing action. A well-founded and developed strategy for the search for diuretics among 6-substituted pteridine-2,4,7(1H,3H,8H)-triones has identified a number of effective compounds that by diuretic effect are superior to the reference drugs "Hydrochlorothiazide" and "Triamterene". Importantly, the results of molecular docking suggested a mechanism of action of the compounds under study, similar to thiazide diuretics. This action may be related to the tautomerism of these compounds and, as a consequence, their ability to form coordination bonds with the zinc cation and the additional interaction of halogens in the active site of CA II. It was possible to detect the presence of potassium-sparing action, probably due to the ability to inhibit epithelial sodium channels (ENaC). The obtained results substantiate the further purposeful search for potential diuretics among this class of compounds.

The Emerging Role of Implementing Machine Learning in Food Recommendation for Chronic Kidney Diseases Using Correlation Analysis

Kidneys are vital organs in the human body, and their effective functioning determines life quality. Chronic kidney illness is a kind of nephrotic syndrome in which the kidneys’ capacity to cope normally steadily deteriorates and remains asymptomatic for a long period as the disease progresses. An early CKD detection would help the patient recover faster and easier. Using an artificial intelligence system that can effectively aid in CKD detection in time and suggest the required food nutrition for its treatment and recovery would reap immense benefits for healthcare professionals as well as the patient. ML is a part of AI technology that has been used for effective medical development. This technology helps physicians in the accurate diagnosis of kidney disease and helps in effective treatment prediction by recommending required nutrition. The present research relates to the use of ML in proper kidney disease diagnosis and food recommendations for treatment accordingly. A correlation analysis has been done in this research to observe the strength of ML using the effective finding for renal malfunctioning and identifying the best food products that could help in its treatment and recovery. IBM SPSS version 26 has been used for this research. The correlation analysis has been done to observe the impact of eight independent variables that are age, gender, blood sugar, serum albumin, creatinine, potassium, bacteria, and pus secretion on the two dependent variables that are the risk of CKD occurrence and ML accuracy. The results have exposed that the autonomous values consist of a strong positive correlation with the dependent variable ( p &lt; 0.005 ). The statistical significance values have proved that the dependent values are statistically significant (0.001). The value of ML accuracy at a 95% confidence level has been observed at 88.85%, and the CKD occurrence value is 86.95%. The results have proved that the ML algorithm detects the risk of CKD occurrence accurately in each stage via analyzing blood sugar, creatinine, and potassium levels. The result also shows that the risk of CKD enhances with an increase in age.

Mineralocorticoid receptors in non-alcoholic fatty liver disease.

Liver diseases are the fourth common death in Europe responsible for about 2 million death per year worldwide. Among the known detrimental causes for liver dysfunction are virus infections, intoxications and obesity. The mineralocorticoid receptor (MR) is a ligand-dependent transcription factor activated by aldosterone or glucocorticoids but also by pathological milieu factors. Canonical actions of the MR take place in epithelial cells of kidney, colon and sweat glands and contribute to sodium reabsorption, potassium secretion and extracellular volume homeostasis. The non-canonical functions can be initiated by inflammation or an altered micro-milieu leading to fibrosis, hypertrophy and remodelling in various tissues. This narrative review summarizes the evidence regarding the role of MR in portal hypertension, non-alcoholic fatty liver disease, liver fibrosis and cirrhosis, demonstrating that inhibition of the MR in vivo seems to be beneficial for liver function and not just for volume regulation. Unfortunately, the underlying molecular mechanisms are still not completely understood. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc.

Gitelman Syndrome: a Сlinical and Molecular Overview

Gitelman syndrome (OMIM #263800) is an autosomal recessive renal tubular disorder due to loss of function mutations of SLC12A3 gene, encoding the thiazide-inhibitable, electroneutral Na+-Cl– cotransporter (NCC) of the distal convoluted tubule. Clinical consequences include chronic normotensive hypokalemic alkalosis, hypomagnesemia, hypocalciuria, polyuria/nocturia, chronic asthenia, muscular cramps, chondrocalcinosis and rarely cardiac arrhythmias.Impaired reabsorption of glomerular filtrate through NCC drives compensatory reabsorption of Na+ in more distal tubular segments (connecting and cortical collecting tubules) via both the «electrogenic» channel ENa (which also enhances tubular secretion of potassium and protons, explaining the hypokalemic alkalosis), and pendrin-dependent electroneutral NaCl reabsorption. Thus volume depletion is seldom severe in these patients.There exists wide variability and severity of clinical symptoms between subjects, ranging from an almost asymptomatic disease to a severely disabling one. More than 400 SLC12A3 mutations have been so far described, evenly distributed along the protein sequence and without any hot spot. Mutation detection rate by gene sequencing actually is about 80 %. There are no genotype-phenotype correlations.Commonly considered a benign condition, Gitelman syndrome may be associated with reduced quality of life, increased medicalization and high hospitalization rate.

Eplerenone–A novel Mineralocorticoid receptor antagonist for the clinical application

Aldosterone is produced from the zona glomerulosa of the adrenal cortex in the adrenal gland, which is main mineralocorticoid hormone. Upon binding the mineralocorticoid receptor, it regulates sodium and potassium absorption, secretion, and retention, thereby maintaining stable blood pressure levels. However, abnormal aldosterone synthesis and metabolism could be pathogenic and contribute to multiple organ fibrosis and structural remodeling. For instance, hyperaldosteronemia is critically involved in the development of hypertension, heart failure (HF), and renal disease. Therefore, mineralocorticoid receptor antagonists (MRAs) that could fight against high concentrations of aldosterone play an important role in the treatment of diseases caused by hyperaldosteronism. Eplerenone, as a novel selective MRA, has better therapeutic efficiency and fewer side effects comparing to the classical drug spironolactone. In this review, first, we go through the biosynthesis and biologic properties of aldosterone and then introduce how hyperaldosteronemia facilitates certain diseases progression. Aldosterone is an important part of the renin-angiotensin-aldosterone system (RAAS), which plays a crucial role in essential hypertension, atrial tremor, and tissue fibrosis. Second, we summarize current evidence of clinical application of eplerenone in the control of primary aldosteronism, hypertension, HF, nephropathy, insulin resistance, and liver damage. It is exciting that many studies have shown that the use of eplerenone in these diseases yields good outcomes accompanied with fewer adverse effects such as hyperkalemia, metabolic acidosis, hypotension, and acute kidney failure, which indicates that eplerenone is a strong and safe MRA and inhibitor of RAAS system. This review focuses on therapeutic efficacy and disadvantages of eplerenone when treating a series of different diseases. Ultimately, we hope to shed light on future therapeutic strategies in diseases associated with hyperaldosteronemia.

HEPARIN-INDUCED RENAL TUBULAR ACIDOSIS MASQUERADING AS HYPERKALEMIA IN A PATIENT WITH SARS-COV-2

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Renal tubular acidosis (RTA) is defined as inadequate excretion of acids via the kidneys to maintain the acid-base balance. In RTA type 4, there is either deficiency or resistance to aldosterone leading to impaired regulation of electrolytes and hydrogen ions. This leads to hyponatremia, hyperkalemia, and acidemia. We present an unsuspecting etiology to RTA type 4 in a critically ill. SARS-CoV-2 patient as noted by heparin use for VTE prophylaxis. [1,2] CASE PRESENTATION: A 72-year-old male with history of chronic kidney disease, leukemia in remission presents with 6-day history of flu-like symptoms including intermittent diarrhea, fevers, decreased appetite, shortness of breath and generalized malaise with exposure to several known sick contacts with SARS-CoV-2. The patient was admitted to the ICU for acute hypoxic respiratory failure and started on Decadron, Remdesivir, Azithromycin, Ceftriaxone, Lovenox, Zinc, and vitamin C and subsequently intubated on day 10. Creatinine up trended and peaked at 3.51 mg/dL on hospital day 14. He developed hyperkalemia initially presumed to be secondary to acute kidney injury. His platelet counts declined by >50%, >10 days after hospitalization. Due to concern for HIT, argatroban was started but stopped due to bleeding. As fondaparinux is contraindicated in renal failure, he was restarted on heparin when HIT ab (-) result was obtained. Serum potassium peaked at 6.7 mmol/L on day 21. He was treated with calcium gluconate, insulin D50, Patiromer 8.4 g with no significant improvement in potassium levels. Due to concerns that use of heparin may be causing hyperkalemia by suppressing aldosterone, heparin was discontinued. Subsequently, serum potassium levels improved to normal range. DISCUSSION: In RTA type 4, either low levels of aldosterone or from kidneys not responding to aldosterone, impaired sodium reabsorption and potassium secretion occurs.[2]. Persistent hyperkalemia in whom there is no apparent cause such as potassium supplements or a potassium-sparing diuretic or renal failure, hypoaldosteronism must be considered [3-5].In COVID-19, there exists a higher propensity for thromboembolic disease and often prevention with heparin can serve as the best treatment. Heparin has a direct toxic impact on the adrenal zona glomerulosa cells, which may be facilitated by a drop in the number and affinity of adrenal angiotensin II receptors [4,6]. This reduction in aldosterone can lead to severe hyperkalemia [6]. CONCLUSIONS: This case is unique because hyperkalemia was noted to be refractory to the typical standard treatment given the etiology was hypoaldosteronism likely secondary to heparin use. Most patients with RTA if treated adequately in the early stages do not develop permanent kidney failure, have better mortality and morbidity outcomes and necessitate a broad etiologic differential. REFERENCE #1: Rodriguez Soriano J. Renal tubular acidosis: the clinical entity. J Am Soc Nephrol 2002;13:2160. REFERENCE #2: Renal Tubular Acidosis. www.kidney.niddk.nih.gov.U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. National Institutes of Health, NIH Publication No. 09–4696, October 2008. REFERENCE #3: DeFronzo RA. Hyperkalemia and hyporeninemic hypoaldosteronism. Kidney Int 1980;17:118. DISCLOSURES: No relevant relationships by Vidya Baleguli, source=Web Response No relevant relationships by Martin Herrera, source=Web Response No relevant relationships by Riaz Mahmood, source=Web Response No relevant relationships by Erine Raybon-Rojas, source=Web Response

Auditory Threshold Variability in the SAMP8 Mouse Model of Age-Related Hearing Loss: Functional Loss and Phenotypic Change Precede Outer Hair Cell Loss.

Age-related hearing loss (ARHL) is the most common sensory deficit in aging society, which is accompanied by increased speech discrimination difficulties in noisy environments, social isolation, and cognitive decline. The audiometric degree of ARHL is largely correlated with sensory hair cell loss in addition to age-related factors not captured by histopathological analysis of the human cochlea. Previous studies have identified the senescence-accelerated mouse prone strain 8 (SAMP8) as a model for studying ARHL and age-related modifications of the cochlear redox environment. However, the SAMP8 population exhibits a large variability in auditory function decline over age, whose underlying cause remains unknown. In this study, we analyzed auditory function of SAMP8 mice by measuring auditory brainstem response (ABR) thresholds at the age of 6 weeks (juvenile), 12 weeks (young adult), and 24 weeks (adult). Consistent with previous studies, SAMP8 mice exhibit an early progressive, age-related decline of hearing acuity. However, a spatiotemporal cytohistological analysis showed that the significant increase in threshold variability was not concurrently reflected in outer hair cell (OHC) loss observed in the lower and upper quartiles of the ABR threshold distributions over age. This functional loss was found to precede OHC loss suggesting that age-related phenotypic changes may be contributing factors not represented in cytohistological analysis. The expression of potassium channels KCNQ4 (KV7.4), which mediates the current IK,n crucial for the maintenance of OHC membrane potential, and KCNQ1 (KV7.1), which is an essential component in potassium circulation and secretion into the endolymph generating the endocochlear potential, showed differences between these quartiles and age groups. This suggests that phenotypic changes in OHCs or the stria vascularis due to variable oxidative deficiencies in individual mice may be predictors of the observed threshold variability in SAMP8 mice and their progressive ARHL. In future studies, further phenotypic predictors affected by accumulated metabolic challenges over age need to be investigated as potentially underlying causes of ARHL preceding irreversible OHC loss in the SAMP8 mouse model.

German S3-Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm - Part 2: Treatment monitoring and specific clinical or comorbid situations.

German S3-Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm - Part 2: Treatment monitoring and specific clinical or comorbid situations.

MiR-139-5p mediates the palmitate-induced inhibition of insulin secretion by targeting neuronal pentraxin 1 in INS-1 cells.

High fatty acid reduces insulin secretion in pancreatic β-cells and miR-139-5p is increased in diabetic pancreatic tissues and induces islet β-cell apoptosis. However, to date, there is no study exploring whether or not miR-139-5p is involved in high fatty acid-induced insulin secretion. In the present study, INS-1 cells were exposed to different concentrations (0.1, 0.2, and 0.4 mM) of palmitate for different time periods (12, 24, and 48 h). The expression levels of miR-139-5p and neuronal pentraxin 1 (NPTX1) were evaluated by real-time PCR and western blot analysis. The regulation of NPTX1 by miR-139-5p was examined by luciferase assay. Cell transfection was conducted using Lipo8000 or Lipofectamine RNAiMAX. Potassium or glucose-stimulated insulin secretion levels were used to verify the function of miR-139-5p or NPTX1 in insulin secretion. Insulin secretion levels were detected by radioimmunoassay. We found that miR-139-5p was increased in INS-1 cells stimulated with palmitate. In addition, miR-139-5p was also elevated in islets of high-fat diet-fed mice and db/db mice compared to those in islets of normal diet-fed mice and wild-type mice. Knockdown of miR-139-5p could reverse high fatty acid-induced insulin secretion defects in INS-1 cells. Furthermore, we demonstrated that NPTX1 is a target of miR-139-5p. miR-139-5p mediated palmitate-induced insulin secretion defects by targeting NPTX1. Moreover, palmitate treatment declined the expression of NPTX1 and the NPTX1 expression was also decreased in islets of high-fat diet-fed mice and db/db mice. Impaired NPTX1 expression is involved in fatty acid-induced insulin secretion defects. Collectively, our results illustrate that the induction of β-cell insulin secretion defects by fatty acids is mediated, at least in part, by miR-139-5p via downregulation of NPTX1 expression.

Proteinase-activated receptor-2 (PAR2) on blood pressure and electrolyte handling in the late pregnant rat.

What is the central question of this study? Pregnancy requires marked renal sodium and potassium retention and cumulative plasma volume expansion, in the setting of reduced blood pressure. Research in male rodents has shown that activation of PAR2 can produce peripheral vasodilatation, stimulate renal sodium chloride reabsorption and inhibit renal potassium secretion. Here, we investigate PAR2 activation in virgin and normal pregnant rats. What is the main finding and its importance? PAR2 expression and sensitivity to activation are increased in pregnancy. This implicates a possible role for PAR2 in supporting the renal/vascular adaptations of pregnancy required for normal maternal plasma volume expansion. A healthy pregnancy involves renal and systemic haemodynamic adaptations, which allow renal sodium and potassium retention and cumulative plasma volume expansion, accompanied by a decline in blood pressure attributable to a reduction in the total peripheral vascular resistance. When these adaptations do not occur, pregnancy is compromised. The mechanisms permitting these opposing adaptations are largely unknown. Research in male rodents has shown that activation of PAR2 can produce peripheral vasodilatation, stimulate renal sodium chloride reabsorption and inhibit renal potassium secretion. Here, we investigate PAR2 activation in female virgin and normal late pregnant (LP) rats. We measured the mRNA expression of PAR2 in the renal cortex, outer medulla and inner medulla of virgin and LP rats using quantitative real-time PCR. We also measured in vivo blood pressure, natriuretic and kaliuretic responses to PAR2-activating peptide (SLIGRL-NH2 ) in anaesthetized virgin and LP rats. We found that PAR2 mRNA was increased in the inner medulla of LP rats. We also found that LP rats had larger decreases in blood pressure and increases in net sodium retention compared with virgin rats. These findings suggest that pregnancy enhances sensitivity to the blood pressure-lowering and sodium-retaining effects of PAR2.